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Just Undo It. How to Transform a Hoodie into Nearly Everything. A hoodie is not just a hoodie. In a world full of stuff, smart items should be transformable, editable. They should engage the possibility to be transformed into something else. We do not need a new object. We rather need to get rid of some of them, to reduce the complex network of things around us. Just undo it is a collection of reversible objects that could be made from a hoodie at no cost. How to videos here. Related posts:
802 F.Supp. 752 (1992) STATE of New York, the New York State Department of Social Services, and Cesar A. Perales, Commissioner of the New York State Department of Social Services, Plaintiffs, v. Louis W. SULLIVAN, M.D., United States Secretary of Health and Human Services, and the U.S. Department of Health and Human Services, Defendants. No. 89-CV-817. United States District Court, N.D. New York. October 6, 1992. *753 Robert Abrams, Atty. Gen. of the State of New York, Albany (Edward M. Scher, Asst. Atty. Gen., of counsel), for plaintiffs. Gary L. Sharpe, U.S. Atty., N.D. New York, Albany (Paul D. Silver, Asst. U.S. Atty., of counsel), for defendants. MEMORANDUM-DECISION AND ORDER MUNSON, Senior District Judge. Presently before the court are cross-motions for summary judgment pursuant to Fed.R.Civ.P. 56. The court heard oral argument on November 28, 1991 in Albany, New York. For the reasons stated below, the court grants defendants' cross-motion for summary judgment and denies plaintiffs' motion. I. BACKGROUND This action is premised on defendants' refusal to reimburse plaintiffs for certain expenditures incurred in administering Title XIX of the Social Security Act, 42 U.S.C. §§ 1396, et seq., ("Title XIX" or "Medicaid"). The complaint asserts the existence of a federal question as the basis for jurisdiction. 28 U.S.C. §§ 1331, 1361. Pursuant to Title XIX, New York State is entitled to submit claims for reimbursement to the federal government to defray certain expenditures in administering the Medicaid program within its borders. A two-year statute of limitations for the presentation of such claims is imposed by 42 U.S.C. § 1320b-2, with certain exceptions, which include the "audit exception." On December 5, 1986, the New York State Department of Social Services submitted claims that were over two years old, arguing, nonetheless, that their payment was justified under the "audit exception." The United States Department of Health and Human Services ("HHS") rejected these claims as untimely. The subject claims were submitted to the Health Care Financing Administration ("HCFA"), a branch of HHS, as part of the New York State auditing process known as the Shares Reclassification System ("SRS"). SRS consists of a method of comparing state and federal computer-generated files for purposes of ascertaining state Medicaid expenditures which were initially mischaracterized as ineligible for federal funding. The audit in question determined that there should have been a reduction in the dollar value of all of the claims analyzed, but that the overall reduction should have been offset by a limited upward adjustment of $873,607, consisting of Medicaid expenditures incurred between July 1, 1983 and December 31, 1983. While the downward adjustment was accepted by the HCFA, the limited upward adjustment was disallowed. This decision was then appealed to HHS's Departmental Appeals Board ("DAB").[1] The DAB affirmed the HCFA's decision on September 1, 1988, finding: 1. The state audit was a true audit. 2. An audit which serves as the subject matter of the "audit exception" may be either a federal or state audit. Accordingly, New York's audit qualified for consideration under the "audit exception." 3. In order for the "audit exception" to be activated, it is necessary that the Federal Government accept the late claims. In support of this conclusion, the DAB noted the wording of 45 C.F.R. 95.4 which defines "audit exception" as "a proposed adjustment by the responsible Federal agency to any expenditure claimed by a State by virtue of an audit." 4. There were no actions taken by defendants which demonstrated their acceptance of the disputed claims. HCFA's acceptance of the downward adjustments did not, on that basis alone, compel the Board to accept any untimely upward adjustments. 5. The "audit exception" only applies if it is first demonstrated that "extreme situations" are involved, whereby it *754 would be "patently unfair to a state to outlaw its claim merely because of the passage of time." Plaintiffs disputed claims were found not to be submitted under "extreme circumstances." Exhibit ("Exh.") 1 attached to Document ("Doc.") 3, at 2-10. By summons and complaint filed in this court on June 27, 1989, the State alleges that the decisions of the HCFA and the DAB violate the Social Security Act. The State served interrogatories and requests for production of documents, and defendants responded with a motion to preclude discovery. In anticipation of bringing the instant motions, plaintiffs agreed to withdraw their discovery demands, without prejudice. Defendants thereafter withdrew their motion to preclude discovery, without prejudice. The parties have now cross-moved for summary judgment. In the alternative, plaintiffs seek an order compelling defendants to provide affidavits explaining why the HCFA denied audit exception treatment for the subject upward adjustment. Both parties agree that the only issue before the court regarding the cross-motions for summary judgment is whether the DAB's determination that the proposed upward adjustment of $873,607 did not fall under the "audit exception" of 42 U.S.C. § 1320b-2(a),[2] complies with the meaning and intent of the statute. See Plaintiffs' Memorandum of Law, Doc. 11, at 7-8; Defendants' Memorandum of Law, Doc. 13, at 3. Both parties also agree that the scope of judicial review of the DAB's action is governed by the Administrative Procedure Act ("APA"), 5 U.S.C. § 706(2). Plaintiffs argue that the decision of the DAB should be overturned because it violates three separate subsections of the APA. Specifically, it violates subsection (2)(A) by virtue of being arbitrary, capricious, and otherwise not in accordance with law; it violates subsection (2)(C) by virtue of being in excess of statutory jurisdiction, authority, or limitations; and it violates subsection (2)(D) by virtue of failing to observe the procedure required by law. 5 U.S.C. § 706. Substantively, plaintiffs object to the DAB's consideration of whether the State's tardiness in making the claim was due solely to "extreme circumstances." Plaintiffs contend that such an analysis is not required, nor permitted, by the language of 42 U.S.C. § 1320b-2 or 45 C.F.R. § 95.4,[3] and its use is therefore arbitrary as a matter of law. These provisions do not mention the term "extreme circumstances," nor do they state that the existence of such circumstances is a condition precedent to the invocation of the "audit exception." Plaintiffs contend that use of the "extreme circumstances" rationale might be appropriate in applying the "good cause" exception of 42 U.S.C. § 1320b-2(b),[4] but not in applying the "audit" exception of § 1320b-2(a). The use of this standard is tantamount to improper legislating by defendants, plaintiffs contend, rather than the proper administrative interpretation of a *755 regulation. As such, plaintiffs argue that the decision of the DAB rejecting the upward adjustment because the audit did not stem from an extreme situation is invalid and their motion for summary judgment should be granted. Plaintiffs also argue that, absent an analysis of whether "extreme circumstances" caused the State's filing of the late reimbursement claim, the government is constrained to consider only the actual wording of the Social Security Act and its implementing regulations to determine whether the State's reimbursement claim was valid. Such an analysis would require that the federal government grant "audit exception" treatment to the disputed claims because defendants approved of: (1) the substantive nature of the claims considered by the audit, (2) the method of analysis adopted by the audit, and (3) the accuracy of the audit's claims by accepting the accuracy of the entire audit. According to plaintiffs, "the presentation of an audit constitutes a self-operative mechanism allowing the triggering of the `audit exception.'" Plaintiffs' Memorandum of Law, Doc. 11, at 19. In accepting the downward adjustment by the State, plaintiffs argue that the HCFA thereby accepted the accuracy of the entire audit in issue because there was no way, without requesting more data, in which to distinguish the claims constituting the upward, as opposed to downward, adjustment. This is so because the audit in question is unique; the nature of the analysis engaged in by defendants to assure the correct amount of the refund was necessarily the very same analysis they would have had to conduct to determine the accuracy of the amounts for which plaintiffs sought audit exception treatment. Such an analysis revolves around establishing the validity of the audit process. As a result, plaintiffs contend that defendants' acceptance of the amount of the upward adjustment necessarily implied their acceptance of the accuracy of the audit methodology (which was the only valid objection to denying "audit exception" treatment). Last, plaintiffs contend that even if the court denies their motion for summary judgment, it should compel defendants to specify the reasons for rejecting the upward adjustment under the audit exception. It is not sufficient, plaintiffs argue, for the HCFA to deny the adjustment solely on the basis that the statute of limitations expired, as this would make the audit exception meaningless. Defendants contend that "great weight" must be accorded a government agency's interpretation of its governing statute, Clarke v. Securities Industry Ass'n, 479 U.S. 388, 403-04, 107 S.Ct. 750, 759, 93 L.Ed.2d 757 (1987) (quoting Investment Company Institute v. Camp, 401 U.S. 617, 626-27, 91 S.Ct. 1091, 1097, 28 L.Ed.2d 367 (1971)), and an agency's interpretation may not be rejected unless it is "manifestly contrary" to the statute, Chevron U.S.A. v. Natural Resources Defense Council, Inc., 467 U.S. 837, 844, 104 S.Ct. 2778, 2782, 81 L.Ed.2d 694 (1984). Furthermore, defendants assert that where a statute explicitly delegates "substantive authority" to the Secretary for rule-making and interpretation of the statute, the Secretary's regulations are entitled to a higher standard of deference by the court. Since Congress explicitly delegated substantive authority to the Secretary of HHS for the rule-making necessary to implement the statutory provisions involved in the case at bar, defendants allege that the Secretary's regulations at 45 C.F.R. §§ 95.7-95.34 are entitled to the higher standard of deference and must be upheld absent a finding that they are "arbitrary or capricious." Defendants further argue that the decisions of the HCFA and the DAB finding that the claims in question do not come under the audit exception, defined by 45 C.F.R. § 95.4 as "a proposed adjustment by the responsible Federal agency to any expenditure claimed by a state by virtue of an audit," were not arbitrary and capricious. Based on this definition, defendants contend that the Secretary of HHS has reserved for himself the authority to accept or reject late filings based on state audits. Thus, the critical fact is not whether there is an audit, but whether the federal government accepts it. Defendants cite to a portion *756 of the DAB's decision addressing this point: The regulation makes it clear that a proposed adjustment to claims for prior year costs based on a state audit is not enough to constitute an `audit exception.' The federal government — the responsible federal agency — must propose to make an adjustment in the claims for prior years. Only then does the statute of limitations not run on the time for filing or amending such claims. Exh. 1 attached to Doc. 3, at 4 (quoting New York State Dep't of Social Services, DAB Dec. No. 521, at 7 (1984)). According to defendants, there has been no such proposed adjustment by the HCFA in the case at bar. On the contrary, this dispute arose solely because the HCFA rejected the State's proposed adjustment by disallowing the State's claims. Furthermore, defendants argue that acceptance of the entire audit cannot be implied from the HCFA's acceptance of overpayments identified by the State, because the issue of late claims is governed by a different statutory scheme than the issue of overpayments. Specifically, there is no time limitation on the statutory requirement that the Secretary recover overpayments, whenever and however discovered, pursuant to 42 U.S.C. § 1396b(d)(2)(A). Defendants also reject the argument that the DAB improperly mixed the "good cause" exception of 42 U.S.C. § 1320b-2(b) with the audit exception of § 1320b-2(a) when it held that the audit exception only applied in extreme situations. What the DAB in fact held was that the occurrence which plaintiffs described as an audit exception was simply an instance of faulty process causing a problem which could have been uncovered earlier by the State. Defendants further contend that the DAB's interpretation that proof of "extreme circumstances" is necessary to obtain relief under the audit exception, merely amplifies and defines the terms of the statute in a reasonable manner. In so interpreting the regulation, defendants argue that the DAB was legitimately concerned with the possibility that states would rush to the courthouse arguing that they are entitled to an audit exception every time they failed to timely object. Since the DAB's decision is not an arbitrary and capricious interpretation of the statute or regulation, defendants contend that it cannot be held unlawful and that summary judgment should therefore be granted in their favor. II. DISCUSSION Summary judgment is appropriate when "there is no genuine issue as to any material fact and the moving party is entitled to judgment as a matter of law." Fed. R.Civ.P. 56(c). The facts of this case are undisputed. In reviewing the DAB's decision, the court must engage in a two-fold inquiry to determine (1) whether the DAB's interpretation of the audit exception in 42 U.S.C. § 1320b-2(a) and its implementing regulations was reasonable and (2) whether the DAB's application of the interpretation to the facts was rational. Courts generally will defer to an agency's interpretation of its own regulation unless that interpretation is plainly erroneous. Falk v. Secretary of the Army, 870 F.2d 941, 946 (2d Cir.1989); see also Chevron U.S.A., 467 U.S. at 844, 104 S.Ct. at 2782. The agency's interpretation should be followed "unless there are compelling indications that it is wrong." Red Lion Broadcasting Co. v. FCC, 395 U.S. 367, 381, 89 S.Ct. 1794, 1802, 23 L.Ed.2d 371 (1969); see also Chemical Manufacturers Ass'n v. Natural Resources Defense Council, Inc., 470 U.S. 116, 125, 105 S.Ct. 1102, 1107, 84 L.Ed.2d 90 (1985). In reviewing an agency's interpretation of its own regulation, the court must determine whether Congress has "directly addressed the precise question at issue." Chevron U.S.A., 467 U.S. at 843, 104 S.Ct. at 2782. If Congress has addressed the issue, "the court, as well as the agency, must give effect to the unambiguously expressed intent of Congress." Id. If, however, "the statute is silent or ambiguous with respect to the specific issue, the question for the court is whether the agency's answer is based on a permissible construction of the *757 statute." Id. For the agency interpretation to be accepted, it need only be shown that it is "sufficiently reasonable." Federal Election Comm'n v. Democratic Senatorial Campaign Comm., 454 U.S. 27, 39, 102 S.Ct. 38, 46, 70 L.Ed.2d 23 (1981). Because Title XIX of the Social Security Act does not set forth the standards for review of the DAB's substantive decisions, the court must look to the standards articulated in the Administrative Procedure Act for guidance. 5 U.S.C. §§ 551 et seq. The pertinent portions of the APA state: To the extent necessary to decision and when presented, the reviewing court shall decide all relevant questions of law, interpret constitutional and statutory provisions, and determine the meaning or applicability of the terms of an agency decision. The reviewing court shall ... (2) hold unlawful and set aside agency action, findings, and conclusions found to be— (A) arbitrary, capricious, an abuse of discretion, or otherwise not in accordance with law; ... (C) in excess of statutory jurisdiction, authority, or limitations, or short of statutory right; (D) without observance of procedure required by law.... 5 U.S.C. § 706. The court will first consider whether the DAB's decision was "arbitrary, capricious, an abuse of discretion, or otherwise not in accordance with law" pursuant to 5 U.S.C. § 706(2)(A). In Motor Vehicle Mfrs. Ass'n v. State Farm Mut. Auto. Ins. Co., 463 U.S. 29, 103 S.Ct. 2856, 77 L.Ed.2d 443 (1983), the Supreme Court delineated the boundaries of the court's review in applying the arbitrary and capricious standard. A reviewing court may not set aside an agency rule that is rational, based on consideration of the relevant factors, and within the scope of the authority delegated to the agency by the statute.... The scope of review under the "arbitrary and capricious" standard is narrow and a court is not to substitute its judgment for that of the agency. Nevertheless, the agency must examine the relevant data and articulate a satisfactory explanation for its action including a "rational connection between the facts found and the choice made." In reviewing that explanation, we must "consider whether the decision was based on a consideration of the relevant factors and whether there has been a clear error of judgment." Normally, an agency rule would be arbitrary and capricious if the agency has relied on factors which Congress has not intended it to consider, entirely failed to consider an important aspect of the problem, offered an explanation for its decision that runs counter to the evidence before the agency, or is so implausible that it could not be ascribed to agency expertise. Motor Vehicle Mfrs. Ass'n, 463 U.S. at 42-43, 103 S.Ct. at 2866; see also Bersani v. Environmental Protection Agency, 674 F.Supp. 405, 413 (N.D.N.Y. 1987), aff'd, 850 F.2d 36 (2d Cir.1988), cert. denied, 489 U.S. 1089, 109 S.Ct. 1556, 103 L.Ed.2d 859 (1989). Keeping these principles in mind, the court now turns to an examination of the issues at hand. Plaintiffs contend that the DAB's decision to deny audit exception treatment to the claimed overpayments was arbitrary and capricious as a matter of law because (1) the DAB impermissibly imposed the existence of "extreme circumstances" as a prerequisite for application of the audit exception, and, (2) by accepting the methodology of the audit, defendants accepted both the upward and downward adjustments. While plaintiffs concede that the DAB has some limited authority to interpret a statute it is charged with enforcing, they argue that the DAB sought to add a new provision by applying the extreme circumstances rationale, rather than interpret the existing provision. The court disagrees. The court finds that the DAB's consideration of whether the State's tardiness in making the claim was due to an "extreme situation" was not arbitrary and capricious as a matter of law. Nothing in the statute or regulations forbids the agency from making such a determination. Section *758 1320b-2(a) does not define the term audit exception. Rather, Congress gave the Secretary of HHS the authority to make and publish rules and regulations "as may be necessary for the efficient administration of the functions with which [the Secretary] is charged under this chapter." 42 U.S.C. § 1302(a). Pursuant to that authority, the Secretary issued a regulation defining audit exception as "a proposed adjustment by the responsible Federal agency to any expenditure claimed by a state by virtue of an audit." 45 C.F.R. § 95.4. Clearly, the regulation is ambiguous in that it does not define under what circumstances a federal agency must accept or reject claimed adjustments by a state. Therefore, it is necessary and proper for the DAB to detail the regulation's application. See Martin v. Occupational Safety and Health Review Comm'n, ___ U.S. ___, ___, 111 S.Ct. 1171, 1173, 113 L.Ed.2d 117 (1991) (reviewing court should defer to agency's reasonable interpretation of an ambiguous regulation). The interpretation given by the DAB does not violate the plain language of the statute or the language of the pertinent regulation. Further, the interpretation does not conflict with the intent of Congress. Plaintiffs, although spending a significant portion of their memorandum of law analyzing the pertinent statute, fail to cite any legislative history which would indicate any congressional intent contrary to the interpretation given by the DAB. It is well settled that "[i]n that process of filling `any gap left, implicitly or explicitly, by Congress,' the court must respect the interpretation of the agency which Congress has delegated the responsibility for administering the statutory program." I.N.S. v. Cardoza-Fonseca, 480 U.S. 421, 448, 107 S.Ct. 1207, 1221, 94 L.Ed.2d 434 (1987). Accordingly, the court finds that the DAB's application of "audit exception" is a permissible construction of the relevant regulation. The court further concludes that even absent a determination that the audit exception only applies to "extreme situations," based on the language of 45 C.F.R. 95.4, the DAB's decision denying audit exception treatment to the proposed upward adjustment was not arbitrary and capricious. Both parties agree that in order to invoke the audit exception, the appropriate federal agency must "accept" the proposed audit. Plaintiffs go on to argue that defendants are required to grant audit exception treatment to those state claims (including the subject disputed claims) which are submitted within the context of an audit, provided that the substantive nature of the claims considered by the audit, the method of analysis adopted by the audit, and the accuracy of the audit's claims have been approved by defendants. The court does not agree. The issues of overpayments and underpayments are governed by different statutory schemes. All overpayments by statute must be repaid to the federal government, no matter when they are discovered. 42 U.S.C. § 1396b(d)(2)(A)[5]; Perales v. Heckler, 762 F.2d 226, 227-28 (2d Cir.1985). Conversely, underpayments are subject to a two-year statute of limitations. 42 U.S.C. § 1320b-2(a). Therefore, the State cannot use the action of the Secretary to collect overpayments, which is mandated by statute, to prove that the audit which identified the overpayments was accepted in its entirety by the federal government. In addition, to affirm plaintiffs' position would be to permit the State to first label virtually any late filing an audit exception, and then permit the State to define when the federal agency has accepted the audit exception. Such an outcome would render the statute of limitations contained in § 1320b-2(a) meaningless and would undermine the intent of Congress in preventing states from filing claims in excess of two years old. In sum, the court concludes that defendants' *759 acceptance of the amount of downward adjustment did not necessarily imply their acceptance of the accuracy of the audit methodology and the substantive permissibility of all claims considered by the audit. As such, defendants' action in denying audit exception treatment to the subject upward adjustment was not arbitrary, capricious, an abuse of discretion, or otherwise not in accordance with law. The court also concludes that the decision of the DAB was not "in excess of statutory jurisdiction, authority, or limitations, or short of statutory right." 5 U.S.C. § 706(2)(C). Reviewing agency interpretations of statutes and regulations to insure that they are not in excess of statutory jurisdiction involves deference to the administrative determinations, unless they are plainly erroneous or inconsistent with the relevant statutes. Rydeen v. Quigg, 748 F.Supp. 900, 904 (D.D.C.1990) (citing Udall v. Tallman, 380 U.S. 1, 16, 85 S.Ct. 792, 801, 13 L.Ed.2d 616 (1965)), aff'd, 937 F.2d 623 (Fed.Cir.1991), cert. denied, ___ U.S. ___, 112 S.Ct. 974, 117 L.Ed.2d 138 (1992). As discussed above, the court does not find the DAB's decision to be either plainly erroneous or inconsistent with the relevant regulation. Finally, the court concludes that the DAB did not fail to observe any procedure required by law. 5 U.S.C. § 706(2)(D). Plaintiffs have not identified any specific procedures required by law that defendants have failed to observe, and the court finds no procedural irregularities in the DAB's determination which would warrant setting aside the agency's action pursuant to 5 U.S.C. § 706(2)(D). Therefore, plaintiffs' motion for summary judgment based on defendants' violation of 5 U.S.C. § 706(2)(A), (C), or (D) is denied. Alternatively, plaintiffs seek an order compelling defendants to provide affidavits explaining why the HCFA denied audit exception treatment for the subject upward adjustment. See Citizens to Preserve Overton Park, Inc. v. Volpe, 401 U.S. 402, 420, 91 S.Ct. 814, 825, 28 L.Ed.2d 136 (1971) (court may require some explanation in order to determine if agency acted within scope of its authority if bare record before the court does not disclose the factors considered by the agency or the agency's construction of the evidence); 1902 Atlantic Ltd. v. Hudson, 574 F.Supp. 1381, 1397 (E.D.Va.1983) ("where an agency's failure to explain its rationale frustrates judicial review, a court's scrutiny of explanatory affidavits is permissible"). Specifically, plaintiffs complain that the HCFA letter of disallowance gave no specific rationale for the rejection of the proposed upward adjustment. It was not until the case reached the DAB that a rationale for the decision was set forth, and plaintiffs argue that the HCFA should be required to explain its own decision. The court finds no basis for granting plaintiffs' request. The principles of law recited by plaintiffs are inapplicable to the case at bar because the specific decision on appeal to this court is that of the DAB, not the HCFA. A careful reading of the DAB's decision leads this court to conclude that the grounds upon which the agency acted are clearly disclosed and sustained by the record. Therefore, plaintiffs' request is denied. III. CONCLUSION In summary, the DAB's decision to deny audit exception treatment to the proposed upward adjustment does not create a material issue of fact, in that no evidence has been presented to suggest that the decision was arbitrary and capricious, in excess of statutory jurisdiction, or that the DAB failed to observe procedure required by law. Giving due deference to the DAB's decision, defendants are thus entitled to summary judgment as a matter of law and their motion is hereby granted. Consequently, plaintiffs' motion for summary judgment and alternative request for explanatory affidavits from the HCFA are hereby denied. The clerk of the court is directed to enter judgment in favor of defendants and dismiss plaintiffs' complaint in its entirety. It is So Ordered. NOTES [1] At the time of the appeal, the name of the reviewing body was the Departmental Grant Appeals Board, which was subsequently changed to the Departmental Appeals Board, without change in structure or function. [2] Section 1320b-2(a) provides: [A]ny claim by a State for payment with respect to an expenditure made during any calendar quarter by the State in carrying out [Medicaid] shall be filed ... within the two-year period which begins on the first day of the calendar quarter immediately following such calendar quarter; and payment shall not be made under this chapter on account of any such expenditure if claim therefor is not made within such two-year period; except that this subsection shall not be applied so as to deny payment with respect to any expenditure involving court-ordered retroactive payments or audit exceptions, or adjustments to prior year costs. [3] Section 95.4 defines "audit exception" as "a proposed adjustment by the responsible Federal agency to any expenditure claimed by a State by virtue of an audit." [4] Section 1320b-2(b) provides: The Secretary shall waive the requirement imposed under subsection (a) of this section with respect to the filing of any claim if he determines (in accordance with regulations) that there was good cause for the failure by the State to file such claim within the period prescribed under subsection (a) of this section. Any such waiver shall be only for such additional period of time as may be necessary to provide the State with a reasonable opportunity to file such claim. A failure to file a claim within such time period which is attributable to neglect or administrative inadequacies shall be deemed not to be for good cause. [5] Section 1396b(d)(2)(A) states: The Secretary shall then pay to the State ... the amount so estimated, reduced or increased to the extent of any overpayment or underpayment which the Secretary determines was made under this section to such State for any prior quarter and with respect to which adjustment has not already been made under this subsection.
Structure determination and conformation analysis of symmetrical dimers. Conformational and stereochemical analysis of six new symmetrical dimers was performed using proton-proton vicinal coupling measured from (1)H NMR and (13)C satellites of (1)H NMR signals, natural abundance (13)C-edited nuclear overhauser effect (NOE) experiments, comprehensive NOE analysis and molecular modeling. The (13)C satellite analysis and (13)C-edited NOE experiments were carried out to extract spectral information between equivalent protons. Molecular modeling was applied for estimations of three-dimensional parameters of the studied dimers, which were subsequently used to generate a set of theoretical NOE for each possible conformation. The J-coupling, (13)C-edited NOE and quantitative NOE analyses showed the predominance of gauche conformation for three dimers, whereas a mixture of gauche and anti conformations (45:55) for three other dimers was established by quantitative NOE analysis. X-ray crystallographic study confirmed the stereochemistry of one of the dimers and revealed a discrepancy in conformation stability between liquid and solid states.
News Categories Student Gives Thanks for Donors’ Generosity Michelle Buckner is among students who received scholarships with funds donated to the College of Education. Scholarship recipients in the College of Education met and mingled with donors at the college’s annual Autumn Awards Dessert Reception Oct. 25 at the Meridian Club in Fullerton. Graduate student Michelle Buckner is among the 53 students who received scholarships made possible by the $59,500 donated to the College of Education for 2012-13 awards. She followed College of Education Dean Claire Cavallaro and faculty members, who took turns at the podium to applaud donors for their generosity. Buckner’s remarks: On behalf of all the scholarship recipients and myself, I would like to start by saying, thank you, thank you, thank you to our donors. My name is Michelle Buckner and I’m currently working on a master’s of science in elementary curriculum and instruction and a multiple subject teaching credential. When I went back to school this last fall, my husband Ryan became the sole provider. We knew it would be a challenge financially, going from two incomes to one, but we felt the Lord telling us that it was the right time. We were confident Ryan’s income could cover our household expenses, but we hadn’t figured out where the rest of the money would come from for school. Even with financial aid covering the cost of tuition, there’s still the cost of books, parking passes, ink cartridges and all of the other costs that go along with higher education. That’s where you, or donors like you, came in. Through your support, I’ve been able to continue in my program and focus on what I need to focus on — school. I am so amazed by all of you, donors. To think that you would give so generously, and to complete strangers. I want you to know that your money has not only been well spent, but, even better, well invested. Through your giving, you are inspiring students like me to keep pressing forward. You’re helping us get that much closer to accomplishing our goals and dreams in life. As corny as it may sound, your scholarships are changing lives. Donors, thank you, again, for you generosity. You may not always get to see the fruits of your giving, but you are making a difference.
Q: Connecting to database on SQL server from WAMPSERVER 2.5 I've got a WAMPSERVER 2.5 development server. It's running PHP 5.512. I'm trying to connect to our live SQL Server. I've installed and activated the version 32 files, and used the following code: <?php $link = sqlsrv_connect('obscured_ip:obscured_port', array('Database'=>'obscured_database','UID'=>'obscured_uid', 'PWD'=>'obscured pwd')); if (!$link) die(print_r(sqlsrv_errors(), true)); ?> I'm getting the following error: Array ( [0] => Array ( [0] => IMSSP [SQLSTATE] => IMSSP 1 => -49 [code] => -49 2 => This extension requires the Microsoft ODBC Driver 11 for SQL Server. Access the following URL to download the ODBC Driver 11 for SQL Server for x86: http://go.microsoft.com/fwlink/?LinkId=163712 [message] => This extension requires the Microsoft ODBC Driver 11 for SQL Server. Access the following URL to download the ODBC Driver 11 for SQL Server for x86: http://go.microsoft.com/fwlink/?LinkId=163712 ) 1 => Array ( [0] => IM002 [SQLSTATE] => IM002 1 => 0 [code] => 0 2 => [Microsoft][ODBC Driver Manager] Data source name not found and no default driver specified [message] => [Microsoft][ODBC Driver Manager] Data source name not found and no default driver specified ) ) The link specified there just takes me back to the driver download page. What am I doing wrong? A: The URL in the error points to the wrong page. This is the correct one: https://www.microsoft.com/en-us/download/details.aspx?id=36434
Hi, I need suggestions. I started a lace weight, very open shawl/scarf for my niece to wear at her wedding. I have frogged the thing 15+ times and I am weary with the whole process. The yarn weight is like knitting with hair and I do not know if that is my problem or knot. I have knit many other lace patterns using charts and written directions and never had this problem. I would like suggestions for a very pretty, open lace, quick pattern which is not so simple that I am bored but definitely not like the pattern I bought at the LYS. It is called Fame Trend. I look forward to your suggestions. Thanks DogCatMom 02-07-2012, 01:48 AM I went on line to try and find a picture or illustration of this shawl, or its pattern. The only "Fame Trend" I can find is a kind of yarn made by Marks & Kattens. Is there another possible name for the pattern? DCM salmonmac 02-07-2012, 06:53 AM A quick search (http://www.ravelry.com/patterns/search#sort=best&query=knit fame trend shawl) on Ravelry (free to join) turned up several with Fame Trend yarn including this one (http://www.ravelry.com/patterns/library/colorama-crescent-shawl-in-4-sizes). It may help in doing lace work to insert a lifeline (http://www.knittinghelp.com/video/play/using-a-lifeline). It at least keeps frogging to a minimum and helps preserve sanity. That's a wonderful idea for your niece's wedding. Good luck with it. ewalker 02-07-2012, 08:06 PM The pattern is 09112 Fame Trend Lace Knit Shawl Marks & Kattens. I am only using their pattern, my yarn ball band is hiding but it is a very fine yarn. Thanks for your help. ewalker 02-07-2012, 08:09 PM Isn't it beautiful. I might go insane on that one. Mine will be smaller or non-existent. Thanks for your help.
552 S.E.2d 220 (2001) CREEK POINTE HOMEOWNER'S ASSOCIATION, INC. and Kenneth C. Kremer, Plaintiffs, v. Richard HAPP, Defendant and Third-Party Plaintiff, v. WEYERHAEUSER REAL ESTATE COMPANY, INC., Third-Party Defendant. No. COA00-556. Court of Appeals of North Carolina. September 18, 2001. *222 Harris, Shields, Creech and Ward, P.A., by C. David Creech, for plaintiff-appellant. McCotter, McAfee, & Ashton, PLLC, by Charles K. McCotter, Jr., for defendant-appellee. Chesnutt, Clemmons, Thomas & Peacock, P.A., by Gary H. Clemmons for third party defendant-appellee. BIGGS, Judge. Plaintiff, Creek Pointe Homeowner's Association, Inc., appeals from the trial court's dismissal of its claims for lack of standing, pursuant to N.C.R. Civ. P. 12(b)(6). This matter arises out of a dispute over a fence that Richard Happ (defendant), a resident of the Creek Pointe subdivision, placed across Deep Creek Road, in Creek Pointe. We reverse the decision of the trial court. The pertinent facts are as follows: Defendant owns lots 27 through 31 in Creek Pointe, which is located in Pamlico County, about sixteen miles from New Bern, North Carolina. His lots comprise over 200 acres, and lie on either side of Deep Creek Road. This land includes the entire eastern portion of Creek Pointe subdivision. His lots are contiguous; they are bordered by Deep Creek Road, by Goose Creek, and by a small triangular portion of lot 22. Defendant purchased the lots in 1994, and erected the fence shortly thereafter. In November, 1999, the Creek Pointe Homeowner's Association (association) and individual plaintiff Kenneth C. Kremer (Kremer), one of the owners of lot 22, brought suit against defendant, seeking an injunction to require the defendant to remove the fence across Deep Creek Road, and to bar him from replacing it with another fence. The plaintiffs asked for compensatory and *223 punitive damages and for attorneys' fees. In their complaint, plaintiffs alleged that the fence violated a restrictive covenant granting an easement in favor of all Creek Pointe residents and entitling them to the use of all roads in Creek Pointe, including Deep Creek Road. Defendant's answer asserted that permission to erect a fence had been a condition of his contract of sale with Weyerhaeuser Real Estate Co., Inc. (developer), and also that the Creek Pointe Homeowner's Association previously had consented to the fence. In addition, defendant filed a motion under N.C.R. Civ. P. 19, "Necessary Joinder of Parties," seeking dismissal for failure to join all individual homeowners as necessary parties, and a motion under Rule 12(b)(6), seeking dismissal of all claims of the association for lack of standing or interest. Defendant also filed a third party complaint against the developer. In January, 2000, the defendant filed a motion for summary judgment against both plaintiffs. This was followed by the developer's February, 2000, motion for summary judgment, and by the association's motion of 15 February 2000 seeking an injunction to prohibit defendant from harassing its members. All motions were heard on 25 February 2000, at which time the trial judge issued the following orders: 1. Granted defendant's 12(b)(6) motion, dismissing all claims as to the association based on lack of standing or interest. 2. Ordered that plaintiff Kremer's wife, all other Creek Pointe homeowners, and the developer, all must be joined as necessary parties to the suit. 3. Ordered the fence moved so that it did not block any part of lot 22. 4. Denied the injunction regarding harassment of association members. 5. Denied the developer's motion for summary judgment. 6. Denied defendant's motion for summary judgment. On 27 March 2000, the association filed notice of appeal from the dismissal of their claims for lack of standing or interest. It is this appeal that is presently before this Court. The other orders entered by the trial court in this matter are not before this Court. We first note that the trial court did not dismiss the case as to plaintiff Kremer. Thus, its ruling that the association lacked standing is an interlocutory order. See Jenkins v. Wheeler, 69 N.C.App. 140, 316 S.E.2d 354, disc. review denied, 311 N.C. 758, 321 S.E.2d 136 (1984) (order dismissing claims against one defendant is interlocutory where other defendants remain in suit). Interlocutory orders generally are not immediately appealable. Bailey v. Gooding, 301 N.C. 205, 270 S.E.2d 431 (1980); Mabrey v. Smith, 144 N.C.App. 119, 548 S.E.2d 183 (2001). However, an interlocutory order may be appealed before final judgment under two circumstances: (1) there is a certification by the trial court that there is no just reason to delay the appeal, or (2) the ruling affects a substantial right. Evans v. United Servs. Auto. Ass'n, 142 N.C.App. 18, 541 S.E.2d 782, cert. denied, 353 N.C. 371, 547 S.E.2d 810 (2001); Smith v. Young Moving & Storage, Inc., 141 N.C.App. 469, 540 S.E.2d 383 (2000), aff'd, 353 N.C. 521, 546 S.E.2d 87 (2001); Norris v. Sattler, 139 N.C.App. 409, 533 S.E.2d 483 (2000). The determination of whether a substantial right is affected is made on a case by case basis. Collins v. Talley, 135 N.C.App. 758, 522 S.E.2d 794 (1999); Stafford v. Stafford, 133 N.C.App. 163, 515 S.E.2d 43, aff'd, 351 N.C. 94, 520 S.E.2d 785 (1999). The reviewing court must determine whether denial of immediate review exposes a party to multiple trials with the possibility of inconsistent verdicts. Murphy v. Coastal Physician Grp., Inc., 139 N.C.App. 290, 533 S.E.2d 817 (2000); Moose v. Nissan of Statesville, 115 N.C.App. 423, 444 S.E.2d 694 (1994). In the present case we find that, although there was no certification by the trial judge, the order dismissing all claims as to the association affects a substantial right of appellants and is, therefore, appealable. See Jenkins, 69 N.C.App. 140, 316 S.E.2d 354 (substantial right affected where order dismissed claims against one of several defendants, thus raising the possibility of multiple trials against different members of the same *224 group). See also Bernick v. Jurden, 306 N.C. 435, 293 S.E.2d 405 (1982). The issue before this Court is whether the trial court erred in its conclusion that the Creek Pointe Homeowner's Association lacked standing to join Kremer as a plaintiff in this action. The pertinent features of the association are as follows: The creation of the association was contemplated by the developer, who stated in the Declaration of Covenants, Conditions, and Restrictions that, upon the sale of 75% of the lots in Creek Pointe, "[t]here shall be created, ... The Creek Pointe Homeowner's Association." The association was incorporated in November, 1989. Its membership consists of the owners of all lots in Creek Pointe. Its Articles of Incorporation state that "the specific purposes for which it is formed are to provide for maintenance, preservation and architectural control of the residence lots and roads within [Creek Pointe.]" The Articles also state that the association has "any and all powers, rights, and privileges which a corporation organized under the Non-Profit Corporation Law of the State of North Carolina by law may now or hereafter have or exercise." In North Carolina, homeowners' associations historically have enjoyed the general right to participate in litigation. Our appellate courts have considered suits brought by homeowners' associations on a case-by-case basis, and have permitted such associations, when appropriate, to pursue their claims in court. See, e.g., Village Creek Prop. Owners' Ass'n, Inc. v. Town of Edenton, 135 N.C.App. 482, 520 S.E.2d 793 (1999) (property owners' association held to have standing to challenge rezoning of neighboring property); McGinnis Point Owners Ass'n v. Joyner, 135 N.C.App. 752, 522 S.E.2d 317 (1999) (homeowners' association successfully sues to enforce restrictive covenant requiring property owners to pay annual assessment). The association asserts standing under the North Carolina Planned Community Act (NCPCA), N.C.G.S. Chapter 47F. Their argument is based primarily upon the following provision of the statute: Subject to the provisions of the articles of incorporation or the declaration and the declarant's rights therein, the [homeowners'] association may: ... (4) Institute, defend, or intervene in litigation or administrative proceedings on matters affecting the planned community[.] N.C.G.S. 47F-3-102 (1999), Powers of owners' association, 102(4). The association's argument is that this is a matter "affecting the planned community," and thus that the statute assures them of standing to bring suit. However, we do not read the NCPCA as conferring an automatic right upon homeowners' associations, but rather as reiterating the common law rule that, when otherwise proper, a homeowners' association may participate in a lawsuit. Moreover, the statute makes no further attempt to resolve questions of jurisdiction or standing. It does not define the phrase "affecting the planned community," or otherwise restrict the potential range of litigation. The statute does not employ the term `standing' in its recitation of an association's rights; nor does it address issues of standing in any of its other provisions. We conclude that, although the NCPCA clearly authorizes homeowners' associations as a general class to institute, defend, or intervene in litigation, this statute does not diminish our judicial responsibility to evaluate whether the association has standing to bring this suit under the specific fact situation presented. In this regard, we note another relevant provision of NCPCA, N.C.G.S. § 47F-1-108 (1999), "Supplemental general principles of law applicable," which states: The principles of law and equity as well as other North Carolina statutes ... supplement the provisions of this Chapter, except to the extent inconsistent with this Chapter. When these principles or statutes are inconsistent or conflict with this Chapter, the provisions of this Chapter will control. We find nothing in the NCPCA that is inconsistent with our common and statutory law regarding issues of jurisdiction and standing. Therefore, we hold that the NCPCA does not automatically confer standing upon homeowners' associations in every case, and that questions of standing should be resolved by our courts in the context of the specific factual circumstances presented and with reference *225 to the "principles of law and equity as well as other North Carolina statutes" that supplement the NCPCA. Accordingly, we will examine the case sub judice in this manner. Jurisdiction in North Carolina depends on the existence of a justiciable case or controversy. Town of Ayden v. Town of Winterville, 143 N.C.App. 136, 544 S.E.2d 821 (2001); Town of Pine Knoll Shores v. Carolina Water Service, 128 N.C.App. 321, 494 S.E.2d 618 (1998). Standing is a necessary prerequisite to the court's proper exercise of subject matter jurisdiction. Peacock v.. Shinn, 139 N.C.App. 487, 533 S.E.2d 842, disc. review denied, 353 N.C. 267, 546 S.E.2d 110 (2000); Transcontinental Gas Pipe Line Corp. v. Calco Enter., 132 N.C.App. 237, 511 S.E.2d 671, disc. review denied, 351 N.C. 121, 540 S.E.2d 751 (1999). "Standing" refers to the issue of whether a party has a sufficient stake in an otherwise justiciable controversy that he or she may properly seek adjudication of the matter. Sierra Club v. Morton, 405 U.S. 727, 92 S.Ct. 1361, 31 L.Ed.2d 636 (1972). The relationship between standing and the requirement of a justiciable controversy has been expressed as follows: "Judicial intervention in a dispute is normally contingent upon the presence of a justiciable controversy. Standing is that aspect of justiciability focusing on the party seeking a forum rather than on the issue he wants adjudicated." Bremner v. City & County of Honolulu, 96 Hawai`i 134, 28 P.3d 350 (App. 2001). "The gist of standing is whether there is a justiciable controversy being litigated among adverse parties with substantial interest affected so as to bring forth a clear articulation of the issues before the court." Texfi Industries v. City of Fayetteville, 44 N.C.App. 268, 269-270, 261 S.E.2d 21, 23 (1979), aff'd, 301 N.C. 1, 269 S.E.2d 142 (1980). An association may have standing to bring suit either as a plaintiff, to redress injury to the organization itself, or as a representative of injured members of the organization. The leading case on the authority of an association to bring suit on behalf of its members is Hunt v. Washington State Apple Advertising Commission, 432 U.S. 333, 97 S.Ct. 2434, 53 L.Ed.2d 383 (1977). In Hunt, the United States Supreme Court established three prerequisites for an association to sue in a representative capacity: [A]n association has standing to bring suit on behalf of its members when: (a) its members would otherwise have standing to sue in their own right; (b) the interests it seeks to protect are germane to the organization's purpose; and (c) neither the claim asserted, nor the relief requested, requires the participation of individual members in the lawsuit. Hunt, 432 U.S. at 343, 97 S.Ct. at 2441, 53 L.Ed.2d at 394. The Court expanded on the third requirement, addressing the significance of the type of relief sought as follows: [W]hether an association has standing to invoke the court's remedial powers on behalf of its members depends in substantial measure on the nature of the relief sought. If in a proper case the association seeks a declaration, injunction, or some other form of prospective relief, it can reasonably be supposed that the remedy, if granted, will inure to the benefit of those members of the association actually injured. Indeed, in all cases in which we have expressly recognized standing in associations to represent their members, the relief sought has been of this kind. Id. The criteria articulated in Hunt v. Washington State have been applied several times by our appellate courts. See, e.g., River Birch Associates v. City of Raleigh, 326 N.C. 100, 388 S.E.2d 538 (1990) (applying Hunt to issue of whether homeowners' association had standing); Northeast Concerned Citizens, Inc. v. City of Hickory, 143 N.C.App. 272, 545 S.E.2d 768, disc. review denied, 353 N.C. 526, 549 S.E.2d 220 (2001) (citizens' association lacked standing to challenge zoning ordinance where not all members had individual standing to sue); Landfall Group v. Landfall Club, Inc., 117 N.C.App. 270, 450 S.E.2d 513 (1994) (association lacked standing to bring suit because one of its members would not have had standing as an individual to bring action). Therefore, this Court will consider the trial court's ruling in the context of the requirements for standing to sue in a *226 representative capacity articulated in Hunt v. Washington State, as these criteria have been interpreted by our state courts. We find that the association meets the first prong of the Hunt test, in that the individual members of the Creek Pointe Homeowner's Association would have standing to bring suit as individuals. The suit alleges violation of the "Declaration of Covenants and Restrictions" filed by the developer with the Pamlico County Register of Deeds. The declaration was filed in 1989, and was incorporated by reference as part of the "Articles of Incorporation" of the Creek Pointe Homeowner's Association. The pertinent restriction establishes an easement granting access to subdivision roads in favor of all landowners in Creek Pointe. "[G]enerally, grantees in a subdivision are beneficiaries of any and all restrictive covenants imposed upon the subdivision so as to give them standing to challenge alleged violations of the restrictive covenants." Taylor v. Kenton, 105 N.C.App. 396, 401, 413 S.E.2d 576, 579 (1992) (plaintiffs had standing to enforce covenant, although the document setting out covenants did not specifically grant this right). See also Hawthorne v. Realty Syndicate, Inc., 300 N.C. 660, 268 S.E.2d 494 (1980) (affirming Court of Appeals' holding that plaintiff landowners in subdivision had standing to enforce restrictive covenant applicable to neighborhood). This Court finds also that the association meets the second criteria enunciated in Hunt for standing: that the alleged injury be "germane to the organization's purpose." The stated purpose of the Creek Pointe Homeowner's Association is to "provide for maintenance, preservation and architectural control of the residence lots and roads within [Creek Pointe]." Plaintiff's suit seeks to regain access to one of the private roads within Creek Pointe. The controversy over defendant's fence is one that implicates the core functions of the association. The third prerequisite for representational standing is that "neither the claim asserted nor the relief requested requires the participation of individual members in the lawsuit." We will evaluate the plaintiffs' claims and the remedies sought, to determine whether any of the association's members are necessary parties to the suit. The complaint seeks "just compensation for their property rights" for Creek Pointe residents, asking specifically for "damages in an amount in excess of [$10,000,]" as well as "punitive damages against Happ in a sum in excess of [$10,000,]" and attorney's fees. Thus, the suit seeks both compensatory and punitive money damages, while Hunt contemplated situations in which only injunctive or declarative relief was sought. The calculation of damages would require consideration of the homeowners' individual circumstances. Plaintiff Kremer alleged that the fence actually prevents access to part of his land; another homeowner might assert that the fence reduced the value of his property, spoiled the view from the front porch, or prevented the use of the road itself. An organization generally lacks standing to sue for money damages on behalf of its members if the damage claims are not common to the entire membership, nor shared equally, so that the fact and extent of injury would require individualized proof. Warth v. Seldin, 422 U.S. 490, 95 S.Ct. 2197, 45 L.Ed.2d 343 (1975). "[W]here an association seeks to recover damages on behalf of its members, the extent of injury to individual members and the burden of supervising the distribution of any recovery mitigates against finding standing in the association." River Birch Associates v. City of Raleigh, 326 N.C. 100, 130, 388 S.E.2d 538, 555 (1990) (citing Hunt for its holding that homeowners' association lacked standing where it sought money damages for some of its members). "Indeed, courts have routinely held that associations may not bring claims for monetary relief on behalf of their members." Pennsylvania Psychiatric Society v. Green Spring Health Services, Inc., ___ F.Supp. ___, 2000 WL 33365907 (W.D.Pa. 24 March 2000). In the case sub judice, any monetary damages owed to plaintiffs would call for "individualized proof," and would not necessarily be common to all. The financial impact of the fence upon various members of the association could vary from significant to minimal. Therefore, we find that the participation of *227 individual homeowners is necessary to the suit. If plaintiffs had sought only declarative or injunctive relief, the association may have had standing to sue in its representative capacity. The assertion by Creek Pointe homeowners of a right to unfettered access to all roads within the subdivision rests upon their ownership of a lot in Creek Pointe and their membership in the association. Thus, "[t]he interest of [individual homeowners] in the [Creek Pointe roads] is indirect. Any interest the home owners have in [the roads] derives through their membership in the Homeowners' Association .... [which can] adequately represen[t] such interest[.]" River Birch, 326 N.C. at 128-129, 388 S.E.2d at 554. However, having determined that this suit's pursuit of monetary damages requires the participation of individual homeowners, we necessarily find that the association does not meet the third criteria for standing under Hunt v. Washington State to bring suit as the representative of its members. Consequently, we hold that the homeowners' association lacked standing, under the criteria articulated in Hunt and followed in subsequent cases, to bring suit as the representative of individual members of the association. We next consider whether the association has standing to join Kremer as a separate plaintiff, rather than as the representative of homeowners. To bring suit on its own behalf, an association need only meet the "irreducible constitutional minimum" of a sufficient stake in a justiciable case or controversy. Lujan v. Defenders of Wildlife, 504 U.S. 555, 112 S.Ct. 2130, 119 L.Ed.2d 351 (1992) (the "irreducible constitutional minimum" of Article III of the U.S. Constitution requires plaintiff who wishes to pursue claim in federal court to demonstrate (1) injury in fact, (2) causal relationship between injury and conduct complained of, and (3) likelihood that injury would be redressed by favorable verdict); Transcontinental Gas Pipe Line, 132 N.C.App. 237, 511 S.E.2d 671, (reiterating holding of Lujan in concurring opinion). In the instant case, the Declaration of Covenants, Conditions, and Restrictions, and the By-laws of the association, state that the association has a duty to maintain the private roads within Creek Pointe. Clearly, the presence of a fence across one of the subdivision's roads injures the association in its ability to carry out this duty. The injury is causally connected to the defendant's alleged behavior, and likely would be redressed by a favorable verdict in this action. Therefore, we hold that on the facts of this case, the association had standing to bring this suit on its own behalf. See District Council 20, American Federation of State, County and Municipal Employees, 150 F.Supp.2d 136 (U.S.Dist.Ct.,D.C., 2001) (court finds that Hunt precludes plaintiff organization from suing in representative capacity, but allows association to remain in suit for purpose of litigating claims for declaratory and injunctive relief). Accordingly, we reverse the trial court's ruling that the Creek Pointe Homeowner's Association lacks standing to participate in this action, and hold that the association has standing to pursue claims alleging injury to the association itself. The association also argues that the trial court erred in considering the defendant's motion to dismiss the association's claims for lack of standing "after" it had entered an order joining other homeowners as necessary parties. We disagree. Both rulings were part of the orders issued at the conclusion of the hearing on 25 February 2000. Further, the cases cited by plaintiff for the proposition that after ordering necessary parties joined, no actions may be taken that are "determinative of a claim arising in the action," all address situations in which substantive matters were determined in the absence of necessary parties. In the case sub judice, the court took no actions affecting the resolution of the issues to be tried. The parties raise several other issues in their briefs, including arguments about whether it is significant that the appellant is Creek Pointe Homeowner's Association Inc., while the original declaration referred to the Creek Pointe Homeowner's Association (emphasis added). We do not find it necessary to resolve these questions. For the reasons discussed above, we hold that the trial court erred by dismissing all claims as to the Creek Pointe Homeowner's *228 Association, and hold that the association has standing to pursue claims against this defendant on its own behalf. Accordingly, we reverse its order dismissing all claims of the Creek Pointe Homeowner's Association. Reversed. Judge SMITH concurs. Judge WALKER concurring in part and dissenting in part. WALKER, Judge, concurring in part and dissenting in part. I respectfully dissent from that part of the majority opinion which holds that while the North Carolina Planned Community Act (NCPCA) authorizes homeowners' associations as a general class to institute, defend or intervene in litigation, the statute does not abrogate the common law by advancing "a new right upon homeowners' associations" to representative standing. I agree with the position taken by both plaintiffs and third-party defendant Weyerhaeuser Real Estate Company, Inc. (Weyerhaeuser) that the NCPCA confers representative standing upon the Creek Pointe Homeowner's Association (Creek Pointe) to enforce the easement right of lot owners to Deep Creek Road consistent with its declaration, articles of incorporation and bylaws. See N.C. Gen.Stat. § 47F-3-102(4)(1999). The NCPCA provides that homeowners' associations may "[i]nstitute, defend, or intervene in litigation or administrative proceedings on matters affecting the planned community." Id. This section applies retroactively to homeowners' associations formed prior to the NCPCA's effective date of 1 January 1999. See N.C. Gen.Stat. § 47F-3-102(4), commentary (1999); see also Patrick K. Hetrick, Of "Private Governments" and the Regulation of Neighborhoods: The North Carolina Planned Community Act, 22 Campbell L.Rev. 1, 18 (1999). The majority concludes that this language "simply reiterates" the common law rule regarding homeowners' association standing. However, the language of N.C. Gen.Stat. § 47F-3-102(4) must be considered in conjunction with the overall scheme of planned communities and the objectives of the NCPCA. Admittedly, the statute does not automatically confer representative standing upon a homeowners' association in every case.[1] Nevertheless, I construe the NCPCA to allow a homeowners' association, both as a real party in interest and in a representative capacity, to pursue litigation in matters affecting the common areas within the planned community; provided such actions are consistent with its declaration, articles of incorporation and bylaws. Practically speaking, a homeowners' association assures lot owners that basic needs such as ground care and street maintenance are fulfilled. However, the association also provides its lot owners with common emotional, psychological, and social advantages. See Harvey Rishikof and Alexander Wohl, Private Communities or Public Governments: "The State Will Mark the Call," 30 Val. U.L.Rev. 509, 513 (1996). Agreed to rules regarding the use of common areas and restrictions on what the lot owners are allowed to display or include in their individual units provide a feeling of conformity that many find reassuring. Id. The creation of this sense of commonality requires lot owners, in forming a planned community, to make a collective assignment to the homeowners' association of certain interests enabling the lot owners to collectively take action in matters affecting the common areas. I believe that, upon the formation of a planned community, the NCPCA envisions that the lot owners collectively assign to the homeowners' association their real property interests in the common areas. Thus, when a matter arises, as in the case sub judice, affecting the use and control of a common area, the homeowners' association, in accordance with N.C. Gen.Stat. § 47F-3-102(4) is conferred with representative standing to institute litigation on behalf of the lot owners. My reading of N.C. Gen.Stat. § 47F-3-102(4) is compatible with other statutory language dealing with real property interests *229 found elsewhere in the NCPCA. For example, under N.C. Gen.Stat. § 47F-3-112, a homeowners' association, upon approval of eighty percent (80%) of the lot owners, may convey, encumber or otherwise voluntarily transfer portions of any common area within the planned community. See N.C. Gen.Stat. § 47F-3-112(a)(1999). Such transfers become "free and clear of any interest of any lot owner or the association in or to the common [area] conveyed or encumbered, including the power to execute deeds or other instruments." N.C. Gen.Stat. § 47F-3-112(b)(1999)(emphasis added). The NCPCA's official commentary notes this section was included to "clarify that if conveyance or encumbrance is authorized by the required percentage of owners, common [areas] may be conveyed or encumbered free and clear of any easements, rights of way or claims which might be asserted by individual lot owners in or to that common area by virtue of their ownership of lots." N.C. Gen.Stat. § 47F-3-112, commentary (1999). Other provisions within the NCPCA demonstrate that upon formation the lot owners assign to the homeowners' association their real property interest in common areas. In an eminent domain proceeding affecting a common area, the NCPCA requires that the portion of an award attributable to the common area taken is to be paid to the association, rather than distributed pro rata to the lot owners. See N.C. Gen.Stat. § 47F-1-107 (1999). This statutory requirement ensures that all the lot owners in a planned community receive compensation for the taking. Consequently, if a body with eminent domain authority seeks to acquire a common area the court would be required to disperse any monetary compensation to the homeowners' association regardless of the disparate impact the eminent domain might have on the individual lot owners. Therefore, in an eminent domain proceeding, only the homeowners' association need be named as a party defendant. In such a case the homeowners' association's evidence establishing the damages may include testimony from individual lot owners. The same rationale applies to the case sub judice. In order to receive compensatory or punitive damages, Creek Pointe would have to present evidence demonstrating how Happ's erection of a fence has damaged the planned community; including all the individual lot owners. Thus, permitting Creek Pointe representative standing ensures the protection of all the lot owners' interests. The NCPCA's recognition of representative standing is also reflected in the statutory language dealing with the termination of a homeowners' association. In the event the lot owners decide to terminate the planned community, the NCPCA requires that upon termination the remaining common areas vest in the lot owners as tenants in common. See N.C. Gen.Stat. § 47F-2-118(e)(1999). This vesting of remaining common areas results in the return to the lot owners of the real property interest assigned to the homeowner's association at its inception. Based on my analysis of the NCPCA, I must disagree with the majority's conclusion that the third prong of Hunt has not been satisfied. I conclude that neither the claim asserted nor the relief requested requires the participation of the individual lot owners in this lawsuit. See Hunt v. Washington State Apple Advertising Commission, 432 U.S. 333, 343, 97 S.Ct. 2434, 2441, 53 L.Ed.2d 383, 394 (1977). Weyerhaeuser as a third-party defendant supports the position of the plaintiffs in this action. Additionally, Weyerhaeuser created this subdivision and formed the homeowners' association. Obviously, evidence from Weyerhaeuser will be crucial in establishing the common areas within Creek Pointe, including Deep Creek Road. Notwithstanding defendant Happ's contention as to standing, he elected to assert a counterclaim against the homeowners' association alleging a superior right to this road which enables him to close it. Therefore, the individual lot owners are not pursuing a claim or relief for which their participation would be required. I concur with the majority opinion that the homeowners' association has standing to pursue claims for declaratory and injunctive relief. NOTES [1] For example, a homeowners' association would not have representative standing to initiate litigation on behalf of a lot owner whose sole cause of action is one for the breach of a contract with a builder.
Adsorptive removal of antibiotics from water using magnetic ion exchange resin. The occurrence of antibiotics in the environment has recently raised serious concern regarding their potential threat to aquatic ecosystem and human health. In this study, the magnetic ion exchange (MIEX) resin was applied for removing three commonly-used antibiotics, sulfamethoxazole (SMX), tetracycline (TCN) and amoxicillin (AMX) from water. The results of batch experiments show that the maximum adsorption capacities on the MIEX resin for SMX, TCN and AMX were 789.32, 443.18 and 155.15μg/mL at 25°C, respectively, which were 2-7 times that for the powdered activated carbon. The adsorption kinetics of antibiotics on the MIEX resin could be simulated by the pseudo-second-order model (R2=0.99), and the adsorption isotherm data were well described by the Langmuir model (R2=0.97). Solution pH exhibited a remarkable impact on the adsorption process and the absorbed concentrations of the tested antibiotics were obtained around the neutral pH. The MIEX resin could be easily regenerated by 2mol/L NaCl solution and maintained high adsorption removal for the tested antibiotics after regeneration. Anion exchange mechanism mainly controlled the adsorption of antibiotic and the formation of hydrogen binding between the antibiotic and resin can also result in the increase of adsorption capacity. The high adsorption capacity, fast adsorption rate and prominent reusability make the MIEX resin a potential adsorbent in the application for removing antibiotics from water.
Q: What grammatical structure is this parenthetical? An equivalent formulation, generalizable to interacting systems, is to consider... I want to know what kind of grammatical structure the part "generalizable to interacting systems" is. It is not a participle construction, right? What is it? A: Generalizable is an adjective, and the phrase generalizable to interacting systems post-modifies formulation. It could also be expressed as which is generalizable to interacting systems.
Cashmere Collection – Gaajri Known for its prominent Paisley Motifs with ditzy patterns of Floral, this beauty has an eye-catching view of an authentic Jamwar design. With an exotic mix of colors like Vermilion, Gold, and Blue this wrap is rich in its color composition. Filled with Softness, your child will feel cocooned in this fluffy wrap. Nowhere does it fall short in rendering a safe and a supportive carry. When you come across Cashmere Collection you’re bound to experience Magic, see Beauty and feel Love. It has our finest and exclusive collection of wraps. Additional information Size 3, 4, 5, 6, 7 7 reviews for Cashmere Collection – Gaajri Rated 5 out of 5 Ana Herceg- Jaklenec–March 8, 2018 Hard to describe this wrap… It’s thin, soft, cuddly, yet supportive. It’s beautiful. Just like all the Almitras. I dreamed of owning one, and now I do!!! And I want more!!! Love the way colours change in the light. Rated 5 out of 5 Gaila–March 8, 2018 So thin and soft, but strong from the wool. Perfect with the littlest babe due to the thin floppiness, but the strong cushy wool easily holds up to my 35-lb toddler-monster as well! There is just the right amount of texture for passes to move and tighten easily as you’re wrapping, and then stay exactly put until you are ready to unwrap. And the colors are beautiful, looking anywhere from a complex dark pink to rich red depending on the lighting. Rated 5 out of 5 Miekske Dingens–March 8, 2018 Loving the design, the colour and the blend. So soft! <3 Ideal to carry our son. I love to carry him, because it makes our bond stronger Rated 5 out of 5 Lauren Calvert–March 9, 2018 This wrap is truly stunning. It was perfect for my tiny squish. Supportive and oh so pretty! Rated 5 out of 5 Johanne Hansen–March 9, 2018 This wrap is one of my favorite things in the whole world! So supportive and cushy on the shoulders, warm, soft and cuddly ❤ perfect for our Scandinavian winter weather, with the yummy wool and beautiful deep colors to bring some joy to the dark and grey days. It wraps easily, and because of the wooll-fibres, it locks in place and doesn’t slide, I love that! I have loved this wrap since the day it arrived in my doorstep, and will forever treasure the memories of carrying my sleeping baby close to my heart ❤ Rated 5 out of 5 Maria Monrad–March 9, 2018 My daughter was 10 months when i bought gaarji. A Heavy 10 months old. Eventhough the wrap is amazingly Thin it felt like a cloud when wearing her. It is the most beautiful wrap and it is so thin and light that it is easy to stuff in your purse “just in case”. Only problem for me was my Extreme dryness on my Hands Got stuck in the woolen fibres.
Contact Us Vandal Victory Pumpkin Pancakes Our “Vandal Victory Pumpkin Pancakes” are a delicious surprise to wake up to the day after Thanksgiving. When all the guests are at the house, impress them with this tasty twist on a breakfast and keep the festivities alive. The pumpkin in the pancakes, enhanced with cinnamon and nutmeg, add depth to the flavor profile and richness to the texture. Cranberries, from whole cranberry sauce, add a hint of deep red and a sweet poignant taste. This complements the simple cranberry syrup that can be used as an addition to this gourmet meal. Whether you are shopping at after-Thanksgiving sales or going out for a game of football, our “Vandal Victory Pumpkin Pancakes” will ensure that your breakfast is a success! - Ashlee Eskelsen and Jeni Dillon Yield: 6 pancakes (serves 2) Griddle: 350⁰F Cook: 3-5 minutes Ingredients: 1 cup pancake mix of your choice ½ cup water ½ tsp cinnamon ¼ tsp nutmeg ¼ rolled oats ¾ cup cranberry sauce ¼ cup canned pumpkin ¾ cup quick cranberry sauce ¼ cup maple syrup Directions: Mix pancake mix, water, nutmeg, cinnamon, rolled oats, and canned pumpkin together in a bowl until a lumpy consistency is obtained. Reheat cranberry sauce with about 1 tablespoon water. Drain berries and rinse, reserving sauce in a separate bowl. Mix cranberry sauce with maple syrup and a pinch of cinnamon.
Deadline Extended Again For Isaac-Related Flood Claims In La. Louisiana property owners with flood insurance policies whose homes or other structures were damaged during Hurricane Isaac have an additional 30 days to file claims for their flood-related losses. This means most policyholders have until Feb. 21 to complete their proof of loss. The National Flood Insurance Program (NFIP) usually requires claims to be reported within 60 days from the date of loss. Three extensions have been granted, however, because access to NFIP-insured homes and other buildings was delayed due to infrastructure damage and high floodwaters. The Federal Emergency Management Agency (FEMA) administers the program. With the latest 30-day extension on flood insurance claims, Louisianians have 180 days from the date of their insured loss to submit a claim, known as proof of loss. Hurricane Isaac first made landfall in Louisiana on Aug. 28, 2012, with heavy rainfall and flooding occurring within several days before and after it hit. For this reason the date of loss varies for property owners. "Many Isaac survivors continue to gather information that will help adjusters determine their flood insurance loss," said Federal Coordinating Officer Gerard M. Stolar of FEMA. "However, we urge folks who haven't yet filed their proof of loss to do so as soon as possible." Failure to submit the proof of loss could cause policyholders to miss out on benefits from their flood insurance policy, NFIP specialists said. Since Isaac made landfall, the NFIP has paid out more than $416 million on 13,159 claims in Louisiana. Policyholders with questions about flood insurance or concerns about their claims may contact their local insurance agent, call FEMA program experts at 1-866-331-1679 or 1-866-330-7286, or visit www.floodsmart.gov.
London Canoe Slalom Invitational The London Canoe Slalom Invitational was an international Canoe Slalom event held at the Lee Valley White Water Centre between July 28 and 31 2011. The Regatta was closed to the media and public. It was a 2012 Olympics test event and was part of the London Prepares series Results References Canoe Slalom Invitational Category:Canoeing and kayaking competitions in the United Kingdom Category:2011 in canoeing Category:Canoeing in England Category:2011 in English sport
{ "translations" : { "_%n window_::_%n windows_" : ["%n okno", "%n okna", "%n oken"] }, "pluralForm" : "nplurals=3; plural=(n==1) ? 0 : (n>=2 && n<=4) ? 1 : 2;" }
// PSSProxyClientDlg.h : 头文件 // #pragma once #include "afxwin.h" #include <WinSock2.h> #define MAX_BUFF_20 20 class CConvertBuffer { public: CConvertBuffer() {}; ~CConvertBuffer() {}; int GetBufferSize(const char* pData, int nSrcLen) { char szData[3] = {'\0'}; int nPos = 0; int nCurrSize = 0; int nConvertSize = 0; bool blState = false; //转换后的字符串是否有效 bool blSrcState = true; //元字符串是否有效 unsigned char cData; while(nPos < nSrcLen) { if(pData[nPos] == '\r' || pData[nPos] == '\n' || pData[nPos] == ' ' || nPos == nSrcLen - 1) { if(nPos == nSrcLen - 1) { szData[nCurrSize++] = pData[nPos]; } szData[nCurrSize] = '\0'; if(blSrcState == true) { blState = ConvertStr2char(szData, cData); if(blState == true) { nConvertSize++; } } nCurrSize = 0; blSrcState = true; nPos++; } else { if(nCurrSize < 2) { szData[nCurrSize++] = pData[nPos]; } else { blSrcState = false; } nPos++; } } return nConvertSize; }; bool Convertstr2charArray(const char* pData, int nSrcLen, unsigned char* pDes, int& nMaxLen) { char szData[3] = {'\0'}; int nPos = 0; int nCurrSize = 0; int nConvertSize = 0; bool blState = false; //转换后的字符串是否有效 bool blSrcState = true; //元字符串是否有效 while(nPos < nSrcLen) { if(pData[nPos] == '\r' || pData[nPos] == '\n' || pData[nPos] == ' ' || nPos == nSrcLen - 1) { if(nPos == nSrcLen - 1) { szData[nCurrSize++] = pData[nPos]; } szData[nCurrSize] = '\0'; if(nConvertSize < nMaxLen && blSrcState == true) { blState = ConvertStr2char(szData, pDes[nConvertSize]); if(blState == true) { nConvertSize++; } } nCurrSize = 0; blSrcState = true; nPos++; } else { if(nCurrSize < 2) { szData[nCurrSize++] = pData[nPos]; } else { blSrcState = false; } nPos++; } } nMaxLen = nConvertSize; return true; }; private: bool Get_binary_Char(unsigned char cTag, unsigned char& cDes) { if(cTag >='A'&& cTag <='F') { cDes = cTag - 'A' + 10; return true; } else if(cTag >='a'&& cTag <='f') { cDes = cTag - 'a' + 10; return true; } else if(cTag >= '0'&& cTag<= '9') { cDes = cTag-'0'; return true; } else { return false; } } bool ConvertStr2char(const char* pData, unsigned char& cData) { if(pData == NULL || strlen(pData) != 2) { return false; } char cFirst = pData[1]; unsigned char cTemp = 0; bool blStste = Get_binary_Char(cFirst, cTemp); if(false == blStste) { return false; } cData = cTemp; char cSecond = pData[0]; blStste = Get_binary_Char(cSecond, cTemp); if(false == blStste) { return false; } cTemp = cTemp << 4; cData = cData | cTemp; return true; } }; // CPSSProxyClientDlg 对话框 class CPSSProxyClientDlg : public CDialog { // 构造 public: CPSSProxyClientDlg(CWnd* pParent = NULL); // 标准构造函数 // 对话框数据 enum { IDD = IDD_PSSPROXYCLIENT_DIALOG }; protected: virtual void DoDataExchange(CDataExchange* pDX); // DDX/DDV 支持 private: void InitView(); bool Connect(const char* pIP, int nPort); void Close(); void Send_Data(const char* pSendBuff, int nLen); private: SOCKET m_sckClient; // 实现 protected: HICON m_hIcon; // 生成的消息映射函数 virtual BOOL OnInitDialog(); afx_msg void OnSysCommand(UINT nID, LPARAM lParam); afx_msg void OnPaint(); afx_msg HCURSOR OnQueryDragIcon(); DECLARE_MESSAGE_MAP() public: CEdit m_txtServerIP; CEdit m_txtServerPort; CEdit m_txtSendData; afx_msg void OnBnClickedButton1(); };
J-S42027-17 NON-PRECEDENTIAL DECISION - SEE SUPERIOR COURT I.O.P. 65.37 COMMONWEALTH OF PENNSYLVANIA IN THE SUPERIOR COURT OF PENNSYLVANIA Appellee v. DRU MICHAEL SMITH FAILOR Appellant No. 1664 MDA 2016 Appeal from the Judgment of Sentence August 23, 2016 In the Court of Common Pleas of Cumberland County Criminal Division at No(s): CP-21-CR-0002532-2015 BEFORE: OLSON, J., MOULTON, J., and FORD ELLIOTT, P.J.E. MEMORANDUM BY MOULTON, J.: FILED SEPTEMBER 19, 2017 Dru Michael Smith Failor appeals from the August 23, 2016 judgment of sentence entered in the Cumberland County Court of Common Pleas after he pled guilty to arson endangering property (reckless endangerment of inhabited building), retaliation against witness or victim, and six counts of recklessly endangering another person.1 We affirm. The trial court set forth the following factual and procedural history: The underlying incident in this matter began with [the Victim] filing for a Protection From Abuse [(“PFA”)] order against [Failor]. A final PFA order was entered by stipulation against [Failor] on December 24, 2014. On June 15, 2015, while Victim was protected by the final PFA order, [Failor] elected to travel with several friends to the residence where Victim was living. While [Failor]’s friends attempted to talk him out of it, [Failor] threw a firework at ____________________________________________ 1 18 Pa.C.S. §§ 3301(c)(2), 4953(a), and 2705, respectively. J-S42027-17 Victim’s residence. The firework failed to ignite, and [Failor] left the property. Subsequently, [Failor] returned to Victim’s residence and threw a second firework at it. The second firework landed on the residence’s wooden deck and ignited, sparking a fire which caused over $44,000 in damage to the residence and drove Victim, as well as friends and relatives of Victim also staying at the residence[,] including Victim’s infant child, into the streets. [Failor] was identified as the responsible party by several witnesses, who contacted Victim and the police regarding the incident. [Failor] was arrested and charged with the underlying offenses. Prior to trial, [Failor] contacted the witnesses in question and, in a consensually recorded conversation, threatened to kill each and every one of them if [he] was convicted of the charges against him. On July 11, 2016, the date [Failor] was scheduled to appear for trial in this matter, [Failor] entered a plea of guilty to the charges of Arson (Endangering Property), Retaliation Against a Witness or Victim, and six counts of Recklessly Endangering Another Peron. [Under the terms of the plea agreement, the court dismissed charges of arson (endangering persons), risking catastrophe, criminal mischief (damaging property by fire), and loitering and prowling at night time.][2] Following entry of his pleas, [Failor] was sentenced on August 23, 2016, to a term of incarceration of one to three years for the Arson (Endangering Property) charge, and a consecutive two to four year term for Retaliation Against a Witness or Victim. On the Recklessly Endangering Another Person charges, [Failor] was sentenced to concurrent terms of two years of probation, set consecutive to the term of incarceration. . . . Following sentencing, [Failor] timely filed a pro se post- sentence motion for reconsideration on August 30, 2016, and a counseled motion for reconsideration on September ____________________________________________ 2 18 Pa.C.S. §§ 3301(a)(1)(i), 3302(b), 3304(a)(1), and 5506, respectively. -2- J-S42027-17 []2, 2016. [Failor]’s motion for reconsideration was denied by Order of Court dated September 7, 2016[.] Opinion Pursuant to Pa.R.A.P. 1925(a), 12/9/16, at 3-4 (“1925(a) Op.”). On October 7, 2016, Failor filed a timely notice of appeal. Failor raises one question on appeal that contains two issues: “Did the court abuse its discretion by imposing a sentence which was manifestly excessive, unreasonable, and an abuse of discretion, as the trial court had no basis for imposing an aggravated range sentence or for imposing sentences consecutively?” Failor’s Br. at 7 (some capitalization omitted). “Challenges to the discretionary aspects of sentencing do not entitle an appellant to review as of right.” Commonwealth v. Allen, 24 A.3d 1058, 1064 (Pa.Super. 2011). Before we address such a challenge, we must first determine: (1) whether the appeal is timely; (2) whether Appellant preserved his issue; (3) whether Appellant’s brief includes a concise statement of the reasons relied upon for allowance of appeal with respect to the discretionary aspects of sentence; and (4) whether the concise statement raises a substantial question that the sentence is appropriate under the sentencing code. Commonwealth v. Austin, 66 A.3d 798, 808 (Pa.Super. 2013) (quoting Commonwealth v. Malovich, 903 A.2d 1247, 1250 (Pa.Super. 2006)). Failor filed a timely notice of appeal, preserved his discretionary aspects of sentencing claims in a motion for reconsideration of sentence, and included a concise statement of the reasons relied upon for allowance of appeal pursuant to Pennsylvania Rule of Appellate Procedure 2119(f). We -3- J-S42027-17 must now determine whether Failor’s issue raises a substantial question for our review. We evaluate whether a particular sentencing issue raises a substantial question on a case-by-case basis. Commonwealth v. Dunphy, 20 A.3d 1215, 1220 (Pa.Super. 2011). A substantial question exists where a defendant raises a “plausible argument that the sentence violates a provision of the sentencing code or is contrary to the fundamental norms of the sentencing process.” Commonwealth v. Dodge, 77 A.3d 1263, 1268 (Pa.Super. 2013) (quotation omitted). A claim that the sentence imposed was excessive and unreasonable, when that sentence is above the aggravated range under the Sentencing Guidelines, presents a substantial question for our review. See Commonwealth v. Sheller, 961 A.2d 187, 190 (Pa.Super. 2008) (finding that appellant’s “contention that the [trial] court exceeded the recommended range in the Sentencing Guidelines without an adequate basis raises a substantial question for this Court to review”). “The imposition of consecutive, rather than concurrent sentences may raise a substantial question in only the most extreme circumstances, such as where the aggregate sentence is unduly harsh, considering the nature of the crimes and the length of imprisonment.” Commonwealth v. Moury, 992 A.2d 162, 171-72 (Pa.Super. 2010). However, a “challenge to the imposition of . . . consecutive sentences as unduly excessive, together with [a] claim that the court failed to consider [the defendant’s] -4- J-S42027-17 rehabilitative needs and mitigating factors upon fashioning its sentences, presents a substantial question.” Commonwealth v. Swope, 123 A.3d 333, 340 (Pa.Super. 2015). We conclude that Failor has raised a substantial question as to whether his aggravated-range sentence for retaliation is manifestly excessive. We also conclude that Failor has raised a substantial question as to whether the court failed to consider his rehabilitative needs and mitigating factors and in imposing the aggregate sentence. Accordingly, we will review the merits of his claims. “Sentencing is a matter vested within the discretion of the trial court and will not be disturbed absent a manifest abuse of discretion.” Commonwealth v. Crump, 995 A.2d 1280, 1282 (Pa.Super. 2010). First, Failor argues that he was sentenced to an aggravated-range sentence based on inappropriate factors. According to Failor, the trial court “imposed a sentence under the retaliation charge that was . . . motivated by the allegation that . . . Failor committed an arson endangering persons.” Failor’s Br. at 16. Failor asserts that “[i]t is manifestly unjust to dismiss the arson endangering persons charge and then use that same language/conduct to impose an aggravated range sentence for the retaliation charge.” Id. This claim is without merit. It is well settled that “[a] sentence is invalid if the record discloses that the sentencing court may have relied in whole or in part upon -5- J-S42027-17 impermissible consideration. . . . [including] unreliable information.” Commonwealth v. Downing, 990 A.2d 788, 793 (Pa.Super. 2010) (quoting Commonwealth v. Karash, 452 A.2d 528, 528-29 (Pa.Super. 1982)). Further, “the evidence upon which a sentencing court relies must be accurate and there must be evidentiary proof of the factor[] upon which the court relied.” Id. (internal citations and quotations omitted). Here, the trial court cited three factors in support of an aggravated- range sentence: (1) the amount of damage to the property; (2) the risk of serious injury to the victims; and (3) Failor’s prior conviction for criminal mischief on March 15, 2016. N.T., 8/23/16, at 14-15. At the guilty plea hearing, Failor admitted that he threw the firework at the home because the victim had filed for and received a PFA order against Failor. Failor’s retaliation conviction shared the same underlying factual basis that might have been used to prove the arson endangering persons charge, which was dismissed as a part of the plea agreement. The dismissal of that arson charge did not preclude the trial court from considering the factual basis for the plea to retaliation. Therefore, we conclude that the trial court acted within its discretion in sentencing Failor in the aggravated range for the retaliation conviction. Next, Failor argues that the trial court failed to consider mitigating factors in imposing the aggregate sentence. According to Failor, the trial court “based [its] decision on [its] personal sympathies, [its] rancor towards -6- J-S42027-17 [] Failor, and [its] revulsion of [] Failor’s offenses.” Failor’s Br. at 16. Failor asserts that the trial court ignored his “potential for rehabilitation [and] his . . . manifestation of social conscience and responsibility through contrition, repentance, and cooperation with law enforcement agencies.” Id. at 18 (quoting Commonwealth v. Frazier, 500 A.2d 158, 160 (Pa.Super. 1985)). Failor contends that he exhibited these matters by pleading guilty and apologizing for his actions during his allocution. Failor also asserts that the trial court failed to consider Failor’s “need to work and maintain employment in order to pay the significant amount of restitution order by the court,” and that Failor’s conviction will now make him “virtually unemployable.” This claim does not merit relief. Section 9721(b) of the Sentencing Code requires that in selecting from [sentencing] alternatives . . . the court shall follow the general principle that the sentence imposed should call for confinement that is consistent with the protection of the public, the gravity of the offense as it relates to the impact on the life of the victim and on the community, and the rehabilitative needs of the defendant. 42 Pa.C.S. § 9721(b). Further, “[w]here pre-sentence reports exist, we . . . presume that the sentencing judge was aware of relevant information regarding [the defendant’s] character and weighed those considerations along with mitigating statutory factors.” Commonwealth v. Gonzalez, 109 A.3d 711, 732 (Pa.Super.) (quoting Commonwealth v. Devers, 546 A.2d 12, 18 (Pa. 1988)), app. denied, 125 A.3d 1198 (Pa. 2015). This Court has stated that: -7- J-S42027-17 A pre-sentence report constitutes the record and speaks for itself. . . . [S]entencers are under no compulsion to employ checklists or any extended of systematic definitions of their punishment procedure. Having been fully informed by the pre-sentence report, the sentencing court’s discretion should not be disturbed. This is particularly true . . . in those circumstances where it can be demonstrated that the judge had any degree of awareness of the sentencing considerations, and there we . . . presume also that the weighing process took place in a meaningful fashion. Commonwealth v. Macias, 968 A.2d 773, 778 (Pa.Super. 2009) (quoting Devers, 546 A.2d at 18). Here, the trial court reviewed the pre-sentence investigation report and victim impact statements. The trial court also heard from the Commonwealth and Failor and heard Failor’s allocution. We are convinced that the trial court imposed an individualized sentence that took into consideration any mitigating factors presented and the factors under section 9721(b). Accordingly, we find no abuse of discretion. Judgment of sentence affirmed. Judgment Entered. Joseph D. Seletyn, Esq. Prothonotary Date: 9/19/2017 -8-
Q: Do men have more Chochma than women? I've seen many blogs and other modern day books write that men have more Chochmah than women. Some examples: A man’s forte is chochma, and a woman’s is binah. Kabbalah teaches that men have more Chochma (wisdom) and women a greater measure of Bina (understanding). Men are from Chochmah; Women are from Binah The first of the properties is that of chochmah, translated loosely as “wisdom,” which is a male principle. Men's brains with their superior Chochmah mode... Women are more attuned to binah and malchut. Men are more inclined to chochma and tiferet. Is there a valid source for this? The closest thing I'm aware of is Yomah 66b אין חכמה לאשה אלא בפלך וכן הוא אומר (שמות לה, כה) וכל אשה חכמת לב בידיה טוו but I don't think that's a valid Mekor at all. See the end of this article for example. Also see there for a number of sources that women are referred to as having significant amounts of Chochmah (although there's no implication there who has more- men or women). A: Daf al Hadaf to Niddah 45b says clearly that men have more Chochmah than women. He bases this on the contradiction between Shabbos 33b (נשים דעתן קלות) and Niddah 45b (בינה יתירה באשה יותר מבאיש) and explains this to be the distinction between the two Gemaras. He also quotes Yoma 66b as support, despite your issues with this. He quotes 2 sources for his claim: the Sefer Chasam Sofer quoted earlier on that page in Daf al Hadaf (Seder Avodas Hayom, which I have been unable to find), which makes some comments which I will not explain here in English והמעיין יעיין. The Maharal in Chiddushei Agados here, who makes this distinction openly. He discusses the difference between men and women as שכל הנבדל vs. שכל היולאני, and associates the שכל הנבדל with Chochma, and the שכל היולאני with Binah.
FORT RUCKER, Ala. (January 17, 2013) -- With the arrival of the new year, some people think about making new, healthy habits, and Fort Rucker is helping people make one good change by continuing to make on-post recycling accessible and easy. Fort Rucker offers many ways to recycle, including the Picerne Military Housing program, the environmental center and the hazardous waste center, and according to Colleen Quinlan, Fort Rucker Environmental Office hazardous waste manager, waste in landfills is a growing epidemic that the post is helping to diminish. "It is super easy to drop things off at our centers. No hassle, no paperwork and no fees. We couldn't make it any easier. You can live off post, you can bring your neighbors' stuff, you can be a civilian, you can work on post -- it doesn't matter," she said. The recycling center collects what is considered typical, recyclable material year round. "We take cardboard, aluminum cans, paper, mixed plastics, old toner cartridges and even used oil. We also take metals, like brass, and we even accept compact discs now," Quinlan said. The fact that anyone can use the hazardous waste and environmental centers, with their accessible locations, and the fact that they collect materials at office buildings make them a good choice when it comes to local recycling, according to Melissa Lowlavar, environmental branch chief. "We have paper and cardboard recycling bins set up around the installation. They are set out at a variety of locations all over post. We have several in Bldg. 5700 alone. They are at almost every office building-- we have over 100 set out," she said. The centers also collect electronic waste, such as compact discs and monitors, as well as wood pallets. "We are trying to be a good steward and help the community recycle to help the environment. We need to save the resources that we have and reuse what can be reused," said Lowlavar. "Sooner or later there isn't going to be any more land to make landfills out of. We want to sustain what we have for future generations." The centers have a few rules, though, when it comes to dropping things off to be recycled. "People have to separate what they bring in and food residue cannot be in any of the containers," said Lowlavar. Officials also request that pizza boxes not be brought in, and that bottles and cans that used to contain liquids be washed out. The trouble-free way of recycling, according to hazardous waste officials, is just one more reason to use the facilities. "It's just as easy as taking something to the dump as it is to bring it to us. It can even be more efficient than to leave it sitting around the house. Children can even do it. It's too easy," said Kevin Bryan, Fort Rucker assistant air manager. The military community is no stranger to recycling, but the hazardous waste manager said smaller communities do not have as many opportunities to recycle, and that is why the Fort Rucker opportunities should be taken advantage of. Locals, like Sabrina Vail, agree. "I am from Washington state, so I am used to recycling everything. It was odd to come to a place where recycling is not a major concern. It was really nice to see [the post] offering a place so I can safely get rid of products that I don't use anymore," she said. Picerne has a separate recycling program that Soldiers and Families that live on post can utilize that has just as many opportunities to recycle with just as much ease. "Each home comes with a 35-gallon rolling-recycling container that is picked up every Monday, and the program is free to use and you don't have to sign up for it," said Michael Gregory, director of capital improvements, maintenance and purchasing Picerne Military Housing. The materials that are allowed in each container are: aluminum, steel and tin cans; cardboard; paper bags; books; No. 1 and 2 plastic bottles; any type of paper; and pizza boxes. Picerne began its recycling mission 2006 and, according to Gregory, has seen growth each year. "This year it looks to be about 220 tons of material that we have recycled and about 1,200 tons has been collected since 2006," he said. Picerne also helps recycle when it demolishes houses, furbishes homes and constructs new homes. "One thing we do is cut old duplex homes in two and take some of the cement and recycle it. We are always looking for new ways to be more Earth friendly and being more sustainable," said Brandon Masters, Picerne Military Housing communications manager. For anyone wanting to recycle materials, the recycling center at Bldg. 9322 and hazardous waste center at Bldg. 1315 are open Mondays through Fridays from 8 a.m. to 4 p.m.
using System; using System.Collections.Generic; using System.Linq; using WebApi.Hal.Exceptions; using WebApi.Hal.Interfaces; namespace WebApi.Hal { public class Hypermedia : IHypermediaResolver, IHypermediaBuilder { private readonly IDictionary<Type, Link> selfLinks = new Dictionary<Type, Link>(); private readonly IDictionary<Type, IList<Link>> hypermedia = new Dictionary<Type, IList<Link>>(); private readonly IDictionary<Type, object> appenders = new Dictionary<Type, object>(); public static IHypermediaBuilder CreateBuilder() { return new Hypermedia(); } public static IHypermediaResolver CreateResolver() { return new Hypermedia(); } public void RegisterAppender<T>(IHypermediaAppender<T> appender) where T : class, IResource { if (appender == null) throw new ArgumentNullException(nameof(appender)); var type = typeof(T); if (appenders.ContainsKey(type)) throw new DuplicateHypermediaResolverRegistrationException(type); appenders.Add(type, appender); } public void RegisterSelf<T>(Link link) where T : IResource { if (link == null) throw new ArgumentNullException(nameof(link)); var type = typeof(T); if (selfLinks.ContainsKey(type)) throw new DuplicateSelfLinkRegistrationException(type); selfLinks.Add(type, link); } public void RegisterSelf<T>(Link<T> link) where T : class, IResource { if (link == null) throw new ArgumentNullException(nameof(link)); var type = typeof(T); if (selfLinks.ContainsKey(type)) throw new DuplicateSelfLinkRegistrationException(type); selfLinks.Add(type, link); } public void RegisterLinks<T>(params Link[] links) where T : class, IResource { if (links == null) throw new ArgumentNullException(nameof(links)); var type = typeof(T); if (hypermedia.ContainsKey(type)) hypermedia[type] = hypermedia[type].Union(links).Distinct(Link.EqualityComparer).ToList(); else hypermedia.Add(type, links.Distinct(Link.EqualityComparer).ToList()); } public IHypermediaResolver Build() { return this; } public IHypermediaAppender<T> ResolveAppender<T>(T resource) where T: class, IResource { var type = resource.GetType(); if (!appenders.ContainsKey(type)) return null; return (IHypermediaAppender<T>) appenders[type]; } public IEnumerable<Link> ResolveLinks(IResource resource) { var type = resource.GetType(); return hypermedia.ContainsKey(type) ? hypermedia[type] : new Link[0]; } public string ResolveRel(IResource resource) { var type = resource.GetType(); return selfLinks.ContainsKey(type) ? selfLinks[type].Rel : type.Name.ToLowerInvariant(); } public Link ResolveSelf(IResource resource) { var type = resource.GetType(); if (!selfLinks.ContainsKey(type)) return null; var clone = selfLinks[type].Clone(); clone.Rel = Link.RelForSelf; return clone; } } }
<!DOCTYPE HTML PUBLIC "-//W3C//DTD HTML 4.01 Transitional//EN" "http://www.w3.org/TR/html4/loose.dtd"> <!--NewPage--> <HTML> <HEAD> <!-- Generated by javadoc (build 1.6.0_34) on Tue May 26 09:04:07 BST 2015 --> <TITLE> GraphicsLine (Apache FOP 2.0 API) </TITLE> <META NAME="date" CONTENT="2015-05-26"> <LINK REL ="stylesheet" TYPE="text/css" HREF="../../../../../stylesheet.css" TITLE="Style"> <SCRIPT type="text/javascript"> function windowTitle() { if (location.href.indexOf('is-external=true') == -1) { parent.document.title="GraphicsLine (Apache FOP 2.0 API)"; } } </SCRIPT> <NOSCRIPT> </NOSCRIPT> </HEAD> <BODY BGCOLOR="white" onload="windowTitle();"> <HR> <!-- ========= START OF TOP NAVBAR ======= --> <A NAME="navbar_top"><!-- --></A> <A HREF="#skip-navbar_top" title="Skip navigation links"></A> <TABLE BORDER="0" WIDTH="100%" CELLPADDING="1" CELLSPACING="0" SUMMARY=""> <TR> <TD COLSPAN=2 BGCOLOR="#EEEEFF" CLASS="NavBarCell1"> <A NAME="navbar_top_firstrow"><!-- --></A> <TABLE BORDER="0" CELLPADDING="0" CELLSPACING="3" SUMMARY=""> <TR ALIGN="center" VALIGN="top"> <TD BGCOLOR="#EEEEFF" CLASS="NavBarCell1"> <A HREF="../../../../../overview-summary.html"><FONT CLASS="NavBarFont1"><B>Overview</B></FONT></A>&nbsp;</TD> <TD BGCOLOR="#EEEEFF" CLASS="NavBarCell1"> <A HREF="package-summary.html"><FONT CLASS="NavBarFont1"><B>Package</B></FONT></A>&nbsp;</TD> <TD BGCOLOR="#FFFFFF" CLASS="NavBarCell1Rev"> &nbsp;<FONT CLASS="NavBarFont1Rev"><B>Class</B></FONT>&nbsp;</TD> <TD BGCOLOR="#EEEEFF" CLASS="NavBarCell1"> <A HREF="class-use/GraphicsLine.html"><FONT CLASS="NavBarFont1"><B>Use</B></FONT></A>&nbsp;</TD> <TD BGCOLOR="#EEEEFF" CLASS="NavBarCell1"> <A HREF="package-tree.html"><FONT CLASS="NavBarFont1"><B>Tree</B></FONT></A>&nbsp;</TD> <TD BGCOLOR="#EEEEFF" CLASS="NavBarCell1"> <A HREF="../../../../../deprecated-list.html"><FONT CLASS="NavBarFont1"><B>Deprecated</B></FONT></A>&nbsp;</TD> <TD BGCOLOR="#EEEEFF" CLASS="NavBarCell1"> <A HREF="../../../../../index-all.html"><FONT CLASS="NavBarFont1"><B>Index</B></FONT></A>&nbsp;</TD> <TD BGCOLOR="#EEEEFF" CLASS="NavBarCell1"> <A HREF="../../../../../help-doc.html"><FONT CLASS="NavBarFont1"><B>Help</B></FONT></A>&nbsp;</TD> </TR> </TABLE> </TD> <TD ALIGN="right" VALIGN="top" ROWSPAN=3><EM> fop 2.0</EM> </TD> </TR> <TR> <TD BGCOLOR="white" CLASS="NavBarCell2"><FONT SIZE="-2"> &nbsp;<A HREF="../../../../../org/apache/fop/afp/goca/GraphicsImage.html" title="class in org.apache.fop.afp.goca"><B>PREV CLASS</B></A>&nbsp; &nbsp;<A HREF="../../../../../org/apache/fop/afp/goca/GraphicsSetArcParameters.html" title="class in org.apache.fop.afp.goca"><B>NEXT CLASS</B></A></FONT></TD> <TD BGCOLOR="white" CLASS="NavBarCell2"><FONT SIZE="-2"> <A HREF="../../../../../index.html?org/apache/fop/afp/goca/GraphicsLine.html" target="_top"><B>FRAMES</B></A> &nbsp; &nbsp;<A HREF="GraphicsLine.html" target="_top"><B>NO FRAMES</B></A> &nbsp; &nbsp;<SCRIPT type="text/javascript"> <!-- if(window==top) { document.writeln('<A HREF="../../../../../allclasses-noframe.html"><B>All Classes</B></A>'); } //--> </SCRIPT> <NOSCRIPT> <A HREF="../../../../../allclasses-noframe.html"><B>All Classes</B></A> </NOSCRIPT> </FONT></TD> </TR> <TR> <TD VALIGN="top" CLASS="NavBarCell3"><FONT SIZE="-2"> SUMMARY:&nbsp;<A HREF="#nested_classes_inherited_from_class_org.apache.fop.afp.modca.AbstractAFPObject">NESTED</A>&nbsp;|&nbsp;<A HREF="#fields_inherited_from_class_org.apache.fop.afp.goca.AbstractGraphicsCoord">FIELD</A>&nbsp;|&nbsp;<A HREF="#constructor_summary">CONSTR</A>&nbsp;|&nbsp;<A HREF="#method_summary">METHOD</A></FONT></TD> <TD VALIGN="top" CLASS="NavBarCell3"><FONT SIZE="-2"> DETAIL:&nbsp;FIELD&nbsp;|&nbsp;<A HREF="#constructor_detail">CONSTR</A>&nbsp;|&nbsp;<A HREF="#method_detail">METHOD</A></FONT></TD> </TR> </TABLE> <A NAME="skip-navbar_top"></A> <!-- ========= END OF TOP NAVBAR ========= --> <HR> <!-- ======== START OF CLASS DATA ======== --> <H2> <FONT SIZE="-1"> org.apache.fop.afp.goca</FONT> <BR> Class GraphicsLine</H2> <PRE> java.lang.Object <IMG SRC="../../../../../resources/inherit.gif" ALT="extended by "><A HREF="../../../../../org/apache/fop/afp/modca/AbstractAFPObject.html" title="class in org.apache.fop.afp.modca">org.apache.fop.afp.modca.AbstractAFPObject</A> <IMG SRC="../../../../../resources/inherit.gif" ALT="extended by "><A HREF="../../../../../org/apache/fop/afp/goca/AbstractGraphicsDrawingOrder.html" title="class in org.apache.fop.afp.goca">org.apache.fop.afp.goca.AbstractGraphicsDrawingOrder</A> <IMG SRC="../../../../../resources/inherit.gif" ALT="extended by "><A HREF="../../../../../org/apache/fop/afp/goca/AbstractGraphicsCoord.html" title="class in org.apache.fop.afp.goca">org.apache.fop.afp.goca.AbstractGraphicsCoord</A> <IMG SRC="../../../../../resources/inherit.gif" ALT="extended by "><B>org.apache.fop.afp.goca.GraphicsLine</B> </PRE> <DL> <DT><B>All Implemented Interfaces:</B> <DD><A HREF="../../../../../org/apache/fop/afp/Streamable.html" title="interface in org.apache.fop.afp">Streamable</A>, <A HREF="../../../../../org/apache/fop/afp/StructuredData.html" title="interface in org.apache.fop.afp">StructuredData</A></DD> </DL> <HR> <DL> <DT><PRE>public class <B>GraphicsLine</B><DT>extends <A HREF="../../../../../org/apache/fop/afp/goca/AbstractGraphicsCoord.html" title="class in org.apache.fop.afp.goca">AbstractGraphicsCoord</A></DL> </PRE> <P> A GOCA graphics straight line drawn from the given absolute position <P> <P> <HR> <P> <!-- ======== NESTED CLASS SUMMARY ======== --> <A NAME="nested_class_summary"><!-- --></A> <TABLE BORDER="1" WIDTH="100%" CELLPADDING="3" CELLSPACING="0" SUMMARY=""> <TR BGCOLOR="#CCCCFF" CLASS="TableHeadingColor"> <TH ALIGN="left" COLSPAN="2"><FONT SIZE="+2"> <B>Nested Class Summary</B></FONT></TH> </TR> </TABLE> &nbsp;<A NAME="nested_classes_inherited_from_class_org.apache.fop.afp.modca.AbstractAFPObject"><!-- --></A> <TABLE BORDER="1" WIDTH="100%" CELLPADDING="3" CELLSPACING="0" SUMMARY=""> <TR BGCOLOR="#EEEEFF" CLASS="TableSubHeadingColor"> <TH ALIGN="left"><B>Nested classes/interfaces inherited from class org.apache.fop.afp.modca.<A HREF="../../../../../org/apache/fop/afp/modca/AbstractAFPObject.html" title="class in org.apache.fop.afp.modca">AbstractAFPObject</A></B></TH> </TR> <TR BGCOLOR="white" CLASS="TableRowColor"> <TD><CODE><A HREF="../../../../../org/apache/fop/afp/modca/AbstractAFPObject.Category.html" title="interface in org.apache.fop.afp.modca">AbstractAFPObject.Category</A>, <A HREF="../../../../../org/apache/fop/afp/modca/AbstractAFPObject.Type.html" title="interface in org.apache.fop.afp.modca">AbstractAFPObject.Type</A></CODE></TD> </TR> </TABLE> &nbsp; <!-- =========== FIELD SUMMARY =========== --> <A NAME="field_summary"><!-- --></A> <TABLE BORDER="1" WIDTH="100%" CELLPADDING="3" CELLSPACING="0" SUMMARY=""> <TR BGCOLOR="#CCCCFF" CLASS="TableHeadingColor"> <TH ALIGN="left" COLSPAN="2"><FONT SIZE="+2"> <B>Field Summary</B></FONT></TH> </TR> </TABLE> &nbsp;<A NAME="fields_inherited_from_class_org.apache.fop.afp.goca.AbstractGraphicsCoord"><!-- --></A> <TABLE BORDER="1" WIDTH="100%" CELLPADDING="3" CELLSPACING="0" SUMMARY=""> <TR BGCOLOR="#EEEEFF" CLASS="TableSubHeadingColor"> <TH ALIGN="left"><B>Fields inherited from class org.apache.fop.afp.goca.<A HREF="../../../../../org/apache/fop/afp/goca/AbstractGraphicsCoord.html" title="class in org.apache.fop.afp.goca">AbstractGraphicsCoord</A></B></TH> </TR> <TR BGCOLOR="white" CLASS="TableRowColor"> <TD><CODE><A HREF="../../../../../org/apache/fop/afp/goca/AbstractGraphicsCoord.html#coords">coords</A>, <A HREF="../../../../../org/apache/fop/afp/goca/AbstractGraphicsCoord.html#relative">relative</A></CODE></TD> </TR> </TABLE> &nbsp;<A NAME="fields_inherited_from_class_org.apache.fop.afp.modca.AbstractAFPObject"><!-- --></A> <TABLE BORDER="1" WIDTH="100%" CELLPADDING="3" CELLSPACING="0" SUMMARY=""> <TR BGCOLOR="#EEEEFF" CLASS="TableSubHeadingColor"> <TH ALIGN="left"><B>Fields inherited from class org.apache.fop.afp.modca.<A HREF="../../../../../org/apache/fop/afp/modca/AbstractAFPObject.html" title="class in org.apache.fop.afp.modca">AbstractAFPObject</A></B></TH> </TR> <TR BGCOLOR="white" CLASS="TableRowColor"> <TD><CODE><A HREF="../../../../../org/apache/fop/afp/modca/AbstractAFPObject.html#LOG">LOG</A>, <A HREF="../../../../../org/apache/fop/afp/modca/AbstractAFPObject.html#SF_CLASS">SF_CLASS</A>, <A HREF="../../../../../org/apache/fop/afp/modca/AbstractAFPObject.html#SF_HEADER_LENGTH">SF_HEADER_LENGTH</A></CODE></TD> </TR> </TABLE> &nbsp; <!-- ======== CONSTRUCTOR SUMMARY ======== --> <A NAME="constructor_summary"><!-- --></A> <TABLE BORDER="1" WIDTH="100%" CELLPADDING="3" CELLSPACING="0" SUMMARY=""> <TR BGCOLOR="#CCCCFF" CLASS="TableHeadingColor"> <TH ALIGN="left" COLSPAN="2"><FONT SIZE="+2"> <B>Constructor Summary</B></FONT></TH> </TR> <TR BGCOLOR="white" CLASS="TableRowColor"> <TD><CODE><B><A HREF="../../../../../org/apache/fop/afp/goca/GraphicsLine.html#GraphicsLine(int[], boolean)">GraphicsLine</A></B>(int[]&nbsp;coords, boolean&nbsp;relative)</CODE> <BR> &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;Constructor</TD> </TR> </TABLE> &nbsp; <!-- ========== METHOD SUMMARY =========== --> <A NAME="method_summary"><!-- --></A> <TABLE BORDER="1" WIDTH="100%" CELLPADDING="3" CELLSPACING="0" SUMMARY=""> <TR BGCOLOR="#CCCCFF" CLASS="TableHeadingColor"> <TH ALIGN="left" COLSPAN="2"><FONT SIZE="+2"> <B>Method Summary</B></FONT></TH> </TR> <TR BGCOLOR="white" CLASS="TableRowColor"> <TD ALIGN="right" VALIGN="top" WIDTH="1%"><FONT SIZE="-1"> <CODE>&nbsp;void</CODE></FONT></TD> <TD><CODE><B><A HREF="../../../../../org/apache/fop/afp/goca/GraphicsLine.html#writeToStream(java.io.OutputStream)">writeToStream</A></B>(java.io.OutputStream&nbsp;os)</CODE> <BR> &nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;DataStream objects must implement the writeToStream() method to write its data to the given OutputStream</TD> </TR> </TABLE> &nbsp;<A NAME="methods_inherited_from_class_org.apache.fop.afp.goca.AbstractGraphicsCoord"><!-- --></A> <TABLE BORDER="1" WIDTH="100%" CELLPADDING="3" CELLSPACING="0" SUMMARY=""> <TR BGCOLOR="#EEEEFF" CLASS="TableSubHeadingColor"> <TH ALIGN="left"><B>Methods inherited from class org.apache.fop.afp.goca.<A HREF="../../../../../org/apache/fop/afp/goca/AbstractGraphicsCoord.html" title="class in org.apache.fop.afp.goca">AbstractGraphicsCoord</A></B></TH> </TR> <TR BGCOLOR="white" CLASS="TableRowColor"> <TD><CODE><A HREF="../../../../../org/apache/fop/afp/goca/AbstractGraphicsCoord.html#addCoords(byte[], int)">addCoords</A>, <A HREF="../../../../../org/apache/fop/afp/goca/AbstractGraphicsCoord.html#getDataLength()">getDataLength</A>, <A HREF="../../../../../org/apache/fop/afp/goca/AbstractGraphicsCoord.html#isRelative()">isRelative</A>, <A HREF="../../../../../org/apache/fop/afp/goca/AbstractGraphicsCoord.html#toString()">toString</A></CODE></TD> </TR> </TABLE> &nbsp;<A NAME="methods_inherited_from_class_org.apache.fop.afp.goca.AbstractGraphicsDrawingOrder"><!-- --></A> <TABLE BORDER="1" WIDTH="100%" CELLPADDING="3" CELLSPACING="0" SUMMARY=""> <TR BGCOLOR="#EEEEFF" CLASS="TableSubHeadingColor"> <TH ALIGN="left"><B>Methods inherited from class org.apache.fop.afp.goca.<A HREF="../../../../../org/apache/fop/afp/goca/AbstractGraphicsDrawingOrder.html" title="class in org.apache.fop.afp.goca">AbstractGraphicsDrawingOrder</A></B></TH> </TR> <TR BGCOLOR="white" CLASS="TableRowColor"> <TD><CODE><A HREF="../../../../../org/apache/fop/afp/goca/AbstractGraphicsDrawingOrder.html#getName()">getName</A></CODE></TD> </TR> </TABLE> &nbsp;<A NAME="methods_inherited_from_class_org.apache.fop.afp.modca.AbstractAFPObject"><!-- --></A> <TABLE BORDER="1" WIDTH="100%" CELLPADDING="3" CELLSPACING="0" SUMMARY=""> <TR BGCOLOR="#EEEEFF" CLASS="TableSubHeadingColor"> <TH ALIGN="left"><B>Methods inherited from class org.apache.fop.afp.modca.<A HREF="../../../../../org/apache/fop/afp/modca/AbstractAFPObject.html" title="class in org.apache.fop.afp.modca">AbstractAFPObject</A></B></TH> </TR> <TR BGCOLOR="white" CLASS="TableRowColor"> <TD><CODE><A HREF="../../../../../org/apache/fop/afp/modca/AbstractAFPObject.html#copySF(byte[], byte, byte)">copySF</A>, <A HREF="../../../../../org/apache/fop/afp/modca/AbstractAFPObject.html#copySF(byte[], byte, byte, byte)">copySF</A>, <A HREF="../../../../../org/apache/fop/afp/modca/AbstractAFPObject.html#truncate(java.lang.String, int)">truncate</A>, <A HREF="../../../../../org/apache/fop/afp/modca/AbstractAFPObject.html#writeChunksToStream(byte[], byte[], int, int, java.io.OutputStream)">writeChunksToStream</A>, <A HREF="../../../../../org/apache/fop/afp/modca/AbstractAFPObject.html#writeObjects(java.util.Collection, java.io.OutputStream)">writeObjects</A></CODE></TD> </TR> </TABLE> &nbsp;<A NAME="methods_inherited_from_class_java.lang.Object"><!-- --></A> <TABLE BORDER="1" WIDTH="100%" CELLPADDING="3" CELLSPACING="0" SUMMARY=""> <TR BGCOLOR="#EEEEFF" CLASS="TableSubHeadingColor"> <TH ALIGN="left"><B>Methods inherited from class java.lang.Object</B></TH> </TR> <TR BGCOLOR="white" CLASS="TableRowColor"> <TD><CODE>clone, equals, finalize, getClass, hashCode, notify, notifyAll, wait, wait, wait</CODE></TD> </TR> </TABLE> &nbsp; <P> <!-- ========= CONSTRUCTOR DETAIL ======== --> <A NAME="constructor_detail"><!-- --></A> <TABLE BORDER="1" WIDTH="100%" CELLPADDING="3" CELLSPACING="0" SUMMARY=""> <TR BGCOLOR="#CCCCFF" CLASS="TableHeadingColor"> <TH ALIGN="left" COLSPAN="1"><FONT SIZE="+2"> <B>Constructor Detail</B></FONT></TH> </TR> </TABLE> <A NAME="GraphicsLine(int[], boolean)"><!-- --></A><H3> GraphicsLine</H3> <PRE> public <B>GraphicsLine</B>(int[]&nbsp;coords, boolean&nbsp;relative)</PRE> <DL> <DD>Constructor <P> <DL> <DT><B>Parameters:</B><DD><CODE>coords</CODE> - the x/y coordinates for this object<DD><CODE>relative</CODE> - is this a relative drawing order</DL> </DL> <!-- ============ METHOD DETAIL ========== --> <A NAME="method_detail"><!-- --></A> <TABLE BORDER="1" WIDTH="100%" CELLPADDING="3" CELLSPACING="0" SUMMARY=""> <TR BGCOLOR="#CCCCFF" CLASS="TableHeadingColor"> <TH ALIGN="left" COLSPAN="1"><FONT SIZE="+2"> <B>Method Detail</B></FONT></TH> </TR> </TABLE> <A NAME="writeToStream(java.io.OutputStream)"><!-- --></A><H3> writeToStream</H3> <PRE> public void <B>writeToStream</B>(java.io.OutputStream&nbsp;os) throws java.io.IOException</PRE> <DL> <DD>DataStream objects must implement the writeToStream() method to write its data to the given OutputStream <P> <DD><DL> <DT><B>Specified by:</B><DD><CODE><A HREF="../../../../../org/apache/fop/afp/Streamable.html#writeToStream(java.io.OutputStream)">writeToStream</A></CODE> in interface <CODE><A HREF="../../../../../org/apache/fop/afp/Streamable.html" title="interface in org.apache.fop.afp">Streamable</A></CODE><DT><B>Overrides:</B><DD><CODE><A HREF="../../../../../org/apache/fop/afp/goca/AbstractGraphicsCoord.html#writeToStream(java.io.OutputStream)">writeToStream</A></CODE> in class <CODE><A HREF="../../../../../org/apache/fop/afp/goca/AbstractGraphicsCoord.html" title="class in org.apache.fop.afp.goca">AbstractGraphicsCoord</A></CODE></DL> </DD> <DD><DL> <DT><B>Parameters:</B><DD><CODE>os</CODE> - the outputsteam stream <DT><B>Throws:</B> <DD><CODE>java.io.IOException</CODE> - an I/O exception of some sort has occurred.</DL> </DD> </DL> <!-- ========= END OF CLASS DATA ========= --> <HR> <!-- ======= START OF BOTTOM NAVBAR ====== --> <A NAME="navbar_bottom"><!-- --></A> <A HREF="#skip-navbar_bottom" title="Skip navigation links"></A> <TABLE BORDER="0" WIDTH="100%" CELLPADDING="1" CELLSPACING="0" SUMMARY=""> <TR> <TD COLSPAN=2 BGCOLOR="#EEEEFF" CLASS="NavBarCell1"> <A NAME="navbar_bottom_firstrow"><!-- --></A> <TABLE BORDER="0" CELLPADDING="0" CELLSPACING="3" SUMMARY=""> <TR ALIGN="center" VALIGN="top"> <TD BGCOLOR="#EEEEFF" CLASS="NavBarCell1"> <A HREF="../../../../../overview-summary.html"><FONT CLASS="NavBarFont1"><B>Overview</B></FONT></A>&nbsp;</TD> <TD BGCOLOR="#EEEEFF" CLASS="NavBarCell1"> <A HREF="package-summary.html"><FONT CLASS="NavBarFont1"><B>Package</B></FONT></A>&nbsp;</TD> <TD BGCOLOR="#FFFFFF" CLASS="NavBarCell1Rev"> &nbsp;<FONT CLASS="NavBarFont1Rev"><B>Class</B></FONT>&nbsp;</TD> <TD BGCOLOR="#EEEEFF" CLASS="NavBarCell1"> <A HREF="class-use/GraphicsLine.html"><FONT CLASS="NavBarFont1"><B>Use</B></FONT></A>&nbsp;</TD> <TD BGCOLOR="#EEEEFF" CLASS="NavBarCell1"> <A HREF="package-tree.html"><FONT CLASS="NavBarFont1"><B>Tree</B></FONT></A>&nbsp;</TD> <TD BGCOLOR="#EEEEFF" CLASS="NavBarCell1"> <A HREF="../../../../../deprecated-list.html"><FONT CLASS="NavBarFont1"><B>Deprecated</B></FONT></A>&nbsp;</TD> <TD BGCOLOR="#EEEEFF" CLASS="NavBarCell1"> <A HREF="../../../../../index-all.html"><FONT CLASS="NavBarFont1"><B>Index</B></FONT></A>&nbsp;</TD> <TD BGCOLOR="#EEEEFF" CLASS="NavBarCell1"> <A HREF="../../../../../help-doc.html"><FONT CLASS="NavBarFont1"><B>Help</B></FONT></A>&nbsp;</TD> </TR> </TABLE> </TD> <TD ALIGN="right" VALIGN="top" ROWSPAN=3><EM> fop 2.0</EM> </TD> </TR> <TR> <TD BGCOLOR="white" CLASS="NavBarCell2"><FONT SIZE="-2"> &nbsp;<A HREF="../../../../../org/apache/fop/afp/goca/GraphicsImage.html" title="class in org.apache.fop.afp.goca"><B>PREV CLASS</B></A>&nbsp; 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If you missed my previous post on Understanding Postgres Performance its a great starting point. On this particular post I’m going to dig in to some real life examples of optimizing queries and indexes. It all starts with stats I wrote about some of the great new features in Postgres 9.2 in the recent announcement on support of Postgres 9.2 on Heroku. One of those awesome features, is pg_stat_statements. Its not commonly known how much information Postgres keeps about your database (beyond the data of course), but in reality it keeps a great deal. Ranging from basic stuff like table size to cardinality of joins to distribution of indexes, and with pg_stat_statments it keeps a normalized record of when queries are run. First you’ll want to turn on pg_stat_statments: CREATE extension pg_stat_statements; What this means it would record both: SELECT id FROM users WHERE email LIKE 'craig@heroku.com'; and SELECT id FROM users WHERE email LIKE 'craig.kerstiens@gmail.com'; To a normalized form which looks like this: SELECT id FROM users WHERE email LIKE ?; Understanding them from afar While Postgres collects a great deal of this information dissecting it to something useful is sometimes more mystery than it should be. This simple query will show a few very key pieces of information that allow you to begin optimizing: SELECT (total_time / 1000 / 60) as total_minutes, (total_time/calls) as average_time, query FROM pg_stat_statements ORDER BY 1 DESC LIMIT 100; The above query shows three key things: The total time a query has occupied against your system in minutes The average time it takes to run in milliseconds The query itself Giving an output something like: total_time | avg_time | query ------------------+------------------+------------------------------------------------------------ 295.761165833319 | 10.1374053278061 | SELECT id FROM users WHERE email LIKE ? 219.138564283326 | 80.24530822355305 | SELECT * FROM address WHERE user_id = ? AND current = True (2 rows) What to optimize A general rule of thumb is that most of your very common queries that return 1 or a small set of records should return in ~ 1 ms. In some cases there may be queries that regularly run in 4-5 ms, but in most cases ~ 1 ms or less is an ideal. To pick where to begin I usually attempt to strike some balance between total time and long average time. In this case I’d start with the second probably, as on the first one I could likely shave an order of magnitude off, on the second I’m hopeful to shave two order of magnitudes off thus reducing the time spent on that query from a cumulative 220 minutes down to 2 minutes. Optimizing From here you probably want to first example my other detail on understanding the explain plan. I want to highlight some of this with a more specific case based on the second query above. The above second query on an example data set does contain an index on user_id and yet there’s still high query times. To start to get an idea of why I would run: EXPLAIN ANALYZE SELECT * FROM address WHERE user_id = 245 AND current = True This would yield results: QUERY PLAN -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Aggregate (cost=4690.88..4690.88 rows=1 width=0) (actual time=519.288..519.289 rows=1 loops=1) -> Nested Loop (cost=0.00..4690.66 rows=433 width=0) (actual time=15.302..519.076 rows=213 loops=1) -> Index Scan using idx_address_userid on address (cost=0.00..232.52 rows=23 width=4) (actual time=10.143..62.822 rows=1 loops=8) Index Cond: (user_id = 245) Filter: current Rows Removed by Filter: 14 Total runtime: 219.428 ms (1 rows) Hopefully not being too overwhelmed by this due to having read the other detail on query plans we can see that it is using an index as expected. The difference is its having to fetch 15 different rows from the index then discard the bulk of them. The number of rows discarded is showcased by the line: Rows Removed by Filter: 14 This is just one more of the many improvements in Postgres 9.2 alongside pg_stat_statements. To further optimize this we would great a conditional OR composite index. A conditional would be where only current = true, where as the composite would index both values. A conditional is commonly more valuable when you have a smaller set of what the values may be, meanwhile the composite is when you have a high variability of values. Creating the conditional index: CREATE INDEX CONCURRENTLY idx_address_userid_current ON address(user_id) WHERE current = True; We can then see the query plan is now even further improved as we’d hope: EXPLAIN ANALYZE SELECT * FROM address WHERE user_id = 245 AND current = True QUERY PLAN -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Aggregate (cost=4690.88..4690.88 rows=1 width=0) (actual time=519.288..519.289 rows=1 loops=1) -> Index Scan using idx_address_userid_current on address (cost=0.00..232.52 rows=23 width=4) (actual time=10.143..62.822 rows=1 loops=8) Index Cond: ((user_id = 245) AND (current = True)) Total runtime: .728 ms (1 rows) If you’re looking for a deeper resource on Postgres I recommend the book The Art of PostgreSQL. It is by a personal friend that has aimed to create the definitive guide to Postgres, from a developer perspective. If you use code CRAIG15 you’ll receive 15% off as well.
Mary Tighe Mary Tighe (9 October 1772 – 24 March 1810) was an Anglo-Irish poet. Life and career Mary Blackford (or Blanchford) was born in Dublin, 9 October 1772. Her parents were Theodosia Tighe, a Methodist leader, and William Blachford (d.1773?), a Church of Ireland clergyman and librarian. She had a strict religious upbringing, and when she was twenty-one she married Henry Tighe (1768–1836), her first cousin and a member of the Parliament of Ireland for Inistioge, County Kilkenny. The marriage is said to have been unhappy, though little is known. The couple moved to London in the early nineteenth century. She became acquainted with Thomas Moore, an early admirer of her writing, and others interested in literature. Although she had written since girlhood, she published nothing until Psyche (1805), a six-canto allegorical poem in Spenserian stanzas. Psyche was admired by many and praised by Moore in his poem, "To Mrs. Henry Tighe on reading her Psyche". Having suffered for at least a year, Mary Tighe endured a serious attack of tuberculosis in 1805. In February 1805 Moore states that she had "a very serious struggle for life" and in August of the same year that she was 'ordered to the Madeiras'. Moore also claimed that "another winter will inevitably be her death". Tighe lived for another five years and spent her last few months as an invalid at her brother-in-law's estate in Woodstock, County Wicklow, Ireland. She was buried in the church at nearby Inistioge. Her diary was destroyed, though a cousin had copied out excerpts. The year following her death, a new edition of Psyche was released, along with some previously unpublished poems; it was this edition that established her literary reputation. John Keats was one of her admirers and paid tribute to her in his poem, "To Some Ladies". Pam Perkins writes that "[d]espite the bleakness of many of the short poems in the 1811 volume, in much of the nineteenth-century writing on Tighe there is a tendency to make her an exemplar of patiently (and picturesquely) long-suffering femininity, a tendency exemplified most famously in Felicia Hemans's tribute to her, 'The Grave of a Poetess'." A statue of her was sculpted by Lorenzo Bartolini, and was held at Woodstock House until it was burned down in 1922. According to the Uffizi, the statue was commissioned by her son after her death, and was delivered to Ireland around 1820. Psyche "Psyche, or the legend of love" is Mary Tighe's rendition of the Greco-Roman folktale of Cupid and Psyche, which is recorded in The Golden Ass (or Metamorphoses) by Lucius Apuleius, the Silver Age Roman author. Psyche, or the Legend of Love was privately printed in a run of only 50 copies in 1805. It was republished posthumously in 1811 with other, previously unpublished works by Longman, London. The story is about a princess named Psyche who is so beautiful that the people of her kingdom begin to worship her as the goddess Venus. Venus becomes envious of the attention that Psyche receives and sends her son Cupid to Psyche to make her fall in love with a monster. Instead Cupid falls in love with Psyche, and marries her without his mother's knowledge. He whisks her away to a far-away palace, where she is served by invisible servants, and he visits her only at night, so she cannot discover his true identity. One night Psyche's curiosity gets the better of her, and after he falls asleep she lights a lamp to see her husband's face. When she realises her husband is no monster, rather a god, she is so surprised a drop of oil falls from her lamp and burns Cupid, waking him. He flees, and to regain her husband Psyche seeks the help of his mother Venus, who sends her out to complete various tasks in penance. In her final task, she is sent to retrieve a box from the underworld containing some of Proserpina's beauty. Although instructed not to look inside the box, she opens it, and Psyche is overcome by a never-ending sleep. Cupid saves her, and in the end Psyche is transformed into a goddess herself by Jupiter. The bulk of Tighe's version of the story is taken from Apuleius, but her poem, written in Spenserian stanzas, is riddled with small details which point to Cupid's and Psyche's shared characteristics and equal standing, implying that their love is mutual, and this idea is taken further in the heavily adapted second half of the epic, where Cupid joins Psyche on her penitent journey. In the first encounter between the two lovers, Tighe mirrors a passage from Apuleius but reverses the roles, showing the similarities between the two. As Cupid comes to Psyche at his mother's request, ready to use his love-inducing arrows, he leans over her, but is then overcome by her beauty and: The dart which in his hand now trembling stood, As o'er the couch he bent with ravished eye, Drew with its daring point celestial blood From his smooth neck's unblemished ivory: (canto 1, 244–247). Much of the same imagery is found in the Metamorphoses, but later in Apuleius’ narrative, as Psyche is overcome at the sight of Cupid and the weapons that testify to his divinity. Tighe was familiar with the ancient novel, so this similarity is likely deliberate. The novelist writes: Now Psyche, with her insatiable mind, examined these with more than a little curiosity, and as she was studying and admiring the weapons of her husband, trembling she drew one arrow from the quiver to test the point on the tip of her thumb, but she pressed too deeply, so that tiny drops of rosy-red blood dotted her skin like dew. Thus did unknowing Psyche suddenly fall in love with Love, burning more and more with desire for Desire. (Apul. Met. 5.23). The many similarities between the two passages strengthen the relationship and the comparison between the two figures. Arrows are held with “trembling” hands, blood stains perfect skin, and neither is aware of the fateful prick. In Tighe’s version, Cupid is as much a victim of himself as Psyche is, and she makes explicit that her feelings are mutual. In a major departure from Apuleius’ storyline, Cupid accompanies Psyche on her series of trials, disguised as a white knight on his own journey to regain his beloved. This unique element of Tighe’s narrative serves to emphasise the equal responsibility of both genders in romantic relationships. When the white knight first introduces himself to Psyche, hiding his true identity as Cupid, he tells her: “I too (he said) divided from my love, “The offended power of Venus deprecate, “Like thee, through paths untrodden, sadly rove “In search of that fair spot prescribed by fate, “The blessed term of my afflicted state,” (canto 3, 127–131). By describing him thus, Cupid becomes a male version of Psyche, needing to perform his own series of trials to become worthy of his lover. The tasks Venus sends them to do cease to be a form of penance and become a mutual journey, and both lovers grow as individuals, helping each other to defeat various vices and temptations, in a very moralising and Christian version of the Roman tale. She also makes allusions to Spencer's Fairie Queene during Psyche's final task set by Venus. "A cruel monster now her steps pursued, Well known of yore and named the Blatant Beast. Other works Selena (unpublished novel). The manuscript is held in the National Library of Ireland. It is available online: Tighe, Mary, and Harriet K. Linkin. Selena. Farnham, Surrey, England: Ashgate, 2012. print and online access. Mary: a Series of Reflections during 20 Years (Posthumous; edited and privately printed by her brother-in-law, William Tighe, 1811) References Bibliography — Electronic edition prepared by Harriet Kramer Linkin, Melissa Davis, and Jerry Parks (July 1997); re-formatted and corrected by Harriet Kramer Linkin (September 2001). Further reading Blain, Virginia, et al., eds. "Tighe, Mary." The Feminist Companion to Literature in English. New Haven and London: Yale UP, 1990. 1081. Linkin, Harriet Kramer. "Romanticism and Mary Tighe's Psyche: Peering at the Hem of her Blue Stockings.” Studies in Romanticism 35.1 (1996). Linkin, Harriet Kramer. “Skirting around the Sex in Mary Tighe’s Psyche.” Studies in English Literature 42.4 (2002). External links Mary Tighe (née Blachford) at the Eighteenth-Century Poetry Archive (ECPA) Category:1772 births Category:1810 deaths Category:18th-century Irish poets Category:19th-century Irish poets Category:19th-century Irish women writers Category:19th-century Irish writers Category:19th-century deaths from tuberculosis Category:People from Dublin (city) Category:Infectious disease deaths in Ireland Category:Irish women poets Category:18th-century women writers
Get the FREE Mirror Football newsletter by email with the day's key headlines and transfer news Sign up Thank you for subscribing We have more newsletters Show me See our privacy notice Invalid Email Joe Kinnear took Newcastle manager Alan Pardew to meet owner Mike Ashley in topless resort St Tropez and assured him: “I’ve got your back covered.” Director of football Kinnear has been dismayed by the “negativity” which has engulfed the Toon’s difficult start to the season. And he flew home from a scouting mission in Europe last night to learn stewards had removed a banner proclaiming him as “clown of the comedy club” at the goalless impasse with West Ham at St James’ Park on Saturday. But Kinnear, 66, refuses to become the fall-guy for Newcastle’s problems, which were accelerated by Arsenal’s £10million bid for midfielder Yohan Cabaye on the eve of a heavy opening defeat at Manchester City. In a frank, no-holds-barred interview with Mirror Sport, Kinnear insisted: “I don’t understand where the negativity has come from – we are two games into a 38-game season and already the doom-and-gloom merchants are looking for a scapegoat. “Alan Pardew has signed 16 players costing £60m in the last two years, Newcastle United’s wage bill is now comfortably in the top 10 in the country, and he will continue to get all the support the club can reasonably provide. “Last week we flew to Nice, and we were met by a private helicopter transfer to Mike Ashley’s yacht off St Tropez, and we spent seven hours thrashing out every idea, and how we plan to take the club forward. “I listened to every word Alan and the owner had to say – along with chief scout Graham Carr, who was also there – and we talked about the next stage for Newcastle United and where we wanted to go. “Before the season started, we had sat down and agreed the squad was big enough, and strong enough, to finish in the top half of the table. But we are working together – not plotting against each other. “There seems to be a perception, from outside the club, that we are at loggerheads, but I don’t know why people are jumping on the bandwagon because it is a false picture.” (Image: Serena Taylor) The only time Kinnear has acted alone, in terms of player recruitment, was to seal the season-long loan deal which brought France striker Loic Remy to Tyneside earlier this month. And he did so in the knowledge that QPR had pipped Pardew in the £8m race for Remy last January. Kinnear admitted: “I sanctioned the one-year loan deal for Loic Remy, and if it goes pear-shaped I will take responsibility for it. “But if he scores goals and does well for us, Alan will be happy with our end of the deal; the player will be happy because he will come into contention for a World Cup place with France; and if both those things happen, Remy will go back to QPR as a World Cup player with a higher value than when he joined them, so everyone will come out of it well.” Kinnear’s return in June to ­the Newcastle, where his brief stint as manager was curtailed by a heart problem in 2009, was slammed as a backward step by supporters. His second coming was immediately laid open to ridicule when he gave a car-crash radio interview in which he pronounced the names of players wrongly and even referred to former managing director Derek Llambias as “Derek Lambisi.” He conceded: “That gave people a stick to beat me with, but my ­intentions for the club are impeccable and we are working incredibly hard – together – to try and deliver good results on the pitch.”
Koji Uehara — the man of many high fives — has officially announced his retirement. Uehara, 44, who recorded the final out of the Boston Red Sox’ 2013 World Series championship, finished his Major League Baseball career with an impressive 2.85 earned run average to go along with 95 saves. The right-hander made his MLB debut as a 34-year-old with the Baltimore Orioles in 2009 after 10 seasons in Japan. He pitched for nine seasons in the United States between four teams, including the Red Sox from 2013-2016. Over the course of those four campaigns in Boston, Uehara recorded a 2.19 ERA in 230 relief appearances. During the Red Sox’ 2013 world championship season, Uehara posted an astounding 1.61 ERA with 101 strikeouts in 74 1/3 innings, finishing seventh in the Cy Young voting. That postseason, he allowed just one run in 13.2 innings pitched and tied a single-postseason record with seven saves. Koji Uehara was the least stressful closer the Red Sox will ever have. Man, he was good, and fun. — Chad Finn (@GlobeChadFinn) May 20, 2019 While pitching for the Red Sox, Uehara became notorious for celebrating with his teammates with high fives all around, sparking the popular Twitter hashtag #HighFiveCity. Between his animated personality and deadly changeup, Uehara quickly became a fan favorite in Boston. Following his final MLB season in 2017 with the Chicago Cubs, Uehara returned to the Yomiuri Giants of the Tokyo-based Central League where he began his professional baseball career in 1999.
Introduction ============ Zinc is an essential trace element in the human body, with approximately two grams in healthy adults. The daily amount of zinc required by an adult is 10--15 mg and this is absorbed primarily from the upper gastrointestinal tract, especially the small intestine \[[@B1], [@B2]\]. Zinc is involved in the activation of approximately 300 different metallo-enzymes and metal-activated enzymes *in vivo* and is regarded as essential for the metabolism of nucleic acids and proteins \[[@B3], [@B4]\]. Therefore, it has been determined that zinc deficiency causes various pathological conditions in humans. Among these, it is known that, in patients with C-viral chronic liver disease, the blood zinc concentration decreases with progression of the disease from chronic hepatitis (CH) to compensated liver cirrhosis (LC), to decompensated LC, to hepatocellular carcinoma (HCC) \[[@B5]--[@B9]\]. It is also known that patients with liver failure or HCC are in an especially severe state of zinc deficiency and the liver damage is found to improve with zinc supplementation \[[@B10], [@B11]\]. Recently, it was reported that the hepatitis C virus (HCV) NS5A protein is a zinc metalloprotein and that zinc is closely involved in the activation of the NS5A protein \[[@B12]\]. Also, it has been reported that the rate of HCV eradication is higher when interferon (IFN) therapy for C-viral CH is combined with zinc supplementation, compared to IFN therapy alone \[[@B5], [@B13]\]. Thus, it would appear that zinc supplementation has a clear influence on the clinical profiles of C-viral CH or LC. However, there has been no report to date as to what influence zinc supplementation has on the long-term outcome of C-viral CH or LC. We gave polaprezinc (orally administered, 150 mg/day) to patients with C-viral CH or LC and studied prospectively the influence of zinc supplementation on the long-term outcome. Patients and Methods ==================== Patients -------- A total of 70 Japanese patients with CH or LC, who were examined by the first author at Nihon University Itabashi Hospital from September 1999 through January 2001, gave informed consent to their participation in this study. All of the patients were positive for serum HCV RNA (Amplicor HCV Monitor, Roche Diagnostic K.K., Tokyo, Japan) and were observed for more than three years. All were negative for serum hepatitis B surface antigen (HBsAg, enzyme-linked immunosorbent assay, EIA, Dinabot, Tokyo, Japan), LE cells, anti-smooth muscle antibody (fluorescence antibody method, FA), and anti-mitochondria antibody (FA). No heavy drinkers (more than 30 g ethanol intake per day) were included in the study. Patients whose blood alanine aminotransferase (ALT) levels remained persistently in the abnormal range (\>40 international units; IU/L) for more than 6 months were enrolled in the study. The criteria for diagnosing patients as having LC were as follows: continuation of abnormal blood ALT levels for more than 6 months, ICGRs of more than 10% at 15 min, platelet counts below 100,000/mm^3^, the presence of esophageal varices, and the presence of LC pattern and splenomegaly on abdominal diagnostic imaging. Blood samples were obtained only from patients who gave informed consent. The follow-up schedule was as follows: the patients underwent abdominal ultrasonography every 3 or 6 months, and abdominal CT examination every 6 to 12 months, for the detection of HCC. When space occupying lesions (SOL) were detected in the livers of patients with CH or LC by dynamic CT during the time periods stated above, enhancement of SOL was observed at the early phase of dynamic CT and the disappearance of SOL staining was observed at the late phase. A precise diagnosis was made by abdominal angiography. When SOL in the liver were not enhanced in the early phase of dynamic CT, or if a precise diagnosis by abdominal angiography could not be made, tumor biopsy was carried out and a precise diagnosis was made on the basis of the pathological findings. Blood samples were collected on this occasion and stored frozen at −80°C. Study design ------------ According to the χ^2^ test, when the event occurrence rate of the control group is set to 30% and that of the treated group is set to 10%, the number of cases required to obtain a significant difference between the event occurrence rates is 62. Therefore, we planned to study 35 cases in the treated group and 35 cases in the untreated group. The HCV RNA positive patients who visited first author's outpatient clinic between September 1999 and January 2001 numbered 175. Among 85 of these patients, it was estimated that 5 were asymptomatic HCV carriers, 50 had achieved ALT levels continuously within the normal range following medication, 20 had been treated with IFN alpha, and 10 diagnosed as HCC. The remaining 90 patients (51.4%) were the target population for this study; they had declined to give their consent for IFN therapy or had been treated but achieved only low sustained virologic response (SVR) rates because of refractory chronic hepatitis C, or IFN therapy was contraindicated because of complications such as depression, interstitial pneumonia, renal dysfunction, cardiovascular disease, etc., or they did not wish to receive IFN administration because of the relatively high frequency of complications and side effects of IFN or ribavirin therapy. Furthermore, IFN therapy is not indicated by national insurance criteria for patients diagnosed with LC in Japan. The reason we selected a study population who had not undergone IFN therapy was as follows: because IFN therapy may lead to a reduction in serum zinc concentrations or may affect the absorption of zinc from the small intestine, it was thought possible that IFN therapy could influence the serum zinc concentration in treated patients. The patients who were treated with polaprezinc gave their consent to administration of the drug after the benefits and potential risks had been explained to them. Furthermore, the benefits and potential risks of administration of Rebamipide (Mucosta; Otsuka pharmaceutical, Osaka, Japan) and Teprenone (Selbex; Eizai, Tokyo, Japan) also were explained to them. These patients were randomized following a complete explanation of the purpose of the study, namely to determine whether administration of polaprezinc or other drugs modified the clinical profiles in the subjects and other effects of zinc supplementation. The patients who agreed to take polaprezinc or the other drugs were permitted to choose which drug they preferred. Therefore, we administered polaprezinc to patients with CH or LC who opted for zinc supplementation after detailed explanation and we administered the other drugs to patients with CH or LC who chose not to take zinc supplementation. No consent to administration of these drugs was obtained from 10 patients. In the final analysis, there were 36 treated and 34 untreated cases. All 70 patients gave their consent to participate in the study. The study period was planned initially to continue for three years from when observations commenced. Among the 70 patients, three with CH and one with LC stopped visiting the clinic during the three year period. Furthermore, during the study period, IFN therapy was initiated in four patients at their request. Therefore, in the final analysis, there were 32 patients in the polaprezinc treated group and 30 in the untreated group. The clinical background factors of the patients are shown in Table [1](#T1-a){ref-type="table"}a, which compares the clinical background factors between patients with CH and LC, and Table [1](#T1-b){ref-type="table"}b, which compares the clinical background factors between patients with and without zinc supplementation. The primary end points were set as aspartate aminotransferase (AST), ALT and HCV RNA levels, platelet counts, and the occurrence of HCC. For the C-viral CH and LC patients, the initial collection of blood was made on the day of registration. The second collection of blood was made one year later and the third, within the following two years. We measured the zinc concentrations of these samples and investigated the changes in zinc concentrations from the day of registration. This study was in a accordance with the ethical standards as formulation in the Helsinki Declaration of 1975. Administration of polaprezinc ----------------------------- 1.0 g Promac® (ZERIA Pharmaceutical Co., Ltd., Tokyo, Japan) containing 150 mg polaprezinc was administered orally twice daily: after breakfast and after dinner. Medications administered prior to the study were continued during the study. Patients whose serum zinc concentrations had increased by more than 5.0 µg/ml three years after the study began, compared to the start of the study, were classified as zinc responders, while those whose zinc concentrations remained within 5.0 µg/ml were zinc non-responders (stable), and those whose zinc concentrations decreased more than 5.0 µg/ml were zinc non-responders (decreased). Measurement of serum zinc concentrations ---------------------------------------- Serum zinc concentrations were evaluated using conventional atomic absorption spectrometry using a Z-6100 polarized Zeeman Atomic Absorption Spectrophotometer (HITACHI, Tokyo, Japan) within 48 h of collection of blood \[[@B14], [@B15]\]. Silicone-coated syringes and needles were used for collecting the blood, which was transferred into zinc-free test tubes. Serum separation was done carefully to avoid haemolysis. Haematological and biochemical examinations ------------------------------------------- Serum levels of AST, levels of ALT, platelet counts and HCV RNA concentrations were determined once every two months. Determination of HCV RNA concentrations was performed using the Amplicor monitor method (Amplicor HCV Monitor, Roche Diagnostic K.K.). The results of HCV RNA testing were classified into low and high groups according to whether the value was greater or less than 100 kilo international units (kiu)/ml. Determination of HCV genotype was performed by the method of Okamoto *et al.* \[[@B16]\] and the results were interpreted according to the classification of Simmonds *et al.* \[[@B17]\]. Long-term outcome of patients ----------------------------- We compared the long-term outcome of patients with CH or LC in terms of the cumulative probability of occurrence of HCC, according to whether they were treated with polaprezinc or untreated and according to changes in serum concentrations of zinc. Statistical analysis -------------------- The serum concentrations of zinc were compared using the chi-square test for independence. Cumulative incidence curves were determined with the Kaplan-Meier method and the differences between groups were assessed using the log-rank test. The remaining parameters were compared using analysis of variance and Fisher's Protected Least Significant difference post hoc test with Statview 4.5 software (Abacus Concepts, Berkeley, CA). A *p* value of less than 0.05 was considered significant. Multivariate regression analysis -------------------------------- Other variables among the 32 cases were investigated as risk factors for occurrence of HCC. Independent factors of sex, age, CH or LC, ALT level, AST level, platelet count, HCV RNA concentration (more than 100 kiu/ml vs less than 100 kiu/ml), HCV genotype (genotype 1 vs genotype 2), and changes in zinc concentration were identified by logistic regression analysis using a stepwise method of analysis of factors for the risk of developing HCC using SPSS 11.0 software (SPSS Inc., Chicago, IL). Furthermore, we investigated the factors at the start of the study that contributed to whether patients administered polaprezinc become zinc responders. Independent factors of sex, age, CH or LC, ALT level, AST level, platelet count, HCV RNA concentration (more than 100 kiu/ml vs less than 100 kiu/ml), HCV genotype (genotype 1 vs genotype 2), and serum zinc concentration were identified by the Cox proportional hazard model using a stepwise method of analysis of factors for the risk of developing HCC using SPSS11.0 software (SPSS Inc.). Results ======= Evaluation of zinc concentrations in C-viral chronic liver disease ------------------------------------------------------------------ In patients with C-viral chronic liver diseases, the median zinc concentration was 65.0 µg/dl (range; 50--109) in the CH group and 53.0 µg/dl (29--91) in the LC group. The median zinc concentration in the LC group was significantly lower than that in the CH group (*p* = 0.0006). The median zinc concentration of the polaprezinc administration group was 64.0 µg/ml (range; 41--88) and of the untreated group was 53.5 µg/dl (range; 35--68). Efficacy of administration of polaprezinc ----------------------------------------- We examined changes in serum zinc concentrations in patients divided into the polaprezinc administration group and untreated group. In the polaprezinc administration group, compared to the initial examination, 15/32 (46.9%) patients were zinc responders, 12/32 (37.5%) were zinc non-responders whose serum zinc concentrations were stable and 5/32 (15.6%) were zinc non-responders whose serum zinc concentrations decreased. On the other hand, in the untreated group compared to the initial examination, the serum zinc concentrations of 1/30 (3.3%) patients had increased at three years, in 14/30 (46.7%) they remained stable and in 15/30 (50%) they decreased. In this analysis, the proportion of patients whose serum zinc concentrations increased was significantly greater in the polaprezinc administration group than the untreated group (*p*\<0.0001), and the proportion of patients whose serum zinc concentrations decreased in the untreated group was significantly greater than in the polaprezinc administration group (*p*\<0.0001). Next, when the polaprezinc administration group was divided into two groupsaccording to the median zinc concentration at start of the study, a high zinc group (≥64 µg/dl, *n* = 17) and a low zinc group (\<64 µg/dl, *n* = 15), the efficacy of polaprezinc administration in the low zinc group was 11/15 (73.4%) for zinc responders, 4/15 (13.3%) for zinc non-responders whose serum zinc concentrations were stable and 2/15 (13.3%) for zinc non-responders whose serum zinc concentrations decreased. On the contrary, the efficacy of polaprezinc administration in the high zinc group was 4/17 (23.5%) for zinc responders, 10/17 (58.8%) for zinc non-responders whose serum zinc concentrations were stable and 3/17 (17.7%) for zinc non-responders whose serum zinc concentrations decreased. Comparison of changes of zinc concentrations among patients with or without polaprezinc administration ------------------------------------------------------------------------------------------------------ The changes of serum zinc concentrations in the polaprezinc administration group and the untreated group were compared. The results showed that in the polaprezinc administration group three years after the study started, the serum zinc concentrations had increased by about 10% compared to the level at the start of the study. However, in the untreated group the serum zinc concentrations had decreased by about 5% three years after the start of the study, compared to the level at the start of the study (Fig. [1](#F1){ref-type="fig"}). The polaprezinc administration group showed a significant increase in serum zinc concentrations compared to the untreated group (*p* = 0.0036). Then, the changes in the serum zinc concentrations relative to the daily dose of zinc administered per kg body weight were compared. In the group of patients for whom the daily dose of zinc administered was less than 0.6 mg/kg, the serum zinc concentrations increased during the early period of administration from the level prior to administration but there was a tendency to decrease later. However, in the group for whom the daily dose of zinc was more than 0.6 mg/kg, the serum zinc concentrations showed a tendency to increase from one year after the start of administration (Fig. [2](#F2){ref-type="fig"}). Next, we compared the changes in serum zinc concentrations between two groups of patients who were administered polaprezinc, those with low (low zinc group \<64 µg/dl) and high (high zinc group; ≥64 µg/dl) serum zinc concentrations at the start of the study. The serum zinc concentrations in the low zinc group at one year after the start of administration had increased by 12.1 ± 19.3%, and at three years had increased by 18.3 ± 24.8%, compared to the level at the start of administration. On the other hand, that of the high zinc group at one year after the start of administration had decreased by 1.4 ± 21.3%, and at three years had decreased by 2.3 ± 14.2%, compared to the level at the start of administration. The changes in serum zinc concentrations in the low zinc group were significantly greater than those of the high zinc group (Fig. [3](#F3){ref-type="fig"}, *p* = 0.0002). Comparison between the polaprezinc administration and untreated groups in terms of changes of blood and biochemical data ------------------------------------------------------------------------------------------------------------------------ When the reductions of AST or ALT levels, compared to the levels after the start of the study, were compared between the polaprezinc administration and untreated groups, the reductions of ALT or AST levels in the polaprezinc administration group were significantly greater than in the untreated group (Table [2](#T2){ref-type="table"}, *p* = 0.0019, *p* = 0.0069). Furthermore, the change of platelet counts in the polaprezinc administration group was significantly less than in the untreated group (*p* = 0.0001). However, the changes in HCV RNA levels did not differ between the two groups (*p* = 0.6736). Next, when the polaprezinc administration group was divided into high and low zinc groups, the reductions of AST levels and ALT levels in the low zinc group were significantly greater than those of the high zinc group (Fig. [4](#F4){ref-type="fig"}; *p* = 0.0008, *p* = 0.0193). Although a significant correlation was not found, the reductions of HCV RNA levels in the low zinc group tended to be greater than those of the high zinc group (*p* = 0.0506). However, the change of platelet counts did not differ between the low and high zinc groups (*p* = 0.3169). Although the achievement of reduction of AST or ALT levels was significantly greater for the zinc responders than the zinc non-responders in the low group (*p* = 0.0274), there was no such difference in the high group (*p* = 0.5349). The cumulative incidence of HCC in patients with C-viral CH or LC ----------------------------------------------------------------- The incidence of HCC development after the initial examination in patients with C-viral liver disease was 4/48 (3.8%) for CH and 4/14 (28.6%) for LC, up to March 2005. The cumulative incidence of HCC, the assessment of which was started prospectively after the initial measurement of the zinc concentration, was compared between the polaprezinc administration group (median observation period, 4.877 years, range; 1.315--5.466) and untreated group (median observation period, 5.167 years, range; 1.271--5.436). HCC occurred in four patients (12.5%) in the polaprezinc administration group and in four patients (12.1%) in the untreated group. The cumulative incidence of HCC over three years was 13.1% in the polaprezinc administration group and 13.3% in the untreated group. The difference between the two groups was not statistically significant. However, considering the patients who were administered polaprezinc according to whether they were zinc responders (15 patients; median observation period, 4.718 years, range; 1.575--5.419) or zinc non-responders, (17 patients; mean observation period, 5.036 years, range; 1.271--5.466), the incidence of HCC after the initial examination was 4/17 (17.6%) for the zinc non-responders and 0/15 for the zinc responders. The incidence of HCC after the initial examination was 4/5 (80%) for the zinc non-responders whose serum zinc concentrations decreased and 0/12 for the zinc non-responders whose serum zinc concentrations were stable. The cumulative incidence of HCC was compared between these groups. The cumulative incidence of HCC over five years was 26.1% in the zinc non-responders and 0% in the zinc responders (Fig. [5](#F5){ref-type="fig"}). Then we compared the changes of serum zinc concentration with or without HCC development in patients with polaprezinc administration group and the control group. The serum zinc concentrations in patients who developed HCC decreased significantly compared to those who did not, however, the changes of serum zinc concentrations in the control group did not differ significantly between those who developed HCC and those who did not (Fig. [6](#F6){ref-type="fig"}a, b). Multivariate analysis --------------------- In order to identify risk factors for the development of HCC in patients administered polaprezinc, univariate analyses were made using logistic regression analysis (Table [3](#T3){ref-type="table"}). The analyses revealed that zinc non-response was a significant risk factor (risk ratio; 0.048, 95% confidence interval (CI); 0.003--0.712, *p* = 0.0274), although a low platelet count also was a significant risk factor (risk ratio; 0.684, 95% CI; 0.475--0.984, *p* = 0.0408). Then, we examined the risk factors for the development of HCC in patients administered polaprezinc by multivariate analysis using logistic regression analysis. The analyses revealed that no significant risk factor was observed. Furthermore, in order to identify factors contributing to zinc non-responsiveness to polaprezinc administration, multivariate analyses were made using the Cox proportional hazard model. The analyses revealed that liver cirrhosis (risk ratio; 0.001, 95% CI; 0.000246--0.512) and high serum zinc concentration at the start of the study (risk ratio; 0.734, 95% CI; 0.556--0.968) were contributory factors. Discussion ========== Polaprezinc is composed of zinc and L-carnocin. In Japan, it has been used to treat gastric ulcers in general clinical practice since 1994. The medicine we used in this study was Promac granules, 1.0 g/day. Promac contains 150 mg of polaprezinc per gram and also contains D-mannitol, cornstarch, calmerose calcium, polyvinyl pyrrolidone K, and aminoalkylacrylate polymer E as additives. Promac was administered orally twice a day, after breakfast and after dinner, to a total of 1.0 g. Therefore, the daily administration of zinc was 33.9 mg. In this study, we compared the long-term outcome between the Promac (polaprezinc) administration group and the untreated group. The results showed that, in the polaprezinc administration group, the average serum zinc concentrations had increased by 9.8% three years after the treatment started compared to the level before the start of treatment. However, in the untreated group, the serum zinc concentrations had decreased by approximately 5% compared to the level at the commencement of therapy. There were fifteen cases (46.9%) in the polaprezinc administration group whose serum zinc concentrations increased, significantly more than in the untreated group, in which there was only one case (3.3%). On the contrary, the patients whose serum zinc concentrations decreased numbered only five (15.6%) in the polaprezinc administration group but 15 (50%) in the untreated group. Therefore, it was confirmed that the serum zinc concentrations increased following the administration of polaprezinc, even in patients with C-viral CH or LC. In this study, polaprezinc was administered at a fixed amount, regardless of the height and/or weight of the patient. When the changes in serum zinc concentrations were compared according to the daily dose of zinc administered per kg body weight, the number of patients who became zinc responders was significantly higher in the group of patients of lower weight (data not shown). Therefore, it suggested that there were cases in which administration of the daily dose of 150 mg polaprezinc was insufficient. In fact, in the group that was administered a daily dose of zinc below 0.6 mg/kg, the serum zinc concentrations increased slightly immediately after the start of administration, but after that a tendency to decrease was observed. However, in the group that was administered a daily dose of zinc above 0.6 mg/kg, the serum zinc concentrations increased gradually after the start of administration and exceeded the levels in the group administered a daily dose of zinc less than 0.6 mg/kg. Therefore, when polaprezinc is used clinically, attention must be paid to the individual's body weight. Comparing the long-term outcomes, the polaprezinc administration group showed a clear reduction in ALT and AST levels, compared to the untreated group. Although the platelet counts decreased compared to the level at the start of administration, the reduction was clearly less than that of the untreated group. The ALT and AST levels also had a tendency to decrease in the group with increased zinc concentrations. Therefore, this prospective study confirmed that the serum zinc concentrations gradually reduced without zinc supplementation in patients with C-viral CH or LC. The serum zinc concentrations increased or remained unchanged in 84.3% of patients with C-viral chronic liver disease when zinc was administered, but 15.6% of patients showed a reduction in their zinc concentrations. It is known that serum zinc concentrations decreased in patients with liver disease in parallel with the development of disease stage because zinc absorption from the intestine decreases and the zinc content of the liver reduces due to the decrease in the number of functional hepatocytes \[[@B18]--[@B22]\]. However, our study suggests that the serum zinc concentrations can increase in the majority of patients if a sufficient quantity of zinc is administered. When the patients administered polaprezinc were divided into two groups whose serum zinc concentrations were more than 64 µg/dl (high zinc group) and less than 64 µg/dl (low zinc group), the reduction of AST and ALT levels in the low zinc group was significantly greater than in the high zinc group. Therefore, zinc supplementation in patients with CH or LC with low serum zinc concentrations was more effective than in those with high serum zinc concentrations. Specifically, patients with low serum zinc concentrations seemed to achieve a greater reduction in serum AST or ALT levels following zinc supplementation, regardless whether the zinc concentration increased or decreased. On the other hand, patients with high serum zinc concentrations, whose serum zinc concentrations did not increase with the daily dose of zinc given, also did not achieve a reduction of ALT levels and perhaps require a greater degree of zinc supplementation. The significance of maintaining the serum zinc concentrations at a high level in C-viral liver disease is that, by achieving a continuous low level of ALT, it is possible to slow the progression of liver fibrosis and, further, to restrain the development of liver carcinogenesis. Also, in patients with a decreased reserve of liver function, such as those with decompensated cirrhosis, it is possible to prolong the survival period by increasing their zinc concentrations, leading to improvement in hyper-ammonia and recovery of liver function. Our study showed no significant difference in the cumulative incidence of HCC between the group administered polaprezinc and the untreated group. However, comparing the zinc responders and zinc non-responders, regardless of polaprezinc administration, the cumulative incidence of HCC was significantly lower in the former, suggesting that the influence of zinc supplementation on the long-term outcome of C-viral CH or LC is significant. Therefore, we report that zinc supplementation for C-viral CH or LC is clinically useful. Multivariate analysis of the clinical background factors was performed on the zinc non-responders in the group administered polaprezinc. The results showed that there was no significant relationship between the age, body weight or BMI, platelet count, ALT level, AST level, or the HCV RNA level. However, when the changes in the serum zinc concentrations were evaluated according to the daily dose of zinc administered per kg body weight, in the polaprezinc administration group for whom the daily dose of zinc was more than 0.6 mg/kg the number of cases whose serum zinc concentrations increased compared to the level before the start of therapy was significantly high, whereas in the group with zinc administration at daily dose of zinc less than 0.6 mg/kg the number of cases whose serum zinc concentrations decreased was significantly high. Therefore, it seems necessary to consider the daily dose of zinc administered per kg body weight on an individual basis and to increase the daily dose of zinc administered per day for patients of greater body weight. In addition, the data suggest that, for the zinc non-responders in the polaprezinc administration group, increasing the daily dose of polaprezinc could lead to an improvement in the long-term outcome of the patient. As for the reason why ALT and AST levels reduced with zinc administration, the following may be suggested: It is known that zinc has an anti-oxidant effect. It has an inhibitory action on iron-dependent radical reactions and on lipid peroxidation. It has been assumed that the state of zinc deficiency in chronic liver disease first leads to an increase in hepatic phospholipids, resulting in intensification of lipid peroxidation, and thereby causes hepatic cell injury \[[@B23], [@B24]\]. Therefore, it is assumed that zinc administration inhibits lipid peroxidation and subsequently alleviates hepatic cell injury and improves the AST and ALT levels. Zinc complexes with ferritin in hepatocytes. With zinc administration, complexing of zinc and ferritin also increases in the liver. This zinc-ferritin complex is readily used by apoenzymes that require zinc. Therefore, it is suggested that the ferritin level in hepatocytes may decrease with increasing zinc concentration, and zinc consequently enhances the chelation of iron in the liver. As a result, there should be a reduction in oxidative stress from iron in the hepatocytes and a decrease in aminotransferase levels \[[@B25]\]. In fact, it has been reported that the action of polaprezinc inhibiting gastric mucosal injury is due to the strong anti-oxidant action and membrane stabilizing action \[[@B26]--[@B28]\]. Therefore, in a similar manner in the liver, liver function improves and liver fibrosis is suppressed by the anti-oxidant action and membrane stabilization effect of polaprezinc. The reason the incidence of HCC in zinc responders may be reduced more than that of zinc non-responders may be as follows: Serum ALT or AST levels reduced through the anti-oxidant effect of zinc. Also, zinc deficiency is known to affect certain mediators of innate immunity, such as the function of neutrophils, NK cells and complement \[[@B29], [@B30]\]. Furthermore, the numbers and activity of NK cells are dependent on serum zinc concentrations \[[@B31]\]. Zinc supplementation results in significantly greater numbers of cytotoxic and helper T and NK cells than are seen in the control group \[[@B32], [@B33]\]. Finally, we also compared the changes of serum zinc concentrations, levels of AST and ALT, and the cumulative incidence of HCC development between the patients with CH and those with LC. The serum zinc concentrations increased and the serum levels of AST and ALT were reduced after three years of polaprezinc administration in both groups. Furthermore, in the CH group, the cumulative incidence of HCC development in the zinc responders was significantly lower than that in the zinc non-responders. However, the cumulative incidence of HCC development did not differ significantly between the zinc responders and non-responders in the LC group. We assume that liver cirrhosis constitutes a high carcinogenic state and the development of HCC could not be prevented simply by polaprezinc administration. In conclusion, we performed zinc supplementation for patients with C-viral CH and LC and the following results were obtained: The serum zinc concentration increased in approximately half of the patients who received the zinc supplement. Compared to the untreated patients, the AST and ALT levels decreased significantly. Compared to the untreated patients, the reduction in the platelet counts was significantly lower. The factors that inhibited increases in serum zinc concentrations following administration of polaprezinc included low serum zinc concentration states such as liver cirrhosis. Furthermore, the reductions of AST and ALT levels in the low zinc group were significantly greater than those of the high zinc group. The zinc responders had a significantly lower cumulative incidence of HCC than the zinc non-responders.Thus, it was confirmed that zinc supplementation for patients with C-viral CH or LC improves both the degree of the liver damage and the long-term outcome. The authors thank Professor Masao Omata and Haruhiko Yoshida, MD (Department of Gastroenterology, Graduate School of Medicine, University of Tokyo) for helpful advice regarding this article. ![Changes in serum zinc concentrations in patients with C-viral chronic hepatitis (CH) and liver cirrhosis (LC), with and without zinc administration. The median serum zinc concentration in the group of patients who had been administered polaprezinc was significantly higher than that of the untreated group (*p* = 0.0036).](jcbn08-246f01){#F1} ![The changes in the serum zinc levels were compared according to the quantity of polaprezinc administered per kg body weight. In the group administered less than 0.6 mg/kg zinc, the serum zinc level increased above that before the start of administration during the early stage of administration, but decreased later. However, in the group administered more than 0.6 mg/kg, the serum zinc level increased continuously from one year after the start of administration.](jcbn08-246f02){#F2} ![Comparison of changes of serum zinc concentrations in the polaprezinc administration group between the low zinc group, whose serum zinc concentrations were below 64 µg/dl, and the high zinc group, whose serum zinc concentrations were above 64 µg/dl. The change of serum zinc concentrations in the low zinc group was significantly greater than that of the high zinc group (*p* = 0.0002).](jcbn08-246f03){#F3} ![When the polaprezinc administration group was divided into two, the high zinc group and the low zinc group, the reductions of AST levels and ALT levels in the low zinc group were significantly greater than those of the zinc high group (*p* = 0.0008, *p* = 0.0193).](jcbn08-246f04){#F4} ![The cumulative incidence of HCC was compared between the responders and the non-responders, based on changes in serum zinc concentrations between the initial and final examinations. The cumulative incidence of HCC over four years was 24.9% in the zinc non-responders and 0% in the zinc responders. The cumulative incidence of HCC over four years in the zinc responders was clearly less than that in the zinc non-responders.](jcbn08-246f05){#F5} ![Changes of serum zinc concentration in patients with or without HCC development in the polaprezinc administration group and control group. The changes of serum zinc concentrations were significantly lower in the patients who developed HCC than those who did not (a). However, the changes of serum zinc concentrations in the control group did not differ significantly between those who developed HCC and those who did not (b).](jcbn08-246f06){#F6} ###### Comparison of clinical characteristics between patients with chronic hepatitis and liver cirrhosis (*n* = 62) Parameter Chronic hepatitis Liver Cirrhosis ---------------------------- ------------------- ------------------ Number 48 (77.4%) 14 (22.6%) Gender (male) 33 (68.8%) 5 (35.7%) Age 59.0 (26--72) 62.5 (45--74) AST^a^ (U/L) 54.0 (25--131) 78.0 (46--138) ALT^b^ (U/L) 73.0 (27--231) 83.5 (36--201) Platelet count (×10^−4^) 17.3 (13--26.4) 9.75 (6.3--12.6) HCV genotype  1b 38 (79.2%) 14 (100%)  2a 7 (14.6%) 0  2b 3 (6.3%) 0 HCV RNA level (kiu^c^/ml) 480.5 (8.4--850) 725.0 (7.4--850) Observation period (years) 5.04 (3.17--6.4) 4.6 (3.32--5.43) \* Median (range). ^a^ AST, Aspartate aminotransferase; the upper limit of the normal range is 38 IU per liter. ^b^ ALT, Alanine aminotaransferase; the upper limit of the normal range is 44 IU per liter. ^c^ Kilointernational unit. ###### Comparison of clinical characteristics between patients with and without zinc supplementation. (*n* = 62) Parameter Promac administrations Controls ---------------------------- ------------------------ ------------------- Number 30 32  Chronic hepatitis  Liver cirrhosis Gender (male) 33 (68.8%) 5 (35.7%) Age 55.9 (26--72) 61.4 (46--74) AST (U/L) 61.0 (40--118) 82.1 (46--138) ALT (U/L) 86.3 (41--231) 93.39 (45--201) Platelet count (×10^−4^) 18.2 (13--26.4) 8.9 (6.3--10.0) HCV  1b 38 (79.1%) 14 (100%)  2a 7 (14.6%) 0  2b 3 (6.3%) 0 HCV RNA level (kiu/ml) 499.6 (8.4--850) 576.0 (7.4--850) Observation period (years) 5.04 (3.12--5.46) 4.59 (3.05--5.43) ###### Comparison of the rate of changes of AST levels, ALT levels, platelet counts and HCV RNA levels between the polaprezinc administrationsgroup and untreated group, after the day of registration Months AST\* ALT^¶^ Platelet count^‡^ HCV RNA ------------ -------------- ------------- ------------------- ------------- ------------- -------------- -------------- -------------- +2 Months −12.4 ± 23.6 8.9 ± 29.1 −15.7 ± 29.0 4.7 ± 30.0 0.6 ± 8.2 −7.5 ± 7.4 −19.4 ± 38.0 −9.2 ± 33.3 +4 Months 17.2 ± 29.3 9.8 ± 49.0 −20.8 ± 31.6 9.5 ± 64.6 0.2 ± 8.1 −5.8 ± 10.1 −22.9 ± 42.5 −4.1 ± 29.6 +6 Months −21.2 ± 30.9 16.5 ± 65.9 −26.5 ± 41.0 7.6 ± 116.3 0.9 ± 10.1 −5.7 ± 8.8 −17.2 ± 43.9 3.1 ± 32.6 +8 Months −23.1 ± 21.7 11.6 ± 54.6 −23.8 ± 34.7 11.6 ± 84.6 0.3 ± 6.2 −8.3 ± 7.2 −17.9 ± 41.9 −5.9 ± 50.5 +10 Months −24.7 ± 25.0 9.7 ± 49.3 −29.9 ± 31.3 5.2 ± 58.8 0.7 ± 11.2 −8.7 ± 7.3 −16.1 ± 51.9 −17.6 ± 49.9 +12 Months −15.6 ± 36.4 10.6 ± 57.8 −22.0 ± 37.8 5.6 ± 81.1 0.1 ± 7.9 −8.3 ± 10.4 −11.8 ± 49.5 −3.4 ± 65.5 +14 Months −9.1 ± 36.1 10.5 ± 55.5 −17.4 ± 36.6 7.3 ± 67.2 2.7 ± 13.5 −6.7 ± 13.0 −13.4 ± 53.4 6.0 ± 70.1 +16 Months −9.2 ± 44.3 16.9 ± 58.1 −9.7 ± 44.1 11.0 ± 69.9 3.9 ± 18.1 −7.2 ± 9.5 −21.0 ± 45.4 3.9 ± 58.4 +18 Months −16.9 ± 29.2 16.8 ± 49.5 −21.3 ± 32.5 11.4 ± 60.8 1.0 ± 11.1 −8.8 ± 12.9 23.1 ± 184.0 2.9 ± 57.2 +20 Months −8.6 ± 51.7 9.1 ± 41.3 −15.8 ± 43.4 13.6 ± 74.0 1.3 ± 10.7 −10.7 ± 11.8 2.4 ± 77.8 10.5 ± 64.7 +22 Months −15.9 ± 50.0 6.2 ± 38.8 −22.2 ± 45.6 8.4 ± 51.9 1.4 ± 11.3 9.8 ± 12.1 −17.6 ± 51.7 10.1 ± 61.8 +24 Months −12.8 ± 34.2 14.7 ± 49.9 −18.7 ± 41.0 8.3 ± 46.0 0.8 ± 13.0 −8.8 ± 10.7 6.9 ± 86.6 10.5 ± 59.8 +26 Months −15.3 ± 42.5 9.1 ± 52.0 −18.8 ± 40.8 7.9 ± 56.4 −2.5 ± 13.0 −8.1 ± 12.6 −16.2 ± 60.3 6.1 ± 70.1 +28Months −15.9 ± 39.7 13.8 ± 54.6 −25.9 ± 40.6 10.0 ± 74.5 −1.5 ± 15.0 9.4 ± 15.1 7.4 ± 100.6 12.5 ± 69.1 +30Months −18.0 ± 32.9 13.0 ± 50.4 −24.2 ± 37.7 13.0 ± 54.4 −4.5 ± 11.9 −11.6 ± 14.3 1.3 ± 78.4 5.4 ± 61.2 +32 Months −18.0 ± 33.4 17.6 ± 77.6 −26.2 ± 34.7 16.4 ± 91.0 −4.9 ± 15.4 −11.4 ± 12.8 −4.1 ± 76.2 9.8 ± 66.9 +34 Months −21.4 ± 3.19 19.9 ± 66.6 −25.5 ± 36.9 17.7 ± 73.6 −5.5 ± 16.2 −10.8 ± 14.1 −5.2 ± 66.5 4.0 ± 52.8 +36 Months −20.5 ± 37.1 22.2 ± 69.9 −26.2 ± 42.9 18.5 ± 70.0 −5.6 ± 14.7 −5.2 ± 19.9 −10.1 ± 65.4 12.2 ± 51.6 Mean (%) ± standard deviation (S.D.) are shown. AST: aspartate aminotransferase; ALT: alanine aminotransferase. \**p* = 0.0019 by the Repeated measure ANOVA for the comparison between Polaprezinc and Untreated groups, ^¶^*p* = 0.0069 by the Repeated measure ANOVA for the comparison between Polaprezinc and Untreated groups, ^‡^*p* = 0.0001 by the Repeated measure ANOVA for the comparison between Polaprezinc and Untreated groups. ###### Clinical characteristics of the patients with or without occurrence of HCC at the beginning of the study Paramater Hepatocellular carcinoma *p* value -------------------------- -------------------------- ------------------- -------- Number 4 28 Gender (male) 3 (75%) 18 (64.8%) 0.6659 Age 65.2 (59.7--67.7) 55.3 (26.5--70.1) 0.0890 AST (U/L) 73.0 (51--138) 53.5 (40--116) 0.2320 ALT (U/L) 88.5 (65--201) 89.5 (40--231) 0.7954 Platelet count (×10^−4^) 9.6 (8.3--17.2) 16.7 (7.4--25.7) 0.0213 Zinc concentration 51.0 (41--73) 64.5 (45--88) 0.1.09 HCV genotype  1b 4 (100%) 24 (85.8%) 0.7214  2a 0 2 (7.1%)  2b 0 2 (7.1%) HCV RNA level (kiu/ml) 435.0 (140--710) 600.0 (7.4--850) 0.4665 Zinc supplementation 0.0493  Zinc responders 0 15 (53.6%)  Zinc non responders 4 (100%) 13 (46.4%) \* Median (range). Gender, Genotype, Efficacy of supplementation were analyzed by chi-square test for independence, other factors by student's *t* test.
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Three weeks after the regional election in Schleswig-Holstein, Sven Lohse has had enough: after repeated threats he has closed his "Tivoli" inn in Aukrug near Neumünster. His offence in the eyes of his antagonists: he rented his premises for AfD events. On 3 March the party leader Frauke Petry opened the regional electoral campaign there, accompanied by protests. The party on election night was also celebrated there. As the "Kieler Nachrichten" reported on Tuesday, in recent months there have been numerous attacks on the inn. Entrance doors were vandalised with graffiti, horse manure was dumped in front of the door with shredded AfD posters. Car tyres were punctured. Ultimately, the janitor's too. Lohse filed complaints. The police suspected political motives. On the internet, left-wing extremists boasted about the actions. But there have been no arrests so far.
i be z(-4). Suppose 2*n - i = -2*n. Let p(x) = 13*x + 4. What is n*p(f) + 7*w(f)? 2*f - 1 Let y(w) = -w**2 + w - 1. Let l(x) = 5*x**2 - 2*x + 4. Let t(j) = -5*j**2 + 2*j - 4. Let d(q) = -6*l(q) - 5*t(q). Calculate -d(c) + 4*y(c). c**2 + 2*c Let c(r) = r**2 - r + 1. Let x(b) = 10*b**2 - 6*b + 6. Give 12*c(k) - 2*x(k). -8*k**2 Let s(q) = 4*q - 2. Let k(t) = t + 1. Let n(r) = -7*r - 4. Let j(x) = -5*k(x) - n(x). What is 9*j(m) - 4*s(m)? 2*m - 1 Let s(a) = 9 + 3 + a - 5 + 3*a. Let m(k) = -1 - 4*k + 6*k - 3 - 4*k. What is -7*m(z) - 4*s(z)? -2*z Let k(x) = 7*x**3 - 4*x**2 + 4*x - 4. Suppose -7 = 4*a - a - 5*g, 4*g - 8 = 3*a. Let d(u) = 8*u**3 - 5*u**2 + 5*u - 5. Determine a*d(h) + 5*k(h). 3*h**3 Let k(j) = 11*j - 11. Let p(c) = -5*c + 5. Let v(w) = -6*k(w) - 13*p(w). Let d(g) = -5*g + 3. Suppose 35 = 3*r + 8. Calculate r*v(h) - 2*d(h). h + 3 Let r(i) = -i**2 + i - 1. Let c(o) = -2*o**2 + 1. Let f be 4/(-18) - 55/(-45). Give f*c(h) + r(h). -3*h**2 + h Let c(y) = y - 4. Let i be 14/4*40/35. Let w(q) = q - 3. Determine i*w(k) - 3*c(k). k Let x(r) = -r**2 - 2*r + 4. Suppose 0 = -0*d + 2*d + 8, -b + 3*d - 14 = 0. Let n(t) = -4*t**2 - 9*t + 17. Calculate b*x(j) + 6*n(j). 2*j**2 - 2*j - 2 Let x(p) = -p**3 - 2*p**2 + p. Let y(u) = -6*u**3 - 5*u**2 - 2*u - 1. Let b(h) = h**3 + h. Let n(r) = -4*b(r) - y(r). Give 2*n(d) + 5*x(d). -d**3 + d + 2 Let y(b) = -29*b**3 - 6*b - 6. Let n(q) = -552*q**3 - 115*q - 115. Determine -6*n(t) + 115*y(t). -23*t**3 Let i(o) = 9 + 7*o - 8*o**2 - o**2 - 11*o. Let a(b) = 5*b**2 + 2*b - 5. Determine -11*a(p) - 6*i(p). -p**2 + 2*p + 1 Let v(x) = -x - 4. Let b(y) = 3*y + 11. Let c(k) = -k**2 - 11*k + 1. Let t be c(-5). Suppose -5*z = -w - t, 1 - 9 = -2*z. Give w*v(a) - 4*b(a). -a Let w(i) = 5*i**3 - 5*i - 5. Let g(h) = -6*h**3 + 6*h + 5. Determine -4*g(f) - 5*w(f). -f**3 + f + 5 Let u(i) = 4*i**3 + 5*i**2 + 5. Let j = -2 + -5. Let g(q) be the third derivative of q**6/20 + 7*q**5/60 + 7*q**3/6 + 115*q**2. Determine j*u(n) + 5*g(n). 2*n**3 Let x(y) = 2*y + 2. Let p(z) = 2*z + 2. What is -6*p(r) + 5*x(r)? -2*r - 2 Let f(m) = 4*m**2 + 13*m - 10. Suppose -5*h - 1 = -3*x + 3, 5*x = 3*h - 20. Let r(g) = 2*g**2 - 2 - g**2 + g - 1 + 3*g. What is x*r(v) + 2*f(v)? v**2 - 2*v + 1 Let u(l) = 3*l - 1. Let a(d) = d + 1. What is 6*a(j) + 6*u(j)? 24*j Let f(j) = -16*j**2 + 10*j - 7. Let z(t) be the third derivative of -t**5/12 + t**4/8 - t**3/3 + 2*t**2 + 6*t. What is 2*f(a) - 7*z(a)? 3*a**2 - a Let h(j) = -j**3 - 7*j**2 - 2*j. Let p(i) = 2*i**3 + 13*i**2 + 3*i. Calculate 5*h(o) + 3*p(o). o**3 + 4*o**2 - o Let x(r) = -11*r**3 - 13*r + 13. Let n(b) = 5*b**3 + 6*b - 6. Let t be 1/1 + 0 + 1. Suppose -t*g = g - 27. Let w be 4/6*g*-1. Determine w*x(l) - 13*n(l). l**3 Let j(x) = -x - 1. Let p(g) = 5*g + 8. Suppose -k + 0 = -6. What is k*j(v) + p(v)? -v + 2 Let h(a) = 2*a - 7. Let x(r) = -5*r + 15. Let j(y) = -13*h(y) - 6*x(y). Let z be j(-1). Let c(o) = 5*o - o + 2 + 0. Let w(f) = 5*f + 3. What is z*w(u) + 4*c(u)? u - 1 Suppose 3*k - 50 = -17. Let y(a) = 16*a**3. Let q(v) = 3*v**3 + 0 + 0. Calculate k*q(l) - 2*y(l). l**3 Let f(y) = y**3 - 6*y**2 + 4*y - 5. Let q be -1 + 6*2/3. Let v = q + -1. Let i(p) = -2*p + 6 - 3*p + 7*p**2 - 3*p**3 + v*p**3. What is -5*f(o) - 4*i(o)? -o**3 + 2*o**2 + 1 Let m(q) = 43*q. Let s(f) = 14*f. Determine 6*m(z) - 17*s(z). 20*z Let c(t) = 8*t - 2. Let s(i) = -i**2 + i - 1. Determine c(m) - 2*s(m). 2*m**2 + 6*m Let l(b) be the third derivative of b**5/15 + 6*b**2. Let j(c) = 2*c**2. Calculate -7*j(t) + 3*l(t). -2*t**2 Let w = -7 - -15. Let s(p) = 5 + 5 - 4*p + 6 - 15. Let v(z) = 6*z - 2. Let u(d) = 3*d - 4. Let r be u(3). What is r*v(f) + w*s(f)? -2*f - 2 Let b = 9 + -20. Let n(v) = 9*v - 3. Let z = 14 - 9. Let l(a) = 4*a - 1. Let k(r) = z*l(r) - 2*n(r). Let x(q) = 4*q + 2. Calculate b*k(j) + 6*x(j). 2*j + 1 Let a(q) = 7*q - 3. Let m(f) = 14*f - 5. Determine 7*a(j) - 4*m(j). -7*j - 1 Let z(b) = b**2 - 1. Let w(u) = 10*u**2 - 11. Let h be 2 - (23 + 1/1). Let a = 19 - 17. What is a*w(o) + h*z(o)? -2*o**2 Let h(p) = -2*p + 3. Let x(k) = -6*k + 0*k + 2*k + 7. Suppose 21 = 3*a - 0*a. What is a*h(f) - 3*x(f)? -2*f Let n(i) = 10*i**2 - i. Let r be (-10)/15 - (-23)/3. Let v(u) = 7*u**2 - u. Calculate r*v(w) - 5*n(w). -w**2 - 2*w Let r(h) = -3*h**2 - 3*h. Let v(s) = -s**2 - s. Determine r(b) - v(b). -2*b**2 - 2*b Let b(q) = -q**2 + 1. Let l(x) = 5 - 5*x**2 + 0 + 4*x - 3*x**2. Let r(i) = -6*b(i) + l(i). Suppose -3 = 3*g + 6. Let k(j) = j. What is g*k(h) + r(h)? -2*h**2 + h - 1 Let h(d) = 11*d - 3. Let j(p) = -6*p + 2. Determine -3*h(o) - 5*j(o). -3*o - 1 Let b = 8 + -3. Suppose 0 = b*u + 10 - 40. Let c(x) = -7*x**2 + 6. Let d(q) = -6*q**2 + 5. What is u*d(t) - 5*c(t)? -t**2 Let f(l) = -2*l**2 + 4*l - 1. Let o(b) = 4*b**2 - 9*b + 3. What is -5*f(r) - 2*o(r)? 2*r**2 - 2*r - 1 Let s(x) = -6*x - 3. Suppose 4*b + 4*n - 8 = 0, 0 = 4*n - 3 + 15. Suppose 4*q - b*q = -3. Let y(h) = -q - 2*h + 4 - 2. What is -3*s(j) + 8*y(j)? 2*j + 1 Let y(m) = m**2 - m + 1. Let i(d) = -2*d**2 + d - 4. Give -i(p) - y(p). p**2 + 3 Let r(c) = c - 4. Let g = -8 + 6. Let f = -2 + g. Let y(s) = 2*s - 7. Give f*y(i) + 7*r(i). -i Let r(b) be the second derivative of b**3/6 - b**2/2 + 3*b. Let l(m) = 2*m - 2. Calculate l(f) - r(f). f - 1 Let q = 9 + -7. Suppose 0 = -q*t - 5*o - 19, -4*o - 16 = -4. Let h(m) = m**2 - m - 1. Let j(f) = 4*f**2 - 3. Determine t*h(p) + j(p). 2*p**2 + 2*p - 1 Let g(f) = 6*f**3 - 6*f**2 - 5*f + 6. Let l(k) = k**3 + 0*k + 2*k + 1 - 3*k - k**2. Determine g(r) - 5*l(r). r**3 - r**2 + 1 Let m(w) = 11*w**3 + 2*w + 3. Let r(t) = 22*t**3 + 3*t + 5. What is -5*m(h) + 3*r(h)? 11*h**3 - h Let b(r) = -2*r**2 - 5*r - 5. Suppose 3*t + 2*o - 99 = 67, -156 = -3*t + 3*o. Let k be t/(-8) + (-1)/4. Let v(x) = 2*x**2 + 6*x + 6. What is k*b(y) - 6*v(y)? 2*y**2 - y - 1 Let x(f) = -7*f**2 + 7*f + 1. Let v(a) be the first derivative of -a**3/3 + a**2/2 - 67. Calculate 5*v(l) - x(l). 2*l**2 - 2*l - 1 Let s(b) = b - 1. Let k(d) = 5*d - 5. Let h = -22 + 11. Let f = h - -10. Determine f*k(z) + 4*s(z). -z + 1 Let u(q) = 9*q**3 - 4*q**2 - 7*q + 5. Let j(o) = o**3 + o**2 - o - 1. Let v(l) = l**3 - 6*l**2 + 7. Let b(h) = 4*j(h) + v(h). Determine 7*b(a) - 4*u(a). -a**3 + 2*a**2 + 1 Let s(y) = -4*y**3 - y**2 + 2*y. Let h(u) = -u**3 - u**2 + u. Calculate 3*h(o) - s(o). o**3 - 2*o**2 + o Let l(k) = k**2 - 5*k + 1. Let u(j) = -2*j**2 + 6*j - 1. What is -4*l(z) - 3*u(z)? 2*z**2 + 2*z - 1 Let q(y) = y. Let o be (0 + 12/8)/((-6)/(-8)). Let c(s) = 1. Determine o*q(l) - c(l). 2*l - 1 Suppose 5*y = -5*d - 21 - 24, 5*d = -3*y - 35. Let i(m) = m**3 - 5*m**2 - 5*m + 1. Let k(u) = 4*u - 1 - u - u**3 + 3*u + 6*u**2. Determine y*k(r) - 6*i(r). -r**3 - 1 Let m(l) = -l. Let a(w) = -3*w + 11. Give a(b) - 2*m(b). -b + 11 Let v(j) = 6*j + 4. Suppose 5*y - 3*s + 40 = 2*s, -2*y = -3*s + 21. Let f(x) = x + 1. Calculate y*f(g) + v(g). 3*g + 1 Let k(z) = 33 - 40 - 2*z**2 - z**2. Let f(a) = -2*a**2 - 5. Give 7*f(u) - 5*k(u). u**2 Let f(i) = i**3 - 2*i**2 - 4*i + 2. Let y(t) = t**3 - 5*t**2 + t. Let c be y(5). Let m(o) = -2*o**3 + 5*o**2 + 9*o - 5. Determine c*f(x) + 2*m(x). x**3 - 2*x Let z(o) = o**3 + 4*o**2 - 2*o - 1. Let s(u) = u + 2. Let y be s(-4). Let p(c) = -c**3 - 5*c**2 + 3*c + 2. What is y*p(x) - 3*z(x)? -x**3 - 2*x**2 - 1 Let z(w) = 0*w - w - 2*w + 2*w + 9. Let c be z(9). Suppose c = 3*y - 0*y - 6. Let a(s) = -4*s - 13. Let f(t) = -t - 4. Determine y*a(k) - 7*f(k). -k + 2 Let b(f) = 4*f - 13. Let c(r) = -3*r. Let p(d) = -d + 1. Let v(m) = -c(m) + 4*p(m). Give 4*b(i) + 14*v(i). 2*i + 4 Let z(t) be the first derivative of -t**2 + 1 - 8/3*t**3 + 8*t. Let s(p) = -7*p**2 - 2*p + 7. What is -6*s(j) + 5*z(j)? 2*j**2 + 2*j - 2 Let i(y) = y - 4. Let w be i(8). Suppose -w*r + r = -12. Let s(h) = -2*h - 3. Suppose 4*j + 0*j = 4. Let k(c) = 1. Give j*s(o) + r*k(o). -2*o + 1 Let d(i) = -6*i**2 + 14*i + 14. Suppose -4*s = -7*s - 33. Let u(t) = 2*t**2 - 5*t - 5. Calculate s*u(l) - 4*d(l). 2*l**2 - l - 1 Let i(b) = 4*b**3 - 5*b - 3. Let q = 125 - 120. Let m(d) = 7*d**3 - 9*d - 5. What is q*i(l) - 3*m(l)? -l**3 + 2*l Let s = -4 - -7. Suppose 0 = s*z + u + 3, 4 + 0 = -4*z - 2*u. Let t(k) = k**2 + k + 1. Suppose 1 = 3*r - 5. Let h(b) = 2*b + 3. Calculate r*t(v) + z*h(v). 2*v**2 - 1 Let i = 1 + 1. Let f(t) = 3
D. J. Richardson Dietrich James "D. J." Richardson (born February 11, 1991) is an American professional basketball player for Aix Maurienne Savoie Basket of the LNB Pro B. He attended Peoria Central for his first three years of high school and transferred to Findlay Prep in Henderson, Nevada for his senior year. He played collegiately at the University of Illinois. High school As a junior at Peoria Central Richardson was selected to first-team All-State by the Champaign-Urbana News-Gazette and second-team All-State by the AP and Chicago Sun-Times. In his senior year at Findlay College Prep, Richardson, along with Texas recruit Avery Bradley, led the Findlay College Prep Pilots to a high school national championship after beating Oak Hill 74-66 and finishing their season 33-0. College career Richardson joined fellow 2009 recruits, including Brandon Paul, on the University of Illinois 2009–10 men's basketball team coached by Bruce Weber. Andy Katz of ESPN called Richardson and Paul "the best freshman backcourt not at Kentucky John Wall and Eric Bledsoe". Richardson was named Big Ten Freshman of the Year by the coaches and was unanimously selected to the Big Ten All-Freshman team. Richardson finished his career ranked 13th on Illini all-time scoring list (1,477 points, third in made 3-pointers (278), and tied for third in games played (138). After his senior season, Richardson was selected to participate in the Portsmouth Invitational Tournament. College Statistics |- | style="text-align:left;"| 2009–10 | style="text-align:left;"| Illinois | 36 || 35 || 30.9 || .399 || .390 || .775 || 2.7 || 2.1 || 0.7 || 0.2 || 10.5 |- | style="text-align:left;"| 2010–11 | style="text-align:left;"| Illinois | 34 || 30 || 26.8 || .415 || .385 || .758 || 1.8 || 1.9 || 0.7 || 0.2 || 8.4 |- | style="text-align:left;"| 2011–12 | style="text-align:left;"| Illinois | 32 || 31 || 34.7 || .387 || .348 || .774 || 3.0 || 1.7 || 0.8 ||0.2 || 11.6 |- | style="text-align:left;"| 2012–13 | style="text-align:left;"| Illinois | 36 || 36 || 33.8 || .363 || .322 || .815 || 3.9 || 1.6 || 1.3 || 0.2 || 14.5 |- | style="text-align:center;" colspan="2"| Career | 138 || 132 || 31.5 || .388 || .355 || .787 || 2.8 || 1.8 || 0.9 || 0.2 || 13.6 |- Professional career After going undrafted in the 2013 NBA Draft, Richardson worked out for the Utah Jazz in mid-September 2013. On October 24, 2013, Richardson signed to play professionally in Austria for the UBC Güssing Knights. In January 2014 Richardson signed to play for Toros de Aragua of the Venezuelan Professional Basketball League, however he suffered an ankle injury that forced the team to cut him before playing a game. On July 31, 2014 Richardson signed with Korikobrat which competes as a member of the Korisliiga in Finland. After that season, he signed with Kouvot from the same Korisliiga for the 2015–16 season. He eventually won the Finnish championship with Kouvot. On February 26, 2018, Richardson joined Aries Trikala of the Greek Basket League. References External links Profile at FIBA.com Profile at Eurobasket.com Profile at FightingIllini.com Category:Living people Category:1991 births Category:Aix Maurienne Savoie Basket players Category:American expatriate basketball people in Austria Category:American expatriate basketball people in Belgium Category:American expatriate basketball people in Finland Category:American expatriate basketball people in France Category:American expatriate basketball people in Germany Category:American expatriate basketball people in Greece Category:American expatriate basketball people in Poland Category:American men's basketball players Category:Aries Trikala B.C. players Category:Basketball players from Illinois Category:Findlay Prep alumni Category:Illinois Fighting Illini men's basketball players Category:Kobrat players Category:Kouvot players Category:Parade High School All-Americans (boys' basketball) Category:s.Oliver Würzburg players Category:Stal Ostrów Wielkopolski players Category:Shooting guards Category:Spirou Charleroi players Category:Sportspeople from Peoria, Illinois
Atheists in America are getting a bit more love this year it seems. According to a new study released by Pew Research, atheists, and even Muslims, are becoming more accepted by mainstream society. The study asked how each participant felt towards each religious group, using warm or cold as their gauge. The higher the number, the warmer one’s feelings towards a particular religious group. In 2014, atheists polled at 41 points, compared to Jews at 63 points and Catholics at 62. In contrast, in the same year, Muslims came in at 40 points. Now, the updated study suggests atheists have jumped to 50 points, Muslims to 48, and Jews and Catholics both jumped 4 points. Americans certainly are not in love with atheists and Muslims, but the jump in points certainly shows that things are turning around. The jump in warmer feelings toward Muslims is actually rather shocking given the last few years of political campaigning vilifying them and the recent Muslim ban issued by Donald Trump’s administration. As atheism becomes more normalized, I think the numbers will continue to rise, maybe only slightly, but I think the overall feelings towards nonbelievers will simply level out. Age seems to play a major factor in this thinking as well. Among all age groups over 30, atheists and Muslims rank among the lowest. Yet, in the 30-49 age group, atheists are still ranked above Muslims and interestingly enough Mormons. However, the biggest change is in the 19-29 group. This group prefers Buddhists with 66 points, brings in atheists at 59 points, ranking them fourth, and drops Mormons all the way down to 54 points, putting them under Muslims who came in at 58, making them just about equal with mainstream Christians. As this age group rises through the years, I think this is the kind of trend we will see. Likely, in the next decade or so, most religious groups would likely begin to equal out. One thing is certain, the poll gives hope that the stranglehold religion holds on American society is weakening and as the older generations move out, the younger ones are holding many different feelings about religious belief.
Physiomesh Lawsuit There are currently 2,597 Physiomesh lawsuits filed in Federal court nationwide. In March of 2017, consolidation for a Physiomesh Multi District Litigation (MDL) was requested. The Judicial Panel on Multidistrict Litigation (JPML) heard consolidation arguments on May 25, 2017. On June 2, 2017, MDL 2782 was created and all Physiomesh cases filed in Federal court were consolidated into the Northern District of Georgia under the Honorable Richard W. Story. There are also over 20 Physiomesh cases filed in NJ State court, which is the home of both defendants Ethicon and Johnson & Johnson. In February of 2018, consolidation for an Ethicon multi-layered hernia mesh multicounty litigation (MCL) was request. On July 17, 2018, the New Jersey Supreme Court created a MCL for all pending and to be filed lawsuits in New Jersey state court alleging injuries arising from the use of Physiomesh. The New Jersey Physiomesh MCL was assigned to Atlantic County under Judge John C. Porto for centralized management. Attorney C. Brett Vaughn of the Hollis Law Firm continues to play an active role in the New Jersey Physiomesh MCL. Lawyers at the Hollis Law Firm have filed Physiomesh cases in both the MDL and MCL, depending on the specific facts of each plaintiff’s Physiomesh lawsuit. The Physiomesh lawsuit is against Ethicon, a subsidiary of Johnson & Johnson. The Physiomesh is made from polypropylene and is intended for hernia repair. Ethicon has been battling lawsuits for years against its transvaginal mesh products, which are also made from polypropylene. Ethicon continues to deny the life-threatening complications that polypropylene causes. However, Ethicon issued a market withdrawal on the Physiomesh in May of 2016. The US FDA has NOT Recalled the Physiomesh Contrary to popular belief, the US FDA has not recalled the Physiomesh. Below is an excerpt that the Hollis Law Firm received in September of 2016 from Ethicon’s legal counsel, Butler Snow. A full version of the letter from Butler Snow can be viewed here. Apparently Ethicon didn’t recall the Physiomesh in the United states, because the FDA didn’t require them to. Instead, the FDA allowed Ethicon to perform a market withdrawal. Ethicon “voluntarily withdrew” the Physiomesh after independent studies revealed high rates of complications associated with the Physiomesh. The previous high rates of patient and surgeon complaints were never enough to sway Ethicon or its parent company Johnson & Johnson into removing the Physiomesh from the market. Ethicon and Johnson & Johnson did not want to recall the Physiomesh and lose all of the profits that the Physiomesh was generating. Prior to removing the Physiomesh from the market, Ethicon created the Physiomesh Open in an attempt to fix the defects of the original Physiomesh. Ethicon submitted a 510(k) application for the Physiomesh open on June 12, 2014, and received clearance on October 23, 2014. Ethicon gave the Physiomesh Open about half a year to gain market traction before they finally decided to “voluntarily withdrawal” the regular Physiomesh from the market. What is the Difference Between a Recall and a Market Withdrawal? A recall is to be issued by the company on its own initiative, by FDA request, or by FDA order under statutory authority when the product may cause adverse health consequences. A market withdrawal is appropriate only when there is no evidence of manufacturing or distribution problems. Additionally, safety alerts are sent to hospitals, physicians, and patients to notify them of the potentially dangerous side-effects of a product when it is recalled, but not when a product is simply “withdrawn from the market.” The FDA has three different classification for recalled medical devices. The FDA’s recall definition page can be viewed here and the excerpts are below. Read the definitions below, then the adverse events later in this article, and determine if the FDA was justified in allowing Johnson & Johnson and its subsidiary Ethicon to conduct a market withdrawal instead of a recall. Was a Medical Device Safety Alert Issued in the United States for the Physiomesh? No, a medical device safety alert was never issued in the United States for the Physiomesh. The FDA notes that a medical device safety alert should be issued if a device may present an unreasonable risk of substantial harm. Ethicon, Johnson & Johnson, and the FDA didn’t think that the American public deserved to be made aware of the substantial risk of injury associated with the Physiomesh. However, an urgent field safety notice was issued in Switzerland on May 25, 2016, noting that reoperation and recurrence rates after laparoscopic ventral hernia repair using the Ethicon Physiomesh Composite Mesh were higher than the average rates. Ethicon even believed that the higher rates of reoperation and recurrence could be do the the characteristics of the Physiomesh. Unfortunately, Ethicon admitted to physicians that they were unable to instruct how to reduce the failure rate of the Physiomesh. A full version of the Switzerland urgent field safety notice can be viewed here. After Ethicon withdrew the Physiomesh, the Getinge Group (parent company of Atrium Medical Corporation) sent a letter trying to convince doctors to start using Atrium’s C-Qur Hernia Mesh. Atrium has already faced several lawsuits from the FDA and consumers regarding the C-Qur hernia mesh. Having the Physiomesh off the market is great, but replacing it with another defective hernia mesh does no good. FDA Clearance of Ethicon’s Physiomesh The FDA originally cleared Ethicon’s Physiomesh on April 9, 2010. Ethicon used the FDA 510(k) clearance program for the Physiomesh. The 510(k) clearance program allowed Ethicon to skip rigorous pre-market research and studies, which are required for PreMarket Approval (PMA). Ethicon claimed that the Physiomesh was substantially similar to the Proceed hernia patch, which Ethicon also manufactures. Ethicon submitted a modified version of the Physiomesh (Physiomesh Open) for FDA 510(k) clearance on June 12, 2014. The FDA approved a second model of the Physiomesh on October 23, 2014. However, the FDA noted that 510(k) clearance did not mean that the Physiomesh complied with any Federal statutes, regulations, acts, the FDA or other regulatory agencies. Physiomesh Components Ethicon utilizes a light-weight polypropylene (plastic) to manufacture the base layer (middle) of the Physiomesh. Polypropylene is the same material that Ethicon makes their trans-vaginal mesh and bladder slings from. Ethicon has faced thousands of lawsuits over its trans-vaginal mesh and bladder slings made from polypropylene. Ethicon added an absorbable film coating to each side of a polypropylene sheet to create the Physiomesh. The coating on each side of the Physiomesh is made of polyglecaprone, which is intended to be absorbed by the body after implantation. The polyglecaprone coatings alone are not able to adhere to the polypropylene. A polydioxanone film is utilized on each side of the polypropylene to bond the polyglecaprone coatings to the polypropylene mesh. In total, there are 5 layers to the Physiomesh. Every layer except the polypropylene in the middle of the Physiomesh is intended to be absorbed by the body after implantation. Physiomesh: A Defective Design The Physiomesh is one the most defect hernia meshes that the Hollis Law Firm has investigated to date. Ethicon has been aware that the Physiomesh was defectively designed and dangerous to implant in patients since its creation. There are numerous defects that physicians have been reporting to Ethicon (Johnson & Johnson) and the FDA since the product was released! Below are several design defects of the Physiomesh, backed up by Physician FDA adverse event reports. The Physiomesh is Too Weak, Resulting in Mesh Rupture The Physiomesh utilizes a lighter weight polypropylene than Ethicon previously used it its hernia mesh products. A “light-weight” polypropylene mesh simply means that less polypropylene is utilized to make the mesh. Manufacturers started using less polypropylene in hopes that there would be less complications associated with hernia mesh. The “light-weight” polypropylene is also significantly weaker than the old “heavy-weight” polypropylene. As a result, many patients have experienced the Physiomesh tear apart inside of them. Physicians frequently report patients experiencing their bowels blowing through the middle of the Physiomesh! Somehow, the United States Food and Drug Administration still has NOT recalled the Physiomesh! Is the FDA Aware that the Physiomesh is Too Weak? Dual-Sided Coating Prevents Adequate Incorporation Unlike all other coated hernia meshes, the Physiomesh has a thick coating on both sides of the polypropylene. If the Physiomesh is not coated on both sides, the coating easily slides off of the polypropylene. Utilizing a dual-sided coating enabled each coating to stick to the other coating and not just the polypropylene. The coating is intended to prevent the bowel from being exposed to the underlying polypropylene. Polypropylene will essentially stick or adhere to any tissue or organs in the human body. If the polypropylene sticks to the bowel, it can cause severe injuries such as a bowel obstruction. However, if a mesh is coated on both sides, the mesh will not properly incorporate into the abdominal wall. The inability of the Physiomesh to properly incorporate results in the mesh free floating and moving around in the patient’s abdominal cavity. Hernia recurrence, severe pain, and even bowel complications are common in patients in which the Physiomesh fails to incorporate. Is the FDA Aware that the Dual-Sided Coating Prevents Incorporation? Coating Does Not Protect the Bowel from Adhesion Formation Our hernia mesh lawyers learned something very significant from the Physiomesh; it takes less inflammation/irritation for adhesions to form between the mesh and the bowel than it does for the mesh to incorporate into the abdominal wall. Adhesions and incorporation are describing the same process, the development of internal scar tissue, occurring on opposite sides of the mesh. The bowel is much more sensitive than the abdominal wall, and as a result, scar tissue forms easier between the mesh and bowel than the mesh and abdominal wall. This was something that initially surprised both our hernia mesh attorneys and our medical experts. It intuitively makes sense that the bowel would be more sensitive to scar tissue formation, but somehow it’s something that’s not been previously studied. Regardless, the physician adverse event reports to the FDA supply all the necessary evidence. Is the FDA Aware that the Physiomesh’s Coating is Ineffective? Apr 2017: Physiomesh FDA Adverse Event Report MDR# 6465145 “Six weeks later the patient was sent to pain management due to continuing serious pain. In 2014 the patient was rushed to er due to incarcerated loop of small bowel within ventral hernia and the mesh… Patient has been on disability since 2012 and had to go to pain management for seven years.” Physiomesh FDA Adverse Event Report MDR# 6465145 “Six weeks later the patient was sent to pain management due to continuing serious pain. In 2014 the patient was rushed to er due to since 2012 and had to go to pain management for seven years.” Jan 2017: Physiomesh FDA Adverse Event Report MDR# 6264418 “Within a week or two after the procedure, the patient was seeing a doctor for abdominal pain. In 2016, the patient developed severe abdominal pain after eating and ct scan of abdomen showed a partial small bowel obstruction. The patient was admitted for observation and treatment with hydrated iv antibiotics. Five days later the patient required exploratory laparotomy. Surgical findings were acute and chronic inflammation, multiple adhesions, hemorrhage and ischemia in the small bowel. During the open bowel resection, ninety centimeters of small bowel was removed. The patient was on pca dilaudid for four days. Weight loss was twenty five pounds…. The patient is still not feeling well with episodes of vomiting.” Physiomesh FDA Adverse Event Report MDR# 6264418 “Within a week or two after the procedure, the patient was seeing a doctor for abdominal pain. In 2016, the patient developed severe abdominal pain after eating and ct scan of abdomen showed a The patient was admitted for observation and treatment with hydrated iv antibiotics. Five days later the patient required exploratory laparotomy. Surgical findings were acute and chronic inflammation, multiple adhesions, hemorrhage and ischemia in the small bowel. During the The patient was on pca dilaudid for four days. Weight loss was twenty five pounds…. The patient is still not feeling well with episodes of vomiting.” Oct 2016: Physiomesh FDA Adverse Event Report MDR# 6057564 “Hospitalization was prolonged for the patient who possibly developed severe complications requiring operation. During reoperation, loose adhesions of the greater omentum to the upper edge of the mesh and tangential to its surface were found.” Physiomesh FDA Adverse Event Report MDR# 6057564 “Hospitalization was prolonged for the patient who possibly developed During reoperation, and tangential to its surface were found.” May 2016: Physiomesh FDA Adverse Event Report MDR# 5650261 “Six months after surgery, the patient experienced severe stomach pains… it was noted that the small intestine was stuck to the mesh.” Prone to Folding Over After Center Stripe Degrades Medical device manufacturers are also obligated to inform the FDA when studies or literature reveal complications or defects in their products. In November of 2015, Ethicon reported a literature review to the FDA. In the study, a patient experienced bowel complications after being implanted with the Physiomesh and “adhesions were found on the majority of the mesh surface. Recurrence presented in the long [axis] of the mesh in the line of the stripe built into the mesh… It was opined by the study authors that recurrence occurred at the time point the stripe underwent degradation. It was also opined by the study authors that stiffness of the mesh in the long [axis] could be an independent factor causing recurrence.” Packaging Prone to Micro Perforations and Tears The Physiomesh utilizes a foil package to keep the hernia mesh sterile. The foil packaging of the Physiomesh is prone to excessive wrinkling, which weakens the sterile packaging and allows micro perforations to form. The small holes that form in the sterile packaging of the Physiomesh are extremely hard to detect and greatly increase the risk that a surgeon implants a contaminated medical device. As a result, high rates of infection have been observed with the Physiomesh. As can be seen in the photos, the holes in the packaging of the Physiomesh are difficult to detect until the packaging is held up to a light source. With the packaging defect being so hard to detect, it’s surprising that so many adverse events have been reported on this specific defect. Is the FDA Aware that the Packaging of the Physiomesh is Prone to Micro Perforations? Physiomesh Complications The Physiomesh has been associated with high rates of bowel obstructions, seromas, fistulas, infections, rashes, pain, hernia recurrence, mesh shrinkage, and mesh failure. The hernia recurrence rate is high with the Physiomesh due to poor incorporation and the mesh tearing easily. Subsequent surgeries are typically required due to complications related to the Physiomesh. Scientific Articles on Ethicon’s Physiomesh: June 2017: The Importance of Registries in the Postmarketing Surveillance of Surgical Meshes. Data from the Herniamed German Registry, one of two large independent hernia registries that found high rates of complications associated with Ethicon’s Physiomesh. The analysis compares the 1-year follow-up data collected for all patients with incisional hernia who had undergone elective laparoscopic intraperitoneal only mesh repair either with Physiomesh (n=1380) or with other hernia meshes (n=3834). Patient’s implanted with the Physiomesh were approximately 250% more likely to suffer a hernia recurrence. The study authors concluded by noting “The importance of real-world data for postmarketing surveillance of surgical meshes has been demonstrated in this registry-based study. Randomized controlled trials are needed for premarket approval of new devices. The role of sponsorship of device studies by the manufacturing company must be taken into account. August 2016: Tissue Integration and Inflammatory Reaction in Full-Thickness Abdominal Wall Repair Using an Innovative Composite Mesh. Physiomesh was compared to two other composite hernia mesh products. The Physiomesh resulted in the development of more seromas and less tissue integration than the other studied hernia mesh products. June 2016: Outcomes of Bridging Versus Mesh Augmentation in Laparoscopic Repair of Small and Medium Midline Ventral Hernias. A study comparing various techniques utilized to close a hernia defect with Physiomesh. Many patients experienced hernia recurrence regardless of the technique utilized. March 2016: Comparison of Two Different Concepts of Mesh and Fixation Technique in Laparoscopic Ventral Hernia Repair: A Randomized Controlled Trial. 25 patients were implanted with Physiomesh. Within 6 months of hernia mesh implantation, 20% of those implanted with Physiomesh had experienced a hernia recurrence in the first 6 months and then the study was terminated. The authors of the study concluded that “Although this clinical trial was terminated prior to the preplanned recruitment goal, the obtained results from the enrolled patients indicate that the [Physiomesh] system associated with significantly greater hernia recurrences and postoperative pain…” August 2015: Long-Term Evaluation of Adhesion Formation and Foreign Body Response to Three New Meshes. Physiomesh was compared to two other new hernia mesh products. Physiomesh demonstrated significantly lower incorporation strengths than the other hernia mesh products. Fractioning of the the Physiomesh coating was also observed over time, which lead to scar plate formation, but little to no abdominal wall adherence. October 2014: Biaxial Analysis of Synthetic Scaffolds for Hernia Repair Demonstrates Variability in Mechanical Anisotropy, Non-Linearity and Hysteresis. The mechanical properties 13 hernia mesh products were evaluated, including Physiomesh. Significant differences were observed depending on which mesh was implanted and how it was secured. The authors noted that hernia mesh materials are currently utilized as if they are uniform and interchangeable, when that is simply not the case. Additional instructions and training from Ethicon could have resulted more successful hernia repairs. October 2013: Ventralight ST and SorbaFix Versus Physiomesh and Securestrap in a Porcine Model. 5 animals were implanted with Physiomesh and 5 animals were implanted with Ventralight. Animals implanted with Physiomesh exhibited significantly more inflammation, fibrosis, and hemorrhage. Sept 2012: Biomechanical and Histological Evaluation of Abdominal Wall Compliance with Intraperitoneal Onlay Mesh Implants in Rabbits: A Comparison of Six Different State-of-the-Art Meshes The Physiomesh was found to be the least comfortable of the six hernia meshes. Should the FDA Recall the Physiomesh? After reviewing all of the above information, what do you think? Was the FDA justified in allowing Johnson & Johnson and Ethicon to conduct a market withdrawal instead of recalling the Physiomesh? Remember, a market withdrawal is only appropriate if there is no evidence of a defect. If you think that the FDA should have recalled the Physiomesh, let us and everyone else know by sharing this page on social media and commenting that the FDA should recall the Physiomesh on our Physiomesh YouTube video. Additionally, call your state representatives and other elected officials, and ask them why the FDA is protecting Johnson & Johnson instead of the public. The FDA must be reformed or the American public will lose even more faith in our medical industry. Physiomesh Device Tags (Product Stickers) The hernia mesh device tags are necessary to prove which hernia mesh was utilized during an operation. It is not uncommon for an operative report to use a generic name instead of the brand name when describing a hernia mesh. Many surgeons use the name of a company’s original polypropylene mesh to describe any hernia mesh made by that company. For instance, some surgeons will call all Ethicon hernia meshes “prolene” and all Bard Davol hernia meshes “marlex.” There are so many new hernia meshes constantly coming to the market that many surgeons can’t even remember which one they are implanting. Device tags are not always easy to locate. Some hospitals do not maintain or include device tags as part of the medical record chart. At times, it is necessary to contact the surgical department directly. Obtaining medical device tags can be a frustrating and time consuming process, luckily the Hollis Law Firm has staff trained and experienced in tracking down medical device tags. Device tags are also known as “product stickers” and the “Product Traceability Label.” The device tags note that Ethicon is the manufacturer of the Physiomesh. This particular Physiomesh was 15x20cm. The PHY1520V is the catalog number (also known as the reference number), which is used for when ordering a particular Physiomesh. The expiration date for this Physiomesh was October, 2014. This Physiomesh’s LOT number was EM8DDQA0. The LOT number corresponds to a group of Physiomeshes that were manufactured at a particular location at a particular time. LOT numbers are useful in determining if a product defect is an isolated incident or a systemic problem. The Physiomesh’s defects are a systemic problem. Johnson and Johnson’s subsidiary Ethicon withdrew all LOT numbers of the Physiomesh from the market. The Hollis Law Firm’s Physiomesh lawyers are reviewing injuries associated with all Physiomesh LOT numbers. Physiomesh: Ethicon Hernia Mesh Lawsuit Please call us to speak to one of our trained hernia mesh team members. An attorney and a medical professional will look over your Physiomesh case and let you know what they believe the best course of action is for you. The specific facts of your lawsuit will determine if your lawsuit is compensable and to what amount. The Hollis Law Firm represents hernia mesh victims nationwide. All case evaluations and consultations are FREE, CONFIDENTIAL, and carry NO RISK or OBLIGATION. Call 1-800-701-3672 for an Ethicon Physiomesh lawsuit evaluation. Physiomesh lawsuits are starting to mount across the nation. Many attorneys have finally realized that the Physiomesh is a defective hernia mesh. The hernia mesh lawyers at the Hollis Law Firm understand that the problem is larger than just Physiomesh. Visit our general hernia mesh lawsuit page for more information on other hernia meshes. Follow our Physiomesh Lawyer FaceBook page to stay up-to-date on everything Physiomesh. Content Created By: C. Brett Vaughn RN, BSN, JD
This invention relates generally to corrosion inhibitors and more specifically to the use of additives for extending the effectiveness of acid corrosion inhibitors, particularly in oil field acidizing operations.
By: Michael Feldman Closing the books on 2017, Cray announced one of the worst financial reports in recent memory, reporting a net loss of $133.8 million. It marks the first time since 2009 that the company went into the red and represents the second worst net loss in its history. Revenue took a beating, as well. For 2017, the company took in just $392.5 million– down from $628.6 million it collected in 2016. The last time Cray’s was in this sort of revenue territory was 2012, when it brought in $421.1 million. Some of the poor results can be attributed to a valuation allowance the company decided to apply against all its US deferred tax assets. A new US tax law, known as Tax Cuts and Jobs Act of 2017, has enabled companies to repatriate foreign profits at a low one-time-only corporate tax rate. Cray, as well as other companies, are taking advantage of this provision for their 2017 finances. In Cray’s case, the impact was a charge of $108 million. But that only explains the depth of the losses. The big problem for Cray in 2017 was a sluggish supercomputer market. On the investor call reporting the 2017 financial results, Cray CEO Peter Ungaro characterized what has been going on as a “significant downturn” in the high performance computing space. The downturn, he said, applied across all its market segments and geographies. He attributed the slump to a combination of five factors: a challenging government funding environment worldwide, a slowdown in the pace of technology improvement in processors, an increase in memory costs, a retrenchment in the energy market, and a significant number of large customers that delayed replacing older systems. Regarding the latter, Ungaro noted that many supercomputers in the field are now operating well beyond their typical four-year lifespan. “All told, we believe our target market was down by 60 percent in 2017, when compared to our peak in 2015,” said Ungaro. That was the year the company brought in $724.7 million of revenue. One bright spot for Cray is their growing footprint in the commercial HPC space, which increased on both a dollar basis and as a percentage of revenue. Ungaro noted that Cray finished 2017 with more than 12 percent of its revenue coming from commercial customers – up from single digits in 2016. Another area for optimism is Cray’s continuing dominance of the weather/climate modeling space. Its latest successes in this area are the two multi-petaflop XC40 supercomputers installed in India – one at the Indian Institute of Tropical Meteorology (IITM), in Pune, and the other at the National Centre for Medium Range Weather Forecast (NCMRWF), in Noida. The one in Pune, named Pratyush, is a four-petaflop supercomputer and is now the most powerful system in that country. Another hopeful area is the AI market. Cray’s first big win here was last November, when they announced Samsung had bought a CS-Storm GPU-accelerated cluster to be used for AI and deep learning research workloads, including for systems related to autonomous cars. An unnamed financial service firm also chose a GPU-accelerated CS-Storm for deep learning, which will be used to add more smarts to the company’s casualty and property insurance claims. The data analytics space is another area where Cray is trying to expand its presence, primarily with its Urika-GX system. In 2017, it sold a pair of these to a government agency who apparently needed such platform for its analytics needs. When it comes to future growth, both AI and analytics are recurring themes for Cray, which sees those applications as a way to latch onto markets that are growing a good deal faster than traditional HPC. The same goes for the supercomputer-maker’s expansion into high-performance storage (thanks mainly to the ClusterStor acquisition), the third leg of Cray’s big data strategy. For this year, things are looking up. The company is seeing early signs of a rebound on big systems procurements. Some of that Ungaro attributed to the perception that government budgets in the US and elsewhere appear to be firming up. Overall, they expect to bid on three times as much business this year as they did in 2017. And since Cray’s win rates have historically been quite good, that suggests a lot more revenue would start to enter the pipeline this year. Of course, only a portion of that will be booked for the current year; most of it will be realized in 2019 and beyond. For 2018, the company is projecting it will grow revenue by 10 to 15 percent compared to 2017. Note that that won’t get them back to their 2016 revenue levels and certainly not to their record year of 2015. Nevertheless, it could return Cray to the kind of growth trajectory it enjoyed in the first half of the decade. “We’ll continue to expand on our value proposition as we’ll be refreshing our entire product line in 2018,” said Ungaro. “Stay tuned for more on that in the coming quarters.” Looking further into the future, Cray expects the global push to exascale to help accelerate its momentum into the next decade. Being the only supercomputer specialist left standing, Cray is positioned quite well for the gold rush to exascale. Over the first half of the next decade, we should see multiple machines deployed by all the major powers. And since each of these systems will be worth hundreds of millions of dollars, even a relatively small number of wins would make a big difference to Cray’s bottom line. “It is looking like the supercomputing market is shaping up to be strong over the next several years,” concluded Ungaro. “And with this unique exascale opportunity on top of that, the period from the early 2020s through the mid-2020s may shape up as one of the best high-end supercomputing markets in history.”
The Seven Seas Mariner offers only the most luxurious suites which range between 24m2 and 112m2 and leave nothing to be desired. Every suite has an amazing balcony and walk-in closet along with a safe. In these roomy, stylishly furnished suites you can easily escape the hustle and bustle of the rest of the ship. Dining Information Tantalise your taste buds at one of the four gourmet restaurants on board, where there is everything from regional specialties to International cuisine. Go to the elegant Compass Rose Restaurant, the more casual La Veranda, the Prime 7 classic steak restaurant, the Signatures which is known for its French cuisine or at the Pool Grill for something in between meals. A nice relaxing coffee or snack can be enjoyed at the onboard café, Coffee Connection, or visit one of the other six bars and lounges. Entertainment Thanks to the theatre on board there is never a dull moment. There are phenomenal shows from musicals to cabaret along with artistic performances and the ship’s very own six-piece orchestra. You will find entertainment in the lounges from a number of different musicians which perform every day and then you can visit the nightclub later on in the evening. Activities Aboard the Seven Seas Mariner there is much in the way of leisure of activities. If you prefer to have a more peaceful time on board then visit the well-stocked library where you can read, play a game of chess or rent a DVD. The Connoisseur Club invites you to try a glass of rare, vintage cognac with a particularly superior cigar before venturing into the casino. For those who need to work while on board there are two conference rooms perfect to hold meetings, lectures or other events. There is a special personalised consultation available for those who want information on trips to the destination countries. Wellness and Fitness So that you can still stay healthy on board you can visit the gym, do a few laps on the jogging track or take part in one of the many fitness courses run by qualified instructors. The Canyon Ranch Spaclub offers a wide range of excellent treatments which can be tailored to your personal requirements. Then afterwards why not pay a visit to the salon on board? Features There is a butler service available to those staying in suites of the following categories: Seven Seas, Mariner, Grand and Master. Dress Code During the day time it is perfectly acceptable to wear casual attire but due to the ethos of luxury on board we recommend more formal clothing during meal times. In the evenings it would be advisable for men to come in a suit and women to wear an evening dress. Whilst all information is correct at the time of publication, offers are subject to change. Please note that many of the prices shown on this website are not shown in real time. While we endeavour to keep our pricing as up-to-date as possible, the advertised prices shown here may differ slightly from the live prices in our booking system. Our agency reserves the right to correct errors without penalty.
The global economy took another turn for the worse as Japan plunged into recession following two consecutive quarters of growth. Please consider Japan’s economy shrinks annualized 3.5%. Quote: Japan’s economy shrank an annualised 3.5 per cent between July and September, the steepest decline since the earthquake-hit first quarter of 2011, as exporters suffered big falls in shipments to key markets such as China and Europe. In a speech on Monday, Masaaki Shirakawa, Bank of Japan governor, said there was “no question that the [central bank] should exert every effort to enhance its easing effects as much as possible”. He said domestic demand was “unlikely to increase at a pace that will outperform the weakness in exports”. The Japanese government’s monthly survey of “economy watchers” – which includes barbers, hoteliers, car dealers and others who deal with consumers – has recorded six falls in a row since April. Last month the index stood at a level little better than that of April 2011, in the immediate aftermath of the quake. Japanese manufacturers from Nissan to Shiseido have reported steep falls in sales of their products in China, following a wave of demonstrations against Tokyo’s nationalisation of some of the islands in mid-September. Japan’s top seven automakers have cut their projections for Chinese sales by a fifth, for the fiscal year to March, according to calculations by the Nikkei newspaper. Joe Salerno, in "Gold Standards: True and False," provides some sound guidance on discussion of a return to gold. What is ultimately desired is a return to a market-chosen money, which has historically been a commodity — gold or silver money, not a gold- or silver-"backed" money. Salerno's caution continues to be relevant. He argues, Quote: A significant development in the current controversy over the role of gold in the U.S. monetary system, which has potentially important implications for both monetary theory and policy, has gone largely unnoticed by commentators on both sides of the debate. I am referring to the emergence of a new defense of gold that differs fundamentally from the traditional case for the gold standard. This development has been obscured by the diversity of plans for monetary reform coming out of the pro-gold camp. A close examination of these proposals, however, reveals that they are of two distinct types; they differ not only in the reasons they offer for considering a gold standard desirable, but also in their conception of what monetary arrangements constitute a "gold standard." First, there are the proposals that embody the traditional "hard money" arguments for the gold standard. These arguments focus on the desirability of a free-market commodity money vis-à-vis a government-monopolized paper fiat money. The basic thrust of the hard money proposals is to render government monetary policy superfluous by restoring a genuine gold standard under which the quantity and value of money is determined solely by market forces. The second group of pro-gold writers, whose proposals have received the most publicity, have eschewed the traditional hard-money case for gold and in its stead constructed a quite novel case purporting to demonstrate that gold can provide government monetary authorities with an effective instrument for managing the money-supply process within the established fiat-money framework. For this group, the raison d'être of a gold-based monetary regime is that it facilitates the achievement of government monetary policy objectives. Needless to say, the gold standard envisioned by these policy-oriented advocates differs quite radically from the ideal of the hard-money group. The gold "price rule," which is the monetary reform favored by most policy-oriented gold advocates, bears only a superficial resemblance to the traditional conception of the gold standard. (emphasis added) Good thing that came after 2 quarters of economic growth or they may be in trouble. Not that China's boycott is anything to scoff at, but this is one of those times where I suffer from the American, "I don't give a shit" syndrome. Keep pumping out video games and porn and we don't care how bad your economy is. We'll still buy those two things. __________________''i'm a bi dude!!! take me up the arse while i stick my tongue inside dolf!!!1'' Good thing that came after 2 quarters of economic growth or they may be in trouble. Not that China's boycott is anything to scoff at, but this is one of those times where I suffer from the American, "I don't give a shit" syndrome. Keep pumping out video games and porn and we don't care how bad your economy is. We'll still buy those two things. At the same time, in the other thread, you are arguing for devastating economic reforms to the agricultural industry in the name of "getting our food right." Perhaps the problem might be too many altruistic crusaders who do give a shit about their various social causes, like controlling what people eat through taxation, regulation, and a return to a more primitive, communal lifestyle... One of the most common reasons why fortune can turn into misfortune is that the long-term consequences of the apparent good luck are very expensive. This idea is embodied in a chess concept of the “poisoned pawn,” where you are offered a free pawn in exchange for creating a fatal flaw in your position. It’s an experience many American students know about. Quote: If student loans are good debt, how do you account for the reaction of Christina Mills, 30, of Minneapolis, when she found out her payment on college and law school loans would be $1,400 a month? “I just went into the car and started sobbing,” says Mills, who works for a nonprofit. “It was more than my paycheck at the time.” Medical student Thomas Smith, 25, of Hamilton, N.J., is $310,000 in debt and is struggling to make ends meet even before beginning to repay his loans. “I don’t even know what I eat,” he says. “I just go to the supermarket and buy the cheapest thing I can and buy as much of it as I can.” Then there’s Michael DiPietro, 25, of Brooklyn, who accumulated about $100,000 in debt while getting a bachelor’s degree in fashion, sculpture, and performance, and spent the next two years waiting tables. He has since landed a fundraising job in the arts but still has no idea how he will pay back all that money. “I’ve come to the conclusion that it’s an obsolete idea that a college education is like your golden ticket,” DiPietro says. “It’s an idea that an older generation holds on to.” At the same time, in the other thread, you are arguing for devastating economic reforms to the agricultural industry in the name of "getting our food right." Perhaps the problem might be too many altruistic crusaders who do give a shit about their various social causes, like controlling what people eat through taxation, regulation, and a return to a more primitive, communal lifestyle... You don't understand any more about international economics then you do about agriculture. This isn't about a gold standard, it's about a boycott from one of their biggest buyers. It's not really worth it to talk to you, because you're incapable of seeing anything. Yes, we need to feed people. Japan's not our problem. And they're cool. Their economy isn't perfect, but it's not devastated. Jesus Christ, look at the world around you. The amount of stupidity that you inflict is crippling sometimes. __________________''i'm a bi dude!!! take me up the arse while i stick my tongue inside dolf!!!1'' At the same time, in the other thread, you are arguing for devastating economic reforms to the agricultural industry in the name of "getting our food right." Perhaps the problem might be too many altruistic crusaders who do give a shit about their various social causes, like controlling what people eat through taxation, regulation, and a return to a more primitive, communal lifestyle... Nothing wrong with that. I still can't believe the majority of Californians voted against knowing what the hell big companies are putting into their food. Like one of the only things liberalism usually stands for that is actually a good thing and it lost??? You don't understand any more about international economics then you do about agriculture. This isn't about a gold standard, it's about a boycott from one of their biggest buyers. It's not really worth it to talk to you, because you're incapable of seeing anything. Yes, we need to feed people. Japan's not our problem. And they're cool. Their economy isn't perfect, but it's not devastated. Jesus Christ, look at the world around you. The amount of stupidity that you inflict is crippling sometimes. You claim to be some loser from a trailer in Kentucky and yet you know everything there is about global economics? More stupid Brooklyn people: Then there’s Michael DiPietro, 25, of Brooklyn, who accumulated about $100,000 in debt while getting a bachelor’s degree in fashion, sculpture, and performance, and spent the next two years waiting tables. He has since landed a fundraising job in the arts but still has no idea how he will pay back all that money. “I’ve come to the conclusion that it’s an obsolete idea that a college education is like your golden ticket,” DiPietro says. “It’s an idea that an older generation holds on to.” You don't understand any more about international economics then you do about agriculture. This isn't about a gold standard, it's about a boycott from one of their biggest buyers. It's not really worth it to talk to you, because you're incapable of seeing anything. Yes, we need to feed people. Japan's not our problem. And they're cool. Their economy isn't perfect, but it's not devastated. Jesus Christ, look at the world around you. The amount of stupidity that you inflict is crippling sometimes. There is no such fucking thing as "International Economics." I am old enough remember not just the panic that Japan was going to buy us out but also when plastics used to be synonymous with "cheap" and "Made in Japan." I hardly think that you are in the position to get all pissy and begin handing out labels. More stupid Brooklyn people: Then there’s Michael DiPietro, 25, of Brooklyn, who accumulated about $100,000 in debt while getting a bachelor’s degree in fashion, sculpture, and performance, and spent the next two years waiting tables. He has since landed a fundraising job in the arts but still has no idea how he will pay back all that money. “I’ve come to the conclusion that it’s an obsolete idea that a college education is like your golden ticket,” DiPietro says. “It’s an idea that an older generation holds on to.” Did he think there were, like, a ton of jobs in that field? I will bet that that never crossed his mind as he took advantage of his "right" to an education. What really pisses me completely off about The Peoples Democratic Republic of Kalafornia.... All those fuckers voted for this ruination of that state... Now like fucking vermin....there leaving in droves. Only to land in some nice quiet burg....where they will set a course to fuck that town, county and state UP. If you move from PDRK.... Leave your Marxism at the state line.... else wise.... You voted for it....YOU SUFFER WITH IT. Prop30, step 4 to Barry'O' bail-out. One lining for it.... With Barry'O' Goose stepping back into the Why Howz.... All but those bitter-clinger states could be PDRK lite. __________________An Armed man is a citizen. A disarmed man lives in Kalafornia, Chicago, New York, Colorado.... I've interviewed thousands of people and read ten times as many resumes over the years, and I came to the conclusion a long time ago that too many people were going to college. They had access to what will turn out to be free taxpayer money to attend schools that wouldn't exist if it weren't for student loans. These 3rd and 4th tier colleges have no academic standards as long as their students can fork over their tuition. They hand out meaningless degrees and turn out graduates like a sausage factory. Too many of these people can't read, can't spell, or have poor communication skills which automatically disqualify them from the fields they were pursuing in college. It's nothing more than a scam. I've interviewed thousands of people and read ten times as many resumes over the years, and I came to the conclusion a long time ago that too many people were going to college. They had access to what will turn out to be free taxpayer money to attend schools that wouldn't exist if it weren't for student loans. These 3rd and 4th tier colleges have no academic standards as long as their students can fork over their tuition. They hand out meaningless degrees and turn out graduates like a sausage factory. Too many of these people can't read, can't spell, or have poor communication skills which automatically disqualify them from the fields they were pursuing in college. It's nothing more than a scam. I've interviewed thousands of people and read ten times as many resumes over the years, and I came to the conclusion a long time ago that too many people were going to college. They had access to what will turn out to be free taxpayer money to attend schools that wouldn't exist if it weren't for student loans. These 3rd and 4th tier colleges have no academic standards as long as their students can fork over their tuition. They hand out meaningless degrees and turn out graduates like a sausage factory. Too many of these people can't read, can't spell, or have poor communication skills which automatically disqualify them from the fields they were pursuing in college. It's nothing more than a scam. In how many threads have I railed about the same theme you're presenting here? Those colleges have had to dumb down the curricula in order to take advantage of all that 'free' money the government was handing out. And as the student ranks swelled they merely followed the laws of supply and demand and raised their tuition's. And people sit around and grouse about the results as shown in the examples above. It's easy for the nay-Sayers to point to those examples as the exceptions, mere anecdotal fluff thrown around to make a point. Unfortunately those 'anecdotal' stories are proving to be the rule and the success stories are the exceptions. The entire premise of government subsidized higher education is built on the success of the post WWII GI bill. Which was an unqualified success due in part to two particular aspects of the bill. The first being that it was NOT open to everyone and the second being that the colleges did not adjust their standards downwards to try to capture the 'windfall profits' associated with the program. (Nor did they immediately ramp up courses in fringe degree programs, which few, if any, served any legitimate societal need.) The entire model is as bad as the Social Security model, a snake swallowing it's own tail with the student becoming mere fodder for the system. Young people spending valuable working years studying some specialty in which they will never be gainfully employed. Compounding all of this is the fact that the so much value is placed on this 'higher education' that the colleges are quickly becoming mere 'finishing schools' for the public education sector. Students are having to spend their first semester, and in some cases their first year, taking college courses that are essentially teaching what they should have learned in High School. And High School diplomas have become nothing more than really bad jokes. And education is but one of the many 'causes' that the liberal continually offers up the same solution......"more money." If it were merely a matter of money most of our social ills would have disappeared long ago. Ishmael __________________ “The American Republic will endure until the day Congress discovers that it can bribe the public with the public's money.” ― Alexis de Tocqueville I've interviewed thousands of people and read ten times as many resumes over the years, and I came to the conclusion a long time ago that too many people were going to college. They had access to what will turn out to be free taxpayer money to attend schools that wouldn't exist if it weren't for student loans. These 3rd and 4th tier colleges have no academic standards as long as their students can fork over their tuition. They hand out meaningless degrees and turn out graduates like a sausage factory. Too many of these people can't read, can't spell, or have poor communication skills which automatically disqualify them from the fields they were pursuing in college. It's nothing more than a scam. when I first started teaching in College I actually believed that MOST were not equipped to attend and do so JUST FOR THE GIVEAWAYS Indeed, they stayed as long as teh handouts lasted and if you were BLACK and LATINO.....in NY....you would see people in the 30's and early 40's STILL in school, no major, collecting monthly checks Location: Don't let the sun burn a hole in your ass, William Blake: rise now, and drive your cart and plow over the bones of the dead! Posts: 71,876 Quote: Originally Posted by renard_ruse Nothing wrong with that. I still can't believe the majority of Californians voted against knowing what the hell big companies are putting into their food. Like one of the only things liberalism usually stands for that is actually a good thing and it lost???
Join AIYA QLD! The Australia-Indonesia Youth Association (AIYA) - Queensland... Chapter is looking for new team members to join the committee. Check out the open job descriptions and find out how you can apply here. Yuk! buff.ly/2v78MVXpic.twitter.com/LQOaTRfYLa Canberra, 23 May – Come to AIYA ACT’s annual Networking Night! Held in the Indonesian Embassy, mingle between students and professionals, create networks, and be inspired by the benefits of studying Indonesian! buff.ly/2IEYXnIpic.twitter.com/eyPCbKTyv8 Blog This is the third and last movie screened during the Indonesian Film Festival (IFF) 2018 to be reviewed on the AIYA Blog. View the first two reviews here and here. Themes: rape, gore and violence. Potential spoilers ahead. The premise is simple. A woman beheads the head of her rapist and tries to report the crime to the police, using the man’s head as evidence. The story then unfolds, and Marlina presents us the pains and struggles that are all too familiar to women, in four acts. I’ll be the most miserable woman tonight. Marlina (Marsha Timothy) lives alone in remote Sumba. One day, a man named Markus comes to her house unannounced, nonchalantly telling her that his cronies will come and raid her place, take her livestock, and sleep with her – all seven of them. There is an air of arrogance and entitlement about Markus; he does not bother to make eye contact with Marlina and his voice is strikingly calm for his stereotypically violent character. Markus’ cronies later arrive, and Marlina manages to poison all except two of them and beheads Markus, while being raped. She carries Markus’ head to the police station the next day, encountering her pregnant friend Novi along the way and escaping the remaining of Markus’ cronies who seek to retrieve his head. Being set in Sumba, the movie’s cinematography is astounding. A lot of meticulous care was ostensibly put into it, as a lot of scenery matches the themes of the movie; locations are displayed as arid and unfriendly, yet whimsical. The devil was definitely in the detail as well. The characters speak with a Sumba accent and the plot revolves heavily on the Sumba culture of burying the departed as a ‘whole perfection’, a reason why Markus’ cronies are so desperate to retrieve his head. As she journeys through Sumba, all of Marlina’s emotional turmoil culminates in the scene where she breaks down, a scene in which her face is not shown. This is exemplary of Marsha Timothy’s quality acting in the movie, as the scene is arguably as powerful as (if not more powerful than) the many close-ups of her face in the movie, in which the audience can clearly see the subtle changes in her emotions as the plot thickens. The extremely disturbing rape scene was also exceptionally done, and the sudden heavy atmosphere in the cinema became unbearably palpable. Nonetheless, there is humour in Marlina. The struggles burdened by the women in Marlina are shared with the other women in the movie through mutual understanding. There is one comical scene, a breath of fresh air, in which one elderly lady is giving her traditional ‘wisdom’ on giving birth to Novi, unfazed by the body-less head being carried around by Marlina. In the seemingly inhospitable Sumba, these women manage to encourage and empower each other in their own ways. Marlina the Murderer in Four Acts delivers. This ‘satay western’ explores challenges and inequality, revenge and female empowerment against a breathtaking Sumba setting. As the credits rolled, there was a sense of relief in the air; Markus and his cronies were, in the end, more miserable than Marlina. In the news Estimates suggest that of the 1,000 fighters which have travelled to the Middle East from SE Asia to join the Islamic State in the last five years, 700 have come from Indonesia. Such figures indicate significant challenges faced by the Indonesian government to curb the threat of returning foreign fighters as well as the threat of homegrown violent extremism. Indonesia has experienced an outburst of extreme terrorist violence, this time, with a confronting twist: family suicide bombers. The Lowy Institute’s Sidney Jones unpacks how ISIS has turned jihad into a family affair. The authoritarian Soeharto regime sought to privilege a small number of business tycoons. Indonesia at Melbourne investigates what has happened to Soeharto’s cronies and their current relationship to power to mark the 20-year anniversary of the fall of the New Order regime. Foreigners working in Indonesia make up just a fraction of its population (0.04%). Yet, employing foreign workers is a topic that divides the nation, making it the perfect issue ahead of the 2019 presidential election campaign. The term “unicorn” is used to describe digital startups in Indonesia as they constitute magical entities with amazing capabilities. The Jakarta Post reports on the latest Indonesian summit, attended by the Communications and Information Minister Rudiantara where he appointed four ‘virtual ambassadors’ who he considers to be pioneers of Indonesia’s digital economy. Last Friday, Mt Merapi in Central Java erupted, with local residents being told to evacuate the area. Minor tremors were also felt in surrounding areas including Surakarta, Boyolali and Klaten. Grab your tickets using the above links to secure your spot! For any questions about any of the screenings, please contact your local chapter. Other events: Sydney, TONIGHT – Join the Sydney Southeast Asia Centre’s annual Politics in Action Forum, bringing political updates from Southeast Asia to researchers and practitioners from across the disciplines and beyond. Sydney, 19 May- The Indonesian Students’ Association (PPIA) at University of New South Wales are excited to host another ICON, or Indonesian Ideas Conference, later this May. For more information about this year’s theme, it’s exciting lineup of conference speakers and to purchase tickets, head to the event page! Canberra, 23 May – Come to AIYA ACT’s annual Networking Night! Held in the Indonesian Embassy, mingle between students and professionals, create networks, and be inspired by the benefits of studying Indonesian! Sydney, 26 May – Come see EPILOGUE, an original musical production created and performed by members the University of Technology Sydney’s Indonesian Student Association (PPIA) on 26 May at the UTS Great Hall, Ultimo. Click here for tickets! Sydney, 26 May – Attend the launch of Call Me A Winner, the first book by Indonesian writer Novia Myta. It will be held at the Love Life Store, 78 Queen Street, Concord West at 10am. Register now as spots are limited! Opportunities International Internships is seeking a new Indonesia Program Facilitator. You will help deliver and support International Internships’ Indonesia-based programs including study intensives and internships. The position is based in Jakarta and commences in June 2018. For more information, click here! Indonesian teachers wanted! Wonthaggi Secondary College is seeking two Indonesian teachers. The roles are for an Indonesian/English teacher (graduate, ongoing) and an Indonesian/second subject TBA (contract). The school is located in picturesque South East Gippsland in the town of Wonthaggi. If you’re interested check out Recruitment Online or contact Kate Hill: hill.katherine.d@edumail.vic.gov.au. A University of Adelaide student is completing a research unit, looking at AIYA as an actor in the Australia-Indonesia relationship. If you would like to contribute and have 5 minutes to spare, please fill out the survey. Are you a youth leader (21-35 years old) in the Australia-Indonesia space? CAUSINDY wants you for its annual youth conference! This year’s program will be held from 5-8 September in Makassar, the vibrant maritime capital of South Sulawesi and gateway to eastern Indonesia. Applications close 4 June 2018. Don’t miss out! Indonesia Development Forum (Jakarta, 10-11 July 2018) is hosting a competition to tackle regional disparities across the Indonesian archipelago. You must submit either a blog, vlog, or infographic which discusses how you would overcome regional inequalities (#AtasiKesenjangan) in Indonesia?’ Join AIYA NSW! AIYA NSW is on the hunt for new executive committee members. Positions available include: Treasurer, Professional Programs Offer, Communications Team Member(s), Education Team Member(s), Socio-cultural Team Member(s) and Professional Programs Team Member(s). See the full position description here. If you have any questions, please email nsw@aiya.org.au. Applications are due Friday 25 May 2018, 11:59pm. Jokowi may be without a challenger in the next presidential election. Whilst Prabowo Subianto, the 2014 runner-up, has accepted his party’s endorsement, it is unclear whether he can assemble a viable coalition as the August deadline looms. However, the potential lack of a challenger raises serious questions about the health of Indonesia’s democracy. Recent research has revealed Indonesia’s enormous capacity to store electricity generated from renewable sources such as solar and wind through pumped hydro energy storage (PHES). Most excitingly, the research suggests Indonesia has more than enough PHES sites to support a 100% renewable energy grid. The Lowy Institute has recently published its 2018 Asian Power Index. It reports that Indonesia’s economy is projected to overtake Japan’s and Russia’s by 2030. Head to their interactive website to analyse power distributions in the region. Amidst the political and economic turmoil that lead to Soeharto’s demise in 1998, it was the property and businesses of ethnic Chinese Indonesian who were most frequently targeted by rioters. Jemma Purdey assesses the likelihood such violence will reappear in Indonesia, especially leading up to the 2019 presidential election. Indonesia’s higher education is falling behind in global rankings and remains highly concentrated within Java. These issues need to be tackled hand-in-hand if Indonesia wishes to properly reform its higher education system. The founder of ACICIS, David Hill is retiring in July. In an interview, he shares his concern about reluctance of Australian universities’ to permit students to study in Indonesia for part of their degrees and well as the dwindling number of Australian students studying the Indonesian language. On the blog This week, Amelinda Devina Tjoadri reviews the film ‘Pengabdi Setan’ (Satan’s Slaves), a remake of the 1982 original and the latest film by director Joko Anwar to have stunned Indonesian audiences. Check it out! Events AIYA is proud to announce that our chapters are hosting screenings of the incredible Indonesian documentary, Banda: The Dark Forgotten Trail, across Australia. Grab your tickets using the above links to secure your spot! For any questions about any of the screenings, please contact your local chapter. AsiaLink Business is hosting ‘#ASEANinAus: The next steps in seizing the digital opportunity’: A series of pop-forums in Melbourne, Sydney and Brisbane exploring how sunrise industries are transforming SE Asia’s economic, consumer and social landscapes and how Australian organisations and innovators can connect into the region’s rapidly evolving and dynamic digital architecture. If you’re interested, get your tickets using the links below! Perth, TONIGHT – AIYA WA hosts a live stream of the opening night performances of the First International Gathering of Indigenous Peoples in Ubud, Bali, Indonesia (Indigenous Celebration Bali). The event will be held at Murdoch Guild Tavern, Murdoch University at 6pm. Head to the event page to get your tickets! Melbourne, 15 May – ACICIS and AIYA Victoria are pleased to present a networking event and catch-up for Melbourne-based alumni of the Australian Consortium for ‘In-Country’ Indonesian Studies. Reuni, yuk! Yogyakarta, 16 May – AIYA Yogyakarta are hosting their final language exchange for the semester. Come along to the AOA Resto and Creative Space, Depok at 3:30pm to join in! Melbourne, 16 May – Join AIYA Victoria for another language exchange, held at RMIT Swanston Academic Building 80, 6pm. Sydney, 18 May – Join the Sydney Southeast Asia Centre’s annual Politics in Action Forum, bringing political updates from Southeast Asia to researchers and practitioners from across the disciplines and beyond. Sydney, 19 May- The Indonesian Students’ Association (PPIA) at University of New South Wales are excited to host another ICON, or Indonesian Ideas Conference, later this May. For more information about this year’s theme, it’s exciting lineup of conference speakers and to purchase tickets, head to the event page! Canberra, 23 May – Come to AIYA ACT’s annual Networking Night! Held in the Indonesian Embassy, mingle between students and professionals, create networks, and be inspired by the benefits of studying Indonesian! Sydney, 26 May – Come see EPILOGUE, an original musical production created and performed by members the University of Technology Sydney’s Indonesian Student Association (PPIA) on 26 May at the UTS Great Hall, Ultimo. Click here for tickets! Sydney, 26 May – Attend the launch of Call Me A Winner, the first book by Indonesian writer Novia Myta. It will be held at the Love Life Store, 78 Queen Street, Concord West at 10am. Register now as spots are limited! Opportunities Join the Asialink’s team in Sydney! Every year Asialink Business’ Sydney office offers a fantastic internship opportunity to the AIYA network. Click here for more information on the position. Application date has now been EXTENDED to May 12, 11:59pm. Join AIYA Jakarta! Join the AGM for AIYA Jakarta and become part of the committee! AGM will commence at 5:30pm, 17 May and will be held at Gado-Gado Boplo, Menteng. Please send expressions of interest and CV to jakarta@aiya.org.auprior to the AGM. Join AIYA NSW!AIYA NSW is on the hunt for new executive committee members. Positions available include: Treasurer, Professional Programs Offer, Social Media Manager, Marketing Manager, Education Team Member(s), Socio-cultural Team Member(s) and Professional Programs Team Member(s). See full position description here. If you have any questions, please email nsw@aiya.org.au. Applications are due Friday 25 May 2018, 11:59pm. A sunny Saturday afternoon spent indoors all suited up and shoulder-to-shoulder with strangers seems like a mediocre event. But PPIA Monash’s Australia Indonesia Business Conference (AIBC) at Monash University Conference Centre was anything but that! The inspiring lineup of speakers guided us all through the tasks for the day (21/04): breaking barriers and building connections. After the opening address and welcome, everyone headed off to hear from speakers in one of two panel rooms. I was fortunate enough to hear from 2Tor Co-Founder Lawrence Tann and AIC Engagement Coordinator Ghian Tjandaputra. From b-boy to 2tor Lawrence focused on how he found the courage to start his own successful business called 2Tor, an app for peer-to-peer mentoring. Dressed in a smart white shirt, he surprised us all in explaining how his idea for this newly launched app came from breakdancing. As a b-boy (break-dancer) he wanted to help his friends get recognised and find work. From this humble beginning he was quickly shut down because the idea was too niche. Along with friends, he went away and took on a ‘normal’ office job, but just could not let go. They took their Monash business studies to task and built a business case and plan which lead to successful seed funding. Now, they have 4,000 pre-registered tutors eager to teach what they know across Melbourne. 2tor is focused on making sure these people are quality and safe while rolling the company out. Lawrence said he broke into this space by never giving up and staying humble. This ensured he continued to build a community to support his app and personal growth. From student to diplomat After a bite for morning tea and a chat with new friends, I sat with Ghian from AIC for his talk. He provided a lively talk that went to space with Elon Musk before finding his ikagai (which is Japanese for purpose based on a very intersectional approach). Ghian got the audience to question their bias through Musk’s ‘first principles thinking’ approach. From this interrogation of fundamentals Ghian elaborated on how he applied this to question his own assumptions about seemingly being fated to go from Monash directly to Indonesian Government diplomat. In question time, Ghian elaborated that nine years of being outside Indonesia has been important in developing the critical distance needed to see the first principles of his thinking. This made it easier to establish ikagai, which is about more than passion. He emphasised that people need to do more than do what they want to do – do what you enjoy and help the world. Using this nuanced self-awareness, he has launched into a four-year (and counting) career with the AIC, diplomatically strengthening the bilateral relationship. Further crowd questions uncovered that his key value is diversity; this has enriched his ability to embrace different people and ideas in his work. Diversity and community launched these two careers through persistent barriers. “Failure is learning, and humility is hunger” Meanwhile, AIYA Victoria President Stephen Sebastian Tedja listened to innovator and businessman Alexander Rusli, before we both sat down with him for his thoughts on breaking barriers at the end of the evening. This was an exciting talk that covered his interesting career, tips for students and graduates plus some ideas on the Australian-Indonesian relationship. Alex has worked in many different companies and industries, liking being someone who solves problems by taking action. Alex explained how opportunity and personal interest drove him to move between diverse roles, including as Australian academic, Indonesian government advisor, technology innovator and more. Alex enjoys using quick concrete decisions to be constantly impactful by addressing core issues. An awareness of the market is essential, which is why he praised government culture shifts that promote people faster so they are better able to make realistic changes for Indonesia. This man of action stressed that failure is learning, experience is growing, and humility is hunger. These three maxims combine to make a graduate a powerful recruit who adds value to an organisation. His other ingredient is speed; the world is fast, so make mistakes quickly, learn quicker and get the next opportunity faster. Alex stated “the fear of failure needs to be erased … to pivot quickly” towards the next opportunity. He also stressed that if you aren’t working, make plans and connections constantly – just like the conference attendees. Alex emphasised that students must balance study with getting on-the-ground insights; study and then work to chase your passions with experience. Building resilience through shared communities After a short snack and room change we were back to the plenary to be delighted by Monash Business School’s Director of Engagement Professor Edward Buckingham. Despite the casual presentation sprinkled with Indonesian and Mandarin, he gave our minds some serious work. Everyone explored Donald Rumsfield’s known-unknown matrix to build strategies that get us out of routines and address the unpredictable. Professor Buckingham urged the students to find commonality in the uncommon, to go beyond their familiar friends, and to seek new experiences. Professor Buckingham closed with how getting of your comfort zone is about getting in touch with ideas you have not thought of before. Transforming the uncomfortable and the unknown is the professor’s advice to break barriers. AIYA later chatted with him and focused on strategies to build resilience through shared communities. He discussed how getting in early with a network like AIYA is important to make lasting connections. This gives students the opportunity to have new experiences they would have never dreamed of, and also to build resilience. He added that sometimes, diving into the deep end can be too much, so you need to know your boundaries and be aware of others’ limits too. His advice is for students to record their experiences, set regular goals to expand their world, and reflect on change often. More poor Indonesians than the Australian population The day didn’t end there! Pak Eko Putro Sandjojo, Indonesia Minister of Village Development, Disadvantages, Regions and Transportation, captivated the crowd with a detailed explanation of his Ministry’s work. Pak Sandjojo made it quickly clear that he is a hard-headed man with a head for facts. He draws motivation to act from the fact that more Indonesians live in poverty than the population of Australia. His passion keeps him calm under immense pressure. Mr Sandjojo stamped out corruption in his own department, lifting them up national public service ranks and gaining acclamation. One thousand employees were found corrupt according to an official investigation. He had no problem standing by his decision, which is admirable given the months of protests and legal proceedings against him. Mr Sandjojo emphasised it is up to strong government administration at a village level to lift people out of poverty. That is his focus in delivering training, audits and targeted construction works across Indonesia. Yet just as he focuses on Indonesia beyond the city limits, Jakarta awarded him a prestigious public service medal. They recognise that strong villages reduce the strain on cities like theirs, which are already overworked. He finished with a reminder from Made Utari Rumyanti that it was Kartini Day, and explained how his wife has been instrumental in his extraordinary efforts to break barriers in his work. Final thoughts Over some delicious dinner (thanks Bu Diana!), AIYA got the exclusive chance to chat with Lutfi, PPIA Monash Co-Project Manager for AIBC 2018. The motivated team leader is studying a Bachelor of International Business and Political Science to get a hard start on his future in the Indonesian public service. For Lutfi, this was a chance to get inspired and discover some real skills in project management. Mr Sandjojo made it clear to him that you need to lead with faith and surround yourself with great people to make excellent things happen. This clearly was already in his mind as evidenced by the quality international event- speakers came from across Australia and Indonesia to inspire people on this day. Lutfi made it clear that PPIA Monash has responded to their members interests when selecting this topic. He discussed the trick in balancing studies with passion to make a future for yourself. The idea of getting out of your comfort zone requires breaking barriers such as fear of unknown. That is what Lutfi hopes people got from the conference; a bit of confidence and insight to do what you want to do. With the day done, it was all about what we can do. Going forward, how can we break barriers every day and reach the next goal? If you attended the event, this proved not too hard to do with so much semangat on show and new friends for a passion-filled future. Citarum River is the largest and longest river in West Java but also one of the most polluted in the world. However, a dysfunctional bureaucracy and sectoral ego continue to hinder the implementation of effective, comprehensive clean-up programs to save the live-sustaining Citarum river. Following the arrest of 14 members of the Muslim Cyber Army for defamation, spreading hoaxes and hate speech in March, research conducted by the Southeast Asian Freedom of Expression Network (SAFEnet) sheds light on the strategies and motivations of this nebulous, poorly-understood network. Indonesia at Melbourne is speaking to Muslim feminist Lies Marcoes on her reflections of the reform process, 20 years since the fall of Soeharto and the New Order regime. Read the interview here! Sharing her personal experience, Inna Hudaya discusses how the legal, social and political realities of Indonesia’s abortion laws continue to disenfranchise Indonesian women and may have dangerous consequences for their health and fertility. Three Indonesian cities, Jakarta, Makassar in South Sulawesi and Banyuwangi in East Java are proposed to be included in the ASEAN Smart Cities Network. Its part of a broader effort to encourage the use of technology to advance city designs in ways that accord with the needs and potential of the region. Grab your tickets using the above links to secure your spot! For any questions about any of the screenings, please contact your local chapter. Perth, 4 May – Join AIYA WA for the next business breakfast hosted by Australia Indonesia Business Council (AIBC) with Ambassador to Australia for Indonesia, H.E. Mr Y. Kristiarto S. Legowo and Hon. Bill Johnston MLA will also be addressing this gathering. We look forward to seeing you there! Yogyakarta, 9 May – Come along to the AIYA Yogyakarta Trivia Night to test your knowledge of Indonesia and Australia and compete for ultimate trivia glory! The event will take place from 6:30pm – 8:30pm at Bjong Ngopi Nologaten and is free for members. Ayo! Jawa Barat, 10 May – Join AIYA Jawa Barat for their next Language Exchange to be held at CafeOz in Bandung, from 7-9:30pm. Check out their Facebook or Instagram pages for more details! AsiaLink Business is hosting ‘#ASEANinAus: The next steps in seizing the digital opportunity’: A series of pop-forums in Melbourne, Sydney and Brisbane exploring how sunrise industries are transforming SE Asia’s economic, consumer and social landscapes and how Australian organisations and innovators can connect into the region’s rapidly evolving and dynamic digital architecture. Sydney, 18 May – Join the Sydney Southeast Asia Centre’s annual Politics in Action Forum, bringing political updates from Southeast Asia to researchers and practitioners from across the disciplines and beyond. Canberra, 23 May – Come to AIYA ACT’s annual Networking Night! Held in the Indonesian Embassy, mingle between students and professionals, create networks, and be inspired by the benefits of studying Indonesian! Opportunities Join the Asialink’s team in Sydney! Every year Asialink Business’ Sydney office offers a fantastic internship opportunity to the AIYA network. Click here for more information on the position. Applications close on 6 May. Join AIYA National! We are on the hunt for a Web and IT Officer. Applications are due TODAY, 4 April 2018. Join AIYA Jakarta! AIYA Jakarta is looking to fill the roles of Events Officer, Membership and Partnerships Officer, Treasurer and Secretary, Communications Officer, and General Committee Member at its upcoming AGM in April. If you would like to be part of the AIYA Jakarta team, please send a one-page expression of interest and your CV to jakarta@aiya.org.au. CAUSINDY (Conference of Australian and Indonesian Youth) is looking for passionate young Australian and Indonesian professionals to join the team for the upcoming conference as Chief Comms Officer, Tech Officer, Digital Content Office, and Programs Officer. Check out the job descriptions and how you can apply here. Applications for the AIC’s ReelOzInd! Short Film Festival are now open! This year’s theme is ‘Youth’. Ayo, bikin film, yuk! Submission close on 31 July 2018. Want to take your business abroad? Telstra, in association with Austrade and the Australia Indonesia Business Council, is hosting a virtual event designed to help people successfully expand their business into Indonesia. Register your interest here! Last Thursday, on the 19th of April, the Jawa Barat Chapter had their first relaunch event: a ‘soft opening’ called ‘Apa kabar, Jabar?’ The event was held at Bamboo Shack in Dago, Bandung, and was organized by the newly-formed AIYA Jawa Barat leadership team including current ACICIS student and new President Philip Hibbard. Many people, both Indonesian and Australian, attended the night. The atmosphere was full of excitement when the new members of AIYA JaBar were welcomed. At the event, we all shared our knowledge and experiences about what it’s like to live in Australia and Indonesia. In particular, we shared about culture, social life, government, economy, entertainment, and many other topics. We also enjoyed funny riddles and sharing sessions. A few of us thought the sharing sessions were most fun, because we could hear about unique experiences. Some of those experiences included hearing from the Australians who are studying in Indonesia, and the Indonesians who have studied in Australia. This welcome night should be regarded as the first of many future AIYA JaBar events, and has made a positive impression for all involved. We look forward to building strong ties between Australia and Indonesia through sharing our understanding and experiences in the future! Some of the committee members and event participants posing with the national flags. PPIA Victoria’s special lecture with The Honourable Mr Edwin Hidayat Abdullah, Indonesian Deputy of Energy, Logistics, Metro and Tourism from the Ministry of State-Owned Enterprises, emphasised that diversity is resilience on Friday night. The mostly Indonesian crowd attentively listened to the 45-minute English language lecture on the range of tourism operations that exist in Indonesia. The ‘10 new Balis’ project has already been discussed from many perspectives. This time, it was a focus on economics, specifically its role in one in ten world jobs; its projected 14% share of Indonesian GDP; its function in motivating the Indonesian infrastructure boom; and much more. A focus beyond Bali aims to shift 40% of all Indonesia tourist arrivals across Indonesia. This supports Joko ‘Jokowi’ Widodo’s Nawacita (‘National Vision’) and develops a robust economy. Mr Abdullah cogently explained how easy it is to capitalise on the natural beauty of Indonesia’s 17,000 islands through experience tourism. He discussed the diverse work being done to spread word of the wonderful times that can be had on beaches, in resorts, with locals and without cost. In response to the role of technology to supercharge these efforts, the Ministry has launched an app called Xplorin that creates connections between all the different opportunities already available. While natural beauty is the draw, it can also be a danger. Recent volcanic eruptions emphasise how Indonesia is at risk of billions of rupiah lost through travel cancelations and empty hotels if this project fails. Strength in diversity is emphasised by the long list of tourism modes being implemented across the archipelago by the Ministry. There will be environmental, luxury, cultural and homestay options, with many more besides. This is drawing major chains like Paramount to establish themselves in new frontiers like Mandalika. This success champions the Ministry’s track record in clearing road blocks to benefit everyone. All the projects emphasise the importance of addressing ‘government, business and local interest’. That order seems to suggest the way things have been done in Indonesia for a long time, but there is also the feeling of innovation. The homestay programs and cultural tourism involve the local population without creating over-dependence. My own experience in remote communities makes it clear that this is integral to Indonesia’s long-term success. Question time focused primarily on two aspects – environment and community. Abdullah Mansoer, President Director of Indonesia Tourism Development Centre, Edi Setiono, Director of Taman Wisata Candi Borobudur and Prambanan, and Haryo Yunianto, Director of Patra Jasa, joined Mr Abdullah onstage. The four individuals answered a variety of questions from the enthusiastic student crowd. Evelynd from Monash University asked about the intersection between reducing floating plastic and tourism. She suggested that environmental issue is one block to increased tourism. Mr Mansoer responded with a focus on the work being done to involve Bali locals in beach clean-up work. In response to a push to go beyond, there was acknowledgment that these strategies could be more broadly implemented with the right support. Diski Naim from the Indonesia Diaspora Network asked about the role his members can have to promote Indonesian tourism. He made the point that they uniquely understand both why Indonesia is amazing and how Australians would best understand that. I added the Australia-Indonesia Youth Association would be able to support such an effort even further due to their position in the bilateral relationship. All the officials present agreed that something must be organised and officially supported to make the most of this impressive people power. This notion provided in-principle support to Mr Naim’s idea that community goes beyond experience branding when getting Indonesia into local minds. All questions emphasised the importance of a diverse and decentralised system. On the night, Bhineka Ika Tunggul (‘Strength in Diversity’, Indonesia’s national motto) was indeed linked to a robust and capable Indonesia for the future of tourism. Attempts to map Indonesia’s political spectrum have long observed that parties differ little on matters of policy and ideology. A preliminary investigation of party’ elites views has reaffirmed the only obvious difference between Indonesian political parties is the degree to which they believe Islam should play a role in public affairs. In the news Can Jakarta and Canberra become soulmates? In his latest keynote speech, the Governor for NSW His Excellency General the Hon David Hurley states that Australia’s relationship with Indonesia needs to go beyond the successful management of incidents. In light of the recent wave of blasphemy charges in Indonesia, Dr Dirk Tomsa discusses why blasphemy is such a serious offence and what these cases have in common with Dr Melissa Crouch in the latest episode of the Talking Indonesia podcast. RA Kartini’s legacy to female education has meant that many women are seeking higher education abroad. Many Indonesian women find that support from multiple stakeholders is vital during their study. Reflections upon Australia’s support network provided to international students highlight how Indonesia too can better support its women in higher education, Gerna Lysistrata writes. On the blog With the return of the Indonesian Film Festival (IFF) in Melbourne this weekend, Lachlan Haycock reviews, ‘Ziarah: Tales of the Otherwords’, the sombre tale a 92-year old woman’s quest to find the grave of her husband lost after the war. Events AIYA is proud to announce that our chapters are hosting screenings of the incredible Indonesian documentary, Banda: The Dark Forgotten Trail, across Australia. Brisbane – 19 May, Queensland College of Art, South Bank Campus, Griffith University Sydney – 24 May, Randwick Ritz Darwin – 26 May, Charles Darwin University Perth – 5 June, Baylis Theatre, University of Western Australia Grab your tickets using the above links to secure your spot! For any questions about any of the screenings, please contact your local chapter. Melbourne, 26 April – 2 May – The annual Indonesian Film Festival returns, with some of the biggest films of the past year. Get your tickets now to Pengabdi Setan, Marlina the Murderer in Four Acts, Banda and more! Perth, 4 May – Join AIYA WA for the next business breakfast hosted by Australia Indonesia Business Council (AIBC) with Ambassador to Australia for Indonesia, H.E. Mr Y. Kristiarto S. Legowo and Hon. Bill Johnston MLA will also be addressing this gathering. We look forward to seeing you there! Sydney, 18 May – Join the Sydney Southeast Asia Centre’s annual Politics in Action Forum, bringing political updates from Southeast Asia to researchers and practitioners from across the disciplines and beyond. Canberra, 23 May – Come to AIYA ACT’s annual Networking Night! Held in the Indonesian Embassy, mingle between students and professionals, create networks, and be inspired by the benefits of studying Indonesian! Opportunities Join the Asialinks team in Sydney! Every year Asialink Business’ Sydney office offers a fantastic internship opportunity to the AIYA network. Click here for more information on the position. Applications close on 6 May. The National Australia Indonesia Language Awards (NAILA) is looking for volunteers! Check out the open roles here and how you can be part of a team dedicated to improving the bilateral relationship and Indonesian language studies in Australia. Applications are due TODAY, 30 April 2018. Join AIYA National! We are on the hunt for a Web and IT Officer. We have extended the deadline to 4 May so be sure to apply before then! Join AIYA Jakarta! AIYA Jakarta is looking to fill the roles of Events Officer, Membership and Partnerships Officer, Treasurer and Secretary, Communications Officer, and General Committee Member at its upcoming AGM in April. If you would like to be part of the AIYA Jakarta team, please send a one-page expression of interest and your CV to jakarta@aiya.org.au. CAUSINDY (Conference of Australian and Indonesian Youth) is looking for passionate young Australian and Indonesian professionals to join the team for the upcoming conference as Chief Comms Officer, Tech Officer, Digital Content Office, and Programs Officer. Check out the job descriptions and how you can apply here. Applications for the AIC’s ReelOzInd! Short Film Festivalare now open! This year’s theme is ‘Youth’. Ayo, bikin film, yuk! Submission close on 31 July 2018. Australia Awards in Indonesia is pleased to announce that applications for Australia Awards Scholarships are now open until 30 April. The scholarships provide opportunities for individuals to gain an internationally recognised master or doctoral qualification from an Australian university and have the chance to pursue a career that makes a difference. Want to take your business abroad? Telstra, in association with Austrade and the Australia Indonesia Business Council, is hosting a virtual event designed to help people successfully expand their business into Indonesia. Register your interest here! The 13th Indonesian Film Festival (IFF) is on this weekend in Melbourne. As the most prominent celebration of Indonesian cinema in Australia, IFF is screening a selection of eclectic films, including Ziarah: Tales of the Otherwords (2017). Full information about all six films – plus how to book tickets – is available on the IFF Australia website. Ziarah is preoccupied with notions of death, history, legacy and stories, and not unduly so. From the beginning, the film is dominated by imagery of cemeteries and dead bodies, talk of old age, and recounts of past events. Characters are always telling stories of the land and the people on it, giving their versions of decades-old events and gradually building an impression of a broader historical truth that in this case becomes very personal. Set in rural Java, the film is subdued and introspective, with a slow place, meditative soundscape and numerous long takes. Combined with unobtrusive music and a generally static camera setup, this makes for a film that often feels more like a documentary than a work of fiction. This could have even been a deliberate choice to enhance verisimilitude given the film’s underlying themes. At one point, a passing extra glances deliberately into the camera, which aside from being a highly amusing error only strengthens the documentary-style tone the film evokes – it’s as if we are onlookers to a very real series of events. Mbah Sri (Ponco Sutiyem) sets out on an impressive solo journey for one of her age, to find the grave of her husband who was lost after the war. The character’s visible age and fragility – she’s 92 years old – reinforce the notion of a far-off history pushing through into the present. When asking where their graves are, don’t look for the gravestones. Look at the earth that is freed by their blood. Often shot with sparse dialogue, Mbah Sri is accompanied by a kind of unspoken melancholy along her journey, upping the emotional stakes and also helping the audience relish in her youthful zeal to find answers to age-old questions so late in life. Mbah Sri’s journey is paralleled by her grandson’s (Rukman Rosadi) troubled attempts to plan, buy the land for and build a house for himself and his fiancé. The two storylines interweave in a way that further emphasises the struggles of coming to terms with the past by showing the family’s effort to move on and look to the future. Short filmmaker B.W. Purba Negara’s first foray into feature-length directing is contemplative and deliberate, and lets the truth at the heart of the story come to the fore without any extraneous directorial touches. The film also features some pleasing Indonesian countryside to accompany the appropriately rural, low-key tone. The English subtitles, too, will be a blessing for those with little knowledge of mumbled Javanese. A review from the Jakarta Post described the film as a metaphor for Indonesia’s ahistorical society, but it works on several levels: as a quiet depiction of life in the villages, a personal quest for solace and self-fulfilment, or a treatise on the enduring legacy of conflict and loss. Don’t forget to select a film (or three) to watch this weekend at IFF in Melbourne. Plus, coming soon on the AIYA Blog: reviews for Pengabdi Setan and Marlina the Murderer in Four Acts.
Q: What are some examples of categorical imperatives/universalizable maxims relevant to modern ethics? I know this question has been widely asked, and that the answer may not be as straightforward as the question, which is partly why I'm asking. It's been a long time since I sat in a philosophy class, but I'm seeing Kant's name pop up in relation to human-AI value alignment, which is one of my preoccupations. What are some examples of categorical imperatives? By "categorical imperatives" one can mean universalized maxims, but I'm also interested in alternative formulations in the context of modern ethics. A: The terminology of hypothetical and categorical imperatives is rather specific to Kant. Roughly, hypothetical imperatives give commands conditioned on one’s purposes (if you wish to succeed in life study hard, etc.), while categorical imperatives are unconditional, absolute. The problem with authentic examples is that according to Kant “There is therefore only a single categorical imperative, and it is this: act only according to that maxim through which you can at the same time will that it become a universal law”. But Kant clearly does not distinguish between ethics and meta-ethics (principles for selecting ethical principles), a distinction to which modern philosophy became sensitivized by developments in logic and semantics in the early 20th century, and his “single categorical imperative” is a meta-ethical principle. Using the term loosely, all irreducible absolute commands of ethics proper are “categorical imperatives”. For example, so are the ten commandments of Judaism and Christianity, and their analogs in other religions. Kant’s implication is that all such absolute commands reduce to his universalizable maxims, and only they do. His reasoning to that effect is long-winded, our Philip Klöcking does his best to explain it here. The ideas of absolute commands and of objective morality, as well as their identification with universalizable maxims, came under heavy fire in modern philosophy. The former point is obvious in the context of postmodernist relativization of epistemological, ethical, etc., principles to history and culture, so I will focus on the latter. MacIntyre argued that many dubious maxims are very well universalizable: "keep all your promises except one", "let everyone except me be treated as a means" (he denies that Kant’s derivation of the “formula of humanity” from “the” categorical imperative is valid). Anscombe and Mackie pointed out that the idea of objective “oughts” is implicitly based on the idea of God as the lawgiver, and does not make much sense without it, as Hume’s critique of is-ought derivations shows, see virtue ethics. Moreover, the “categorical imperatives” in ethics, including “do not kill”, invariably lead to “wrong” conclusions resulting in growing lists of exceptions or sophistic distinctions like the Thomist doctrine of double effect. The latter attempts to distinguish between foreseeable harmful side effects of bringing about a good end, and harmful means of bringing about the same good end. The distinction turns on whether one merely foresees killing 1 person in the process of saving 5, or intends to kill the said 1 to save the said 5. Many see this as a distinction without a difference, along with its sister distinction between acts and omissions. Mackie in Ethics characterizes both as artificial, and explains how moral dilemmas undermine the idea of absolute commands in general: “The main reason why it has been thought important by Catholic moralists is that it seems necessary if there are to be absolute moral rules, for example ones which forbid murder, adultery, or apostasy in any circumstances. If an agent is equally responsible for all the foreseen consequences of an immediate action (or failure to act) as well as for that action itself, there will be conflict cases where different rules, or even different applications of the' same rule, require incompatible actions, so that the rule (or rules) cannot (both) be absolute. […] There is, indeed, one other way in which absolute prohibitions could be maintained… we could distinguish positive acts from omissions and frame absolute rules only about positive acts. No conflict cases could then arise, because in any conceivable set of circumstances all prohibitions of kinds of positive act (including the bringing about of certain evils as known second effects) could be obeyed at once by complete inaction. But do we want to maintain absolutism in either of these ways?” The problem of causal responsibility is complex even aside from the issues of double effect, see Is it a logical flaw to blame someone for an event if they were simply its causal factor?, and is often approached by analyzing “intentions”. But Anscombe offered a general objection to ethical theories, which, like Kant’s, judge not merely actions, but actions combined with intentions. It is known as the problem of relevant descriptions. The same action may be intentional under one description but not under another (in Anscombe’s example under “pumping water” but not under “contracting muscles”), this is not unlike the interpretational sophistry of double effect. For Kant’s universalization scheme to work at all we should be able to ascribe intentions to others, and he apparently did not appreciate how problematic that is. Here is from Shumski’s The Problem of Relevant Descriptions and the Scope of Moral Principles: “In her seminal attack on modern moral philosophy, G. E. M. Anscombe claims that Kant's ‘rule about universalizable maxims is useless without stipulations as to what shall count as a relevant description of an action with a view to constructing a maxim about it’. Although this so-called problem of relevant descriptions has received considerable attention in the literature, there is little agreement on how it should be understood or solved… I argue that the problem consists in the fact that Kant's formula of universal law seems to stand in need of an account of moral sensibility that does not render the formula superfluous. But, as my discussion of existing solutions reveals, there can be no such account.” This is not to say that universalizability, at least in a weak sense of abstracting from individual traits, do not have a place in modern ethics, see Do “if everybody did it” arguments commit a fallacy? Mackie in Ethics calls universalizability an "in some sense indisputable" condition on moral systems. And he endorses "categorical imperatives", as unconditional rules of behavior imposed by a society or institution for pragmatic reasons, e.g. facilitating decision making under predictive uncertainty or ensuring better outcomes in the prisoner's dilemma situations.
Metal Cats: Hardcore Metal Musicians Pose With Their Cats Musicians and fans of the metal music community often get a bad rap because of their dark, gruff and tattooed looks. The adorable set of photos published in Metal Cats by Alexandra Crockett sets out to change all that by getting accomplished metal musicians to pose with their feline friends and show off their softer sides. The people posing in these photos represent bands with names that are anything but cuddly – Napalm Death, Cattle Decapitation, Murder Construct, Skeletonwitch and Lightning Swords Of Death. But despite these fearsome band names and their black leather, spikes, tattoos and muscles, it’s clear that they share a close relationship with their loveable animals just like the rest of us. What’s even better is that these musicians, most of whom have thousands of supporters worldwide, aren’t just putting their faces behind the cause. A series of benefit concerts will be held along the U.S. West Coast, and the proceeds from these concerts, along with a portion of the book’s proceeds, will go to no-kill animal shelters at each of the four cities visited by the benefit shows.
Assessment of the adherence of community health workers to dosing and referral guidelines for the management of fever in children under 5 years: a study in Dangme West District, Ghana. Community health workers (CHW) manage simple childhood illnesses in many developing countries. Information on CHWs' referral practices is limited. As part of a large cluster-randomised trial, this study assessed CHWs' adherence to dosing and referral guidelines. Records of consultations of children aged 2-59 months with fever managed by CHWs were analysed. Appropriate use of drugs was defined as provision of the correct drug pack(s) for the child's age group. Symptoms requiring referral were categorised into danger signs, respiratory distress and symptoms indicating other illnesses. Multivariate logistic regression examined symptoms most likely to be noted as requiring referral and those associated with provision of a written referral. Most children (11 659/12 330; 94.6%) received the appropriate drug. Only 161 of 1758 (9.2%) children who, according to the guidelines required referral were provided with a written referral. Not drinking/breastfeeding, persistent vomiting, unconsciousness/lethargy, difficultly breathing, fast breathing, bloody stool, sunken eyes and pallor were symptoms significantly associated with being identified by CHWs as needing referral or receiving a written referral. CHWs' adherence to dosing guidelines was high. Adherence to referral guidelines was inadequate. More effort needs to be put into strengthening referral practices of CHWs within comparable community programmes.
All relevant data are within the paper. Introduction {#sec001} ============ δ-Crystallin is a taxon-specific eye lens protein. It is the major soluble protein in the eye lens of reptiles and birds and functions as a structural protein to maintain the refraction properties of the lens \[[@pone.0145957.ref001],[@pone.0145957.ref002]\]. δ-Crystallin and argininosuccinate lyase (ASL) are homologous proteins. ASL is responsible for the conversion of argininosuccinate into arginine and fumarate in the urea cycle. δ-Crystallin and ASL share about 70% amino acid sequence identity and function as homotetramers, with four identical multi-subunit active sites \[[@pone.0145957.ref001]--[@pone.0145957.ref006]\]. δ-Crystallin and ASL have similar X-ray crystal structures. Each monomer consists of three domains. The helices in domain 2 of each monomer associate to form a central helix bundle, comprising the core structure of the protein ([Fig 1A](#pone.0145957.g001){ref-type="fig"}) \[[@pone.0145957.ref004],[@pone.0145957.ref005],[@pone.0145957.ref007]--[@pone.0145957.ref010]\]. The active sites of the enzyme are located in a cleft between three different monomers \[[@pone.0145957.ref004]\]. The quaternary structure of δ-crystallin consists of a double dimer. The contact surface between the two dimers is smaller than the interface within the primary dimer of the structure \[[@pone.0145957.ref011]\]. Hydrogen bonding, salt bridges and hydrophobic interactions are the major forces which stabilize the quaternary structure of the protein. ![The structure of goose δ--crystallin.\ (A) The quaternary structure (PDB accession no: 1XWO) and (B) the A-B dimeric pairs from diagonal subunits. Monomers of A, B, C and D are colored as green, blue, yellow and gray, respectively. Residues of K315 and W74/W169 are highlighted as CPK and colored as magenta and yellow, respectively. (C) Superimposition of wild-type and K315A mutant proteins present as green and grey color, respectively. A expand view of the interactions of K315 at the interface of A and B subunit is highlighted in (D). Residues of K315 and A315 are displayed as stick models. The interactions are present by dashed green lines.](pone.0145957.g001){#pone.0145957.g001} In the presence of guanidinium chloride (GdmCl), tetrameric δ-crystallin is unfolded *via* a multistep pathway involving subunit dissociation into a monomeric molten globule intermediate, followed by denaturation \[[@pone.0145957.ref012],[@pone.0145957.ref013]\]. The dimeric form is transiently detected during this unfolding/refolding process. These dimers are unstable and they are prone to self-associate into protein aggregates, and this process competes with the formation of native tetramers \[[@pone.0145957.ref008]\]. Hence, the assembly of two dimers acts as a kinetic barrier in the refolding pathway \[[@pone.0145957.ref014]\]. The proper assembly of double dimers is thus important for producing a stable δ-crystallin quaternary structure. The N-terminus of δ-crystallin has been identified as being critical for the proper assembly of the double dimers \[[@pone.0145957.ref008]\]. In the quaternary structure, the first 25 N-terminal amino acid residues protrude into the neighboring monomer and interact with a hydrophobic cavity. When this sequence of amino acids was deleted the protein became unstable and was prone to form protein aggregates. The salt bridge formed by residues of R302 and E330, located in the helix bundle at the dimer-dimer interface, is also important interaction for stabilization of the quaternary structure of δ-crystallin. When this interaction was disrupted by site-directed mutagenesis, the exchange rate of subunits was dramatically accelerated \[[@pone.0145957.ref015]\]. The interactions of E327 with both K299 and R302 and the interaction of E267 with Y158 at the dimer interface were found to stabilize the quaternary structure of δ-crystallin in a cooperative manner. Mutations of the residues involved in both these interactions caused the majority of dimers to dissociate, whilst only partial dissociation was observed when these interactions were individually disrupted, as judged by sedimentation velocity experiments \[[@pone.0145957.ref011]\]. Inspection of the structure of δ-crystallin showed that the primary interactions between two symmetrically associated monomers in diagonal positions were provided by residues located at the top and bottom sides of the helical bundles ([Fig 1B](#pone.0145957.g001){ref-type="fig"}). K315 is one of the residues symmetrical located at this interface, interacting with the same residue in other monomers by hydrogen bonds ([Fig 1C and 1D](#pone.0145957.g001){ref-type="fig"}). Substitution of this residue with leucine resulted in part dissociation of the quaternary structure. In contrast, the K315A mutant protein was relatively stable. This protein was unfolded into an intermediate with a stable conformation at 3 M urea \[[@pone.0145957.ref011]\]. This phenomenon was not observed for the K315L mutant protein, which was unfolded under the same conditions. The results lead to the hypothesis that the bulky and charged side-chain of K315 might affect the stability of the intermediate during the process of protein unfolding. When wild-type δ-crystallin was unfolded in GdmCl, the first transition for subunit dissociation resulted in a monomeric intermediate with a molten globule conformation \[[@pone.0145957.ref012],[@pone.0145957.ref013]\]. During the refolding of 5 M GdmCl denatured δ-crystallin a marked hysteresis was observed, suggesting that the quaternary structure of that inappropriate assembled species might be related to the conformation of the refolded monomers \[[@pone.0145957.ref014],[@pone.0145957.ref016]\]. The presence of stable intermediate during unfolding of K315A mutant protein in the presence of urea suggests that the interactions provided by this residue at the interfaces might provide an energy barrier for subunit dissociation. In this study, the effects of this interaction on the folding pathway of wild-type and mutant proteins were investigated using urea as a denaturant. The different distributions of dissociated component from wild-type and mutant proteins, as measured by sedimentation velocity experiment, suggests the quaternary structure dissociates in different ways for wild-type and mutant proteins. Structural simulation supports different dissociation processes for the two proteins. These results highlight the critical role of K315 in stabilizing the quaternary structure of δ-crystallin. The residue appears to control both the dissociation of dimers into monomers and the stability of the produced monomers. The monomers dissociated from the K315A mutant protein with a stable and compact conformation provided a good model for studying the folding mechanism of the δ-crystallin. This study reveals the conformational status of the monomers, which determines whether functional protein or aggregates are formed. Materials and Methods {#sec002} ===================== Protein production and purification {#sec003} ----------------------------------- The recombinant wild-type and the K315A mutant δ-crystallin or αA-crystallin plasmid were transformed and over-expressed in *E*. *coli* BL21 (DE3) with induction by isopropyl-β-[D]{.ul}-thiogalactopyranoside (IPTG). Proteins were purified as previously described \[[@pone.0145957.ref008],[@pone.0145957.ref017]\]. The supernatants of crude cell extracts were loaded onto a Q-Sepharose anion exchange column (HiPrep 16/10 Q XL, GE Healthcare) pre-equilibrated in buffer A (50 mM Tris-HCl buffer, pH 7.5) and eluted with a linear gradient of 0 to 0.4 M NaCl in buffer A. Recombinant protein was eluted at approximately 0.15 M NaCl. The eluted protein was pooled and treated with ammonium sulfate to 1.2 M. After filtration, the sample was loaded onto a hydrophobic interaction column (Source™ 15PHE) pre-equilibrated in buffer A containing 10% (v/v) glycerol and 1.2 M ammonium sulfate and eluted with a linear gradient to the same buffer lacking ammonium sulfate. The retained proteins were eluted at \~0.3 M ammonium sulfate. Fractions were pooled and loaded onto S-300 Sephacryl column (26 mm x 85 cm) pre-equilibrated in 50 mM Tris-acetic acid buffer, pH 7.5. Fractions were analyzed by SDS-PAGE and protein concentrations determined by the method of Bradford \[[@pone.0145957.ref018]\]. Proteins possessing a C-terminal His~6~ tag were purified on Ni affinity column (Chelating Sepharose FF, GE Healthcare) then desalted using a Sephadex G-25 column (26 mm x 12 cm) as previously reported \[[@pone.0145957.ref011]\]. Equilibrium unfolding and refolding experiments {#sec004} ----------------------------------------------- Equilibrium unfolding experiments were carried out by overnight incubation of δ-crystallin with various concentrations of urea or GdmCl in 50 mM Tris-acetic acid buffer, pH 7.5 at 25°C. The refolding experiments were undertaken by dilution of equilibrium-denatured δ-crystallin to a series of urea or GdmCl concentrations in the same buffer. The experiments for equilibrium unfolding of monomeric δ-crystallin were undertaken by overnight incubation of δ-crystallin in 1.5 M urea at 25°C followed by addition of various concentrations of GdmCl to the solution followed by incubation for 2 hrs. The refolding experiments were carried out by dilution of the denatured δ-crystallin into a solution containing 1.5 M urea and 0.8, 3 or 5 M GdmCl in 50 mM Tris-acetic acid buffer, pH 7.5. To analyze the conformation and quaternary structure of the refolded δ-crystallin, the refolding experiments were undertaken by 20-fold dilution of the denatured monomeric δ-crystallin with buffer. Data analysis {#sec005} ------------- The transition region in [Fig 2B](#pone.0145957.g002){ref-type="fig"} for the reversible dissociation of K315A mutant δ-crystallin in urea solution was analyzed using the following method. The unfolding process was described as a two-state transition for the conversion of the tetramer (T) into monomers (M). The thermodynamic parameters were obtained by global fitting of the tryptophan fluorescence signal to [Eq 1](#pone.0145957.e001){ref-type="disp-formula"} \[[@pone.0145957.ref019]\]: $$y_{0} = \{(y_{\text{n}} + m_{\text{f}}\lbrack\text{D}\rbrack) + (y_{\text{u}} + m_{\text{u}}\lbrack\text{D}\rbrack)\text{exp}(-(\Delta G_{\text{u}}{}^{0}\,-\, m\lbrack\text{D}\rbrack)/RT)\}/\{ 1 + \text{exp}(-(\Delta G_{\text{u}}{}^{0}\,-m\lbrack\text{D}\rbrack)/RT)\}$$ where *y* is the observed signal from tryptophan fluorescence, *y*~n~ and *y*~u~ are the signals in the folded and unfolded states, and *m*~f~ and *m*~u~ are the slopes of the baselines preceding and following the transition region. Δ*G*~u~^0^ is the free energy difference in the absence of urea and *m* is the variation in the free energy of unfolding with the urea concentration. ![The unfolding transition of the wild-type and mutant δ-crystallin.\ Changes in average emission wavelength (AEW) of tryptophan fluorescence are represented as a function of GdmCl (A) and urea (B) concentration. (C) The integrated area of the fluorescence emission spectrum of ANS at varied urea concentration. The labels of (●) and (○), and (▲) and (∆) represent the unfolding and refolding of wild-type and K315A mutant protein, respectively. In (B) and (C), the dark or grey open circles and triangles represent the refolding transition from 3.5 or 4 M urea denatured wild-type and 2.5 or 6 M urea denatured mutant protein, respectively. The (■) and (□) in (B) represent the changes of mean residue of ellipticity (MRE) in the unfolding of wild-type and mutant protein, respectively. The protein concentrations used in the assays were 0.03, 0.2 and 0.1 mg/mL for tryptophan fluorescence, CD and ANS fluorescence measurements, respectively.](pone.0145957.g002){#pone.0145957.g002} Reversible unfolding of monomeric K315A mutant δ-crystallin were described as a four state process (M↔I~1~↔I~2~↔U). The unfolding curve from tryptophan fluorescence was analyzed using a four-state unfolding model described as the transition from N to U with two intermediates, I~1~ and I~2~, in the process. The thermodynamic parameters were calculated by fitting the data to [Eq 2](#pone.0145957.e002){ref-type="disp-formula"} \[[@pone.0145957.ref008],[@pone.0145957.ref020]\]: $$\begin{array}{l} {y_{0} = \{ y_{\text{N}} + y_{\text{I}1}\mspace{2mu}\text{exp}\{ - (\Delta G_{1}{}^{0} - m_{1}\lbrack\text{D}\rbrack)\mspace{2mu}/\mspace{2mu} RT\} + y_{\text{I}2}\mspace{2mu}\text{exp}\{ - (\Delta G_{1}{}^{0} - m_{1}\lbrack\text{D}\rbrack + \Delta G_{2}{}^{0} - m_{2}\lbrack\text{D}\rbrack)\mspace{2mu}/\mspace{2mu} RT\} +} \\ {y_{\text{U}}\,\text{exp}\{ - (\Delta G_{1}{}^{0} - m_{1}\lbrack\text{D}\rbrack + \Delta G_{2}{}^{0} - m_{2}\lbrack\text{D}\rbrack + \Delta G_{3}{}^{0} - m_{3}\lbrack\text{D}\rbrack)\mspace{2mu}/\mspace{2mu} RT\}\}\mspace{2mu}/\mspace{2mu}\{ 1 + \text{exp}\{ - (\Delta G_{1}{}^{0} - m_{1}\lbrack\text{D}\rbrack)\mspace{2mu}/\mspace{2mu} RT\}} \\ {+ \text{exp}\{ - (\Delta G_{1}{}^{0} - m_{1}\lbrack\text{D}\rbrack + \Delta G_{2}{}^{{}_{0}} - m_{2}\lbrack\text{D}\rbrack)\mspace{2mu}/\mspace{2mu} RT\} + \text{exp}\{ - (\Delta G_{1}{}^{0} - m_{1}\lbrack\text{D}\rbrack + \Delta G_{2}{}^{0} - m_{2}\lbrack\text{D}\rbrack + \Delta G_{3}{}^{0} -} \\ {m_{3}\lbrack\text{D}\rbrack)\mspace{2mu}/\mspace{2mu} RT\}\}} \\ \end{array}$$ where *y*~I1~ and *y*~I2~ are the signals in the I~1~ and I~2~ states. Δ*G*~1~^0^, Δ*G*~2~^0^ and Δ*G*~3~^0^ are the free energy differences in the absence of GdmCl for N to I~1~, I~1~ to I~2~ and I~2~ to U transition, respectively, and *m*~*1*~, *m*~*2*~ and *m*~*3*~ are the variation in the free energy of unfolding with the GdmCl concentration. Enzymatic activity assay {#sec006} ------------------------ δ-crystallin was assayed for ASL activity by monitoring the absorption of fumarate at 240 nm in a Perkin-Elmer Lambda 40 spectrophotometer. Assays were performed at least in triplicate in 50 mM Tris-HCl buffer (pH 7.5) with 1 mM sodium argininosuccinate as substrate. A molar absorption coefficient of 2.44 x 10^3^ M^-1^cm^-1^ was used for all calculations \[[@pone.0145957.ref021]\]. Fluorescence studies {#sec007} -------------------- The fluorescence spectra were measured on a Perkin-Elmer LS-50 luminescence spectrophotometer at 25°C. Intrinsic tryptophan fluorescence spectra of the protein were recorded with excitation wavelength set at 295 nm and using 5 nm band-width for both excitation and emission wavelength. All spectra were corrected for buffer or denaturant absorption. The average emission wavelength was utilized for data analysis \[[@pone.0145957.ref022]\]. The ANS (1-anilinonaphthalene-8-sulfonic acid) (Molecular Probes; Eugene, Oregon) was used as probe to bind with proteins and the fluorescence was recorded from 450 to 550 nm with the excitation wavelength set at 370 nm. The band-widths were set at 5 nm for both the excitation and emission wavelengths. The final concentration of ANS was 0.2 mM. Circular dichroism studies {#sec008} -------------------------- The circular dichroism (CD) spectra were measured on a Jasco J-810 spectropolarimeter at 25°C. Experiments were performed in 20 mM Tris-acetic acid buffer (pH 7.5) with a 1 mm path-length over a wavelength range from 200 to 250 nm. All spectra were averaged from three accumulations and were buffer corrected. The observed ellipticity (θ) (degrees) was converted into the mean residue ellipticity \[θ\] by the equation: \[Θ\] = Θ×M~MRW~/10×*d*×*c* \[[@pone.0145957.ref023]\], where M~MRW~ is the mean residue weight, *d* is the light path (cm), and *c* is the concentration of protein in g/ml. Analytical ultracentrifugation studies {#sec009} -------------------------------------- The protein sedimentation were performed on a Beckman-Coulter (Palo Alto, CA) XL-A analytical ultracentrifuge (AUC) with an An50 Ti rotor at 20°C with 130 000 *g* in standard double sectors aluminum centerpieces. The radial scans were recorded with a time interval of 7-min and a step size of 0.003 cm. All data were fitted to the continuous c(s) distribution model and a continuous size-distribution with respect to frictional ratio (*f/f*~o~) model using the SEDFIT program \[[@pone.0145957.ref024],[@pone.0145957.ref025]\]. The partial specific volume of the protein, solvent density and viscosity were calculated using the SEDNTERP program \[[@pone.0145957.ref026]\]. The solvent density and viscosity of varied urea concentrations were calculated and included in the fitting. Non-denaturing gradient gel electrophoresis {#sec010} ------------------------------------------- Electrophoresis was performed using a PhastSystem (GE Healthcare). The samples were subjected a PhastGel 4--15% gradient gel which contains the Native Buffer Strip (0.88 M L-alanine, 0.25 M Tris/HCl pH 8.8) attached to the surface of the gel and both electrodes. The electrophoresis was carried out at 10 mA and 15^***°***^C for 400 Vh. After electrophoresis, the gel was fixed in 20% (w/v) trichloroacetic acid and stained with Coomassie Brilliant Blue R250. Protein aggregation measurements {#sec011} -------------------------------- The turbidity of protein solution was measured using a PerkinElmer Lambda 40 spectrophotometer equipped with a Peltier temperature control accessory to monitor the light scattering at 360 nm. All measurements were carried out at 25°C. Spectra were corrected using measurements recorded for native protein in the absence of denaturants. The aggregation rate was calculated by fitting the data to the single or double exponential equation: $$y_{\text{t}} = y_{0} + {\sum\limits_{i = 1}^{n}y_{\text{i}}}\left\lbrack {1 - \text{exp}\left( {- k_{\text{i}}t} \right)} \right\rbrack$$ Where *y*~t~ is the signal at time t, *y*~0~ is the signal of the final state, *y*~i~ is the change in amplitude, and *k*~i~ is the rate constant for aggregation. Data for the linear increase in signals was fitted to a linear equation using SigmaPlot 10. Thioflavin T assay {#sec012} ------------------ The assay was performed by setting the excitation wavelength at 440 nm and measuring the emission spectrum from 460 to 600 nm. Proteins unfolded in denaturant were diluted into 50 mM Tris-acetic acid buffer (pH 7.5) to give 0.05 mg/ml of protein in the presence of thioflavin T (ThT) (50 μM). The spectrum of ThT alone was used as a correction for each assay. Structural simulation {#sec013} --------------------- The crystal structure of goose δ--crystallin (PDB code: 1XWO) with all water molecule removed was subjected to the CHARMm force field and energy minimized with the smart minimization algorithm to satisfy (RMS Gradient \~0.1 kcal/mol/Å). The implicit solvent model of Generalized Born was included in the calculation. The structural model was used as a template to build the K315A mutant model using the build mutant protocol (Accelrys Discovery Studio 3.5, Accelrys Inc.). The best scoring model conformation was selected for energy minimization. Molecular Dynamics (MD) simulations were performed using the standard dynamics cascade protocol. The structures of wild-type and mutant δ-crystallin in the CHARMm force field were subjected to initial energy minimization for 500 steps by steepest descent followed by a conjugate gradient for 500 steps. The minimized models were then heated from 50 to 300 K in 2 ps MD simulations followed by equilibration for 2 ps at 300 K in the absence of any structural restraint. Finally, the equilibrated models were submitted to MD simulations for 100 ps at NVT (constant number of particles, volume, and temperature) using the Berendsen coupling algorithm \[[@pone.0145957.ref027]\]. Results {#sec014} ======= Conformational reversibility of δ-crystallins in the presence of denaturants {#sec015} ---------------------------------------------------------------------------- Wild-type and K315A mutant δ-crystallin purified to near homogeneity were used for all analysis. Equilibrium unfolding experiments were conducted by incubation of proteins in buffer supplemented with different GdmCl or urea concentrations overnight. Tryptophan fluorescence was used to monitor the conformational changes during the unfolding process in the microenvironment around the tryptophan residues ([Fig 2A and 2B](#pone.0145957.g002){ref-type="fig"}). There are two tryptophan residues, W74 and W169, in the structure of δ-crystallin. They are located in the solvent accessible domain 1 and the helix bundle of domain 2, respectively ([Fig 1A and 1B](#pone.0145957.g001){ref-type="fig"}). Unfolding of the wild-type and K315A mutant protein follows a multistep process in GdmCl solution and was not reversible after 20-fold dilution ([Fig 2A](#pone.0145957.g002){ref-type="fig"}). As shown in [Fig 2A](#pone.0145957.g002){ref-type="fig"}, the dramatic changes in the signal for the first transition were due to subunit dissociation as reported previously, with the GdmCl concentrations for half transition (\[D\]~1/2~) at 1 ± 0.05 and 0.5 ± 0.01 M for wild-type and K315A mutant protein, respectively \[[@pone.0145957.ref028]\]. Unfolding of the two proteins in urea solution followed a three-state process, with the \[D\]~1/2~ values in the first transition at 3.6 ± 0.1 and 1.7 ± 0.1 M urea, respectively ([Fig 2B](#pone.0145957.g002){ref-type="fig"}) \[[@pone.0145957.ref008],[@pone.0145957.ref012]\]. The differences in the denaturant concentration required for the half transition clearly show the potency of GdmCl when disrupting of the conformation of δ-crystallin \[[@pone.0145957.ref011]\]. In the presence of urea, the K315A mutant protein was dissociated and stayed in a stable conformation between 2 and 5 M urea. The conformation was more stable than for wild-type protein at urea concentrations exceeding 4 M. When the urea was removed by 20-fold dilution into buffer, the denatured mutant protein was able to refold into a conformation similar to the original state ([Fig 2B](#pone.0145957.g002){ref-type="fig"}). In contrast, dilution of 3.5 or 4 M urea denatured wild-type δ-crystallin or 6 M urea denatured K315A mutant protein did not result in the restoration of the properly folded conformation. These results suggest that the reversible assembly of the quaternary structure of δ-crystallin is correlated with the conformation of the dissociated monomers. The exposure of hydrophobic surfaces in the presence of urea was investigated using ANS titration. A dramatic increase in fluorescence was observed at around 3 M and 1 M urea, for wild-type and the K315A mutant, respectively, indicating that subunit dissociation had occurred due to the exposure of hydrophobic areas (Figs [2C](#pone.0145957.g002){ref-type="fig"} and [3](#pone.0145957.g003){ref-type="fig"}). The result is consistent with the observed changes in the tryptophan micro-environment as probed by tryptophan fluorescence ([Fig 2B](#pone.0145957.g002){ref-type="fig"}). The highest signals occurred around 2 and 5 M urea for the mutant and wild-type protein, respectively. Dilution of the 2.5 M urea denatured K315A mutant protein resulted in restoration of a native-like conformation. However, dilution of 4 or 6 M urea denatured wild-type or mutant protein, respectively, resulted in higher levels exposure of hydrophobic areas. ![Sedimentation velocity analysis.\ The continuous sedimentation coefficient distribution of (A) wild-type and (B) K315A mutant protein at different urea concentration were shown. Peaks in grey color represent the unfolded wild-type and mutant protein in 0, 2.5, 3, 3.5 and 4.5 M urea and in 0, 0.25, 0.7, 1.3, 1.5, 2, 2.5, 3.5 and 4.5 M urea, respectively. Wild-type and mutant protein denatured in 3.5 and 2.5 M urea were diluted to final 0.6 and 0.3 M urea, respectively, in 50 mM Tris-acetic acid buffer, pH 7.5, were shown as dark gray peaks. The protein concentration used in all assays was 0.2 mg/mL.](pone.0145957.g003){#pone.0145957.g003} Since α-helices are the major secondary structure in δ-crystallin, the ellipticity at 222 nm was used to analyze the structural changes induced by the presence of urea ([Fig 2B](#pone.0145957.g002){ref-type="fig"}). The results showed both proteins retaining relatively stable α-helical structure at concentrations of urea below 2 M. There was about 13% and 30% loss of the structure at 3 M and 4 M urea, respectively. Effect of urea on the size-and-shape changes of δ-crystallin variants {#sec016} --------------------------------------------------------------------- The size and size-and-shape changes of wild-type and K315A mutant protein in different urea concentrations were determined by sedimentation velocity measurements and using continuous *c*(*s*) distribution and *c*(*s*, *f*/*f*~*0*~) distribution analysis, respectively (Figs [3](#pone.0145957.g003){ref-type="fig"} and [4](#pone.0145957.g004){ref-type="fig"}) ([S1](#pone.0145957.s001){ref-type="supplementary-material"} and [S2](#pone.0145957.s002){ref-type="supplementary-material"} Figs) \[[@pone.0145957.ref029]\]. In the absence of urea, the two proteins appeared as one major component with sedimentation coefficients about 8.5 and 8.4 S, respectively ([Fig 3](#pone.0145957.g003){ref-type="fig"}). This peak corresponds to tetrameric δ-crystallin \[[@pone.0145957.ref011]\]. They possessed the native conformation as judged from the friction ratio (*f*/*f*~0~) distribution profile (with the centre region below 1.5 as shown by red in the contour) ([Fig 4A and 4B](#pone.0145957.g004){ref-type="fig"}). ![Size-and-shape distribution analysis.\ The sedimentation velocity experiments were performed and presented as the c(*s*, *f*/*f*~o~) distribution for (A) wild-type, (B) and (C) K315A protein in the absence and presence of 1.5 M urea, respectively. (D), K315A protein dissociated in 1.5 M urea was diluted to final of 0.26 M urea in 50 mM Tris-acetic acid buffer (pH 7.5).](pone.0145957.g004){#pone.0145957.g004} At 2.5 M urea two components were observed for wild-type protein with sedimentation coefficients about 6.6 and 3.2 S, and these are assumed to be the dissociated dimeric and monomeric forms. The S values of the two peaks decreased with increasing urea concentration. The proportion of the second (monomeric) peak increased from 6% to 27% to 60% in the presence of 2.5, 3.0 to 3.5 M urea, respectively. Dilution of the denatured wild-type protein at 3.5 M urea resulted in refolding into one major component with an S value of 8.1 ([Fig 3A](#pone.0145957.g003){ref-type="fig"}). Measurement of ASL activity showed that around 25% activity was recovered following refolding ([Table 1](#pone.0145957.t001){ref-type="table"}). 10.1371/journal.pone.0145957.t001 ###### Specific activity of δ-crystallin under the denaturant effect. ![](pone.0145957.t001){#pone.0145957.t001g} Renaturation conditions Specific activity(nmol/min/mg) ------------------------------------------------------------------------------ ------------------------------------------ [Wild-type]{.ul} no treatment 4.4 ± 0.1 refolded from 3.5 M urea[^a^](#t001fn001){ref-type="table-fn"} 1.1 ± 0.2 refolded from 5 M GdmCl[^b^](#t001fn002){ref-type="table-fn"} \-[^d^](#t001fn004){ref-type="table-fn"} [K315A mutant]{.ul} no treatment 0.28 ± 0.03 refolded from 1.5 M urea 0.26 ± 0.1 refolded from 2.5 M urea 0.23 ± 0.08 refolded from 5 M GdmCl \- refolded from 1.5 M urea and 5 M GdmCl[^c^](#t001fn003){ref-type="table-fn"} 0.9 ± 0.01 0.04 M urea and 0.13 M GdmCl 1.5 ± 0.05 ^a^ The proteins unfolded in 3.5, 2.5 or 1.5 M urea were 20-fold diluted with 50 mM Tris-acetic acid buffer (pH 7.5). ^b^ The proteins unfolded in 5 M GdmCl were 40-fold diluted and incubated for overnight. ^c^ The mutant protein was unfolded in 1.5 M urea for overnight followed by addition of 5 M GdmCl and incubation for 2 hrs. Then, the protein was diluted 40-fold and incubated for overnight before activity measurement. ^d^ no detectable activity. Subunit dissociation was observed at about 1.2 M urea for the K315A mutant protein, with S values for the major peak of 6.8 and a shoulder at about 4.5 S ([Fig 3B](#pone.0145957.g003){ref-type="fig"}). A single peak with an S value of 4.5 was observed for the mutant protein at \~1.5 M urea. This species is thought to be dissociated monomers possessing the native conformation as judged from the friction ratio (*f*/*f*~0~) distribution profile ([Fig 4C](#pone.0145957.g004){ref-type="fig"}). The monomers were reassembled into a similar quaternary structure of wild-type protein after removing the urea ([Fig 4D](#pone.0145957.g004){ref-type="fig"}). When the urea concentration was increased to 4.5 M, the S values for the single component were gradually decreased to about 2.4 ([Fig 3B](#pone.0145957.g003){ref-type="fig"}). Dilution of the protein denatured with 2.5 M urea resulted in refolding into one major peak with a S value of 8.1 S. The refolded protein showed around 80% ASL activity was recovered ([Table 1](#pone.0145957.t001){ref-type="table"}). Conformational reversibility of monomeric K315A mutant δ-crystallin {#sec017} ------------------------------------------------------------------- Since K315A mutant protein was reversible dissociated into stable monomers at 1.5 M urea, the conformational reversibility of monomers was investigated. Monomeric K315A mutant protein that had been produced by equilibrium incubation of the native protein in 1.5 M urea was treated with various GdmCl concentrations. Unfolding of monomeric K315A mutant proteins followed a multistep pathway as measured by both tryptophan and ANS fluorescence ([Fig 5A and 5B](#pone.0145957.g005){ref-type="fig"}). Stable intermediates were identified from the unfolding curve of ANS fluorescence which included the highest ANS fluorescence region at around 1 M GdmCl and a steady state at \~ 3 M GdmCl ([Fig 5B](#pone.0145957.g005){ref-type="fig"}). The monomeric protein had lost about 30 and 55% of its secondary structures at 1 and 3 M GdmCl, respectively. The changes in tryptophan fluorescence were correlated with the exposure of hydrophobic areas, which suggests the possible four-state unfolding model for monomeric δ-crystallin. ![The unfolding and refolding of GdmCl denatured monomeric K315A mutant δ-crystallin.\ (A) Changes in average emission wavelength (AEW) of tryptophan fluorescence and (B) the integrated area of the fluorescence emission spectrum of ANS are presented as a function of GdmCl concentration. Monomeric K315A mutant δ-crystallin was incubated in 1.5 M urea before introducing varied GdmCl concentration. The labels of (●) and (○) represent the unfolding and refolding of monomeric K315A mutant protein, respectively. The (▲) and (∆) in (B) are the refolding transition from 3 and 0.8 M GdmCl denatured monomeric protein, respectively. The solid line in (A) is the best fitted result. The fitting residuals are shown as open triangles in (A). (C) The non-denaturing gel electrophoresis. Lanes 1 and 2 represent the wild-type and mutant protein without denaturant treatment, respectively. Samples from refolding of 5 M GdmCl denatured wild-type and mutant protein for time period of zero or overnight are shown in lanes 3--4 and 5--6, respectively. The protein concentrations used in the assays were 0.03, 0.1 and 0.1 mg/mL for (A), (B) and (C), respectively.](pone.0145957.g005){#pone.0145957.g005} Dilution of monomeric K315A mutant protein denatured in 5 M GdmCl resulted in refolding to a similar conformation as the original monomeric state ([Fig 5A and 5B](#pone.0145957.g005){ref-type="fig"}). However, dilution of 1 and 3 M GdmCl denatured monomeric protein resulted in the increasing of the ANS fluorescence, indicating higher exposure of hydrophobic area ([Fig 5B](#pone.0145957.g005){ref-type="fig"}). The results suggest the conformation of the partly unfolded intermediate could affect the folding reversibility of the monomeric K315A δ-crystallin mutant. Thermodynamic parameters calculation {#sec018} ------------------------------------ K315A mutant δ-crystallin that denatured in 3 M urea was reversible folded back to the original conformation after dilution ([Fig 2B](#pone.0145957.g002){ref-type="fig"}). Signal changes in the tryptophan fluorescence with different urea concentration were used to calculate the thermodynamic parameters by directly fitted to the two-state mechanism ([Eq 1](#pone.0145957.e001){ref-type="disp-formula"}) \[[@pone.0145957.ref019]\]. The free energy difference in the absence urea (ΔG^0^) for the transition was determined to be 6.5 ± 0.3 kcal/mol ([Table 2](#pone.0145957.t002){ref-type="table"}). 10.1371/journal.pone.0145957.t002 ###### Thermodynamic parameters for K315A mutant δ-crystallin. ![](pone.0145957.t002){#pone.0145957.t002g} Equilibrium unfolding Δ*G*~u~^0^ (kcal/mol) *m* (kcal/mol/M) \[D\]~1/2~ (M) ---------------------------------------------- ----------------------- ------------------ ---------------- T ↔ M[^a^](#t002fn001){ref-type="table-fn"} 6.5 ± 0.3 3.8 ± 0.2 1.7 ± 0.05 M↔I~1~[^b^](#t002fn002){ref-type="table-fn"} 1.3 ± 0.2 2.1 ± 0.4 0.6 ± 0.04 I~1~↔I~2~ 2.6 ± 0.8 1.2 ± 0.2 2.1 ± 0.2 I~2~↔U 8.9 ± 0.4 2.3 ± 0.1 3.9 ± 0.1 ^a^ The reversible dissociation process was described as a two-state transition from the conversion of the tetramer (T) to monomeric intermediate (M). \[D\]~1/2~ is the concentration of denaturant at which the transition is half completed. The data was calculated by global fitting to [Eq 1](#pone.0145957.e001){ref-type="disp-formula"}. ^b^ The data were fitted to a 4-state unfolding model ([Eq 2](#pone.0145957.e002){ref-type="disp-formula"}) described as the transition from M to U. Two intermediates, I~1~ and I~2~, were assumed in the process before denatured species (U). These data are the mean ± SD of at least three independent experiments. The changes of tryptophan fluorescence as a function of GdmCl concentration were used to calculate the thermodynamic parameters for the reversible unfolding of the monomeric K315A δ-crystallin mutant ([Fig 5A](#pone.0145957.g005){ref-type="fig"}). The unfolding curve was best fitted into a four-state model \[[@pone.0145957.ref008],[@pone.0145957.ref020]\]. The \[GdmCl\]~1/2~ for the transitions from the M to I~1~, I~1~ to I~2~ and I~2~ to U (denaturation) were about 0.6 ± 0.04 M, 2.1 ± 0.2 M and 3.9 ± 0.1 M, respectively. The thermodynamic parameters determined are summarized in [Table 2](#pone.0145957.t002){ref-type="table"}. The total free energy difference (ΔG^0^) for folding of monomeric K315A δ-crystallin mutant was determined to be 12.8 ± 0.7 kcal/mol. Reversibility of the quaternary structure from denatured monomeric K315A mutant δ-crystallin {#sec019} -------------------------------------------------------------------------------------------- To determine the ability about refolding of denatured monomeric K315A mutant followed by reassembly to a tetrameric protein, the monomeric proteins that denatured by GdmCl were diluted with buffer to remove both of the urea and GdmCl. The results showed that the quaternary structure of K315A mutant protein was recovered from the denatured monomers instantly after dilution. The amount of the assembled protein was increased with the incubation time possessing about 60% of the activity recovered ([Fig 5C](#pone.0145957.g005){ref-type="fig"} and [Table 1](#pone.0145957.t001){ref-type="table"}). In contrast, dilution of 5 M GdmCl denatured wild-type δ-crystallin, the quaternary structure was recovered after overnight incubation with no detectable activity ([Table 1](#pone.0145957.t001){ref-type="table"}). The similar result was also shown for 5 M GdmCl denatured K315A mutant protein. These results suggested the different pathway for protein folding that seems due to the distinct conformation of the denatured protein caused by different means of denaturation. Protein aggregate formation from refolding of monomeric intermediate {#sec020} -------------------------------------------------------------------- Since refolding of partly unfolded monomeric mutant δ-crystallin resulted in a conformation with high exposure of hydrophobic regions, the occurrence of protein aggregation in the process was determined using light scattering measurement. No protein aggregation was detected upon dilution of 0.84, 3 and 5 M GdmCl denatured monomeric mutant protein into buffer containing 1.5 M urea. However, when 0.84 and 3 M GdmCl denatured monomeric mutant protein was diluted into buffer, protein aggregation was occurred. The rates for aggregate formation were calculated to be *ca*. 0.14 and 0.0004 min^-1^, respectively ([Fig 6A](#pone.0145957.g006){ref-type="fig"}). When αA-crystallin, the chaperone protein, was added in a 5:1 ratio to 0.84 M GdmCl denatured monomeric mutant protein in folding buffer, no change in the rate of protein aggregation was observed. Formation of aggregates by αA-crystallin alone did not occur under the same conditions. It is notable that upon dilution of 5 M GdmCl denatured monomeric mutant protein into buffer, no aggregation occurred. ![Aggregates formation from refolding of denatured monomeric K315A mutant δ-crystallin.\ (A) Light scattering measurement. Monomeric K315A mutant δ-crystallin was incubated in 1.5 M urea before introducing varied GdmCl concentration. Refolding of 0.84, 3 and 5 M GdmCl denatured monomeric K315A mutant protein by dilution with 50 mM Tris-acetic acid buffer (pH7.5) or the buffer containing 1.5 M urea are shown as (●, ▲ and ■) or (○, ∆, and □), respectively. The label of (♦) represents refolding of 0.84 M GdmCl denatured monomers by dilution with buffer including αA-crystallin. αA-Crystallin alone in 1.5 M urea and 0.84 M GdmCl is shown as (◊). The protein concentrations of monomeric K315A and αA-crystallin used in the assays were 0.1 and 0.5 mg/mL, respectively. (B) The fluorescence spectrum of ThT were shown from refolding of 0.84 (dark), 3 (gray) and 5 M (dark gray) GdmCl denatured monomeric K315A mutant protein by dilution with buffer and incubated for zero (solid-line), 1 (dash-line) or 2 (dot-line) hrs, respectively.](pone.0145957.g006){#pone.0145957.g006} The structural features of the protein aggregate were investigated using the thioflavin T assay \[[@pone.0145957.ref030]\]. An increase in fluorescence intensity resulting from binding of ThT with the aggregates over time was observed following dilution of 0.84 and 3 M GdmCl denatured monomeric mutant δ-crystallin into buffer ([Fig 6B](#pone.0145957.g006){ref-type="fig"}). The results suggest the possible formation of ordered aggregates. No changes in the signal were observed during the incubation period upon refolding of 5 M GdmCl denatured monomeric mutant protein. Molecular dynamics simulation {#sec021} ----------------------------- To determine the effect of the interactions provided by K315 at the diagonal subunits in disassembly of the quaternary structure, a MD simulation were run for 100 ps for wild-type and mutant δ-crystallin in the absence of any structural restraints. From the simulation trajectory, the dynamic motion for disassembly of the quaternary structure and conformational changes in the tertiary structure were elucidated. The distances between the C~α~ of D237 and R182, R302 and E330 and the two K315 or A315 residues were measured to evaluate the extent for subunit dissociation between the A-C, A-D and A-B dimeric pairs, respectively ([Fig 7A](#pone.0145957.g007){ref-type="fig"}). These residues interact with each other by hydrogen bonding or salt bridges at the dimeric pair interface in the native structure. These interactions are lost on replacement of K315 with A315. The results showed that the distances between D237 and R182, R302 and E330 and the two A315 residues increased linearly at a similar rate, except that the rate of change for the R302-E330 interaction in wild-type protein was about half of that for the mutant protein. In contrast, no changes in the distance between the K315 residues were observed before 80 ps. Inspection of the time-course at 20 ps in wild-type protein showed that the primary dimers of subunit A and C or B and D showed were separated, while the diagonal dimers of subunit A and B or C and D were connected by the interactions of residue K315 ([Fig 7B](#pone.0145957.g007){ref-type="fig"}). However, the subunits for both of the primary and diagonal dimers were separated from each other in the mutant protein. The results suggest a different disassembly process for tetrameric wild-type and mutant proteins. ![Molecular dynamics simulations.\ (A) The distances between the C~α~ of specific residues located at the interfaces along the simulation. (B) The conformation of wild-type and K315A mutant protein at trajectory frame of 20 ps.](pone.0145957.g007){#pone.0145957.g007} Discussion {#sec022} ========== The quaternary structure of δ-crystallin is assembled as two pairs of closely associated dimers. Previous mutagenesis studies have used to investigate the interactions at the interfaces of double dimers to elucidate their role in the stabilization of the quaternary structure \[[@pone.0145957.ref011]\]. The unique stable conformation from unfolding of K315A mutant protein in the presence of urea suggests that the interactions provided by this residue at the interfaces may play a critical role in stabilization of the quaternary structure of δ-crystallin. Lys-315 is the only residue which is arranged symmetrically at the diagonal subunit interfaces ([Fig 1B](#pone.0145957.g001){ref-type="fig"}). The ε-amino group in the side-chain of this residue forms hydrogen bonds with the carbonyl groups of M312, V313 and K315 within the symmetric subunit (from PISA analysis: <http://www.ebi.ac.uk/msd-srv/prpt_int/cgi-bin/piserver>) ([Fig 1D](#pone.0145957.g001){ref-type="fig"}). Substitution of this residue by alanine reduces the structural stability of the protein. The results from the previous study showed about a 9°C reduction in the thermal stability of the secondary structure and the changes in the micro-environment surrounding the tryptophan residues \[[@pone.0145957.ref011]\]. This mutant protein was also more susceptible to chemical denaturation, since about half of the concentration of denaturant was required to disrupt its quaternary structure compared to wild-type protein. Both of the wild-type and mutant protein showed similar and not reversible denaturation in the presence of GdmCl. However, differences in the denaturation pathway were observed when urea was used as the denaturant. The results suggest that the non-covalent interactions between the intra and inter-subunits might be disrupted by the ionic character of GdmCl, with subunit dissociation and denaturation occurring simultaneously for both proteins \[[@pone.0145957.ref031]\]. The previous studies showing the presence of only a monomeric molten globule intermediate in the dissociation pathway of wild-type δ-crystallin in GdmCl supports this assumption \[[@pone.0145957.ref012],[@pone.0145957.ref013]\]. Thus, the role of K315 in the folding process of δ-crystallin cannot be distinguished under the strong denaturant. Around 2\~5 M urea, the K315A mutant δ-crystallin is in a stable conformation, as judged by tryptophan fluorescence measurements ([Fig 2B](#pone.0145957.g002){ref-type="fig"}). Subunit dissociation occurs under these conditions, resulting in the exposure of hydrophobic regions (Figs [2C](#pone.0145957.g002){ref-type="fig"} and [3B](#pone.0145957.g003){ref-type="fig"}). Only monomers were identified in this state, as measured by sedimentation velocity analysis. The monomers that dissociated from the tetramers at \~1.5 M urea possessed a nearly identical content of secondary structure as native protein and native-like conformation (Figs [2B](#pone.0145957.g002){ref-type="fig"} and [4C](#pone.0145957.g004){ref-type="fig"}). Monomers in this conformation were able to refold and re-associate into tetramers with a similar conformation as the native protein, and possessed significant ASL activity. When the urea concentration was increased to 2.5 M, the conformational changes led to further exposure of hydrophobic regions. However, following this conformational change at higher urea concentrations, protein folding was not reversible. The contrasting result found for wild-type protein was that the dissociation and denaturation were concurrent under the effect of urea ([Fig 3A](#pone.0145957.g003){ref-type="fig"}). In this condition, the conformation of the dissociated monomers was partly unfolded, as judged from the reduced level of α-helix ([Fig 2B](#pone.0145957.g002){ref-type="fig"}). The dissociated monomers seem to refold into alternative conformations then re-associate into tetramers with only part of the catalytic activity recovered ([Table 1](#pone.0145957.t001){ref-type="table"}). These results indicated that the conformation of the monomers seems related to the assembly pattern for functional protein. It is interesting that the interactions provided by K315 at the interfaces seem to affect the disassembly pathway of the quaternary structure of wild-type protein. It was found that both of the dimers and monomers were dissociated from the wild-type protein at around 2 to 4 M urea, as measured by sedimentation velocity while only monomers were dissociated from the mutant protein ([Fig 3](#pone.0145957.g003){ref-type="fig"}). These results suggest that the interactions provided by K315 at the interfaces seem to increase the energy barrier for dimeric dissociation. When these interactions were disrupted by mutation, the monomers could be isolated with intact conformation from the tetramers earlier than for the wild-type protein in urea. Thus, the steps for dissociation and denaturation could be distinguished in the unfolding process of the K315A mutant δ-crystallin. In this study, the dynamic motion of protein structure in the process was simulated for elucidation the dissociation mechanism of δ-crystallin. From the trajectory, the tetramers were found to disassemble at the early stage. Due to the interactions by K315, the interfaces between the diagonal dimers remain connected while distances increase between the subunits of the primary dimers in wild-type protein. In contrast, the subunits between both of the diagonal and primary dimers were dissociated in the K315A mutant protein ([Fig 7](#pone.0145957.g007){ref-type="fig"}). As δ-crystallin was assembled by two close contact dimers as transthyretin, dissociation at the two primary dimer interfaces would be expected to occur at the initial stage \[[@pone.0145957.ref004],[@pone.0145957.ref032]\]. The simulation result provides a novel pattern for dissociation of the double dimeric protein consistent with the results of sedimentation velocity experiments. A possible explanation for this earlier dissociation of the subunit from the primary dimers compared to diagonal dimers is differences in solvent accessibility. Unlike the location of the interfaces between the subunits of the primary dimer, the position of K315 is buried at the interior interfaces away from solvent. Thus, the interactions of K315 at the interfaces of the protein seem to elevate the stability of the quaternary structure. For wild-type protein, two diagonal dimers were presumed to disassemble initially from the tetramers followed by subunit dissociation of the diagonal dimers. However, dissociation at the interfaces of two primary dimers would assume to be the first step in the unfolding process of the K315A mutant protein ([Fig 8](#pone.0145957.g008){ref-type="fig"}). ![A working model proposed for the folding pathway of wild-type and K315A mutant δ-crystallin.\ The tetrameric wild-type (T) and K315A mutant (T\*) δ-crystallin was dissociated through the diagonal dimer (D) and primary dimer (D\*) to monomers with partial unfolded (M) and stable (M\*) conformation, respectively. Monomers of the wild-type or the mutant protein were then denatured through intermediate (I or I\*) into respective unfolded form (U or U\*). The monomers (M) of wild-type protein in partial unfolded conformation was associated in alternative pathway to form dimers (D~1~), and then assembled into tetramers (T~1~) or aggregates (A). The aggregation was prevented by αA-crystallin. Refolding followed by assembly of the intermediates (I~1~\* and I~2~\*) of the mutant protein resulted in the aggregates (A~1~ and A~2~) formation and the chaperone function of αA-crystallin was invalid in this process.](pone.0145957.g008){#pone.0145957.g008} The detail mechanism for folding of monomeric protein remains elusive due to the monomers dissociated from wild-type δ-crystallin were in a molten globule conformation. Thus, the monomers that reversible dissociated from K315A mutant δ-crystallin with a stable conformation and possessing similar level of secondary structure as the original state, and this would be a good model for studying the folding process. The monomeric protein was reversible denatured in a four-state mechanism in the presence of GdmCl and two intermediates were detected in the process ([Fig 5](#pone.0145957.g005){ref-type="fig"}). Refolding of the partly unfolded intermediate was not reversible which in turn resulted in a conformation with more exposure of hydrophobic regions. Only denatured δ-crystallin was reversible folded into the monomers with a similar conformation to the original state. It is interesting that the refolded monomers were able to reassemble into tetramer instantly upon dilutions, with substantial recovery of activity ([Fig 5](#pone.0145957.g005){ref-type="fig"} and [Table 1](#pone.0145957.t001){ref-type="table"}). This contrasts with the slow refolding of GdmCl denatured wild-type protein into its tetrameric form with no detectable activity. The slow recovery of the quaternary structure for the latter protein is due to an energy barrier for the appropriate assembly of double dimers, as reported previously \[[@pone.0145957.ref014]\]. The results suggest that the conformation of the denatured monomers which was unfolded by stepwise dissociation or directly unfolded with 5 M GdmCl could be different. The consequence of this might be that protein folding occurs *via* different pathways leading to the refolded monomers with different conformations to associate into native structure or alternative structures without function. Protein aggregates are prone to form during the reassembly process from refolding of partly unfolded monomeric intermediates of δ-crystallin. The intermediate with the highest exposure of hydrophobic conformation is particularly prone to aggregate formation ([Fig 5](#pone.0145957.g005){ref-type="fig"}). Aggregate formation by monomeric intermediates with defined conformations was also reported for transthyretin under mildly acidic conditions \[[@pone.0145957.ref033]\]. The result implies that the conformational status of the monomers influences subunit association. It is interesting that the presence of α-crystallin seems to increase the formation of aggregates from the monomeric intermediates of δ-crystallin with partly unfolded conformation, while α-crystallin alone was not affected under these conditions ([Fig 6](#pone.0145957.g006){ref-type="fig"}). The studies for αA peptide which induces the aggregation of soluble α-crystallin suggested that the mechanism for aggregate formation might due to the changes in the hydrophobicity of α-crystallin induced by the peptide \[[@pone.0145957.ref034],[@pone.0145957.ref035]\]. Our previous study reported that aggregate formation during refolding of GdmCl denatured wild-type δ-crystallin was due to the improper assembling of double dimers and was prevented by the presence of α-crystallin \[[@pone.0145957.ref014]\]. In this study, the aggregate formation was caused by assembly of the refolded monomeric intermediate which facilitated the aggregate formation of α-crystallin. It thus postulated that the electrostatic interaction with the substrate seems to be key factors to determine the chaperon-like or anti-chaperone activity of the α-crystallin \[[@pone.0145957.ref034],[@pone.0145957.ref036]\]. The underlying mechanism requires further investigation. Nonetheless, the result highlights the conformational status of the monomers which play a critical role in the folding pathway for reversible oligomerization or aggregate formation. In conclusion, the folding pathways of wild-type and mutant δ-crystallin are summarized as the working models shown in [Fig 8](#pone.0145957.g008){ref-type="fig"}. This model depicts the key interactions from K315 at the interfaces of diagonal subunits not only to stabilize the quaternary structure of δ-crystallin but also to act as the energy barrier for dissociation of stable monomers. The stability might be one of the reasons for recruitment of the metabolic enzyme ASL into the lens as a crystallin protein \[[@pone.0145957.ref037]\]. The single polypeptide chain of δ-crystallin after translation would be assumed to fold into functional tetramers as the proposed refolding pathway for K315A mutant. However, due to the interactions by K315, the tetrameric protein would be assumed to dissemble in an alternative manner to form the diagonal dimers, followed by simultaneous subunit dissociation and denaturation. Monomers in this status might associate into dimers *via* a different pathway which then assemble slowly into a non-native tetrameric form or self-associate into aggregates which can be prevented by the presence of α-crystallin. The reversible folding of the monomers that dissociated from the K315A mutant protein with near native conformation provided the folding mechanism of the δ-crystallin. In this process, the ordered aggregate formation from re-association of the partly unfolded intermediate reveals a specific status of the protein to avoid the chaperone function of α-crystallin. This model proposes a possible mechanism about the aggregate formation for lens protein under stress effect and their interaction with α-crystallin. This study reveals the key role of monomers that dissociated from the oligomeric crystallin; their conformational status determines the levels of aggregate formation. Supporting Information {#sec023} ====================== ###### Sedimentation velocity analysis of wild-type δ-crystallin. \(A\) and (B), the panels show the raw sedimentation and theoretical fitted data (solid lines), and the fitting residual, respectively. (C) Grayscale of residual bitmap. The raw sedimentation data were fitted to the continuous size distribution model including the solvent using the SEDFIT program \[[@pone.0145957.ref025]\]. (TIF) ###### Click here for additional data file. ###### Sedimentation velocity analysis of K315A mutant δ-crystallin. \(A\) and (B), the panels show the raw sedimentation and theoretical fitted data (solid lines), and the fitting residual, respectively. (C) Grayscale of residual bitmap. The raw sedimentation data were fitted to the continuous size distribution model using the SEDFIT program \[[@pone.0145957.ref025]\]. (TIF) ###### Click here for additional data file. We thank Dr M. D. Lloyd (University of Bath, U. K.) for reading of this manuscript before publication. ANS : 1-anilinonaphthalene-8-sulfonic acid GdmCl : guanidinium hydrochloride CD : circular dichroism AEW : average emission wavelength λ~max~ : maximum emission wavelength C~m~ : half concentration of denaturant required in protein unfolding MD : molecular dynamics [^1]: **Competing Interests:**The authors have declared that no competing interests exist. [^2]: Conceived and designed the experiments: HJL WYC. Performed the experiments: CWH HCL WCK CYC. Analyzed the data: CWH CYC. Wrote the paper: CWH HJL.
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About Yuvan Shankar Raja Male singer Yuvan Shankar Raja from India, famous due to bollywood Playback Singer Yuvan Shankar Raja Singer Biography, Interview & Pictures Yuvan Shankar Raja (Tamil: யுவன் சங்கர் ராஜா ; born 31 August 1979) is an Indian film score and soundtrack composer, singer and occasional lyricist. He has predominantly scored music for Tamil as well as several Telugu films. His musical career began in 1996, at age 16, as he composed the film score for Aravindhan. After initial struggle, he made his big break with the Thulluvadho Ilamai soundtrack (2001), and evolved as one of Tamil cinema's most sought-after composers by the mid-2000s. Within a span of 14 years, Yuvan Shankar Raja worked on over 85 films. Considered a versatile composer, he often strives for different and innovative music and has explored and used elements of various genres in his compositions that range from folk to heavy metal. He is particularly known for his use of western music elements in his pieces and often credited with having introduced Hip hop to the Tamil film and music industry and having started the "era of remixes" in Tamil Nadu. Being immensely popular among the younger generation, he is frequently referred to as the "Rockstar", and the "Youth Icon of Tamil Film Music". In addition, Yuvan Shankar Raja is recognized for his background score in films (re-recording) that have fetched him accolades among critics. He has won two Filmfare Awards; the Best Music Director Award in 2004 for his score in the drama 7G Rainbow Colony at age 25, remaining the youngest winner of the award, and the Special Jury Award in 2009 for his Telugu musical Oy!. Besides, he received two nominations for Filmfare Awards, one Tamil Nadu State Film Award in 2006 and the Cyprus International Film Festival Award in 2006 for Raam, becoming the first and only Indian composer to win it. Early life Born on 31 August 1979, in Chennai, India into a Tamil family, Yuvan Shankar Raja is the third and youngest child of musician and film composer Ilaiyaraaja and his wife Jeeva. He is the younger brother of music director Karthik Raja and playback singer-cum-music director Bhavatharini. Yuvan once confessed, that his brother Karthik Raja is more talented than him, but did not get a successful break into the music business, since he did not get a "good team to work with". His father as well as his siblings have sung many songs under his direction. Film director and film composer Gangai Amaran and R. D. Bhaskar are his uncles and their sons Venkat Prabhu, Premji Amaran and Parthi Bhaskar, who are working in the Tamil film industry as well, are his cousins. Moreover, Yuvan Shankar and both the sons of Gangai Amaran, do often associate with each other and have often worked together, the results of which have been very successful. Venkat Prabhu's films have had all musical score by Yuvan, while Premji had assisted him composing music for some years, before becoming an independent composer aside from the fact, that both have sung several songs under the direction of Yuvan Shankar Raja. Yuvan Shankar did his schooling at St. Bede's Anglo Indian Higher Secondary School in Chennai, and discontinued his education after his tenth class. He started learning music from Jacob Master, attending piano classes at "Musee Musical" in Chennai, which is affiliated to Trinity College in London, UK|UK]]. Yuvan Shankar Raja stated, that he always wanted to become a pilot and travel "all around the world", but as he grew up "with music around him", he eventually became a musician.[18] He admires the work of his father and other composers such as S. D. Burman, R. D. Burman, M. S. Viswanathan and Naushad and the voices of singers Lata Mangeshkar, Asha Bhosle, P. B. Sreenivas and P. Susheela. Career Film score and soundtracks Early years (1997-2000) In 1996, following his mother's suggestion to take up music as a profession, Yuvan Shankar Raja started composing tunes for an album. It was then that T. Siva, the producer of the Tamil language film Aravindhan, after hearing some of the tunes, asked to compose a trailer music. As the producer was so much impressed of which, he gave Yuvan Shankar the assignment to compose the entire film score including a soundtrack for that film. After consulting and getting consent from his parents, he accepted the offer; his music career started. His entry into the Tamil film and music industry had happened at age 16, thus becoming one of the most youngest composers ever in the industry, which, he says, was "purely accidental". However, both the soundtrack album as well as the film itself failed to attract audiences and to do well and Yuvan Shankar Raja's following projects Velai (1998) and Kalyana Galatta (1998) were not successful either; his compositions for these films did not receive good reviews or responses, with one reviewer labelling the music and re-recording in the latter as "cacophony" and "poor". This eventually caused that he hardly got any film projects and assignments. During this time of struggling, he was approached and assigned by director Vasanth to compose the music for his film Poovellam Kettuppar (1999). The soundtrack received very positive response, bring described as "fresh" and "different", with a critic from The New Indian Express citing that his "absolutely enchanting musical score [...] bears testimony to his ‘Raja’ surname." The album became very popular, particularly songs like "Irava Pagala" and "Chudithar Aninthu", gaining him first time notice, especially among young people and children. The album would make possible his first breakthrough in the industry and proved to be a major turning point in his career. After working for two Sundar C. films, Unakkaga Ellam Unakkaga (1999) and Rishi (2000), which both fared averagely at the box office, he got to work for A. R. Murugadoss' directorial debut in 2000, the action flick Dheena starring Ajith Kumar, which went on to become a blockbuster and Yuvan Shankar Raja's first major successful film. Yuvan Shankar's songs were equally successful, which are considered to have played a major role for the film's great success. whilst his background score in the film was also well appreciated. Rise to prominence (2001-2003) Thanks to this film's enormous success, he eventually broke into the Tamil music scene as offers were pouring in subsequently. He was mainly approached by many young new directors. In 2001 he had three album releases, the first being Thulluvadho Ilamai, collaborating with Selvaraghavan for the first time. The soundtrack album of Thulluvadho Ilamai particularly appealed to the younger generation. The film itself, marking the debut of Selvaraghavan's brother Dhanush, released one year later and became a sleeper hit at the Chennai box office. This was followed by Bala's Nandha (2001), for which he received rave reviews. He then gained notice by churning out "youthful music" in the college-life based April Maadhathil (2002), the romantic comedy films Kadhal Samrajyam (2002), and Mounam Pesiyadhe (2002), Ameer's directorial debut film, and the triangular love story Punnagai Poove (2002), in which he also made his on-screen debut, appearing in some scenes and one song sequence. At the same time he made his Telugu debut with Seshu and Malli Malli Chudali and also composed for the Tamil films Junior Senior and Pop Carn, starring Malayalam actors Mammootty and Mohan Lal, respectively, all of which performing poorly at the box offices, though. In 2003 Selvaraghavan's first independent directorial, the drama-thriller film Kaadhal Kondein released, which is considered a milestone for Yuvan Shankar Raja. His work in the film, particularly his background score, was unanimously praised, leading to the release of a separate CD consisting of several film score pieces, a la "Hollywood-style", which was reportedly the first film score CD release in India. Furthermore, the film went on to become a blockbuster, cementing the film's lead artist Dhanush and Yuvan Shankar in the Tamil film and music industry. The same year, he worked in Vishnuvardhan's debut film, Kurumbu, which featured the first remix song in a Tamil film. By that time, in a career spanning less than a decade, Yuvan Shankar Raja had established himself as one of the leading and most-sought after music directors in the Tamil film industry, despite having worked predominantly with newcomers and in low-budget productions. Success (2004-2007) Yuvan Shankar's 2004 releases, 7G Rainbow Colony, another Selvaraghavan film, and Silambarasan's Manmadhan, were both critically and commercially successful films, featuring acclaimed as well as popular music by Yuvan Shankar Raja, which also contributed to the films' successes.[35][37][38] His work in the former, in particular, got critically acclaimed and eventually led him to win the Best Music Direction Award at the 2004 Filmfare Awards South;[39] receiving the award at the age of 25, he remains the youngest winning music composer of the award. From since, he has had nine to ten releases every year on average, turning him into one of the most busiest and prolific Indian film composers.[6][40] His first of nine album releases of 2005 was Raam. His score for the Ameer-directed thriller, labelled as "soul-stirring", fetched him further accolades[41][42] and eventually yielded a win at the 2006 Cyprus International Film Festival for Best Musical score in a Feature Film,[43][44] the first such award for an Indian composer. His success streak continued with his following releases of that year, low-budget films such as Arinthum Ariyamalum, Kanda Naal Mudhal and Sandakozhi surprisingly becoming successful ventures at the box office, since also Yuvan Shankar's compositions like "Theepidikka",[45] "Panithuli" and "Dhavani Potta" from the respective soundtracks enjoyed popularity and played an important role for the films's successes.[46] After the release of the soundtrack for the S. J. Suryaah-starring romantic comedy, Kalvanin Kadhali that also enjoyed popularity post the film's release,[44][47] his final album of 2005, Pudhupettai, released, which saw him once again collaborating with director Selvaraghavan. The ten-track experimental album, receiving exceptionally rave reviews, was considered Yuvan Shankar Raja's finest work till then and being hailed as a "musical masterpiece".[48][49] The soundtrack and score of the film featured a traditional orchestral score played by the "Chapraya Symphony" of Bangkok,[50] the first time in a Tamil film. Critics felt that this project, in particular, proved his abilities and talent to produce innovative and experimentative scores as well.[51] Karthik Srinivasan from milliblog commented that "Yuvan’s imagination soars way beyond the confines of a Tamil movie OST", describing the album as "clearly one of the most innovative albums in recent times".[52] The film itself, releasing only in May 2006, did average business, despite opening to outstanding reviews. He next worked on the romantic comedies Happy and Azhagai Irukkirai Bayamai Irukkirathu and the gangster film Pattiyal, which all released in early 2006. His Happy songs and score received positive reviews, with critics labelling the "youthful music" as "excellent", and the film's "main strength", whilst his score for Pattiyal was highly praised by critics; a Sify reviewer wrote, "Yuvan Shankar Raja’s music and background score is the life of the film". Further more, both films went on to become very successful ventures, both commercially and critically. His subsequent releases that year include Silambarasan's debut directorial, Vallavan and the action entertainer Thimiru. Yuvan Shankar Raja was hailed as the "real hero" of the former, which featured some of the year's most listened tracks like "Loosu Penne" and "Yammadi Aathadi", while the latter film ranked amongst the year's highest-grossing films. In November 2006, the Paruthiveeran soundtrack album got released, which saw the composer foraying into pure rural folk music, using traditional music instruments. Though initially releasing to mixed reviews, with critics doubting whether the songs could attract modern youth audience, his first attempt at rural music turned out to be a major success, following the film's outstanding run at the box office. The film, Ameer's third feature film as well as Karthi's debut venture, received universal critical acclaim after its release in February 2007 and became a blockbuster, whilst particularly the song "Oororam Puliyamaram" was a chartbuster number in Tamil Nadu. In 2007, he had a record ten album releases in one year. The first was the soundtrack of the romantic drama film Deepavali, following which the audios of the sports comedy film Chennai 600028, the Telugu family entertainer Aadavari Matalaku Ardhalu Verule, Vasanth's thriller film Satham Podathey and the romantic films Thottal Poo Malarum and Kannamoochi Yenada released, with the former three being well-received besides garnering positive reviews. The films, Chennai 600028, Venkat Prabhu's directorial debut, and Aadavari Matalaku Ardhalu Verule, Selvaraghavan's Telugu debut, in particular, were high commercial successes and became one of the year's most successful films in Tamil and Telugu, respectively. In late 2007 then, the audio and the film Kattradhu Thamizh got released. The soundtrack album, which was released as Tamil M. A., as well as the film itself, had been met with exceptionally positive reviews and critical acclaim. The music was widely considered a "musical sensation" and noted to be a proof of Yuvan Shankar Raja's "composing skills". However, despite outstanding reviews by critics, the venture failed to evoke the interest of the audience and did not enjoy much popularity. His final release of 2007 was Billa, a remake of the 1980 Rajinikanth-starrer of the same title. This film, remade by Vishnuvardhan, starring Ajith Kumar in the title role, also featured two remixes from the original version. The film emerged one of the top-grossers of the year, whilst also fetching rave reviews for Yuvan Shankar's stylish musical score. Recent work (2008-present) In 2008, five films, featuring Yuvan's music were released, two of them being the Tamil and Kannada remakes of Aadavari Matalaku Ardhalu Verule, titled Yaaradi Nee Mohini and Anthu Inthu Preethi Banthu, respectively, which partly featured the original score and songs. The Tamil version, in particular, was able to repeat the success of the original film, emerging a high commercial success, while yielding Yuvan his second Filmfare nomination. The other releases that year include Seeman's Vaazhthugal, Venkat Prabhu's comedy-thriller Saroja, Ajith Kumar's action thriller Aegan and Silambarasan Rajendar's masala flick Silambattam, out of which, Saroja and Silambattam proved to be successful at the box office, with Yuvan Shankar's score in the former and his songs in the latter garnering accolades and several awards at the 2009 Isaiyaruvi Tamil Music Awards. Out of his nine 2009 releases, hardly any managed to succeed, in spite of receiving widespread critical acclaim, since the respective films failed at the box office. Excluding the romantic comedy Siva Manasula Sakthi, featuring his most popular song of the year "Oru Kal", his other films were box-office bombs, while few songs like "Siragual" (Sarvam) and "Aedho Saigiral" (Vaamanan) still became popular. He had also provided a rural score again in Kunguma Poovum Konjum Puravum and a sarangi-based score for the urban action drama of Ameer's Yogi, both going unnoticed. His score for his Telugu romantic musical Oy!, meanwhile, fetched him the Special Jury Award at the 2010 South Filmfare Awards. In late 2009, the soundtrack album of Paiyaa released, which was regarded as a "blockbuster album" and "magnum opus", as it went on to become exceptionally popular, much prior to the film's release, and probably one of Yuvan Shankar Raja's biggest success of his career. The song "Thuli Thuli" had become the first Tamil song to be featured in the India Top 20 list for April 2010, indicating it was the most frequently played Tamil song on all Indian FM radio stations in the history of Tamil film music. The film itself became one the highest earners of the year, particularly supported by Yuvan's score and songs. Along with Paiyaa, songs from three more films for which he composed music that year - Naan Mahaan Alla, Baana Kaathadi and Boss Engira Bhaskaran - featured among the Top 10 chartbusters of the year. Besides Tamil films, he has also scored music for films in other South Indian languages. Around 35 of the Tamil films, for which he had composed music, were afterwards dubbed into Telugu, Kannada or Malayalam languages as were the respective soundtracks. Apart from these ones, he also worked "straightly" on Telugu projects such as Seshu, Malli Malli Chudali, Happy, Raam, Raju Bhai and Aadavari Matalaku Ardhalu Verule, making him a well-known popular composer in Andhra Pradesh, too. His latest Telugu album Oy! has become a grand success as it topped the charts for several weeks. In 2010 he composed his first Bollywood song "Haq Se" as part of the ensemble soundtrack of the film Striker, starring his close friend Siddharth, which received thoroughly positive reviews. His latest soundtracks, which got popular among the masses, include Vaanam, Naan Mahaan Alla, Goa and Paiyaa. He is currently working on nearly ten projects simultaneously, including Venkat Prabhu's Mankatha, starring Ajith Kumar, Ameer's Aadhi Bhagavan, the N. Lingusamy directorial Vettai, Vishnuvardhan's first Telugu film The Shadow, the Mani Ratnam-produced Bloody Paki, his first proper Bollywood project, and half-a-dozen other small-budget films. Yuvan Shankar Raja's collaborations with several film directors such as Selvaraghavan, Ameer Sultan, Vishnuvardhan, Venkat Prabhu and Linguswamy have always resulted in highly successful soundtracks. Likewise he has often worked together with noted Tamil poet Vaali and young Tamil lyricists including Na. Muthukumar, Pa. Vijay and Snehan to come up with much-loved compositions. Other work Playback singing Besides, Yuvan Shankar Raja is a noted playback singer as well. As of August 2011, he has sung over 80 songs, mostly his own composed songs and several times for his father Ilaiyaraaja and his brother Karthik Raja. He lent his voice first in 1988, when he was eight years old for a song in the film En Bommukutty Ammavukku, composed by his father. Since, he frequently sang for his father in films such as Anjali (1990), Chatriyan (1990), Thalattu Ketkuthamma (1991), Friends (2001), Kaathal Jaathi (2002) and Ramana (2003). Under his brother's direction, he had sung in the films Naam Iruvar Namakku Iruvar (1998) and Ullam Kollai Poguthae (2001). He had also performed a song for the film Siddu +2 (2010), composed by his friend Dharan,[83] and had lent his voice for the theme song for the World Classical Tamil Conference 2010, set to tune by A. R. Rahman. However, he is better known as a singer of his own composed songs. Films, featuring some of his most popular songs as a singer, include Thulluvadho Ilamai, April Maadhathil, Pudhupettai, Pattiyal, Azhagai Irukkirai Bayamai Irukkirathu (in which he had sung all songs),[85] Deepavali, Kattradhu Thamizh, Siva Manasula Sakthi, Sarvam, Paiyaa and Naan Mahaan Alla, the latter earning him a Filmfare nomination for the Best Male Playback Singer Award. Non-cinematic output Aside from scoring film music and soundtracks, he also produces personal music albums from time to time. In his very early years, in 1999, when he was not familiar to most people yet, he made the Tamil pop album The Blast, that contained 12 tracks, featuring vocals by Kamal Haasan, Unnikrishnan and Nithyashree Mahadevan. However, the album went downright unnoticed. In 2008, he started working on his second album, the rights of which had been acquired by Sony BMG then. Reportedly a bilingual album produced in both Tamil and Hindi, the album never was released. In 2010, he joined hands with former President of India A. P. J. Abdul Kalam for a grand music video album titled "Song of Youth".The popular song of the same title, based on which the album is made, was written by Kalam and is set to tunes by Yuvan Shankar Raja, who, along with Kalam and many other celebrities from the field of sports and entertainment, will feature in the video as well. The album is a trilingual, produced in the three languages Tamil, Hindi and English and is expected to release in 2011. Concerts In January 2009, Yuvan had announced his first live performance, which was planned to be held at the Rogers Centre in Toronto, Canada on 25 April 2009. According to Yuvan, the show would have featured around 30 songs, sung by well-known singers and his father Ilaiyaraaja, as well as some stage dances in between by actresses Sana Khan and Meenakshi. However, the concert had been postponed eventually, with Yuvan Shankar stating, that he was working on novel ideas to make the show memorable and hence, postponed the concert. In October 2009 then, he announced that a world tour, titled "Oru Naalil", is planned with a three-hour stage show to be held in various cities all over the world. The tour began with a show on 1 December 2009 at the Sharjah Cricket Association Stadium in Dubai, United Arab Emirates, featuring performances by singers like Shankar Mahadevan, Hariharan, Karthik, Harish Raghavendra and Silambarasan and professional dancers from Mumbai, which was expected to be followed by shows in Canada, the U. S. and South Africa. Also it was planned to conduct the shows in Muscat, Oman and Kuwait, but following the Dubai concert, the tour was cancelled. In October 2010, Yuvan Shankar Raja disclosed that he had signed for his first live concert in Chennai. The concert, which was sponsored, organized and later telecasted on STAR Vijay, was held at YMCA Grounds, Nandanam, Chennai, on 16 January 2011. Additionally, a promotional music video, "I'll Be There for You", composed and sung by Yuvan Shankar, himself, directed by Vishnuvardhan and shot by Nirav Shah, was made, while STAR Vijay aired a 3-week, 14 episode serial on Yuvan Shankar Raja as a run-up to the concert. Personal life Yuvan Shankar Raja married his longtime girlfriend Sujaya Chandran on 21 March 2005, at Mayor Sri Ramanathan Chettiyar Hall in Chennai, India. Chandran hat met him in 2002 as a fan at a music cultural program in London and both fell in love later. Chandran was a London-based singer and the daughter of Dr. C. R. Velayutham and Dr. Sarojini Chandran. They had a secret registered marriage in September 2003 in London, before the formal public wedding was held in 2005 with the consent of their parents. In August 2007, they filed for divorce with mutual consent, which was granted in February 2008, after 6 months. The reason for the divorce was cited to be "irreconcilable differences". On 1 September 2011, he married Shilpa Mohan at the Tirumala Venkateswara Temple, Tirupati in Andhra Pradesh. The marriage was held in a simple ceremony with family members and close friends being present only. Shilpa was revealed to be a B.Pharm graduate from the University of Adelaide, Australia. A wedding reception was arranged a day later in Chennai. Filmography * The films are listed in order of the album release date, irrespective of the film release date. * The year next to the title of the affected films indicates the release year of the either dubbed or remade version in the named language later than the original version. * • indicates original language release. Indicates simultaneous makes, if featuring in more languages * ♦ indicates a remade version, the remaining ones being dubbed versions * Filmfare Best Music Director Award (Tamil) for 7G Rainbow Colony (2004) * Filmfare Special Jury Award for Oy! (2009) * Tamil Nadu State Film Award for Best Music Director for Pattiyal (2006) * Cyprus International Film Festival Award For Best Musical Score Feature Film for Raam (2006) * Vijay Award for Favourite Song for "En Kadhal Solla" (Paiyaa) (2010) Nominations * Filmfare Award for Best Music Director – Telugu for Aadavari Matalaku Ardhalu Verule (2007) * Filmfare Award for Best Music Director – Tamil for Yaaradi Nee Mohini (2008) * Filmfare Award for Best Music Director – Tamil for Paiyaa (2010) * Filmfare Award for Best Music Director – Tamil for Naan Mahaan Alla (2010) * Filmfare Award for Best Male Playback Singer – Tamil for "Iragai Pole" - Naan Mahaan Alla (2010) * Vijay Award for Best Music Director for Paruthiveeran (2007) * Vijay Award for Best Music Director for Saroja (2008) * Vijay Award for Best Music Director for Siva Manasula Sakthi (2009) * Vijay Award for Best Music Director for Paiyaa (2010) Other awards * o Ananda Vikatan Award for Best Composer of the Year (2007) o Ananda Vikatan Award for Best Male Playback Singer of the Year for "Neethane" (Sarvam) (2009) o Big FM Tamil Entertainment Awards - Most Entertaining Music Director of the Year Award for Paiyaa (2011) o Cinema Rasigargal Sangam Best Music Director Award for Billa (2007) o CJA Cine Critics' Best Music Director Award for Kattradhu Thamizh (2007) o GV South Indian Cinematographers Association (SICA) Best Music Director Award (2007) o Isaiyaruvi Tamil Music Awards + Isaiyaruvi Album of the Year - Paruthiveeran (2007) + Isaiyaruvi Best Folk Song of the Year - "Oororam Puliyamaram" (Paruthiveeran) (2007) + Miranda Crazy Song of the Year - "Saroja Saamaan Nikalo" (Chennai 600028) (2007) + Isaiyaruvi Sensational Youth Album - Silambattam (2008) + Crazy Song of the Year - "Where Is The Party" (Silambattam) (2008) + Isaiyaruvi Best Remix Song of the Year - "Vechikkava" (Silambattam) (2008) o Jayam Charitable Trust Film Music Awards + Best Sensational Musician (2007) + Best Singer of the Year Special Award for "Arabu Naade" (Thottal Poo Malarum) (shared with Haricharan) (2007) o Medimix-Dinakaran Best Music Director Award for Manmadhan (2004) o Mirchi Music Awards South + Mirchi Music Award for Best Music Composer of the Year for "Oru Kal Oru Kannadi" (Siva Manasula Sakthi) (2009) + Mirchi Music Award for Best Album of the Year for Paiyaa (2010) + Mirchi Music Award for Mirchi Listeners’ Choice – Best Song of the Year for "En Kadhal Solla" (Paiyaa) (2010) + Mirchi Music Award for Mirchi Listeners’ Choice – Best Album of the Year for Paiyaa (2010) o Spell Bound Best Music Director Award for Vallavan (2006) o Vijay Music Awards + Best Singer with the Maximum Hits of 2010 + Popular Duet of the Year - "Idhu Varai" (Goa) (2011) + Popular Song sung by a Music Director – "En Kadhal Solla" (Paiyaa) (2011) + Mirchi Listeners Choice of the Year - "Thuli Thuli" (Paiyaa) (2011)
Bearcats Men’s Basketball Hopeful Third Time Is The Charm Versus Hartford When the Binghamton Bearcats face the Hartford Hawks Saturday evening at 8:30 at Albany’s SEFCU Arena they hope that the third time is the charm. BU has played the Hawks tough in two regular season meetings but came out of both with losses. Binghamton lost on a put-back bucket with less than four seconds left in a January 23 game at the Events Center. Then last week in Hartford BU went to overtime before dropping an 89-83 decision. Jordan Reed went off for 33 points to pace the Bearcats. WNBF News/ Roger Neel Photo The Hawks have one of the conference’s best forwards in Mark Nwakamma who is averaging 15.1 points per game and 5.9 rebounds per outing. Wes Cole is averaging 9.4 points per game and is one of the top three-point shooters in the country. The Bearcats expect to have speedster Marlon Beck back in the lineup after missing the Vermont game with a lower leg injury. Airtime is set for 8:15 Saturday evening on News Radio 1290 WNBF and wnbf.com. Welcome back to News-Breakers Club It appears that you already have an account created within our VIP network of sites on . To keep your personal information safe, we need to verify that it's really you. To activate your account, please confirm your password. When you have confirmed your password, you will be able to log in through Facebook on both sites. *Please note that your prizes and activities will not be shared between programs within our VIP network. Welcome back to News-Breakers Club It appears that you already have an account on this site associated with . To connect your existing account just click on the account activation button below. You will maintain your existing VIP profile. After you do this, you will be able to always log in to http://wnbf.com using your original account information.
Lord's Diner drops plans for 21st and Grove The Lord's Diner this afternoon withdrew a controversial proposal to open a satellite diner at 21st and Grove. "Regrettably, over the past few months, we have reached an impasse in our efforts to move forward with a Lord's Diner in the northeast community," executive director Wendy Glick said in a prepared statement. "Out of respect for those who have voiced concerns, we are withdrawing our proposal for a Lord's Diner at 21st and Grove." She said the diner has no immediate plans to look elsewhere for a possible satellite location. Never miss a local story. Sign up today for a free 30 day free trial of unlimited digital access. After several months of study, the Lord's Diner tentatively agreed to rent the former Boys and Girls Club building at 21st and Grove from the city of Wichita for $15,000 a year. Under the plan, the diner would have had an option to buy the building for $150,000, minus any rent already paid. The Wichita City Council was scheduled to take up the proposal Tuesday, but Glick said Catholic Diocese of Wichita officials today asked Mayor Carl Brewer to withdraw the item from the agenda. Since plans to open a satellite location at 21st and Grove were announced, the diner has received an outpouring of opposition from those who thought it would detract from efforts they've made to improve the 21st Street corridor. The Wichita Ministerial League, which represents about 25 predominantly African-American churches, held a meeting Thursday that drew more than 50 people, most of them adamantly opposed to the 21st Street plan. Glick said concerns raised at that meeting, and in conversations with community leaders, convinced those who operate the diner to abandon the 21st Street plan.
743 N.E.2d 247 (2001) STATE BOARD OF TAX COMMISSIONERS, Appellant (Respondent Below), v. INDIANAPOLIS RACQUET CLUB, INC., Appellee (Petitioner Below). No. 49S10-0011-TA-631. Supreme Court of Indiana. March 6, 2001. *248 Karen M. Freeman-Wilson, Attorney General of Indiana, Jon Laramore, Deputy Attorney General, Indianapolis, IN, Attorneys for Appellant. Stephen E. DeVoe, B. Keith Shake, Indianapolis, IN, Attorneys for Appellee. ON PETITION FOR REVIEW BOEHM, Justice. We hold that the Tax Court erred in concluding that Indiana Code section 6-1.1-31-6 requires the State Board of Tax Commissioners and the county land valuation commission to consider all of the listed factors as to each parcel. The State Board may adopt rules providing that actual sales of comparable properties may serve as a proxy for these factors. However, in this case we conclude that the Indianapolis Racquet Club has demonstrated that the county commission and the State Board failed to follow the State Board's rules in valuing IRC's land by including it among noncomparable properties in its land order. Accordingly, we remand to the State Board. *249 Factual and Procedural Background Indianapolis Racquet Club (IRC) is the owner of two parcels of property located in Washington Township at 82nd and Dean Road on the north side of Indianapolis.[1] The facility consists of sixteen indoor tennis courts, eight outdoor courts, and associated locker rooms and retail and administrative space. This litigation arises out of the 1989 assessments of IRC's property. Specifically, IRC maintains that this property was improperly classified in the Marion County Land Valuation Order as part of the "82nd Street Corridor" rather than designated "Township-other." Land in the "82nd Street Corridor" is assessed at a base rate of $3.00 to $4.00 per square foot, and land classified as "Township-other" is assessed at a base rate of $1.50 to $3.00 per square foot. After inclusion in the "82nd Street Corridor," IRC's land was assessed by the Washington township assessor at a base rate of $3.00 per square foot. IRC petitioned for review with the Marion County Board of Review, and the Board ruled against it in late 1990 and early 1991. Further review by the State Board resulted in hearings in the fall of 1995 and final determinations adverse to IRC in the summer of 1996. IRC then petitioned the Tax Court, and, on January 31, 2000, the Tax Court ordered the petition remanded to the State Board. The Tax Court concluded that the Marion County Land Commission and the State Board had erred in classifying IRC's property as part of the "82nd Street Corridor" because they had failed to consider the nine statutory criteria listed in Indiana Code section 6-1.1-31-6. Indianapolis Racquet Club, Inc. v. State Bd. of Tax Comm'rs, 722 N.E.2d 926, 935 (Ind.Tax 2000). The Tax Court directed the State Board to reconsider the land classification using all of the statutory criteria and to determine the appropriate base rate. Id. The State Board petitioned for review. Standard of Review Review of a decision of the Tax Court is subject to the same "clearly erroneous" standard of review as that provided in Indiana Trial Rule 52(A), which provides for appeal from trial court findings and conclusions. We consider the evidence most favorable to the judgment on appeal and do not reweigh the evidence. Chidester v. City of Hobart, 631 N.E.2d 908, 910 (Ind.1994). In conducting our review, we recognize that the Indiana Tax Court was established to develop and apply specialized expertise in the prompt, fair, and uniform resolution of state tax cases. Indiana Dep't of State Revenue v. Caylor-Nickel Clinic, P.C., 587 N.E.2d 1311, 1313 (Ind.1992). Therefore, with regard to issues within the particular purview of the Tax Court, we exercise cautious deference. Id. I. Indiana Code Section 6-1.1-31-6 and Use of Actual Sales Data as a Proxy Indiana Code section 6-1.1-31-6 provides: (a) With respect to the assessment of real property, the rules of the state board of tax commissioners shall provide for: (1) the classification of land on the basis of: (i) acreage; (ii) lots; (iii) size; (iv) location; (v) use; (vi) productivity or earning capacity; (vii) applicable zoning provisions; *250 (viii) accessibility to highways, sewers, and other public services or facilities; and (ix) any other factor that the board determines by rule is just and proper .... The Tax Court concluded that the commission and the State Board had erred in failing to consider all of the listed factors under subsection (a)(1) in arriving at the classification of IRC's property within the "82nd Street Corridor." The State Board counters that the statute does not support the position that all of these factors must be considered as to each land valuation order. Rather, the State Board argues that the statute requires only that it take these factors into consideration in promulgating its rules for assessment of real property. The State Board contends that the Tax Court erred in concluding each of the statutory factors must be applied by the local assessing authority to each individual parcel, and claims that such a requirement would create a substantial if not enormous administrative burden to no good end. The State Board's rules provide, in broad brush, that actual sales data of comparable properties, where available, reflect the sum of the effects of these factors on individual parcels. The State Board argues that it is within its expertise to promulgate rules providing for use of sales data as a proxy for the statutory factors, and that the existing rules establish an acceptable practice for making mass assessments. Consistent with its position in this Court, the State Board has determined that land is to be assessed by comparison to actual sales of comparable properties, with adjustments to account for differences in frontage, improvements, depth, and similar factors to arrive at a value of land in the area. Ind.Admin.Code tit. 50, r. 2.1-2-1 to -2 (1987). Under this method, land value maps are developed that divide political subdivisions into neighborhoods "based on characteristics that distinguish [each] from surrounding neighborhoods, such as value ranges of improvements, zoning, or other restrictions on land use." Id. The Tax Court found this practice inconsistent with the statute. Although it acknowledged that "[t]he plain language of the section does not concretely require the State Board to consider each of the nine factors in classifying land ... it could be reasonably interpreted to have such meaning." IRC, 722 N.E.2d at 933. Considered in light of the General Assembly's constitutional mandate to provide "for a uniform and equal rate of property assessment and taxation," Ind. Const. art. X, § 1, the Tax Court concluded, the "logical" interpretation is that the General Assembly intended for the State Board to consider the listed factors in "placing a particular parcel within a specific category of a land valuation order." IRC, 722 N.E.2d at 933. All parties agree that the statute requires consideration of the listed factors in promulgating rules for assessing parcels. The statute says that in so many words. It reads: "[w]ith respect to the assessment of real property, the rules of the state board of tax commissioners shall provide for...." I.C. § 6-1.1-31-6 (emphasis added). The State Board disagrees with the Tax Court in the next step of the analysis. The State Board contends that a rule providing a rational basis to value parcels in light of the statutory factors is sufficient. The Tax Court reasoned that a more particularized judgment is required and that the statutory factors must be evident as to each parcel. We agree with the State Board. We see no barrier to procedures designed to arrive at a fair assessment that reflects the statutory factors, but does not take each factor into account as to each individual parcel. The statute does not use the term "land order." But land orders classifying parcels as to land valuation are adopted pursuant to the rules governing assessment promulgated by the State Board. *251 The rules of the State Board are found in title 50 of the Indiana Administrative Code, article 2.1, rule 2 (i.e., the "1989 Real Property Assessment Manual"), which details procedures for local assessors to follow in the valuation of land. As the Tax Court has frequently pointed out, land orders are initially proposed by county commissions, but become rules of the State Board after review by the Board. IRC, 722 N.E.2d at 931; Precedent v. State Bd. of Tax Comm'rs, 659 N.E.2d 701, 704 (Ind.Tax 1995); Poracky v. State Bd. of Tax Comm'rs, 635 N.E.2d 235, 236-37 (Ind.Tax 1994); Mahan v. State Bd. of Tax Comm'rs, 622 N.E.2d 1058, 1062 (Ind.Tax 1993); Johnson County Farm Bureau Coop. Ass'n v. Indiana Dep't of State Revenue, 568 N.E.2d 578, 586 (Ind.Tax 1991). Although the legislature has dictated factors that must be considered in the State Board's rules for assessment of real property, it has left it to the Board's discretion to adopt rules that accomplish that end. In simple terms, the statute directs the goal, but not the means. This is standard operating procedure for administrative agencies. Cf. I Kenneth Culp Davis & Richard J. Pierce, Jr., Administrative Law Treatise § 2.6, at 67 (3d ed. 1994) ("[The legislature] routinely delegates to agencies the power to make major policy decisions in the form of rules of conduct that bind all citizens. When [a legislative body] delegates authority to an agency, it accompanies that grant of power with substantive standards."). The State Board has followed the statutory directive. By rule, see 50 IAC 2.1-2-1 to -2, the State Board has adopted the procedure for the adoption of land orders, which themselves become rules if adopted pursuant to that procedure. The State Board has determined that use of comparable sales in formulating the land order meets the requirement to consider the relevant statutory factors. This is a far different proposition from the Tax Court's view that construes the statute to require every factor to be considered not only in the promulgation of the State Board's rules, as the statute expressly provides, but also in the individual valuation of every parcel of land, unless the criterion is simply inapplicable. We agree with the State Board and IRC that use of comparable sales is an appropriate assessment procedure, and that it is well within the discretion of the State Board to promulgate rules that give appropriate consideration to the nine statutory factors by looking to actual sales data, and making the rational assumption that the cumulative effect of the individual factors is reflected in the sales prices reached by buyers and sellers in the market. Accordingly, we disagree that the State Board or local assessors are required to assess each parcel in the light of the effect of each statutory factor on its valuation. II. The Land Order Under its rules, the State Board has approved the use of actual market sales data as a proxy for some of the listed criteria of Indiana Code section 6-1.1-31-6. We agree with the State Board that this practice has been implicitly authorized by the General Assembly in the General Assembly's approval of generally accepted appraisal practices. See Ind.Code § 6-1.1-31-3(4) (1998) ("The state board of tax commissioners may consider: ... (4) generally accepted practices of appraisers, including generally accepted property assessment valuation and mass appraisal principles and practices...."). Under the State Board's own rules, however, the use of actual sales data presumes that the parcels included in the data are comparable to the property sought to be assessed. The rules demand first that neighborhoods be rationally identified: "Each neighborhood can be delineated based on characteristics that distinguish it from surrounding neighborhoods." Ind.Admin.Code tit. 50, r. 2.1-2-1(c) (1987). Second, the rules demand that values to be used for any given neighborhood be "determined by comparing several sales of similar properties." Id. Thus, the political subdivision must be correctly broken down into neighborhoods *252 consisting of comparable parcels of property and the parcels within a neighborhood must be comparable with those from which the sales data is derived. IRC's principal contention is not that the 1989 Assessment Manual failed to account for the criteria set forth in Indiana Code section 6-1.1-31-6. Nor does IRC challenge the legitimacy of the State Board's rules. To the contrary, Stephen DeVoe, President of IRC, testified that, "we think as a taxpayer we're entitled to have the procedures in the manual followed." Consistent with this view, IRC's primary argument all along has been that its property differs significantly from the surrounding properties with which it has been grouped and that IRC would have been more properly classified as "other." In simple terms, IRC does not challenge the use of sales of comparable properties to establish the land values of its parcels. It simply contends that it was not grouped with comparable parcels when it was classified in the "82nd Street Corridor." Because we agree that a land order may look to sales of comparable properties to determine assessment value, the issue in this case is whether the township assessor correctly classified IRC as part of the "82nd Street Corridor" and whether the State Board was correct in adhering to that determination. Kevin Fasick, the chief values deputy for the Washington Township's Assessor office in 1989, testified at trial that several characteristics of IRC had not been taken into account in its 1989 assessment. Notably it did not consider that one of the parcels did not abut 82nd Street and that neither parcel had direct access to 82nd Street. It is also significant that no consideration was given to the fact that, unlike the other properties in the area, IRC was zoned "SU-3," which does not allow the high-intensity retail traffic of the surrounding properties. In reviewing a decision of the State Board, the Tax Court is to give great deference to the State Board when the Board acts within the scope of its authority. Wetzel Enters., Inc. v. State Bd. of Tax Comm'rs, 694 N.E.2d 1259, 1261 (Ind. Tax 1998). The Tax Court is to reverse a final determination of the State Board only when its decision is unsupported by substantial evidence, is arbitrary or capricious, constitutes an abuse of discretion, or exceeds statutory authority. Id. The taxpayer bears the burden of demonstrating that the State Board's final determination is invalid. IRC, 722 N.E.2d at 930 (citing Clark v. State Bd. of Tax Comm'rs, 694 N.E.2d 1230, 1233 (Ind.Tax 1998)). Because we have concluded that the State Board's rules require that properties within a land grouping be comparable and that sales data be obtained from the sale of properties that are truly comparable, we agree with the Tax Court that IRC has met its burden of demonstrating that the State Board's final determination was invalid. Specifically, the lack of frontage on 82nd Street and lack of access to 82nd Street differentiate it from the high value retail properties in the corridor. The same is true of IRC's zoning. The State Board argues that, even if this Court determines that its final determination was invalid, IRC should still lose because IRC cannot prove that it was harmed by the land valuation order. Citing State Board of Tax Commissioners v. Town of St. John, 702 N.E.2d 1034, 1040 (Ind.1998), the State Board also notes that a taxpayer does not have a constitutional entitlement to a precisely accurate assessment of property. More specifically, the State Board notes that IRC's property was valued at a base rate of $3.00 per square foot, which is at the top of the range for property classified as "other" in Washington Township. Thus, even if IRC's property is reclassified as "other" it is possible that IRC's base rate will not change. We disagree with the State Board's conclusion that because of this possibility IRC has failed to establish that the State Board's final determination is invalid. The State Board admits the existence of several factors *253 that devalue IRC's property in comparison with surrounding properties. It also concedes that these factors were not considered in the classification of IRC's property. If nothing else, it is clear that, if the local assessing authority had determined that IRC's property belonged to the "other" category, IRC would not have been worse off than it is now. We think it indisputable that, in order for a determination to be valid, both the initial classification and the base rate must have been derived according to the State Board's rules. Cf. Zakutansky v. State Bd. of Tax Comm'rs, 696 N.E.2d 494, 497 (Ind.Tax 1998) (remanding to State Board where incorrect cost schedule to assess buildings was used, although under the proper cost schedule the assessment might not vary significantly). Because IRC has proved that its classification was not arrived at according to the State Board's rules, it has carried its burden of showing that the State Board's final determination was invalid. It has also submitted evidence that suggests its property is neither comparable to surrounding properties nor the market data used as a proxy for the criteria of Indiana Code section 6-1.1-31-6. On remand, as the Tax Court pointed out, IRC "bears the burden of going forward with probative evidence concerning the proper classification of [its property] within the Order and the appropriate base rate to be assigned the parcels." IRC, 722 N.E.2d at 941. Conclusion We remand to the State Board for further proceedings consistent with this opinion. SHEPARD, C.J., and DICKSON, SULLIVAN, and RUCKER, JJ., concur. NOTES [1] The State Board concedes that it inadvertently omitted from its "Petition for Review" caption a second party to this action, Racquet Square Associates (RSA). The State Board initially moved to amend its petition and then withdrew its motion. Accordingly, the State Board is not petitioning for review from the Tax Court's determinations affecting the assessment of RSA's property.
// Mgmt // Copyright (C) 2013-2020+ James Shubin and the project contributors // Written by James Shubin <james@shubin.ca> and the project contributors // // This program is free software: you can redistribute it and/or modify // it under the terms of the GNU General Public License as published by // the Free Software Foundation, either version 3 of the License, or // (at your option) any later version. // // This program is distributed in the hope that it will be useful, // but WITHOUT ANY WARRANTY; without even the implied warranty of // MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the // GNU General Public License for more details. // // You should have received a copy of the GNU General Public License // along with this program. If not, see <http://www.gnu.org/licenses/>. package deployer import ( "context" "fmt" "strconv" "strings" "sync" "github.com/purpleidea/mgmt/etcd/interfaces" "github.com/purpleidea/mgmt/util/errwrap" etcd "go.etcd.io/etcd/clientv3" etcdutil "go.etcd.io/etcd/clientv3/clientv3util" ) const ( deployPath = "deploy" payloadPath = "payload" hashPath = "hash" ) // SimpleDeploy is a deploy struct that provides all of the needed deploy // methods. It requires that you give it a Client interface so that it can // perform its remote work. You must call Init before you use it, and Close when // you are done. type SimpleDeploy struct { Client interfaces.Client Debug bool Logf func(format string, v ...interface{}) ns string // TODO: if we ever need to hardcode a base path wg *sync.WaitGroup } // Init validates the deploy structure and prepares it for first use. func (obj *SimpleDeploy) Init() error { if obj.Client == nil { return fmt.Errorf("the Client was not specified") } obj.wg = &sync.WaitGroup{} return nil } // Close cleans up after using the deploy struct and waits for any ongoing // watches to exit before it returns. func (obj *SimpleDeploy) Close() error { obj.wg.Wait() return nil } // WatchDeploy returns a channel which spits out events on new deploy activity. // It closes the channel when it's done, and spits out errors when something // goes wrong. If it can't start up, it errors immediately. The returned channel // is buffered, so that a quick succession of events will get discarded. func (obj *SimpleDeploy) WatchDeploy(ctx context.Context) (chan error, error) { // key structure is $NS/deploy/$id/payload = $data path := fmt.Sprintf("%s/%s/", obj.ns, deployPath) // FIXME: obj.wg.Add(1) && obj.wg.Done() return obj.Client.Watcher(ctx, path, etcd.WithPrefix()) } // GetDeploys gets all the available deploys. func (obj *SimpleDeploy) GetDeploys(ctx context.Context) (map[uint64]string, error) { // key structure is $NS/deploy/$id/payload = $data path := fmt.Sprintf("%s/%s/", obj.ns, deployPath) keyMap, err := obj.Client.Get(ctx, path, etcd.WithPrefix(), etcd.WithSort(etcd.SortByKey, etcd.SortAscend)) if err != nil { return nil, errwrap.Wrapf(err, "could not get deploy") } result := make(map[uint64]string) for key, val := range keyMap { if !strings.HasPrefix(key, path) { // sanity check continue } str := strings.Split(key[len(path):], "/") if len(str) != 2 { return nil, fmt.Errorf("unexpected chunk count of %d", len(str)) } if s := str[1]; s != payloadPath { continue // skip, maybe there are other future additions } var id uint64 var err error x := str[0] if id, err = strconv.ParseUint(x, 10, 64); err != nil { return nil, fmt.Errorf("invalid id of `%s`", x) } // TODO: do some sort of filtering here? //obj.Logf("GetDeploys(%s): Id => Data: %d => %s", key, id, val) result[id] = val } return result, nil } // calculateMax is a helper function. func calculateMax(deploys map[uint64]string) uint64 { var max uint64 for i := range deploys { if i > max { max = i } } return max } // GetDeploy returns the deploy with the specified id if it exists. If you input // an id of 0, you'll get back an empty deploy without error. This is useful so // that you can pass through this function easily. // FIXME: implement this more efficiently so that it doesn't have to download // *all* the old deploys from etcd! func (obj *SimpleDeploy) GetDeploy(ctx context.Context, id uint64) (string, error) { result, err := obj.GetDeploys(ctx) if err != nil { return "", err } // don't optimize this test to the top, because it's better to catch an // etcd failure early if we can, rather than fail later when we deploy! if id == 0 { return "", nil // no results yet } str, exists := result[id] if !exists { return "", fmt.Errorf("can't find id `%d`", id) } return str, nil } // GetMaxDeployID returns the maximum deploy id. If none are found, this returns // zero. You must increment the returned value by one when you add a deploy. If // two or more clients race for this deploy id, then the loser is not committed, // and must repeat this GetMaxDeployID process until it succeeds with a commit! func (obj *SimpleDeploy) GetMaxDeployID(ctx context.Context) (uint64, error) { // TODO: this was all implemented super inefficiently, fix up for perf! deploys, err := obj.GetDeploys(ctx) // get previous deploys if err != nil { return 0, errwrap.Wrapf(err, "error getting previous deploys") } // find the latest id max := calculateMax(deploys) return max, nil // found! (or zero) } // AddDeploy adds a new deploy. It takes an id and ensures it's sequential. If // hash is not empty, then it will check that the pHash matches what the // previous hash was, and also adds this new hash along side the id. This is // useful to make sure you get a linear chain of git patches, and to avoid two // contributors pushing conflicting deploys. This isn't git specific, and so any // arbitrary string hash can be used. // FIXME: prune old deploys from the store when they aren't needed anymore... func (obj *SimpleDeploy) AddDeploy(ctx context.Context, id uint64, hash, pHash string, data *string) error { // key structure is $NS/deploy/$id/payload = $data // key structure is $NS/deploy/$id/hash = $hash path := fmt.Sprintf("%s/%s/%d/%s", obj.ns, deployPath, id, payloadPath) tPath := fmt.Sprintf("%s/%s/%d/%s", obj.ns, deployPath, id, hashPath) ifs := []etcd.Cmp{} // list matching the desired state ops := []etcd.Op{} // list of ops in this transaction (then) // we're append only, so ensure this unique deploy id doesn't exist //ifs = append(ifs, etcd.Compare(etcd.Version(path), "=", 0)) // KeyMissing ifs = append(ifs, etcdutil.KeyMissing(path)) // don't look for previous deploy if this is the first deploy ever if id > 1 { // we append sequentially, so ensure previous key *does* exist prev := fmt.Sprintf("%s/%s/%d/%s", obj.ns, deployPath, id-1, payloadPath) //ifs = append(ifs, etcd.Compare(etcd.Version(prev), ">", 0)) // KeyExists ifs = append(ifs, etcdutil.KeyExists(prev)) if hash != "" && pHash != "" { // does the previously stored hash match what we expect? prevHash := fmt.Sprintf("%s/%s/%d/%s", obj.ns, deployPath, id-1, hashPath) ifs = append(ifs, etcd.Compare(etcd.Value(prevHash), "=", pHash)) } } ops = append(ops, etcd.OpPut(path, *data)) if hash != "" { ops = append(ops, etcd.OpPut(tPath, hash)) // store new hash as well } // it's important to do this in one transaction, and atomically, because // this way, we only generate one watch event, and only when it's needed result, err := obj.Client.Txn(ctx, ifs, ops, nil) if err != nil { return errwrap.Wrapf(err, "error creating deploy id %d", id) } if !result.Succeeded { return fmt.Errorf("could not create deploy id %d", id) } return nil // success }
ALBANY — The city's downtown residential permit parking system is now tentatively scheduled to start Jan. 15, and officials are urging eligible residents to have their permits in hand before then. In October, city officials began issuing the permits to residents of three zones within three-quarters of a mile of Empire State Plaza, but implementation of the system has been delayed as city workers install 1,400 street signs to alert motorists to the new restrictions. The color-coded signs, covered in paper, have begun to appear throughout the affected neighborhoods. Residents are being asked not to uncover them yet to avoid confusion. Permits cost $25 and are available, with proof of residency in one of the three zones, between 10 a.m. and 4 p.m. at the city clerk's office on the second floor of City Hall. For more information about the system and the required proof of residency, visit the city's website at www.albanyny.gov. Broadly, the plan will affect the Center Square, Washington Park, Hudson/Park and Park South, Mansion, Pastures and Ten Broeck Triangle neighborhoods. It will be in effect from 8 a.m. to 6 p.m. weekdays. Anyone will be allowed to park for up to two hours, even in permit-only spaces. But parking for longer than two hours will require motorists to have the correct color parking decal for that neighborhood. Violations will cost $50. Parking spaces adjacent to commercial properties, like those on Lark Street, are not affected by the system. After more than two years of planning, officials had initially hoped the system would take effect Oct. 1, but the logistics of issuing the permits to potentially thousands of residents, as well as ordering and posting the signs, caused delays. So far, only about 800 resident permits have been sold citywide, according to Councilman Richard Conti, who represents much of Zone A around Center Square. An additional 200 $10 visitor permits have been sold to residents to accommodate guests, City Clerk Nala Woodard said. Woodard urged residents to apply for their permits before the system goes into effect to ensure they get their permit in time and to avoid the last-minute crush of applicants. Ideally, Woodard said, he would like to get most permits issued before Jan. 15. Overall, up to 2,750 parking spaces are covered by the system, with many more residents than that eligible to receive a permit. Having a permit does not guarantee a parking space. Once it starts, the system will be in effect for at least two years. Making the program a two-year trial was one of the city's concessions to get state lawmakers to sign off on it after more than two decades of opposition from state-employee unions that represent thousands of workers who will be forced to find alternatives to the free on-street parking many have enjoyed for years. jcarleo-evangelist@timesunion.com • 518-454-5445 • @JCEvangelist_TU
Q: How do I set container within React Material UI's AppBar Component? When I see MUI's default AppBar, its children looks so apart especially in wide screen size. The logo is located completely left, and other navs is located too much right. So Items look so apart each other. What I want to do is like Bootstrap's component, I want to apply maximum width like below image. How do I set container within AppBar? This is what I tried. <AppBar> <ToolBar> <Grid container style = {{ maxWidth: 1170 }} > <Typography>Logo</Typography> </Grid> </ToolBar> </AppBar> But it's not worked... A: You may try using <CssBaseline /> <AppBar position="static"> <Container maxWidth="lg"> <ToolBar> <Typography>Logo</Typography> </ToolBar> </Container> </AppBar>
An ad-tech firm says it has discovered a large and sophisticated advertising-fraud operation in which fake websites and infected computers were used to scam advertisers and publishers out of upward of hundreds of thousands of dollars a day. Denmark-based Adform, identifier of the scheme, named it “Hyphbot” and estimates that it has been going on since at least August. According to Adform, the fraudsters behind the Hyphbot scheme created more than 34,000 different domain names and more than a million different URLs, many designed to attempt to fool advertisers into thinking they were buying ad inventory from big-name publishers such as the Economist, the Financial Times, The Wall Street Journal and CNN. It is a tactic known in the industry as “domain spoofing.” The perpetrators then generated a wave of nonhuman, or “bot,” traffic that loaded the fraudulent sites, which made money mostly through video ads. Video ads are lucrative because they carry higher rates than other online display ads. Fake traffic is a serious issue for advertisers because it means they have wasted money buying ads that were served to computer programs, rather than real people who might go on to purchase their products. And real publishers get cheated out of potential advertising revenue. Adform says much of the impact of the scheme could have been thwarted if publishers and ad-tech companies had implemented and kept up-to-date with a new industry initiative called Ads.txt, which is designed to stamp out domain spoofing. Adform’s investigation suggested that the people behind Hyphbot used a network of data centers and unwitting consumers’ computers, infected by malware, to access more than half a million IP addresses, mostly from the U.S., to mimic real browsing behavior on the network of fake sites. The suspicious URLs were presenting themselves in ad auctions via at least 14 different ad exchanges at a rate of up to 1.5 billion requests to ad buyers a day. Adform began informing the majority of ad exchanges affected on Sept. 28, two days after it began its analysis. Since then, it has seen a reduction in the fraudulent traffic, although Hyphbot is still believed to be active. Adform also informed the Federal Bureau of Investigation in the U.S. and Metropolitan Police in the U.K. Adform’s full findings were independently reviewed by two industry experts before the publication of the white paper. Jon Slade, the chief commercial officer of the Financial Times, said the publisher was “not surprised” to hear of another fraud scheme based around spoofing. Last month, the Financial Times ran its own investigation and found 25 ad exchanges had been offering fraudulent ad space, purporting to be from FT.com. “We are urging all actors in the supply chain to urgently implement and adopt the Ads.txt standard,” Mr. Slade said. “It’s one of the best bets for a cleanup that we have.” Dow Jones, the unit of News Corp that includes The Wall Street Journal, said it implemented Ads.txt about a month ago and echoed the FT’s sentiment that solving the larger problem “requires the participation of all parties involved.” A spokesman for Turner, the Time Warner unit that operates CNN, said it also implemented Ads.txt earlier this year. The Economist declined to comment. It is difficult to extrapolate exactly how much money the scheme has made so far. Adform describes Hyphbot as “likely the biggest bot network” to hit the online ad industry. Jay Stevens, Adform’s chief revenue officer, gave a “conservative” estimate that, at its height, the scheme could have been generating at least $500,000 a day. Hyphbot has the potential to be “three to four times” bigger than Methbot because it spoofed more web domains and used a larger bot network to generate the fake traffic, according to Adform’s research findings, outlined in a white paper published Tuesday. An estimated $6.5 billion in ad spending is expected to be wasted this year due to fraud, according to a report released in May by White Ops and the Association of National Advertisers. But, that amount is down 10% from 2016, suggesting some industry efforts to tackle the problem may be working. Ads.txt is a mechanism that allows publishers to display to ad buyers all the legitimate sellers of their ad inventory via a text file on their websites. Buyers and their ad-tech vendors can crawl those files —such as thisone from WSJ.com—and know to only to buy a particular website’s ads from those listed sellers. More than 36,000 web domains have adopted Ads.txt since it was introduced five months ago by the Interactive Advertising Bureau, the U.S. trade body said. Publishers adopting Ads.txt isn’t a full solution. It requires everyone else in the chain—from ad buyers to demand-side platforms and ad exchanges—to sign up and ensure the files are updated and scraped regularly in order for the initiative to work effectively. Aside from Ads.txt, Adform has also listed other suggested remedies in its Hyphbot white paper, which include encouraging ad-tech vendors to check their data warehouses for suspicious patterns of bid requests outlined in its report and shutting off associated networks. CONTENT FROM OUR SPONSOR Visual data on social media can reveal significant insights about consumers’ product preferences and uses, but the sheer amount of information available can be daunting. Riviter, a startup whose software can analyze social posts using AI and product attribution recognition, is helping brands turn that data into valuable insights. Please note: The Wall Street Journal News Department was not involved in the creation of the content above.
// Copyright 2010 Dolphin Emulator Project // Licensed under GPLv2+ // Refer to the license.txt file included. #include "InputCommon/ControllerInterface/XInput/XInput.h" #ifndef XINPUT_GAMEPAD_GUIDE #define XINPUT_GAMEPAD_GUIDE 0x0400 #endif namespace ciface { namespace XInput { static const struct { const char* const name; const WORD bitmask; } named_buttons[] = {{"Button A", XINPUT_GAMEPAD_A}, {"Button B", XINPUT_GAMEPAD_B}, {"Button X", XINPUT_GAMEPAD_X}, {"Button Y", XINPUT_GAMEPAD_Y}, {"Pad N", XINPUT_GAMEPAD_DPAD_UP}, {"Pad S", XINPUT_GAMEPAD_DPAD_DOWN}, {"Pad W", XINPUT_GAMEPAD_DPAD_LEFT}, {"Pad E", XINPUT_GAMEPAD_DPAD_RIGHT}, {"Start", XINPUT_GAMEPAD_START}, {"Back", XINPUT_GAMEPAD_BACK}, {"Shoulder L", XINPUT_GAMEPAD_LEFT_SHOULDER}, {"Shoulder R", XINPUT_GAMEPAD_RIGHT_SHOULDER}, {"Guide", XINPUT_GAMEPAD_GUIDE}, {"Thumb L", XINPUT_GAMEPAD_LEFT_THUMB}, {"Thumb R", XINPUT_GAMEPAD_RIGHT_THUMB}}; static const char* const named_triggers[] = {"Trigger L", "Trigger R"}; static const char* const named_axes[] = {"Left X", "Left Y", "Right X", "Right Y"}; static const char* const named_motors[] = {"Motor L", "Motor R"}; static HMODULE hXInput = nullptr; typedef decltype(&XInputGetCapabilities) XInputGetCapabilities_t; typedef decltype(&XInputSetState) XInputSetState_t; typedef decltype(&XInputGetState) XInputGetState_t; static XInputGetCapabilities_t PXInputGetCapabilities = nullptr; static XInputSetState_t PXInputSetState = nullptr; static XInputGetState_t PXInputGetState = nullptr; static bool haveGuideButton = false; void Init() { if (!hXInput) { // Try for the most recent version we were compiled against (will only work if running on Win8+) hXInput = ::LoadLibrary(XINPUT_DLL); if (!hXInput) { // Drop back to DXSDK June 2010 version. Requires DX June 2010 redist. hXInput = ::LoadLibrary(TEXT("xinput1_3.dll")); if (!hXInput) { return; } } PXInputGetCapabilities = (XInputGetCapabilities_t)::GetProcAddress(hXInput, "XInputGetCapabilities"); PXInputSetState = (XInputSetState_t)::GetProcAddress(hXInput, "XInputSetState"); // Ordinal 100 is the same as XInputGetState, except it doesn't dummy out the guide // button info. Try loading it and fall back if needed. PXInputGetState = (XInputGetState_t)::GetProcAddress(hXInput, (LPCSTR)100); if (PXInputGetState) haveGuideButton = true; else PXInputGetState = (XInputGetState_t)::GetProcAddress(hXInput, "XInputGetState"); if (!PXInputGetCapabilities || !PXInputSetState || !PXInputGetState) { ::FreeLibrary(hXInput); hXInput = nullptr; return; } } } void PopulateDevices() { if (!hXInput) return; XINPUT_CAPABILITIES caps; for (int i = 0; i != 4; ++i) if (ERROR_SUCCESS == PXInputGetCapabilities(i, 0, &caps)) g_controller_interface.AddDevice(std::make_shared<Device>(caps, i)); } void DeInit() { if (hXInput) { ::FreeLibrary(hXInput); hXInput = nullptr; } } Device::Device(const XINPUT_CAPABILITIES& caps, u8 index) : m_subtype(caps.SubType), m_index(index) { // XInputGetCaps can be broken on some devices, so we'll just ignore it // and assume all gamepad + vibration capabilities are supported // get supported buttons for (int i = 0; i != sizeof(named_buttons) / sizeof(*named_buttons); ++i) { // Only add guide button if we have the 100 ordinal XInputGetState if (!(named_buttons[i].bitmask & XINPUT_GAMEPAD_GUIDE) || haveGuideButton) AddInput(new Button(i, m_state_in.Gamepad.wButtons)); } // get supported triggers for (int i = 0; i != sizeof(named_triggers) / sizeof(*named_triggers); ++i) { AddInput(new Trigger(i, (&m_state_in.Gamepad.bLeftTrigger)[i], 255)); } // get supported axes for (int i = 0; i != sizeof(named_axes) / sizeof(*named_axes); ++i) { const SHORT& ax = (&m_state_in.Gamepad.sThumbLX)[i]; // each axis gets a negative and a positive input instance associated with it AddInput(new Axis(i, ax, -32768)); AddInput(new Axis(i, ax, 32767)); } // get supported motors for (int i = 0; i != sizeof(named_motors) / sizeof(*named_motors); ++i) { AddOutput(new Motor(i, this, (&m_state_out.wLeftMotorSpeed)[i], 65535)); } ZeroMemory(&m_state_in, sizeof(m_state_in)); } std::string Device::GetName() const { switch (m_subtype) { case XINPUT_DEVSUBTYPE_GAMEPAD: return "Gamepad"; case XINPUT_DEVSUBTYPE_WHEEL: return "Wheel"; case XINPUT_DEVSUBTYPE_ARCADE_STICK: return "Arcade Stick"; case XINPUT_DEVSUBTYPE_FLIGHT_STICK: return "Flight Stick"; case XINPUT_DEVSUBTYPE_DANCE_PAD: return "Dance Pad"; case XINPUT_DEVSUBTYPE_GUITAR: return "Guitar"; case XINPUT_DEVSUBTYPE_DRUM_KIT: return "Drum Kit"; default: return "Device"; } } std::string Device::GetSource() const { return "XInput"; } // Update I/O void Device::UpdateInput() { PXInputGetState(m_index, &m_state_in); } void Device::UpdateMotors() { // this if statement is to make rumble work better when multiple ControllerInterfaces are using // the device // only calls XInputSetState if the state changed if (memcmp(&m_state_out, &m_current_state_out, sizeof(m_state_out))) { m_current_state_out = m_state_out; PXInputSetState(m_index, &m_state_out); } } // GET name/source/id std::string Device::Button::GetName() const { return named_buttons[m_index].name; } std::string Device::Axis::GetName() const { return std::string(named_axes[m_index]) + (m_range < 0 ? '-' : '+'); } std::string Device::Trigger::GetName() const { return named_triggers[m_index]; } std::string Device::Motor::GetName() const { return named_motors[m_index]; } // GET / SET STATES ControlState Device::Button::GetState() const { return (m_buttons & named_buttons[m_index].bitmask) > 0; } ControlState Device::Trigger::GetState() const { return ControlState(m_trigger) / m_range; } ControlState Device::Axis::GetState() const { return std::max(0.0, ControlState(m_axis) / m_range); } void Device::Motor::SetState(ControlState state) { m_motor = (WORD)(state * m_range); m_parent->UpdateMotors(); } } }
// // Generated file. Do not edit. // #include "generated_plugin_registrant.h" #include <argon2_ffi/argon2_ffi_plugin.h> #include <file_chooser/file_chooser_plugin.h> #include <biometric_storage/biometric_storage_plugin.h> #include <url_launcher_linux/url_launcher_plugin.h> void fl_register_plugins(FlPluginRegistry* registry) { g_autoptr(FlPluginRegistrar) argon2_ffi_registrar = fl_plugin_registry_get_registrar_for_plugin(registry, "Argon2FfiPlugin"); argon2_ffi_plugin_register_with_registrar(argon2_ffi_registrar); g_autoptr(FlPluginRegistrar) file_chooser_registrar = fl_plugin_registry_get_registrar_for_plugin(registry, "FileChooserPlugin"); file_chooser_plugin_register_with_registrar(file_chooser_registrar); g_autoptr(FlPluginRegistrar) biometric_storage_registrar = fl_plugin_registry_get_registrar_for_plugin(registry, "BiometricStoragePlugin"); biometric_storage_plugin_register_with_registrar(biometric_storage_registrar); g_autoptr(FlPluginRegistrar) url_launcher_linux_registrar = fl_plugin_registry_get_registrar_for_plugin(registry, "UrlLauncherPlugin"); url_launcher_plugin_register_with_registrar(url_launcher_linux_registrar); }
Q: IE incompatability with window.location.href I'm using a callback from an AJAX post request to navigate to a new page, but it is not working on Internet Explorer. My code is as follows: $.ajax({ type: "POST", url: phpUrl, data: data, async: false, success: function() { if (navigator.appName == 'Microsoft Internet Explorer'){ window.location.href("/step2.php")} else{ window.location.href = "/step2.php"} }, dataType:'json' }); This works fine on FF/Safari/Chrome but when I test it on IE it does not work. Is there a better way of redirecting to a new page? I'm using async:false as my data was not loading on Chrome/Safari if I did not use a callback as the page would just change before the POST request was complete. A: It's the parentheses. href is not a function, so trying to invoke it—window.location.href("/step2.php")—is a TypeError. Assign to href like you do on the next line, or better, use location.assign(): location.assign('/step2.php'); While you can directly assign to location's properties (location.href='...';) to cause the browser to navigate, I recommend against this. Internally, doing so is just calling location.assign() anyway, and assigning to properties does not always behave the same in all browsers. Regarding, async:false, never do that. If you make a synchronous XHR request, you're doing it wrong. 8.4% of reported IE9 hangs were due to synchronous XHR blocking the browser. Given that you have it in a callback, the assignment to location won't happen until the POST completes, so I'm not sure what you mean by "the page would change before the POST completes." (Did you forget to cancel a form's submit?)
For years, Texas gun owners have groused about the application fee for a license to carry a handgun. The state charges $140 for a new license — enough money to buy about 750 rounds of 9mm ammunition — and $70 for a renewal, required every five years. State Representative Joe Moody of El Paso, a Democrat, introduced a measure to lower that fee, but there’s a catch: Gun owners would have to prove that they have the means to safely store their firearms. The proposal, crafted by the advocacy group Texas Gun Sense and introduced in November, would reduce the licensing fee by as much as $40 if the applicant proves he or she purchased a safe, case, cabinet or “other device” designed to lock up their gun. If adopted, the law would also instruct the Texas Department of Public Safety to create a firearm-safety education program, and distribute pamphlets to gun dealers to then give to customers whenever they buy a firearm. The push to reward safety-conscious gun owners reflects a carefully calibrated political maneuver in a state where guns are as woven into the culture as chili and cowboy boots. “We thought, ‘How can we start to tiptoe into this issue with a bill that wouldn’t necessarily mandate anything but would incentivize people?” Andrea Brauer, the executive director of Texas Gun Sense, told The Trace. Stay Informed Subscribe to receive The Trace’s newsletters on important gun news and analysis. Email address The Canon Sent every Saturday. Our guide to the week's most revealing, must-read reporting on gun issues. The Daily Bulletin Sent weekday mornings. Get up to speed with The Trace’s latest articles and other important news of the day. Leave this field empty if you're human: The proposal, she said, is aimed at “rewarding best practices for gun safety. People shouldn’t be able to argue with that.” Concealed carry licensing fees have become a popular target for lawmakers around the South. In March, Florida Governor Rick Scott signed a measure trimming the state’s fee from $70 to $60 for new applications and from $60 to $50 for renewals. Tennessee followed suit by slashing the price of a lifetime permit from $500 to $315, a savings that took effect on Sunday. When the new legislative session commences in Virginia next week, Delegate Scott Lingamfelter, a Republican, will push to eliminate the $35 fee that concealed carry applicants pay for a background check. Moody’s proposal will be one of dozens of gun-related bills up for debate when Texas lawmakers kick off an intense 140-day legislative session January 10. Three bills would forbid state agencies from enforcing federal firearm regulations. Another would let superintendents and other school officials carry weapons into board meetings. Because the Texas legislature meets for regular business only once every two years, lawmakers will be rushing to get their bills heard before the session ends May 29. More than 1.14 million Texans have a license to carry a handgun in public, a 342 percent increase from 2006, when about 258,000 had a license, according to the state’s Department of Public Safety. State laws enacted last year allow license holders to bring concealed weapons on college campuses and openly carry firearms in most public establishments. Moody’s proposal focuses on keeping guns out of the hands of children and teenagers. The most recent statistics from the Centers for Disease Control and Prevention show that 505 people died in accidental shootings in 2013 — or more than one per day — most of them in a home. Like many areas of gun policy, the research on safe storage laws is scant, but they have been linked to declines in unintentional gun injuries among young people. Unsecured firearms also provide easy opportunities for thieves. As part of its continuing investigation into gun thefts, The Trace has obtained statistics on reported gun thefts from police departments in a dozen Texas cities, including Austin and El Paso. Collectively these cities have tallied at least 50,904 guns lost or stolen since 2006, or 14 per day. By definition these guns fall into the hands of criminals, fueling underground markets and violence. The proposal would become moot if lawmakers succeed in scrapping handgun licensing fees altogether. Republican legislation to that effect has already been filed in the state House and Senate. Lieutenant Governor Dan Patrick threw his weight behind the Senate version in November, denouncing Texas’s fee as among the highest in the country. Gun owners, he said, shouldn’t “be deprived of their right to self-protection” because of “onerous” charges. The National Rifle Association also signaled its support, noting that the Senate version has a low bill number, a sign that lawmakers consider it a high priority. Another measure, championed by State Representative Jonathan Stickland, a Republican from Bedford, would allow people to carry handguns without any permit at all, a policy known as “constitutional carry.” (Under Stickland’s bill, people who want to carry guns in public also wouldn’t have to pass a proficiency course that is currently required of license applicants.) Stickland said in a recent interview that his GOP colleagues would pay a political price if they failed to adopt the bill. But observers like Larry Arnold, legislative director of the Texas Concealed Handgun Association, have doubts about whether lawmakers will even let constitutional carry come up for a vote in 2017, given that a similar measure provoked intense debate during the last legislative session before ultimately stalling. “We had two fairly large bills last time,” Arnold said, alluding to the open and campus carry laws. “It may take another couple of legislatures before they move up to something as big as constitutional carry. But given the momentum behind the fact that other states are doing it, it’s certainly a possibility.” Even if lawmakers embrace Moody’s secure storage incentive as a compromise, the educational program mandated by the proposal could be a sticking point. The bill says only that the program should encourage safety and raise awareness about gun handling and secure storage practices. Arnold told The Trace that such a program is unnecessary because groups like his and the NRA already offer safety instruction. He said he is also wary about the program becoming a vehicle for gun control. “We’d like to know who’s going to do that and what’s going to be in it,” Arnold said. “Some of the educational programs we’ve seen basically say, ‘Don’t own firearms.’” Repeated attempts to contact Representative Moody for comment were unsuccessful. Lawmakers mulling measures to reduce or eliminate the licensing fee are forced to wrestle with the prospect of losing tens of millions of dollars in annual revenue. Officials have already sounded alarms about deep cuts in the next budget as the state grapples with unexpectedly high Medicaid costs and a cooling economy. A spokesman for the Texas comptroller told The Trace that handgun licensing fees generated $24.5 million in income during the last fiscal year alone. Arnold acknowledged the difficulties in replacing that revenue and said that reducing the licensing fee might come at the cost of cuts to other programs. He said his organization would be taking a closer look at how Moody’s bill is worded, and stopped short of rejecting the proposal rewarding secure storage practices as a palatable compromise. But he did suggest that encouraging people to lock up their guns could be a mistake. “That keeps you from getting them when you need them,” he said.
/* Dijit Editor RTL icons*/ /*editorIcons_rtl.css is located in dijit/images editorIcons_rtl.css contains references to the dijit editor widget icons. There are 46 icons used to map to the related editor funtionality in the editor's toolbar. */ /* Editor */ .dijitEditorRtl .dijitEditorIcon { background-image: url('images/editorIconsEnabled_rtl.png'); /* editor icons sprite image for the enabled right to left state */ } .dijitEditorRtlDisabled .dijitEditorIcon { background-image: url('images/editorIconsDisabled_rtl.png'); /* editor icons sprite image for the disabled right to left state */ } /* Toolbar */ .dijitToolbarRtl .dijitToolbarSeparator { background-image: url('images/editorIconsEnabled_rtl.png'); } /* took this information above from editorRtl.css - good or bad? */
NEW YORK (TheStreet) -- Shares of BlackBerry (BBRY) are up by 1.61% to $7.28 in early afternoon trading on Tuesday, despite reports that JPMorgan (JPM) plans to eliminate support for the company's wireless devices next year, according to the Wall Street Journal. Some JPMorgan employees will now have to pay for their own devices in a cost cutting move that could potentially save the country's largest bank tens of millions of dollars annually, sources told the Journal. BlackBerry's mobile devices have been losing their prior prestige as Android and iPhone devices have dominated the mobile market in recent years. The company's market share was 0.4% in 2014 compared to 81.5% for Android (GOOGL) and 14.8% for the iPhone (AAPL). Meanwhile, JPMorgan is looking for ways to cut costs as the Fed's decision to keep interest rates near zero have hurt the company's loan operations this year. TheStreet has additional coverage of JPMorgan's earnings release here. Separately, TheStreet Ratings team rates BLACKBERRY LTD as a Sell a ratings score of D. TheStreet Ratings Team has this to say about their recommendation: We rate BLACKBERRY LTD (BBRY) a SELL. This is driven by several weaknesses, which we believe should have a greater impact than any strengths, and could make it more difficult for investors to achieve positive results compared to most of the stocks we cover. The company's weaknesses can be seen in multiple areas, such as its weak operating cash flow and generally disappointing historical performance in the stock itself. Highlights from the analysis by TheStreet Ratings Team goes as follows:
226 Kan. 68 (1979) 595 P.2d 1102 MILDRED R. HILLHOUSE, Appellant, v. FARMERS INSURANCE COMPANY, INC., A CORPORATION, AND FREDERICK BAILEY, Appellees. No. 49,729 Supreme Court of Kansas. Opinion filed June 9, 1979. Donald W. Vasos, of Scott, Daily, Vasos & Lester, of Kansas City, argued the cause and was on the brief for the appellant. Robert D. Benham, of McAnany, Van Cleave & Phillips, P.A., of Kansas City, argued the cause and was on the brief for the appellees. The opinion of the court was delivered by MILLER, J.: The sole issue in this case is the validity of a provision in an automobile insurance policy excluding government-owned motor vehicles from the definition of "uninsured motor vehicles." We hold that the limiting definition is an attempt to reduce coverage required by the Kansas Uninsured Motorist statute, K.S.A. 40-284, and is therefore void and unenforceable. Plaintiff, Mildred R. Hillhouse, sustained personal injury when the car she was driving was rear ended by a dump truck owned by the city of Kansas City, Missouri, and driven by Frederick Bailey, a city employee. It developed that Bailey had no driver's license; he was intoxicated; he owned no car of his own and had no personal policy of liability insurance. Kansas City, Missouri, under the authority of Mo. Rev. Stat. 71.185, had purchased liability insurance and had a policy in effect on the date of the occurrence; the city and its insurance carrier, however, denied liability because Bailey was on a personal errand and was not authorized to use the city's truck at the time and place of the collision. Plaintiff was insured in two separate policies of automobile liability insurance issued in Kansas by defendant Farmers Insurance Company. When Kansas City's insurer denied coverage, plaintiff brought this action under the uninsured motorist provision of her policies, by which Farmers agrees: "To pay all sums which the insured ... shall be legally entitled to recover as damages from the owner or operator of an uninsured motor vehicle because of *69 bodily injury sustained by the insured, caused by accident and arising out of the ownership, maintenance or use of such uninsured motor vehicle .... "DEFINITIONS "`Uninsured Motor Vehicle' means (1) a land motor vehicle ... with respect to the ownership, maintenance or use of which there is ... applicable insurance or bond but the company writing the same (a) denies coverage thereunder...." Farmers moved for summary judgment, alleging that plaintiff's injuries did not arise out of the operation or use of an "uninsured motor vehicle." This claim is based upon a further definition contained in the policy; it reads: "`The term "Uninsured Motor Vehicle" shall not include: * * * "(b) a motor vehicle * * * which is owned by the United States or Canada, or any state or province or any agency or political subdivision of any of them, * * *'" The trial court sustained the motion and Mrs. Hillhouse appeals. Uninsured motorist coverage is mandated by K.S.A. 40-284, and is required, with certain exceptions, in every automobile liability insurance policy issued in this state. We recently discussed the purpose of the statute and cited many of our cases construing it, in Simpson v. Farmers Ins. Co., 225 Kan. 508, 592 P.2d 445 (1979), and we need not repeat what we said there. Consistently in our cases, however, we have held invalid and void various clauses which attempted to dilute or limit the statutorily mandated coverage. We have not overlooked the arguments of counsel or the cases from other jurisdictions cited by counsel in their excellent briefs. The majority of those cases hold the government-owned vehicle exclusion void as an unauthorized limitation on the state mandated uninsured motorist coverage. But we need not rely upon cases from other jurisdictions since our own cases, cited in and including Simpson, are controlling: policy provisions which attempt to condition, limit, or dilute the broad coverage mandated by K.S.A. 40-284 are void. The definition clause quoted above, which attempts to exclude all government-owned vehicles from uninsured motorist coverage, is an unwarranted invasion of the broad coverage required by the statute and it is therefore void. The judgment of the district court, sustaining Farmers' motion for summary judgment, is reversed.
Journals and notebooks, fine papers and pens, inks and their ilks, a few other things, and the occasional rant Wednesday, February 10, 2010 My First Sock There are holes and weird picked-up stitches and some places are too loose, but I love it because I taught myself how to do it by reading a book on how to knit socks. Classes for Beginner's Level 2 have just started, and we're just learning more of the basics, like adding and decreasing stitches. I now know how to knit a sock, gusset, instep, and all. 4 comments: I am sooo jealous. I've been wanting to learn to knit socks. I've done baby blankets, shawls, beanies, tons of washcloths and socks is my new adventure but i've been afraid cause it looks a little intimidating. My niece is having a baby this July so I guess i'm gonna have to take the bull by the horns and just try. Did you use double pointed needles. So far all the instructions i've seen say these needles are necessary and I guess that's what is spooking me a little. i already have enough trouble with just 2 regular needles..... :) Hi Martha! Yes, you have to use the double pointed needles to knit in the round as there are only 30 or 40 stitches and so it's too small for the connected needles. But it's actually easier than I thought. I've been using Ann Budd's Getting Started Knitting Socks, which has a lot of photos with its step-by-step instructions. If I can do it decently, anyone can do it!
Contact us EDUCATION: MUSIC FOR LIFE The North Carolina Symphony leads the most extensive music education program of any symphony orchestra. Each year, we serve more than 55,000 North Carolina students of all ages and provide training and resources for teachers in alignment with the curriculum set by the North Carolina Department of Public Instruction. Music education has been a pillar of our mission for more than seven decades, and we are proud to build the next generation of musicians and music lovers. We are grateful to our music education supporters for their dedication to the importance of the arts in the lives of young people.
Q: C# Как написать событие когда 1 label касается другого Подскажите пожалуйста, как написать событие когда один label касается другого? A: В общем случае будет достаточно такого метода: public bool CollisionDetection() { var rectangle1 = label1.Bounds; var rectangle2 = label2.Bounds; return rectangle1.IntersectsWith(rectangle2); } Метод необходимо вызывать в функции, отвечающей за передвижение label'ов.
alter table ACT_RE_PROCDEF add ENGINE_VERSION_ nvarchar(255); update ACT_RE_PROCDEF set ENGINE_VERSION_ = 'activiti-5'; alter table ACT_RE_DEPLOYMENT add ENGINE_VERSION_ nvarchar(255); update ACT_RE_DEPLOYMENT set ENGINE_VERSION_ = 'activiti-5'; alter table ACT_RU_EXECUTION add ROOT_PROC_INST_ID_ nvarchar(64); create index ACT_IDX_EXEC_ROOT on ACT_RU_EXECUTION(ROOT_PROC_INST_ID_); update ACT_GE_PROPERTY set VALUE_ = '6.0.0.0' where NAME_ = 'schema.version';
Hall of Fame-ness is in the air. Terrell Davis recently, FINALLY, got his long overdue golden jacket. From one great RB to another... details Hall of Fame speech advice to Terrell Davis ▶️ https://t.co/ilR4CfMPVX (via @RichEisenShow) pic.twitter.com/AqpQcX444X — NFL Network (@nflnetwork) July 21, 2017 The Contributors Committee will vote Friday and Pat Bowlen better be one of its two choices if the Pro Football Hall of Fame wants to keep any semblance of trust from Broncos fans that it understands the importance of this franchise to the success of the NFL. But today, the Seniors Committee is debating - and one of the Broncos eligible is long overdue for his bust in Canton. Randy Gradishar. The linebacker’s importance to the Orange Crush defense was so immense that MHR voters elected Gradishar to our own Hall of Fame the first year it existed (and before we separated out early-era and modern-era players). That means, according to MHR, Gradishar is in the same league as John Elway, Terrell Davis and Floyd Little - a rather impressive list. Then again, Gradishar was impressive. Another player I believe is Hall of Fame worthy is Randy Gradishar. The #Broncos LB was a force in the middle, making 7 Pro Bowls in 10 yrs. pic.twitter.com/v5FklHPQiq — Ken Gelman (@kengfunk) July 6, 2017 A first-round draft pick in 1974, Gadishar was the 14th pick overall. He played alongside Tom Jackson, creating the "Orange Crush" defense that led the Broncos to their first Super Bowl appearance in the 1977-78 season. During No. 53’s tenure with the Broncos, the "Orange Crush" allowed the third-fewest rushing yards in the NFL, behind only the Steelers’ "Steel Curtain" and the Cowboys' "Doomsday" defenses. Gradishar played 10 seasons for the Denver Broncos and is considered one of the best defensive players in the team's history. In that time, he had 20 interceptions, three of which became touchdowns, as well as 13 fumble recoveries, one leading to a TD. Playing in an era that featured more running game, Gradishar’s turnover-causing stats are even more amazing. The MHR member who nominated Gradishar for the Hall of Fame back in 2015 had this eloquent reasoning: "For those lucky enough to see Randy Gradishar in his prime, you saw the epitome of an NFL player. He was better than his peers, including Jack Lambert, and often was recognized for this during his career.” - Gradishar53 Gradishar, a two-time finalist for the Pro Football Hall of Fame, was selected for seven Pro Bowls and was a five-time First Team All-Pro. He was named the NFL Defensive Player of the Year in 1978 and was inducted into the Broncos’ Ring of Fame in 1989, that year’s only selection. Four years ago, BroncoMike (one of our own HOF writers) did some research on why Gradishar truly is deserving, even among the modern-era players. And it’s glorious: Stat Randy Gradishar Mike Singletary Brian Urlacher Ray Lewis Seasons 10 12 13 17 Games 145 179 182 228 Tackles 2,049+ 1,488 1,353 2,061 Avg/G 14.1 8.3 7.4 9.0 Interceptions 20 7 22 31 Avg/G 0.14 0.04 0.12 0.14 Fumble Rec. 13 12 15 20 Avg/G 0.09 0.07 0.08 0.09 Sacks 20.5* 19 41.5 41.5 Avg/G 0.14 0.10 0.22 0.18 Pro Bowls 7 10 8 13 All Pro 5 8 4 7 Other DPOY 1978 DPOY 1985, 1988 DPOY 2005 DPOY 2000, 2003 As BroncoMike had noted from the stats above, only Ray Lewis has more total tackles than Gradishar. If Gradishar isn’t in the Hall, then Brian Urlacher and Ray Lewis don’t deserve to be enshrined either. But we know that’s an idiotic statement since both of those players are also deserving of the highest honor.” - BroncoMike, 2013 And even then, Lewis played seven more seasons than his 1980s counterpart in order to edge him out by a meager 12 tackles. Gradishar also averaged five more tackles per game than his closest competitor. Looking at turnovers, Gradishar joins Urlacher and Lewis in the “20 INT Club” while comparing very favorably to Mike Singletary and Urlacher. Lewis outgained him, but he had 83 more games to do it. It’s ironic that both Lewis and Urlacher are eligible in 2018. Lewis is a sure first-ballot inductee while Urlacher has a good shot. The late Pro Football Weekly personnel analyst Joel Buchsbaum wrote in 2002 of the travesty of not yet including Gradishar among the elite. "Maybe the smartest and most underrated ever. Had rare instincts, was faster than Lambert and very effective in short-yardage and goal-line situations. The fact he is not in the Hall of Fame is a shame and may be attributed to the fact he was a sure tackler but not a lights-out hitter or look-at-me type of player." Perhaps this year - with MHR’s help similar to its Terrell Davis campaign - the Senior committee will finally realize Gradishar is a “look-at-him” type of player. But please let us know in the comments why we already know this :) Poll How likely is it that Randy Gradishar will be one of the two choices for Senior members in the Hall of Fame Class of 2018? This poll is closed. 22% He has an outside shot (88 votes) 43% I’m counting on MHR to push him through! (166 votes) 30% The Pro Football Hall of Fame is dead to me (118 votes) 3% "Shasta" (12 votes) 384 votes total Vote Now More on Gradishar - docllv’s picks of the day Randy Gradishar: HOF Credentials - Mile High Report Frankly put, if Brian Urlacher and Ray Lewis are HOF worthy, so is Randy Gradishar. Included are career comparisons of the production Gradishar, Singletary, Urlacher and Lewis had during their perspective careers. Randy Gradishar should be the next Bronco to get into the Hall of Fame - Mile High Report This needs to change. It should come when the seniors committee meets in the next few months.
Q: Syntax Errors Implementing URL Redirect Handler I'm attempting to implement a URL redirect handler using a method suggested in a previous post of mine: How To Capture Session Key Generated From URL Redirector ...however I'm getting 3 errors when attempting to do so: Syntax error on token "(", ; expected MainActivity.java /test/src/com/example/test line 68 Java Problem The method manualRedirectHandler(String) is undefined for the type MainActivity.MyTask MainActivity.java /test/src/com/example/test line 66 Java Problem Syntax error, insert ";" to complete LocalVariableDeclarationStatement MainActivity.java /test/src/com/example/test line 68 Java Problem SOURCE: package com.example.test; import java.io.IOException; import java.io.InputStream; import java.net.URI; import java.net.URISyntaxException; import java.net.URL; import org.apache.http.HttpEntity; import org.apache.http.HttpResponse; import org.apache.http.client.HttpClient; import org.apache.http.client.methods.HttpGet; import org.apache.http.entity.BufferedHttpEntity; import org.apache.http.impl.client.DefaultHttpClient; import org.jsoup.Jsoup; import org.jsoup.nodes.Document; import org.jsoup.nodes.Element; import org.jsoup.select.Elements; import android.app.Activity; import android.app.ProgressDialog; import android.graphics.Bitmap; import android.graphics.BitmapFactory; import android.os.AsyncTask; import android.os.Bundle; import android.widget.ImageView; import android.widget.TextView; public class MainActivity extends Activity { TextView tv; String url = "http://testcloud.edu/apps/users/results.cfm?lname=FOO&fname=BAR"; String tr; Document doc; @Override public void onCreate(Bundle savedInstanceState) { super.onCreate(savedInstanceState); setContentView(R.layout.activity_main); tv = (TextView) findViewById(R.id.TextView01); new MyTask().execute(url); } private class MyTask extends AsyncTask<String, Void, String> { ProgressDialog prog; String title = ""; @Override protected void onPreExecute() { prog = new ProgressDialog(MainActivity.this); prog.setMessage("Loading...."); prog.show(); } @Override protected String doInBackground(String... params) { ImageView img = (ImageView) findViewById(R.id.imageView1); { try { manualRedirectHandler(url); Document manualRedirectHandler(String url) throws IOException{ Response response = Jsoup.connect(url.replaceAll(" ", "%20")).followRedirects(false).execute(); int status = response.statusCode(); if (status == HttpURLConnection.HTTP_MOVED_TEMP || status == HttpURLConnection.HTTP_MOVED_PERM || status == HttpURLConnection.HTTP_SEE_OTHER) { String redirectUrl = response.header("location"); System.out.println("Redirect to: " + redirectUrl);//key will be here return manualRedirectHandler(redirectUrl); } return Jsoup.parse(response.body()); } String imageURL = "http://0.tqn.com/d/webclipart/1/0/5/l/4/floral-icon-5.jpg"; HttpGet httpRequest = null; httpRequest = new HttpGet(URI.create(imageURL)); HttpClient httpclient = new DefaultHttpClient(); HttpResponse response = (HttpResponse) httpclient .execute(httpRequest); HttpEntity entity = response.getEntity(); BufferedHttpEntity b_entity = new BufferedHttpEntity(entity); InputStream input = b_entity.getContent(); Bitmap bitmap = BitmapFactory.decodeStream(input); img.setImageBitmap(bitmap); doc = Jsoup.connect(params[0]).get(); Element tableElement = doc.select(".datagrid").first(); Elements tableRows = tableElement.select("tr"); for (Element row : tableRows) { Elements cells = row.select("td"); if (cells.size() > 0) { title = cells.get(0).child(0).attr("href") + " ; " + cells.get(0).text() + "; " + cells.get(1).text() + "; " + cells.get(2).text() + "; " + cells.get(3).text(); } } } catch (IOException e) { e.printStackTrace(); } return title; } } @Override protected void onPostExecute(String title) { super.onPostExecute(title); prog.dismiss(); tv.setText(title); } } } EDIT (after first answer): @Override public void onCreate(Bundle savedInstanceState) { super.onCreate(savedInstanceState); setContentView(R.layout.activity_main); tv = (TextView) findViewById(R.id.TextView01); new MyTask().execute(url); } private class MyTask extends AsyncTask<String, Void, String> { ProgressDialog prog; String title = ""; @Override protected void onPreExecute() { prog = new ProgressDialog(MainActivity.this); prog.setMessage("Loading...."); prog.show(); } @Override protected String doInBackground(String... params) { ImageView img = (ImageView) findViewById(R.id.imageView1); { try { String imageURL = "http://0.tqn.com/d/webclipart/1/0/5/l/4/floral-icon-5.jpg"; HttpGet httpRequest = null; httpRequest = new HttpGet(URI.create(imageURL)); HttpClient httpclient = new DefaultHttpClient(); HttpResponse response = (HttpResponse) httpclient .execute(httpRequest); HttpEntity entity = response.getEntity(); BufferedHttpEntity b_entity = new BufferedHttpEntity(entity); InputStream input = b_entity.getContent(); Bitmap bitmap = BitmapFactory.decodeStream(input); img.setImageBitmap(bitmap); doc = Jsoup.connect(params[0]).get(); Element tableElement = doc.select(".datagrid").first(); Elements tableRows = tableElement.select("tr"); for (Element row : tableRows) { Elements cells = row.select("td"); if (cells.size() > 0) { title = cells.get(0).child(0).attr("href") + " ; " + cells.get(0).text() + "; " + cells.get(1).text() + "; " + cells.get(2).text() + "; " + cells.get(3).text(); } } } catch (IOException e) { e.printStackTrace(); } return title; } } void manualRedirectHandler(url); Document manualRedirectHandler(String url) throws IOException { Response response = Jsoup.connect(url.replaceAll(" ", "%20")).followRedirects(false).execute(); int status = response.statusCode(); if (status == HttpURLConnection.HTTP_MOVED_TEMP || status == HttpURLConnection.HTTP_MOVED_PERM || status == HttpURLConnection.HTTP_SEE_OTHER) { String redirectUrl = response.header("location"); System.out.println("Redirect to: " + redirectUrl);//key will be here return manualRedirectHandler(redirectUrl); } return Jsoup.parse(response.body()); } @Override protected void onPostExecute(String title) { super.onPostExecute(title); prog.dismiss(); tv.setText(title); } } } ISSUES (with edit): Syntax error on token "url", VariableDeclaratorId expected after this token MainActivity.java /test/src/com/example/test line 108 Java Problem url cannot be resolved to a type MainActivity.java /test/src/com/example/test line 108 Java Problem Type mismatch: cannot convert from Connection.Response to HttpConnection.Response MainActivity.java /test/src/com/example/test line 112 Java Problem A: The problem is at this line: Document manualRedirectHandler(String url) throws IOException{ You can't declare a method inside a method in java, you should move it outside of the doInBackground method. Or declare an inner class inside the method doInBackground and of course that inner class can contain the manualRedirectHandler method.
Map Viewer The active fire map is a service offered and produced by NASA from data collected by satellites. The information collected is treated very quickly and made available to the public in a few hours. With all this we can know in a rather objective way the approximate place where a point of fire has occurred and the magnitude of it. - Topographic maps of Belgium offered by the Institut géographique national (IGN) at different scales (Between 1:4,000,000 and 1:2,500) - Map of the open Street Map collaborative project where users themselves map the world - Aerial photographs of Belgiumdel - CADastral mapping of SPF Finances - Open Street Map (OSM) - Traces made by users of the Strava app
Operation Chaos The Vietnam Deserters Who Fought the CIA, the Brainwashers, and Themselves A JAPANESE FISHING boat, moving north to Soviet waters. Six Americans in the forward hold below the captain’s cabin. Trying to stay warm. Trying to keep their nerve. Trying not to vomit too loudly. One is too drunk to feel seasick. He’s up on his feet, swigging from a bottle of sake, peering into the moonless night, swearing he can see dolphins in the water and helicopters in the sky. The others don’t bother to look. But when the beam of a searchlight streams through the crack in the door, all six scramble to the porthole, jostling to catch sight of the ship that has come down from the ice floes to meet them. Most of us would find it hard to pinpoint the single act that determined the course of our lives. Mark Shapiro can reenact his with the cutlery. When we spent the day together in San Diego, he collected me in a cream-colored vintage Volvo wagon, which was where most of our interview took place—stationary in the hotel parking lot or riding around the streets, where other drivers expressed their admiration for the age of his vehicle by beeping their horns and keeping a wary distance. But we did stop for lunch. And using the implements with which he was about to eat pasta, Mark illustrated the moment during the small hours of April 23, 1968, when he crossed from one life to another. His knife and fork became two ships on the churning waves of the Sea of Japan. One was the fishing vessel that brought him and his five companions from a little harbor at the northeast tip of Hokkaido island. The other was the Soviet coast guard craft that edged alongside, and that, slammed by the relentless sea, appeared like a cliff soaring and sinking before them. Between the two vessels was a six-foot span of furious air, through which Mark and his comrades were ordered to jump. Time was limited. The coast guards had boarded the fishing boat and were inspecting the captain’s paperwork and checking the hold for contraband, the bureaucratic pretext for maneuvering so close. The Soviets had dragged a mattress to the cutter’s deck of their ship and were holding it up like a firefighters’ life net. One by one, displaying varying degrees of bravado and terror, the Americans slithered across the fishing boat’s deck and around a funnel to reach an area unprotected by railings and open to the sea. One by one they jumped. Into the arms of a gang of Russian sailors, and into history. * * * IT TOOK THREE years to persuade Mark Shapiro to meet me. His first email was a blunt rejection. “I do not wish,” he wrote, “to be contacted again on the matter.” But the deserter grapevine brought him news of my inquiries and he changed his mind. Intimations of mortality also had something to do with it. Mark’s health was fragile. He had heart trouble, and he slept with an oxygen cylinder by his bed. A tumor, he said, was growing in his skull. (He traced his finger over the place where it lay buried.) He knew that his time was limited and wanted to answer a question that was gnawing away at him. He wanted to expose the mole within the American Deserters Committee. His suspect was not among the five who traveled with him from Japan. The man upon whom Mark’s suspicions turned—the man he’d been trying to catch out for years—had arrived in Sweden months before him, and he was one of the founders of the ADC. I said I would do my best. I knew the bones of Mark’s story from the accounts of his peers. On his tour of duty with the army in Vietnam, he’d found it hard to stomach talk of “gooks” and “slant-eyed bastards.” Then, out on patrol one day, the soldier beside him was felled by a Viet Cong bullet. A murderous wake-up call for twenty-two-year-old Corporal Shapiro, with an unblemished service record and good prospects for promotion as a military cryptographer. I was ready to take down more details, but Mark seemed incapable of fleshing out his narrative. Instead, he told me a story about his recent visit to a hypnotherapist. “I told him that there was something in my past that I wanted to remember,” he said. “And I didn’t tell him any more than that. The guy was a little skeptical. He asked for the money in advance.” The next thing Mark remembers is having his cash pressed back into his hand, and the therapist, visibly perturbed, assuring him that some stones were best left unturned. “So,” Mark told me, with a shrug, “I have nothing to say about Vietnam. It’s a form of amnesia.” I accepted the explanation. I was already used to thinking of my interviewees as jigsaws with missing pieces. Mark’s decision to desert was not so lost to him. It was a textbook example of the act. In the first days of 1968, he read a newspaper article about four men who had successfully escaped the war. They had been on leave in Japan but were now poised to begin new lives in neutral Sweden. Their names were Craig Anderson, Rick Bailey, John Barilla, and Michael Lindner, but the press nicknamed them “the Intrepid Four,” after the U.S. aircraft carrier that had sailed without them from Yokosuka, the Japanese home of the Seventh Fleet. Another expression was also used to describe them. Defectors. Used in recognition of what many saw as an act of treachery. On their journey from east to west, the Intrepid Four had passed through the Soviet Union and accepted several weeks of Russian hospitality. Maybe more than hospitality. They had shared their anti-war sentiments with the international press, attended celebrations for the fiftieth anniversary of the Russian Revolution, shaken hands with members of the Politburo, and flown from Leningrad to Stockholm with a $1,000 stipend from the Kremlin in their pockets. But they looked pretty happy in the photographs, waving and smiling on the tarmac at Stockholm Arlanda Airport, with their neat new haircuts and sharp new suits. And nobody was asking them to kill anyone in an increasingly unpopular war. Mark decided to follow their example and booked himself some R & R in Tokyo. The news reports offered another helpful detail. The Intrepid Four did not make their journey unaided. They had been smuggled into Russia by an outfit called Beheiren, a group of activists who were fast becoming the focus of the Japanese anti-war movement. Beheiren had organized a rally in Tokyo at which Joan Baez had performed. It had taken out full-page ads in the Washington Post declaring that 82 percent of the Japanese population was opposed to the Vietnam War. It had sent its members to U.S. naval bases with leaflets encouraging sailors to desert, intending to make a provocative gesture—and had been rather surprised to find the offer being taken up. All over Japan, doctors, teachers, shopkeepers, and Buddhist monks began preparing hiding places and airing the spare bedding. Beheiren, however, was a loose-knit organization, and when Mark arrived in Tokyo, determined to make contact, nobody seemed to know its address. “So,” he explained, “I got into a cab and just said, ‘Beheiren.’” The driver thought for a moment and made for Tokyo University and the office of Oda Makoto, a Harvard-educated novelist and academic who was the group’s most visible spokesperson—the man who had gone before the cameras to announce the disappearance of the Intrepid Four. Makoto made some calls, and his associates sprang instantly into action. By the end of the day Mark had checked out of his hotel and was installed in a Beheiren safe house. He soon discovered that he wasn’t the only deserter being sheltered by the group. Five others were also in hiding, kept in circulation among the homes of sympathizers across Japan until the time was right to make the journey to Russia. “When I eventually met the others it was a shock,” Mark said. “We had nothing in common, and it was immediately clear that two of them were nutcases.” His first American companion fit squarely into the category. Philip Callicoat was a nineteen-year-old sailor whose swaggering manner was at odds with his lowly status as a cook’s helper on board the USS Reeves. Perhaps the attitude was a gift from his background: his father was a Pentecostal minister who press-ganged his enormous brood of children into service as the Singing Callicoats—a gospel act best known for having saved Ed Sullivan from humiliation by breaking into an unscheduled second number when a chimp act went badly wrong during a live TV show. Phil Callicoat had turned up at the Soviet Embassy seeking advice on how to defect, but his motives had less to do with politics and more to do with having drunk the last of his $120 savings in an all-night Tokyo jazz bar. Navy discipline did not suit him, and he had recently been confined to his ship for twenty-eight days for vandalism. He and Mark were brought together on a train from Osaka to Tokyo, then put up for the night in the apartment of a visiting French academic. Mark sensed that Phil was going to be trouble, and he was right. The fugitives were taken to Tokyo International Airport, where three more deserters made a party of five. The noisiest was Joe Kmetz, a bullish New Yorker whose opposition to the war, he said, had earned him a month in a dark isolation cell on a diet of bread, water, and lettuce heads. The oldest of the group, twenty-eight-year-old Edwin Arnett, was a skinny, stooping Californian who chewed his fingernails and spoke in slow, somnolent tones. He was not a clever man. His educational progress had halted after the eighth grade, after which he’d trundled gurneys in a New York hospital and spent two years in the merchant marine. The army had expressed no interest in him until 1967, when a Defense Department initiative called “Project 100,000”—cruelly nicknamed the “Moron Corps”—admitted a huge swathe of low-achieving men. The other deserters called him “Pappy”—partly in honor of his age, partly to distance themselves from his oddness. The sanest of the gang, it seemed clear to Mark, was its only African American: Corporal Terry Marvel Whitmore, a marine infantryman from Memphis, Mississippi, who had been wounded in action in Vietnam and received a Christmas bedside visit from President Lyndon B. Johnson, who saluted his bravery and pinned a Purple Heart to the pillow. When Whitmore learned he was also to receive the honor of being returned to the front as soon as he was upright, he discharged himself from the military hospital at Yokohama and lay low with a Japanese girlfriend, pretending to anyone who asked that he was a student from East Africa—and hoping not to encounter any actual East Africans. Their Beheiren guide, a Mrs. Fujikowa, encouraged the deserters to behave discreetly on their trip. Easier said than done. As they boarded the plane, Mark got into an argument with the flight attendant about the size of his suitcase. When they landed at their destination, Nemuro airport on the island of Hokkaido, Phil Callicoat struck up a loud conversation with a local bar owner whose establishment offered more than just cocktails. Before they could get into any serious trouble, the deserters were steered toward a pair of waiting cars and driven for four hours to a remote spot on the coast, where a gaggle of Beheiren sympathizers were huddled around a radio unit, exchanging messages with a Soviet ship—which informed them that the handover would have to wait until the following night. The plan postponed, the Americans were taken to a nearby fishing village, where the captain of their escape vessel was waiting at his home to greet them. He poured out the sake and told his nervous guests not to worry. He had been a kamikaze pilot in the Second World War, and he had come back. The following night, the captain supplied the deserters with a change of clothes calculated to increase their chances of passing as Japanese fishermen during the short walk from his house to the floodlit harbor. Terry Whitmore wrapped himself in a blanket to conceal his conspicuous blackness. Fortified with more alcohol, the deserters went out into the freezing night and climbed aboard their host’s fishing boat. They were told to stay belowdecks and keep quiet: most of the crew were unaware of their existence. As the vessel began chugging from the harbor, a sixth man stumbled into the hold: army private Kenneth Griggs, born in Seoul but adopted as a baby by a white couple from Boise, Idaho. Griggs—who introduced himself under his Korean name, Kim Jin-Su—had spent the better part of a year hiding out in the Cuban Embassy in Tokyo, and he seemed to have made good use of the free literature. His reasons for desertion were expressed as an intense critique of U.S. imperialism. He had a position to maintain: he had already said his piece in a four-minute film, shot by Beheiren and screened for journalists in a Tokyo restaurant. When the Russian coast guard pulled alongside, Kim was the first to jump, leaping with reckless enthusiasm into Soviet-administered space. Joe Kmetz, his fears numbed by alcohol, went just as eagerly. Callicoat followed, sliding across the deck and launching himself with a Tarzan yodel. Mark went next. Hesitated. Watched the rust-marked hull of the Russian ship surge up and down before his eyes. “Jump, you dumb cunt!” shouted Kmetz, unsympathetically. Arms flailing, Mark made it, his suitcase tossed after him by the Japanese skipper. Edwin Arnett, though, was in a worse state, paralyzed by the sight of the rising, falling ship. Whitmore muscled past him, hurled himself across the divide, and was caught by two burly Russian sailors before he hit the deck. Left behind, Arnett seemed unable to compute the physics of the situation. Instead of jumping as the Russian ship fell, he jumped as it rose, colliding with the railing and leaving himself dangling over the sea by one leg. Whitmore and one of the Russians dragged him back to safety. * * * THE SOVIET SHIP was old. The plumbing hissed and thudded. The deserters registered the signs in Cyrillic and knew that they had passed from one political sphere to the next. But the Russians made them comfortable, allocating the deserters quarters beside the officers and giving them as much vodka as they could hold. For their whole time in the Soviet Union, it seemed to Mark, they were carried on a small river of colorless alcohol. “I guess,” he reflected, “they thought it would increase the amount of careless talk.” There were toasts at dinner. To each other. To the interpreter, an incongruously flamboyant man with a cigarette holder. To the captain, who ended the meal by challenging his guests to a drinking game. Only Callicoat accepted, pushing a hunk of black bread inside his mouth and taking a huge slug of some unidentified spirit. He was soon carried back to his bunk. For four days and nights the deserters knocked back vodka, dined on salmon, looked through the portholes, and watched the thickening ice. The interpreter took the opportunity to steer each man away from the group for a thorough discussion of his background and history. On April 25 the ship neared the coast of Sakhalin island, where a patrol boat brought the passengers ashore. Officials confiscated their passports and identity papers. A doctor examined Arnett’s injured leg and shrugged. Then, for four dizzying, vodka-sluiced, bouquet-filled, flashbulb-illuminated weeks, Mark Shapiro and his comrades went on a publicity tour of the USSR: Vladivostok, Moscow, Tbilisi, Gorki, Leningrad, with a short break in the Black Sea resort of Batumi. They accepted flowers from little girls. They saw circus shows. They browsed at the GUM department store. They visited Lenin’s tomb. (“Who’s Lenin?” asked Terry Whitmore.) They saw more circus shows. All under the supervision of a small staff of well-mannered KGB officers and neckless security men in Al Capone fedoras. Some of the security men, they learned, had also kept an eye on the Intrepid Four. One had been taught a single phrase of English, which he repeated over and over again: American cinema—I love you. In Leningrad the deserters were installed in the Hotel Astoria, where Mark shared a room with Terry Whitmore. “Terry could hear this whining noise,” Mark recalled. “He was convinced that the Russians were bugging the room. So he turned everything over, looking for a hidden microphone. But it was only the sound of the elevator. Just being in Russia made us all nervous.” Their edginess caused conflict: Kim and Callicoat got into a fistfight, apparently over Kim’s plan to acquire and burn an American flag. On the rare occasions they were allowed to wander about on their own, the deserters assumed they were being followed. Assumed, too, that they were being informed on by the local women who were so eager to come up to their rooms—not least because they seemed so fascinated by the intricacies of the U.S. Navy. The minders never objected to these one-night stands, as long as they took place in the hotel. Conversely, when Whitmore and Kmetz broke bounds and spent the night with two women in an apartment, the security guys were not pleased and accused them of going out on a spying mission for the CIA. It wasn’t, it seems, a very relaxing evening: the women expected payment and though the Americans obliged, they were soon interrupted by a jealous husband, who upended the dining table in anger and then, rather more weirdly, began to show a gentle curiosity in the texture of Terry Whitmore’s hair. The grand propaganda coup of the trip happened on May 3. The broadcast of We Cannot Be Silent, a half-hour television program in which the six deserters were interviewed about their experiences in Vietnam. Joe Kmetz, hiding under his shades, said the war was a sickness. Terry Whitmore compared the conflict in Indochina to the U.S. Civil War. Phil Callicoat read out a protest poem of his own composition. Kim Jin-Su played the ideologue, suggesting that a nuclear strike on the States might be the only way to defeat “stormtroopers and criminals who are carrying out Washington’s policy of annihilating the Vietnamese as a race and proud people.” He delivered his message down the barrel of the camera. “For those of you on the battlefields,” he said, “I would advise you to follow me and hundreds of others, and just remember that it may take guts to go, but it takes balls to say no.” I asked Mark about his contribution to the film. “I said as little as I could,” he replied. “It was Pappy Arnett who did most of the talking.” Arnett couldn’t shut up. In his droning monotone, he gave testimony that shocked and baffled the world. He said that he’d been trained at a special intelligence school at Fort Meade, Maryland, where he had learned forty ways of torturing a suspect. He said that he’d been assigned to a chemical warfare unit, and arrived on the coast of Vietnam aboard a ship loaded with gas that could cause hemorrhages, paralysis, and blindness. He spoke of saltwater poured in the wounds of prisoners, of GIs making necklaces with the ears of dead North Vietnamese. He said that his commanding officer had “treated the sweeps we made through peasant villages as a turkey shoot”; described how the same officer had executed a Puerto Rican serviceman who refused to join the hunting party and then recorded the dead man as a victim of the Viet Cong; and reported that on another occasion, a superior had disemboweled a baby and thrown the tiny corpse back into its mother’s arms. The interviewer, Yuri Fokin of the Soviet television service, was silent. The camera operator began to weep. The other deserters were horrified. They might have been more horrified had they known the truth: that Edwin C. Arnett had been an army cook on board a floating maintenance shop moored in Cam Ranh Bay. The only violence he had witnessed in Indochina had been inflicted upon potatoes. * * * VIETNAM WAS THE place the bodies were buried or flown back from, the place where the bombs fell and the air burned. But the Vietnam conflict raged far beyond the borders of a former French colony on the South China Sea. It was an undeclared world war, fought between the representatives of two opposing ideologies to spare them the agony of adding Moscow, Peking, and Washington to a list that had begun with Hiroshima and Nagasaki. Nothing about it was clean or uncomplicated. In 1954, the Geneva Accords split Vietnam into two zones, the Communist north, administered from Hanoi by the revolutionary leader Ho Chi Minh, and the non-Communist south, ruled from Saigon by a succession of Western-backed leaders, who were advised—and sometimes hired and fired—by the hidden hand of the Central Intelligence Agency. From 1960, the National Liberation Front, a Communist insurgency also known as the Viet Cong, added its firepower to the argument. Away from the bullets, the war’s foreign stakeholders invested their millions. China and the Soviet Union supplied expertise, money, and guns. The United States matched that commitment and, from 1965, sent roughly 2.7 million ground troops into the territory. Most found a place in the war’s decade-long ritual—boredom and terror in the battle zone, rest and recuperation in Tokyo, funerals and homecomings back in the States. But thousands of GIs rejected their roles and became deserters. The act carried the penalty of imprisonment and hard labor—and the possibility of becoming an unwitting combatant in the propaganda war. As Mark Shapiro’s little platoon went in a vodka haze on their guided tours around Russia, Yuri Andropov, the head of the KGB and future leader of the USSR, must surely have permitted himself a smile of satisfaction, if not a high-kicking rendition of “Kalinka” on top of his mahogany desk. He and his colleagues had been expecting the deserters’ arrival since the first week of March. It had been their idea to use a Japanese fishing boat to transport the men. (The Intrepid Four had been put aboard a Soviet passenger steamer, which had caused some diplomatic awkwardness.) They had planned their itinerary, scheduled their media appearances, authorized the Novosti Press Agency to offer them a book deal. To obscure the KGB’s involvement, they had appointed a state-backed peace group, the Soviet Afro-Asian Solidarity Committee, as official sponsor of the trip. The Central Committee of the Communist Party had even discussed some of the deserters individually, causing phonetic Russian renderings of their names to be added to the Politburo minutes: Knet, Arnet, Kollikot. During the first week of May 1968 those names chuntered from telex machines all over the world. America’s journalists went hunting for more details. A former Singing Callicoat responded to the sudden reappearance of her brother Phil: “I thought he was dead or we would have heard from him by now,” she said. “If it’s true, we disown him,” said Joe Kmetz’s stepbrother. But Arnett’s tales dominated the headlines, in all their wound-salting, village-burning, baby-killing horror. Before the tour came to an end, Yuri Andropov paid the deserters a visit. Mark remembered his polite manners and exceptional English, the feeling of being inspected. Had the deserters been used? Of course they had. But the process was more complex than exploitation. “They showed us the country,” said Mark, “in the hope that it would make us more supportive of Russia in later years. In my case it worked. I sometimes wonder whether I wasn’t a little brainwashed on that trip.” He wasn’t talking Benzedrine injections and a psychedelic light show, but something subtler. Something that ensured that he never developed an enthusiasm for capitalism and, during his years of exile in Sweden, was always happy to pop into the Soviet Embassy for a chat. Something that put him at odds with America for the rest of his days. * * * THE SOVIETS DID not grant every wish of the deserters but hinted that they might help realize their future plans. Each man was given a pencil and a piece of paper and asked to describe his ideal post-military life. Whitmore and Kmetz looked at a map and plumped for a future in Finland. Kim dreamed of a new life in North Korea. But the six knew that Sweden would be their first port of call, and they were given the name of a helpful contact in Stockholm: Bertil Svahnström, a veteran foreign correspondent and vice chair of the Swedish Committee for Vietnam, an alliance of liberals and Social Democrats opposed to the war in Indochina. They were also given a friendly warning. “They told us,” said Mark, “to keep our distance from a man named Michael Vale and an organization called the American Deserters Committee.” Vale, said their KGB guide, would try to contact them and gain their confidence. On May 24, 1968, a fleet of limousines arrived at the Hotel Astoria to drive the deserters to the Leningrad airport, where they each received $300 in cash from the Soviet Afro-Asian Solidarity Committee and bear hugs and kisses from their minders. After an hour staring at the legs of the Swedish cabin crew, the deserters touched down at Stockholm Arlanda Airport to a repeat of the reception that had greeted the Intrepid Four six months before. On that occasion, the waiting photographers had borrowed the iconography of a visiting rock band. Stepping from the plane in identical black suits, John, Craig, Mike, and Rick were framed as the Fab Four of Vietnam War desertion. The Soviets must have seen this, too, and counted it a mistake. The new band of six arrived unscrubbed, unsmartened: authentic members of the counterculture. The Rolling Stones to the Intrepid Four’s Beatles. In the shots from that day, Kim pouts from behind a pair of shades. Mark, in a Red Army fur hat, has a foot perched on his battered suitcase. Whitmore is dragging on a cigarette. Callicoat smiles wryly. Joe Kmetz, a chubby wise guy with a guitar dangling from his right hand, squares off with the camera like a nightclub bouncer. Edwin Arnett hovers at the back, eyes downcast, pale, serious. And, as it would turn out, doomed. As the Russians had predicted, Bertil Svahnström was the first person to welcome the deserters to Sweden—a friendly, patrician figure happy to be acting as envoy for liberal opposition to the Vietnam War, and to be a conduit for messages from Moscow. But there was little opportunity for private conversation. Reporters and photographers had already swarmed into the arrivals lounge. A press conference was coalescing around the deserters. Reporters fired off questions. Were the men Communists? Had they been influenced by their Russian hosts? Terry Whitmore said the questions were stupid. Joe Kmetz got to his feet and declared that nobody would say a word until the representatives of U.S. press agencies had left the room. “We’ll talk with everybody but Americans,” he insisted. He didn’t trust them. They wrote bullshit and they were probably working for the CIA. The hacks from Associated Press and United Press International had little choice but to withdraw. Svahnström looked quietly pleased at that. Once the questions had been exhausted, the deserters were whisked into detention by a phalanx of Swedish policemen so courteous that they carried their bags to the waiting cars. Svahnström followed behind in his Volvo. They were taken to a police station in Märsta, a northern suburb of Stockholm—a holding pen for asylum seekers to this day. Here, the men were searched, questioned, given Coke and hot dogs, and permitted to relax in front of the television. They watched a program in which the African American singer Lou Rawls received a rapturous reception from the studio audience. (“At least Sweden ain’t Mississippi,” thought Whitmore.) Although they were told not to smoke in the cells, Joe Kmetz managed to light one of his Russian cigarettes by heating a piece of metal in a plug socket. Before lights-out, Svahnström came to speak to them. The deserters, he said, would soon be released and issued with permits to remain in Sweden. He could help them negotiate the complexities of the local benefits system, find accommodation and a job. But he also repeated the warning of their Soviet hosts. Recently, Svahnström explained, a group had been established to help fugitive GIs in Sweden. Its representatives would soon be paying them a visit. But the men from the American Deserters Committee, he said, were not to be trusted. They were ideological extremists who would attempt to make the newcomers follow their hard political line. As the men considered Svahnström’s warning, one of the American news agencies banished from the Arlanda Airport press conference was exacting its revenge. On May 26, UPI sent out a story by Virgil Kret, a correspondent in Tokyo, that was calculated to humiliate the man who had bawled its reporter out of the arrivals lounge. Kret claimed to have interviewed Joe Kmetz in February, just before Beheiren took the fugitive marine under its wing. The encounter, he said, had taken place in a bar in Tokyo, where Kmetz, drunk and disconsolate, confessed that he’d been hiding for the past sixteen months in the room of a one-eyed Japanese woman ten years his senior, drinking Suntory whisky and cursing his fate. “He found it difficult to speak, and when he did he spoke English like a Japanese bar girl,” wrote Kret. “He pronounced ‘wife’ as ‘wifu,’ ‘house’ as ‘housu,’ ‘Vietnam’ as ‘Vietnamu.’” Kret advised him to get a lawyer and turn himself in. “Never happen!” exclaimed Kmetz. “Never happen! They’ll put me in the monkey housu until I’m an old man!” After this, Kret reported, a member of Beheiren came to collect Kmetz from the bar and take him to a safe house. He was, said the reporter, “the most unhappy and desperate person that I have ever known.” Was this story true? Was Virgil Kret for real? Apparently so. But the nature of his reality offered a warning about what awaited some of the deserters further down the line. I found his old stories for UPI and the Los Angeles Times and a mention of his presence at a California charity dinner attended by Mr. and Mrs. Zeppo Marx. But an article from an underground newspaper revealed that Kret had been expelled from Japan in 1969, accused of involvement in revolutionary politics. It also noted that in 1975, a source had warned Kret of an imminent assassination attempt on President Gerald Ford. Unfortunately, the source transpired to be God, who issued the tip, Kret claimed, in the form of a “time poem.” The trail ended with a long-neglected blog called The Obituary of the World, in which Kret explained that he had received telepathic warning of God’s declaration of war against the Earth, and that the Almighty had already supplied the codes that would enable him to launch nuclear revenge upon those who had wounded him most grievously. The Buffalo Bills football team would be among the first to perish. Nothing new had been posted on the site since 2008. Since when, I couldn’t help noticing, the Bills have consistently failed to reach the NFL playoffs. * * * WHEN THE REPRESENTATIVES of the American Deserters Committee turned up at the police station, Mark and his comrades were ready to be suspicious. But the men who came to speak with them didn’t seem to be the dangerous figures described by Bertil Svahnström and the KGB. Their manner was friendly and reasonable. They explained that the Swedish welfare system would provide a modest income and that a network of sympathetic Swedes would be only too happy to offer them temporary accommodation. For many of Stockholm’s activist elite—left-leaning actors, journalists, and academics—a deserter in the spare bedroom had become that season’s most fashionable accessory. Bill Jones, the chairman of the ADC, was a twenty-one-year-old former seminarian from St. Louis, Missouri, who’d deserted from Germany during his training as an army medic. Earnestness seemed his defining quality. Bill explained that he had hoped to meet the deserters in Leningrad, but Svahnström and the Swedish Committee for Vietnam had declined to pay for the ticket. Bill’s colleague Michael Vale was older and more self-assured. A short, stocky man with a crinkly smile and unironed clothes, Vale was not a deserter but a professional translator from Cincinnati, Ohio, with an address book full of Swedish intellectuals and an apartment in Stockholm where everyone was welcome. Unlike the patrician figure of Svahnström, Vale talked the language of rebellion and revolt. In that moment, it was not clear how profound a revolution he had in mind. Nor was it possible to know that joining the American Deserters Committee would send some of its members to a prison they would never escape.
Q: Filter Firebase Realtime Database data based on authentication I'm using Firebase Realtime Database as the datastore for an Android app, and right now I'm trying to implement some basic filtering based on user permissions. Here's my database: { "admins" : { `user1hash` : true }, "clients" : { "client1hash" : { "owner": "user1hash", "name" : "Client 1" }, "client2hash" : { "owner": "user1hash", "name" : "Client 2" }, "client3hash" : { "owner": "user2hash", "name" : "Client 3" } } } I followed the examples in the Query-based Rules section here https://firebase.google.com/docs/database/security/securing-data and defined my rules like this: { "rules": { "clients": { ".indexOn": "owner", ".read": "auth.uid != null && (root.child('admins/' + auth.uid).val() == true || query.orderByChild == 'owner' && query.equalTo == auth.uid)", ".write": "auth.uid != null", ".validate": "newData.hasChildren(['owner']) && newData.child('owner').val() == auth.uid" } } } And this is my client code (Android): FirebaseDatabase database = FirebaseDatabase.getInstance(); String authUser = FirebaseAuth.getInstance().getCurrentUser().getUid(); DatabaseReference clientsDatabase = database.getReference("clients").orderByChild("owner").equalTo(authUser).getRef(); clientsDatabase.addListenerForSingleValueEvent(new ValueEventListener() { @Override public void onDataChange(DataSnapshot dataSnapshot) { // handle success } @Override public void onCancelled(DatabaseError databaseError) { // handle error } }); So basically I just want to be able to fetch all clients, but filter the results according to the access rules of the current user. Access rules are pretty simple, an user can only see the clients where he is the owner, except for admin users who can see all clients. For example if this was run by user1 which is an admin he should see all three clients, but if this is run by user2 which is a regular user he should only see client 3. This implementation is working for admins, but I get a permissions error for regular users. I tried the rules simulator in Firebase console, but it doesn't provide any documentation on how to use queries. Anyway I tried adding the query as a regular URL query string like /clients?orderByChild=owner&equalTo=user2hash, but this returns an empty error on the simulator with no description of the cause. The error I'm getting on the Android side doesn't have any description either, just a generic permissions error. A: The problem is in this statement: DatabaseReference clientsDatabase = database.getReference("clients") .orderByChild("owner") .equalTo(authUser) .getRef(); Specifically that last line getRef(), which throws everything away that you've done to build the query. The above statement leaves clientsDatabase exactly the same as: DatabaseReference clientsDatabase = database.getReference("clients"); Which explains quite well why the statement fails. You need to keep the Query that you get back and attach your listener on that: DatabaseReference clientsDatabase = database.getReference("clients"); Query query = clientsDatabase.orderByChild("owner").equalTo(authUser); query.addListenerForSingleValueEvent(new ValueEventListener() { ...
Background {#Sec1} ========== Innate immune pathways play important roles in defending cells against pathogenic virus infections. These invading viruses are recognized by pattern recognition receptors (PRRs) to activate the expression of type I interferons (IFNs), which exert antiviral effects through upregulating the expression of IFN-stimulated genes (ISGs), such as ISG54 and 56 and MxA \[[@CR1]\]. Therefore, type I IFNs have been used as therapeutic agents against viral infections in humans \[[@CR2], [@CR3]\]. In addition, type III IFNs (i.e., IFN-λs), which can be induced by PRR signaling to activate antiviral responses in cells, have also been used as antiviral agents to treat chronic viral infections \[[@CR4], [@CR5]\]. PRRs, such as cytoplasmic retinoic acid-inducible gene I (RIG-I)-like receptors and transmembrane Toll-like receptors (TLRs), recognize viral nucleic acids to initiate the IFN signaling pathway. RIG-I-like receptors comprise RIG-I and MDA5. RIG-I recognizes 5′-triphosphate (5′ppp) containing short double-stranded RNA, whereas MDA5 senses long double-stranded RNA or highly ordered RNA structure \[[@CR6]--[@CR8]\]. TLR3 also senses long double-stranded RNA, while TLR7 and TLR8 detect U-rich and GU-rich single-stranded RNA, respectively \[[@CR9]\]. Because of these properties, PRRs vary in recognizing different RNA viruses. Previous studies reported that RIG-I is involved in detecting orthomyxoviruses, paramyxoviruses, and flaviviruses, whereas MDA5 is involved in the recognition of picornaviruses \[[@CR10], [@CR11]\]. However, both RIG-I and MDA5 are involved in the activation of the innate immune response during West Nile virus infection \[[@CR12], [@CR13]\], while the genome of dengue virus can only be recognized by RIG-I but not MDA5 \[[@CR14]\]. In addition, the 5′ region of the Zika virus (ZIKV) genome is an RIG-I agonist \[[@CR14]\]. The expression of PRRs could also be cell type- or tissue-specific \[[@CR15], [@CR16]\]. For example, TLR7 could be highly expressed in human plasmacytoid dendritic cells (pDCs) compared to other circulating immune cells and non-immune cells \[[@CR17], [@CR18]\]. The function and expression of RIG-I-like receptors and TLRs may also be species-specific \[[@CR19], [@CR20]\]. These studies suggest that the functions of PRRs may differ by cell types and species. The central nervous system (CNS) has been thought to be an immune-privileged area. However, previous studies have shown that the cells residing in the CNS express PRRs \[[@CR21]\]. For example, TLR3 and TLR8 are expressed by cortical and dorsal root ganglion neurons, while TLR7 is highly expressed in the spinal cord \[[@CR15], [@CR22]\]. In addition, the cytoplasmic PRRs RIG-I and MDA5 are expressed in human neural cells \[[@CR23]\]. Microglia and astrocytes are able to produce RIG-I and MDA5, which may function as innate immune response mediators \[[@CR24], [@CR25]\]. Furthermore, several studies have shown that the expression of IFN-β is upregulated in the brains of mice infected with La Cross virus and Theiler's murine encephalomyelitis virus \[[@CR26], [@CR27]\]. Therefore, PRR-mediated innate immune responses could be evoked in the CNS during viral infection. The expression and function of PRRs vary in different stem cells. Several TLRs have been identified in mesenchymal stem cells (MSCs) to regulate proliferation and differentiation of the cells \[[@CR28], [@CR29]\]. In addition, the expression of RIG-I-like receptors (RLRs) RIG-I and MDA5 can be activated in MSCs after poly(I:C) transfection, and the induced expression of the RLRs stimulated IFN-β production and apoptosis in MSCs \[[@CR30]\]. However, TLR3 and MDA5 are not expressed in embryonic stem cells (ESCs), though RIG-I is expressed but not functional in stimulating the innate immune response in ESCs \[[@CR31]\]. Neural stem cells (NSCs), which are localized in the subventricular zone of the brain, are progenitors for all neural lineage cells. Previous studies demonstrated that TLR2 and TLR4 are expressed in adult NSCs and are involved in self-renewal of the cells \[[@CR32]\] and that TNF-α can be secreted from these undifferentiated stem cells under stimulation by TLR2 and TLR4 agonists \[[@CR33]\]. In addition, TLR3 is expressed in NSCs to negatively regulate the proliferation of the cells \[[@CR34]\]. Although accumulating evidence shows that NSCs are susceptible to various neurotropic viruses, such as ZIKV, Japanese encephalitis virus (JEV), and herpes simplex virus \[[@CR35]--[@CR38]\], it remains unclear whether infections of these viruses can evoke innate immune responses. In this study, we examined IFN responses in human NSCs triggered by various agonists or infection with ZIKV or JEV. The results show that the transcription of type I and III IFNs was increased during poly(I:C) transfection. In addition, the expression of the IFN-stimulated antiviral genes, such as ISG56 and MxA, and the viral RNA sensors RIG-I, MDA5, and TLR3 are induced in NSCs by poly(I:C) transfection or IFN-β treatment. We further reveal that RIG-I, MDA5, and TLR3 function in response to their specific ligands for stimulating IFN-β transcription in NSCs. Moreover, our results demonstrate that infection of ZIKV with NSCs dramatically induces the expression of IFN-β in the RIG-I-dependent pathway. This work provides insights into the innate immune response in human NSCs during neurotropic virus infection. Methods {#Sec2} ======= Cells and virus {#Sec3} --------------- Human NSCs derived from the NIH-approved H9 hESCs were obtained from Invitrogen (Thermo-Fisher Scientific, MA, USA). Cells were cultured in a complete medium consisting of 1× KnockOut™ D-MEM/F12, 2 mM GlutaMAX™-I Supplement, 20 ng/ml b-FGF, 20 ng/ml EGF, and 2% StemPro^(R)^ neural supplement (all from Thermo-Fisher Scientific, MA, USA). Culture dishes were coated with CELLStart™ (Thermo-Fisher Scientific, MA, USA) before use. The cells were incubated at 37 °C and 5% CO~2~ in a humidified incubator. THP-1 cell (BCRC number 60430) was purchased from the Bioresource Collection and Research Center (BCRC), Taiwan. THP-1 cells were cultivated in RPMI medium supplemented with 10% FBS. Vero cell was provided by Dr. Shin-Ru Shih at Chang Gung University. Vero cells were cultivated in DMEM medium supplemented with 10% FBS, 1% non-essential amino acid, 1% [l]{.smallcaps}-glutamine, and 1% penicillin/streptomycin (all from Thermo-Fisher Scientific, MA, USA). Human peripheral blood cells were collected from healthy volunteers with informed consent approved by an institutional review board (Chang Gung Medical Foundation institutional review board, IRB: 201800368B0). ZIKV (PRVABC59) was obtained from the Center for Disease Control, Taiwan. JEV (T1P1) was a kind gift obtained from Prof. Robert, Y.-L. Wang at Chang Gung University. Virus infection {#Sec4} --------------- For virus infection, cells were seeded in culture plates for approximately 24 h before infection. After washing, the virus was added to the cells at a specified multiplicity of infection (MOI). After 2 h of adsorption, unbound viral particles were removed, and fresh medium was added for subsequent incubation. Preparation of reagents {#Sec5} ----------------------- Poly(I:C) (Sigma-Aldrich, MO, USA) was prepared at 5 mg/ml in PBS. Poly(I:C) HMW/LyoVecTM (InvivoGen, CA, USA) was prepared at 0.125 mg/ml in endotoxin-free water. Poly(A:U) (InvivoGen, CA, USA) was prepared at 1 mg/ml in sterile physiologic water. Motolimod and GS9620 (Selleckchem, MA, USA) were prepared at 1 mM in DMSO. IFN-β recombinant protein (Peprotech, NJ, USA) was prepared at 1 mg/ml in sterilized water. Preparation of 5′pppRNA {#Sec6} ----------------------- To synthesize 5′pppRNA, the linear pcDNA3 plasmid digested with NotI was used for in vitro transcription. The MEGAscript T7 Kit (Thermo-Fisher Scientific, MA, USA) was used to synthesize the RNA transcripts. One microgram of linearized DNA templates was mixed with 75 mM ATP, 75 mM UTP, 75 mM CTP, 75 mM GTP (2 μl of each nucleotide), 2 μl of 10× reaction buffer, 2 μl of enzyme mix, and nuclease-free water to a volume of 20 μl. After incubation at 37 °C for 4 h, TURBO DNase (2 U/l) was added for another 15 min. Synthesized RNAs were then purified with RNeasy Protect Minikit (Qiagen, Hilden, Germany) and stored at − 80 °C. Cell transfection {#Sec7} ----------------- Cells were seeded in CELLStart-coated plates and incubated in medium until 90% confluence. Lipofectamine 2000 (Thermo-Fisher Scientific, MA, USA) and reagents A and B were prepared according to the manufacturer's protocol. Reagent A was prepared by mixing 100 μl of opti-MEM with 1 μg of poly(I:C), 1 μg of 5′pppRNA, 1 μg of poly(I:C) HMW, 1 μg of poly(A:U), GS9620 (1 μM), and motolimod (20 μM). Two microliters of Lipofectamine 2000 was diluted in 100 μl opti-MEM for reagent B preparation. Reagents A and B were mixed and incubated at room temperature for 20 min. The mixtures were then added into tested cells for transfection. Knockdown assay {#Sec8} --------------- Specific siRNAs (Sigma-Aldrich, MO, USA) were prepared with a concentration of 100 μM using RNase-free distilled water. Lipofectamine 2000 RNAiMAX (Thermo-Fisher Scientific, MA, USA) was used for transfecting siRNAs. Reagent A containing siRNA diluted in 100 μl opti-MEM and reagent B containing 4 μl Lipofectamine 2000 RNAiMAX diluted in 100 μl opti-MEM were prepared. Reagents A and B were mixed and incubated at room temperature for 5 min. The prepared mixtures were then added to the cells and incubated at 37 °C, 5% CO~2~ for 6 h. The old medium was decanted, and fresh expansion medium was added for incubation. The knockdown efficiencies were examined after 72 h of transfection by immunoblot analysis. IFN-β ELISA assay {#Sec9} ----------------- The supernatant of human neural stem cells transfected with poly(I:C) was harvested at 6, 12, and 24 h at post-transfection. The supernatant was centrifuged at 5000 rpm, 10 min, 4 °C for removing cell debris. The expression of IFN-β protein was detected with VerKine™ human IFN-beta ELISA kit (PBL Assay Science, NJ, USA). According to the manufacturer's instruction, the 50-μl sample diluent, standard and samples were added to the wells and incubated at RT for 1 h. The contents of wells were aspirated, and the wells were washed three times with wash buffer. The 100-μl diluted antibody solution was added to the wells and incubated at RT for 1 h, to aspirate the antibody solution and wash the wells. The 100-μl diluted HRP solution was added to the wells and incubated at RT for 1 h, to aspirate the HRP solution and wash the wells. The 100-μl TMB substrate solution was added to the wells and incubated at RT for 15 min and then 100-μl stop solution was added to wells to stop the reaction and to read the plated at 450 nm absorbance by Synergy 2 Multi-Mode microplate reader (BioTek, VT, USA). IFN-β antibody blocking assay {#Sec10} ----------------------------- Human neural stem cells were seeded in 24-well plates coated by CELLStart and grew to about 90% confluent in complete medium. The cells were infected with ZIKV at an MOI of 1, and then the IFN-β antibody (Thermo-Fisher Scientific, MA, USA) was added in the new complete medium after virus adsorption. The total RNA was harvested, and RT-qPCR was performed to detect viral replication at 24 h post-infection. RNA isolation and RT-qPCR {#Sec11} ------------------------- Total RNA was isolated using TRIzol reagent (Life Technologies, CA, USA). One microgram of total RNA was used to synthesize cDNA using the RevertAid First Strand cDNA Synthesis Kit (Thermo-Fisher Scientific, MA, USA) according to the manufacturer's instructions. DNase I (Promega, WI, USA) was used to remove genomic DNA, and 50 mM EDTA was used to inactivate DNase I. A total of 1 μl of cDNA sample with 5 μM primers and SYBR green (KAPA Biosystems, MA, USA) was used to perform qPCR. qPCR assays were carried out in 384-well plates and analyzed by the Roche Light Cycler 480 (Roche, Basel, SW). Each sample was assayed in triplicate, and 18 s rRNA was used as a reference gene. The relative quantification of each gene was calculated by the 2^−ΔΔCT^ method. The primers used in the assay are shown in Additional file [5](#MOESM5){ref-type="media"}: Table S1. Plaque assay {#Sec12} ------------ Vero cells were expanded in DMEM containing10% FBS and seeded on 6-well plate at the concentration of 5 × 10^5^ cells/well. After incubation overnight, the cells were infected by serially diluted virus solution. After 2 h of adsorption, the virus suspension was removed and washed twice with PBS. DMEM supplemented with 2% FBS and 0.3% agarose was then added to the cells. Cells were fixed with 10% formaldehyde for 1 h after 5 days of incubation. The agarose medium was rinsed out, and the fixed cells were stained with 0.5% crystal violate. Western blot {#Sec13} ------------ The cultured cells were washed with PBS and lysed with ice-cold protein lysis buffer (1% NP-40, 50 mM Tris, and 150 mM NaCl) supplemented with 1× protease inhibitor cocktail. The cell lysate was incubated on ice for 30 min and centrifuged at 13,000 rpm for 10 min at 4 °C. The Bradford method (Bio-Rad Laboratories, CA, USA) was used to measure the protein concentration of the supernatant. Protein samples were separated by 8 or 12% SDS-polyacrylamide gel electrophoresis and then transferred onto a polyvinylidene fluoride membrane (PVDF) (GE, MA, USA). The protein-containing membrane was blocked with 5% skim milk in Tris-buffered saline Tween-20 (TBST, 20 mmol/ml Tris-HCl, pH 7.4, 150 mmol/l NaCl, and 0.1% Tween-20) at room temperature. The membrane was then incubated with rabbit anti-RIG-I (1:1000, Pro-Sci, CA, USA), rabbit anti-MDA5 (1:2000, Enzo, NY, USA), rabbit anti-TLR3 (1:1000, Abcam, Cambridge, UK), rabbit anti-IRF3 (1:1000, Santa Cruz, CA, USA), rabbit anti-phosphorylated IRF3-Ser396 (1:1000, Cell signaling, CA, USA), rabbit anti-phosphorylated IRF7-Ser471/472 (1:1000, Cell signaling, CA, USA), or mouse anti-β-actin (1: 20000, Sigma-Aldrich, MO, USA). Subsequently, the membrane was probed with anti-mouse or anti-rabbit secondary antibody conjugated with horseradish peroxidase (1:5000, Jackson ImmunoResearch Laboratories, PA, USA). The protein was detected with a chemiluminescence reagent (PerkinElmer, MA, USA) and a Chemi™ imaging system (Bio-Rad, CA, USA). Immunofluorescence assay {#Sec14} ------------------------ Seeded NSCs were washed with PBS and fixed with ice-cold 4% paraformaldehyde for 15 min at room temperature. The cells were then permeabilized with 0.5% Triton X-100 in TBS for 5 min and blocked with 2% FBS in TBS for 30 min at room temperature. The cells were incubated with primary antibodies: rabbit anti-sox2 (1:200, cell signaling, CA, USA), mouse anti-nestin (1:200, Millipore, MA, USA), rabbit anti-MAP2 (1:200, Millipore, MA, USA), mouse anti-β-tubulin III (1:200, Millipore, MA, USA), rabbit anti-GFAP (1:200, Stem Cell Technologies, BC, CA), rabbit anti-phosphorylated IRF3 (Ser396) (1:200, cell signaling, CA, USA), or mouse anti-ZIKV E protein (1:500, GeneTex, CA, USA) at 4 °C overnight. The cells were then washed three times with TBS and incubated with Dylight 594-conjugated donkey anti-mouse secondary antibody or Dylight 488-conjugated goat anti-rabbit secondary antibody (1:1000, Jackson ImmunoResearch Laboratories, PA, USA) for 1 h at room temperature. The cells were then washed three times with TBS, and the cell nuclei were counterstained with DAPI (4′,6-diamidino-2-phenylindole) (Sigma-Aldrich, MO, USA). The images were collected with a fluorescence microscope (Olympus BX51, Olympus, Tokyo, JP). Cellular viability assay {#Sec15} ------------------------ MTT \[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide\] (Sigma-Aldrich, MO, USA) was prepared in PBS to get a stock solution (5 mg/ml). The culture medium was removed, and MTT solution diluted in complete medium (1 mg/ml) was added to the cells. The cells were then incubated at 37 °C, 5% CO~2~ for 4 h. The MTT solution was removed, and the violet formazan crystals were dissolved with 0.04 N HCl in isopropanol. The absorbance was measured at 570 nm with an ELISA reader (BioTek, VT, USA). Statistical analysis {#Sec16} -------------------- Measurement data were expressed as the mean ± standard deviation (SD). Statistical significance was determined by Student's *t* test or two-way ANOVA. Results {#Sec17} ======= Characterization of human NSCs {#Sec18} ------------------------------ To characterize human NSCs, the cells were expanded (Fig. [1](#Fig1){ref-type="fig"}a), and the expression of SOX2 and nestin was analyzed by immunofluorescence staining. The results showed that all cells expressed these two markers (Fig. [1](#Fig1){ref-type="fig"}b, c). In addition, the neuronal and glial differentiation potentials were analyzed by in vitro differentiation procedures (Fig. [1](#Fig1){ref-type="fig"}d). After treatment with the differentiation media, the cell morphology changed drastically. The differentiated neuron-like cells showed concentrated cell bodies with elongated dendrites, while astrocyte-like cells expressed branched processes (Fig. [1](#Fig1){ref-type="fig"}e, f). Immunofluorescent staining was used to confirm the differentiation. The differentiated neuronal cells positively expressed MAP2 and β-tubulin III, which are usually used to identify the postmitotic neurons (Fig. [1](#Fig1){ref-type="fig"}g, h). Furthermore, GFAP was detected in differentiated astrocyte-like cells (Fig. [1](#Fig1){ref-type="fig"}i). The results demonstrated the characteristics and differentiation potentials of the human NSCs used in this research. Fig. 1Characterization of human neural stem cells. **a** Bright-field image of hNSCs. Scale bar = 50 μm. Immunostaining images of hNSCs showing the expression of SOX2 (**b**) and nestin (**c**). The nuclei are counterstained by DAPI. Scale bar = 50 μm. **d** Schematic diagram of neuronal and astrocytic differentiation from hNSCs. Bright-field images of neurons (**e**) and astrocytes (**f**) derived from hNSCs. Scale bar = 50 μm. Immunostaining images of hNSC-differentiated neuronal cells showing the expression of MAP2 (**g**) and β-tubulin III (**h**). The nuclei were counterstained by DAPI. Scale bar = 20 μm. **i** Immunofluorescence results in hNSC-converted astrocytic cells showing the expression of GFAP. The nuclei were counterstained by DAPI. Scale bar = 20 μm Activation of type I and III IFN expression in human NSCs {#Sec19} --------------------------------------------------------- To investigate the innate immunity of human NSCs in response to viral infections, the capability of IFN induction of the cells was examined under specific agonist stimulation. Initially, the human NSCs were transfected with poly(I:C) for 3, 6, 12, and 24 h, and then the mRNA expression of IFN-α/β (type I) and λ1 (type III) was detected. We found that mRNA levels of IFN-β and λ1 significantly increased in human NSCs transfected with poly(I:C), whereas IFN-α was not significantly increased (Fig. [2](#Fig2){ref-type="fig"}a). In addition, the increased transcriptional activation of IFN-β and λ1 stimulated by poly(I:C) in human NSCs was confirmed by transfection of poly(I:C) in a dose-dependent manner (Fig. [2](#Fig2){ref-type="fig"}b). Consistent with the mRNA expression, the protein levels of IFN-β were significantly increased in human NSCs transfected with poly(I:C) (Fig. [2](#Fig2){ref-type="fig"}c). Since the activation of type I IFN transcription is dependent on the activation of IRF3, we further determined IRF3 activation by examining the phosphorylated form (Ser-396) of IRF3 in the transfected cells. As shown in Fig. [2](#Fig2){ref-type="fig"}d, phosphorylated IRF3 was detected in the extracts of NSCs transfected with poly(I:C). We consistently observed phosphorylated IRF3 in the poly(I:C)-transfected NSCs by immunofluorescence (Fig. [2](#Fig2){ref-type="fig"}e). Although activation of IRF7 could also upregulate the activation of type I IFN, we did not detect the phosphorylated IRF7 in human NSCs transfected with poly(I:C) (Fig. [2](#Fig2){ref-type="fig"}f). The results demonstrate that human NSCs are competent to express type I and III IFNs in response to stimulation of dsRNA analogs. Fig. 2Poly(I:C) transfection upregulates mRNA expression of IFN-β and λ1 in hNSCs. **a** RT-qPCR analysis of IFN-β, α, and λ1 expression in poly(I:C)-transfected hNSCs (1 μg). The experiments were triplicated, and the error bars represented the standard deviation (SD). **b** Human NSCs were transfected with 0.2, 1, and 2 μg of poly(I:C) by Lipofectamine 2000 (LF2K), and the expression of IFN-β and IFN-λ1 was analyzed by RT-qPCR. The experiments were performed in triplicate, and the error bars represented the SD. **c** The supernatants of human NSCs transfected with 1 μg poly(I:C) were harvested at 6, 12, and 24 h post-transfection, and the protein expression of IFN-β was determined using ELISA. The experiments were performed in triplicate, and the error bars represented the SD. Student's *t* test was used for statistical analysis. \**p* \< 0.05, \*\**p* \< 0.01, \*\*\**p* \< 0.001. **d** Western blot analysis was applied to examine the expression of phospho-IRF3 (p-IRF3) and total IRF3 at different time points in poly(I:C)-transfected hNSCs (1 μg). **e** Immunofluorescence images of p-IRF3 and nestin in human NSCs transfected with LF2K only (**a**) and poly(I:C) (**b**). The cell nuclei were counterstained with DAPI. Scale bar = 20 μm. **f** Western blot analysis was applied to examine the expression of phospho-IRF7 (p-IRF7) at different time points in poly(I:C)-transfected hNSCs (1 μg). β-actin was used as an internal control Human NSCs are competent in the activation of antiviral gene transcription {#Sec20} -------------------------------------------------------------------------- Our previous results have demonstrated that type I IFNs can be induced in human NSCs. We further determined whether the downstream antiviral genes activated by type I IFN can be expressed in NSCs by detecting mRNA of the ISGs, including ISG56 and MxA, and viral RNA sensors RIG-I, MDA5, and TLR3. As shown in Fig. [3](#Fig3){ref-type="fig"}a, mRNA expression of the ISGs increased in the poly(I:C)-transfected NSCs. The immunoblots also probed the increasing protein expression levels of RIG-I, MDA5, and TLR3 (Fig. [3](#Fig3){ref-type="fig"}b). In addition, the NSCs were treated with IFN-β for 1, 2, 3, and 4 h, and then the mRNA expression of RIG-I, MDA5, TLR3, ISG56, and MxA was detected. As shown in Additional file [1](#MOESM1){ref-type="media"}: Figure S1A, treatment with IFN-β dramatically increased the mRNA levels of the aforementioned antiviral ISGs. Increasing amounts of RIG-I, MDA5, and TLR3 were also observed in the IFN-β-treated NSCs (Additional file [1](#MOESM1){ref-type="media"}: Figure S1B). The effects were further confirmed by treating NSCs with two different doses of IFN-β (Additional file [1](#MOESM1){ref-type="media"}: Figure S1C and D). Hence, the results imply that the activation of type I IFN in NSCs results in the induction of downstream antiviral gene expression. Fig. 3Expression of RIG-I, MDA5, TLR3, ISG56, and MxA is upregulated in poly(I:C)-transfected hNSCs. **a** RT-qPCR analysis was performed to detect the expression of RIG-I, MDA5, TLR3, ISG56, and MxA in human NSCs transfected with 1 μg poly(I:C) for the indicated time. The experiments were performed in triplicate, and the error bars represented the SD. Student's *t* test was used for statistical analysis. \**p* \< 0.05, \*\**p* \< 0.01, \*\*\**p* \< 0.001. **b** Immunoblot analysis was performed to detect the expression of RIG-I, MDA5, and TLR3 in poly(I:C)-transfected human NSCs. β-actin was used as an internal control The role of pathogen recognition receptors in human NSCs in the production of type I IFN {#Sec21} ---------------------------------------------------------------------------------------- Previous results have shown that the expression of viral RNA sensors, including cytoplasmic PRRs RIG-I and MDA5 and the endosomal viral RNA sensor TLR3, could be induced in human NSCs by transfection of poly(I:C) (Fig. [3](#Fig3){ref-type="fig"}). These results indicate that these pathogen sensors can be normally expressed and induced by the pathogen-associated molecular pattern (PAMP) in human NSCs. To further determine the role of the PRRs in activating type I IFN signaling, specific ligands of the PRRs were used to stimulate the transcription of IFN-β in human NSCs. The NSCs were individually transfected with in vitro-transcribed RNA with 5′-triphosphate (5′pppRNA) and poly(I:C) high molecular weight (HMW), which are the ligands of RIG-I and MDA5, respectively. At 12 and 24 h post-transfection, total RNA of the transfected NSCs was collected and subjected to RT-qPCR to detect IFN-β mRNA. We found that the expression of IFN-β mRNA in NSCs was enhanced by the transfection of the ligands (Fig. [4](#Fig4){ref-type="fig"}a). In addition to measuring IFN-β mRNA, activation of IRF3 in the NSCs stimulated by the specific ligands was determined by immunoblotting of phosphorylated IRF3. The results demonstrated that IRF3 was consistently activated by RIG-I and MDA5 ligands, 5′pppRNA and poly(I:C) HMW, respectively, which dramatically induced IFN-β transcription (Fig. [4](#Fig4){ref-type="fig"}b). Fig. 4RIG-I and MDA5 agonists stimulate the expression of IFN-β in hNSCs. **a**, **b** Human NSCs were transfected with 5′pppRNA or poly(I:C) HMW. Total RNA was collected at 12 and 24 h post-transfection, and RT-qPCR assay was performed to examine the relative amount of IFN-β mRNA (**a**). The expression of phospho-IRF3 and total IRF3 was detected through a western blot assay. β-actin was used as an internal control. (**b**). **c** Human NSCs were transfected with siRNA specific for RIG-I or MDA5 by Lipofectamine RNAiMAX 2000 and then transfected with 1 μg 5′pppRNA for 24 h. RT-qPCR analysis was performed to detect the expression of IFN-β transcripts while western blot was applied to confirm the knockdown efficiency. **d** Human NSCs were transfected with siRNA targeting RIG-I or MDA5 and then transfected with 1 μg of poly(I:C) HMW for 24 h. RT-qPCR analysis was performed to detect the expression of IFN-β transcripts while western blot was applied to confirm the knockdown efficiency. The experiments were performed in triplicate, and the error bars represented the SD. Student's *t* test was used for statistical analysis. \**p* \< 0.05, \*\**p* \< 0.01, \*\*\**p* \< 0.001 To validate the role of RIG-I and MDA5 in activating the innate immune response in NSCs, we examined IFN-β transcription under stimulation with specific agonists in NSCs with knocked down RIG-I or MDA5 expression. As anticipated, knockdown of RIG-I expression reduced the 5′pppRNA-activated transcription of IFN-β in the NSCs, while knockdown of MDA5 expression did not (Fig. [4](#Fig4){ref-type="fig"}c). Surprisingly, we found that the expression of IFN-β mRNA initiated by poly(I:C) HMW was decreased by knockdown of either RIG-I or MDA5 (Fig. [4](#Fig4){ref-type="fig"}d), suggesting that the long dsRNA ligand may be sensed by RIG-I or MDA5 in NSCs. Additionally, total RNA extracted from Enterovirus A71 (EV-A71)-infected cells, which was considered as a MDA5 ligand \[[@CR39]\], was used to validate the result above. We found that IFN-β mRNA expression initiated by total RNA of EV-A71-infected cells was also decreased in the NSCs that were knocked down with either RIG-I or MDA5 siRNA (Additional file [2](#MOESM2){ref-type="media"}: Figure S2A), in contrast to the result obtained from HeLa cells (Additional file [2](#MOESM2){ref-type="media"}: Figure S2B). Collectively, the results demonstrate that the cytoplasmic PRRs RIG-I and MDA5 can be induced and serve the role for sensing their ligands in NSCs. In addition, we examined the expression and function of the endosomal PRRs TLR3, TLR7, and TLR8 in NSCs. The NSCs were separately transfected with poly(A:U), GS9620, and motolimod, which are agonists of TLR3, TLR7, and TLR8, respectively. At 12 and 24 h after transfection, total RNA of the NSCs was collected to examine the expression of IFN-β mRNA. The results showed that stimulation with poly(A:U) could induce IFN-β mRNA expression in human NSCs. In contrast, the ligands of TRL7 and TLR8 only weakly induced transcription of IFN-β mRNA (Fig. [5](#Fig5){ref-type="fig"}a), though the ligands were potent enough to activate IFN-β mRNA expression in THP-1-derived macrophages and peripheral blood mononuclear cells (PBMC) (Fig. [5](#Fig5){ref-type="fig"}b). The results indicate that endosomal PRR TLR3, but not TLR7 or TLR8, is functional in the activation of IFN-β mRNA production in NSCs. Fig. 5Poly(A:U), but not GS9620 and motolimod, is able to induce the IFN-β upregulation in hNSCs. **a** RT-qPCR analysis was performed to detect the IFN-β expression in NSCs transfected with poly(A:U) (1 μg), GS9620(1 μM), and motolimod (20 μM) for the indicated time points. **b** RT-qPCR analysis was performed to detect the IFN-β expression in PMA-primed THP-1 cells transfected with poly(A:U) (1 μg) and human PBMCs transfected with GS9620 (1 μM) and motolimod (20 μM). The experiments were performed in triplicate, and the error bars represented the SD. Student's *t* test was used for statistical analysis. \**p* \< 0.05, \*\**p* \< 0.01, \*\*\**p* \< 0.001. n.s., non-significant Infection of ZIKV and JEV induces IFN-β expression mediated by RIG-I-like receptors in human NSCs {#Sec22} ------------------------------------------------------------------------------------------------- ZIKV and JEV infect human CNS and cause severe neurological complications. It is critical to explore whether these neurological tropism viruses could infect human NSCs and elicit innate immune responses. Therefore, we examined the expression of type I and III IFNs in response to infection with these viruses. We found that both ZIKV and JEV could infect and replicate in NSCs, and the infection strongly induced IFN-β expression. IFN-λ1 expression was also strongly induced in JEV-infected NSCs, but not in ZIKV infection (Fig. [6](#Fig6){ref-type="fig"}a, b). In addition, knockdown of RIG-I, but not MDA5, decreased ZIKV-induced IFN-β mRNA expression in the NSCs, while JEV-induced IFN-β mRNA expression could be affected by knockdown of either RIG-I or MDA5 (Fig. [6](#Fig6){ref-type="fig"}c, d). The results demonstrate that ZIKV or JEV can be replicated and elicit the innate immune responses of type I IFN in human NSCs. Moreover, we conclude that RIG-I is involved in the activation of the type I IFN response for both ZIKV and JEV in NSCs. Interestingly, the result indicates that MDA5 may also play a role in JEV-induced IFN-β production in NSCs. We further examined the role of RIG-I and MDA5 in ZIKV replication in human NSCs. We demonstrated that the ZIKV replication was significantly increased in cells knocked down with RIG-I, but not MDA5 siRNA (Additional file [3](#MOESM3){ref-type="media"}: Figure S3). These results imply that RIG-I plays an important role in regulating the ZIKV replication through the induction of IFN-β in human NSCs. Fig. 6Transcription of IFN-β expression is increased in ZIKV- and JEV-infected hNSCs. **a** Human NSCs were infected with Zika virus at an MOI of 1, and RT-qPCR was applied to detect the mRNA levels of Zika virus RNA (vRNA), IFN-β, and IFN-λ1 at indicated time points. **b** RT-qPCR analysis was performed to examine the mRNA expression levels of JEV virus RNA, IFN-β, and IFN-λ1 in hNSCs that infected by JEV at an MOI of 1. **c** Human NSCs were transfected with siRNA targeting RIG-I or MDA5 and then infected with Zika virus at an MOI of 1 for 48 h. RT-qPCR was used to analyze the relative amounts of IFN-β mRNA, and western blot assay was performed to confirm the knockdown efficiency. **d** Human NSCs transfected with siRNA targeting RIG-I or MDA5 were infected with JEV at an MOI of 1 for 48 h. RT-qPCR analysis was performed to analyze the expression of IFN-β mRNA, and western blot assay was used to confirm the knockdown efficiency. The experiments were performed in triplicate, and the error bars represented the SD. Student's *t* test was used for statistical analysis. \**p* \< 0.05, \*\**p* \< 0.01, \*\*\**p* \< 0.001. n.s., non-significant Activation of IFN-β signaling suppresses replication of Zika virus in human NSCs {#Sec23} -------------------------------------------------------------------------------- As shown previously, ZIKV infection induced RIG-I-mediated IFN-β transcription. We further determined whether the activation of IFN-β production could inhibit ZIKV replication. The NSCs were transfected with 5′pppRNA, which is an agonist for stimulating the RIG-I pathway, and then infected with ZIKV. We found that the NSCs transfected with the RIG-I agonist induced IFN-β transcription (Additional file [4](#MOESM4){ref-type="media"}: Figure S4A) and consequently inhibited the replication of ZIKV at 24 and 48 h after infection (Additional file [4](#MOESM4){ref-type="media"}: Figure S4B and C). In addition, the NSCs treated with IFN-β protein prior to ZIKV infection could maintain the viability from cell death caused by the infection (Fig. [7](#Fig7){ref-type="fig"}a). Correspondingly, IFN-β treatment suppressed the synthesis of ZIKV protein and RNA in the NSCs (Fig. [7](#Fig7){ref-type="fig"}b, c, respectively). We further confirmed the inhibitory effect by examining the production of infectious ZIKV in the supernatant of NSCs treated with IFN-β by plaque formation assay (Fig. [7](#Fig7){ref-type="fig"}d). For examining the effect of IFN-β secreted from ZIKV-infected human NSCs in viral replication, we treated the ZIKV-infected human NSCs with anti-IFN-β antibody to block the secreted IFN-β. IFN-β neutralization could increase the expression levels of ZIKV vRNA, compared to the untreated control (Fig. [7](#Fig7){ref-type="fig"}e). Collectively, the results demonstrate that activation of IFN-β transcription or direct treatment with IFN-β inhibits ZIKV replication in human NSCs. Based on the results, we conclude that human NSCs have an intact innate immune response in activating the RIG-I signaling pathway to counteract ZIKV infection. Fig. 7IFN-β treatment inhibits the replication of ZIKV in hNSCs. **a** Human NSCs were treated with different doses of IFN-β protein and then infected with ZIKV. The cellular viability was assessed by MTT assay. The experiments were performed in triplicate, and the error bars represented the SD. The two-way ANOVA was used for statistical analysis. \**p* \< 0.05, \*\**p* \< 0.01, \*\*\**p* \< 0.001. **b** Immunofluorescence staining was performed to detect the expression of ZIKV E protein in ZIKV-infected hNSCs that were treated with different doses of IFN-β protein. **c** RT-qPCR analysis was performed to detect ZIKV vRNA in ZIKV-infected hNSCs that treated with different doses of IFN-β. The experiments were performed in triplicate, and the error bars represented the SD. Student's *t* test was used for statistical analysis. \**p* \< 0.05, \*\**p* \< 0.01, \*\*\**p* \< 0.001. **d** Growth curves of ZIKV in hNSCs treated with 0, 0.1, and 1 ng/ml IFN-β. The experiments were performed in triplicate, and the error bars represented the SD. The two-way ANOVA was used for statistical analysis. \**p* \< 0.05, \*\**p* \< 0.01, \*\*\**p* \< 0.001. **e** Human NSCs were infected with ZIKV at an MOI of 1, and then anti-IFN-β antibody (100 ng/ml and 500 ng/ml) was added to the cells after virus adsorption. Total RNA was harvested at 24 h post-infection, and RT-qPCR was performed to detect the virus RNA. The experiments were performed in triplicate, and the error bars represented the SD. Student's *t* test was used for statistical analysis. \**p* \< 0.05, \*\**p* \< 0.01, \*\*\**p* \< 0.001 Discussion {#Sec24} ========== NSCs are progenitors residing in specific areas that possess self-renewal and neuro-regenerating abilities. Recent studies have shown that NSCs are susceptible to infection by various neurotropic viruses, including ZIKV, JEV, EV-A71, and CVB3, which cause various deleterious neurological disorders \[[@CR40]--[@CR43]\]. However, little is known regarding whether the innate immune responses could be induced by viral pathogens in these cells and how the cells respond to IFNs. In the present study, we demonstrate that NSCs are able to produce IFN-β (type I) and λ1 (type III) upon transfection with poly(I:C), which is a synthetic analog of double-stranded RNA for mimicking viral infection. We also detected the activation of IRF3 in the poly(I:C)-transfected NSCs. However, IFN-α mRNA was not significantly induced in the human NSCs. It has been reported that activation of IRF7 plays an essential role for the transcription of IFN-α \[[@CR44]\]. Consistently, we did not detect IRF7 activation in human NSCs upon poly(I:C) transfection. Therefore, IFN-α may not be as critical as IFN-β in antiviral response in human NSCs. In addition, IFN-stimulated antiviral genes, such as ISG56 and MxA, and the viral RNA sensors RIG-I, MDA5, and TLR3 can be expressed in NSCs after poly(I:C) transfection or IFN-β treatment. We further demonstrated that the cytoplasmic viral RNA sensors RIG-I and MDA5, as well as the endosomal PRR TLR3, play a role in the response to specific ligands for stimulating IFN-β transcription in NSCs. Furthermore, our results also show that infection of ZIKV or JEV to NSCs dramatically induces the expression of IFN-β. However, IFN-λ1, which is a type III IFN, was not significantly induced in ZIKV-infected human NSCs. This finding is consistent with previous publications describing that ZIKV does not induce type III IFN in human PBMCs and dendritic cells \[[@CR45], [@CR46]\] and that glioblastoma U-251 infected with ZIKV only induces 1--1.5-fold expression of IFN-λ1 \[[@CR47]\]. The cytoplasmic PRR RIG-I plays a critical role in the induction of IFN-β. However, we found that MDA5 is also involved in the detection of JEV infection to induce IFN-β expression in NSCs. Collectively, this research demonstrates that human NSCs have the ability to activate IFN signals against neurotropic viral pathogens. In the CNS, neural lineage cells, including neurons and astrocytes, have been demonstrated to produce IFN-β \[[@CR48], [@CR49]\], while oligodendrocytes produce limited type I IFN in response to poly(I:C) \[[@CR50]\]. Our results further show that neural progenitor cells could also produce type I IFNs upon poly(I:C) stimulation or viral infection. Several cell types, such as pDCs and monocyte-derived DCs, have been demonstrated to produce IFN-λ1 during viral infection \[[@CR51]\]. A previous study also showed that IFN-λ1 could be induced in human astrocytes in response to poly(I:C) via TLR3 \[[@CR52]\]. Our results showed that stimulation with poly(I:C) not only triggers the transcription of IFN-β but also induces IFN-λ1 transcription in neural progenitor cells; hence, NSCs may be one of the cell types that produce IFN-λ1 in response to viral infections. The cytoplasmic PRRs RIG-I and MDA5 are able to recognize specific pathogen RNA to induce IFN expression. However, a previous study showed that MDA5 is not expressed in human ESCs (hESCs) and that RIG-I is expressed but not responsive to its RNA ligand in hESCs \[[@CR31]\]. In contrast, differentiated neural lineage cells, such as murine cortical neurons, possess functional RIG-I to mediate the production of proinflammatory cytokines in response to JEV infection \[[@CR53]\]. Furthermore, differentiated human neuronal cells are also equipped with functional RIG-I and MDA5 to activate type I IFN expression upon poly(I:C) stimulation or Sendai virus infection \[[@CR23]\]. Interestingly, a previous study suggested that knockdown of RIG-I expression decreased the proliferation of undifferentiated neural progenitor cells in JEV-infected animals caused by an increase in JEV replication and cell cycle inhibitors \[[@CR54]\]. Nevertheless, our data indicate that human NSCs, like differentiated neural lineage cells, have functional RIG-I- and MDA5-mediated antiviral signaling pathways to respond to neurotropic virus infections. In addition to cytosolic RLRs, endosomal TLR3, TLR7, and TLR8 are also capable of recognizing foreign nucleic acids to activate downstream innate immune responses. Few studies have investigated the expression and function of TLRs in neural progenitor cells. Previous studies revealed that the expression of TLR3 is decreased in the brain during embryo development. In addition, TLR3 signaling negatively regulates the proliferation of neural progenitor cells and hippocampal neurogenesis \[[@CR34], [@CR55]\]. Furthermore, the expression of TLR7 and TLR8 in the mouse brain is strongly regulated during development. The expression of TLR7 and TLR8 increases gradually from embryonic stages to postnatal days 4 and 21, respectively, and then subsequently declines \[[@CR56], [@CR57]\], and these TLRs play important roles in the regulation of neural differentiation \[[@CR58], [@CR59]\]. However, it was not clear whether these TLRs play roles in mediating innate immune responses in neural progenitor cells. We found that poly(A:U), the ligand of TLR3, was able to trigger IFN-β expression in those progenitor cells. Nevertheless, although TLR7 and TLR8 are expressed in NSCs, these TLRs lack the ability to induce type I IFN production in response to their specific ligands in the cells. These results imply that TLR7 and TLR8 may not be functional in activating the innate immune response in NSCs. Since previous studies have identified the role of TLR7 in the activation of the antiviral response in differentiated neural cells \[[@CR23], [@CR60]\], it is hypothesized that TLR7 plays a different role in neural progenitor cells. Viral infections can be recognized by PRRs to trigger antiviral innate immune responses, such as the production of type I IFN. However, many viruses have developed strategies to subvert the host innate immune response. For example, NS1 and NS4B proteins of ZIKV are able to bind TBK1 and suppress the oligomerization of TBK1 and consequently limit the production of type I IFN, while NS2B-NS3 causes degradation of Jak1 protein and impairs the JAK-STAT pathway \[[@CR61], [@CR62]\]. Nonetheless, innate immune responses induced by a virus could be different among cell types. Our results show that infection with ZIKV dramatically induces IFN-β expression in NSCs and that induction or treatment with IFN-β is able to inhibit ZIKV replication in NSCs. In addition, the cytoplasmic pathogen sensor RIG-I mediates IFN-β transcription in ZIKV-infected NSCs. Since we have also found that treatment with IFN-β could induce downstream antiviral ISGs, such as ISG56 and MxA, in NSCs, this research clearly demonstrates that NSCs have intact RIG-I antiviral signaling pathways to interfere with viral propagation. Conclusion {#Sec25} ========== Our data show that human neural progenitor cells can elicit type I and III IFNs and downstream antiviral ISGs and that the cytosolic RLRs RIG-I and MDA5, as well as the endosomal receptor TLR3, play an important role in the induction of IFNs. In addition, our results show that neural progenitor cells can be infected with neurotropic viruses, including ZIKV and JEV. This event may disrupt neuro-regeneration and result in pathogenesis in the CNS. Nevertheless, since we have also found that IFN-β can restrict the propagation of ZIKV and enhance the survival of NSCs, the administration of IFN may provide a treatment strategy to protect NSCs from infections by neurotropic viruses. Supplementary information ========================= {#Sec26} **Additional file 1: Figure S1.** Expression of RIG-I, MDA5, TLR3, ISG56 and MxA is upregulated in IFN-β-treated hNSCs. (A) RT-qPCR analysis was performed to detect the transcripts of RIG-I, MDA5, TLR3, ISG56 and MxA in human NSCs treated with 1 ng/ml IFN-β at the indicated time. The experiments were performed in triplicate, and the error bars represented the SD. (B) Immunoblot analysis was performed to examine the protein levels of RIG-I, MDA5 and TLR3 in 1 ng/ml IFN-β-treated hNSCs. β-actin was used as an internal control. (C) RT-qPCR analysis was performed to detect the mRNA levels of RIG-I, MDA5, TLR3, ISG56 and MxA in hNSCs treated with different doses of IFN-β for 2 h. The experiments were performed in triplicate, and the error bars represented the SD. (D) Immunoblot analysis was applied to detect protein levels of RIG-I, MDA5 and TLR3 in hNSCs treated with the indicated concentrations of IFN-β for 6 h. **Additional file 2: Figure S2.** Expression of IFN-β is regulated by MDA5 and RIG-I in hNSCs . (A)Human NSCs and (B)HeLa cells were transfected with siRNA against RIG-I or MDA5 by Lipofectamine RNAiMAX 2000 and then transfected with 2 μg of total RNA extracted from EV-A71-infected Vero cells for 24 h. The expression of IFN-β mRNA was analyzed with RT-qPCR. Western blot was applied to confirm the knockdown efficiency. The experiments were performed in triplicate, and the error bars represented the SD. The Student's *t* test was used for statistical analysis. \*, *p* \< 0.05, \*\*, *p* \< 0.01, \*\*\*, *p* \< 0.001. **Additional file 3: Figure S3.** RIG-I knockdown increases the replication of ZIKV in human NSCs. (A) Human NSCs were transfected with siRNA targeting RIG-I or MDA5 for 72 h, and then infected with ZIKV at an MOI of 1. Total RNA was collected to examine the mRNA expression of IFN-β using RT-qPCR. Western blot was performed to confirm the knockdown efficiency. (B) The expression of ZIKV vRNA was detected using RT-qPCR. (C) The viral growth curves were examined by performing plaque assay. The experiments were performed in triplicate, and the error bars represented the SD. The Student's *t* test was used for statistical analysis. \*, p\<0.05, \*\*, p \< 0.01, \*\*\*, p \< 0.001. **Additional file 4: Figure S4.** RIG-I agonist 5'pppRNA inhibits ZIKV replication in hNSCs. (A-C) Human NSCs were transfected with 1 μg of 5'pppRNA for 6 h and then infected with ZIKV at an MOI of 1. Total RNA was harvested at 24 and 48 h post infection. The relative levels of IFN-β mRNA (A) and ZIKV virus RNA (vRNA) (B) were detected by using RT-qPCR. (C) Supernatants of the hNSCs were collected at 24 and 48 h post infection and virus titers were determined by plaque forming assay. The experiments were performed in triplicate, and the error bars represented the SD. The Student's *t* test was used for statistical analysis. \*, p\<0.05, \*\*, p \< 0.01, \*\*\*, p \< 0.001. **Additional file 5.** **Table S1.** The primers used in the RT-qPCR assay. CNS : Central nervous system NSC : Neural stem cell MSC : Mesenchymal stem cells PRR : Pattern recognition receptor PAMP : Pathogen-associated molecular pattern IFN : Interferon TNF : Tumor necrosis factor TLR : Toll-like receptor RIG-I : Retinoic acid-inducible gene I MDA5 : Melanoma differentiation-associated protein 5 IRF3 : Interferon regulatory factor 3 IRF7 : Interferon regulatory factor 7 ISG : Interferon-stimulated gene MxA : Myxovirus resistance gene A 5′ppp : 5′-Triphosphate HMW : High molecular weight PBMC : Peripheral blood mononuclear cells pDC : Plasmacytoid dendritic cells ZIKV : Zika virus JEV : Japanese encephalitis virus EV-A71 : Enterovirus A 71 MOI : Multiplicity of infection **Publisher's Note** Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Supplementary information ========================= **Supplementary information** accompanies this paper at 10.1186/s13287-019-1521-5. We appreciate Professor Shin-Ru Shih at Chang Gung University for supporting virus stock and Vero cells for our research. JYL carried out the experiments and performed the data analysis. RLK and HIH analyzed the results and prepared the draft. HIH supervised the experiment. All authors read and approved the final manuscript. This work was financially supported by the Research Center for Emerging Viral Infections from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan and the Ministry of Science and Technology (MOST), Taiwan (MOST108-3017-F-182-001). This work was also supported by the Ministry of Science and Technology, Taiwan (MOST-107-2320-B-182-001, MOST-108-2320-B-182-033, and MOST-106-2362-B-182-001), Chang Gung University (BMRPB33), and Chang Gung Memorial Hospital, Taiwan (CMRPD1G0431). The data that support the findings of this study are available from the corresponding author upon reasonable request. Peripheral blood mononuclear cells were isolated from the human blood, after written informed consent. All protocols were approved by Chang Gung Medical Foundation institutional review board (IRB: 201800368B0). Not applicable The authors declare that they have no competing interests.
# 快速开始 建议先使用java定义接口jar,并使用[erlanalysis](https://github.com/apache/dubbo-erlang/tree/master/tools/erlanalysis) 工具解析java接口至Erlang lib ## 导入依赖库 ### 使用 Rebar 编译工具。 Add dubblerl to rebar.config with your project ```erlang {deps, [ {dubboerl, {git, "https://github.com/apache/dubbo-erlang.git", {branch, "master"}}} ]}. ``` ### 使用 erlang.mk 编译工具 `待补充` ## 导入接口库 Suppose the interface lib you exported is called dubbo_service. * If you didn't upload your lib to your git repository, It is recommended that you copy the `dubbo_service` lib into the project's `apps` directory. * If it is upload to your git repository, you can import like this: ```erlang {deps, [ {dubboerl, {git, "https://github.com/apache/dubbo-erlang.git", {branch, "master"}}}, {dubbo_service,{git,"${INTERFACE_LIB_URL}",{branch,"master"}}} %% replace ${INTERFACE_LIB_URL} with your lib git repos url ]}. ``` ## 消费者配置 Please reference [Reference Config](./reference.md) ## Init dubbolib in your project It is need you ```erlang dubboerl:init(). ``` ## 如何调用? ### 同步调用 ```erlang Request = #userInfoRequest{requestId = 123, username = "testname"}, {ok,RequestRef,Response,RpcContent} = userOperator:queryUserInfo(Request,#{sync=> true}). ``` If it occur error, is reponse `{error,Reason}`. ### 异步调用 Default is Async call. ```erlang Request = #userInfoRequest{requestId = 123, username = "testname"}, {ok,RequestRef} = userOperator:queryUserInfo(Request). %% you can receive the message after. handle_cast({msg_back,RequestRef,Response,RpcContent},State). ``` ## 示例 参考项目 [dubboerl_demo](https://github.com/apache/dubbo-erlang/tree/master/samples)
MANILA, Philippines - Department of Social Welfare and Development (DSWD) Assistant Secretary Dr. Lorraine Badoy has shared the heart-wrenching plight of farmers from Mindanao who allegedly escaped Hacienda Luisita. PHOTO CREDIT: Facebook/Lorraine Badoy In her viral Facebook post, Badoy divulged that a group of T’boli farmers were seen sleeping in the streets near Aguinaldo. Luckily, good samaritans Ricky Medenilla and Pia Castro found them, took them to their homes and fed them. The farmers were eventually brought to the DSWD. Apparently, the group of farmers were recruited to work for Hacienda Luisita with a promise of P500 a day salary. Hundreds of farmers left their families in Mindanao to seek greener pastures in the Cojuangco-owned hacienda. Unfortunately, the promise of a better life didn’t seem to await them in Hacienda Luisita. Instead of paying them P500 a day, farmers reportedly received a maximum of P160 a week. “When the dust had settled, the highest they were paid was 160 pesos a WEEK. Often it went down to as low as 40 pesos a week,” Badoy wrote in her post. Aside from the terrible pay, the farmers were supposedly made to pay for the food they consume that include rotten sardines and noodles. In some days, these farmers allegedly scrounge garbage in search for food since they had nothing to eat. In addition, Badoy alleged that the farmers were made to pay P6,000 for a sack of rice they consume. The amount was reportedly deducted from their “50 peso-a-week take home pay.” “I want justice for them. I want them paid over and beyond what they were promised—for all the grief, all the abuses, all the hardships they’ve had to endure in the hands of the greedy oligarchs. A case has been filed against Hacienda Luisita and it is in the DOLE. I want us all to be so invested in it and watch it with eagle eyes,” Badoy added. Aside from taking the farmers into their custody, Medenilla and Castro also raised funds which the farmers can use to buy seedlings and fertilizers. “The farmers will be guided by the DSWD to approach credible peasant organizations that are accredited by the DSWD. These peasant organizations will then help them buy seeds and fertilizers WITH THE MONEY YOU GAVE THEM--which are what they need and want in the first place,” Badoy wrote in a recent update. On Wednesday, February 22, the farmers already boarded the bus that would take them home. Read Badoy’s full post below. Located in Tarlac, Hacienda Luisita is a 6,000-hectare sugar plantation primarily owned by the family of former Presidents Benigno Aquino III and the late Corazon Aquino. --Mini, The Summit Express Don't miss our regular updates and awesome stories, Like us on Facebook, follow us on Twitter or subscribe via E-mail.
Seminars Seminars DOGS WELCOMEPlease let us know if you’re planning on bringing a dog, so that we can make sure we have sufficient supplies. Nosework is one of fastest growing new dog sports around, and it’s easy to see why! It’s fun both the dogs and the handlers. Nosework is a great way to develop a relationship of mutual trust with your dog and can help build a dog’s confidence and focus, making it a wonderful sport for dogs of all ages. Join us at this MCOA nosework seminar, where we will discuss the various organizations that offer nosework trials and how they differ from each other, the basic concepts of nosework training, the handler/dog partnership. Bring your dog, as we will be introducing them to Birch and teaching them to “find it”! Please attend this seminar if you have or ever plan to have another Mastiff Puppy. We will cover the 10 things every Mastiff puppy should know by the time it is six months old. We will use food, encouragement, capturing behaviors and luring into behaviors to teach you and your puppy these very important 10 things. We will discuss how to teach your puppy each behavior and then how to maintain it for the life of the dog. This seminar is for you and your puppy (or old dog) to attend together. We will mix up the material to have short lecture times with plenty of practice time. Please bring your dog on a six foot leash, small soft treats and a toy your puppy loves. This is our favorite seminar to teach, so please join us with your dog and we promise you both will have fun. Introduction to AKC’s new Trick Dog titles After we have tired out you and your puppy in the 10 things seminar we will discuss the new AKC Trick dog titles and how to earn them. We hope to have time to show you how to teach some of the more complex tricks and we will if time allows.
i was just poking around a few chinese sites rcently, and i came across the blog of maxzhou88 (the guy who posted a lot of the nanjing chinese rpg dumps on that weird ie-only site)... as it turns out (as far as i can ascertain from google translations) he once worked for a taiwan-owned chinese company that developed a number of the "Super Game" FC pirate originals. and he's posted some stuff from the development of these games on his blog! including source codes, graphics, in-development ROMs and other stuff. I never would have considered there were strict anti-piracy measures in effect over at piracy companies I guess it sort of works either way, but did you perhaps mean to say "pirate companies" rather than "piracy companies"? It reads a little funny to me but maybe it's not as wrong as I thought when I started typing this response. Oh this got frontpaged, awesome. something else i just noticed is the mention of Realtec, which is slightly interesting - that's the company that released a few mostly piss-poor unlicensed (but entirely original) Megadrive titles in the US, and i think at some point licensed some of Codemasters' stuff for asian release, but it seems like they were also somehow behind SuperGame. Oh this got frontpaged, awesome. something else i just noticed is the mention of Realtec, which is slightly interesting - that's the company that released a few mostly piss-poor unlicensed (but entirely original) Megadrive titles in the US, and i think at some point licensed some of Codemasters' stuff for asian release, but it seems like they were also somehow behind SuperGame. I noticed that too, and wondered if it was just coincidence. Does anyone want to take a look at their Mega Drive games and see if there are credits of any kind? Specific names might at least point us to a region. They feel like Eastern games to me, but I don't really know that. well! i recently played through Balloon Boy for some reason (i say "played through", i cheated past most of it). and there are indeed credits, including one "Xue-Ren Song" who is mentioned as one of the taiwan staff in the blog post. well! i recently played through Balloon Boy for some reason (i say "played through", i cheated past most of it). and there are indeed credits, including one "Xue-Ren Song" who is mentioned as one of the taiwan staff in the blog post. Yeah, indeed. Like this one. With "Lee Dan Fai" as "director" which is actually was the name of the former president of Taiwan R.O.C. from 1988. It is in Cantonese denotation form. Otherwise in Mandarin: "Lee Tang Hui".
import pytest from flask import Flask @pytest.fixture def app(): _app = Flask(__name__) _app.secret_key = "anything" _app.testing = True @_app.route("/") def index(): return "index" return _app @pytest.yield_fixture def appctx(app): with app.test_request_context("/") as ctx: yield ctx @pytest.fixture def mockredis(mocker): _mr = mocker.Mock(name="mockredis") mocker.patch("flask_sse.StrictRedis", return_value=_mr) mocker.patch("flask_sse.StrictRedis.from_url", return_value=_mr) return _mr
--- --- [**A shotgun sampling solution for the common input problem in neural connectivity inference**]{}\ Daniel Soudry\*$^{1}$, Suraj Keshri$^{2}$, Patrick Stinson$^{1}$, Min-hwan Oh$^{2}$, Garud Iyengar$^{2}$, Liam Paninski$^{1}$\ **[1]{} Department of Statistics, Department of Neuroscience, the Center for Theoretical Neuroscience, the Grossman Center for the Statistics of Mind, the Kavli Institute for Brain Science, and the NeuroTechnology Center, Columbia University, New York, NY, USA\ **[2]{} Department of Industrial Engineering and Operations Research, Columbia University, New York, NY, USA\ $\ast$ E-mail: daniel.soudry@gmail.com**** Abstract {#abstract .unnumbered} ======== Inferring connectivity in neuronal networks remains a key challenge in statistical neuroscience. The “common input” problem presents the major roadblock: it is difficult to reliably distinguish causal connections between pairs of observed neurons from correlations induced by common input from unobserved neurons. Since available recording techniques allow us to sample from only a small fraction of large networks simultaneously with sufficient temporal resolution, naive connectivity estimators that neglect these common input effects are highly biased. This work proposes a “shotgun” experimental design, in which we observe multiple sub-networks briefly, in a serial manner. Thus, while the full network cannot be observed simultaneously at any given time, we may be able to observe most of it during the entire experiment. Using a generalized linear model for a spiking recurrent neural network, we develop scalable approximate Bayesian methods to perform network inference given this type of data, in which only a small fraction of the network is observed in each time bin. We demonstrate in simulation that, using this method: (1) The shotgun experimental design can eliminate the biases induced by common input effects. (2) Networks with thousands of neurons, in which only a small fraction of the neurons is observed in each time bin, could be quickly and accurately estimated. (3) Performance can be improved if we exploit prior information about the probability of having a connection between two neurons, its dependence on neuronal cell types (e.g., Dale’s law), or its dependence on the distance between neurons. Author Summary {#author-summary .unnumbered} ============== Optically imaging the activity in a neuronal circuit is limited by the scanning speed of the imaging device. Therefore, commonly, only a small fixed part of the circuit is observed during the entire experiment. However, in such an experiment it can be hard to infer from the observed activity patterns whether (1) a neuron A directly affects neuron B, or (2) another, unobserved neuron C affects both A and B. To deal with this issue, we propose a shotgun observation scheme, in which, at each time point, we randomly observe a small percentage of the neurons from the circuit. And so, no neuron remains completely hidden during the entire experiment and we can eventually distinguish between cases (1) and (2). Previous inference algorithms cannot handle efficiently so many missing observations. We therefore develop a scalable algorithm, for data acquired using shotgun observation scheme - in which only a small fraction of the neurons are observed in each time bin. Using this kind of simulated data, we show the algorithm is able to quickly infer connectivity in spiking recurrent networks with thousands of neurons. Introduction ============ The simultaneous activity of hundreds - and even thousands - of neurons is now being routinely recorded in a wide range of preparations. The number of recorded neurons is expected to grow exponentially over the years [@Stevenson2011]. This, in principle, provides the opportunity to infer the “functional connectivity” of neuronal networks, *i.e.* a statistical estimate of how neurons are affected by each other, and by stimulus. The ability to accurately estimate large, possibly time-varying, neural connectivity diagrams would open up an exciting new range of fundamental research questions in systems and computational neuroscience [@Alivisatos2012]. Therefore, the task of estimating connectivity from neural activity can be considered one of the central problems in statistical neuroscience - attracting much attention in recent years (e.g., see [@NYK03b; @Paninski2004; @PILL05a; @Rigat06; @Nykamp2007; @Pillow2007; @Pillow2008; @Mishchenko2011c; @Stetter2012; @Paninski2012; @Pakman2012; @Gerhard2013; @Lutcke2013; @Memmesheimer2014; @Fletcher2014] and references therein). Perhaps the biggest challenge for inferring neural connectivity from activity — and in more general network analysis — is the presence of hidden nodes which are not observed directly [@Pillow2007; @Nykamp2008; @Vidne08; @Mishchenko2011b; @Turaga2013a; @Romano2014; @Tyrcha2014]. Despite swift progress in simultaneously recording activity in massive populations of neurons, it is still beyond the reach of current technology to simultaneously monitor a complete network of spiking neurons at high temporal resolution (though see [@Ahrens2013] for some impressive recent progress in that direction). Since estimation of functional connectivity relies on the analysis of the inputs to target neurons in relation to their observed spiking activity, the inability to monitor all inputs can result in persistent errors in the connectivity estimation due to model miss-specification. More specifically, “common input errors — in which correlations due to shared inputs from unobserved neurons are mistaken for direct, causal connections — plague most naive approaches to connectivity estimation. Developing a robust approach for incorporating the latent effects of such unobserved neurons remains an area of active research in connectivity analysis [@Pillow2007; @Nykamp2008; @Vidne08; @Mishchenko2011b; @Turaga2013a; @Romano2014; @Tyrcha2014]. In this paper we propose an experimental design which greatly ameliorates these common-input problems. The idea is simple: if we cannot observe all neurons in a network simultaneously, maybe we can instead observe many overlapping sub-networks in a serial manner over the course of a long experiment. Then we use statistical techniques to patch the full estimated network back together, analogously to “shotgun genetic sequencing [@Venter1998]. Obviously, it is not feasible to purposefully sample from many distinct sub-networks at many different overlapping locations using multi-electrode recording arrays, since multiple re-insertions of the array would lead to tissue damage. However, fluorescence-based imaging of neuronal calcium [@RKFS08; @Grewe2010] or voltage [@Hochbaum2014] dynamics make this approach experimentally feasible. In the ideal experiment, we would target our observations so they fully cover a neuronal circuit together with all its inputs (Figure \[fig:observation schemes\]). However, in each time step, we would only observe a random fraction of all targeted neurons. In this shotgun approach only a small fraction of the network is observed at any single time. However, connectivity estimation with missing observations is particularly challenging since exact Bayesian inference with unobserved spikes is generally intractable. Therefore, Markov Chain Monte-Carlo (MCMC) methods have been previously used to infer the unobserved activity (spikes) by sampling [@Pillow2007; @Mishchenko2011c; @Mishchenko2011a]. However, such methods typically do not scale well for large networks. MCMC methods are computationally expensive (though, sometimes highly parallelizable), and usually take a long time to converge. Variational approaches [@Fletcher2014], may speed up inference, but have not been shown to be robust to missing observations. Fortunately, as we show here, given a shotgun sampling scheme, it is not actually required to infer the unobserved spikes. We considerably simplify the loglikelihood using the expected loglikelihood approximation[@Park2011; @Sadeghi12; @Ramirez2013], and a generalized Central Limit Theorem (CLT) [@Diaconis1984] argument to approximate neuronal input as a Gaussian variable when the size of the network is large. The simplified loglikelihood depends only on the empiric second order statistics of the spiking process. Importantly, these sufficient statistics can be calculated even with partial observations, by simply “ignoring” any unobserved activity. In order to obtain an accurate estimation of the connectivity, this simplified loglikelihood can be very efficiently maximized — together with various types of prior information. An abundance of such prior information is available on both connection probabilities and synaptic weight distributions as a function of cell location and identity [@Song2005]. In addition, cutting edge labeling and tissue preparation methods such as Brainbow [@Lichtman2008] and CLARITY [@Chung2013] are beginning to provide rich anatomical data about “potential connectivity (e.g., the degree of coarse spatial overlap between a given set of dendrites and axons) that can be incorporated into these priors. Exploiting this prior information can greatly improve inference quality, as was already demonstrated in previous network inference papers [@Pillow2007; @Mishchenko2011c; @Jonas2014]. We present numerical results which demonstrate the effectiveness of our approach on a on a simulated recurrent network of spiking neurons. First, we demonstrate that the shotgun experimental design can largely eliminate the biases induced by common input effects, as originally intended (Figure \[fig: Common Input Problem\]). Specifically, we show that we can quickly infer the network connectivity for large networks, with a low fraction of neurons observed in each time bin. For example, our algorithm can be used to infer the connectivity of a sparse network with $O\left(10^{3}\right)$ neurons and $O\left(10^{5}\right)$ connections, given $O\left(10^{5}\right)$ timebins of spike data in which only $10\%-20\%$ of the neurons are observed in each time bin, after running less than a minute on a standard laptop (Figure \[fig:Sparsity-1\]). This is achieved by assuming only a sparsity inducing prior on the weights. Our parameter scans suggest that our method could be used for arbitrarily low observation ratios (Figure \[fig:Parameter-scans P\_obs T\]) and arbitrarily high number of neurons (Figure \[fig:Parameter-scans N-T\]), given long enough experiments. Then, we demonstrate (Figure \[fig:Prior Results\]) the usefulness of the following additional pieces of prior information: (1) Dale’s Law - all outgoing synaptic connections from the same neuron have the same sign. (2) Neurons have several types - and connection strength between two types is affected by the identity of these types. (3) The probability of connection between neurons is distance dependent. Performance can also be improved by using external stimuli (Figure \[fig:The-effect-of-stimulus\]), similar to the stimulus that can be induced by persistent light sensitive ion channels [@Berndt2009]. Results \[sec:-Results\] ======================== Suppose we wish to perform an experiment in order to measure the functional connectivity in a neuronal circuit by simply observing its activity. In this experiment, we optically capture the neuronal spikes, visible through the use of genetically encoded calcium [@Wallace2008] or voltage [@Hochbaum2014] indicators. Current imaging methods (*e.g.*, two-photon or light sheet microscopy) record this neuronal activity by scanning through the neuron tissue. The scanning protocol, and consequently, the identity of the observed neurons, have various constraints. An important constraint is the maximal scanning speed of the recording device. Since the scanning speed is limited, we cannot observe all the neurons in the circuit all the time with sufficient spatio-temporal resolution. We must decide where to focus our observations. Commonly, observations are focused on a fixed subset of the neurons in the circuit. However, as we will show here, this procedure can generate persistent errors due to unobserved common inputs, that generate spurious correlations in the network activity. To prevent this, we propose a shotgun observation approach, in which we scan the network at a random order (Figure \[fig:observation schemes\], *top*). Thus, at each time bin of experimental data, only a random fraction of the neurons in the network are observed. Intuitively, the main goal of such an approach is to evenly distribute our observations on all pairs of neurons, so that all the relevant spike correlations could be eventually estimated. Note that simple serial scanning of the circuit in contiguous blocks does not accomplish this purpose (Figure \[fig:observation schemes\], *bottom*). However, several other scanning schemes do (random or deterministic) - including the random shotgun scheme, on which we focus here. In this section we test the shotgun scheme on simulated $T$-long spike data from a recurrent spiking neural network with $N$ neurons. Specifically, we use a Generalized Linear network Model (GLM [@BRIL88; @Rigat06; @Pillow2007], see Eqs. \[eq: logistic\]-\[eq: U\]) with synaptic connectivity matrix $\mathbf{W}$. Typically, $\mathbf{W}$ is sparse, so $p_{\mathrm{conn}}$, the average probability that two neurons are directly connected to each other, is low. To infer $\mathbf{W}$ we use the inference method described in section \[sec:Bayesian Inference\]. This approximate Bayesian method can exploit various priors (section \[sub:Priors\]), such as the sparsity of $\mathbf{W}$, to improve estimation quality. We define $p_{\mathrm{obs}}$ as the fraction of neurons observed at each timebin, *i.e.*, the observation probability in the shotgun scheme. For a general list of basic notation, see Table \[tab:Basic-notation\]. We start (section \[sub:Dealing-with-common\]) with a qualitative demonstration that the shotgun approach can be used without the usual persistent bias resulting from common inputs. Then, in section \[sub:Connectivity-estimation-with\], we perform quantitative tests to show that our estimation method is effective for various network sizes, observation probabilities, and stimulus input amplitudes. This is done using only a sparsity prior. Lastly, in section \[sub:Additional-priors\], we show how more advanced priors can improve estimation quality. We conclude (section \[sec:Discussion\]) that the limited scanning speed of the any imaging device recording neuronal activity is not a fundamental barrier which prevents consistent estimation of functional connectivity. Dealing with common input\[sub:Dealing-with-common\] ---------------------------------------------------- In this section we use a toy network with $N=50$ neurons to visualize the common input problem, and its suggested solution - the “shotgun” approach. Errors caused by common inputs are particularly troublesome for connectivity estimation, since they can persist even when $T\rightarrow\infty$. Therefore, for simplicity, in this case we work in a regime where the experiment is long and data is abundant ($T=5\cdot10^{6}$). In this regime, any prior information we have on the connectivity becomes unimportant so we simply use the Maximum Likelihood (ML) estimator (Eq. \[eq: W\_MLE\]). We chose the weight matrix $\mathbf{W}$ to illustrate a “worst-case common input condition (Figure \[fig: Common Input Problem\]A). Note that the upper-left third of $\mathbf{W}$ is diagonal (Figure \[fig: Common Input Problem\]B): *i.e.*, neurons $i=1,\ldots,16$ share no connections to each other, other than the self-connection terms $W_{i,i}$. However, we have seeded this $\mathbf{W}$ with many common-input motifs, in which neurons $i$ and $j$ (with $i,j\leq16$) both receive common input from neurons $k$ with $k\geq17$. If we use a “shotgun” approach and observe the whole network with $p_{\mathrm{obs}}=16/50$, we obtain a good ML estimate of the network connectivity, including the $16\times16$ upper-left submatrix (Figure \[fig: Common Input Problem\]C). Now suppose instead we concentrate all our observations on these $16$ neurons, so $p_{\mathrm{obs}}=1$ within that sub-network, but all the other neurons are unobserved. If common input was not a problem then our estimation quality should improve on that submatrix (since we have more measurements per neuron). However, if common noise is problematic then we will “hallucinate many nonexistent connections (i.e., off-diagonal terms) in this submatrix. Figure \[fig: Common Input Problem\]D illustrates exactly this phenomenon. In contrast to the shotgun case, the resulting estimates are significantly corrupted by the common input effects. Connectivity estimation with a sparsity inducing prior\[sub:Connectivity-estimation-with\] ------------------------------------------------------------------------------------------ Next, we quantitatively test the performance of Maximum A Posteriori (MAP) estimate of the network connectivity matrix $\mathbf{W}$, using a sparsity prior (section \[sub:Sparse-prior\]) on a simulated neural network model. ### Network model \[sub:Network-model\] The neurons are randomly placed on a 1D lattice ring in locations $x\in\left[0,1\right)$. To determine the connection probability (the probability that $W_{i,j}$ is not zero) we used $f\left(d\right)=\exp\left(-ad\right)$, where $d$ is the distance between two neurons, and $a$ was chosen so that the network sparsity is $p_{\mathrm{conn}}=0.25$. For self connectivity, we simply used $W_{i,i}=-1$ to account for the refractory period. All the non-zero off-diagonal weights $W_{i,j}$ are sampled uniformly from the range $\left[0,1\right]$. Also, all outgoing weights from a neuron have the same sign, following Dale’s law, where $50\%$ of the neurons are inhibitory (the rest excitatory). These parameters were chosen to obtain a balanced spontaneous network activity (*i.e.*, without ‘epileptic’ activity where all the neurons are extremely synchronous). Initially, we do not have any external inputs. The neurons are firing spontaneously, with no external input. We sampled each neuronal bias from $b_{i}\sim\mathcal{N}\left(-1.2,0.1\right)$ to obtain a mean firing probability of $0.2-0.25$ in each time bin. The rest of the parameters are individually set for each figure - $N$, the number of neurons, $T$, the number of timebins and $p_{\mathrm{obs}}$, the observation probability. ### Quality Measures We use four measures to assess the quality of the estimated matrix $\hat{\mathbf{W}}$ in comparison with the “ground truth” matrix $\mathbf{W}$. First, we define $$\left\langle \left\langle W\right\rangle \right\rangle \triangleq\frac{1}{N^{2}}\sum_{i,j}W_{i,j}\,.$$ The measures we use are: - The square root of the coefficient of determination ($R^{2}$): $$R\triangleq\sqrt{1-\frac{\sum_{i,j}\left(W_{i,j}-\hat{W}\right)^{2}}{\sum_{i,j}\left(W_{i,j}-\left\langle \left\langle W\right\rangle \right\rangle \right)^{2}}}\label{eq:R}$$ - Correlation: $$C\triangleq\frac{\sum_{i,j}\left(W_{i,j}-\left\langle \left\langle W\right\rangle \right\rangle \right)\left(\hat{W}_{i,j}-\left\langle \left\langle \hat{W}\right\rangle \right\rangle \right)}{\sqrt{\sum_{i,j}\left(W_{i,j}-\left\langle \left\langle W\right\rangle \right\rangle \right)^{2}\sum_{i,j}\left(\hat{W}_{i,j}-\left\langle \left\langle \hat{W}\right\rangle \right\rangle \right)^{2}}}\label{eq:C}$$ - Zero matching: $$Z\triangleq1-\frac{1}{2}\frac{\sum_{i,j}\left(\mathcal{I}\left(W_{i,j}=0\right)\mathcal{I}\left(\hat{W}_{i,j}\neq0\right)+\mathcal{I}\left(W_{i,j}\neq0\right)\mathcal{I}\left(\hat{W}_{i,j}=0\right)\right)}{\sum_{i,j}\mathcal{I}\left(W_{i,j}=0\right)}\label{eq:Z}$$ - Sign matching: $$S\triangleq1-\frac{1}{2}\frac{\sum_{i,j}\left|\mathrm{sign}\left(W_{i,j}\right)-\mathrm{sign}\left(\hat{W}_{i,j}\right)\right|\mathcal{I}\left(W_{i,j}\neq0\right)\mathcal{I}\left(\hat{W}_{i,j}\neq0\right)}{\sum_{i,j}\mathcal{I}\left(W_{i,j}\neq0\right)\mathcal{I}\left(\hat{W}_{i,j}\neq0\right)}\label{eq:S}$$ High values indicate high quality of estimation, with $1$ indicating zero error. To simplify the presentation scale, if some measure becomes negative or imaginary, we just set it to zero. ### Visualizing the inferred connectivity In Figure \[fig:Sparsity\], for visualization purposes, we examine a toy network with $N=50$ neurons. In Figure \[fig:Sparsity-1\], we examine another network with $N=1000$ neurons, which is closer to the scale of the number of recorded neurons in current calcium imaging experiments. As can be seen in both figures, the weight matrix can be estimated accurately for high values of observation probability $p_{\mathrm{obs}}$, and reasonably well even for low value of $p_{\mathrm{obs}}$. For example, in the network with $N=50$ neurons (Figure \[fig:Sparsity\]) we see a quite reasonable performance when $p_{\mathrm{obs}}=0.1$, *i.e.*, only five neurons are observed in each timestep. Even if $p_{\mathrm{obs}}=0.04$, i.e., only two neurons observed in each timestep, we can still infer quite well the sign of inferred connections. Note that our method works well even if the neuron model is not a GLM, as we assumed. We demonstrate this using a leaky integrate and fire neuron model (Figure \[fig: LIF\]). ### Parameter scans Next, we aimed to quantify how inference performance changes with the number of neurons, $N$ (Figure \[fig:Parameter-scans N-T\]) and observation probability $p_{\mathrm{obs}}$ (Figure \[fig:Parameter-scans P\_obs T\]). On all measures, the performance changed qualitatively the same (therefore, in subsequent figures, we will focus the correlation measure). For any given fixed parameter ($N$ or $p_{\mathrm{obs}}$), performance smoothly improves when $T$ increases. These scans suggest we can maintain a good quality of connectivity estimation for arbitrarily values of $N$ or $p_{\mathrm{obs}}$ - as long as we sufficiently increase $T$. Specifically, if we closely examine these figures, we find that, approximately, $T$ should be scaled as $$T\propto\frac{N}{p_{\mathrm{obs}}^{2}}\,\label{eq: T to N-P scaling}$$ in order to maintain good estimation quality. This scaling can be explained intuitively. Suppose first that $p_{\mathrm{obs}}=1$. Then the total number of spike measurements is $NT$, and the number of non-zero network parameters (synaptic weights) is $N^{2}p_{\mathrm{conn}}$ - where we recall that $p_{\mathrm{conn}}$ is the connection probability between two neurons. Therefore, in order to maintain a fixed ratio of measurements per parameter we must scale $T\propto Np_{\mathrm{conn}}$ (to first order in $N$). Now suppose $p_{\mathrm{obs}}<1$. Then the total number of spike measurements is $NTp_{\mathrm{obs}}$, and the number of non-zero parameters is still $N^{2}p_{\mathrm{conn}}$. Therefore, it might seem that in order to maintain a fixed ratio of measurements per parameter we must scale $T\propto Np_{\mathrm{conn}}/p_{\mathrm{obs}}$. However, this ignores the adverse affect of the unobserved common input. Let’s examine the neuronal input (Eq. \[eq: U\]) $$U_{i,t}=U_{i,t}^{\mathrm{obs}}+U_{i,t}^{\mathrm{unobs}}+b_{i}\,,$$ where $U_{i,t}^{\mathrm{obs}}\triangleq\sum_{k:O_{k,t}=1}W_{i,k}S_{k,t-1}$ is the input current arriving from the observed neurons and $U_{i,t}^{\mathrm{unobs}}\triangleq\sum_{k:O_{k,t}=0}W_{i,k}S_{k,t-1}$ is the input current arriving from the unobserved neurons. The latter, $U_{i,t}^{\mathrm{unobs}}$, can be effectively considered as “noise”, which makes it harder to infer the weights in $U_{i,t}^{\mathrm{obs}}$. Since the number of terms in $U_{i,t}^{\mathrm{unobs}}$ is $1/p_{\mathrm{obs}}$ times more than the number in $U_{i,t}^{\mathrm{obs}}$, we have, approximately $\mathrm{Var}\left(U_{i,t}^{\mathrm{obs}}\right)/\mathrm{Var}\left(U_{i,t}^{\mathrm{unobs}}\right)\propto p_{\mathrm{obs}}$, if the neurons are not highly correlated and $p_{\mathrm{obs}}$ is small. Therefore, the signal to noise ratio for estimating the weights should also scale approximately as $p_{\mathrm{obs}}$. In order to compensate for this, we should increase $T$ by $1/p_{\mathrm{obs}}$ . Taking this into account gives the quadratic scaling in $1/p_{\mathrm{obs}}$ that we observe (Eq. \[eq: T to N-P scaling\]). For exact analytical results on this issue see [@Mishchenko2015]. ### The effect of stimulus inputs\[sub:Stimulus\] Next, we demonstrate how stimulus inputs can be used to improve the quality of estimation. Here we use a simple periodic pulse stimulus, similar to that generated by light activated persistent ion channels [@Berndt2009]. Since only a brief optical stimulus is required to activate these channels, this minimizes cross-talk between optical recording (*e.g.*, calcium imaging) and optical stimulation. Therefore, such type of stimulus is generally beneficial in all-optical experiments (but may not be necessary, given recent advances [@Rickgauer2014]). Here, we used a single external input $X\left(t\right)$ which similarly stimulates all the neurons in the circuit (*i.e.*, **$\mathbf{G}=\boldsymbol{1}^{N\times1}$** in Eq. \[eq: U\]). The stimulus $X\left(t\right)$ has a period of $T_{0}=10^{3}$ time-steps, where the pulse is “ON” $50\%$ of the time. We tested various pulse magnitudes, and added white noise to the pulse with a variance which is $10\%$ of the pulse magnitude. We used the same simulation parameters as in section \[sub:Network-model\], with $N=50$, $T=10^{5}$ and $p_{\mathrm{obs}}=0.2$. The only exception is that we decreased $\mathbf{b}$ by $4$ to achieve a low firing rate regime at zero stimulus. As can be seen in Figure \[fig:The-effect-of-stimulus\], this type of stimulus has a strong effect on reconstruction performance, and there is an “optimal magnitude” for improving reconstruction. A main reason for this effect is that the stimulus magnitude directly determines $m\triangleq\frac{1}{N}\sum_{i=1}^{N}m_{i}$, the mean spike probability (*i.e.*, the firing rate). This directly affects the number of spike pair combinations observed during the experiment. Such spike pairs are necessary for a high quality of inference, since they constitute the sufficient statistics in our posterior (Eq. \[eq:P(S|W,B\*)\]). Therefore if the stimulus (and therefore, firing rate $m$) is too low or high, we observe fewer spike pair combinations, and this decreases inference quality. However, introducing strong variable stimulus can also reduce inference quality, by masking the effect of weak connections on spiking. Therefore, the optimal inference quality is achieved here at for $m\approx0.13$, and not at $m=0.25$ - the mean spike probability in which the maximal number of spike pair combinations is observed[^1]. Additional priors\[sub:Additional-priors\] ------------------------------------------ Next, we incorporate into our inference procedure additional prior information. We show that incorporating stronger prior information improves inference performance. ### Network model The network is the same as in section \[sub:Network-model\], except we now choose the weight magnitude differently, as described in Figure \[sub:Priors\]. We use $f\left(d\right)=\left(1+\exp\left(15d-1.3\right)\right)^{-1}$ to select non-zero weights ($f\left(d\right)$ in Figure \[fig:Schematic-description\]), and choose connection amplitudes according to $W_{ij}\sim\mathcal{N}(V_{ij},\sigma^{2}),$ where $\sigma=0.07$ and $\mathbf{V}$ is a block matrix (with a $2\times2$ block structure), corresponding to the two types of neurons inhibitory and excitatory (each covers half the network). We choose $V_{i,j}=1.1$ for excitatory to excitatory connections, $V_{i,j}=0.9$ for excitatory to inhibitory connections, $V_{i,j}=-1.8$ for inhibitory to excitatory connections, and $V_{i,j}=-2.2$ for inhibitory to inhibitory connections. Again, these specific parameters were chosen in order to create a balanced spontaneous network activity. ### Results We tested various combinations of priors: 1. That most connections are zero (sparsity). We use either $L0$ or $L1$ penalties (section \[sub:Sparse-prior\]). \[enu:spar\] 2. That neurons are either excitatory or inhibitory (Dale’s law). We use the method in [@Mishchenko2011c section 2.5.2]. \[enu:Dale\] 3. That neuronal types affect connection amplitude. We use the stochastic block model (section \[sub:Stochastic-block-model\]), in which we either know the number of these types (*i.e.*, we just know the rank of $\mathbf{V}$), or we know exactly how the types affect connection amplitude (*i.e.*, we know $\mathbf{V}$).\[enu:sbm\] 4. That the connection probability is distance dependent. We modify the sparsity penalty (section \[sub:Distance-dependence\]) using $f\left(d\right)=1/\left(1+\mathrm{exp}\left(ad+b\right)\right)$, where we either do not know $a$ and $b$, or do know them. \[enu:dd\] In Figure \[fig:Prior Results\], we show the correlation quality measure (Eq. \[eq:C\]) for different prior combinations. As can be seen, each additional prior incorporated into our connectivity estimate improves its quality. We find that usually the prior on the distance dependence of the connectivity has a more significant impact then the prior on type-dependence. Also, both sparsity-inducing priors, $L0$ and $L1$, give similar performance. Typically $L0$ is slightly better when $T$ is low, while $L1$ is slightly better when $T$ is high (not shown). The $L1$ penalty allows somewhat faster optimization then $L0$. However, the $L0$ penalty allows us to more easily incorporate neuronal type-related connectivity information. Therefore when combining prior \[enu:spar\] with priors \[enu:sbm\]-\[enu:dd\], we only use $L0$. Discussion\[sec:Discussion\] ============================ Current technology limits the number of neurons that can be simultaneously observed. Therefore, common approaches to infer functional connectivity of a neural circuit focus all the observations in one experiment on a small part of the circuit - in which all neurons are fully observed at all timebins. However, unobserved input into this sub-circuit can generate significant error in the estimation - and this error does not vanish with longer experiments. To deal with this “common input” problem, we propose a “shotgun” observation scheme, in which we randomly observe neurons from the circuit, so only a small percentage of the network is observed at each time point. Therefore, despite the limited scanning speed of the imaging device, using this method we can arbitrary expand the field of view to include an entire circuit, together with any input to the circuit, so no neuron is completely hidden. However, existing inference algorithms cannot handle efficiently so many missing observations. For this purpose, we develop (section \[sec:Bayesian Inference\]) a new scalable Bayesian inference method. As we demonstrate numerically (section \[sec:-Results\]) this method can be used to estimate the synaptic connectivity of a spiking neural network from spike data sub-sampled at arbitrarily low observation ratios (e.g., $10\%$). Previously, the lowest observation ratio demonstrated was $50\%$, in a two-neuron network [@Pillow2007], or in a simple linear dynamical model for neuronal activity [@Turaga2013a]. Moreover, our method is very fast computationally, and be can be easily used on networks with thousands of neurons. Previous works, which used standard inference methods, in which the unobserved spikes are treated as latent variables (Section \[sec:Other-Inference-Methods\]), are slower by several orders of magnitude. Specifically, previous MCMC methods [@Pillow2007; @Mishchenko2011c] did not go beyond a $50$ neurons, while variational approaches [@Fletcher2014] did not go beyond $100$. Though the latter may be scaled for a larger population, it is not clear if this approach can handle missing observations. The proposed method is capable of incorporating various kinds of prior information (Figure \[fig:Schematic-description\]), such as the sparsity of synaptic connections, Dale’s Law, the division of neurons into types and the fact that the probability of having a connection between two neurons typically decreases with the distance between two neurons. We show that each piece of information can be used to improve estimation quality (Figure \[fig:Prior Results\]). Another way to significantly improve estimation quality, is to adjust the baseline firing rate of the network using the stimulus (Figure \[fig:The-effect-of-stimulus\]). Specifically, we use a pulse-like stimulus, similar to that generated by persistent ion channels [@Berndt2009], which can be used in the context of all-optical experiments with minimal cross-talk between stimulation and recording. More sophisticated types of stimulation schemes (e.g., [@Rickgauer2014]) may improve performance even further [@Shababo2013]. We conclude that, using the shotgun observation scheme, we can remove the persistent bias resulting from the common input problem (Figure \[fig: Common Input Problem\]). Therefore, the limited scanning speed of a imaging device is not a fundamental obstacle hindering functional connectivity estimation. A complete removal of the bias is possible only if all the neurons in the circuit are observed together with all inputs to the circuit (a sufficient number of times). However, in most experimental setups, some neurons would never be observed (*e.g.*, due to opacity of the brain tissue). Therefore, some persistent bias may remain. To deal with this we will need to incorporate any unobserved input into the circuit using a small number of latent variable [@Vidne2012]. Due to intrinsic fluctuations in the neuronal excitability [@Gal2010; @Soudry2014d], such a latent variable approach can be relevant even in cases where potentially the entire circuit could be observed (*e.g.*, in zerbrafish [@Ahrens2013]). Even if all the neuronal inputs are eventually observed, the variance due to the unobserved inputs is still high, since, at any given time, most of the inputs to each neuron will be unobserved (see also [@Mishchenko2015]). As a result, the duration of the experiment required for accurate inference increases quadratically with the inverse of observation probability (Eq. \[eq: T to N-P scaling\] and Figure \[fig:Parameter-scans P\_obs T\]). This issue will persist for any fixed observation strategy that does not take into account any prior information on the network connectivity. However, there might be a significant improvement in performance if we can focus the observations on synaptic connections which are more probable. This way we can effectively reduce input noise from unobserved neurons, and improve the signal to noise ratio. As a simple example, suppose we know the network is divided in to several disconnected components. In this case, we should scan each sub-network separately, *i.e.*, there is no point in interleaving spike observations from two disconnected sub-networks. How should one focus observations in the more general case? We leave this as an interesting open question in Bayesian experimental design methods (“active learning”). Methods\[sec:Methods\] ====================== Preliminaries\[sec:Preliminaries\] ---------------------------------- In this section we describe the statistical methods used for inferring connectivity given data, observed using the shotgun scheme. First, we describe the basic statistical model and framework (section \[sec:Preliminaries\]); our main analytical results on the simplified loglikelihood (section \[sec:Bayesian Inference\]); how to incorporate various types of prior with this loglikelihood (section \[sub:Priors\]); and a few alternative inference methods (section \[sec:Other-Inference-Methods\]). In the supplementary Appendix S1 we provide all the technical details of the algorithms used. ### General Notation A boldfaced letter $\mathbf{x}$ denotes a vector with components $x_{i}$, a boldfaced capital letter $\mathbf{X}$ denotes a matrix with components $X_{i,j}$, $\mathbf{X}^{\left(k\right)}$ denotes the $k$-th matrix in a list, and $\mathbf{X}_{\cdot,k}$ $\left(\mathbf{X}_{k,\cdot}\right)$ the $k$-th column (row) vector of matrix $\mathbf{X}$. For $\mathbf{X}\in\mathbb{R}^{N\times T}$ we define the empiric average and variance[^2] $$\begin{aligned} \left\langle X_{i,t}\right\rangle _{T} & \triangleq & \frac{1}{T}\sum_{t=1}^{T}X_{i,t}\,\,;\,\,\mathrm{Var}_{T}\left(X_{i,t}\right)\triangleq\frac{1}{T}\sum_{t=1}^{T}\left(X_{i,t}-\left\langle X_{i,t}\right\rangle \right)^{2}\end{aligned}$$ We define the matrices $\mathbf{0}^{M\times N}$ and $\mathbf{1}^{M\times N}$ as $M\times N$ matrices in which all the components are equal to zero or one, respectively. For any condition $A$, we make use of $\mathcal{I}\left\{ A\right\} $, the indicator function (*i.e.*, $\mathcal{I}\left\{ A\right\} =1$ if $A$ holds, and zero otherwise). Also, $\delta_{ij}\triangleq\mathcal{I}\left\{ i=j\right\} $, Kronecker’s delta function. If $\mathbf{x}\sim\mathcal{N}\left(\boldsymbol{\mu},\boldsymbol{\Sigma}\right)$ then $\mathbf{x}$ is Gaussian random vector with mean $\boldsymbol{\mu}$ and covariance matrix $\boldsymbol{\Sigma}$, and we denote its density by $\mathcal{N}\left(\mathbf{x}|\boldsymbol{\mu},\boldsymbol{\Sigma}\right)$. ### Model We use a discrete-time neural network. The neurons, indexed from $i=1$ to $N$, produce spikes in time bins indexed from $t=1$ to $T$. The spiking matrix $\mathbf{S}$ is composed of variables $S_{i,t}$ indicating the number of spikes neuron $i$ produces at time bin $t$. We assume each neuron $i$ generates spikes $S_{i,t}\in\left\{ 0,1\right\} $ according to a Generalized Linear network Model (GLM [@BRIL88; @Rigat06; @Pillow2007]), with a logistic probability function $$P\left(S_{i,t}|U_{i,t}\right)=\frac{e^{S_{i,t}U_{i,t}}}{1+e^{U_{i,t}}}\,.\label{eq: logistic}$$ depending on the the input $U_{i,t}$ it receives from other neurons, as well as from some external stimulus. The input to all the neurons in the network is therefore $$\mathbf{U}_{\cdot,t}\triangleq\mathbf{W}\mathbf{S}_{\cdot,t-1}+\mathbf{b}+\mathbf{G}\mathbf{X}_{\cdot,t}\,,\label{eq: U}$$ where $\mathbf{b}\in\mathbb{R}^{N}$ is the bias of neuron $i$; $\mathbf{X}\in\mathbb{R}^{D\times T}$ are the external inputs (with $D$ being the number of inputs); **$\mathbf{G}\in\mathbb{R}^{N\times D}$** is the input gain; and $\mathbf{W}\in\mathbb{R}^{N\times N}$ is the (unknown) network connectivity matrix. The diagonal elements $W_{i,i}$ of the connectivity matrix correspond to the post spike filter accounting for the cell’s own post-spike effects (*e.g.*, refractory period), while the off-diagonal terms $W_{i,j}$ represent the connection weights from neuron $j$ to neuron $i$. The bias $b_{i}$ controls the mean spike probability (firing rate) of neuron $i$. The external input $\mathbf{X}$ can represent a direct (*e.g.*, light activated ion channels) or sensory (*e.g.*, moving grating) stimulation of neurons in the network. The input gain $\mathbf{G}$ is a spatial filter that gives the effect of this input $\mathbf{X}$ on the network. The input gain represents the affect of this input on the network. We assume that spiking starts from some fixed distribution $P\left(\mathbf{S}_{\cdot,0}\right)$. To simplify notation we have assumed in Eq. \[eq: U\] that $\mathbf{U}_{\cdot,t}$ is affected by spiking activity only in the previous time bin ($\mathbf{W}\mathbf{S}_{\cdot,t-1}$). However, it is straightforward to generalize our results to the case that the input (Eq. \[eq: U\]) includes a longer history of the spiking activity[^3]. It is also possible to change Eq. \[eq: logistic\] and assume other spiking models (*e.g.*, Poisson or Binomial). ### Task Our goal is to infer the connectivity matrix $\mathbf{W}$, biases $\mathbf{b}$ and the stimulus gain $\mathbb{\mathbf{G}}$. We assume that we have some prior information on the weights (including $N$), that we know the external input $\mathbf{X}$, and that we noiselessly[^4] observe a subset of the generated spikes. We use a binary matrix $\mathbf{O}$ to indicate which neurons were observed, so $$O_{i,t}\triangleq\mathcal{I}\left[S_{i,t}\,\mathrm{was\, observed}\right]\,.$$ We assume the observation process is uncorrelated with the spikes, and that $\left\langle O_{i,t}\right\rangle _{T}$ and $\left\langle O_{i,t}O_{j,t-k}\right\rangle _{T}$ converge to strictly positive limits when $T\rightarrow\infty$, for all $i,j$ and for $k\in\left\{ 0,1\right\} $. In other words, we need to observe a large number of timebins (proportional to $T$) from each pair of neurons $\left(i,j\right)$ - both simultaneous spike pairs $\left(k=0\right)$ and spike pairs in which one spike arrives one timestep after the other $\left(k=1\right)$. For example, these assumptions are fulfilled if the spikes are uniformly and randomly observed, or if at each time bin a random observation block is chosen (Figure \[fig:observation schemes\], *top*). However, some spike pairs are never observed, if, for example, we only observe a fixed subset of the network, or scan serially in a continuous manner (Figure \[fig:observation schemes\], *bottom*). Bayesian inference of the weights\[sec:Bayesian Inference\] ----------------------------------------------------------- We use a Bayesian approach in order to infer the unknown weights. For simplicity, initially assume that all spikes are observed and that there is no external input $\left(\mathbf{G}=0\right)$. In this case, the log-posterior of the weights, given the spiking activity, is $$\ln P\left(\mathbf{W}|\mathbf{S},\mathbf{b}\right)=\ln P\left(\mathbf{S}|\mathbf{W},\mathbf{b}\right)+\ln P_{0}\left(\mathbf{W}\right)+C\,,\label{eq: log posterior}$$ where $\ln P\left(\mathbf{S}|\mathbf{W},\mathbf{b}\right)$ is the loglikelihood, $P_{0}\left(\mathbf{W}\right)$ is some prior on the weights (we do not assume a prior on the biases $\mathbf{b}$), and $C$ is some unimportant constant (which does not depend on $\mathbf{W}$ or $\mathbf{b}$). Our aim would be to find the Maximum A Posteriori (MAP) estimator for $\mathbf{W}$, together with the Maximum Likelihood (ML) estimator for $\mathbf{b}$, by solving $$\max_{\mathbf{W},\mathbf{b}}\ln P\left(\mathbf{W}|\mathbf{S},\mathbf{b}\right)\,.\label{eq: ML}$$ Next, we show that under some reasonable assumptions, the loglikelihood can be transformed to a simple form. Importantly, this simple form can be easily calculated even if there are some missing observations, and we have an external stimulus $\left(\mathbf{G}\neq0\right)$. Specifically, we consider a GLM spiking network model, as in Eq. \[eq: logistic\], and simplify its loglikelihood $\ln P\left(\mathbf{S}|\mathbf{W},\mathbf{b}\right)$. Using similar techniques as in [@Park2011; @Sadeghi12; @Ramirez2013] (and a few additional ‘tricks’) we use the expected loglikelihood approximation together with a generalized Central Limit Theorem (CLT) argument [@Diaconis1984], in which we approximate the neuronal input to be Gaussian near the limit $N\rightarrow\infty$; then we calculate the “profile likelihood” $\max_{\mathbf{b}}\ln P\left(\mathbf{S}|\mathbf{W},\mathbf{b}\right)$ in which the bias term has been substituted for its maximizing value (Appendix S1, section \[sub:Derivation\]). The end result is $$\begin{aligned} \max_{\mathbf{b}}\ln P\left(\mathbf{S}|\mathbf{W},\mathbf{b}\right) & \approx & T\sum_{i=1}^{N}\left[\sum_{j=1}^{N}\left[W_{i,j}\Sigma_{i,j}^{\left(1\right)}\right]-h\left(m_{i}\right)\sqrt{1+\frac{\pi}{8}\sum_{k,j}W_{i,j}\Sigma_{k,j}^{\left(0\right)}W_{i,k}}\right]\,,\label{eq:P(S|W,B*)}\end{aligned}$$ where we denoted $$\begin{aligned} m_{i} & \triangleq & \left\langle S_{i,t}\right\rangle _{T}\label{eq:m}\\ \Sigma_{i,j}^{\left(k\right)} & \triangleq & \left\langle S_{i,t}S_{j,t-k}\right\rangle _{T}-m_{i}m_{j}\label{eq: Sigma}\\ h\left(m_{i}\right) & \triangleq & -m_{i}\ln m_{i}-\left(1-m_{i}\right)\ln\left(1-m_{i}\right)\label{eq: entropy}\end{aligned}$$ as the mean spike probability, spike covariance and the entropy function, respectively. We make a few comments: 1. Importantly, this loglikelihood depends on the data only through the sufficient statistics $\mathbf{m}$ and $\boldsymbol{\Sigma}^{\left(k\right)}$ (defined in Eqs. \[eq:m\]-\[eq: Sigma\]), which can be estimated even when some observations are missing. Specifically, if we have a only partial observation of $\mathbf{S}$, we define $$\begin{aligned} \tilde{m}_{i} & \triangleq & \frac{\left\langle O_{i,t}S_{i,t}\right\rangle _{T}}{\left\langle O_{i,t}\right\rangle _{T}}\,,\label{eq: m partial}\\ \tilde{\Sigma}_{i,j}^{\left(k\right)} & \triangleq & \frac{\left\langle O_{i,t}O_{j,t-k}S_{i,t}S_{j,t-k}\right\rangle _{T}}{\left\langle O_{i,t}O_{j,t-k}\right\rangle _{T}}-\tilde{m}_{i}\tilde{m}_{j}\,.\label{eq:Sigma Partial}\end{aligned}$$ Recall the observation process is uncorrelated with the spikes, and that $\forall i,j$ and $\forall k\in\left\{ 0,1\right\} $, $\left\langle O_{i,t}\right\rangle _{T}$ and $\left\langle O_{i,t}O_{j,t-k}\right\rangle _{T}$ converge to strictly positive limits when $T\rightarrow\infty$. From Slutsky’s theorem [@Stirzaker2001] we obtain that for $T\rightarrow\infty$ $$\tilde{\mathbf{m}}\rightarrow\mathbf{m}\,;\,\tilde{\boldsymbol{\Sigma}}^{\left(k\right)}\rightarrow\boldsymbol{\Sigma}^{\left(k\right)}\,,$$ given that $m_{i}$ and $\Sigma_{i,j}^{\left(k\right)}$ converge to some limit when $T\rightarrow\infty$. Therefore, when some observations are missing we can simply replace $\mathbf{m}^{\left(k\right)}$ with $\tilde{\mathbf{m}}^{\left(k\right)}$ and $\mathbf{\boldsymbol{\Sigma}}^{\left(k\right)}$ with $\tilde{\boldsymbol{\Sigma}}^{\left(k\right)}$ in the profile loglikelihood (Eq. \[eq:P(S|W,B\*)\]). 2. As we show in Appendix S1, section \[sec:Likelihood-Derivatives\] the profile loglikelihood (Eq. \[eq:P(S|W,B\*)\]) is concave, and so it is easy to maximize the log-posterior and obtain the MAP estimate of $\mathbf{W}$. Additionally, it is straightforward to calculate the gradient, Hessian and the relevant Lipschitz constant of this loglikelihood. Moreover, since the profile loglikelihood (Eq. \[eq:P(S|W,B\*)\]) decomposes over the rows of $\mathbf{W}$ $$\max_{\mathbf{b}}\ln P\left(\mathbf{W}|\mathbf{S},\mathbf{b}\right)=\sum_{i}\max_{\mathbf{b}}\ln P\left(\mathbf{W}_{i,\cdot}|\mathbf{S},\mathbf{b}\right)\,.\label{eq:posterior decomposition}$$ as do many of the log-priors we will use (section \[sub:Priors\]), the optimization problem of finding the MAP estimate can be parallelized over the rows of $\mathbf{W}$. 3. The ML estimator of $\mathbf{W}$ (the maximizer of Eq. \[eq:P(S|W,B\*)\]) can be derived analytically (Appendix S1, section \[sec:Maximum-Likelihood-Estimator\]) by equating the gradient to zero. The result is $$\mathbf{W}_{\mathrm{MLE}}=\mathbf{A}^{-1}\boldsymbol{\Sigma}^{\left(1\right)}\left(\boldsymbol{\Sigma}^{\left(0\right)}\right)^{-1}\,,\label{eq: W_MLE}$$ where $A_{i,j}\triangleq\delta_{i,j}\sqrt{\left(\frac{\pi}{8}h\left(m_{i}\right)\right)^{2}-\left(\boldsymbol{\Sigma}^{\left(1\right)}\left(\boldsymbol{\Sigma}^{\left(0\right)}\right)^{-1}\left(\boldsymbol{\Sigma}^{\left(1\right)}\right)^{\top}\right)_{i,i}\pi/8}\,.$ This estimate would coincide with any MAP estimate when $T\rightarrow\infty$. 4. Note a finite solution exists only if the last expression has a real value. Interestingly, this ML estimate is a rescaled version of the ML estimate in a simple linear Gaussian neuron model. A similar ML estimate was obtained, using similar approximations, for a Poisson neuron model [@Ramirez2013], albeit with a different re-scaling. This may hint at the generality of this form, and its applicability for other non-linear models. 5. Due to an approximation we make in the derivation (Eq. \[eq:Wang approx\]) of the profile loglikelihood (Eq. \[eq: P(S|W,B\*) appendix\]), the scale factor $A_{i,i}$ tends to be smaller then it should be. This “shrinkage” affects all estimators (ML or MAP) based on the profile loglikelihood. However, this issue can be corrected by re-fitting the scale factors, as explained in Appendix S1, section \[sec:Correcting-ampitudes-and\]. 6. If the neural input is small (due to weak weights, low firing rates or a small number of neurons), the profile loglikelihood (Eq. \[eq: P(S|W,B\*) appendix\]) reduces to a simple quadratic form $$\max_{\mathbf{b}}\ln P\left(\mathbf{S}|\mathbf{W},\mathbf{b}\right)\approx T\sum_{i=1}^{N}\left[\sum_{j=1}^{N}\left[W_{i,j}\Sigma_{i,j}^{\left(1\right)}\right]-h\left(m_{i}\right)\frac{\pi}{8}\sum_{k,j}W_{i,j}\Sigma_{k,j}^{\left(0\right)}W_{i,k}\right]\,.\label{eq: Quadratic Loglikelihood}$$ This is similar to the loglikelihood that we would have a obtained if we would have assumed a linear Gaussian neuron model, albeit with a different constants. Therefore, the non-linear nature of the neurons in our model only becomes important when the neuronal input is strong. 7. Though we assumed the network does not have a stimulus ($\mathbf{G}=0$), a stimulus can be incorporated into the inference procedure. To do this, we treat the stimulus $\mathbf{X}_{\cdot,t}$ simply as the activity of additional, fully observed, neurons (albeit $X_{i,t}\in\mathbb{R}$ while $S_{i,t}\in\left\{ 0,1\right\} $). Specifically, we define a new “spikes” matrix $\mathbf{S}^{\mathrm{new}}\triangleq\left(\mathbf{S}^{\top},\mathbf{X}^{\top}\right)^{\top}$, a new connectivity matrix $$\mathbf{W}^{\mathrm{new}}\triangleq\left(\begin{array}{cc} \mathbf{W} & \mathbf{G}\\ 0^{D\times N} & 0^{D\times D} \end{array}\right)\,,$$ and a new observation matrix $\mathbf{O}^{\mathrm{new}}\triangleq\left(\mathbf{O}^{\top},1^{T\times D}\right)^{\top}.$ Repeating the derivations for $\mathbf{S}^{\mathrm{new}},\mathbf{W}^{\mathrm{new}}$ and $\mathbf{O}^{\mathrm{new}}$, we obtain the same profile loglikelihood. Once it is used to infer $\mathbf{W}^{\mathrm{new}}$, we extract the estimates of $\mathbf{W}$ and $\mathbf{G}$ from their corresponding blocks in $\mathbf{W}^{\mathrm{new}}$. 8. Formally, we need to make sure the conditions of CLT-based approximation [@Diaconis1984] are fulfilled for our approximated method to work, and this can become even more challenging with the addition of (arbitrary) external inputs. However, as can be seen from the simulations, such a generalized CLT-based approximation tends to work quite well even when the neuronal input is not strictly Gaussian [@Teh2006; @Ribeiro2011; @Soudry2014]. For example, in Figure \[fig:Sparsity\], on average, there are about three non-zero spikes in the input of each neuron. In Figure \[fig:The-effect-of-stimulus\], our algorithm is still accurate even though the empirical distribution of the inputs cannot be Gaussian - since it is bimodal due to strong the periodical pulse input. Priors and optimization methods \[sub:Priors\] ---------------------------------------------- In this section we examine different priors $P_{0}\left(\mathbf{W}\right)$ on the network connectivity that can be incorporated into the posterior: the sparsity of inter-neuron connections (section \[sub:Sparse-prior\]); the division of neurons into several “types” (section \[sub:Stochastic-block-model\]); and the fact that connection probability decreases with distance (section \[sub:Distance-dependence\]). ### Sparsity inducing prior\[sub:Sparse-prior\] The diagonal elements $W_{i,i}$ of the connectivity matrix are typically negative, corresponding to the post spike filter accounting for the cell’s own (refractory) post-spike effects, while the off-diagonal terms $W_{i,j}$ represent the connection weights from neuron $j$ to neuron $i$. As most neurons are not connected, most of the off-diagonal $W_{i,j}$ are equal to zero, so **$\mathbf{W}$** is a sparse matrix. #### L1 norm. {#l1-norm. .unnumbered} The most popular approach for incorporating prior information about sparsity is to use a Laplace distribution as prior, which adds an $L_{1}$ norm penalty : $$\ln P_{0}(\mathbf{W})=-\sum_{i,j}\lambda_{i,j}\left|W_{i,j}\right|+C\label{eq:L1 prior}$$ for some set of sparsity parameters $\lambda_{i,j}$. In order to take into account the fact that the off-diagonal terms are zero, we set $$\lambda_{i,j}=\left(1-\delta_{i,j}\right)\lambda\,,\label{eq:lambda mask}$$ where $\lambda>0$. This prior has a number of advantages: the resulting log-posterior of $\mathbf{W}$ (given the full spike train $\mathbf{S}$ and the other system parameters) turns out to be a concave function of $\mathbf{W}$, and the maximizer of this posterior, $\hat{\mathbf{W}}_{\mathrm{MAP}}$ is often sparse, i.e., many values of $\hat{\mathbf{W}}_{\mathrm{MAP}}$ are zero. Combining this prior in to the posterior (Eq. \[eq: log posterior\]), together with the simplified profile loglikelihood (Eq. \[eq:P(S|W,B\*)\]), we obtain a LASSO problem for $\mathbf{W}$ [@Tibs96]. By solving this objective we obtain a sparse Maximum A Posteriori (MAP) estimate $\hat{\mathbf{W}}_{\mathrm{MAP}}$. There are many algorithms that can be used to solve such an objective. Usually, the most efficient [@Bach2011] is the FISTA algorithm [@Beck2009]; details are given in Appendix S1, section \[sec:The-FISTA-algorithm\]. In order to set the value of $\lambda$, we assume some prior knowledge (*e.g.*, statistics from anatomical data) about the sparsity of $\mathbf{W}$ - *i.e.*, how many neurons are connected. Using this knowledge it straightforward to set the value of $\lambda$ using a binary search algorithm, as explained in Appendix S1, section \[sec:Setting lambda\]. #### L0 norm. {#l0-norm. .unnumbered} A more direct approach to sparse optimization is to replace the L1 norm with the “L0 norm” penalty[^5] $$\ln P_{0}(\mathbf{W})=-\sum_{i,j}\lambda_{i,j}\mathcal{I}\left[W_{i,j}\neq0\right]+C\,,\label{eq: L0 prior}$$ where the $\lambda_{i,j}$ are given by Eq. \[eq:lambda mask\]. This makes the resulting log-posterior non-concave and hard to maximize. Fortunately, forward greedy algorithms (Appendix S1, section \[sec:Greedy-Algorithms\]) usually work quite well with such a penalty [@Elad2010]. Briefly, these algorithms initially assume that all weights are zero, and then iteratively repeat the following steps: (1) Fix all the weights from the previous step, and choose one (previously zero) weight which would maximally increase the profile loglikelihood (Eq. \[eq:P(S|W,B\*)\]) if it is allowed to be non-zero. (2) Extend the support of non-zero weights to include this weight. (3) Maximize the profile loglikelihood (Eq. \[eq:P(S|W,B\*)\]) over this support, with all the other weights being zero. A few comments are in order: 1. In our case (Eq. \[eq:P(S|W,B\*)\]), all steps can be performed analytically. 2. In such an approach there is no need to set regularization parameters $\lambda_{i,j}$, since we only need to stop the algorithm when the required level of sparsity has been reached. 3. In the case that weights are weak and the profile loglikelihood becomes quadratic (Eq. \[eq: Quadratic Loglikelihood\]) we get the familiar Orthogonal Matching Pursuit algorithm (OMP, [@Elad2010]), which is typically faster. 4. Forward-backward greedy algorithms [@Zhang] can also be used here, and may offer improved performance. We leave this for future work. As we will show later, empirically, $L0$ and $L1$ give comparable performance, with $L0$ being slower. However, the main advantage of this $L0$ approach is that it can be more easily extended to include other types of prior information, as we discuss next. ### Stochastic block model\[sub:Stochastic-block-model\] Neurons can be classified into distinct types [@kandel1991principles], based on structural, synaptic, genetic and functional characteristics. The connection strength between two neurons usually depends on the types of the pre and post synaptic neurons [@Perin29032011; @Seung2014; @Jonas2014]. A well known example for this is “Dale’s Law” - that all neurons are either excitatory or inhibitory. Therefore, all the outgoing synaptic connection from a neuron should have the same sign. This specific information can be incorporated into our estimates of the weight matrix $\mathbf{W}$, by using a greedy approach, as described in [@Mishchenko2011c section 2.5.2]. In this approach we first maximize the posterior without considering Dale’s law, and find an estimate $\hat{\mathbf{W}}$. Then, neurons are classified as excitatory or inhibitory according to the difference in the count of outgoing weights of each sign $\mathcal{C}_{i}\left(\mathbf{\hat{\mathbf{W}}}\right)\triangleq|\{i:\hat{W}_{ij}>0\}|-|\{i:\hat{W}_{ij}<0\}|$. Specifically, setting $\theta$ as some threshold (we arbitrarily chose $\theta=0.25$), a neuron $j$ was classified as excitatory if $\mathcal{C}_{i}\left(\mathbf{\hat{\mathbf{W}}}\right)>\theta$, as inhibitory if $\mathcal{C}_{i}\left(\hat{\mathbf{W}}\right)<-\theta$, and is not classified if $\left|\mathcal{C}_{i}\left(\mathbf{\hat{\mathbf{W}}}\right)\right|<\theta$. Next, we maximize again the posterior with additional constraints - that in all classified neurons, all outgoing weights have the proper sign for their class. This procedure is then iterated. However, in order to include a more general type-related information into the connectivity prior, here we also used a “stochastic block model” approach [@Nowicki2007; @Adams14; @Jonas2014]. We will assume that all the non-zero weights are sampled from a Gaussian distribution with a fixed variance, and a mean $V_{i,j}$ which depends only on the pre and post synaptic types, and thus have a block structure, where each block has a fixed value (**$\mathbf{V}$** in **** Figure \[fig:Schematic-description\]). As a result, in addition to any previous sparsity-inducing log-prior, we will add also the following penalty $$-\lambda_{V}\sum_{i,j}\mathcal{I}\left[W_{i,j}\neq0\right]\left(W_{i,j}-V_{i,j}\right)^{2}\,,\label{eq: sbm penalty}$$ where $\lambda_{V}$ is a regularization parameter, and $\mathbf{V}$ is the aforementioned block structured matrix. If $\mathbf{V}$ is known, we can add this penalty to the $L0$ norm penalty, and solve using the same greedy algorithm, with a modified objective function. However, usually $\mathbf{V}$ is not known, and all we know (approximately) is the number of types. Since the number of types is greater or equal to the rank of $\mathbf{V}$, and this rank is usually much lower then $N$, we can penalize the rank of $\mathbf{V}$. A convex relaxation of this is $\mathbf{\left\Vert V\right\Vert _{*}}$, the nuclear norm [@Fazel], which we add to the log-posterior. Next, we describe how to maximize the full log-posterior (which is a sum of Eqs. \[eq:P(S|W,B\*)\], \[eq: sbm penalty\] and $\mathbf{\lambda_{*}\left\Vert V\right\Vert _{*}}$). We first initialize $\mathbf{V}=\boldsymbol{0}^{N\times N}$. Then we alternate between: (1) holding $\mathbf{V}$ fixed and maximizing the log-posterior over $\mathbf{W}$ (the sum of Eqs. \[eq:P(S|W,B\*)\] and \[eq: sbm penalty\] ) (2) holding $\mathbf{W}$ fixed and maximizing the log-posterior over $\mathbf{V}$ (the sum of Eqs. \[eq: sbm penalty\] and $\mathbf{\lambda_{*}\left\Vert V\right\Vert _{*}}$). The first step can be done using a forward greedy approach, as we did for the $L0$ penalty. The second step can be done using soft-impute algorithm [@Mazumder2010a], assuming we know in advance this rank (which determines $\lambda_{*}$). Thus, we update $\mathbf{W}$ and $\mathbf{V}$ iteratively until convergence. The value of $\lambda_{V}$ is determined using a cross-validation set. More details are given in Appendix S1, section \[sec:Greedy-Algorithms\]. ### Distance dependence\[sub:Distance-dependence\] The probability of a connection between two neurons often declines with distance [@Perin29032011; @Seung2014; @Jonas2014]. This prior information can also be used to our advantage. Suppose first that the probability of two neurons being connected is given by some known function $f\left(d_{i,j}\right)$, where $d_{i,j}$ is the distance between the neurons $i$ and $j$ (Figure \[fig:Schematic-description\]). A simple way to incorporate this knowledge to modify the regularization constants $\lambda_{i,j}$ (Eq. \[eq:lambda mask\]) in either the L1 penalty (Eq. \[eq:L1 prior\]) or the L0 penalty (Eq. \[eq: L0 prior\]) so they are distance dependent $$\lambda_{i,j}=\frac{\left(1-\delta_{i,j}\right)\lambda}{f\left(d_{i,j}\right)}\,.$$ This way the prior probability for a connection reflects this distance dependence - if a connection is less probable, its regularization constant is higher. If $f\left(d\right)$ is unknown, we give it some parametric form. For example, we will use here $f\left(d\right)=\left(1+\exp\left(-ax-b\right)\right)^{-1}$. To find $\left(a,b\right)$, we alternate between maximizing the posterior over $\mathbf{W}$ and then over $\left(a,b\right)$. More details are given in Appendix S1, section \[sec:Greedy-Algorithms\]. Alternative inference methods - unobserved spikes as latent variables \[sec:Other-Inference-Methods\] ----------------------------------------------------------------------------------------------------- Conceptually, having missing spike observations in the data should make it much harder to estimate $\mathbf{W}$ from data. This is because, in this case, we need to modify the posterior (Eq. \[eq: log posterior\]), and replace the complete likelihood $P\left(\mathbf{S}|\mathbf{W},\mathbf{b}\right)$ with the incomplete likelihood $P\left(S_{\mathrm{obs}}|\mathbf{W},\mathbf{b}\right)$ where $$S_{\mathrm{obs}}\triangleq\left\{ \forall i,t:S_{i,t}|O_{i,t}=1\right\} \,,$$ *i.e.,* the set of all observed spikes from **$\mathbf{S}$**. However, in order to obtain $P\left(S_{\mathrm{obs}}|\mathbf{W},\mathbf{b}\right)$ from $P\left(\mathbf{S}|\mathbf{W},\mathbf{b}\right)$ we need to perform an intractable marginalization over an exponential number of unobserved spike configurations. The method we derived here sidesteps this problem. We infer the connectivity matrix $\mathbf{W}$ using a MAP estimate, derived using an approximation of the complete loglikelihood $\ln P\left(\mathbf{S}|\mathbf{W},\mathbf{b}\right)$ (Eq. \[eq: log posterior\]). Though the complete loglikelihood includes all the spikes (even the unobserved ones), in its approximated form we can also handle missing observations. This is done by simply ignoring missing observations and re-normalizing accordingly the sufficient statistics (Eq. \[eq: m partial\]-\[eq:Sigma Partial\]) of the approximated loglikelihood (Eq. \[eq:P(S|W,B\*)\]). This procedure does not affect the asymptotic value of the sufficient statistics, since the observations and spikes are uncorrelated. In contrast, classical inference methods [@Bishop2006] treat the unobserved spikes as latent variables, and attempt to infer them using one of these standard approaches: - Markov chain Monte Carlo (MCMC) - which samples the latent variables and weights from the complete posterior. - Expectation Maximization (EM) - which provides an estimator that locally optimizes the posterior of $W$ given the observed data. - Variational Bayes (VB) - which approximates the complete posterior using a factorized form. We experimented with all these approaches on the posterior, without using any of the simplifying approximations used in our main method (section \[sec:Bayesian Inference\]). In order to clarify the motivation for our main method, we briefly describe these alternative approaches below, including their advantages and disadvantages. ### Markov chain Monte Carlo (MCMC)\[sub:Markov-chain-Monte\] We assume a sparsity promoting spike and slab prior on the weights $$P_{0}\left(\mathbf{W}\right)=\prod_{i,j}\left[\left(1-p_{0}\right)\delta\left(W_{i,j}\right)+p_{0}\mathcal{N}\left(W_{i,j}|\mu_{0},\sigma_{0}^{2}\right)\right]\label{eq:spike and slab}$$ and use a Gibbs approach to sample jointly from $P(\mathbf{S},\mathbf{W}|S_{\mathrm{obs}},\mathbf{b})$: first we sample $\mathbf{S}$ given the observed data and the current sample from $\mathbf{W}$, and then sample $\mathbf{W}$ given $\mathbf{S}$. Note the standard L1 prior on $\mathbf{W}$ (Eq. \[eq:L1 prior\]) would not promote sparsity in this MCMC setting, since then every sample of $\mathbf{W}$ would be non-zero with probability $1$. In the first step we draw one sample from the posterior of $\mathbf{S}$ given the observed data and an estimated $\mathbf{W}$, using the improved Metropolized Gibbs sampler [@Liu1996; @Liu02], as described in Appendix S1, section \[sub:Sampling-the-spikes\]. This sampler is quite simple and is highly parallelizable in this setting, because the graphical model representing the posterior $p(\mathbf{S}|S_{\mathrm{obs}},\mathbf{W},\mathbf{b})$ is local: $\mathbf{S}_{\cdot,t}$ is conditionally independent of $\mathbf{S}_{\cdot,t+2}$ given $\mathbf{S}_{\cdot,t+1}$ since the spiking at time $t$ only directly affects the spiking in the next time step (*i.e.*, model \[eq: logistic\]-\[eq: U\] can be considered a Markov chain in $\mathbf{S}_{\cdot,t}$). Therefore we can alternately sample the spiking vectors $\mathbf{S}_{\cdot,t}$ at all odd times $t$ completely in parallel, and then similarly for the even times. In more general GLM models, where the neuronal input depends on previous $k$ spikes, *i.e.*, $\left\{ \mathbf{S}_{\cdot,t-k}\right\} _{l=1}^{k}$, then the algorithm could be executed using $T/\left(k+1\right)$ parallel computations. We note that more sophisticated sampling methods have been developed for this type of problem [@Mishchenko2011b]; these specialized methods are significantly more efficient if implemented serially, but do not parallelize as well as the simple Gibbs-based approach we used here. The performance of the sampler is exemplified in Figure \[fig:Estimating-the-spikes\], bottom. As can be seen in this Figure, usually (unless connectivity weights are very high) the spike sampler can predict the spikes only in a “small neighborhood” of the visible spikes. In the second step, we sample $\mathbf{W}$ given $\mathbf{S}$. We first note that, with the spike and slab prior the, again the posterior factorizes: $P(\mathbf{W}|\mathbf{S},\mathbf{b})=\prod_{i}P(\mathbf{W}_{i,.}|\mathbf{S}_{i,.},\mathbf{b})$. Thus, we can sample from each $P(\mathbf{W}_{i,.}|\mathbf{S}_{i,.},\mathbf{b})$ in parallel. To sample from $P(\mathbf{W}_{i,.}|\mathbf{S}_{i,.},\mathbf{b})$, we simply Gibbs sample, one element $W_{i,j}$ at a time. One way to do this is described in Appendix S1, section \[sub:Sampling-the-weights\]. The derivation requires the assumption that the weights are small (empirically, it works well if $W_{i,,j}<1$). Alternatively, this assumption is not necessary if we use instead the (slower) approach discussed in [@mohamed2012bayesian], which requires the computation of some one-dimensional integrals. In our case these integrands are log-concave and therefore uni-modal, and can be calculated using a Laplace approximations. Since both methods contain some approximation, we first need to use them to obtain proposals densities for a Metropolis-Hastings scheme, which then generates the $W_{i,j}$ samples [@Liu02]. In general, computational speed is the main disadvantage of the MCMC method - both for the sampling the spikes and for sampling the weights. For large networks, this approach can only be used if the sampling scheme is completely parallelized over many processors. However, MCMC performs rather well on small networks, similarly to our main method (section \[sec:Bayesian Inference\]). An important advantage of the MCMC method over our main method is that it can be used even if some “spike pairs” are never observed, *i.e.* if for some $i,j$, $\left\langle O_{i,t}O_{j,t-k}\right\rangle _{T}$ for $k=0$ or $1$. Therefore, the MCMC method might be used complement our main method to infer the weights in this case. It should also be noted that the MCMC approach offers somewhat simpler methods for hyperparameter selection (via sampling from the hyperparameter posterior), and easier incorporation into larger hierarchical models that can include richer prior information about the network and enable proper sharing of information across networks. ### Expectation Maximization (EM) The EM approach is similar to the methods discussed in [@Pillow2007; @Mishchenko2011c]. The E step requires the computation of an integral over $p(\mathbf{S}|S_{\mathrm{obs}},\mathbf{W})$. Since this integral is high-dimensional and not analytically tractable, we again resort to MCMC methods to sample the spikes, using the same sampler as before. We found that in most cases it was not necessary to take many samples from the posterior; for large enough network sizes $N$ (and for correspondingly long experimental times $T$), $\mathbf{S}$ is large enough that a single sample contains enough information to adequately estimate the necessary sufficient statistics in the E step. See [@Diebolt1994] for further discussion. In the M step we perform maximization over the log-posterior averaged over $p(\mathbf{S}|S_{\mathrm{obs}},\mathbf{W})$, with an L1 prior The EM approach is is still rather slow, since we need to sample from the spikes. Moreover, the EM approach typically suffered from shrinkage and exhibited worse performance then the MCMC approach. ### Variational Bayes (VB)\[sub:Variational-Bayes-(VB)\] Using the standard VB approach [@Bishop2006] and the spike and slab prior on the weights (Eq. \[eq:spike and slab\]) we can approximate the posterior $P(\mathbf{S},\mathbf{W}|S_{\mathrm{obs}},\mathbf{b})$ using a fully factorized distribution $$Q\left(\mathbf{S},\mathbf{W}\right)\triangleq\prod_{i,t}q_{i,t}\left(S_{i,t}\right)\prod_{k,r}q_{k,r}\left(W_{k,r}\right)\,,\label{eq:Q factorized}$$ in which the factors are calculated using $$\begin{aligned} \ln q_{i,t}\left(S_{i,t}\right) & = & \ln\E_{/S_{i,t}}P(\mathbf{S},\mathbf{W}|S_{\mathrm{obs}},\mathbf{b})\\ \ln q_{k,r}\left(W_{k,r}\right) & = & \ln\E_{/W_{k,r}}P(\mathbf{S},\mathbf{W}|S_{\mathrm{obs}},\mathbf{b})\,,\end{aligned}$$ where, for any random variable $X$, $\E_{/X}$ is an expectation performed using the distribution $Q\left(\mathbf{S},\mathbf{W}|X\right)$. This calculation proceeds almost identically to the derivation of the Gibbs samplers (Appendix S1, section \[sec:MCMC-Approach\]), except we need to perform the expectation $\E_{/X}$ over the results. These integrals can be calculated using the CLT and the approximations given in [@Wang2013a sections 2.4 and 4.1]. The factorized form in Eq. \[eq:Q factorized\] assumes that, approximately, all the weights and all the spikes are independent. In this method, which is faster then MCMC, the mean firing rates of the neurons could be estimated reasonably well, as is exemplified in Figure \[fig:Estimating-the-spikes\], bottom. Unfortunately, the weight matrix $\mathbf{W}$ could not be estimated if less than $30\%$ of the neurons were observed in each timestep. This is in contrast to the other methods, in which the observed fraction can be arbitrarily low. We believe this happens because the VB approximation for the spikes ignores spike correlations - which determine the sufficient statistics in this case (as suggested by Eq. \[eq:P(S|W,B\*)\]). However, it is possible that more sophisticated factorized forms (which do not assume spike independence) will still work. Acknowledgments {#acknowledgments .unnumbered} =============== The authors are thankful to Eftychios Pnevmatikakis, Ari Pakman and Ben Shabado for their help and support, and to Ran Rubin, Yuriy Mishchenko and Ron Meir for their helpful comments. This work was partially supported by the Gruss Lipper Charitable Foundation, grant ARO MURI W911NF-12-1-0594, grant DARPA W91NF-14-1-0269, and grant NSF CAREER IOS-0641912. Additional support was provided by the Gatsby Foundation. 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Wang S, Manning CD (2013) [Fast dropout training]{}. ICML 28. Figure Legends {#figure-legends .unnumbered} ============== ![Examples for “good” and “bad” observation schemes. We observe three out of ten neurons in each timebin. Top*:* The observations $\mathbf{O}$ (a zero-one matrix) for a random scanning scheme (*left*) and its observed pairs **** $\left\langle O_{i,t}O_{j,t-1}\right\rangle _{T}=\frac{1}{T}\sum_{t=1}^{T}O_{i,t}O_{j,t-1}$ (*right*). All possible neuron pairs are observed (*i.e.*, $\left\langle O_{i,t}O_{j,t-1}\right\rangle _{T}>0$ for all pairs), so this is a valid “shotgun” observation scheme. Bottom: The observation matrix $\mathbf{O}$ for a continuous serial scanning scheme (*left*) and **** its observed pairs $\left\langle O_{i,t}O_{j,t-1}\right\rangle _{T}$. Since we do not observe spikes pairs for which $\left|i-j\right|>3$ (*i.e.*, $\left\langle O_{i,t}O_{j,t-1}\right\rangle _{T}=0$ for these pairs), this is not a valid “shotgun” observation scheme. \[fig:observation schemes\]](Observations){width="0.8\columnwidth"} ![Visualization of the persistence of the common input problem, despite a large amount of spiking data ($T=5\cdot10^{6}$), and its suggested solution - the shotgun approach. **(A)** The true connectivity - the weight matrix $\mathbf{W}$ of a network with $N=50$ neurons. **(B)** A zoomed-in view of the top 16 neurons in A (white rectangle in A). **(C)** The same zoomed-in view of the top 16 neurons in the ML estimate of the weight matrix $\mathbf{W}$ (Eq. \[eq: W\_MLE\]), where we used shotgun observation scheme on the whole network, with a random observation probability of $p_{\mathrm{obs}}=16/50$. **(D)** The ML estimator of the weight matrix $\mathbf{W}$ of the top 16 neurons if we observe only these neurons. Note the unobserved neurons cause false positives in connectivity estimation. These “spurious connections” do not vanish even though we have a large amount of spike data. In contrast, the shotgun approach (C), does not have these persistent errors, since it spreads the same number of observations evenly over the network. $b_{i}\sim\mathcal{N}\left(-0.5,0.1\right)$.\[fig: Common Input Problem\]](common_input){width="0.8\columnwidth"} ![**Network connectivity can be well estimated even with low observation ratios.** The network has $N=50$ neurons, the experiment length is $T=5\cdot10^{5}$, and we examine various observation probabilities: $p_{\mathrm{obs}}=1,0.2,0.1,0.04$. Left column - weight matrix, middle column - inferred weight vs. true weight, last column - quality of estimation (based on the measures in Eqs. \[eq:R\]-\[eq:S\]). In the first row we have the true weight matrix $\mathbf{W}$. In the other rows we have $\hat{\mathbf{W}}$ - the MAP estimate of the weight matrix with L1 prior (section \[sub:Sparse-prior\]), with $\lambda$ chosen so that the sparsity of $\hat{\mathbf{W}}$ matches that of $\mathbf{W}$. Estimation is possible even with very low observation ratios. \[fig:Sparsity\]](Sparsity_N=50){width="0.8\columnwidth"} ![**Network connectivity can be reasonably estimated, even with model mismatch.** The same as Figure \[fig:Sparsity\], where instead of a logistic GLM (Eq. \[eq: logistic\]), we used a stochastic, discrete time, leaky integrate and fire neuron model. In this model, $V_{i,t}=\left(\gamma V_{i,t-1}+U_{i,t}+\epsilon_{i,t}\right)\mathcal{I}\left[S_{i,t-1}=0\right]$ ($\mathbf{U}$ defined in Eq. \[eq: U\]), $S_{i,t+1}=\mathcal{I}\left[V_{i,t}>0\right]$. We used $\epsilon_{i,t}\sim\mathcal{N}\left(0,1\right)$ as a white noise source. Also, we set $\gamma=0.5$ so that the neuronal timescale would be restricted to a few time bins, as we assumed for simplicity in the current GLM model. We conclude that our estimation method is robust to modeling errors. \[fig: LIF\]](LIF_figure){width="0.8\columnwidth"} ![**Network connectivity can be well estimated even with large networks.** This is the same figure as Figure \[fig:Sparsity\], except now $N=1000$, $T=5\cdot10^{5}$, and $p_{\mathrm{obs}}=1,0.2,0.1$. Since this estimate can be produced in less then a minute on a standard laptop, this demonstrates that our algorithm is scalable to networks with thousands of neurons. \[fig:Sparsity-1\]](Sparsity_N=1000){width="0.8\columnwidth"} ![**Parameter scans for network size $N$ and observation time $T$.** We examine the quality (based on the measures in Eqs. \[eq:R\]-\[eq:S\]) of the MAP estimate of the weight matrix with L1 prior (section \[sub:Sparse-prior\]). Closely inspecting these figures, we find that performance is approximately maintained constant when $N/T$ is constant (but less so when $T=2$). We used an observation probability of $p_{\mathrm{obs}}=0.2$, and different values of **$N$** and $T$. Performance was averaged over three repetitions. \[fig:Parameter-scans N-T\]](scan2_result){width="0.8\columnwidth"} ![**Parameter scans for observation time $T$ and observation probability $p_{\mathrm{obs}}$.** Quality (based on the measures in Eqs. \[eq:R\]-\[eq:S\]) of the MAP estimate of the weight matrix with L1 prior (section \[sub:Sparse-prior\]). Closely inspecting these figures, we find that performance is approximately maintained constant when $1/Tp_{\mathrm{obs}}^{2}$ is constant (but less so when $p_{\mathrm{obs}}=1$). We used a network size of $N=500$ and different values of **$p_{\mathrm{obs}}$** and $T$. Performance was averaged over three repetitions.\[fig:Parameter-scans P\_obs T\]](scan1_result){width="0.8\columnwidth"} ![**The optimal stimulus magnitude.** We examine the effect of a periodic pulse stimulus on mean spike probability $m$ and reconstruction correlation $C$ (Eq. \[eq:C\]). See section \[fig:The-effect-of-stimulus\]) for more details. Parameters: $N=50,T=10^{4},p_{\mathrm{obs}}=0.2,\,\mathrm{and}\, b_{i}\sim\mathcal{N}\left(-5.2,0.1\right)$, a low firing rate regime. We find that there is an optimal stimulus magnitude near mean spike probability of $m=0.13$. \[fig:The-effect-of-stimulus\].](Stim_N=50){width="0.8\columnwidth"} ![**The prior information on the network connectivity.** Type dependence (left): The connection strength between neurons depends on the type of the pre- and post- synaptic neurons. This induces a block structured matrix $\mathbf{V}$, which, when corrupted by noise, gives the connection strength of the non-zero connections. In this figure we have 2 types - excitatory and inhibitory. Distance dependence (right): the connection probability between neurons declines with distance, which affects which synaptic connections exist. We randomly set neuron locations $x\in\left[0,1\right)$ on a ring lattice (so we have more connections near the diagonal). Thus, after the neuronal types and the distance dependence produce the connectivity matrix $\mathbf{W}$. Naturally, the neuronal type also affects connection probability and distance also affects connection amplitude, but here we did not use this information. \[fig:Schematic-description\]](Priors){width="0.8\columnwidth"} ![image](PriorResults){width="0.8\columnwidth"} ![Estimating the spikes using a latent-variable approach with a known network connectivity ($\mathbf{W},\mathbf{b}$). Each raster plot shows the spikes activity in a circular network with local connectivity (spikes are in white). For neurons $10-20$ and times $18-33$ the spiking activity is unobserved. We try to estimate this activity using Variational Bayes method (VB*, Top*), or using Gibbs sampling (*bottom*). In the unobserved rectangle, the shade indicates the probability of having a spike - between $0$ (black) and $1$ (white). Each neuron in the network has excitatory connections to its neighbors and self-inhibition. Given this connectivity, we can see both methods give reasonable estimates near the edges of unobserved rectangle. Further from the edges, the estimation becomes less certain and converges to the mean spike probability for that neuron. \[fig:Estimating-the-spikes\]](VB_Gibbs_index=1){width="0.8\columnwidth"} Supporting Information Captions {#supporting-information-captions .unnumbered} =============================== **Appendix S1.** Mathematical appendix with full derivations and algorithmic details. Tables {#tables .unnumbered} ====== --------------------- ------------------------------------------------------------------------------------ $N$ Total number of neurons $T$ Total number of time bins $p_{\mathrm{obs}}$ Observation probability - the fraction of neurons observed at each timebin $p_{\mathrm{conn}}$ Network sparsity - the average probability that two neurons are directly connected $\mathbf{S}$ $N\times T$ matrix of spike activity $\mathbf{W}$ $N\times N$ matrix of synaptic connection weights **$\mathbf{U}$** $N\times T$ matrix of neuronal inputs $\mathbf{b}$ $N\times1$ vector of neuronal biases $D$ Total number of external inputs $\mathbf{X}$ $D\times T$ matrix of external input to network $\mathbf{G}$ $N\times D$ matrix of input gain $\mathbf{O}$ $N\times T$ binary matrix denoting when spikes are observed $C$ Unimportant constant --------------------- ------------------------------------------------------------------------------------ : Basic notation\[tab:Basic-notation\] Code will be available on author’s website after publication. Derivation of the simplified loglikelihood (Eq. \[eq:P(S|W,B\*)\]) \[sub:Derivation\] ===================================================================================== Recall Eq. \[eq: logistic\] $$P\left(S_{i,t}|U_{i,t}\right)=\frac{e^{S_{i,t}U_{i,t}}}{1+e^{U_{i,t}}}\,.$$ and Eq. \[eq: U\] with $\mathbf{G}=0$ $$\mathbf{U}_{\cdot,t}\triangleq\mathbf{W}\mathbf{S}_{\cdot,t-1}+\mathbf{b}\,.$$ Combining both together for times $t=1,\cdots,T$ and neurons $i=1,\dots,N$, we obtain $$\begin{aligned} & & \ln P\left(\mathbf{S}|\mathbf{W},\mathbf{b}\right)\nonumber \\ & = & \sum_{i=1}^{N}\sum_{t=1}^{T}\ln\left[\frac{e^{S_{i,t}U_{i,t}}}{1+e^{U_{i,t}}}\right]\nonumber \\ & = & \sum_{i=1}^{N}\sum_{t=1}^{T}\left[S_{i,t}U_{i,t}-\ln\left(1+e^{U_{i,t}}\right)\right],\nonumber \\ & = & T\sum_{i=1}^{N}\left[\left\langle S_{i,t}U_{i,t}\right\rangle _{T}-\left\langle \ln\left(1+e^{U_{i,t}}\right)\right\rangle _{T}\right]\nonumber \\ & \overset{\left(1\right)}{\approx} & T\sum_{i=1}^{N}\left[\left\langle S_{i,t}U_{i,t}\right\rangle _{T}-\int\ln\left(1+e^{x}\right)\mathcal{N}\left(x|\left\langle U_{i,t}\right\rangle _{T},\mathrm{Var}_{T}\left(U_{i,t}\right)\right)dx\right]\nonumber \\ & \overset{\left(2\right)}{\approx} & T\sum_{i=1}^{N}\left[\left\langle S_{i,t}U_{i,t}\right\rangle _{T}-\sqrt{1+\pi\mathrm{Var}_{T}\left(U_{i,t}\right)/8}\ln\left(1+\exp\left(\frac{\left\langle U_{i,t}\right\rangle _{T}}{\sqrt{1+\pi\mathrm{Var}_{T}\left(U_{i,t}\right)/8}}\right)\right)\right]\nonumber \\ & \overset{\left(3\right)}{\approx} & T\sum_{i=1}^{N}\sum_{j=1}^{N}W_{i,j}\Sigma_{k,j}^{\left(1\right)}+m_{i}b_{i}\label{eq: P(S|W,b) simplified}\\ & - & \sqrt{1+\pi\sum_{k,j}W_{i,j}\Sigma_{k,j}^{\left(0\right)}W_{i,k}/8}\ln\left(1+\exp\left(\frac{\sum_{k=1}^{N}W_{i,k}m_{k}+b_{i}}{\sqrt{1+\pi\sum_{k,j}W_{i,j}\Sigma_{k,j}^{\left(0\right)}W_{i,k}/8}}\right)\right)\,,\nonumber \end{aligned}$$ where we used the following 1. The neuronal input, as a sum of $N$ variables, tends to converge to a Gaussian distribution, in the limit of large $N$, under rather general conditions [@Diaconis1984]. 2. Eq. 8 from [@Wang2013a], an approximation which builds upon the following “empiric” observation (Figure \[fig:Visualization-of-the-WangApprox\]) $$\int_{-\infty}^{x}\mathcal{N}\left(z|1,0\right)dz\approx\frac{1}{1+e^{-\left(\sqrt{\pi/8}\right)x}}\,.\label{eq:Wang approx}$$ ![**Visualization of the approximation in Eq. \[eq:Wang approx\].** We compare of right hand side (red) and left hand side (blue) of the approximation. Note this approximation breaks if $\left|x\right|$ is too large (*e.g.*, $\left|x\right|>6$). This is because the asymptotic forms of both sides of Eq. \[eq:Wang approx\] are different. For example, it is easy to show that, as $x\rightarrow-\infty$, the left hand side converges as $e^{-\frac{1}{2}x^{2}}/\sqrt{-x}$ while the right hand side converges as $e^{\left(\sqrt{\pi/8}\right)x}$. \[fig:Visualization-of-the-WangApprox\]](WangApprox){width="0.5\columnwidth"} 1. Eq. \[eq: U\] for the neuronal input and Eqs. \[eq:m\]-\[eq: Sigma\] for the spike statistics, which yields $$\begin{aligned} \left\langle U_{i,t}\right\rangle _{T} & = & \sum_{k=1}^{N}W_{i,k}m_{k}+b_{i}\\ \mathrm{Var}_{T}\left(U_{i,t}\right) & = & \sum_{k=1}^{N}\sum_{j=1}^{N}W_{i,j}\Sigma_{k,j}^{\left(0\right)}W_{i,k}\,\end{aligned}$$ Though in Eq. \[eq: P(S|W,b) simplified\] the loglikelihood has already become tractable (and depends only on the sufficient statistics from Eqs. \[eq:m\]-\[eq: Sigma\]), we can simplify it further by maximizing it over $\mathbf{b}$. To do so, we equate to zero the derivative of the simplified loglikelihood (Eq. \[eq: P(S|W,b) simplified\]) $$\begin{aligned} \frac{d}{db_{\alpha}}\ln P\left(\mathbf{S}|\mathbf{W},\mathbf{b}\right) & = & 0\,.\end{aligned}$$ Solving this equation, we obtain $$m_{\alpha}=\left(1+\exp\left(-\frac{\sum_{k=1}^{N}W_{\alpha,k}m_{k}+b_{\alpha}}{\sqrt{1+\pi\sum_{k,j}W_{\alpha,j}\Sigma_{k,j}^{\left(0\right)}W_{\alpha,k}/8}}\right)\right)^{-1}$$ so $$b_{\alpha}=\sqrt{1+\pi\sum_{k,j}W_{\alpha,j}\Sigma_{k,j}^{\left(0\right)}W_{\alpha,k}/8}\ln\left(\frac{m_{\alpha}}{1-m_{\alpha}}\right)-\sum_{k=1}^{N}W_{\alpha,k}m_{k}\,.$$ Substituting this maximizer into Eq. \[eq: P(S|W,b) simplified\], we obtain $$\begin{aligned} \max_{\mathbf{b}}\ln P\left(\mathbf{S}|\mathbf{W},\mathbf{b}\right) & = & T\sum_{i=1}^{N}\left[\sum_{j=1}^{N}\left[W_{i,j}\Sigma_{i,j}^{\left(1\right)}\right]-h\left(m_{i}\right)\sqrt{1+\pi\sum_{k,j}W_{i,j}\Sigma_{k,j}^{\left(0\right)}W_{i,k}/8}\right]\label{eq: P(S|W,B*) appendix}\end{aligned}$$ which is Eq. \[eq:P(S|W,B\*)\]. Likelihood derivatives\[sec:Likelihood-Derivatives\] ==================================================== We examine the profile loglikelihood in Eq. \[eq:P(S|W,B\*)\], divided by $T$ for convenience $$L\left(\mathbf{W}\right)\triangleq\frac{1}{T}\max_{\mathbf{b}}\ln P\left(\mathbf{S}|\mathbf{W},\mathbf{b}\right)\approx\sum_{i=1}^{N}\left[\sum_{j=1}^{N}\left[W_{i,j}\Sigma_{i,j}^{\left(1\right)}\right]-h\left(m_{i}\right)\sqrt{1+\frac{\pi}{8}\sum_{k,j}W_{i,j}\Sigma_{k,j}^{\left(0\right)}W_{i,k}}\right]\,,$$ Its gradient is $$\begin{aligned} \frac{\partial}{\partial W_{\alpha\beta}}L\left(\mathbf{W}\right) & = & \Sigma_{\alpha,\beta}^{\left(1\right)}-\frac{\pi}{8}h\left(m_{\alpha}\right)\frac{\sum_{k}W_{\alpha,k}\Sigma_{k,\beta}^{\left(0\right)}}{\sqrt{1+\pi\sum_{k,j}W_{\alpha,j}\Sigma_{k,j}^{\left(0\right)}W_{\alpha,k}/8}}\,.\label{eq: Grad}\end{aligned}$$ Its Hessian is $$\begin{aligned} \frac{\partial^{2}L\left(\mathbf{W}\right)}{\partial W_{\alpha\beta}\partial W_{\gamma\eta}} & = & \frac{\frac{\pi}{8}h_{2}\left(m_{\alpha}\right)}{\left[1+\pi\sum_{k,j}W_{\alpha,j}\Sigma_{k,j}^{\left(0\right)}W_{\alpha,k}/8\right]^{3/2}}\label{eq:Hessian}\\ & \cdot & \delta_{\gamma,\alpha}\left[\frac{\pi}{8}\sum_{k,j}W_{\alpha,k}W_{\alpha,j}\left(\Sigma_{k,\beta}^{\left(0\right)}\Sigma_{j,\eta}^{\left(0\right)}-\Sigma_{k,j}^{\left(0\right)}\Sigma_{\eta,\beta}^{\left(0\right)}\right)-\Sigma_{\eta,\beta}^{\left(0\right)}\right]\,.\nonumber \end{aligned}$$ #### Concavity {#concavity .unnumbered} In order show that $L\left(\mathbf{W}\right)$ is concave, we need to prove that for any $\mathbf{W}$ and any matrix $\mathbf{Z}\in\mathbb{R}^{N\times N}$ $$\sum_{\alpha,\beta,\gamma,\eta}Z_{\alpha\beta}Z_{\gamma\eta}\frac{\partial^{2}L\left(\mathbf{W}\right)}{\partial W_{\alpha\beta}\partial W_{\gamma\eta}}\leq0\,.$$ Therefore, we need to calculate the sign of $$\begin{aligned} & & \sum_{\alpha,\beta,\eta}Z_{\alpha\beta}Z_{\alpha\eta}\left[\frac{\pi}{8}\sum_{k,j}W_{\alpha,k}W_{\alpha,j}\left(\Sigma_{k,\beta}^{\left(0\right)}\Sigma_{j,\eta}^{\left(0\right)}-\Sigma_{k,j}^{\left(0\right)}\Sigma_{\eta,\beta}^{\left(0\right)}\right)-\Sigma_{\eta,\beta}^{\left(0\right)}\right]\\ & = & \sum_{\alpha}\left[\frac{\pi}{8}\left(\mathbf{W}_{\alpha,\cdot}^{\top}\boldsymbol{\Sigma}^{\left(0\right)}\mathbf{Z}_{\alpha,\cdot}\right)^{2}-\left(1+\frac{\pi}{8}\mathbf{W}_{\alpha,\cdot}^{\top}\boldsymbol{\Sigma}^{\left(0\right)}\mathbf{W}_{\alpha,\cdot}\right)\mathbf{Z}_{\alpha,\cdot}^{\top}\boldsymbol{\Sigma}^{\left(0\right)}\mathbf{Z}_{\alpha,\cdot}\right]\,.\end{aligned}$$ Since (given $T$ is large enough) $\boldsymbol{\Sigma}^{\left(0\right)}$ is positive definite (since $\E\boldsymbol{\Sigma}^{\left(0\right)}$ is a covariance matrix), we can decompose $\boldsymbol{\Sigma}^{\left(0\right)}=\boldsymbol{\Lambda}\boldsymbol{\Lambda}^{\top}$. Denoting $\boldsymbol{u}_{\alpha}\triangleq\boldsymbol{\Lambda}^{\top}\mathbf{W}_{\alpha,\cdot}$ and $\mathbf{v}_{\alpha}\triangleq\boldsymbol{\Lambda}^{\top}\mathbf{Z}_{\alpha,\cdot}$ we get that the last line can be written as $$\begin{aligned} & & \sum_{\alpha}\left[\frac{\pi}{8}\left(\left(\boldsymbol{u}_{\alpha}^{\top}\boldsymbol{v}_{\alpha}\right)^{2}-\boldsymbol{u}_{\alpha}^{\top}\boldsymbol{u}_{\alpha}\boldsymbol{v}_{\alpha}^{\top}\boldsymbol{v}_{\alpha}\right)-\boldsymbol{v}_{\alpha}^{\top}\boldsymbol{v}_{\alpha}\right]\\ & \leq & -\sum_{\alpha}\boldsymbol{v}_{\alpha}^{\top}\boldsymbol{v}_{\alpha}\\ & \leq & 0\,,\end{aligned}$$ where in the second line we used the Cauchy-Schwarz inequality $\left(\boldsymbol{u}^{\top}\boldsymbol{v}\right)^{2}\leq\boldsymbol{u}^{\top}\boldsymbol{u}\boldsymbol{v}^{\top}\boldsymbol{v}$, and in the last we used the fact that $\boldsymbol{x}^{\top}\boldsymbol{x}\geq0$ for any vector $\mathbf{x}$. Therefore, $L\left(\mathbf{W}\right)$ is concave. #### Lipschitz constant {#lipschitz-constant .unnumbered} For the FISTA algorithm (appendix \[sec:The-FISTA-algorithm\]) we are required to calculate the Lipschitz constant of $\nabla L\left(\mathbf{W}\right)$. A Lipschitz constant $l$ of a function $f$ is defined through $$\forall\mathbf{x},\mathbf{y}:\,\,\,\left\Vert f\left(\mathbf{x}\right)-f\left(\mathbf{y}\right)\right\Vert \leq l\left\Vert \mathbf{x}-\mathbf{y}\right\Vert \,.$$ We obtain that, in our case, $$l=\frac{\pi}{8}\max_{\alpha}h_{2}\left(m_{\alpha}\right)\lambda_{\mathrm{max}}\left[\boldsymbol{\Sigma}^{\left(0\right)}\right]\label{eq: Lipshitz constant}$$ is the Lipschitz constant by observing that $$\begin{aligned} & & \left\Vert \frac{\partial}{\partial W_{\alpha\beta}}L\left(\mathbf{W}\right)-\frac{\partial}{\partial W_{\alpha\beta}^{\prime}}L\left(\mathbf{W}^{\prime}\right)\right\Vert ^{2}\\ & = & \sum_{\alpha}\left[-\frac{\pi}{8}h\left(m_{\alpha}\right)\frac{\sum_{k}W_{\alpha,k}\Sigma_{k,\beta}^{\left(0\right)}}{\sqrt{1+\pi\sum_{k,j}W_{\alpha,j}\Sigma_{k,j}^{\left(0\right)}W_{\alpha,k}/8}}-\Sigma_{\alpha,\beta}^{\left(1\right)}-\frac{\pi}{8}h\left(m_{\alpha}\right)\frac{\sum_{k}W_{\alpha,k}^{\prime}\Sigma_{k,\beta}^{\left(0\right)}}{\sqrt{1+\pi\sum_{k,j}W_{\alpha,j}^{\prime}\Sigma_{k,j}^{\left(0\right)}W_{\alpha,k}^{\prime}/8}}\right]^{2}\\ & \leq & \sum_{\alpha,\beta}\left[-\frac{\pi}{8}h\left(m_{\alpha}\right)\sum_{k}\Sigma_{k,\beta}^{\left(0\right)}\left(W_{\alpha,k}-W_{\alpha,k}^{\prime}\right)\right]^{2}\\ & \leq & \left[\frac{\pi}{8}\max_{\alpha}h\left(m_{\alpha}\right)\lambda_{\mathrm{max}}\left[\boldsymbol{\Sigma}^{\left(0\right)}\right]\right]^{2}\sum_{\alpha,k}\left(W_{\alpha,k}-W_{\alpha,k}^{\prime}\right)^{2}\,,\end{aligned}$$ where $\lambda_{\mathrm{max}}\left[\mathbf{X}\right]$ is the maximal eigenvalue of $\mathbf{X}$. Maximum Likelihood Estimator\[sec:Maximum-Likelihood-Estimator\] ================================================================ We wish to find $\mathbf{W}$ that solves $$0=\frac{\partial}{\partial W_{\alpha\beta}}\max_{\mathbf{b}}\ln P\left(\mathbf{S}|\mathbf{W},\mathbf{b}\right)\,.$$ Using Eq. \[eq: Grad\], we obtain $$0=\Sigma_{\alpha,\beta}^{\left(1\right)}-\frac{\pi}{8}h\left(m_{\alpha}\right)\frac{\sum_{k}W_{\alpha,k}\Sigma_{k,\beta}^{\left(0\right)}}{\sqrt{1+\pi\sum_{k,j}W_{\alpha,j}\Sigma_{k,j}^{\left(0\right)}W_{\alpha,k}/8}}\,.\label{eq: Grad L =00003D0}$$ We define $$A_{\alpha,\beta}\triangleq\frac{\frac{\pi}{8}h\left(m_{\alpha}\right)\delta_{\alpha,\beta}}{\sqrt{1+\pi\sum_{k,j}W_{\alpha,j}\Sigma_{k,j}^{\left(0\right)}W_{\alpha,k}/8}}\label{eq:Q}$$ so we can write Eq. \[eq: Grad L =00003D0\] as $$0=\boldsymbol{\Sigma}^{\left(1\right)}-\mathbf{A}\mathbf{W}\boldsymbol{\Sigma}^{\left(0\right)}\,,$$ which is solved by $$\mathbf{W}=\mathbf{A}^{-1}\boldsymbol{\Sigma}^{\left(1\right)}\left(\boldsymbol{\Sigma}^{\left(0\right)}\right)^{-1}\,.$$ Substituting this into Eq. \[eq:Q\], we have $$A_{\alpha,\alpha}=\frac{\frac{\pi}{8}h\left(m_{\alpha}\right)}{\sqrt{1+\left(\boldsymbol{\Sigma}^{\left(1\right)}\left(\boldsymbol{\Sigma}^{\left(0\right)}\right)^{-1}\left(\boldsymbol{\Sigma}^{\left(1\right)}\right)^{\top}\right)_{\alpha,\alpha}\pi A_{\alpha,\alpha}^{-2}/8}}$$ so $$A_{\alpha,\alpha}=\sqrt{\left(\frac{\pi}{8}h\left(m_{\alpha}\right)\right)^{2}-\left(\boldsymbol{\Sigma}^{\left(1\right)}\left(\boldsymbol{\Sigma}^{\left(0\right)}\right)^{-1}\left(\boldsymbol{\Sigma}^{\left(1\right)}\right)^{\top}\right)_{\alpha,\alpha}\pi/8}\,.$$ Correcting amplitudes and biases\[sec:Correcting-ampitudes-and\] ================================================================ We noticed empirically that using Eq. \[eq: P(S|W,B\*) appendix\] as the simplified loglikelihood tends to cause some inaccuracy in our estimates of the weight gains and biases. To correct for this error, we re-estimate the gains and biases in the following way. Suppose we obtain a MAP estimate $\hat{\mathbf{W}}$ (Eq. \[eq: ML\]) after using the above profile likelihood. Next, we examine again the original likelihood (without any approximation) $$\ln P\left(\mathbf{S}|\mathbf{b},\mathbf{W}\right)=\sum_{i=1}^{N}\left[\sum_{t=1}^{T}S_{i,t}\left(\sum_{j=1}^{N}W_{i,j}S_{j-1}+b_{j}\right)-\sum_{t=1}^{T}\ln\left(1+\exp\left(\sum_{j=1}^{N}W_{i,j}S_{j-1}+b_{j}\right)\right)\right]+C\,.$$ We assume that the MAP estimate is accurate, up to a scaling constant in each row, so $W_{i,j}=$$a_{i}\hat{W}_{i,j}$, and we obtain $$\begin{aligned} & & \sum_{i=1}^{N}\left[\sum_{t=1}^{T}S_{i,t}\left(a_{i}\sum_{j=1}^{N}\hat{W}_{i,j}S_{j-1}+b_{j}\right)-\sum_{t=1}^{T}\ln\left(1+\exp\left(a_{i}\sum_{j=1}^{N}\hat{W}_{i,j}S_{j,t-1}+b_{j}\right)\right)\right]+C\nonumber \\ & = & T\sum_{i=1}^{N}\left[a_{i}\sum_{j=1}^{N}\hat{W}_{i,j}\left\langle S_{i,t}S_{j,t-1}\right\rangle _{T}+b_{j}\left\langle S_{i,t}\right\rangle _{T}-\left\langle \ln\left(1+\exp\left(a_{i}\sum_{j=1}^{N}\hat{W}_{i,j}S_{j,t-1}+b_{j}\right)\right)\right\rangle _{T}\right]\label{eq: L(a,b)}\\ & \approx & T\sum_{i=1}^{N}\left[a_{i}\sum_{j=1}^{N}\hat{W}_{i,j}\left(\tilde{\Sigma}_{i,j}^{\left(1\right)}+\tilde{m}_{i}\tilde{m}_{j}\right)+b_{j}\tilde{m}_{i}-\left\langle \ln\left(1+\exp\left(a_{i}z_{i,t}+b_{j}\right)\right)\right\rangle _{T}\right]+C\,,\end{aligned}$$ where in the last line we used the expected loglikelihood approximation with CLT again, and denoted (Recall Eqs. \[eq:m\]-\[eq: Sigma\]) $$z_{i,t}\sim N\left(\sum_{j=1}^{N}\hat{W}_{i,j}\tilde{m}_{j},\sum\limits _{j,k=1}^{N}\hat{W}_{i,j}\hat{W}_{i,k}\tilde{\Sigma}_{j,k}^{\left(0\right)}\right)\,.\label{eq:z_i}$$ Sampling $z_{i,t}$ from \[eq:z\_i\] (we found that about $10^{3}$ samples was usually enough), we can calculate the expectation in (Eq. \[eq: L(a,b)\]). Next, we can now maximize the likelihood in (Eq. \[eq: L(a,b)\]) for each gain $a_{i}$ and bias $b_{i}$, separately $\forall i$, by solving an easy 2D unconstrained optimization problem. The new gains can now be used to adjust our estimation of $\mathbf{W}$. The FISTA algorithm\[sec:The-FISTA-algorithm\] ============================================== We define the proximal operator [@Bach2011] $$\begin{aligned} \left(\mathcal{T}_{\mu}\left(\mathbf{u}\right)\right)_{i} & \triangleq & \max\left(1-\frac{\mu}{\left|u_{i}\right|},0\right)u_{i}\,.\label{eq:Proximal 1}\end{aligned}$$ FISTA solves the following minimization problem $$\min_{\mathbf{W}}\left[f\left(\mathbf{W}\right)+\lambda\left\Vert \mathbf{W}\right\Vert _{1}\right]\,.$$ From [@Beck2009 Eqs. 4.1-4.3], we have the following algorithm \[alg:The-FISTA-algorithm.\], where the component of the gradient $\nabla f\left(\mathbf{W}\right)$ are given by Eq. \[eq: Grad\], and the Lipschitz constant $l$ is given by Eq. \[eq: Lipshitz constant\]. [Input]{} : Initial point $\mathbf{W}^{\left(k\right)}$,$\nabla f$ and $l$ (Lipschitz constant of $\nabla f$). [Initialize]{} : $\mathbf{Y}^{\left(0\right)}=\mathbf{X}^{\left(0\right)}$, $t_{1}=1$,$\mu=\lambda/l$. [Repeat]{} : For $k\geq1$ compute $$\begin{aligned} \mathbf{W}^{\left(k\right)} & = & \mathcal{T}_{\mu}\left[\mathbf{Y}^{\left(k\right)}-\frac{1}{l}\nabla f\left(\mathbf{Y}^{\left(k\right)}\right)\right]\\ t_{k+1} & = & \left(1+\sqrt{1+4t_{k}^{2}}\right)/2\\ \mathbf{Y}^{\left(k+1\right)} & = & \mathbf{W}^{\left(k\right)}+\left(\frac{t_{k}-1}{t_{k+1}}\right)\left(\mathbf{W}^{\left(k\right)}-\mathbf{W}^{\left(k-1\right)}\right)\,.\end{aligned}$$ Setting $\lambda$ using the sparsity constraint\[sec:Setting lambda\] ===================================================================== As explained in section \[sub:Sparse-prior\], we use a sparsity promoting prior (Eqs. \[eq:L1 prior\]-\[eq:lambda mask\]), which depends on a regularization constant $\lambda$, to generate and estimate $\hat{\mathbf{W}}\left(\lambda\right)$ of the connectivity matrix. Though this constant is unknown in advance, we can set it using the sparsity level of **$\mathbf{\hat{\mathbf{W}}\left(\lambda\right)}$**, defined as $$\mathrm{spar}\left(\lambda\right)\triangleq\frac{1}{N}\sum_{i,j}\mathcal{I}\left(\hat{W}_{i,j}\left(\lambda\right)\neq0\right)\,.$$ We aim for this to be approximately equal to some target sparsity level $p_{\mathrm{conn}}$. This is done using a fast binary search algorithm (Algorithm \[alg:A-binary-search algorithm\]), that exploits the fact that $\mathrm{spar}\left(\lambda\right)$ is non-increasing in $\lambda$. This monotonic behavior can be observed from the fixed point of the FISTA algorithm $$\mathbf{W}=\max\left(1-\frac{\lambda/L}{\left|\mathbf{W}-\frac{1}{L}\nabla f\left(\mathbf{W}\right)\right|},0\right)\left[\mathbf{W}-\frac{1}{L}\nabla f\left(\mathbf{W}\right)\right]\,,$$ for which the number of zeros components is clearly non-decreasing with $\lambda$. [Input]{} : Target sparsity level - $p_{\mathrm{conn}}$, tolerance level - $\epsilon$, measured sparsity - $\mathrm{spar}\left(\lambda\right)$. [Initialize]{} : Initial points $\lambda_{H}$ and $\lambda_{L}$, where $\lambda_{H}\gg1\gg\lambda_{L}$. [Repeat]{} :   [$\lambda=\left(\lambda_{H}+\lambda_{L}\right)/2$]{} :   [If]{} : $\left|\mathrm{spar}\left(\lambda\right)-\theta\right|<\epsilon p_{\mathrm{conn}}$ [Return]{} : $\lambda$ [end]{} :   [If]{} : **$\mathrm{spar}\left(\lambda\right)<p_{\mathrm{conn}}$** [$\lambda_{H}=\lambda$]{} :   [else]{} :   [$\lambda_{L}=\lambda$]{} :   [end]{} :   Greedy algorithms \[sec:Greedy-Algorithms\] =========================================== In this appendix we explain how greedy forward algorithms can be used to solve some of the optimization problems described in section \[sub:Priors\]. In this section, we use the notation $X_{\alpha,Q}\triangleq\left\{ X_{\alpha,\beta}|\beta\in Q\right\} $. L0 penalty ---------- In this appendix we explain in detail how to greedily maximize $\max_{\mathbf{b}}\log P(\mathbf{S}|\mathbf{W},\mathbf{b})$ exactly for each row in the weight matrix $\mathbf{W}$ by incrementally extending the support of non-zero weights. Since the problem is separable (and parallelizable) over the rows (Eq. \[eq:posterior decomposition\]), we do this on a single row $\alpha$ - $\mathbf{W}_{\alpha,\cdot}$. For that row, the normalized profile loglikelihood is $$L\left(\mathbf{W}_{\alpha,\cdot}\right)\triangleq\frac{1}{T}\max_{\mathbf{b}}\ln P\left(\mathbf{S}|\mathbf{W}_{\alpha,\cdot},\mathbf{b}\right)\approx\sum_{j=1}^{N}\left[W_{\alpha,j}\Sigma_{\alpha,j}^{\left(1\right)}\right]-h\left(m_{\alpha}\right)\sqrt{1+\frac{\pi}{8}\sum_{k,j}W_{\alpha,j}\Sigma_{k,j}^{\left(0\right)}W_{\alpha,k}}\,,\label{eq: L(W_alpha)}$$ First we define the support of our estimate $\hat{\mathbf{W}}_{\alpha,\cdot}$ (the set of non-zero components) to be $Q\subset\{1,...,N\}$, and we initialize $Q=\emptyset$. Then, we define $Q^{C}$, the complement of the support (the set of zero weights), and initialize $Q^{C}=\{1,...,N\}$. Lastly, we define $\hat{W}_{\alpha,Q}$, the set of non-zero weights. Since $Q=\emptyset$, then we also initialize $\hat{W}_{\alpha,Q}=\emptyset$. Given $Q$ and $\hat{W}_{\alpha,Q}$ from the previous step, we extend the support, by finding for each potential new weight index $\beta\in Q^{C}$ the best weight $$W_{\alpha,\beta}^{*}=\mathrm{argmax}{}_{W_{\alpha,\beta}}L(W_{\alpha,\beta}|\hat{W}_{\alpha,Q}),\label{eq: greedy step 1}$$ where $L(W_{\alpha,\beta}|\hat{W}_{\alpha,Q})$ is simply $L\left(\mathbf{W}_{\alpha,\cdot}\right)$ under the constraint that $\forall i\in Q:$ $W_{\alpha,i}=\hat{W}_{\alpha,i}$, and $\forall i\in Q^{C}\backslash\beta:$ $W_{\alpha,i}=0.$ Substituting these constraints into Eq. \[eq: L(W\_alpha)\], we obtain $$\begin{aligned} L(W_{\alpha,\beta}|\hat{W}_{\alpha,Q}) & = & \hat{W}_{\alpha,Q}^{T}\Sigma_{\alpha,Q}^{(1)}+\Sigma_{\alpha,Q}^{(1)}W_{\alpha,\beta}\label{eq: L(W_a,b|W_a,Q)}\\ & - & h(m_{\alpha})\sqrt{1+\frac{\pi}{8}(\hat{W}_{\alpha,Q}^{T}\Sigma_{Q,Q}^{(0)}\hat{W}_{\alpha,Q}+2\hat{W}_{\alpha,Q}^{T}\Sigma_{Q,\beta}^{(0)}W_{\alpha,\beta}+\Sigma_{\beta,\beta}^{(0)}(W_{\alpha,\beta})^{2}}\,.\nonumber \end{aligned}$$ We can find the maximizing values for $W_{\alpha,\beta}$ exactly, as the equation $$\begin{aligned} \frac{\partial}{\partial W_{\alpha,\beta}}L(W_{\alpha,\beta}|\hat{W}_{\alpha,Q}) & = & 0\end{aligned}$$ is quadratic in $W_{\alpha,\beta}$: $$aW_{\alpha,\beta}^{^{2}}+bW_{\alpha,\beta}+c=0,$$ with $$a\triangleq\left(\frac{\Sigma_{\alpha,\beta}^{(1)}}{\frac{\pi}{8}h(m_{\alpha})}\right)^{2}\frac{\pi}{8}\Sigma_{\beta,}^{(0)}-\left(\Sigma_{\beta,\beta}^{(0)}\right)^{2}$$ $$b\triangleq\left(\frac{\Sigma_{\alpha,\beta}^{(1)}}{\frac{\pi}{8}h(m_{\alpha})}\right)^{2}\frac{\pi}{4}\hat{W}_{\alpha,Q}^{T}\Sigma_{Q,\beta}^{(0)}-2\hat{W}_{\alpha,Q}^{T}\Sigma_{Q,\beta}^{(0)}\Sigma_{\beta,\beta}^{(0)}$$ $$c\triangleq\left(\frac{\Sigma_{\alpha,\beta}^{(1)}}{\frac{\pi}{8}h(m_{\alpha})}\right)^{2}\left(1+\frac{\pi}{8}\hat{W}_{\alpha,Q}^{T}\Sigma_{Q,Q}^{(0)}\hat{W}_{\alpha,Q}\right)-\left(\hat{W}_{\alpha,Q}^{T}\Sigma_{Q,\beta}^{(0)}\right)^{2}\,.$$ Once we have updated the support by finding $W_{\alpha,\beta}^{*}$, the weight that maximizes this log-likelihood, we can update the support $$Q\leftarrow Q\cup\mathrm{argma}x_{\beta\in Q^{C}}L(W_{\alpha,\beta}^{*}|\hat{W}_{\alpha,Q})\,.\label{eq: greedy step 2}$$ Then, we find the maximum likelihood estimate of weights, constrained to the new support, to be $$W_{\alpha,Q}=\underset{\mathbf{W}_{\alpha,\cdot}:W_{\alpha,Q^{c}}=0}{\mathrm{argmax}}L(\mathbf{W}_{\alpha,\cdot})=\frac{1}{A_{\alpha,\alpha}}\Sigma_{Q,Q}^{(0)^{-1}}\Sigma_{\alpha,Q}^{(1)}\,,\label{eq: greedy step 3}$$ where $A_{\alpha,\alpha}=\sqrt{\left(\frac{\pi}{8}h(m_{\alpha})\right)^{2}-\frac{\pi}{8}\Sigma_{\alpha,Q}^{(1)^{T}}\Sigma_{Q,Q}^{(0)^{-1}}\Sigma_{\alpha,Q}^{(1)}}$ and we used similar derivations as in Appendix \[sec:Maximum-Likelihood-Estimator\]. We repeat this process until $|Q|/N$ is within tolerance of our sparsity constraint ($p_{\mathrm{conn}}$). Stochastic block model ---------------------- In the stochastic block model (section \[sub:Stochastic-block-model\]), we add a quadratic penalty to the profile loglikelihood (Eq. \[eq: sbm penalty\]), which penalizes non-zero weights which are far from some block matrix $\mathbf{V}$, which represent the mean value of the non-zero connection strength between the different types of neurons. We do this by first replacing $L(W_{\alpha,\beta}|\hat{W}_{\alpha,Q})$ in Eqs. \[eq: greedy step 1\]-\[eq: greedy step 2\] with $$L(W_{\alpha,\beta}|\hat{W}_{\alpha,Q})-\lambda_{V}(W_{\alpha,\beta}-V_{\alpha,\beta})^{2}\,,\label{eq:modified penalty}$$ where $\mathbf{V}$ represents the underlying block matrix. In order to maximize this, we again differentiate and equate to zero $$\Sigma_{\alpha,\beta}^{(1)}-\frac{\pi}{8}h(m_{\alpha})\frac{\sum_{k}W_{\alpha,k}\Sigma_{k,\beta}^{(0)}}{\sqrt{1+\frac{\pi}{8}\sum_{k,j}W_{\alpha,j}\Sigma_{k,j}^{(0)}W_{\alpha,k}}}-2\lambda(W_{\alpha,\beta}-V_{\alpha,\beta})=0\,.$$ This equation, when expanded out, takes the form $$\left(b^{2}e\right)W_{\alpha,\beta}^{4}+\left(b^{2}d+2abe\right)W_{\alpha,\beta}^{3}+\left(b^{2}c+2abd+a^{2}e-g^{2}\right)W_{\alpha,\beta}^{2}+\left(2abc+2a^{2}d-2fg\right)W_{\alpha,\beta}+\left(a^{2}c-f^{2}\right)=0,$$ where we defined $$\begin{aligned} a & \triangleq & \frac{\Sigma_{\alpha,\beta}^{(1)}+2\lambda V_{\alpha,\beta}}{\frac{\pi}{8}h(m_{\alpha})};\quad b\triangleq\frac{-2\lambda}{\frac{\pi}{8}h(m_{\alpha})};\quad c\triangleq1+\frac{\pi}{8}\left(W_{\alpha,Q}^{T}\Sigma_{Q,Q}^{(0)}W_{\alpha,Q}\right)\\ d & \triangleq & \frac{\pi}{4}W_{\alpha,Q}^{T}\Sigma_{Q,\beta}^{(0)};\quad e\triangleq\frac{\pi}{8}\Sigma_{\beta,\beta}^{(0)};\quad f\triangleq W_{\alpha,Q}^{T}\Sigma_{Q,\beta}^{(0)};\quad g\triangleq\Sigma_{\beta,\beta}^{(0)}\,.\end{aligned}$$ Since the polynomial is quartic, we can find the optimal weight by running a standard polynomial solver (the roots() function in MATLAB). Once the support for the row has the desired sparsity, we include this penalty in the calculation of the optimal set of weights, so instead of Eq. \[eq: greedy step 3\], we have $$\begin{aligned} \hat{W}_{\alpha,Q} & = & \underset{\mathbf{W}_{\alpha,\cdot}:W_{\alpha,Q^{c}}=0}{\mathrm{argmax}}L(\mathbf{W}_{\alpha,\cdot})-\lambda_{V}\sum_{i\in Q}(W_{\alpha,i}-V_{\alpha,i})^{2}\label{eq:modified_W_est}\\ & = & \left(\Sigma_{\alpha,Q}^{(1)}+2\lambda_{V}V_{\alpha,Q}\right)\left(A_{\alpha,\alpha}\Sigma_{Q,Q}^{(0)}+2\lambda_{V}I\right)^{-1}\,.\nonumber \end{aligned}$$ Distance-dependent connectivity ------------------------------- As explained in section \[sub:Distance-dependence\], we can also incorporate into the model a prior on $f(d_{ij})\triangleq P(W_{i,j}\neq0|d_{ij})$, the probability of a connection between neurons $i,j$ as a function of the distance between them $d_{i,j}$. To promote the selection of more probable connections using this prior, we subtract the penalty $\lambda_{d}/f(d_{\alpha,\beta})$ from $L(W_{\alpha,\beta}|\hat{W}_{\alpha,Q})$ in Eqs. \[eq: greedy step 1\]-\[eq: greedy step 2\], or Eq. \[eq:modified penalty\] if we want also to include the stochastic block model prior. While this penalty modifies the model selection step of extending the support, it has no effect on the values of the weights, determined by Eq. \[eq:modified\_W\_est\]. Inferring unknown penalty parameters ------------------------------------ In many situations, we will not know what is the true block model matrix or distance-dependent connectivity function. However, we can infer these parameters from estimates of the weight matrix, as we explain next. ### Inferring $\mathbf{V}$ using the soft-impute algorithm Recall section \[sub:Stochastic-block-model\]. We wish to estimate $\mathbf{V}$ from $\mathbf{\hat{W}}$ by solving (see Eq. \[eq: sbm penalty\] and explanation below) $$\hat{\mathbf{V}}=\underset{_{\mathbf{V}}}{\mathrm{argmin}}\sum_{i,j}\mathcal{I}\left[\hat{W}_{i,j}\neq0\right]\left(\hat{W}_{i,j}-V_{i,j}\right)^{2}+\lambda_{*}\left\Vert \mathbf{V}\right\Vert _{*}\,,\label{eq: low rank estimation}$$ where the last nuclear norm penalty $\lambda_{*}\left\Vert \mathbf{V}\right\Vert _{*}$ promotes a low rank solution $\hat{\mathbf{V}}$. Suppose we know the target $r_{V}\triangleq\mathrm{rank}\left(\mathbf{V}\right)$, *i.e.*, the minimal number of neuron types affecting neuronal connectivity. Then we can use noisy low-rank matrix completion techniques to estimate $\hat{\mathbf{V}}$ from $\mathbf{\hat{W}}$. Specifically, we found that soft-impute ([@Mazumder2010a], described here in Algorithm \[alg:Soft-Impute\]) works well in this estimation task, where all components $\left(i,j\right)$ for which $\hat{W}_{i,j}=0$, are considered unobserved. In the algorithm we iterate over different values of $\lambda_{*}$, starting with a small value (so initially $\mathbf{\hat{V}}$ has a larger rank than desired) and slowly incrementing, until $\hat{\mathbf{V}}$ is of the desired rank $r_{V}$. ### Inferring $f\left(d\right)$ Recall section \[sub:Distance-dependence\]. We assume the distance-dependent connectivity relationship to be of a sigmoidal form $$P(W_{i,j}\neq0|d_{ij};a,b)=f(d_{ij};a,b)=\frac{1}{1+\exp(-(ad_{ij}+b))}\,.$$ If $f$ is unknown, we can run logistic regression on the binarized inferred weight matrix to estimate $\hat{f}$, *i.e.* $$\begin{aligned} (\hat{a},\hat{b}) & = & \mathrm{argmax}{}_{(a,b)}\prod_{i,j=1,...,N}P(W_{i,j}\neq0|d_{ij};a,b)\\ & = & \mathrm{argmax}{}_{(a,b)}\prod_{i,j=1,...,N}\frac{\exp(\mathcal{I}\left[\hat{W}_{ij}\neq0\right](ad_{ij}+b))}{1+\exp((ad_{ij}+b))}\\ \hat{f} & = & f(d_{ij};\hat{a},\hat{b})\,.\end{aligned}$$ ### Full Model Finally, we can combine distance-dependent connectivity and a low-rank mean matrix and infer both $\mathbf{\hat{V}}$ and $\hat{f}$ from $\hat{\mathbf{W}}$ at the same time. Furthermore, once we have an estimate for these parameters, we can use them to find a new estimate $\hat{\mathbf{W}},$ which in turn, allows us to re-estimate both $\mathbf{\hat{V}}$ and $\hat{f}$. Thus, we can iterate estimating $\mathbf{\hat{W}}$ and the penalty parameters $\mathbf{\hat{V}}$ and $\hat{f}$ until we reach convergence (Algorithm \[alg:Infer\_W\_unknown\_params\]). If our model does not include a low-rank mean matrix or distance-dependent connectivity, we can just set the corresponding penalty coefficient to zero. The penalty coefficients $\lambda_{V}$ and $\lambda_{D}$ are selected by finding each penalty coefficient that maximizes the correlation between $\hat{\mathbf{W}}$ and $\mathbf{W}$ while the other coefficient is set to 0. On actual data, where the ground truth is unknown, one may instead maximize prediction of observed spikes (Figure \[fig:Estimating-the-spikes\]) or spike correlations [@Turaga2013a]. We found it is also possible to set the regularization parameters in the case $\mathbf{\hat{V}}$ and $\hat{f}$ are inferred from the data, to their optimal value in the case where $\mathbf{V}$ and $f$ are known - multiplied by $\frac{1}{2}$ to account for uncertainty. Define $L(W_{\alpha,\beta}|W_{\alpha,Q})$ as in Eq. \[eq: L(W\_a,b|W\_a,Q)\]. Initialize solution $\hat{\mathbf{W}}=0^{N\times N}$. **For $\alpha=1,...,N$** Initialize support $Q=\emptyset$ While **$|Q|/N<p_{\mathrm{conn}}$** Find the optimal penalized weight index: $$\beta^{*}=\underset{\beta\in Q^{C}}{\mathrm{argmax}}\max_{W_{\alpha,\beta}}\left[L(W_{\alpha,\beta}|W_{\alpha,Q})-\lambda_{M}(W_{\alpha,\beta}-V_{\alpha,\beta})^{2}-\frac{\lambda_{d}}{f(d_{\alpha,\beta})}\right]$$ Update the support: $$Q=Q\cup\beta^{*}$$ Update the weights: $$\hat{W}_{\alpha,Q}=\left(\Sigma_{\alpha,Q}^{(1)}+2\lambda_{V}V_{\alpha,Q}\right)\left(A_{\alpha,\alpha}\Sigma_{Q,Q}^{(0)}+2\lambda_{V}I\right)^{-1}$$ **Return** $\hat{\mathbf{W}}$ Define $S_{\lambda}(\mathbf{A})\triangleq\mathbf{U}\mathbf{D}_{\lambda}\mathbf{V}^{T}\,,$ where $\mathbf{UD}\mathbf{V}^{T}$ being the singular value decomposition of $\mathbf{A}$, with $\mathbf{D}=\text{diag}(d_{1},...,d_{r})$, and $\mathbf{D}_{\lambda}\triangleq\text{diag}((d_{1}-\lambda)_{+},...,(d_{r}-\lambda)_{+})),$ with $(x)_{+}=\max\left(0,x\right)$. Initialize $\mathbf{Z}=\boldsymbol{0}^{N\times N}$, and some decreasing set **$\lambda_{1}>\lambda_{2}>...>\lambda_{k}$.** **For $\lambda_{1}>\lambda_{2}>...>\lambda_{k}$** $\forall i,j:$ $Y_{i,j}=A_{i,j}+\mathcal{I}\left[A_{i,j}=0\right]Z_{i,j}\,.$ $\mathbf{Z}=S_{\lambda_{k}}(\mathbf{Y})$ **If $\mathrm{rank}\left(\mathbf{Z}\right)=r$, return $\mathbf{Z}$** **End** $\hat{f}^{0}(d)=\infty$ $\mathbf{\hat{V}}^{0}=\boldsymbol{0}^{N\times N}$ **For $t=1,...,k$** $\hat{\mathbf{W}}^{t}=$Infer\_W\_known\_params($\Sigma^{(0)},\Sigma^{(1)},p_{\mathrm{conn}},\lambda_{M},\hat{\mathbf{V}}^{t-1},\lambda_{d},\hat{f}^{t-1},d)$ $(\hat{a},\hat{b})=$$\mathrm{argmax}{}_{(a,b)}\prod_{i,j=1,...,N}\frac{\exp(\mathcal{I}\left[\hat{W}_{ij}\neq0\right](ad_{ij}+b))}{1+\exp((ad_{ij}+b))}$ $\hat{f}^{t}(d)=\frac{1}{1+\exp(-(\hat{a}d+\hat{b}))}$ $\mathbf{\hat{V}}^{t}$=Soft-Impute($\hat{\mathbf{W}^{t}},r_{V}$) **Return $\hat{\mathbf{W}^{t}}$** An MCMC approach for inferring connectivity\[sec:MCMC-Approach\] ================================================================ In this section we give the details of the MCMC approach for inferring the weights (summarized in section \[sub:Markov-chain-Monte\]). To do this we alternate between sampling the spikes (section \[sub:Sampling-the-spikes\]), and sampling the weights (section \[sub:Sampling-the-weights\]). First, recall again Eq. \[eq: logistic\] $$P\left(S_{i,t}|U_{i,t}\right)=\frac{e^{S_{i,t}U_{i,t}}}{1+e^{U_{i,t}}}\,.$$ and Eq. \[eq: U\] (with $\mathbf{G}=0$) $$\mathbf{U}_{\cdot,t}\triangleq\mathbf{W}\mathbf{S}_{\cdot,t-1}+\mathbf{b}\,.$$ Sampling the spikes\[sub:Sampling-the-spikes\] ---------------------------------------------- We denote here $S_{/\left(i,t\right)}$ to be all the component of $\mathbf{S}$ without the $S_{i,t}$ component. In order to do Gibbs sampling, we need to calculate $$\ln P\left(S_{i,t}|S_{/\left(i,t\right)},\mathbf{W},\mathbf{b}\right)=\ln P\left(S_{i,t}|\mathbf{S}_{\cdot,t-1},\mathbf{W},\mathbf{b}\right)+\ln P\left(\mathbf{S}_{\cdot,t+1}|\mathbf{S}_{t},\mathbf{W},\mathbf{b}\right)+C\,,$$ where we can neglect any additive constant that does not depend on $S_{i,t}$. On the right hand side, the first term is $$\begin{aligned} \ln P\left(S_{i,t}|\mathbf{S}_{\cdot,t-1},\mathbf{W},\mathbf{b}\right) & = & \ln\left[\frac{e^{S_{i,t}U_{i,t}}}{1+e^{U_{i,t}}}\right]\\ & = & S_{i,t}U_{i,t}+C\,,\\ & = & S_{i,t}\left(\sum_{k=1}^{N}W_{i,k}S_{k,t-1}+b_{i}\right)\,,\end{aligned}$$ while the second term is $$\begin{aligned} & & \ln P\left(\mathbf{S}_{\cdot,t+1}|\mathbf{S}_{\cdot,t},\mathbf{W},\mathbf{b}\right)\\ & = & \sum_{j}\ln\left[\frac{e^{S_{j,t+1}U_{j,t+1}}}{1+e^{U_{j,t+1}}}\right]\\ & = & \sum_{j}\left[S_{j,t+1}U_{j,t+1}-\ln\left(1+e^{U_{j,t+1}}\right)\right]\\ & = & \sum_{j}\left[S_{j,t+1}\left(\sum_{k=1}^{N}W_{j,k}S_{k,t}+b_{j}\right)-\ln\left(1+\exp\left(\sum_{k=1}^{N}W_{j,k}S_{k,t}+b_{j}\right)\right)\right]+C\\ & = & C+\sum_{j}S_{j,t+1}S_{i,t}W_{j,i}\\ & - & \sum_{j}\left[\ln\left(1+\exp\left(\sum_{k\neq i}^{N}W_{j,k}S_{k,t}+b_{j}+W_{j,i}\right)\right)-\ln\left(1+\exp\left(\sum_{k\neq i}^{N}W_{j,k}S_{k,t}+b_{j}\right)\right)\right]S_{i,t}\,.\end{aligned}$$ Therefore, we can sample the spikes from $$\begin{aligned} P\left(S_{i,t}|S_{/\left(i,t\right)},\mathbf{W},\mathbf{b}\right) & \propto & \exp\left(\alpha_{i,t}S_{i,t}\right)\,,\end{aligned}$$ where $$\begin{aligned} \alpha_{i,t} & \triangleq & b_{i}+\sum_{k=1}^{N}W_{i,k}S_{k,t-1}\\ & + & \sum_{j}\left[S_{j,t+1}W_{j,i}-\ln\left(1+\exp\left(\sum_{k\neq i}^{N}W_{j,k}S_{k,t}+b_{j}+W_{j,i}\right)+\ln\left(1+\exp\left(\sum_{k\neq i}^{N}W_{j,k}S_{k,t}+b_{j}\right)\right)\right)\right].\end{aligned}$$ Note that, for a given $i$, $\alpha_{i,t}$ depends only on spikes from time $t-1$ and $t+1$. Therefore, $S_{i,t}$ samples generated at odd times $t$ are independent from samples $S_{i,t^{\prime}}$ generated at even times $t'$. Therefore, we can sample $S_{i,t}$ simultaneously for all odd times $t$, and then sample simultaneously at all even times $t$. Such a simple block-wise Gibbs sampling scheme can be further accelerated by using the Metropolized Gibbs method [@Liu1996], in which we propose a “flip” of our previous sample. So if $S_{i,t}$ is out previous sample and $S_{i,t}^{\prime}$ is our new sample, we propose that $S_{i,t}^{\prime}=1-S_{i,t}$ and then accept this proposal with probability $$\min\left(1,\frac{1-P\left(S_{i,t}|S_{/\left(i,t\right)},\mathbf{W},\mathbf{b}\right)}{1-P\left(S_{i,t}^{\prime}|S_{/\left(i,t\right)},\mathbf{W},\mathbf{b}\right)}\right)\,.$$ If the proposal is not accepted, we keep our previous sample $S_{i,t}$. Sampling the weights\[sub:Sampling-the-weights\] ------------------------------------------------ We denote here $W_{/\left(i,j\right)}$ to be all the components of $\mathbf{W}$ without the $W_{i,j}$ component, and $$f\left(x\right)\triangleq\frac{1}{1+e^{-x}}\,.$$ In order to do Gibbs sampling, we need to calculate $$\ln P\left(W_{i,j}|\mathbf{S},W_{/\left(i,j\right)},\mathbf{b}\right)=\ln P\left(\mathbf{S}|\mathbf{W},\mathbf{b}\right)+\ln P_{0}\left(W_{i,j}\right)+C\,,$$ where, as before, we can neglect on the right hand side any additive constant that does not depend on $W_{i,j}$. The first term on the right hand side is $$\begin{aligned} & & \ln P\left(\mathbf{S}|\mathbf{W},\mathbf{b}\right)\\ & = & \sum_{i}\sum_{t}\ln\left[\frac{e^{S_{i,t}U_{i,t}}}{1+e^{U_{i,t}}}\right]\\ & = & \sum_{i}\sum_{t}\left[S_{i,t}U_{i,t}-\ln\left(1+e^{U_{i,t}}\right)\right],\\ & = & \sum_{i}\sum_{t}\left[W_{i,j}S_{i,t}S_{j,t-1}-\ln\left(1+\exp\left(\sum_{k=1}^{N}W_{i,k}S_{k,t-1}+b_{i}\right)\right)\right]+C\\ & = & \sum_{i}\sum_{t}\left[W_{i,j}S_{i,t}S_{j,t-1}-\ln\left(1+\exp\left(W_{i,j}S_{j,t-1}\right)\exp\left(\sum_{k\neq j}^{N}W_{i,k}S_{k,t-1}+b_{i}\right)\right)\right]+C\\ & \approx & \sum_{i}\sum_{t}\left[W_{i,j}S_{i,t}S_{j,t-1}-\ln\left(1+\left(1+W_{i,j}S_{j,t-1}+\frac{1}{2}W_{i,j}^{2}S_{j,t-1}\right)\exp\left(\sum_{k\neq j}^{N}W_{i,k}S_{k,t-1}+b_{i}\right)\right)\right]+C\\ & = & \sum_{i}\sum_{t}\left[W_{i,j}S_{i,t}S_{j,t-1}-\ln\left(1+f\left(\sum_{k\neq j}^{N}W_{i,k}S_{k,t-1}+b_{i}\right)\left(W_{i,j}S_{j,t-1}+\frac{1}{2}W_{i,j}^{2}S_{j,t-1}\right)\right)\right]+C\\ & \approx & \sum_{i}\sum_{t}\left[W_{i,j}S_{j,t-1}\left[S_{i,t}-f\left(\sum_{k\neq j}^{N}W_{i,k}S_{k,t-1}+b_{i}\right)\right]\right.\\ & - & \left.\frac{1}{2}W_{i,j}^{2}S_{j,t-1}\left[f\left(\sum_{k\neq j}^{N}W_{i,k}S_{k,t-1}+b_{i}\right)-f^{2}\left(\sum_{k\neq j}^{N}W_{i,k}S_{k,t-1}+b_{i}\right)\right]\right]\,,\end{aligned}$$ where in both approximations we used the fact that a single weight is typically small $W_{i,j}\ll1$. Therefore, denoting $$\begin{aligned} \omega_{i,j} & \triangleq & \sum_{t}\left[S_{i,t}-f\left(\sum_{k\neq j}^{N}W_{i,k}S_{k,t-1}+b_{i}\right)\right]S_{j,t-1}\\ \epsilon_{i,j} & \triangleq & \sum_{t}\left[f\left(\sum_{k\neq j}^{N}W_{i,k}S_{k,t-1}+b_{i}\right)-f^{2}\left(\sum_{k\neq j}^{N}W_{i,k}S_{k,t-1}+b_{i}\right)\right]S_{j,t-1}\,,\end{aligned}$$ we can write $$P\left(\mathbf{S}|\mathbf{W},\mathbf{b}\right)\propto\exp\left(W_{i,j}\omega_{i,j}-\frac{1}{2}W_{i,j}^{2}\epsilon_{i,j}\right)\,.$$ Therefore, $$P\left(W_{i,j}|\mathbf{S},W_{/\left(i,j\right)},\mathbf{b}\right)\propto\exp\left(W_{i,j}\omega_{i,j}-\frac{1}{2}W_{i,j}^{2}\epsilon_{i,j}\right)P_{0}\left(W_{i,j}\right)\,.$$ Assuming spike-and-slab prior $$P_{0}\left(W_{i,j}\right)=f\left(-h_{0}\right)\delta\left(W_{i,j}\right)+f\left(h_{0}\right)\mathcal{N}\left(W_{i,j}|\mu_{0},\sigma_{0}^{2}\right)\,,\label{eq:prior-1}$$ we can use standard Gaussian completion we do spike-and-slab completion - re-normalizing to obtain a proper spike-and-slab distribution. This gives $$P\left(W_{i,j}|\mathbf{S},W_{/\left(i,j\right)},\mathbf{b}\right)=f\left(-h_{i,j}\right)\delta\left(W_{i,j}\right)+f\left(h_{i,j}\right)\mathcal{N}\left(W_{i,j}|\mu_{i,j},\sigma_{i,j}^{2}\right)\,,\label{eq: W_ij distribution for Gibbs}$$ with $$\begin{aligned} \sigma_{i,j}^{2} & \triangleq & \frac{\sigma_{0}^{2}}{1+\epsilon_{i,j}\sigma_{0}^{2}}\\ \mu_{i,j} & \triangleq & \frac{\sigma_{i,j}^{2}}{\sigma_{0}^{2}}\left[\mu_{0}+\sigma_{0}^{2}\omega_{i,j}\right]\\ h_{i,j} & \triangleq & h_{0}+\frac{1}{2}\ln\left(\frac{\sigma_{i,j}^{2}}{\sigma_{0}^{2}}\right)+\frac{\mu_{i,j}^{2}}{2\sigma_{i,j}^{2}}-\frac{\mu_{0}^{2}}{2\sigma_{0}^{2}}\,.\end{aligned}$$ We can than proceed and sample $\mathbf{W}_{\cdot,j}$ from this spike-and-slab distribution (in Eq. \[eq: W\_ij distribution for Gibbs\]) - sampling $W_{i,j}$ simultaneously for all $i$. Now, since we used the approximation that assuming the weights are weak, so this sampling is not exact. Therefore, even if the approximation is very good, we can not use direct sampling, or the error will accumulate over time catastrophically. To correct his, we use this approximation as a proposal distribution in a Metropolis Hastings simulation scheme [@Liu02]. [^1]: This happens if the neurons fire with rate $0.5$ when the pulse is “ON”. Therefore, the average firing rate in this case is $m=0.25$, since the neurons hardly fire when the pulse is “OFF” (which is $50\%$ of the time) [^2]: The following expressions do not depend on $t$, despite the $t$ index, which is maintained for notational convenience. [^3]: *i.e.*, more generally, we can have $\mathbf{U}_{\cdot,t}\triangleq\sum_{k=1}^{L_{1}}r^{\left(k\right)}\mathbf{U}_{\cdot,t-k}+\sum_{k=1}^{L_{2}}\mathbf{W}^{\left(k\right)}\mathbf{S}_{\cdot,t-k}+\mathbf{b}+\mathbf{G}\mathbf{X}_{\cdot,t}$, where $\left\{ r^{\left(k\right)}\right\} _{k=1}^{L_{1}}$ and $\left\{ \mathbf{W}^{\left(k\right)}\right\} _{k=1}^{L_{2}}$ determine the neuronal timescales. [^4]: *i.e.*, for simplicity we ignore for now the problem of inferring the spikes from the experimental data (*e.g.*, which requires spike sorting or deconvolution of the calcium trace). The issue of spike inference was addressed systematically in [@Mishchenko2011c; @Lutcke2013]. [^5]: Formally, this is not an actual norm, and also the prior is not a valid distribution.
On scaffolds and hopping in medicinal chemistry. The molecular scaffold is an oft-cited concept in medicinal chemistry suggesting that the definition of what makes a scaffold is rigorous and objective. However, this is far from the case with the definition of a scaffold being highly dependent on the particular viewpoint of a given scientist. It follows, therefore, that the definition of scaffold hopping and, more importantly, the detection of what constitutes a scaffold hop, is also ill-defined and highly subjective. Essentially, it is agreed that scaffolds should be substantially different from each other, although significantly similar to each other, to constitute a hop. In the latter, the scaffolds must permit a similar geometric arrangement of functional groups to permit the mode of action. However, this leaves the paradox of how to describe both scaffold similarity and dissimilarity simultaneously. In this paper, the current statuses of scaffolds and scaffold hopping are reviewed based on published examples of scaffold hopping from the literature. An investigation of the degree to which it is possible to formulate a more rigorous definition of scaffolds and hopping in the context of molecular topologies is considered. These techniques are adapted from chemoinformatics to be applied in the design of new medicinal compounds.
611 F.Supp. 1080 (1985) Jonathan SMITH, Plaintiff, v. The CITY OF NEW YORK, a municipal entity existing and otherwise created under the laws of the State of New York, the New York City Police Department, a governmental agency, Robert McGuire, Police Commissioner of the New York City Police Department, Anthony Capodieci, Police Officer in and with the New York City Police Department, F. Sherman, Police Officer in and with the New York City Police Department, Defendants and Third Party Plaintiffs. No. 82 Civ. 4457-CSH. United States District Court, S.D. New York. April 1, 1985. *1081 *1082 James I. Meyerson, New York City (Jonathan Moore, New York City, of counsel), for plaintiff. Frederick A.O. Schwarz, Jr., Corp. Counsel, New York City (Judith A. Levitt, Elissa Hutner, Jonathan Pines, New York City, of counsel), for defendants. MEMORANDUM OPINION AND ORDER HAIGHT, District Judge: Months after discovery in this case was closed by Court order, and literally upon the eve of trial, plaintiff has made a number of motions. This opinion addresses them. I. History of the Litigation This action arises out of an altercation between plaintiff Jonathan Smith and two *1083 New York City Police Department officers, the individual defendants Anthony Capodieci and Frederick Sherman, during the early morning hours of December 25, 1981. Smith was involved in an automobile accident. Officers Capodieci and Sherman responded to the scene. An altercation broke out between plaintiff and the officers. It is not necessary for present purposes to recite the respective parties' accounts of the incident, which differ markedly. It is sufficient to say that a scuffle ensued; plaintiff was placed under arrest by Capodieci and Sherman; plaintiff alleges that he sustained personal injuries at the hands of the two police officers; and the police officers allege that they sustained injuries at the hands of plaintiff. Plaintiff commenced this action, alleging constitutional claims within the context of the civil rights statutes, 42 U.S.C. §§ 1981 and 1983. Plaintiff sought compensatory and punitive damages against all defendants. The Office of the Corporation Counsel of the City of New York (hereinafter "Corporation Counsel") appeared and answered on behalf of all defendants, including the two police officers. In an answer served on September 1, 1982, the Corporation Counsel asserted counterclaims on behalf of all defendants, including counterclaims on behalf of the police officers against plaintiff for intentional assault. Issue was fully joined on April 20, 1983 when plaintiff answered the counterclaims. At an initial pre-trial scheduling conference, on November 5, 1982, the Court had specified June 6, 1983 for the completion of all discovery. That deadline was subsequently extended to August 6, 1983. Discovery disputes arose which the Court referred to Magistrate Gershon in an Order dated July 11, 1983. Magistrate Gershon advised the Court in a memorandum dated January 11, 1984 that all outstanding discovery disputes had been resolved. At a hearing on March 9, 1984, the case was marked trial ready. It was called for trial on December 17, 1984. On December 11, 1984, plaintiff noticed the first of the present motions. Other motions shortly followed. The presently pending motions on behalf of plaintiff are as follows: (1) Motion to dismiss the individual defendants' counterclaims, or in the alternative, to disqualify the Corporation Counsel from prosecuting them. Filed December 11, 1984. (2) Motion for leave to conduct additional discovery. Filed January 2, 1985. (3) Motion for leave to amend the complaint "to assert and clarify Monell claims against the City of New York and to otherwise assert claims against the defendant officers Sherman and Capodieci." Filed February 6, 1985. I discuss these motions separately. II. Plaintiff's Motion to Dismiss the Individual Defendants' Counterclaims, or in the Alternative, to Disqualify Corporation Counsel from Prosecuting Them Plaintiff asserts two grounds for his motion to dismiss the individual defendants' counterclaims, or in the alternative to disqualify the Corporation Counsel from prosecuting them. First, plaintiff argues that the pertinent statutory scheme prohibits the Corporation Counsel from rendering legal services to individuals in aid of private claims. Second, plaintiff asserts that even if the Corporation Counsel is not prohibited from such representation by statute, the ethical conflicts presented are such that the Corporation Counsel should be disqualified. I consider these contentions in turn. Preliminarily, it is appropriate to observe that, whatever its timing, plaintiff's invocation of professional ethics must be carefully considered. Unlike motions to amend pleadings or demands for pre-trial discovery, which as noted infra may be denied because they are untimely, an allegation of unethical professional conduct triggers the Court's continuing supervisory responsibility. Dunton v. County of Suffolk, 729 F.2d 903, 908 (2d Cir.1984). Plaintiff's contention *1084 could certainly have been made earlier; but its timing is not a factor in the Court's decision. (a) Authority of the Corporation Counsel to Represent the Police Officers on their Counterclaims The Corporation Counsel is a creature of statute. Accordingly, in order to determine whether or not he is authorized to represent the defendant police officers on their counterclaims, one must first turn to the applicable legislative provisions. I begin with section 50-k of the General Municipal Law of New York State, 23 McKinney's Consol.L. of N.Y. (Supp.1984). This statute is entitled: "Civil actions against employees of the city of New York." The statute deals generally with the defense and indemnification by the city of an employee in any civil action or proceeding in any state or federal court. Specific reference is made to actions such as this one, commenced under the federal civil rights statutes. Section 50-k(2) deals with defense. It provides: "At the request of the employee and upon compliance by the employee with the provisions of subdivision four of this section, the city shall provide for the defense of an employee of any agency in any civil action or proceeding in any state or federal court including actions under sections nineteen hundred eighty-one through nineteen hundred eighty-eight of title forty-two of the United States code arising out of any alleged act or omission which the corporation counsel finds occurred while the employee was acting within the scope of his public employment and in the discharge of his duties and was not in violation of any rule or regulation of his agency at the time the alleged act or omission occurred. This duty to provide for a defense shall not arise where such civil action or proceeding is brought by or on behalf of the city or state or any agency of either." Section 50-k(3) deals with indemnification. It provides: "The city shall indemnify and save harmless its employees in the amount of any judgment obtained against such employees in any state or federal court, or in the amount of any settlement of a claim approved by the corporation counsel and the comptroller, provided that the act or omission from which such judgment or settlement arose occurred while the employee was acting within the scope of his public employment and in the discharge of his duties and was not in violation of any rule or regulation of his agency at the time the alleged damages were sustained; the duty to indemnify and save harmless prescribed by this subdivision shall not arise where the injury or damage resulted from intentional wrongdoing or recklessness on the part of the employee." Section 50-k(4) provides that the city's duty to defend or indemnify an employee is conditioned upon delivery to the Corporation Counsel by the employee of the summons, complaint or other charging instrument within ten days of service upon the employee; and "the full cooperation of the employee in the defense of such action or proceeding and in defense of any action or proceeding against the city based upon the same act or omission, and in the prosecution of any appeal." Section 50-k(9) provides in part: "The provisions of this section shall not be construed in any way to impair, alter, limit, modify, or abrogate or restrict ... any right to defense and/or indemnification provided for any governmental officer or employee by, in accordance with, or by reason of, any other provision of state, federal or local law or common law." The powers and obligations of the Corporation Counsel are also addressed by the New York City Charter and the Administrative Code of the City of New York. Section 394(a) of the Charter provides: "Except as otherwise provided in this chapter or other law, the corporation *1085 counsel shall be attorney and counsel for the city and every agency thereof and shall have charge and conduct of all the law business of the city and its agencies and in which the city is interested." Section 394(c) of the Charter provides: "Except as otherwise provided in this chapter or other law, the corporation counsel shall have the right to institute actions in law or equity and any proceedings provided by law in any court, local, state, or national, to maintain, defend and establish the rights, interests, revenues, property, privileges, franchises or demands of the city or of any part or portion thereof, or of the people thereof, or to collect any money, debts, fines or penalties [sic] or to enforce the laws. He shall not be empowered to compromise, settle or adjust any rights, claims, demands or causes of action in favor of or against the city, and he shall not permit, offer or confess judgment against the city, or accept any offer of judgment in favor of the city without the previous approval of the comptroller, except that with regard to matters involving excise and nonproperty taxes, such previous written approval shall be obtained from the finance administrator; provided, however, that this inhibition shall not operate to limit or abridge the discretion of the corporation counsel in regard to the proper conduct of the trial of any action or proceeding or to deprive such corporation counsel of the powers and privileges ordinarily exercised in the courts of litigation by attorneys-at-law when acting for private clients." Section 395-1.0 of the Administrative Code provides: "The corporation counsel, in his discretion may appear, or direct any of his assistants to appear, in any action or proceeding, whether criminal or civil, which may be brought against any officer, subordinate or employee in the service of the city, or of any of the counties contained therein, by reason of any acts done or omitted by such officer, subordinate or employee, while in the performance of his duty, whenever such appearance is requested by the head of the agency in which such officer, subordinate or employee is employed or whenever the interests of the city require his appearance. The head of the agency in which such officer, subordinate or employee is employed shall submit all pertinent papers and other documents to the corporation counsel." Plaintiff cites no case holding that, under this statutory scheme, the Corporation Counsel lacks authority to represent a city employee on his counterclaim asserted in an action commenced against him. It is apparent from the motion papers that in a number of cases, the Corporation Counsel has done just that, without any lack of authority being suggested. In the one case cited to counsel and disclosed by my research in which the Corporation Counsel's authority to represent a police officer on his counterclaim was challenged, Judge Goettel held for this Court that the statutory scheme conferred such authority. Henry v. City of New York and Police Officer James Delaney, 84 Civ. 2150 (GLG) (S.D.N.Y., decided August 15, 1984). In Henry, Judge Goettel read General Municipal Law § 50-k(2) together with the New York City Charter § 394(c) to confer the necessary authority upon the Corporation Counsel. Judge Goettel noted that, in cases of this nature, the police officer's counterclaim is compulsory under Rule 13(a), F.R.Civ.P., which requires that a counterclaim be pleaded "if it arises out of the transaction or occurrence that is the subject matter of the opposing party's claim and does not require for its adjudication the presence of third parties over whom the court cannot acquire jurisdiction." Judge Goettel derived the Corporation Counsel's authority not only from the specific provisions of section 50-k(2) in respect of defense, but also from the broad authority conferred upon the Corporation Counsel by section 394(c) of the Charter to exercise all of "the powers and privileges ordinarily exercised in the courts of litigation *1086 by attorneys-at-law when acting for private clients." He wrote at slip op. 3-4: "Clearly, the filing of a counterclaim is a power and privilege `ordinarily exercised in the courts of litigation by attorneys-at-law when acting for private clients' and was an act envisioned by the drafters of New York City Charter. Furthermore, Delaney has executed an agreement to reimburse his employer, New York City, for any amounts it would have to pay Henry, out of any amounts Delaney may recover on the counterclaim. Therefore, New York City can be regarded as a genuine party-in-interest to Delaney's counterclaim." The present plaintiff contends that Henry was wrongly decided, primarily because Judge Goettel laid too much emphasis upon the compulsory nature of the police officer's counterclaim, and not enough emphasis upon the issue of Corporation Counsel's authority to prosecute it. On the latter point, plaintiff stresses that section 50-k(2) of the General Municipal Law authorizes the city to "provide for the defense of an employee...." A counterclaim, plaintiff argues, cannot be regarded as "defense." I do not agree. When a citizen asserts a claim against a police officer, the Corporation Counsel is obligated to give, and the officer is entitled to receive, a spirited, thorough, energetic and professional defense. Plaintiff does not really question that general principle; nor, under the statutory scheme, could he reasonably do so. But plaintiff's implementation of that principle into practice is strained and unconvincing. It is that Corporation Counsel may always defend, but may never counterclaim. The argument assumes that these legal postures are separate, independent, discrete, and unrelated to each other. Trial lawyers know in their hearts that this is not a depiction of the real world. The maxim that "the best defense is often a good offense" applies to litigation as in other areas. Indeed, it is particularly applicable to a case such as the one at bar. A fight occurs. All combatants—the soon to be plaintiff citizen and the soon to be defendant police officers—are injured.[1] The combatants blame each other for the incident. Plaintiff sues defendants. A jury will decide who did what to whom, when, and why. Lay jurors contemplating an injured defendant who blames plaintiff for the incident, but does not claim for his injuries, may well question the credibility of defendant's account. Trial counsel are entitled to entertain a reasonable tactical concern about that possible reaction. Counsel need not be satisfied with the trial judge's usual injunction against jury speculation. Thus the bulkhead between "defense" and "offense" (in the form of a counterclaim) is far from water-tight. On the contrary, in these circumstances a counterclaim may fairly be regarded as integral to the defense. Given these practical realities, a plaintiff seeking to disenfranchise the Corporation Counsel from representation of a city employee on a counterclaim should be able to point to an express statutory provision denying that authority, or to provisions which by their clear implication require such a result. Neither is present in this statutory scheme. There are no provisions dealing specifically with counterclaims. But the broad authority and responsibilities laid upon the Corporation Counsel in the General Municipal Law, the New York City Charter, and the Administrative Code all point in the direction of the Corporation Counsel's authority to do what any competent attorney would be required to do in the case. On that point, the compulsory nature of the police officer's counterclaim is a significant factor, properly recognized as such by Judge Goettel in Henry, supra. Section 394(c) of the City Charter does indeed preserve Corporation Counsel's authority— *1087 nay, his obligation—to direct "the proper conduct of the trial," or to exercise "the powers and privilege ordinarily exercised in the courts of litigation by attorneys-at-law when acting for private clients." A private attorney who failed to assert a compulsory counterclaim for an injured defendant in a case of tortious assault could reasonably expect to be sued for malpractice, brought up before the Grievance Committee, or both. I can think of no reason why Corporation Counsel should be under less demanding professional strictures. Certainly the police officer defendant's right to full scale representation is not diminished by section 50-k(9) of the General Municipal Law; on the contrary, that section secures to the defendant "any right to defense ... for any governmental officer or employee by, in accordance with, or by reason of, any other provision of state, federal or local law or common law." As noted supra, these defendants' counterclaims are compulsory under federal law, and are embraced in any practical construction of the term "defense." Lastly, the authority granted to the Corporation Counsel by section 395-1.0 of the Administrative Code to "appear" in such actions contains no implied restrictions on how he can conduct the litigation after appearing in it. I am not persuaded by plaintiff's argument to the contrary, based upon principles of statutory construction which arise from inapposite fact situations. I appreciate that asserting a counterclaim on behalf of city employees may also redound to the tactical benefit of Corporation Counsel's other client, the city itself. The more serious issue arising from that fact is that of potential conflict of interest leading to disqualification, discussed infra. I do not see that it has anything to do with the question of statutory authority. The Corporation Counsel's policy of asserting counterclaims on behalf of police officers in section 1983 claims apparently began on or about March 25, 1982. On that date, Corporation Counsel Frederick A.O. Schwarz, Jr. addressed a letter to then Police Commissioner Robert J. McGuire, advising McGuire "of a slight modification of our defense of civil rights and assault cases brought against police officers...."[2] Mr. Schwarz's letter continues: "On occasion, a case is brought against an officer, and your and our investigations reveal that the officer was himself assaulted in the performance of his duties, by the plaintiff. Frequently, it is advantageous in the litigation to assert a counterclaim on behalf of the officer, both to highlight for the jury that the City is sinned against, and not the sinner, and to reduce, if not eliminate, any judgment for the plaintiff in those cases where there are mutual assaults. "I have learned that in the past, we have generally not pleaded counterclaims in these situations as it was felt that representation of an officer on an affirmative claim might be prohibited as a gift of legal services. I have concluded that since the purpose of asserting a counterclaim is to enhance the City's defense, and reduce any net judgment, there is no such prohibition." Counsel for the present plaintiff lays great emphasis upon Schwarz's prior, self-confessed concern that such representation "might be prohibited as a gift of legal services." Those qualms, whatever their source—Schwarz does not identify the basis of the feared prohibition—are certainly not dispositive of the issue before me. One may readily accept, without citation to specific statute, that the Corporation Counsel should not further or protect, at public expense, the entirely private legal interests of city employees. However, in section 1983 actions initiated by citizen plaintiffs, Schwarz overcame his qualms because "the purpose of asserting a counterclaim is to enhance the City's defense, and reduce any net judgment." I find that reasoning entirely *1088 sufficient to justify the expenditure of public funds. I conclude, therefore, that the Corporation Counsel has the requisite statutory authority—if not the professional duty—to assert counterclaims on behalf of police officers allegedly injured by plaintiffs who bring actions for injuries allegedly wrongfully inflicted by police officers. (b) Ethical Considerations With Respect to the Corporation Counsel's Representation of Police Officers on Counterclaims Alternatively, plaintiff argues that ethical considerations bar multiple representation by the Corporation Counsel because the City and the police officers have "very clearly defined diverse interests." Main brief at 23. Plaintiff asks that the Corporation Counsel be disqualified from representing the officers. Diverse interests requiring disqualification can arise in civil rights actions against local governments and their employees. Dunton v. County of Suffolk, supra, furnishes an example, although not apposite to the case at bar. In Dunton the county attorney undertook the defense, in a section 1983 assault case, of both the county and one of its police officers; but then asserted at trial that the officer "acted as a husband, not even as an officer." 729 F.2d at 906. That denial by the county that the officer was acting within the scope of his public employment—a useful defense to the county in these post-Monell[3]—was obviously prejudicial to the police officer. The Second Circuit, not surprisingly, held that the county attorney should have been disqualified from acting for the police officer. The Dunton conflict does not arise at bar because the City does not deny—indeed, it proclaims—that Capodieci and Sherman were acting within the scope of their public employment and in the discharge of their duties. The Corporation Counsel made that evaluation, as it was required to do by section 50-k(2) of the General Municipal Law, when it undertook the officers' defense. There is no subsequent hint that the office has changed its view, or intends to. In these circumstances, I cannot accept plaintiff's submission that differing interests exist between the City and the officers which require multiple representation. Multiple parties need not have identical interests to avoid ethical problems. Ethical problems arise only when differing interests adversely affect counsel's judgment or dilute his loyalty. The difference, in short, must be "discordant." These concepts are drawn from Canon 5 of the Code of Professional Responsibility, 29 McKinney's *1089 Consol.L. of N.Y. (West 1975) at EC5-14: "Maintaining the independence of professional judgment required of a lawyer precludes his acceptance or continuation of employment that will adversely affect his judgment on behalf of or dilute his loyalty to a client. This problem arises whenever a lawyer is asked to represent two or more clients who may have differing interests, whether such interests be conflicting, inconsistent, diverse, or otherwise discordant." In the case at bar, the City and the police officers make common cause against plaintiff on the merits issues of who provoked the incident, and on the damages issues of the nature and extent of injury. The only potentially troublesome area is that of settlement negotiations. May Corporation Counsel properly cast away a police officer's counterclaim as a "bargaining chip" to obtain a favorable overall settlement? It is clear enough from the motion papers that the officers authorize the Corporation Counsel to do just that. Both officers agreed in writing to personal representation by the Corporation Counsel in accordance with the terms of section 50-k of the General Municipal Law. In addition, each officer endorsed letters addressed to them by the Corporation Counsel in the following terms: "Dear Officer: "As you know, this office is representing you in the above-entitled action. Upon analysis of the case, we believe that it would be legally appropriate and beneficial, both to your defense and that of the City of New York, to interpose a counterclaim for money damages against the plaintiff. "As the City is providing your legal defense in this case, pursuant to the General Municipal Law, we request that you assign to the City any damages awarded to you on the counterclaim in this case up to an amount equal to the judgment and attorney's fees awarded to the plaintiff against you. If there is an award in your favor in excess of any award, including attorney's fees, to the plaintiff, that excess amount will belong to you. And in the event that we are successful on your counterclaim, and the plaintiff is denied any recovery, the entire amount of the judgment will belong to you. "Please return a copy of this letter, with your signature acknowledging your acceptance of the above provisions, to the undersigned at your earliest convenience. Sincerely yours, s/ Elissa Hutner ELISSA HUTNER Assistant Corporation Counsel EH/ea "I hereby assign my rights to any judgment awarded me in the above-captioned action in accordance with the terms set forth above. s/ ____________________________________ Finally, each officer has submitted an affidavit reciting in part: "7. I understood that I was agreeing to give the City any damages I recovered on the counterclaim up to an amount equal to a judgment against me if there were one. I also understood that at some point the Corporation Counsel might determine that it was in the best interest of the City and me personally to settle the case with plaintiff in order to avoid the threat of a potential judgment against me. "8. Therefore, I knowingly agreed to permit the Corporation Counsel to assert the counterclaim on my behalf and to withdraw it if it were deemed to be in my best interest and the City's to do so." Contrary to the lengthy and not always lucid argument of plaintiff's counsel, there is no compelling reason in policy or caselaw which would prohibit the City from offering representation to police officers on these terms and conditions, or prohibiting police officers from accepting them. Policy finds its expression in Canon 5 of the Code. The pertinent Disciplinary Rule *1090 is DR 5-105, which provides in pertinent part: "(A) A lawyer shall decline proferred employment if the exercise of his independent professional judgment in behalf of a client will be or is likely to be adversely affected by the acceptance of the proffered employment, except to the extent permitted under DR 5-105(C). "(B) A lawyer shall not continue multiple employment if the exercise of his independent professional judgment in behalf of a client will be or is likely to be adversely affected by his representation of another client, except to the extent permitted under DR 5-105(C). "(C) In the situations covered by DR 5-105(A) and (B), a lawyer may represent multiple clients if it is obvious that he can adequately represent the interest of each and if each consents to the representation after full disclosure of the possible effect of such representation on the exercise of his independent professional judgment on behalf of each." (footnotes omitted). Several principles pertinent to the case at bar emerge from this Rule. The lawyer's obligation is to guard against any adverse effect upon his independent professional judgment in behalf of a client. There is no per se rule against multiple employment; it is disapproved only if the exercise of the lawyer's independent professional judgment in behalf of one client "will be or is likely to be adversely affected" by his representation of another. And even if the possibility or likelihood of an adverse effect arises, the clients, on the basis of full disclosure, may consent to the multiple representation. In the case at bar, there is no question that if the case is tried, the Corporation Counsel can "adequately represent" the interest of both the City and the police officers. Indeed, as noted supra, no conflict whatsoever presents itself in the trial context. It is only in the context of settlement negotiations that the Corporation Counsel may accurately be seen as advising two clients with potentially divergent interests: in short, the "bargaining chip" syndrome. Settlement negotiations in the instant case have come to nothing. As I understand the positions of the parties from the motion papers and oral argument, plaintiff insists upon a payment to him. Defendants will settle only on the basis of a mutual exchange of releases. From this settlement stalemate defendants argue that any ethical concern with multiple representation in settlement negotiations is academic, and need not be addressed. In the alternative, defendants argue that the police officers consented to the multiple representation after full disclosure of its terms and conditions. I cannot accept that the issue is academic. Even though settlement has not been realized, the Court has an interest in ensuring that at all stages of litigation, including trial, counsel are as a general rule available to advise each client as to the particular, individualized benefits or costs of a proposed settlement. It cannot be gainsaid that the Corporation Counsel, by virtue of the terms and conditions of the multiple representation, holds the police officers' counterclaims in thrall, and may accordingly agree to their reduction or abandonment, if so advised, to obtain an overall settlement beneficial to the City. To that arrangement, the police officers have signified their assent after full disclosure. That full disclosure takes the place of the letters addressed by the Corporation Counsel to the police officers. One of them I have quoted supra; the earlier letters to the officers specifically advised them of their right to retain private counsel at their own expense, although adding the caveat: "If you retain private counsel and a judgment is entered against you, you will under no circumstances be indemnified by the City." *1091 That advice is made necessary by section 50-k(4) of the General Municipal Law, whose provisions appear in the margin.[4] Thus the Corporation Counsel, in dealing with police officers, is bound by the ground rules the legislature laid down. The police officer, acting within the scope of his public employment and in discharge of his duties, is entitled to be indemnified by the City in respect of his personal liability; but only if he requests the City to undertake his defense, and cooperates in the formation or presentation of his defense. In cases where the circumstances justify assertion of an affirmative counterclaim on behalf of the police officer, the Corporation Counsel will press the claim, but on two additional conditions: that the police officer assign to the City any award in his favor, to the extent necessary to offset plaintiff's recovery against the City.[5] Secondly, the police officer cedes to the Corporation Counsel the power to dispose of his counterclaim in settlement negotiations. All these conditions are explained to police officers in the position of the present defendants. They may accept or reject them. The police officers' right to the retention of private counsel is made known. I decline to hold that Canon 5 precludes the City from tendering, or police officers fully advised of their options from accepting, this form of multiple representation. No case cited by the plaintiff or uncovered by my own research condemns multiple representation in circumstances resembling those at bar. On the contrary: there is substantial authority for the proposition that Canon 5 potential conflicts of interest are adequately dealt with by the clients' informed consent, thereby precluding disqualification under Canon 5. See, e.g., Doe v. A Corporation, 709 F.2d 1043, 1050 (5th Cir.1983); Westinghouse Electric Corporation v. Gulf Oil Corporation, 588 F.2d 221, 229 (7th Cir.1978). The Second Circuit has reached the same conclusion in criminal cases. In re Taylor, 567 F.2d 1183, 1191 (2d Cir.1977). Much of the present plaintiff's argument amounts, in essence, to a charge of apparent impropriety. But the Second Circuit has made it clear that, in evaluating motions to disqualify attorneys under the Canons, the appearance of impropriety is not enough; a disqualification motion will not lie "unless an attorney's conduct tends to `taint the underlying trial,'" Board of Education of the City of New York v. Nyquist, 590 F.2d 1241, 1246 (2d Cir.1979), citing and quoting W.T. Grant Co. v. Haines, 531 F.2d 671, 678 (2d Cir.1976). In *1092 the case at bar, no possibility of trial taint arises. The only concern is with the settlement process; but I do not find that the position assumed by the Corporation Counsel, with the police officers' informed consent, rises to the level of an impermissible taint on the proceedings. I am also influenced by the fact that, in civil rights actions where the police officers have allegedly suffered injury at the plaintiff's hands, disqualification of the Corporation Counsel from representing the police officers (even in the face of the officers' consent) would deprive the police officers of a statutory right to indemnity, and bring about duplicative effort and expense on the part of counsel. These are considerations which I may legitimately place in the balancing of the ethical scales. I conclude that ethical considerations do not foreclose the Corporation Counsel's representation of both the City and these particular counterclaiming defendants.[6] There is, in short, no basis in law or policy to disqualify the Corporation Counsel from representing defendant officers on their counterclaims. A fortiori there is no basis to dismiss the counterclaims. III. Plaintiff's Motion to Amend the Complaint I will next discuss plaintiff's last-filed motion: to amend his complaint. As noted supra, that motion was filed on February 6, 1985, in a case marked trial ready on March 9, 1984 after completion of all discovery, and actually called for trial on December 17, 1984. Plaintiff seeks to amend his complaint to assert two additional claims: (1) A claim against the City under Monell which plaintiff's counsel articulates in his notice of motion (¶ 23) as follows: "... [The City] utilized a policy of counterclaim for the purposes of promoting the City's interest by intimidating the Plaintiff into withdrawing a litigation because of the substantial risk that the Plaintiff was placed in by the nature and extent of the multiple [sic] counterclaims brought by the City for the City although claiming to bring the same for the officer employees." (2) A claim which, according to his "Statement of the Nature and Extent of Proposed Amendment" at ¶ 8: "... addresses allegedly defective hiring and retention and training procedures [sic] which lead to the employment and retention of individuals as police officers who pose a risk to the safety of citizens." In aid of these new claims, plaintiff also seeks additional pre-trial discovery. Defendants resist the amendments on the ground that the claims lack substance, and that the motion to amend is untimely. (a) Timeliness Both proposed amendments must be rejected as untimely. The timeliness of amendments to pleadings under Rule 15(a), F.R.Civ.P., was recently addressed by the Second Circuit in Evans v. Syracuse City School District, 704 F.2d 44 (2d Cir.1983), which condemned as an abuse of discretion the trial court's order permitting an amended answer. The Second Circuit in Evans observed that the rule's provision that leave to amend shall be freely granted "when justice so requires" is limited when there is "undue delay, bad faith or dilatory motive" on the part of the moving party, and "undue prejudice to the opposing party. ..." 704 F.2d at 46, citing and quoting *1093 Foman v. Davis, 371 U.S. 178, 182, 83 S.Ct. 227, 230, 9 L.Ed.2d 222 (1962). Delay is closely related to prejudice: the Evans court cited with approval Advocat v. Nexus Industries, Inc., 497 F.Supp. 328, 331 (D.Del.1980), where the court stated: "[T]he longer the period of an unexplained delay, the less will be required of the nonmoving party in terms of a showing of prejudice." Id. at 46-47. The Second Circuit also quoted with approval this statement from Nevels v. Ford Motor Co., 439 F.2d 251, 257 (5th Cir.1971): "[A]mendments should be tendered no later than the time of pretrial, unless compelling reasons why this could not have been done are presented.... [The court] must weigh good cause shown for the delay in moving, vis a vis dilatoriness of counsel resulting in last minute surprise and inability of opposing counsel to meet the tendered issue." It is apparent that the requested amendments would involve substantial additional discovery, which plaintiff in fact demands. Plaintiff minimizes the scope of these additional discovery requests. The suggestion is unpersuasive. The additional discovery is substantial. Additional discovery or preparation required by the belated addition of new claims is a recognized source of prejudice justifying denial of a motion to amend. Mende v. Dun & Bradstreet, Inc., 670 F.2d 129, 131 (9th Cir. 1982). Plaintiff sought these amendments not at pretrial, but literally on the eve of trial. The fact that plaintiff obtained a postponement of trial by means of a meritless motion to disqualify defendants' counsel does not alter the analysis. Prejudice to defendants arises from the considerable additional discovery and trial preparation that would be required. In these circumstances, plaintiff bears a heavy burden of persuasion to explain and justify the delay. That burden is not carried here. As for the claim challenging the City's counterclaim "policy," if (contrary to the Court's conclusion supra) the Corporation Counsel lacked authority to represent the defendant officers, that defect was just as apparent when he asserted the counterclaims in September, 1982. Plaintiff's counsel says that at that time he was "concerned" by Corporation Counsel's assertion of the officers' counterclaims and regarded it as "an interesting tactic"; but that it was not until November, 1984, when the Corporation Counsel proposed settlement on the basis of dropping all claims, that he first: "... focused upon the reality of the counterclaim strategy about which I had always felt concern. The concern had become a focused reality and a focused operative tactic being used by the Defendant parties. My concerns, always felt, had been realized; and, within a short period of time thereafter, I brought to the Court the concern which I had for my client." Affidavit of James I. Meyerson, Esq., verified February 25, 1985, at ¶¶ 6, 17, 18. This is an argument which one cannot take seriously from experienced trial counsel. The officers' counterclaims were as much a "reality," and the "operative tactic" as apparent, when they were first asserted as when, over two years later, the Corporation Counsel included them in an entirely predictable settlement ploy. Plaintiff's counsel also argues that he had not become aware of the City's counterclaim "policy" until defendants filed affidavits opposing plaintiff's motion to dismiss the counterclaims or disqualify counsel. Point II, supra. There is no substance to this. The Corporation Counsel's "policy" of representing allegedly injured officers manifested itself to plaintiff's counsel when these counterclaims were filed, using "policy" in the sense of a reasoned tactical decision. One would not expect that Corporation Counsel asserted the counterclaims by inadvertence. All that the recent motion papers really say is that in March, 1982 Mr. Schwarz decided that it would be good trial tactics to assert counterclaims on behalf of allegedly assaulted police officers in civil rights cases, thus enhancing the "defense of the City and the *1094 officer," letter of March 25, 1982 quoted at fn. 5, supra. These obvious practical considerations could hardly have come to plaintiff's counsel in November, 1984 with the force of unexpected revelation. The proposed amendment attacking the counterclaim policy is untimely. I reach the same conclusion with respect to the second proposed amendment. It is intended to add a new theory to plaintiff's general allegation of improper hiring and retention of police officers. The original complaint, at ¶¶ 32 and 33, keys these defects to a failure to screen out racially prejudiced officers. That theory is repeated in ¶ 32 of the amended complaint, which goes on, in ¶¶ 33 and 34, to allege in general and conclusory terms the hiring and retaining of officers "who pose a risk" to the City's citizens. An "example" of the City's defective policy is said to appear in the appointment and retention of defendant Sherman as a police officer, "notwithstanding that [he] was rejected for military service because of and apparently for psychiatric based reasons," ¶ 33. This is an entirely new theory of liability, again asserted at the eve of trial. But the amendment seeking to assert this new theory of defective hiring procedure is untimely because it is common ground that plaintiff's counsel has known since 1983, as the result of discovery, of Sherman's military classification and the NYPD's testing procedures. Defendants' brief in opposition at 7. (b) Merits Where a proposed amended pleading fails to properly state a claim for relief, leave to amend will be denied. Chapman v. Sheridan-Wyoming Co., 338 U.S. 621, 70 S.Ct. 392, 94 L.Ed. 393 (1950); Marcraft Recreation Corp. v. Francis Devlin Co., 506 F.Supp. 1081, 1087 (S.D.N. Y.1981). In claims asserted under 42 U.S.C. § 1983, "[t]he first inquiry ... is whether the plaintiff has been deprived of a right `secured by the Constitution and laws'" of the United States. Baker v. McCollan, 443 U.S. 137, 140, 99 S.Ct. 2689, 2692, 61 L.Ed.2d 433 (1979). See also Suffolk County Patrolmen's Benevolent Association, Inc. v. County of Suffolk, 751 F.2d 550, 551 (2d Cir.1985) (police officers' challenge to county's procedure for appointing independent counsel in civil rights actions not cognizable under section 1983 because the "procedure violates no ... federally protected right...."). These authorities furnish an alternative basis for denying plaintiff leave to amend his complaint to assert a claim arising out of the City's counterclaim policy. The claim is patently frivolous. Stripped of rhetoric, the essence of plaintiff's claim is that, having elected to commence a section 1983 action against the City and police officers for having assaulted him, he has a federally protected right to be free of counterclaims asserting that he assaulted the officers. To state the claim reveals its lack of substance; no extended discussion is necessary. Plaintiff submits an affidavit saying that he feels "intimidated" and "concerned" about the counterclaims and a possible judgment against him.[7] That is understandable enough; but as plaintiff then makes clear in his affidavit, he intends to go on with the litigation. In essence, plaintiff is saying that he does not like the counterclaims and would prefer that they be made to go away. Of course he would. But he has no federally protected right to make that happen. He must meet the counterclaims on their merits or lack of merits, just as the defendants must meet the claims asserted by plaintiff. Plaintiff's counsel expresses his judgment that "the policy as utilized herein was and is being utilized to intimidate and retaliate against my client and to get my client to withdraw his cause of action." Counsel argues further that "such is improper, illegal and violative of my client's *1095 rights...."[8] I have no doubt that the Corporation Counsel asserts the officers' counterclaims not only to protect the officers' legal interests, but also to improve all defendants' overall litigation position, including possible settlement. What I cannot accept is that the Constitution or the laws of the United States prevent the defendants from doing any of these things. Plaintiff's counsel cited no authorities in support of his new constitutional claim in the 10-page brief in support of the motion to amend the complaint. Those authorities were reserved for the 47-page "reply" brief. There we find compendious citations for familiar principles, none of which is particularly applicable to the case at bar. Thus plaintiff argues that the City's counterclaim policy denies plaintiff access to the courts; that the assertion of the counterclaims constitutes an abuse of process akin to malicious prosecution, and cognizable under section 1983; that the counterclaims should be viewed as a continuation of the excessive police force initially exercised against plaintiff, and part of a continuing coverup of that excessive force; and that by asserting counterclaims against plaintiff, the City deprives plaintiff of the equal protection of the laws. I find no substance in any of these claims. The best proof that plaintiff has not been denied access to the courts lies in the vigorous litigation he is conducting. I decline to equate a compulsory counterclaim with malicious prosecution. Facts permitting an inference that the counterclaims were asserted in bad faith, for the purpose of harassment or coverup, may be adduced at trial; but such conduct is compensable within the framework of the present complaint, and gives rise to no federal cause of action requiring amendment of the pleading. As for equal protection, plaintiff's argument is that the counterclaim policy "is limited solely to litigations instituted against the City and police officers and not to any other public employee who might allegedly suffer injury from a citizen and be sued by the citizen/him/herself for the violation of constitutional rights." Reply brief at 40. Thus, the argument continues, "a citizen might sue a sanitation worker for brutality," but "the City's policy of counterclaim would not apply." Ibid. This is said to violate plaintiff's right as a litigant to equal protection of the laws, since there is allegedly no rational basis for the distinction. The only case cited by plaintiff on the equal protection claim is LeClair v. Saunders, 627 F.2d 606 (2d Cir.1980). The present record does not demonstrate that the Corporation Counsel follows a practice of asserting counterclaims in citizen assault cases only on behalf of its police officer employees. But assuming arguendo that this is the practice, no viable equal protection claim arises. That is because there is a rational basis for devoting the limited resources of the Corporation Counsel's office to the assertion of counterclaims in section 1983 suits against police officers. Alone among City employees, law enforcement officers are upon occasion required by the scope of their public employment and the discharge of their official duties to forcibly restrain citizens. A sanitation worker, to pursue plaintiff's example, who brutalizes a citizen is by definition acting outside the scope of his public employment; the sanitation worker's function is to lay hands on refuse, not on citizens. It is therefore not in the least surprising (if it is the fact) that the Corporation Counsel's litigation policy of asserting counterclaims on behalf of assaulted police officers finds no counterpart among the ranks of other municipal employees. No constitutional claim emerges from these practical realities. LeClair v. Saunders, supra, is entirely inapposite. It involved a claim by dairy farm owners of selective enforcement of a Massachusetts regulation governing dairy farms. The Second Circuit summarized the elements of such a claim: "... liability in the instant type of equal protection case should depend on proof that (1) the person, compared with others *1096 similarly situated, was selectively treated; and (2) that such selective treatment was based on impermissible considerations such as race, religion, intent to inhibit or punish the exercise of constitutional rights, or malicious or bad faith intent to injure a person." 627 F.2d at 609-10 (footnote omitted). Neither element is even arguably present in the case at bar. Assuming the accuracy of plaintiff's factual premise, the City applies its counterclaim policy in all section 1983 actions against police officers where the police officers allege that they were assaulted and seriously injured; and, as noted, there is a rational basis for such a policy. Quite apart from the fact that the proposed amendment is untimely, I deny plaintiff leave to amend his complaint to state a Monell claim arising out of the City's counterclaim policy because the claim is entirely lacking in merit.[9] Although defendants ask me to do so, I decline to base a denial to permit the second proposed amendment upon a facial insufficiency of pleading. Defendants argue that the complaint must allege in haec verba that the City's hiring and retention policies constituted "gross negligence" or "deliberate indifference" to plaintiff's constitutional rights. That is undoubtedly what plaintiff must prove at trial, Owens v. Haas, 601 F.2d 1242, 1246 (2d Cir.1979); but in my view the proposed amended complaint sufficiently pleads the three elements of a section 1983 claim. Batista v. Rodriguez, 702 F.2d 393, 397 (2d Cir.1983). However, the amendment is denied on the ground of untimeliness. Plaintiff's motion to amend his complaint is denied. IV. Plaintiff's Demands for Additional Discovery Plaintiff makes several demands for additional pretrial discovery. Plaintiff's requests for additional discovery "related to the multiple party representation by the Corporation Counsel" are denied. Quite apart from the fact that discovery in the case closed long ago, that multiple representation is impervious to challenge as a matter of law. Accordingly discovery could not lead to admissible trial evidence. In a separate motion, plaintiff demands: *1097 (1) Access to defendant Sherman's military records, "by and through an executed authorization from him," in order that "documents related to his rejection for military service, for psychiatric reasons, can be further analyzed and explored" by plaintiff's expert witness, Dr. Seymour. Plaintiff's brief at 3. (2) Answers to interrogatories, and production of documents, by the City on the general subjects of the City's awareness of Sherman's rejection by the military for psychiatric reasons, and its policies with respect to the hiring as police officers of individuals rejected by the military. (3) All psychological examinations administered by the NYPD to Capodieci and Sherman. (4) Pre-trial depositions of two witnesses, Julio Alvarez and Jose Cortez. It is apparent that item (2) relates solely to the new theory of City liability sought to be asserted in the amended complaint. Since leave to amend to assert that claim has been denied, the discovery requests fall with it, and are also denied. Defendants resist production of the psychological examinations of the defendant officers because in prior discovery proceedings plaintiff's counsel withdrew his demand for them. Plaintiff's counsel acknowledges that is so because, at that time, "I did not have a consulting expert with whom to consult."[10] He now says he located Dr. Seymour in "approximately November, 1984," plaintiff's brief at 2, although apparently the year-end motion papers represent defendants' first awareness of him. The fact that counsel did not find an expert until just before trial does not excuse a failure to plead in timely fashion defective policies in respect of hiring military psychological rejects. Therefore Dr. Seymour's recent arrival on the scene cannot revive that claim, nor its accompanying discovery demands. However, I am not aware of any formal discovery demands by defendants requiring plaintiff to identify his witnesses or suffer preclusion; and I accept counsel's statement that a qualified psychologist willing to testify against the NYPD can prove difficult to locate locally. Therefore I will not preclude Dr. Seymour from testifying. The question therefore arises whether plaintiff is entitled to additional discovery of psychological data in respect of the individual defendants, in order to permit a more informed opinion from the expert witness. To be sure, the discovery deadline has passed; but the litigation process is a search for truth, as well as an exercise in rule enforcement. I have enforced the rules against this plaintiff where the delay was inexcusable and the resulting prejudice to defendants apparent. But I have discretion to enlarge the discovery deadline to permit further development of information pertinent to issues fairly and timely pleaded. Those issues are (1) whether the police officers wrongfully assaulted plaintiff, or plaintiff wrongfully assaulted them; and (2) whether the City was guilty of gross negligence in failing to screen out racially prejudiced officers. The first issue lies at the heart of the claims and counterclaims asserted by the individual parties. The second lies at the heart of plaintiff's Monell claim against the City. If an expert witness is able to formulate an opinion on these issues, it would be probative and relevant. It would appear that psychological test results and other data covering the police officer defendants, generated both by the military and the police, are "reasonably calculated to lead to the discovery of admissible evidence on these issues," that being the test of relevance under Rule 26(b)(1), F.R.Civ.P. But defendants argue that their psychological tests are privileged and not subject to disclosure, citing Elliott v. Webb, 98 F.R.D. 293 (D.Idaho 1983). Elliott did not undertake to lay down a blanket rule of *1098 privilege; after balancing factors it considered relevant, the trial court refused to compel disclosure of police officers' psychological evaluations in a section 1983 case because they were "of a policy or self-evaluative nature." 98 F.R.D. at 297. It does not appear that the individual officers in Elliott v. Webb sought an affirmative recovery by counterclaim. Courts in this circuit have, in other circumstances, tipped the balance in favor of compelled disclosure of psychiatric evaluations. Lora v. Board of Education of City of New York, 74 F.R.D. 565 (E.D.N.Y.1977); cf. In re Doe, 711 F.2d 1187 (2d Cir.1983). I hold that when police officers assert counterclaims in cases of this nature, they voluntarily place their personalities and possible propensities to violence at issue. In these circumstances, the social goal of truth ascertainment outweighs any need to preserve confidentiality.[11] I therefore direct the disclosure to plaintiff's counsel of the City's psychological test results and evaluations of defendants Sherman and Capodieci. I also direct Sherman to execute the necessary authorization permitting disclosure of his military testing. This production will take place pursuant to a protective order limiting viewing of the documents to plaintiff's expert witness and plaintiff's counsel — not to plaintiff. The parties are directed to agree on the terms of the protective order, or submit the dispute for resolution by the Court. The parties are directed to expedite these matters. As soon as plaintiff's expert witness is fully advised, I will grant reciprocal additional discovery and permit defendants discovery of plaintiff's expert pursuant to Rule 26(b)(4), F.R.Civ.P. Since it is clear that plaintiff had ample opportunity to take timely pre-trial depositions of Alvarez and Cortez, I will not compel them now. Plaintiff may, if so advised, subpoena them at trial. CONCLUSION Plaintiff's motion to dismiss the counterclaims, or to disqualify counsel, is denied. Plaintiff's motion to amend the complaint is denied. Plaintiff's motions for additional discovery are denied in part and granted in part.[12] It is SO ORDERED. NOTES [1] In the case at bar, plaintiff's counsel speaks slightingly of the nature of the officers' injuries. It is fair to say that defendants do not accept the full extent of plaintiff's claimed injuries. These contentions will be resolved at trial. They do not affect the present analysis. The procedural remedies available in respect of exaggerated claims are discussed infra, n. 9. [2] The letter appears as Ex. 5 to the affidavit of Elissa Hutner, Esq., Assistant Corporation Counsel, verified January 29, 1985. [3] In Dunton the Second Circuit explained Monell's insertion of potential conflict of interests into an area where municipalities had commonly provided counsel for their employees and themselves when both were sued. Under Monroe v. Pape, 365 U.S. 167, 81 S.Ct. 473, 5 L.Ed.2d 492 (1961), a municipality was not a section 1983 "person" and had no liability. Monell changed all that: "However, since the Supreme Court's decision in Monell v. Department of Social Services, 436 U.S. 658, 98 S.Ct. 2018, 56 L.Ed.2d 611 (1978), municipalities can be held liable under section 1983 for employees' actions taken pursuant to municipal policy. After Monell the interests of a municipality and its employee as defendants in a section 1983 action are in conflict. See Van Ooteghem v. Gray, 628 F.2d 488, 495 n. 7 (5th Cir.1980), aff'd in part, vacated in part on other grounds, 654 F.2d 304 (5th Cir.1981) (en banc) (per curiam), cert. denied, 455 U.S. 909, 102 S.Ct. 1255, 71 L.Ed.2d 447 (1982). A municipality may avoid liability by showing that the employee was not acting within the scope of his official duties, because his unofficial actions would be be pursuant to municipal policy. The employee, by contrast, may partially or completely avoid liability by showing that he was acting within the scope of his official duties. If he can show that his actions were pursuant to an official policy, he can at least shift part of his liability to the municipality. If he is successful in asserting a good faith immunity defense, the municipality may be wholly liable because it cannot assert the good faith immunity of its employees as a defense to a section 1983 action. Owen v. City of Independence, 445 U.S. 622, 100 S.Ct. 1398, 63 L.Ed.2d 673 (1980)." 729 F.2d at 907. [4] The section provides: "The duty to defend or indemnify and save harmless prescribed by this section shall be conditioned upon (a) delivery to the corporation counsel at the office of the law department of the city by the employee of the original or a copy of any summons, complaint, procvess, notice, demand or pleading within ten days after he is served with such document, and (b) the full cooperation of the employee in the defense of such action or proceeding and in defense of any action or proceeding against the city based upon the same act or omission, and in the prosecution of any appeal. Such delivery shall be deemed a request by the employee that the city provide for his defense pursuant to this section. In the event that the corporation counsel shall assume an employee's defense and thereafter the employee fails to or refuses to cooperate in the formation or presentation of his defense, the court shall permit the corporation counsel to withdraw his representation ten days after giving written notice to the employee of his intention to discontinue such representation." (emphasis added). [5] Whether the officer makes a personal recovery depends on the resolution of the claims. Schwarz explained the arrangement in his March 25, 1982 letter to McGuire: "In order to assert counterclaims in aid of our defense of the City and the officer, we will require officers to assign to the City that portion of any judgment recovered on their behalf in the case up to the amount of the plaintiff's judgment, if any. For example, if the plaintiff recovers $5,000, and the officer recovers $10,000, half of the officer's judgment will be used to offset the plaintiff's recovery, and the other half will be kept by the officer. In the converse situation, if a plaintiff is awarded $10,000, and the officer $5,000, the officer would not have a recovery, but rather his award would go to reduce the City's liability." Presumably if plaintiff's claim is rejected and the officer recovers on his counterclaim, the officer keeps it all. [6] In a letter dated March 18, 1985, plaintiff's counsel calls my attention to a much publicized incident occurring on March 15. Defendant Sherman, now a police sergeant, was reportedly driving a police car involved in a hit-and-run accident which killed one pedestrian and injured another. Counsel argues in conclusory fashion that the incident "highlights the conflict which must now surely exist between the City and the defendant police officers" (apparently including Capodieci as well although he was not in the hit-and-run car). On the contrary, the incidents are entirely unrelated. The Corporation Counsel's professional ability to represent the City and Sherman in the case at bar is not in the least affected by the tragedy of March 15. [7] Affidavit of Jonathan Smith, verified February 25, 1985, at ¶ 28. [8] Meyerson affidavit, supra, at ¶ 21. [9] This does not leave plaintiff without remedy, if it should later appear that the counterclaims were pleaded and pressed by the Corporation Counsel in bad faith. The 1983 amendment to Rule 11, F.R.Civ.P., requires that pleadings be signed by counsel. The rule goes on to provide: "The signature of an attorney or party constitutes a certificate by him that he has read the pleading, motion, or other paper; that to the best of his knowledge, information, and belief formed after reasonable inquiry it is well grounded in fact and is warranted by existing law or a good faith argument for the extension, modification, or reversal of existing law, and that it is not interposed for any improper purpose, such as to harass or to cause unnecessary delay or needless increase in the cost of litigation." If a pleading is signed in violation of the rule, the Court: "... shall impose upon the person who signed it, a represented party, or both, an appropriate sanction, which may include an order to pay to the other party or parties the amount of the reasonable expenses incurred because of the filing of the pleading, motion, or other paper, including a reasonable attorney's fee." Indeed, counsel signing pleadings are now required to do more than simply eschew bad faith. The Notes of the Advisory Committee say this of the 1983 amendment to Rule 11: "The new language stresses the need for some prefiling inquiry into both the facts and the law to satisfy the affirmative duty imposed by the rule. The standard is one of reasonableness under the circumstances. See Kinee v. Abraham Lincoln Fed. Sav. & Loan Ass'n, 365 F.Supp. 975 (E.D.Pa.1973). This standard is more stringent than the original good-faith formula and thus it is expected that a greater range of circumstances will trigger its violation. See Nemeroff v. Abelson, 620 F.2d 339 (2d Cir.1980)." Under revised Rule 11, if Corporation Counsel pleads, asserts in settlement negotiations, and sends to trial a $1,000,000 counterclaim for what turns out to be a hangnail, his office may expect to be penalized by sanctions, in all likelihood increasing in severity if a pattern of like conduct in other cases is demonstrated to the trial judge. It is clear that sanctions may be imposed for a Rule 11 violation in circumstances which might not justify an award of attorney's fees to plaintiff under 42 U.S.C. § 1988. [10] Affidavit of James I. Meyerson, verified February 4, 1985 at ¶ 13. [11] In In re Doe, supra, involving a grand jury subpoena, the Second Circuit dealt generally with an asserted patient-psychotherapist privilege. Judge Cardamone's opinion looked to Wigmore for the criteria of a privileged, confidential communication: "To begin, Professor Wigmore has set forth four conditions necessary to the establishment of a privilege against the disclosure of communications. They are: (1) the communication must be one made in the belief that it will not be disclosed; (2) confidentiality must be essential to the maintenance of the relationship between the parties; (3) the relationship should be one that society considers worthy of being fostered; and (4) the injury to the relationship incurred by disclosure must be greater than the benefit gained in the correct disposal of litigation. 8 J. Wigmore, Evidence § 2285, at 527 (McNaughton rev. 1961). Arguably these conditions could obtain in a true psychotherapist-patient relationship." 711 F.2d at 1193. The conditions would appear equally applicable to a psychologist-subject relationship. The court in Doe, while acknowledging the existence of the privilege, declined to apply it because the circumstances did not square with the four conditions of confidentiality. Nor, in my view, does a psychological test administered as a compulsory part of evaluation for military service, or for placement or retention in a police department. To the extent that Elliott v. Webb, supra, constitutes contrary authority, I decline to follow it. [12] In the wake of the March 15, 1985 traffic accident involving Sherman, see fn. 6 supra, plaintiff's counsel has demanded additional discovery in a letter to the Court dated March 22, 1985. That additional discovery is denied. The additional discovery authorized by this opinion is the only additional discovery that will take place in this case.
Jeremy MONTGOMERY - Drunk Driving Source: OPPDate: Fri Jul 20 03:01:07 MST 2018 (CITY OF KAWARTHA LAKES, ON) - On Wednesday July 18, 2018 an officer from the City of Kawartha Lakes detachment of the Ontario Provincial Police (OPP) was investigating a driving complaint on Glenarm Road. The subject vehicle was located shortly after 5:30pm and following an investigation the driver, Jeremy MONTGOMERY, 39 years of age of Woodville, was arrested and charged with Over 80 mg of Alcohol in 100 ml of Blood contrary to section 253(b) of the Criminal Code of Canada. The accused is scheduled to appear in the Ontario Court of Justice in Lindsay on August 16, 2018.
Tumour necrosis factor-alpha plasma levels after flavone acetic acid administration in man and mouse. Flavone acetic acid (FAA) is a synthetic flavonoid with a remarkable spectrum of anticancer activities in mouse tumours, but with no anticancer activity in humans. The mechanism of action of this drug is complex and involves a tumour vasculature action similar to the effects of tumour necrosis factor (TNF). To assess directly the role of TNF in FAA mechanism of action, this cytokine was assayed in both mouse and human plasma after intravenous administration of the drug. In mouse, a species particularly sensitive to FAA antitumour action, FAA plasma concentrations reached 268 micrograms/ml at 0.5 h and remained high (165 micrograms/ml) at 6 h following the intravenous administration of an anticancer efficacious dose (540 mg/m2). After FAA administration in mouse, TNF activity (L929 mouse cell bioassay) increased to 300 pg/ml TNF-alpha-equivalent at 2 h, reached a maximum concentration of 600 pg/ml at 4 h, and declined thereafter to 220 pg/ml at 6 h. TNF activity in mouse plasma was completely abrogated in the presence of mouse TNF-alpha antibodies. FAA added directly to blank mouse plasma did not show TNF activity. In patients receiving the drug as a 6-h intravenous infusion at doses ranging from 3.6 to 8.1 g/m2, FAA plasma levels ranged from 58 to 449 micrograms/ml at the end of infusion. Human TNF-alpha levels assayed with an immunoradiometric assay were either not detectable or very low (< 25 pg/ml) before FAA administration. At completion of the FAA infusion, TNF-alpha remained near background levels in 20 of the 21 courses. A slight increase in plasma TNF-alpha was observed in 1 patient at the 8.1 g/m2 dose level of FAA, from 13 pg/ml before intravenous infusion, to 70 pg/ml at completion of intravenous infusion. Taken together, these data demonstrate a marked interspecies difference with regard to TNF-alpha secretion after FAA treatment, as this cytokine is produced in mice, whereas it is not significantly secreted in pretreated patients. Although the low TNF-alpha levels achieved in mice probably do not explain all of FAA antitumour activity in that species, the observed interspecies difference in TNF-alpha secretion after FAA administration could partly explain the marked difference in FAA antitumour activity observed between mice and humans.
Q: Why is the result of my query only outputting one row? I am disabling dates in a jQuery UI date picker from my database and the code I have is almost working, the only thing is that it is only reading one row from the database. At the minute I have two bookings in the database so there should be two separate bookings in the date picker where days are disabled but there is only one. Can anybody see where I am going wrong? <?php $bookeddates = "SELECT fromdate, todate FROM messages WHERE listing_id = '".$_GET['listingid']."'"; $resultbookeddates = mysql_query($bookeddates) or die(mysql_error() . "<br>" . $bookeddates); $date_list = array(); while ($rowbookeddates = mysql_fetch_assoc($resultbookeddates)) { $from = date('Y-n-j', strtotime($rowbookeddates['fromdate'])); $to = date('Y-n-j', strtotime($rowbookeddates['todate'])); $start_time = strtotime($from); $end_time = strtotime($to); $date_list[] = $from; $current_time = $start_time; while($current_time < $end_time) { //Add one day $current_time += 86400; $date_list[] = date('Y-n-j',$current_time); } $date_list[] = $to; } ?> <script type="text/javascript"> var bookedDays = <?php echo json_encode($date_list); ?>; </script> Resolved, the problem was actually what was being stored in the JavaScript variable. Code above reflects the working code. A: I'm not exactly sure where your while loop parens should go, but you need to move them down. Something like this: <?php $bookeddates = "SELECT fromdate, todate FROM messages WHERE listing_id = '".$_GET['listingid']."'"; $resultbookeddates = mysql_query($bookeddates) or die(mysql_error() . "<br>" . $bookeddates); while ($rowbookeddates = mysql_fetch_assoc($resultbookeddates)) { $from = date('Y-n-j', strtotime($rowbookeddates['fromdate'])); $to = date('Y-n-j', strtotime($rowbookeddates['todate'])); $start_time = strtotime($from); $end_time = strtotime($to); $date_list = array($from); $current_time = $start_time; while($current_time < $end_time) { //Add one day $current_time += 86400; $date_list[] = date('Y-n-j',$current_time); } $date_list[] = $to; } $date_list_res = '["' . implode('","', $date_list) . '"]'; ?> <script type="text/javascript"> var bookedDays = <?php echo $date_list_res; ?>; </script> A: This code: while ($rowbookeddates = mysql_fetch_assoc($resultbookeddates)) { $from = date('Y-n-j', strtotime($rowbookeddates['fromdate'])); $to = date('Y-n-j', strtotime($rowbookeddates['todate'])); } traverses the resultset, assigning its values to $from and $to, replacing the previous value. When the loop finishes, you get the "from" and "to" values for the last record traversed. You should either put the results in an array for further processing, or include the processing code inside the while loop.
IL-1 cytokines in cardiovascular disease: diagnostic, prognostic and therapeutic implications. Interleukins (ILs) are key mediators in the chronic vascular inflammatory response underlying several aspects of cardiovascular disease. Due to their powerful pro-inflammatory potential, and the fact that they are highly expressed by almost all cell types actively implicated in atherosclerosis, members of the IL-1 cytokine family were the first to be investigated in the field of vessel wall inflammation. The IL-1 family is comprised of five proteins that share considerable sequence homology: IL-1alpha, IL-1beta, IL-1 receptor antagonist (IL-1Ra), IL-18 (also known as IFNgamma-inducing factor), and the newly discovered ligand of the ST2L receptor, IL-33. Expression of IL-1s and their receptors has been demonstrated in atheromatous tissue, and serum levels of IL-1-cytokines have been correlated with various aspects of cardiovascular disease and their outcome. In vitro studies have confirmed pro-atherogenic properties of IL-1alpha, IL-1beta and IL-18 such as, up-regulation of endothelial adhesion molecules, the activation of macrophages and smooth muscle cell proliferation. In contrast with this, IL-1Ra, a natural antagonist of IL-1, possesses anti-inflammatory properties, mainly through the endogenous inhibition of IL-1 signaling. IL-33 was identified as a functional ligand of the, till recently, orphan receptor, ST2L. IL-33/ST2L signaling has been reported as a mechanically activated, cardioprotective paracrine system triggered by myocardial overload. As the roles of individual members of the IL-1 family are being revealed, novel therapies aimed at the modulation of interleukin function in several aspects of cardiovascular disease, are being proposed. Several approaches have produced promising results. However, none of these approaches has yet been applied in clinical practice.
The application of a work platform forces to the pump jack “L” frame result in significant stresses in the material and fasteners located at the connection of the vertical and horizontal members. FIG. 2 shows that the “L” frame design currently employed by pump jack manufacturers utilizes outwardly opened, laterally opposing, “C” shaped channels for both the vertical 10 and horizontal 11 frame members. At the connection of the vertical and horizontal members, the flange of the vertical member 10 must be notched 12, or removed as shown in FIG. 3, to facilitate the connection of the horizontal member 11. The notching 12, or removal, of the flange in this area weakens the frameworks at its most structurally critical location in two ways: 1. The removal of flange material in the area local to the most significant stresses. 2. The notching process generates a point where stresses are concentrated. This point 13 is located at the corner of the notch 12. This point 13 of concentrated stress is commonly referred to as a stress riser. As a result, under test loads, the “L” frame vertical member 10 will fail in this structurally critical area.
Over the past few months we’ve made great strides on multiple fronts — closing contracts with known contributors, global suppliers and other strategic partners. These partners have already closed the gap to our soft cap and could complete our entire funding goal. While the support is positive, we are committed to our community, and the last thing we want to do is prevent you from participating. Quality TGE’s often end in gas wars and restrict participants to low ETH contributions because there’s not enough public supply left after private sale contributors take the majority of the allocation. Being a community facing project, we wanted to make sure everyone will be able to participate, so we’ve decided to make changes to our crowd sale process. Instead of our public sale being at the end of June we will open up a public presale for 24 hours to ensure you all the option to join in. The public presale will begin on July 5th. Anyone who has passed the KYC requirements (Apply here: kyc.zeex.me) is eligible to participate, and we invite our community of early adopters to take part before allocations are gone and spaces run out. During the presale, every ETH will give you 20 extra ZIX tokens per ETH contributed. The official public sale price is 1 ETH = 5000 ZIX. So, for example: 5 ETH = 5 X 5100 ZIX = 25,500 ZIX 20 ETH = 20 X 5400 ZIX = 108,000 ZIX 50 ETH = 50 X 6000 ZIX = 300,000 ZIX Minimum contribution: 4 ETH Maximum contribution: 120 ETH Maximum ZIX bonus tier: 6000 ZIX per ETH After the 24 hours of presale has concluded, we will finalize our private sale process, knowing that our community had the opportunity to participate and contribute, even if the final part of the private sale reduces the public sale allocation. Stay tuned, more details are coming soon! We’ll update this post with the latest information about the presale, so make sure to bookmark it, and check our Telegram (https://T.me/zeexme) for exclusive content straight from the source!
#include "epoll.hpp" #include "config.hpp" #include "util/unix.hpp" #include "util/log.hpp" extern "C" { #include <unistd.h> #include <sys/epoll.h> } static TError EpollCreate(int &epfd) { epfd = epoll_create1(EPOLL_CLOEXEC); if (epfd < 0) return TError::System("epoll_create1()"); return OK; } TError TEpollLoop::Create() { TError error = EpollCreate(EpollFd); if (error) return error; Statistics->EpollSources = 0; return OK; } void TEpollLoop::Destroy() { auto lock = ScopedLock(); Sources.clear(); close(EpollFd); EpollFd = -1; } TEpollLoop::~TEpollLoop() { delete[] Events; } TError TEpollLoop::GetEvents(std::vector<struct epoll_event> &evts, int timeout) { evts.clear(); if (MaxEvents != config().daemon().max_clients() + NR_SUPERUSER_CLIENTS) { delete[] Events; MaxEvents = config().daemon().max_clients() + NR_SUPERUSER_CLIENTS; Events = new struct epoll_event[MaxEvents]; } PORTO_ASSERT(Events); int nr = epoll_wait(EpollFd, Events, MaxEvents, timeout); if (nr < 0) { if (errno != EINTR) return TError::System("epoll() error: "); } for (int i = 0; i < nr; i++) evts.push_back(Events[i]); return OK; } TError TEpollLoop::AddSource(std::shared_ptr<TEpollSource> source) { int fd = source->Fd; auto lock = ScopedLock(); if ((int)Sources.size() <= fd) Sources.resize(fd + 256); if (!Sources[fd].expired()) { L_ERR("Duplicate epoll fd {}", fd); return TError("dublicate epoll fd"); } Sources[fd] = source; Statistics->EpollSources++; struct epoll_event ev; ev.events = EPOLLIN | EPOLLHUP; ev.data.fd = fd; if (epoll_ctl(EpollFd, EPOLL_CTL_ADD, fd, &ev) < 0) return TError::System("epoll_add {}", fd); return OK; } void TEpollLoop::RemoveSource(int fd) { auto lock = ScopedLock(); if (fd < (int)Sources.size() && !Sources[fd].expired()) { Sources[fd].reset(); Statistics->EpollSources--; } else L_ERR("Invalid epoll fd {}", fd); if (epoll_ctl(EpollFd, EPOLL_CTL_DEL, fd, nullptr) < 0) L_ERR("Cannot remove epoll {} : {}", fd, TError::System("epoll_ctl")); } TError TEpollLoop::ModifySourceEvents(int fd, uint32_t events) const { struct epoll_event ev; ev.events = events; ev.data.fd = fd; if (epoll_ctl(EpollFd, EPOLL_CTL_MOD, fd, &ev) < 0) return TError::System("epoll_mod {}", fd); return OK; } TError TEpollLoop::StartInput(int fd) const { return ModifySourceEvents(fd, EPOLLIN); } TError TEpollLoop::StopInput(int fd) const { return ModifySourceEvents(fd, 0); } TError TEpollLoop::StartOutput(int fd) const { return ModifySourceEvents(fd, EPOLLOUT); } std::shared_ptr<TEpollSource> TEpollLoop::GetSource(int fd) { auto lock = ScopedLock(); if (fd >= (int)Sources.size()) return nullptr; return Sources[fd].lock(); }
1973 Cleveland Browns season The 1973 Cleveland Browns season was the team's 24th season with the National Football League. After a solid 1972 season, which included a playoff appearance, the Browns got off to a solid start, winning three of their first four games on the way to a 7-3-1 start. However, the Browns did not win another game the rest of the season and settled for third place with a 7-5-2 record. Offseason Draft Roster Exhibition schedule Regular season schedule Season summary Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Week 7 Week 8 Week 9 Week 10 Week 11 Week 12 Week 13 Week 14 Standings References Cleveland Category:Cleveland Browns seasons Cleveland Browns
Q: Hadoop cluster and client connection I have the hadoop cluster. Now i want to install the pig and hive on another machines as a client. The client machine will not be a part of that cluster so is it possible? if possible then how i connect that client machine with cluster? A: First of all, If you have Hadoop cluster then you must have Master node(Namenode) + Slave node(DataNode) The one another thing is Client node. The working of Hadoop cluster is: Here Namenode and Datanode forms Hadoop Cluster, Client submits job to Namenode. To achieve this, Client should have same copy of Hadoop Distribution and configuration which is present at Namenode. Then Only Client will come to know on which node Job tracker is running, and IP of Namenode to access HDFS data. Go to Link1 Link2 for client configuration. According to your question After complete Hadoop cluster configuration(Master+slave+client). You need to do following steps : Install Hive and Pig on Master Node Install Hive and Pig on Client Node Now Start Coding pig/hive on client node. Feel free to comment if doubt....!!!!!!
Service providers (e.g., wireless, cellular, etc.) and device manufacturers are continually challenged to deliver value and convenience to consumers by, for example, providing compelling network services. One area of interest is providing location-based services to a plurality of users and user devices, for example, shared network communication services. In one scenario, a service provider, for instance a merchant (a service provider), may provide a wireless communication network for use by its patrons (users) where the users may or may not need to provide user credentials for accessing the network. In one example, the network may require a security password, which a user may obtain from the service provider. In another example, a service provider may wish to avoid managing and requiring security passwords by providing an open-access network so that the users may conveniently access the network without a need for a password. However, the coverage of a wireless communication network may extend beyond a physical area where a service provider may intend or wish to provide the service at; for example, a merchant may wish to provide access to its network only to customers who are in the immediate area of his business location. Additionally, the users may have a better user-experience if they can easily access the network without access control and manual login. Therefore, service providers and device manufacturers face significant challenges in providing a more efficient and user friendly access control to location-based services.
Clinical, histologic, and immunohistochemical characterization of wart-like lesions on the paw pads of dogs: 24 cases (2000-2007). OBJECTIVE- To determine clinical, histologic, and immunohistochemical findings for dogs with wart-like lesions involving the paw pads. DESIGN- Retrospective case series. ANIMALS- 24 dogs (18 Greyhounds and 6 dogs of other breeds). PROCEDURES- Medical records were reviewed for information on signalment, physical examination findings, concurrent disease processes, location of all lesions, and, when available, results of histologic examination of biopsy specimens. Available biopsy specimens (n = 11) were submitted for immunohistochemical staining and a PCR assay to identify viral inclusion bodies. RESULTS- In Greyhounds, most lesions involved the pads of the third and fourth digits, had a consistent histologic appearance without evidence of inflammation, were negative for papillomavirus, and had an unsatisfactory response to treatment. In other breeds, lesions often involved the pads of non-weight-bearing digits, had histologic evidence of inflammation, were positive for papillomavirus, and responded to surgical treatment. CONCLUSIONS AND CLINICAL RELEVANCE- Results suggested that wart-like lesions involving the paw pads of Greyhounds were a distinct clinical entity with features resembling porokeratosis plantaris discreta in humans. In Greyhounds, these lesions were not associated with an underlying viral etiology and, therefore, should not be considered plantar warts. Alternative treatments should be investigated because current treatments were generally unsuccessful in Greyhounds. Wart-like lesions of the paw pads in other breeds were often associated with papillomavirus, and surgical excision appeared curative.
Q: Invalid left-hand side argument error when concatenating a string with variable in a function I'm attempting to concatenate the value in a function with c and add 5 each time. However, I keep getting the error Uncaught ReferenceError: Invalid left-hand side in assignment. Does anyone know of a workaround? I am assuming I cannot use the + operator as a concatenate and then use it in the +=? I'm confused why this isn't working. var c1 = 0; var c2 = 0; function(d) { d.number; //possible value of 1 or 2 c + d.number += 5; //isn't this c1 += 5, or c2 += 5? "c" + d.number += 5; //also tried this - same error console.log(c1); console.log(c2); ;} A: In case what Pointy said in the comments is not clear, you can "construct" the variable name (as you are trying to do) when it's an object property using the [ ] operator. Here is an example: var cObj = {}; cObj.c1 = 0; cObj.c2 = 0; function(d) { cObj['c' + d.number] += 5; console.log(cObj.c1); console.log(cObj.c2); ;}
Tecumseh Public SchoolsTecumseh Public Schools serves nearly 2,900 learners in preschool through grade 12 in Lenawee County, Michigan. The district provides all learners with the opportunity to explore every facet of their education with a focus on Customized Learning and Project-Based Learning. In addition to a variety of academic paths, learners may also participate in nationally-recognized musical, fine and performing arts programs. Indians Girls Cross Country Runners Continue to Improve The THS Indians Varsity Girls Cross Country team competed at the Jackson Invite at Ella Sharp Park on Saturday, Sept. 22. Running in Division 2, the girls claimed third place out of 12 teams. The team was led by sophomore Kaitlin Knape with a PR of 19:29. This new personal best for Kaitlin moves her up to fifth place on the THS record board. She was followed by senior Katie Selenko with a PR of 20:09, sophomore Bailey Fraker with a PR of 21:02, senior Rachel Stockford (SB 21:21), junior Izzy Brigman (SB 21:27), Faith Stull (SB 22:07), and freshman Brynn Richardson with a PR of 22:09. Earning a medal for the Indians were Kaitlin Knape in 8th place, and Katie Selenko in 12th place. Come out to watch the girls face "Big Bertha," a challenging hill on the course at Heritage Park on Tuesday, Sept. 25 at the SEC White Jamboree. Race time is 4:30 p.m.
Strategic Tactical Engagement and Marketing Strategy for HCP During and Post COVID-19 When it comes down to marketing and understanding your target it's important to ensure your HCP message is based on target and relevance. In the world of life science communication and marketing strategy the majority of the time is spent on brand/ product positioning and therapeutic objectives alongside a communication strategy. Since HCPs are their own target area it's important to fully understand this marketplace so you can provide a quality scientific content focus approach to marketing. During this workshop you will learn how to:
184 Ga. App. 551 (1987) 362 S.E.2d 128 TAYLOR v. CAREER CONCEPTS, INC. 74553. Court of Appeals of Georgia. Decided October 16, 1987. George C. Oetter, Jr., for appellant. William D. Gifford, for appellee. CARLEY, Judge. Appellant-defendant, a Houston County resident, entered into a written contract, agreeing to pay a placement fee to appellee-plaintiff if it found him employment. Several months later, a job opening arose at Gandy's Industries, Inc. (Gandy's), a Bibb County corporation. Appellee contacted appellant about the job opening and eventually appellant was hired to fill the position at Gandy's. When payment of its *552 placement fee was not forthcoming, appellee brought this suit in Bibb County, naming both Gandy's and appellant as defendants. In its complaint, appellee alleged that Gandy's and appellant were jointly and severally liable for the placement fee and were subject to the jurisdiction of the Bibb County court. In his answer, appellant admitted entering into the written contract with appellee but contended that "he contracted only for job placement with employers who would pay the placement fee to [appellee]." Appellant also denied the allegation that he was subject to the jurisdiction of the Bibb County court. Subsequently, Gandy's moved for summary judgment and its motion was granted. Appellee then moved for summary judgment as against appellant. The trial court conducted a hearing on the motion. At the hearing, appellant appeared and apparently defended against the motion on the merits. After the hearing, the trial court granted appellee's motion for summary judgment and appellant appeals from that order. 1. Contending that the Bibb County court did not have jurisdiction over him, appellant enumerates as error the trial court's entry of any judgment in the case. It is undisputed that appellant was a resident of Houston County and that Gandy's was a resident of Bibb County. In its complaint, however, appellee had alleged that appellant and Gandy's were joint obligors. "Suits against joint obligors ... residing in different counties may be tried in either county." Ga. Const. of 1983, Art. VI, Sec. II, Par. IV. Accordingly, appellant's denial in his answer that he was subject to the jurisdiction of the Bibb County court was without merit. At that time, venue was proper in Bibb County as the residence of appellant's alleged joint obligor. "The only time the defense of lack of jurisdiction over the person of the nonresident [defendant] because of [his] nonresidency would be valid ... is in the event of a judgment in favor of the resident joint defendant.... [Cit.]" Lansky v. Goldstein, 136 Ga. App. 607, 608 (2) (222 SE2d 62) (1975). Thus, it was only when summary judgment was subsequently granted in favor of Gandy's that venue in Bibb County became improper as against appellant. "[A]lthough suits against ... joint obligors ... may be brought in the county of the residence of any, if no judgment is taken against a resident defendant, the court loses venue as to the nonresident [defendant] unless the issue of venue is waived." (Emphasis supplied.) Timberlake Grocery Co. v. Cartwright, 146 Ga. App. 746, 747 (247 SE2d 567) (1978). Accordingly, the issue for determination is whether, subsequent to the grant of summary judgment in favor of Gandy's, appellant waived his venue defense. In Maddox v. Brooks, 17 Ga. App. 644 (87 SE 911) (1916), this court held "that if upon the trial of ... a joint action the plaintiff fails to prove a joint undertaking, and dismisses as to the resident *553 defendant, the other defendant may still, prior to verdict, raise ... the question of lack of jurisdiction...." (Emphasis supplied.) After the trial court granted summary judgment in favor of Gandy's appellee's action against appellant did not proceed to a trial and verdict. It did, however, proceed to the trial court's consideration of appellee's motion for summary judgment. Prior to the trial court's grant of appellee's motion for summary judgment, appellant never raised improper venue as a defense. "A party against whom summary judgment has been granted is in the same position as if he suffered a verdict against him. [Cits.]" Summer-Minter & Assoc. v. Giordano, 231 Ga. 601, 604 (203 SE2d 173) (1974). Accordingly, appellant's failure to object to improper venue prior to the entry of the trial court's order was, in effect, a failure to raise the defense prior to suffering a verdict against him. By doing so, appellant waived any venue defense he possessed. This enumeration is without merit. 2. Appellant urges that the written contract is ambiguous and that the question of whether, under its terms, he was obligated to pay the placement fee to appellee should have been submitted to a jury. One section of the contract provided that, upon appellant's acceptance of employment as a result of a referral from appellee, he agreed to pay the placement fee. Another section of the contract provided that, if appellant worked for the employer for more than ten weeks and the employer paid a fee to appellee, then appellant would not be liable to appellee for the fee. "[W]here no dispute of fact is involved, the construction of a plain and definite contract, if needed, is a matter of law for the court; a contract is not ambiguous even though difficult to construe, unless and until an application of the pertinent rules of interpretation leaves it uncertain as to which of two or more possible meanings represents the true intention of the parties. [Cit.]" Pisano v. Security Mgt. Co., 148 Ga. App. 567, 568 (251 SE2d 798) (1978). "The construction which will uphold a contract in whole and in every part is to be preferred, and the whole contract should be looked to in arriving at the construction of any part." OCGA § 13-2-2 (4). Construing the contract in the case at bar as a whole, appellant's obligation to pay the placement fee to appellee was subject to a condition subsequent. Appellant was liable for the fee unless a fee had been paid to appellee by the employer. The two sections of the contract are neither inconsistent nor ambiguous. Therefore, construction of the contract was a matter for the court rather than for a jury. See generally Gulbenkian v. Patcraft Mills, 104 Ga. App. 102 (121 SE2d 179) (1961). This enumeration is without merit. 3. Appellant urges that the trial court erroneously failed to consider evidence of an alleged separate oral agreement. According to appellant, he had a separate oral agreement whereby appellee would not refer him to any employer who would not pay the placement fee. "Parol *554 testimony may be admitted ... to show a distinct collateral understanding, although it may not contradict or vary the writing itself. [Cit.]" Tanner v. Tinsley, 152 Ga. App. 330, 331 (262 SE2d 602) (1979). "`The test to determine whether the oral agreement is one which the law will permit to be [pled] and [proven] is whether the oral agreement constitutes a part of the written contract or whether, instead, it is a separate and distinct oral contract which is not inconsistent with the written contract. If the latter, it admits of pleading and proof. [Cits.]' [Cit.]" Diamondhead Corp. v. Robinson, 144 Ga. App. 60, 62 (240 SE2d 572) (1977). Appellant's alleged oral agreement would vary the terms of the written contract, in effect negating any obligation on the part of appellant to pay appellee a placement fee. 4. Under the written agreement, appellant was required to pay appellee a placement fee subject only to the condition subsequent that Gandy's had paid a fee to appellee. Since Gandy's had paid no fee to appellee, the trial court did not err in granting summary judgment in favor of appellee. Remaining enumerations not otherwise addressed have been considered and have been found to be without merit. Judgment affirmed. Banke, P. J., and Benham, J., concur.
698 F.2d 1222 Pattersonv.Malette 81-1687 UNITED STATES COURT OF APPEALS Sixth Circuit 2/19/82 1 W.D.Mich. AFFIRMED
Grading Aortic Valve Stenosis With Dimensionless Index During Pre-cardiopulmonary Bypass Transesophageal Echocardiography: A Comparison With Transthoracic Echocardiography. The authors hypothesized that grading valvular aortic stenosis (AS) with dimensionless index (DI) during intraoperative pre-cardiopulmonary bypass (pre-CPB) transesophageal echocardiography (TEE) would match the grade of AS during preoperative transthoracic echocardiography (TTE) for the same patients more often than when using peak velocity (Vp), mean pressure gradient (PGm), or aortic valve area (AVA). Retrospective, observational. Single university hospital. The participants in this study included 123 cardiac surgical patients with any degree of AS, who underwent open cardiac surgery between 2010 and 2016 at the Medical University of South Carolina and had Vp, PGm, AVA, and DI values available from reporting databases or archived imaging. None. When using DI, pre-CPB TEE grading of AS severity was 1 grade higher 21.1% of the time and 1 grade lower 13.0% of the time compared with TTE, for an overall disagreement rate of 34.1%. The overall disagreement rates between pre-CPB TEE and TTE for Vp, PGm, and AVA were 39.8%, 33.3%, and 33.3%, respectively. The authors could not demonstrate that DI was better than Vp, PGm, or AVA at matching AS grades between intraoperative pre-CPB TEE and preoperative TTE. When DI was used, pre-CPB TEE was more likely to overestimate than underestimate the severity of AS compared with TTE. However, when Vp or PGm was used, pre-CPB TEE was more likely to underestimate the severity of AS compared with TTE. A comprehensive approach without overemphasis on 1 parameter should be used for AS assessment by intraoperative TEE.
Fluoroscopy: patient radiation exposure issues. Fluoroscopic procedures (particularly prolonged interventional procedures) may involve high patient radiation doses. The radiation dose depends on the type of examination, the patient size, the equipment, the technique, and many other factors. The performance of the fluoroscopy system with respect to radiation dose is best characterized by the receptor entrance exposure and skin entrance exposure rates, which should be assessed at regular intervals. Management of patient exposure involves not only measurement of these rates but also clinical monitoring of patient doses. Direct monitoring of patient skin doses during procedures is highly desirable, but current methods still have serious limitations. Skin doses may be reduced by using intermittent exposures, grid removal, last image hold, dose spreading, beam filtration, pulsed fluoroscopy, and other dose reduction techniques. Proper training of fluoroscopic operators, understanding the factors that influence radiation dose, and use of various dose reduction techniques may allow effective management of patient dose.
Kino Lorber have announced that they are planning to release on Blu-ray director Alain Resnais' film Je t'aime, je t'aime (1968), starring Claude Rich, Olga Georges-Picot, Anouk Ferjac, Alain MacMoy, and Vania Vilers. The release is expected to arrive on the market later this year. The plot centres on Claude Ridder (Claude Rich) who is asked to participate in a mysterious experiment in time travel when he leaves hospital after a failed suicide attempt. The experiment, intended to return him after one minute of observing the past, instead causes him to experience his past in a disjointed fashion. His fate is left ambiguous. Cinematography by Jean Boffety (César et Rosalie, The Things of Life). Special Features: Audio interview with Alain Resnais Booklet essay by Jonathan Rosenbaum (Blu-ray exclusive) Interview with Claude Rich The Meeting of Alain Resnais and Jacques Sternberg Trailer
Rajasthan likely to clip 4,000-Mw solar project to save birds [ezcol_1half]In a major jolt to India’s solar energy programme, theRajasthan government might cancel the 4,000-Mw solarUMPP (ultra mega power project), which was expected to come up near Sambhar Lake. The state government has cited reasons of ecological and environmental impact that could take place if the plant is established at this site. The Vasundhara Raje government has written to the Centre that the area under consideration is a prime site for migratory birds that would perish if a power plant or transmission line is raised there, sources said. However, persons close to the issue said there were political reasons as well, as the project was one of the milestones of the UPA-II (United Progressive Alliance-II) government. The Bharatiya Janata Party-ruled state government is uninterested in going ahead with it. Rather the chief minister is looking at designing a separate solar power programme for the state. The project aimed at a massive scaling up of solar power was launched in September last year, which was supposed to be set up and run by a joint venture of public sector units – Bharat Heavy Electricals Ltd, Power Grid Corporation of India, Solar Energy Corporation of India, Hindustan Salts Limited and Rajasthan Electronics and Instruments Limited. The estimated cost of the project was calculated at Rs 7,500 crore. [/ezcol_1half] [ezcol_1half_end]The land in question, approximately 23,000 acres, is around Sambhar Lake, which under the globalRamsar Convention is also listed as an ecologically sensitive area. The state government is using this argument almost a year after the memorandum of understanding was signed between the PSUs. “The area that is ecologically sensitive is only 5,000 acres, which was avoided in the planning. The rest is very clear land and it is strange the state government has raised this issue now,” said a senior official of Union ministry of new and renewable energy (MNRE). Around 18,000 acres were to be provided by Hindustan Salts as its equity in the project. The ministry is involved in this project through its subsidiary, Solar Energy Corporation of India, and is now looking for new land for this project. Rajasthan currently has a capacity of 666 MW of solar power, second highest in the country after Gujarat. Its mission statement aims to add 4,000 MW by the year-end. “The government in the Union Budget this year announced setting up of four solar UMPPs across the country, including one in Rajasthan. The state was the first to announce a solar UMPP, that too of such a huge capacity. We would have to find a new land for executing this project,” said the MNRE official. The Union Budget has put a lot emphasis on scaling up of clean energy, including setting up of large-scale power plants of plus-500 Mw. Piyush Goyal, minister for coal, power and renewable energy, also pushed for expediting work on solar power projects and have on paper at least a capacity of 5,000-6,000 MW in several states by the month-end.[/ezcol_1half_end]
Don’t! The secret of self-control - alextp http://www.newyorker.com/reporting/2009/05/18/090518fa_fact_lehrer?currentPage=all# ====== biohacker42 Does anyone here, like me, really appreciate Feynman's just the fact's style of writing? Most people describe it as eerily cold, but I love it. Articles like the this one on the other hand, while excellent, bury their valuable information under a lot of fluff. And most people like that kind of writing, but I just find it annoying. Good article, I just wish it was more direct. ~~~ electromagnetic Took a lot of self-control just to read through the damn thing! ~~~ zvikara On the other hand, I could use some more self-control to do actual work instead of reading through HN. ------ audionerd Radiolab summarized the study in a 15 minute segment, if you lack the self- control to read the entire article :) [http://blogs.wnyc.org/radiolab/2009/03/09/mischel’s-marshmal...](http://blogs.wnyc.org/radiolab/2009/03/09/mischel’s-marshmallows/) ------ boredguy8 Of course students who 'sit still' and 'do as their told' do better in an educational system which prioritizes conformity. The kid who decides to open the drawer to find the toys: that's the guy I want on my team. I'm more than willing to farm out grunt work to the 'successful' high delayers. ~~~ jmatt I agree. Here are the choices 1) Do as you are told and get another marshmallow 2) Eat as many marshmallows as you want with no punishment. That doesn't seem to be a very hard choice. I personally like the kid that checks to make sure that no one is looking then eats the inside of the Oreo and returns it. I'm not arguing with the results. I would imagine that on average those that do as they are told and conform do better on average. But I doubt those are the same people that make big discoveries or become successful entrepreneurs. So what happened to the kid that split the Oreo and returned it? That seems like a much more interesting question. ~~~ pbz Why would you like his behavior? While clever, isn't the same as having an adult as an employee who looks around to make sure nobody's watching while stealing from you just enough so you won't notice? I wouldn't want somebody like that on my team. ~~~ jmatt _I wouldn't want somebody like that on my team._ I would. Who is he harming by eating the middle of an Oreo? You imply that his solution to the problem is wrong because it's deceptive. But it's the testers and parents that put him in that situation. I definitely wouldn't hold it against the kid. I think the solution is more unique and out of the box than just sitting there waiting and getting all worked up over it. Recognizing this behavior as clever and out of the box is similar to saying lazy programmers are good programmers. Everyone knows a truly lazy programmer is no good. It's the inclination to do work in a more efficient way that they are really after. So while the kid being potentially deceptive and stealing is bad, his inclinations and temperament may not be. That being said I imagine I would have been the kid that ate the center of the Oreo and put it back... so I may be biased. ------ ambulatorybird I've never had much trouble holding back -- it's pushing myself forward that's the hard part. Any tips on metacogitating my way out of that? ~~~ shellerik If you're not pushing yourself forward what are you doing instead? Perhaps whatever you are doing in place of pushing yourself forward is the marshmallow you need to say no to. ------ pseale This sounds vaguely like the test given to Paul Atreides in Dune, testing to see whether he was Human or an animal. ~~~ radu_floricica Dune is a ridiculously good book. I never understood why it's relatively obscure. Other then perhaps the fact that I tend to grit my teeth when I hear people talking (or making movies) about it with only superficial understanding. ------ maheshsingh Indian Yoga is teaching us about importance of self-control also people can improve their self control through Yoga. People are getting benefited through yoga for self control from thousand of years. Whole concept of yoga is based upon self-control. This research is simply re-inventing the wheel. People who want to improve self-control should try Yoga for at-least couple of months. ~~~ TFrancis Agreed. Additionally, I found meditation was useful for increasing my self- control. Many types of yoga are focused on meditative practices but not all. I think these are just mind tricks (hacks?) and this jives with the research the article presented. ------ robertk Another worldview changing article. I'd love to be a psychologist, but I'm not clever enough. Honestly, these guys are mind hackers. Finding unit tests for the brain. ~~~ tjic You're looking at some of the most interesting research from one of the most clever guys and then generalizing and saying "these guys are super bright". The best folks in any field are super bright. I'm not impressed by 95% of psychologists (but then again, I'm not impressed by 85% of coders...). ~~~ sfk If I'm not mistaken, the comment you responded to was highly sarcastic. ------ noahlt Mischel's team found that they could teach tricks to underperforming kids, who would subsequently perform just as well as the originally patient ones. Does anyone here have good hacker-relevant tips for self-control? (For instance: when tackling a large problem, approach it bottom-up by starting with utility functions.) ------ defen See "A Farewell to Alms" for a really interesting discussion of the rise of low time-preference individuals in medieval England, and the role this played in fomenting the Industrial Revolution. Short interview with the author here: [http://www.gnxp.com/blog/2007/08/10-questions-for-greg- clark...](http://www.gnxp.com/blog/2007/08/10-questions-for-greg-clark.php) ------ jamesbritt "Once you realize that will power is just a matter of learning how to control your attention and thoughts, you can really begin to increase it." Ah, one of my favorite four-letter words: "Just". You _just_ add a second database to the system. You _just_ write the slow parts in C. You _just_ learn how to control your attention and thoughts. ------ beza1e1 For a scientific article two things were lacking: How do they define "successful"? How big is the variance/standard deviation? ~~~ silentbicycle It's a summary of academic research for the New Yorker. If you want statistics on the results, you'll probably need to consult the research itself, not a popular summary. ~~~ sketerpot It would be nice if they gave a link to the research itself. This goes in general for all popular science news. ~~~ timr The research spans multiple decades and research groups. It's not like the results are published neatly in a single article. If you really want to read the primary literature, you've got the name of the researcher and his university. PubMed is your friend. ------ comatose_kid Really interesting. I think that most diets don't work because you're forced into thinking about what you eat (and what you're not supposed to). Perhaps the best diet involves changing your lifestyle so that you're doing things that remove your mind from thinking about eating. ------ Tichy Why newspapers are dying: because they could not adapt to the shortened attention spans of modern times and learn to write shorter articles. It was a little bit interesting, but way, way too long... ------ agbell I wonder if any of the 'Brain Gym' genre of games train this delay gratification? lumosity.com has games targeting attention but they aren't the games mentioned in the article. ~~~ Alex3917 Executive function is determined largely by the amount of self-directed play before age five. That's why electronic toys and baby videos are generally thought to be harmful. edit: I don't know much about Brain Gym, but Pamela Paul has a whole chapter in Parenting Inc. comparing the different ECE programs, which might answer your question. ~~~ swombat Could you define "self-directed play" for those of us who aren't 100% clear on its meaning? ~~~ ekanes Self-directed play is where the child isn't playing according to "rules". Where there's no "right" or "wrong" way to play, and the child is making up their own game/world/etc as they go. Think "Lego" :) ------ rokhayakebe Where in the world is it May 18th? ------ c00p3r That was called the yoga almost 3k years ago. I mean self-control (control of the thoughts and emotions) through behavioral exercises. ~~~ silentbicycle Yeah. Similarly, a big part of Buddhism is trying to be live mindfully, to avoid doing impulsive things that just lead to greater suffering. It's historically tended to get entangled with contemporary religious ideas as it spread throughout the world (not all Buddhists believe in reincarnation, etc.), but none of those are essential. ------ badger7 It's the secret to avoiding procrastination too - if you can't stop mulling over all the other things floating around your head, then don't - _just start_. The other things will be replaced fairly quickly with what you're trying to do, and there you go - you've distracted yourself from your distractions and are now being productive :)
Washington(CNN) The Trump administration has moved to substantially cut its contribution to NATO's collective budget according to several US and NATO officials, a symbolic move that comes as many continue to question President Donald Trump's commitment to the transatlantic alliance as he prepares to attend a summit to mark its 70th anniversary in London next week. Previously the US provided some 22% of NATO's direct funding, which covers the cost of maintaining the NATO headquarters, joint security investments and some combined military operations. It's a largely symbolic move as NATO's direct budget is relatively small, at about $2.5 billion, and is separate from national defense budgets that NATO recommends should stand at 2% of GDP. US defense officials tell CNN that the Trump administration sought to reduce its contribution to about 16%, bringing it in line with Germany's, which provides 14.8% despite the US having a larger economy. US and NATO officials told CNN that the other NATO members are expected to make up the shortfall. Trump has long slammed NATO allies, particularly Germany for not meeting the 2% NATO defense spending target, which only eight of 29 members currently meet. All members pledged to reach the 2% level by 2024 but not all of them currently have plans to do so. Member countries have boosted defense spending considerably in recent years, something Trump has claimed credit for. NATO officials including the Secretary General Jens Stoltenberg have also credited Trump for the rise in spending, with an extra $100 billion spent since 2014 but have also acknowledged the increased threat from Russia following its seizure of Crimea and other factors have helped to prompt the increase. "All Allies have agreed a new cost sharing formula. Under the new formula, cost shares attributed to most European Allies and Canada will go up, while the US share will come down. This is an important demonstration of Allies' commitment to the Alliance and to fairer burden-sharing," a NATO official told CNN. A NATO diplomat told CNN that the new formula was agreed to this week. One US defense official said that the money saved by the US will help fund other US military and security efforts in Europe, including programs in countries such as non-NATO members Ukraine and Georgia, which are seen as being on the frontline with Russia. Member countries contribute to these NATO budgets in accordance with an agreed cost-sharing formula based on gross national income. The civilian budget was set at about $260.5 million for 2019 and is used mainly to fund the NATO headquarters in Belgium and administration costs. There's a military budget of $1.56 billion for 2019, which is used to fund some joint operations and the NATO strategic command center, as well as training and research. That is a fraction of overall spending on defense by member countries, which NATO estimates will total more than $1 trillion in 2019. There is also a joint budget for the NATO Security Investment Programme, which covers major construction and command and control system investments. The budget for that program is capped at $770 million for 2019. CORRECTION: This story has been updated to reflect that the new funding formula was agreed this week.
Partly true But to think that cipher is a slang for cops is not really true. Some rappers call cops "C-Ciphers" (think C-O dropping the P or just for Correction Officers)because they are part of the Nation of Gods & Earths, who have an entire alphabet and language that they use. So that's most likely what you're thinking of. Anyway the cipher meaning here is circle and it originated in the NGE but moved into the rap world and weed world. Because you got people who freestyle or pass weed in a circle. So it just kinda took on that meaning.
--- abstract: 'The Lindblad master equation for an arbitrary [*quadratic*]{} system of $n$ fermions is solved explicitly in terms of diagonalization of a $4n \times 4n$ matrix, provided that all Lindblad bath operators are [*linear*]{} in the fermionic variables. The method is applied to the explicit construction of non-equilibrium steady states and the calculation of asymptotic relaxation rates in the far from equilibrium problem of heat and spin transport in a nearest neighbor Heisenberg $XY$ spin $1/2$ chain in a transverse magnetic field.' address: 'Department of physics, FMF, University of Ljubljana, Jadranska 19, SI-1000 Ljubljana, Slovenia' author: - Tomaž Prosen title: 'Third quantization: a general method to solve master equations for quadratic open Fermi systems' --- Introduction ============ Understanding time evolution of an open quantum system of many interacting particles is of primary importance in fundamental problems of quantum physics, such as decoherence [@zurek; @zeh] and closely related quantum measurement problem [@neumann; @schlos], quantum computation [@chuang; @casati], or the problem of computation of [*non-equilibrium steady states*]{} (NESS) in quantum statistical mechanics [@araki; @ruelle; @jaksic]. Even though application of the methods of Hamiltonian dynamical systems and ergodic theory to quantum systems out of equilibrium gives many promising results [@piere2; @lee; @prosenjpa], the field of open quantum systems is still lacking non-trivial explicitly solvable models, as compared to studies of closed (isolated) quantum systems where we know a large body of the so-called [*completely integrable*]{} systems [@korepin; @fadeev]. Examples of explicitly solvable models of master equations for open quantum systems are limited to quite restricted models of a single particle, single spin or harmonic oscillators (see e.g. [@petruccione; @haake; @alicki]). In this paper we show that the generator of the master equation of a general quadratic system of $n$ interacting fermions which are coupled to a general set of Markovian baths, specified in terms of Lindblad operators which are linear in the fermionic variables - the so called quantum Liouville super-operator (or Liouvillean) - can be explicitly diagonalized in terms of $2n$ [*normal master modes*]{}, i.e. anticommuting super-operators which act on the Fock space of density operators. This can be understood as a complex (non-canonical) version of the Bogoliubov transformation [@lieb] lifted on the operator space, and has very powerful consequences: (i) The NESS of the master equation can be understood as the ‘ground state’ normal mode of the Liouvillean, whereas the long time relaxation rate is given by the eigenmode closest to the real axis. (ii) The covariance matrix of NESS can be computed explicitly in terms of the eigenvectors of $4n\times 4n$ antisymmetric complex matrix. It can be used to completely express physical observables in NESS, such as particle/spin densities, currents, etc. We demonstrate the power of this novel method by applying it to the problem of heat and spin transport far from equilibrium in nearest neighbor Heisenberg XY spin $1/2$ chains subject to a transverse magnetic field. As a result we reproduce [*ballistic transport*]{} in the [*integrable*]{} spatially homogeneous case (see e.g. [@zotos; @saito; @hartmann; @mejia05; @mejia07; @dhar; @prosenjpa] for related recent studies of quantum thermal conductivity in one dimension), and predict [*ideally insulating*]{} behaviour (at all temperatures) in a disordered case of spatially random interactions/field. Apart from obtaining numerical results which go by far beyond what was so far accessible by direct numerical solution of the many-particle Lindblad equation, either directly or by means of quantum trajectories [@petruccione], we also obtain two notable analytical results in the spatially homogeneous (non-disordered) case: (i) We compute the spectral gap of the Liouvillean i.e. the rate of of relaxation to the NESS and show that it scales with the inverse cube of the chain length. (ii) We construct [*evanescent*]{} normal master modes of the Liouvillean, for long chains, by which we explain quantitatively the exponential falloff of energy density or temperature profiles near the bath contacts. The paper is organized as follows. In section \[sect:method\] we shall outline a general method for the diagonalization of the Liouvillean super-operator for finite quadratic open Fermi systems and an explicit construction of NESS. In section \[sect:trivia\] we illustrate the method by working out a simple example of a single fermion or a two level quantum system in a bath. In section \[sect:nontrivia\] we demonstrate the usefulness of the new method by applying it to quantum transport in XY spin chains. In section \[sect:conc\] we discuss possible alternative applications and generalizations of the method and reach some conclusions. General method of solution for the Lindblad equation {#sect:method} ==================================================== The general master equation governing time evolution of the density matrix $\rho(t)$ of an open quantum system, preserving trace and positivity of $\rho$, can be written in the Lindblad form [@lindblad; @alicki] as (we set $\hbar=1$) $$\frac{{ {\rm d} }\rho }{{ {\rm d} }t} = {{\hat {\cal L}}}\rho := -{ {\rm i} }[H,\rho] + \sum_{\mu} \left(2 L_\mu \rho L_\mu^\dagger - \{L_\mu^\dagger L_\mu,\rho\} \right) \label{eq:lind}$$ where $H$ is a Hermitian operator (Hamiltonian), $[x,y]:=xy-yx$, $\{x,y\}:=xy+yx$, and $L_\mu$ are arbitrary operators representing couplings to different baths (at possibly different values of thermodynamic potentials). We are now going to describe a general method of explicit solution of (\[eq:lind\]) for a [*quadratic*]{} system of $n$ fermions (or spins $1/2$) with [*linear*]{} bath operators $$\begin{aligned} H &=& \sum_{j,k=1}^{2n} w_j H_{jk} w_k = {{\underline{w}}} \cdot {{\mathbf{H}}}\, {{\underline{w}}} \label{eq:hamil} \\ L_\mu &=& \sum_{j=1}^{2n} l_{\mu,j} w_j = {{\underline{l}}}_\mu \cdot {{\underline{w}}}\ \label{eq:lindb}\end{aligned}$$ where $w_j$, $j=1,2,\ldots,2n$, are abstract [*Hermitian*]{} Majorana operators satisfying the anti-commutation relations $$\{w_j,w_k\} = 2\delta_{j,k} \qquad j,k =1,2,\ldots, 2n$$ and generate a Clifford algebra. Thus, $2n \times 2n$ matrix ${{\mathbf{H}}}$ can be chosen to be antisymmetric ${{\mathbf{H}}}^T = -{{\mathbf{H}}}$. Throughout this paper ${{\underline{x}}}=(x_1,x_2,\ldots)^T$ will designate a vector (column) of appropriate scalar valued or operator valued symbols $x_k$. Two notable examples, to which our formalism is immediately applicable, are: (i) canonical fermions $c_m$, $m=1,2,\ldots, n$, $$w_{2m-1}= c_m + c_m^\dagger \qquad w_{2m} = { {\rm i} }(c_m- c^\dagger_m) \label{eq:physfermi}$$ or (ii) spins $1/2$ with canonical Pauli operators $\vec{\sigma}_m$, $m=1,2,\ldots, n$, $$w_{2m-1} = \sigma^{{\rm x}}_m \prod_{m'<m} \sigma^{{\rm z}}_{m'} \qquad w_{2m} = \sigma^{{\rm y}}_m \prod_{m'<m} \sigma^{{\rm z}}_{m'} \label{eq:jordan}$$ Here we are not concerned with physical criteria for the validity of the so-called Markovian approximation under which eq. (\[eq:lind\]) is derived, so we shall make no assumptions on the smallness of the bath coupling constants $l_{\mu,j}$. We merely consider the Lindblad equation (\[eq:lind\]) as a possible parametrization of an important subset of [*Markovian*]{} completely positive quantum channels and demonstrate its complete solvability for quadratic systems. Note that generalization of our formalism to [*explicitly time dependent*]{} Hamiltonians $H(t)$ and Lindblad operators $L_\mu(t)$, generating more general and possibly non-Markovian open system dynamics, is straightforward. See e.g. [@wolf] for a discussion of [*Markovianity*]{}. Fock space of operators ----------------------- We begin by associating a Hilbert space structure $x \to {{\vert x \rangle}}$ to a linear $2^{2n}=4^n$ dimensional space ${\cal K}$ of operators, with a canonical basis ${{\vert P_{{{\underline{\alpha}}}} \rangle}}$ with $$P_{\alpha_1,\alpha_2,\ldots,\alpha_{2n}} := w_1^{\alpha_1}w_2^{\alpha_2}\cdots w_{2n}^{\alpha_{2n}} \qquad \alpha_j\in\{ 0,1\}$$ [*orthonormal*]{} with respect to an inner product $${\langle x \vert y \rangle} = 2^{-n} \tr x^\dagger y$$ The form of the canonical basis of the operator space ${\cal K}$ suggests that it is just a usual Fock space with an unusual physical interpretation. Namely we can define the following set of $2n$ adjoint [*annihilation linear maps*]{} $\hat{c}_j$ over ${\cal K}$ $${ {\hat c} }_j {{\vert P_{{{\underline{\alpha}}}} \rangle}} = \delta_{\alpha_j,1} {{\vert w_j P_{{{\underline{\alpha}}}} \rangle}} \label{eq:defanih}$$ and derive the actions of their Hermitian adjoints - the [*creation linear maps*]{} $\hat{c}^\dagger$, ${{\langle P_{{{\underline{\alpha}}}'} \vert}}{ {\hat c} }^\dagger_j{{\vert P_{{{\underline{\alpha}}}} \rangle}} = {{\langle P_{{{\underline{\alpha}}}} \vert}}{ {\hat c} }_j{{\vert P_{{{\underline{\alpha}}}'} \rangle}}^* = \delta_{\alpha'_j,1} {\langle P_{{{\underline{\alpha}}}} \vert w_j P_{{{\underline{\alpha}}}'} \rangle}^*= \delta_{\alpha_j,0} {\langle P_{{{\underline{\alpha}}}'} \vert w_j P_{{{\underline{\alpha}}}} \rangle} $: $${ {\hat c} }^\dagger_j {{\vert P_{{{\underline{\alpha}}}} \rangle}} = \delta_{\alpha_j,0} {{\vert w_j P_{{{\underline{\alpha}}}} \rangle}}$$ Straightforward inspection then shows that they satisfy the canonical anticommutation relations $$\{{ {\hat c} }_j,{ {\hat c} }_k\} = 0 \qquad \{{ {\hat c} }_j,{ {\hat c} }_k^\dagger\} = \delta_{j,k} \qquad j,k=1,2,\ldots, 2n$$ The key is now to realize that the quantum Liouville map ${{\hat {\cal L}}}$ defined by eqs. (\[eq:lind\],\[eq:hamil\],\[eq:lindb\]) can be written as a quadratic form in [*adjoint Fermi maps*]{} ${ {\hat c} }_j,{ {\hat c} }^\dagger_j$ (or for short, [*a-fermions*]{}). [^1]\ \ First, we consider the unitary part of Liouvillean $${{\hat {\cal L}}}_0 \rho := -{ {\rm i} }[H,\rho] \label{eq:exprunitary}$$ Since ${\cal K}$ is a Lie algebra, one defines the [*adjoint representation*]{} of a Lie derivative for an arbitrary $A\in {\cal K}$ back on ${\cal K}$ as, $\ad A {{\vert B \rangle}} := {{\vert [A,B] \rangle}}$. It is now straightforward to compute the action of a Lie derivative of a product of two Majorana operators on an arbitrary basis element $$\begin{aligned} \ad w_j w_k {{\vert P_{{\underline{\alpha}}} \rangle}} &=& {{\vert w_j w_k P_{{\underline{\alpha}}} \rangle}} - {{\vert P_{{\underline{\alpha}}} w_j w_k \rangle}} = \nonumber \\ &=& 2 (\delta_{\alpha_j,1}\delta_{\alpha_k,0} + \delta_{\alpha_j,0}\delta_{\alpha_k,1}){{\vert w_j w_k P_{{\underline{\alpha}}} \rangle}} = \nonumber \\ &=& 2 ({ {\hat c} }_j { {\hat c} }^\dagger_k + { {\hat c} }^\dagger_j { {\hat c} }_k) {{\vert P_{{\underline{\alpha}}} \rangle}} = 2 ({ {\hat c} }^\dagger_j { {\hat c} }_k - { {\hat c} }^\dagger_k{ {\hat c} }_j) {{\vert P_{{\underline{\alpha}}} \rangle}}\end{aligned}$$ Extending this relation by linearity to an arbitrary element of ${\cal K}$, it follows that for an arbitrary quadratic Hamiltonian (\[eq:hamil\]) its Lie derivative has a very similar quadratic form in a-Fermi maps $${{\hat {\cal L}}}_0 = -{ {\rm i} }\ad H = -4{ {\rm i} }\sum_{j,k=1}^{2n} { {\hat c} }^\dagger_j H_{jk} { {\hat c} }_k = -4{ {\rm i} }\, {{\underline{{ {\hat c} }}}}^\dagger\cdot {{\mathbf{H}}}\,{{\underline{{ {\hat c} }}}} \label{eq:unitary}$$ It is worth stressing here that for an arbitrary (complex) matrix ${{\mathbf{H}}}$, ${{\hat {\cal L}}}_0$ (\[eq:unitary\]) conserves the total number of a-fermions ${{\hat {\cal N}}}:= \sum_{j} { {\hat c} }^\dagger_j { {\hat c} }_j = {{\underline{{ {\hat c} }}}}^\dagger\cdot{{\underline{{ {\hat c} }}}}$, namely $[{{\hat {\cal L}}}_0,{{\hat {\cal N}}}] = 0$.\ \ Second, we consider the action of the Lindblad maps $${{\hat {\cal L}}}_\mu \rho := 2 L_\mu \rho L_\mu^\dagger - \{L_\mu^\dagger L_\mu,\rho\} = \sum_{j,k=1}^{2n} l_{\mu,j} l_{\mu,k}^* {{\hat {\cal L}}}_{j,k}\rho \label{eq:exprlindb}$$ where we write ${{\hat {\cal L}}}_{j,k}\rho := 2 w_j \rho w_k - w_k w_j \rho - \rho w_k w_j$. Again we proceed by computing the actions of ${{\hat {\cal L}}}_{j,k}$ on elements of the canonical basis of operator Fock space ${\cal K}$. In order to do so, it is crucial to observe that the question whether $w_j$ commutes or anticommutes with $P_{{{\underline{\alpha}}}}$ depends on the number of a-fermions $|{{\underline{\alpha}}}|:=\sum_{k=1}^{2n} \alpha_k$ in ${{\vert P_{{{\underline{\alpha}}}} \rangle}}$, namely $P_{{{\underline{\alpha}}}}w_j = (-1)^{|{{\underline{\alpha}}}|+\alpha_j} w_j P_{{{\underline{\alpha}}}}$, and hence $${{\hat {\cal L}}}_{j,k} {{\vert P_{{{\underline{\alpha}}}} \rangle}} = \left[2(-1)^{|{{\underline{\alpha}}}|+\alpha_k} w_j w_k - w_k w_j - (-1)^{\alpha_j+\alpha_k} w_k w_j\right] {{\vert P_{{{\underline{\alpha}}}} \rangle}} \label{eq:Ljk1}$$ Observing that $$\begin{aligned} \phantom{(-1)^{\alpha_j}}{{\vert w_j P_{{{\underline{\alpha}}}} \rangle}} &=& ({ {\hat c} }^\dagger_j + { {\hat c} }_j){{\vert P_{{{\underline{\alpha}}}} \rangle}} \\ (-1)^{\alpha_j} {{\vert w_j P_{{{\underline{\alpha}}}} \rangle}} &=& ({ {\hat c} }^\dagger_j - { {\hat c} }_j){{\vert P_{{{\underline{\alpha}}}} \rangle}} \\ (-1)^{|{{\underline{\alpha}}}|} {{\vert P_{{{\underline{\alpha}}}} \rangle}} &=& \exp({ {\rm i} }\pi{{\hat {\cal N}}}) {{\vert P_{{{\underline{\alpha}}}} \rangle}}\end{aligned}$$ one derives from (\[eq:Ljk1\]) the general expression for ${{\hat {\cal L}}}_{j,k}$ $$\begin{aligned} {{\hat {\cal L}}}_{j,k} &=& \left(\hat{\one}+\exp({ {\rm i} }\pi{{\hat {\cal N}}})\right)\left(2 { {\hat c} }^\dagger_j { {\hat c} }^\dagger_k - { {\hat c} }^\dagger_j { {\hat c} }_k - { {\hat c} }^\dagger_k { {\hat c} }_j\right) \nonumber \\ &+& \left(\hat{\one}-\exp({ {\rm i} }\pi{{\hat {\cal N}}})\right)\left(2 { {\hat c} }_j { {\hat c} }_k - { {\hat c} }_j { {\hat c} }^\dagger_k - { {\hat c} }_k { {\hat c} }^\dagger_j\right)\end{aligned}$$ Obviously, the maps ${{\hat {\cal L}}}_{j,k}$, and hence also the total Lindblad part of Liouvillean $\sum_\mu{{\hat {\cal L}}}_\mu$, do not conserve the number of a-fermions. But they conserve its [*parity*]{} i.e. the product of any two creation/annihilation a-Fermi maps commutes with the parity operation ${{\hat {\cal P}}}= \exp({ {\rm i} }\pi{{\hat {\cal N}}})$, with respect to which the operator space can be decomposed into a direct sum ${\cal K} = {\cal K}^+ \oplus {\cal K}^-$, and even/odd operator spaces are orthogonally projected as ${\cal K}^{\pm} = (\hat{\one} \pm \exp({ {\rm i} }\pi{{\hat {\cal N}}})){\cal K}$. Thus the positive parity subspace ${\cal K}^+$ is a linear space spanned by ${{\vert P_{{{\underline{\alpha}}}} \rangle}}$ with [*even*]{} $|{{\underline{\alpha}}}|$. All the maps ${{\hat {\cal L}}}_{j,k}$ now act separately on ${\cal K}^\pm$, ${{\hat {\cal L}}}_{j,k} {\cal K}^\pm \subseteq {\cal K}^\pm$. For example, the maps defined on even parity subspace are indeed quadratic in a-fermions $${{\hat {\cal L}}}_{j,k}\vert_{{\cal K}^+} = 4 { {\hat c} }^\dagger_j { {\hat c} }^\dagger_k - 2 { {\hat c} }^\dagger_j { {\hat c} }_k - 2 { {\hat c} }^\dagger_k { {\hat c} }_j \label{eq:lindbpart}$$ In this paper we shall focus on physical observables which are products of an [*even*]{} number of Majorana fermions – operators $w_j$ – so we shall in the following discuss only Liouville dynamics on the subspace ${\cal K}^+$. The extension to the dynamics of [*odd*]{} observables should be straightforward. Putting the results (\[eq:exprunitary\],\[eq:unitary\],\[eq:exprlindb\],\[eq:lindbpart\]) together we arrive at the final compact quadratic representation of the Liouvillean ${{\hat {\cal L}}}_+ := {{\hat {\cal L}}}\vert_{{\cal K}^+}$ $${{\hat {\cal L}}}_+ = -2\, {{\underline{{ {\hat c} }}}}^\dagger\cdot(2{ {\rm i} }{{\mathbf{H}}} + {{\mathbf{M}}} + {{\mathbf{M}}}^T)\,{{\underline{{ {\hat c} }}}} + 2\,{{\underline{{ {\hat c} }}}}^\dagger\cdot ({{\mathbf{M}}}-{{\mathbf{M}}}^T)\,{{\underline{{ {\hat c} }}}}^\dagger \label{eq:liouv1}$$ where ${{\mathbf{M}}}$ is a complex Hermitian matrix parametrizing the Lindblad operators $$M_{jk} = \sum_{\mu} l_{\mu,j} l_{\mu,k}^*$$ Reduction to normal master modes -------------------------------- Next we want to show that the representation (\[eq:liouv1\]) allows us to reduce it further by a linear transformation of the set of maps $\{{ {\hat c} }_j,{ {\hat c} }_j^\dagger; j=1,2,\ldots,2n\}$ to [*normal master modes*]{} (NMM) in terms of which the complete spectrum of the Liouvillean, as well as its eigenvectors, can be explicitly constructed; in particular the zero-mode eigenvector which is just the physically relevant NESS. In fact we proceed in analogy to Lieb [*et al.*]{} [@lieb] and define $4n$ adjoint Hermitian Majorana maps ${ {\hat a} }_r = { {\hat a} }_r^\dagger$, $r=1,2,\ldots,4n$: $${ {\hat a} }_{2j-1} = \frac{1}{\sqrt{2}}({ {\hat c} }_j + { {\hat c} }^\dagger_j) \qquad { {\hat a} }_{2j} = \frac{{ {\rm i} }}{\sqrt{2}}({ {\hat c} }_j - { {\hat c} }^\dagger_j) \label{eq:aexpr}$$ satisfying the anti-commutation relations $$\{{ {\hat a} }_r,{ {\hat a} }_s\} = \delta_{r,s} \label{eq:clifa}$$ in terms of which the Liouvillean (\[eq:liouv1\]) can be rewritten as $${{\hat {\cal L}}}_+ = {{\underline{{ {\hat a} }}}}\cdot{{\mathbf{A}}}\,{{\underline{{ {\hat a} }}}} - A_0 \hat{\one} \label{eq:liouv2}$$ where ${{\mathbf{A}}}$ is an antisymmetric complex $4n\times 4n$ matrix with entries $$\begin{aligned} A_{2j-1,2k-1} &=&-2{ {\rm i} }H_{jk}-M_{jk}+M_{kj} \nonumber \\ A_{2j-1,2k} &=& \phantom{wj}2{ {\rm i} }M_{kj} \nonumber \\ A_{2j,2k-1} &=& -2{ {\rm i} }M_{jk} \nonumber \\ A_{2j,2k} &=&-2{ {\rm i} }H_{jk}+M_{jk}-M_{kj} \label{eq:explA}\end{aligned}$$ $\hat{\one}$ is an identity map over ${\cal K}$ and $A_0$ is a scalar $$A_0 = 2\sum_{j=1}^{2n} M_{jj} = 2\tr{{\mathbf{M}}}$$ Obviously, the [*bi-linear*]{} Liouvillean (\[eq:liouv2\]) cannot be brought to a normal form with a linear [*canonical*]{} transformation since the matrix ${{\mathbf{A}}}$ – which shall in the following be referred to as a [*shape matrix*]{} of Liouvillean – is not anti-Hermitian like in Hamiltonian systems. So we should proceed in more general terms. We first recall few facts about complex antisymmetric matrices of even dimension. If ${{\underline{v}}}$ is a [*right*]{} eigenvector ${{\mathbf{A}}}{{\underline{v}}} = \beta {{\underline{v}}}$ with complex eigenvalue $\beta$, then ${{\underline{v}}}$ is also a [*left*]{} eigenvector with eigenvalue $-\beta$, ${{\mathbf{A}}}^T {{\underline{v}}} = -{{\mathbf{A}}} {{\underline{v}}} = -\beta {{\underline{v}}}$. Hence eigenvalues always come in pairs $\beta,-\beta$. Let as assume that ${{\mathbf{A}}}$ can be [*diagonalized*]{}[^2], i.e. there exist $4n$ linearly independent vectors ${{\underline{v}}}_r,r=1,\ldots,4n$ with the corresponding eigenvalues $\beta_1,-\beta_1,\beta_2,-\beta_2,\ldots,\beta_{2n},-\beta_{2n}$, $${{\mathbf{A}}}{{\underline{v}}}_{2j-1} = \beta_j {{\underline{v}}}_{2j-1} \qquad {{\mathbf{A}}}{{\underline{v}}}_{2j} = -\beta_j {{\underline{v}}}_{2j} \label{eq:eigv}$$ ordered such that $\re\beta_1\ge \re\beta_2\ge \ldots \ge \re\beta_{2n} \ge 0.$ The $2n$ complex numbers $\beta_j$ shall be referred to as [*rapidities*]{}. It is easy to check that we can always choose and normalize ${{\underline{v}}}_r$ such that[^3] $${{\underline{v}}}_r \cdot {{\underline{v}}}_s = J_{rs} \quad \textrm{where} \quad {{\mathbf{J}}} := \sigma^{{{\rm x}}}\otimes {{\mathbf{I}}}_{2n} = \pmatrix{0 & 1 & 0 & 0 & \cdots \cr 1 & 0 & 0 & 0 & \cdots \cr 0 & 0 & 0 & 1 & \cdots \cr 0 & 0 & 1 & 0 & \cdots \cr \vdots &\vdots & \vdots & \vdots& \ddots \cr} \label{eq:norm}$$ Let ${{\mathbf{V}}}$ be $4n\times 4n$ matrix whose $r$th row is given by ${{\underline{v}}}_r$, $V_{rs} := v_{r,s}$. Then eqs. (\[eq:eigv\],\[eq:norm\]) rewrite as $$\begin{aligned} {{\mathbf{A}}}{{\mathbf{V}}}^T &=& {{\mathbf{V}}}^T{{\mathbf{D}}}\quad \textrm{where}\quad {{\mathbf{D}}} := {\rm diag}\{\beta_1,-\beta_1, \beta_2,-\beta_2,\ldots,\beta_{2n},-\beta_{2n}\} \label{eq:AVVD} \\ {{\mathbf{V}}} {{\mathbf{V}}}^T &=& {{\mathbf{J}}} \label{eq:VVJ}\end{aligned}$$ Expressing ${{\mathbf{V}}}^T$ in terms of (\[eq:VVJ\]) and plugging the result into eq. (\[eq:AVVD\]) we arrive at a very convenient canonical form of a generic complex antisymmetric matrix ${{\mathbf{A}}}$ $${{\mathbf{A}}} = {{\mathbf{V}}}^T {{\mathbf{\Lambda}}} {{\mathbf{V}}}\quad\textrm{where}\quad {{\mathbf{\Lambda}}} = {{\mathbf{D}}}{{\mathbf{J}}} = \pmatrix{0 & \beta_1 & 0 & 0 & \cdots \cr -\beta_1 & 0 & 0 & 0 & \cdots \cr 0 & 0 & 0 & \beta_2 & \cdots \cr 0 & 0 & -\beta_2 & 0 & \cdots \cr \vdots &\vdots & \vdots & \vdots& \ddots \cr} \label{eq:canform}$$ Now we apply decomposition (\[eq:canform\]) to the Liouvillean (\[eq:liouv2\]) $${{\hat {\cal L}}}_+ = {{\underline{{ {\hat a} }}}}\cdot {{\mathbf{V}}}^T {{\mathbf{\Lambda}}}{{\mathbf{V}}}{{\underline{{ {\hat a} }}}} - A_0\hat{\one} = ({{\mathbf{V}}}{{\underline{{ {\hat a} }}}})\cdot{{\mathbf{\Lambda}}}({{\mathbf{V}}}{{\underline{{ {\hat a} }}}}) - A_0\hat{\one} \label{eq:liouv4}$$ Let us define the NMM maps ${{\underline{{ {\hat b} }}}} := ({ {\hat b} }_1,{ {\hat b} }'_1,{ {\hat b} }_2,{ {\hat b} }'_2,\ldots,{ {\hat b} }_{2n},{ {\hat b} }'_{2n}) := {{\mathbf{V}}}{{\underline{{ {\hat a} }}}}$ or $${ {\hat b} }_j = {{\underline{v}}}_{2j-1}\cdot{{\underline{{ {\hat a} }}}} \qquad { {\hat b} }'_j = {{\underline{v}}}_{2j}\cdot{{\underline{{ {\hat a} }}}} \label{eq:bexpr}$$ We note that due to (\[eq:clifa\],\[eq:norm\]) NMM maps satisfy [*almost-canonical*]{} anti-commutation relations $$\{{ {\hat b} }_j,{ {\hat b} }_k\} = 0 \qquad \{{ {\hat b} }_j,{ {\hat b} }'_k\} = \delta_{j,k} \qquad \{{ {\hat b} }'_j,{ {\hat b} }'_k\}=0 \label{acar}$$ namely ${ {\hat b} }_j$ could be interpreted as annihilation map and ${ {\hat b} }'_j$ as a creation map of $j$th NMM, but we should note that ${ {\hat b} }'_j$ is in general [*not*]{} the Hermitian adjoint of ${ {\hat b} }_j$ [@thomas]. In terms of NMM the Liouvillean (\[eq:liouv4\]) now achieves a very convenient normal form $${{\hat {\cal L}}}_+ = -2\sum_{j=1}^{2n} \beta_j { {\hat b} }'_j { {\hat b} }_j - B_0 \hat{\one} \label{eq:liouv3}$$ where $B_0 = A_0 - \sum_{j=1}^{2n}\beta_j$. We shall later show that the constant $B_0$ is in fact equal to $0$. Non-equilibrium steady states and a complete spectrum of the Liouvillean ------------------------------------------------------------------------ The Liouvillean can always be represented in terms of a large but finite $4^n \times 4^n$ matrix. We shall now outline the procedure of complete construction of its spectrum in terms of NMM which are easy to calculate in terms of diagonalization of $4n \times 4n$ matrix ${{\mathbf{A}}}$ as described in the previous subsection. We proceed by constructing the Liouvillean ‘vacuum’. From the representation (\[eq:liouv1\]) it follows immediately that ${{\langle 1 \vert}} = {{\langle P_{(0,0\ldots,0)} \vert}}$ is left-annihilated by ${{\hat {\cal L}}}_+$, ${{\langle 1 \vert}}{{\hat {\cal L}}}_+ = 0$, or equivalently ${{\hat {\cal L}}}_+^\dagger {{\vert 1 \rangle}} = 0$. So we have just shown that $0$ is always an eigenvalue of ${{\hat {\cal L}}}_+$, hence there should also exist the corresponding right eigenvector $\ness$, normalized as ${\langle 1 \vert {\rm NESS} \rangle} = \tr \rho_{\rm NESS} = 1$, which represents physical NESS, i.e. stationary solutions of the Lindblad equation (\[eq:lind\]) $${{\hat {\cal L}}}_+\ness = 0$$ Let us define NMM number maps as ${{\hat {\cal N}}}_j := { {\hat b} }'_j { {\hat b} }_j$. From eqs. (\[acar\]) it follows that ${{\hat {\cal N}}}_j$ satisfy a projection property ${{\hat {\cal N}}}_j^2 = {{\hat {\cal N}}}_j$, so they are diagonalizable since no nontrivial Jordan block could satisfy the projection property. Furthermore, ${{\hat {\cal N}}}_j$ are mutually commuting $[{{\hat {\cal N}}}_j,{{\hat {\cal N}}}_k]=0$, so they can be simultaneously diagonalized and there should exist a vacuum state on which all ${{\hat {\cal N}}}_j$ have value 0. It follows from the stability of completely positive evolution (\[eq:lind\]) that all eigenvalues $\lambda$ of ${{\hat {\cal L}}}_+$ should obey $\re\lambda \le 0$, and since by assumption $\re\beta_j \ge 0$, ${{\langle 1 \vert}}$ and $\ness$ should be the left and right vacua which are simultaneously annihilated by NMM maps $${{\langle 1 \vert}} { {\hat b} }'_j = 0 \qquad { {\hat b} }_j \ness = 0 \label{eq:anihb}$$ and hence also ${{\hat {\cal N}}}_j\ness = 0$. Thus we have also shown that the NMM representation (\[eq:liouv3\]) is only consistent if $B_0=0$ so we find an interesting sum rule for rapidities $$\sum_{j=1}^{2n} \beta_j = 2\tr{{\mathbf{M}}}$$ The complete excitation spectrum and the corresponding left/right eigenvectors of the Liouvillean are given in terms of a sequence of $2n$ binary integers (NMM occupation numbers) ${{\underline{\nu}}}=(\nu_1,\nu_2,\ldots,\nu_{2n})$, $\nu_j\in\{0,1\}$, $${{\langle \Theta^{\rm L}_{{\underline{\nu}}} \vert}}{{\hat {\cal L}}}_+ = \lambda_{{{\underline{\nu}}}} {{\langle \Theta^{\rm L}_{{\underline{\nu}}} \vert}} \qquad {{\hat {\cal L}}}_+ {{\vert \Theta^{\rm R}_{{\underline{\nu}}} \rangle}} = \lambda_{{{\underline{\nu}}}} {{\vert \Theta^{\rm R}_{{\underline{\nu}}} \rangle}}$$ namely $$\begin{aligned} \lambda_{{\underline{\nu}}} &=& -2\sum_{j=1}^{2n} \beta_j \nu_j \label{eq:eval}\\ {{\langle \Theta^{\rm L}_{{\underline{\nu}}} \vert}} &=& {{\langle 1 \vert}}{{ {\hat b} }_{2n}}^{\nu_{2n}}\cdots {{ {\hat b} }_2}^{\nu_2}\,{{ {\hat b} }_1}^{\nu_1} \qquad {{\vert \Theta^{\rm R}_{{\underline{\nu}}} \rangle}} = {{ {\hat b} }_1}^{'\nu_1}\,{{ {\hat b} }_2}^{'\nu_2} \cdots {{ {\hat b} }_{2n}}^{' \nu_{2n}} \ness \label{eq:evec}\end{aligned}$$ where by construction, left and right eigenvectors satisfy the bi-orthonormality relation ${\langle \Theta^{\rm L}_{{\underline{\nu'}}} \vert \Theta^{\rm R}_{{\underline{\nu}}} \rangle} = \delta_{{{\underline{\nu}}}',{{\underline{\nu}}}}$. The main general results: uniqueness of NESS, rate of relaxation to NESS, and expectation values of physical observables ------------------------------------------------------------------------------------------------------------------------ Given a [*physical observable*]{} $X\in {\cal K}^+$ and an [*arbitrary*]{} initial state with a density operator $\rho_0 \in {\cal K}$, the time dependent expectation value of $X$ can be written in terms of the spectral resolution of the Liouvillean, $$\exp(t {{\hat {\cal L}}}_+) = \sum_{{{\underline{\nu}}}} \exp(t \lambda_{{{\underline{\nu}}}}) {{\vert \Theta^{\rm R}_{{{\underline{\nu}}}} \rangle}}{{\langle \Theta^{\rm L}_{{{\underline{\nu}}}} \vert}} \label{eq:propag}$$ namely $${{\langle X(t)\rangle}} = \tr X\rho(t) = \tr\!\!\left[X\exp(t{{\hat {\cal L}}}_+)\rho_0\right] = \sum_{{{\underline{\nu}}}} \exp(t\lambda_{{{\underline{\nu}}}}){{\langle \Theta^{\rm L}_{{{\underline{\nu}}}} \vert}}\rho_0 X{{\vert \Theta^{\rm R}_{{{\underline{\nu}}}} \rangle}} \label{eq:timedeptexp}$$ We remind the reader that ${{\hat {\cal L}}}_+$ correctly represents physical Liouvillean only on the subspace ${\cal K}^+$ of operators with [*even*]{} number of a-fermions. However, since the dynamics is closed on ${\cal K}^+$ and test physical observable $X$ also belongs to ${\cal K}^+$ it follows that the component of $\rho_0$ from ${\cal K}^-$ does not contribute to the expectation value ${{\langle X(t)\rangle}}$. Given the exact and explicit constructions developed in this section we can now make the following rigorous and useful conclusions, assuming throughout that Liouvillean shape matrix ${{\mathbf{A}}}$ is diagonalizable:\ \ [**Theorem 1:**]{} NESS of Lindblad equation (\[eq:lind\]) is [*unique*]{} if and only if the rapidity spectrum $\{\beta_j\}$ does not contain $0$, in our ordering convention, if $\beta_{2n} \ne 0$. In the opposite case, if we have $d \ge 1$ vanishing rapidities, then we have a $2^d$ dimensional convex set of non-equilibrium steady states which can be spanned with ${{\vert \Theta^{\rm R}_{(0,\ldots,0,\nu_{1},\ldots,\nu_{d})} \rangle}}$.\ \ [**Theorem 2:**]{} An arbitrary initial state with a density operator $\rho_0 \in {\cal K}$ converges with time to NESS if and only if all rapidities have [*strictly positive*]{} real parts, $\re \beta_j > 0$. Then, the rate of exponential relaxation to NESS is given by the [*spectral gap*]{} $\Delta$ of the Liouvillean which equals $\Delta=2\re\beta_{2n}$.\ \ [**Theorem 3:**]{} Assume that the rapidity spectrum does not contain 0, i.e. $\beta_{2n}\ne 0$. Then the expectation value of any quadratic observable $w_j w_k$ in a (unique) NESS can be explicitly computed as $$\begin{aligned} {{\langle w_j w_k\rangle}}_{\rm NESS} &=& \delta_{j,k} + {{\langle 1 \vert}}{ {\hat c} }_j { {\hat c} }_k \ness = \label{eq:pairwise} \\ &=& \delta_{j,k} + \frac{1}{2}\sum_{m=1}^{2n} \biggl( v_{2m,2j-1} v_{2m-1,2k-1} - v_{2m,2j} v_{2m-1,2k} \nonumber \\ && \qquad\qquad- { {\rm i} }v_{2m,2j} v_{2m-1,2k-1} - { {\rm i} }v_{2m,2j-1} v_{2m-1,2k}\biggr) \label{eq:pairwise2}\end{aligned}$$ The statements of theorems 1 and 2 simply follow from exact and explicit spectral decomposition (\[eq:eval\],\[eq:evec\],\[eq:propag\]). The proof of theorem 3 is also straightforward: The first expression (\[eq:pairwise\]) follows from the definition of the annihilation maps (\[eq:defanih\]) and the explicit representation of the density operator of NESS, $\rho_{\rm NESS}$, in the canonical basis $P_{{{\underline{\alpha}}}}$. The second, very useful equality (\[eq:pairwise2\]) is then obtained by expressing ${ {\hat c} }_j$ thru (\[eq:aexpr\]) in terms of NMM maps (\[eq:bexpr\]) and using the annihilation relations (\[eq:anihb\]). The quadratic correlator of theorem 3 covers many physically interesting observables such as densities or currents. However if one needs expectation values of more general observables, e.g. an expectation value of a high order monomial ${{\langle P_{{{\underline{\alpha}}}}\rangle}}_{\rm NESS} = {{\langle 1 \vert}}{ {\hat c} }^{\alpha_1}_{1}{ {\hat c} }^{\alpha_2}_2\cdots{ {\hat c} }^{\alpha_{2n}}_{2n}\ness $, then one may use a [*Wick theorem*]{} and rewrite it as a sum of products of pair-wise contractions (\[eq:pairwise\]). Trivial example: A single fermion in a bath {#sect:trivia} =========================================== In order to illustrate the method and demonstrate convenience of the results derived in the previous section we first work out a simple example of a single fermion $n=1$ (or equivalently, an arbitrary qubit, a two-level quantum system), in a thermal bath. We take the most general single fermion Hamiltonian $H = -{ {\rm i} }h w_1 w_2 + {\rm const} = 2h c^\dagger c + {\rm const}'$ and the following bath operators (see e.g. [@haake; @wich]) $$L_1 = \frac{1}{2}\sqrt{\Gamma_1} (w_1 - { {\rm i} }w_2) = \sqrt{\Gamma_1} c \qquad L_2 = \frac{1}{2}\sqrt{\Gamma_2} (w_1 + { {\rm i} }w_2) = \sqrt{\Gamma_2} c^\dagger \label{eq:canlind}$$ where the ratio of coupling constants determine the bath temperature $T$, $\Gamma_2/\Gamma_1 = \exp(-2h/T)$. Leaving out the details of a straightforward calculation, simply following the steps of the previous section, we arrive at the following shape matrix of the Liouvillean (\[eq:liouv2\]) $${{\mathbf{A}}} = -h{{\mathbf{R}}} + {{\mathbf{B}}}_{\Gamma_+,\Gamma_-} \qquad A_0 = \Gamma_+$$ where $${{\mathbf{R}}} := \pmatrix{ 0 & 0 & 1 & 0 \cr 0 & 0 & 0 & 1 \cr \!\!-1 & 0 & 0 & 0 \cr 0 &\!\!\!-1 & 0 & 0} \quad {{\mathbf{B}}}_{\Gamma_+,\Gamma_-} := \pmatrix{ 0 & \frac{{ {\rm i} }}{2} \Gamma_+ &\!\!\!-\frac{{ {\rm i} }}{2}\Gamma_- & \frac{1}{2}\Gamma_- \cr \!\!-\frac{{ {\rm i} }}{2}\Gamma_+ & 0 & \frac{1}{2}\Gamma_- & \frac{{ {\rm i} }}{2}\Gamma_- \cr \frac{{ {\rm i} }}{2}\Gamma_- &\!\!\!-\frac{1}{2}\Gamma_- & 0 & \frac{{ {\rm i} }}{2}\Gamma_+ \cr \!\!-\frac{1}{2}\Gamma_- &\!\!\!-\frac{{ {\rm i} }}{2}\Gamma_- &\!\!\!-\frac{{ {\rm i} }}{2}\Gamma_+ & 0} \label{eq:canbath}$$ and $\Gamma_\pm := \Gamma_2 \pm \Gamma_1$. Further, we compute NMM rapidities $\beta_{1,2} = \frac{1}{2}\Gamma_+ \pm { {\rm i} }h$ and the eigenvector matrix $${{\mathbf{V}}} = \pmatrix{ \frac{\Gamma_-}{\Gamma_+} - 1 & { {\rm i} }\frac{\Gamma_-}{\Gamma_+} + { {\rm i} }& -{ {\rm i} }\frac{\Gamma_-}{\Gamma_+} + { {\rm i} }& \frac{\Gamma_-}{\Gamma_+} + 1 \cr -\frac{1}{4} & -\frac{{ {\rm i} }}{4} & -\frac{{ {\rm i} }}{4} & \frac{1}{4} \cr \frac{\Gamma_-}{\Gamma_+} + 1 & { {\rm i} }\frac{\Gamma_-}{\Gamma_+} - { {\rm i} }& { {\rm i} }\frac{\Gamma_-}{\Gamma_+} + { {\rm i} }& -\frac{\Gamma_-}{\Gamma_+} + 1 \cr \frac{1}{4} & \frac{{ {\rm i} }}{4} & -\frac{{ {\rm i} }}{4} & \frac{1}{4}}\qquad$$ Then, using theorem 3 we compute the expectation value of occupation number ${{\langle c^\dagger c\rangle}} = \frac{1}{2} - \frac{{ {\rm i} }}{2} {{\langle w_1 w_2\rangle}} = \Gamma_2/(\Gamma_1 + \Gamma_2)$ which is what we expect in canonical equilibrium. Non-trivial example: transport in quantum spin chains {#sect:nontrivia} ===================================================== Here we work out a physically more interesting example, namely we construct NESS for the magnetic and heat transport of a Heisenberg XY spin $1/2$ chain, with arbitrary – either homogeneous or positionally dependent (e.g. disordered) – nearest neighbour interaction $$H = \sum_{m=1}^{n-1} \left( J^{{\rm x}}_m \sigma^{{\rm x}}_m \sigma^{{\rm x}}_{m+1} + J^{{\rm y}}_m \sigma^{{\rm y}}_m \sigma^{{\rm y}}_{m+1}\right) + \sum_{m=1}^n h_m \sigma^{{\rm z}}_m \label{eq:hamsc}$$ which is coupled to [*two*]{} thermal/magnetic baths [*at the ends*]{} of the chain, generated by two pairs of canonical Lindblad operators [@wich] (similar to (\[eq:canlind\])) $$\begin{aligned} L_1 &=& \frac{1}{2}\sqrt{\Gamma_1^{\rm L}} \sigma^{-}_1 \qquad L_3 = \frac{1}{2}\sqrt{\Gamma_1^{\rm R}} \sigma^{-}_n \nonumber \\ L_2 &=& \frac{1}{2}\sqrt{\Gamma_2^{\rm L}} \sigma^{+}_1 \qquad L_4 = \frac{1}{2}\sqrt{\Gamma_2^{\rm R}} \sigma^{+}_n \label{eq:bathsc}\end{aligned}$$ where $\sigma^{\pm}_m = \sigma^{{\rm x}}_m \pm { {\rm i} }\sigma^{{\rm y}}_m$ and $\Gamma^{{\rm L},{\rm R}}_{1,2}$ are positive coupling constants related to bath temperatures/magnetizations, for example if spins were non-interacting the bath temperatures $T_{{\rm L},{\rm R}}$ would be given with $\Gamma^{{\rm L},{\rm R}}_2/\Gamma^{{\rm L},{\rm R}}_1 = \exp(-2h_{\rm 1,n}/T_{{\rm L},{\rm R}})$. Applying the inverse of Jordan-Wigner transformation (\[eq:jordan\]), $\sigma^{{\rm x}}_m = (-{ {\rm i} })^{m-1}\prod_{j=1}^{2m-1} w_j$, $\sigma^{{\rm y}}_m = (-{ {\rm i} })^{m-1}(\prod_{j=1}^{2m-2} w_j)w_{2m}$, we rewrite (\[eq:hamsc\],\[eq:bathsc\]) in terms of Majorana fermions $$\begin{aligned} H &=& -{ {\rm i} }\sum_{m=1}^{n-1}\left(J^{{\rm x}}_m w_{2m} w_{2m+1} - J^{{\rm y}}_m w_{2m-1}w_{2m+2}\right) -{ {\rm i} }\sum_{m=1}^n h_m w_{2m-1}w_{2m} \\ L_1 &=& \frac{1}{2}\sqrt{\Gamma_1^{\rm L}} (w_1 - { {\rm i} }w_2) \qquad L_3 = -\frac{(-{ {\rm i} })^n}{2}\sqrt{\Gamma_1^{\rm R}} (w_{2n-1} - { {\rm i} }w_{2n})W \nonumber \\ L_2 &=& \frac{1}{2}\sqrt{\Gamma_2^{\rm L}} (w_1 + { {\rm i} }w_2) \qquad L_4 = -\frac{(-{ {\rm i} })^n}{2}\sqrt{\Gamma_2^{\rm R}} (w_{2n-1} + { {\rm i} }w_{2n})W\end{aligned}$$ where $W=w_{1}w_{2}\cdots w_{2n}$ is a Casimir operator which commutes with all the elements of the Clifford algebra generated by $w_j$ and squares to unity $W^2=1$. Therefore, $W$ [*does not affect*]{} the action of bath operators (\[eq:exprlindb\]) where $L_\mu$ enter quadratically, so we find $$\begin{aligned} {{\hat {\cal L}}}_1 + {{\hat {\cal L}}}_2 &=& -\Gamma_+^{\rm L} ({ {\hat c} }^\dagger_1{ {\hat c} }_1 + { {\hat c} }^\dagger_2{ {\hat c} }_2) - 2{ {\rm i} }\Gamma_-^{\rm L} { {\hat c} }^\dagger_1{ {\hat c} }^\dagger_2 \nonumber \\ {{\hat {\cal L}}}_3 + {{\hat {\cal L}}}_4 &=& -\Gamma_+^{\rm R} ({ {\hat c} }^\dagger_{2n-1}{ {\hat c} }_{2n-1} + { {\hat c} }^\dagger_{2n}{ {\hat c} }_{2n}) - 2{ {\rm i} }\Gamma_-^{\rm R} { {\hat c} }^\dagger_{2n-1}{ {\hat c} }^\dagger_{2n}\end{aligned}$$ leading to the bath shape matrix (\[eq:canbath\]) identical to the single fermion case (\[eq:canlind\]). Again, carefully following the steps of section \[sect:method\], we derive the Liouvillean in the form (\[eq:liouv2\]) with $4n\times 4n$ shape matrix, which we write in a [*block tridiagonal*]{} form in terms of $4\times 4$ matrices as $${{\mathbf{A}}}= \pmatrix{ {{\mathbf{B}}}_{\rm L} - h_1 {{\mathbf{R}}} & {{\mathbf{R}}}_1 & {{\mathbf{0}}} & \cdots & {{\mathbf{0}}} \cr -{{\mathbf{R}}}^T_1 & - h_2 {{\mathbf{R}}} & {{\mathbf{R}}}_2 & \ddots & {{\mathbf{0}}} \cr {{\mathbf{0}}} & -{{\mathbf{R}}}^T_2 & -h_3 {{\mathbf{R}}} & & \vdots \cr \vdots & \ddots & & \ddots & {{\mathbf{R}}}_{n-1} \cr {{\mathbf{0}}} & {{\mathbf{0}}} & \cdots & -{{\mathbf{R}}}^T_{n-1} & {{\mathbf{B}}}_{\rm R} - h_n {{\mathbf{R}}} } \label{eq:bigA}$$ and $A_0= \Gamma_+^{\rm L} + \Gamma_+^{\rm R}$, where ${{\mathbf{B}}}_{\rm L}:={{\mathbf{B}}}_{\Gamma_+^{\rm L},\Gamma_-^{\rm L}}$, ${{\mathbf{B}}}_{\rm R}:={{\mathbf{B}}}_{\Gamma_+^{\rm R},\Gamma_-^{\rm R}}$ (in terms of (\[eq:canbath\])), with $\Gamma_{\pm}^{{\rm L},{\rm R}} := \Gamma_2^{{\rm L},{\rm R}}\pm\Gamma_1^{{\rm L},{\rm R}}$, and $${{\mathbf{R}}}_m := \pmatrix{ 0 & 0 & J^{{\rm y}}_m & 0 \cr 0 & 0 & 0 & J^{{\rm y}}_m \cr -J_m^{{\rm x}}& 0 & 0 & 0 \cr 0 & -J_m^{{\rm x}}& 0 & 0 }$$ We are not able to perform a complete diagonalization of the antisymmetric matrix ${{\mathbf{A}}}$ (\[eq:bigA\]) of the general XY model analytically. For example, even in the spatially homogeneous case $J^{{{\rm x}},{{\rm y}}}_m \equiv J^{{{\rm x}},{{\rm y}}}, h_m\equiv h$ it is not possible to proceed like in the classical harmonic oscillator chain where the corresponding matrix is a sum of a Toeplitz and a bordered matrix [@rieder]. Namely, in our case ${{\mathbf{A}}}$ is a sum of a [*block Toeplitz*]{} and [*block bordered*]{} matrix and its explicit exact diagonalization remains an open problem. However, we stress that even relying on numerical diagonalization of ${{\mathbf{A}}}$ yielding a set of rapidities $\beta_j$ and properly normalized eigenvector matrix ${{\mathbf{V}}}$, represents a dramatic progress with respect to previously existing numerical methods which needed diagonalization of matrices which were exponentially large in $n$. We shall later derive some exact theoretical and analytical results, explaining results of exact numerical computations, in the special case of a [*homogeneous*]{} transverse Ising chain (subsection \[sect:ti\]), and the case of a [*disordered*]{} XY chain (subsection \[sect:disord\]) for which we shall relate NMM to the problem of Anderson localization in one dimension, Let us continue by discussing transport observables in the spin chain whose expectation values in NESS are easy to calculate. Note that the bulk Hamiltonian (\[eq:hamsc\]) can be written in terms of the two-body [*energy density*]{} operator $$\!\!\!\!\!\!\!\!\!\!\!\!\!\!\!\!\!\!\!\!\!\!\!\!\!\!\!\!\!\! H_m = -{ {\rm i} }J^{{\rm x}}_m w_{2m} w_{2m+1} + { {\rm i} }J^{{\rm y}}_m w_{2m-1}w_{2m+2} -\frac{{ {\rm i} }h_m}{2}w_{2m-1}w_{2m}-\frac{{ {\rm i} }h_{m+1}}{2}w_{2m+1}w_{2m+2} \label{eq:hdens}$$ as $H=\sum_m H_m$. One can derive the local [*energy current*]{} $Q_m={ {\rm i} }[H_m,H_{m+1}]$ from the [*continuity equation*]{} $$({ {\rm d} }/{ {\rm d} }t){{\langle H_m\rangle}} = \tr H_m { {\rm d} }\rho/{ {\rm d} }t = {{\langle { {\rm i} }[H,H_m]\rangle}} = -{{\langle Q_{m}\rangle}} + {{\langle Q_{m-1}\rangle}} \label{eq:cont}$$ where $Q_m := { {\rm i} }[H_{m},H_{m+1}] $ $$\begin{aligned} Q_m = &&2{ {\rm i} }(2J^{{\rm y}}_m J^{{\rm x}}_{m+1} w_{2m-1}w_{2m+3} + 2J^{{\rm x}}_mJ^{{\rm y}}_{m+1} w_{2m}w_{2m+4} - \nonumber\\ &&-J^{{\rm y}}_m h_{m+1} w_{2m-1}w_{2m+1} - J^{{\rm x}}_m h_{m+1} w_{2m}w_{2m+2}- \nonumber\\ &&-h_{m+1}J^{{\rm x}}_{m+1}w_{2m+1}w_{2m+3}-h_{m+1}J^{{\rm y}}_{m+1}w_{2m+2}w_{2m+4}) \label{eq:hcurr}\end{aligned}$$ The validity of the above continuity equation (\[eq:cont\]) depends on two assumptions only: (i) All Lindblad operators $L_\mu$ [*commute*]{} with the density $H_m$ in the [*bulk*]{}, $2 \le m \le n-2$ (second equality sign), and (ii) $[H_m,H_{m'}] = 0$ if $|m-m'| \ge 2$ (third equality sign). Using eq. (\[eq:pairwise2\]) of theorem 3 we can now compute NESS expectation values of energy density $H_m$ and energy current $Q_m$, and also of somewhat simpler [*spin density*]{} $$\sigma^{{\rm z}}_m = -{ {\rm i} }w_{2m-1}w_{2m} \label{eq:sdens}$$ and [*spin current*]{} $$S_m = \sigma^{{\rm x}}_{m}\sigma^{{\rm y}}_{m+1}-\sigma^{{\rm y}}_{m}\sigma^{{\rm x}}_{m+1} = -{ {\rm i} }w_{2m}w_{2m+2} -{ {\rm i} }w_{2m-1}w_{2m+1} \label{eq:scurr}$$ which are all quadratic in $w_j$. Note, however, that the spin density satisfies continuity equation $({ {\rm d} }/{ {\rm d} }t){{\langle \sigma^{{\rm z}}_m\rangle}} = -{{\langle S_{m}\rangle}} + {{\langle S_{m-1}\rangle}}$ only in the isotropic case, when $J^{{\rm x}}_m \equiv J^{{\rm y}}_m$. Homogeneous transverse Ising chain {#sect:ti} ---------------------------------- Here we limit our discussion to the spatially homogeneous case $J_n^{{{\rm x}},{{\rm y}}}\equiv J^{{{\rm x}},{{\rm y}}},h_n\equiv h$. We shall show that in this case the eigenvalue problem $${{\mathbf{A}}}{{\underline{v}}} = \beta{{\underline{v}}} \label{eq:evA}$$ for (\[eq:bigA\]) can be most easily and elegantly treated if formulated in terms of an abstract inelastic scattering problem in one dimension, with asymptotic solutions given in terms of free normal modes for the infinite translationally invariant chain ${{\underline{v}}}=(\ldots, {{\underline{u}}} \xi^{m-1},{{\underline{u}}} \xi^{m}, {{\underline{u}}} \xi^{m+1},\ldots)^T$, where $\xi$ is a complex [*quasi–momentum*]{} (Bloch) parameter and ${{\underline{u}}}$ is a 4-dimensional amplitude vector satisfying the condition $$(-{{\mathbf{R}}}^T_1 \xi^{-1} - h {{\mathbf{R}}} + {{\mathbf{R}}}_1 \xi - \beta {{\mathbf{I}}}_4) {{\underline{u}}} = 0 \label{eq:freemode}$$ and the baths playing the role of inelastic (absorbing) scatterers at the edges of a finite lattice. The ‘elastic’ (Hamiltonian) version of this trick has been used to compute temporal correlation functions in kicked Ising chain [@ProsenPTPS]. The singularity condition for the free mode equation (\[eq:freemode\]) results, for a general homogeneous $XY$ model, in eight [*master bands*]{} - different values of momenta $\xi$ for each value of the spectral parameter (rapidity) $\beta$. In order to simplify the discussion - which will still get rather involved - we shall in the following restrict ourselves to the transverse Ising model $J^{{\rm x}}= J, J^{{\rm y}}=0$. In this case we find just two master bands with simple dispersion relations $$\xi_{\pm}(\beta) = \frac{h^2 + J^2 + \beta^2 \pm \omega(\beta)}{2 h J} \quad \omega(\beta):=\sqrt{(h^2+J^2+\beta^2)^2 - (2 h J)^2} \label{eq:dispersion}$$ but each band is doubly-degenerate, since the corresponding amplitude problem (\[eq:freemode\]) has two linearly independent solutions $$\!\!\!\!\!\!\!\!\!\!\!\!\!\!\!\!\!\!\!\! {{\underline{u}}}^\pm_{1}(\beta) = \pmatrix{ -h (h^2 - J^2+\beta^2 \pm \omega) \cr 0 \cr \beta ( h^2 + J^2 + \beta^2 \pm \omega) \cr 0 } \quad {{\underline{u}}}^\pm_{2}(\beta) = \pmatrix{ 0 \cr -h (h^2 - J^2+\beta^2 \pm \omega)\cr 0 \cr \beta ( h^2 + J^2 + \beta^2) \pm \omega) \label{eq:freemodes} }$$ Naively speaking, $\xi_-$ represents left moving and $\xi_+$ right moving free modes, each having two possible polarizations. Note that $\xi_- \xi_+ = 1$. For a general complex $\beta$ we shall choose the branch of square root $\omega(\beta)$ (\[eq:dispersion\]) for which $|\xi_-| \le 1$. Let us now write the scattering problem on the [*left*]{} bath in terms of an ansatz $${{\underline{v}}} = \pmatrix{ {{\underline{u}}}_{\rm L} \cr \psi_1^- {{\underline{u}}}^-_1 + \psi_2^- {{\underline{u}}}^-_2 + \psi_1^+ {{\underline{u}}}^+_1 + \psi_2^+ {{\underline{u}}}^+_2 \cr (\psi_1^- {{\underline{u}}}^-_1 + \psi_2^- {{\underline{u}}}^-_2)\xi_- + (\psi_1^+ {{\underline{u}}}^+_1 + \psi_2^+ {{\underline{u}}}^+_2)\xi_+ \cr (\psi_1^- {{\underline{u}}}^-_1 + \psi_2^- {{\underline{u}}}^-_2)\xi_-^2 + (\psi_1^+ {{\underline{u}}}^+_1 + \psi_2^+ {{\underline{u}}}^+_2)\xi_+^2 \cr \vdots} \label{eq:scatL}$$ where ${{\underline{u}}}_{\rm L}$ represents a $4$-dimensional vector of left-most eigenvector components, $\psi^-_{1,2}$ are the amplitudes of (known) incident free modes, and $\psi^+_{1,2}$ are the amplitudes of the scattered, outgoing free modes. Plugging the scattering ansatz to the eigenproblem (\[eq:evA\]), the first two rows of ${{\mathbf{A}}}$ (\[eq:bigA\]) result in 6 linearly independent equations for 6 unknowns $\psi^+_{1,2},{{\underline{u}}}_{\rm L}$. Eliminating four variables ${{\underline{u}}}_{\rm L}$ we finally arrive to the non-unitary $2 \times 2$ S-matrix $$\pmatrix{ \psi^+_1 \cr \psi^+_2} = {{\mathbf{S}}}^{\rm L} \pmatrix{ \psi^-_1 \cr \psi^-_2} \label{eq:SL} \\$$ with $$\begin{aligned} S^{\rm L}_{11} &=& \tau^{-1} \beta^2 (-(\GLp)^4+4 (\GLp)^2 (\beta^2-3h^2) -16 h (h J^2 + { {\rm i} }\GLm \omega)) \nonumber \\ S^{\rm L}_{12} &=& \tau^{-1} \beta ( (\GLp)^3 + 8{ {\rm i} }\GLm h \beta + 4 \GLp (h^2 - \beta^2)) (2{ {\rm i} }\omega) \nonumber \\ S^{\rm L}_{21} &=& \tau^{-1} \beta ( (\GLp)^3 - 8{ {\rm i} }\GLm h \beta + 4 \GLp (h^2 - \beta^2)) (-2{ {\rm i} }\omega) \nonumber \\ S^{\rm L}_{22} &=& \tau^{-1} \beta^2 (-(\GLp)^4+4 (\GLp)^2 (\beta^2-3h^2) -16 h (h J^2 - { {\rm i} }\GLm \omega)) \label{eq:Sexplicit} \\ \tau &:=& (\GLp)^4 \beta^2 + 8 \beta^2 (h^4 + (J^2 + \beta^2)(J^2 + \beta^2 - \omega) + h^2 (2 \beta^2 - \omega)) \nonumber \\ &-& 2(\GLp)^2 (h^4 + J^4 + 3\beta^4 + J^2 (2 \beta^2-\omega) - \beta^2\omega + h^2 (\omega - 2 J^2 - 4\beta^2)) \nonumber \end{aligned}$$ Similarly, one can solve the scattering problem from the [*right*]{} bath with the scattering ansatz $${{\underline{v}}} = \pmatrix{ \vdots \cr (\psi_1^+ {{\underline{u}}}^+_1 + \psi_2^+ {{\underline{u}}}^+_2)\xi_+^{-2} + (\psi_1^- {{\underline{u}}}^-_1 + \psi_2^- {{\underline{u}}}^-_2)\xi_-^{-2} \cr (\psi_1^+ {{\underline{u}}}^+_1 + \psi_2^+ {{\underline{u}}}^+_2)\xi_+^{-1} + (\psi_1^- {{\underline{u}}}^-_1 + \psi_2^- {{\underline{u}}}^-_2)\xi_-^{-1} \cr \psi_1^+ {{\underline{u}}}^+_1 + \psi_2^+ {{\underline{u}}}^-_2 + \psi_1^- {{\underline{u}}}^-_1 + \psi_2^- {{\underline{u}}}^-_2 \cr {{\underline{u}}}_{\rm R}}$$ defining the right S-matrix $$\pmatrix{ \psi^-_1 \cr \psi^-_2} = {{\mathbf{S}}}^{\rm R} \pmatrix{ \psi^+_1 \cr \psi^+_2}$$ Note that since the two directions of free modes (\[eq:freemodes\]) do not have left-right symmetry an explicit expression for $S^{\rm R}$ is considerably more complicated than (\[eq:Sexplicit\]) and shall not be written out here. We shall now show that there exist two qualitatively different types of NMM - complex rapidities $\beta$ solving (\[eq:evA\]) for sufficiently [*large*]{} $n$. ![ Rapidities $\beta_j$ (black dots) for a transverse Ising chain with $J=1.5,h=1$ and bath couplings $\Gamma^{\rm L}_1=1,\Gamma^{\rm L}_2=0.6$, $\Gamma^{\rm R}_1=1,\Gamma^{\rm R}_2=0.3$, for three different sizes $n=6$ (upper), $n=30$ (middle), and $n=150$ (lower panel). Big blue/red dots indicate positions of evanescent rapidities (solutions of eq.(\[eq:4order\])) for the left/right bath. \[fig:rapid\]](rapid.eps) First, we shall discuss the so called [*evanescent normal master modes*]{}. These are characterized with amplitudes (\[eq:scatL\]) which decay exponentially with the distance from – say the left – bath, so the other – the right boundary condition becomes physically irrelevant in the limit $n\to \infty$. Such solutions $\psi^{+}_{1,2} = 0$ of eq. (\[eq:SL\]) exist exactly when the determinant of S-matrix vanishes $\det S^{\rm L} = 0$. Using (\[eq:Sexplicit\]) the determinant can be written as $\det S^{\rm L} = (\beta/\tau)^2 p^{\rm L}(\beta)$ where[^4] $$\begin{aligned} \!\!\!\!\!\!\!\!\!\!\!\!\!\!\!p^{\rm L}(\beta) &=& (\GLp)^8 \beta^2 - 4(\GLp)^6 ((h^2\!-\!J^2)^2 + (2J^2\!-\!4h^2)\beta^2 + 3\beta^4) \nonumber \\ &-& 16 (\GLp)^4(2 h^2 (h^2\!-\!J^2)^2 - (7h^4\!-\!6 h^2J^2\!+\!2 J^4)\beta^2 + 4(h^2\!-\!J^2)\beta^4 - 3 \beta^6) \nonumber \\ &-& 64 (\GLp)^2(h^4 (h^2\!-\!J^2)^2-2h^2 J^4\beta^2 -(2h^4\!+\!4 h^2 J^2\!-\!J^4)\beta^4 + 2 J^2 \beta^6 + \beta^8) \nonumber \\ &+& 256 h^4 J^4 \beta^2 \label{eq:p}\end{aligned}$$ Thus, for sufficiently large spin chains we find at most four NMM whose rapidities are given as the roots of 4-th order polynomial in $\beta^2$ $$p^{\rm L}(\beta_{\rm evan}) = 0 \label{eq:evan} \label{eq:4order}$$ that are [*not*]{} simultaneously zeroes of $\tau(\beta)$. Clearly, such NMM asymptotically do not depend on the chain size $n$. In addition, we find evanescent NMM corresponding to the right bath simply by replacing $\GLp$ by $\GRp$ in (\[eq:evan\],\[eq:p\]). In fig. \[fig:rapid\] we compare evanescent rapidities computed from eq. (\[eq:evan\]) to numerically calculated spectrum of ${{\mathbf{A}}}$, at several different sizes $n$, for a typical case of transverse Ising chain, $J=1.5,h=1.0$, strongly coupled to two baths at considerably different temperatures, $\Gamma^{\rm L}_1=1,\Gamma^{\rm L}_2=0.6$, $\Gamma^{\rm R}_1=1,\Gamma^{\rm R}_2=0.3$ Note that the same parameter values will be used for numerical demonstrations throughout this subsection. Second, we shall discuss the other extreme of [*soft normal master modes*]{} with rapidities that are closest to the imaginary axis, and thus determining the spectral gap of the Liouvillean and relaxation time to NESS. Composing the scattering from the two baths with the free propagation along the chain (back and forth) we arrive at the general secular equation for the eigenvalue problem (\[eq:evA\]) in terms of a $2\times 2$ determinant $$\det ( \xi_+^{2(n-3)} {{\mathbf{S}}}^{\rm R} {{\mathbf{S}}}^{\rm L}- {{\mathbf{I}}}_2) = 0 \label{eq:sec}$$ In the absence of the baths, $\Gamma^{\rm L,R}_{\pm} = 0$, the solutions of the above problem exist only for real quasi-momenta, namely $\xi_{\pm} = \exp(\pm{ {\rm i} }\vartheta), \vartheta \in {\mathbb{R}}$. For such [*extended*]{} master modes the local coupling to the baths can be considered as a small perturbation, thus only slightly perturbing the Bloch-like bands $\beta(e^{{ {\rm i} }\vartheta}) = \pm { {\rm i} }\varepsilon(\vartheta)$ with ‘energy’ $$\varepsilon(\vartheta) = \sqrt{h^2 + J^2 - 2 |h J| \cos\vartheta}$$ The softest NMM, namely the one for which the coupling to the baths is expected to be the weakest, should have nearly nodes at the ends of the chain, i.e. $\vartheta \approx \pi/n$, or $\vartheta \approx \pi + \pi/n$, and should thus lie near the band edges $\pm { {\rm i} }|h| \pm { {\rm i} }|J|$ (see fig. \[fig:rapid\]). In the following we shall focus our calculation on the band edge $\beta^* = { {\rm i} }(|h| + |J|)$ which, as can be checked aposteriori by a straightforward but tedious calculation, always gives smaller real part of the rapidity than the lower edge ${ {\rm i} }(|h|-|J|)$, and hence really determines the gap of the Liouvillean. So we write $$\beta = { {\rm i} }(|h| + |J|) + z$$ where $z\in{\mathbb{C}}$ is a small parameter, and expand the S-matrices around the band edge $${{\mathbf{S}}}^{\rm L,R} = -{{\mathbf{I}}}_2 + \frac{4g}{\eta^{\rm L,R}} {{\mathbf{Z}}}^{\rm L,R} \sqrt{-{ {\rm i} }z} + {\cal O}(|z|) \label{eq:SZ}$$ where $g:=\sqrt{\frac{|hJ|}{2(|h|+|J|)}}$, $\eta^{\rm L,R}:=(\Gamma^{\rm L,R}_+)^4 + 4 (\Gamma^{\rm L,R}_+)^2(4 h^2 + 2 |h J| + J^2) + 16 h^2 J^2$ and $$\begin{aligned} Z^{\rm L}_{11} &=& 4 |h|(\GLp)^2 + 16|h|(|h|+|J|)(|J|-{ {\rm i} }\GLm) \nonumber \\ Z^{\rm L}_{12} &=& -2 (\GLp)^3 - 16 \GLm |h|(|h|+|J|)-8(2h^2+2|hJ|+J^2) \nonumber\\ Z^{\rm L}_{21} &=& +2 (\GLp)^3 - 16 \GLm |h|(|h|+|J|)+8(2h^2+2|hJ|+J^2) \nonumber\\ Z^{\rm L}_{22} &=& 4 |h|(\GLp)^2 + 16|h|(|h|+|J|)(|J|+{ {\rm i} }\GLm) \label{eq:ZL}\end{aligned}$$ and $$\begin{aligned} Z^{\rm R}_{11} &=& (\GRp)^4(2|h|+|J|)+4(\GRp)^2(8|h|^3+9h^2|J|+4|h|J^2+|J|^3) \nonumber \\ &+& 16 h^2|J|(|J|(3|h|+2|J|)-{ {\rm i} }\GRm(|h|+|J|)) \nonumber \\ Z^{\rm R}_{12} &=& -2 (\GRp)^3 - 16 \GRm |h|(|h|+|J|)-8(2h^2+2|hJ|+J^2) \nonumber\\ Z^{\rm R}_{21} &=& +2 (\GRp)^3 - 16 \GRm |h|(|h|+|J|)+8(2h^2+2|hJ|+J^2) \nonumber\\ Z^{\rm R}_{22} &=& (\GRp)^4(2|h|+|J|)+4(\GRp)^2(8|h|^3+9h^2|J|+4|h|J^2+|J|^3) \nonumber \\ &+& 16 h^2|J|(|J|(3|h|+2|J|)+{ {\rm i} }\GRm(|h|+|J|)) \label{eq:ZR}\end{aligned}$$ Next we expand $\xi_+$ (\[eq:dispersion\]) in $z$, yielding $$\xi_+ = -1 - g^{-1} \sqrt{-{ {\rm i} }z} + {\cal O}(|z|) \label{eq:xi1}$$ and so the [*free propagator*]{} in (\[eq:sec\]) can be written as $$\xi_+^{2(n-3)} = \exp(2n g^{-1}\sqrt{-{ {\rm i} }z}) + {\cal O}(|z|). \label{eq:xiexp}$$ In eqs. (\[eq:SZ\],\[eq:xi1\],\[eq:xiexp\]) the branch cut along the negative real axis has been chosen for $\sqrt{-{ {\rm i} }z}$. Since the product of S-matrices in (\[eq:sec\]) is near identity, the free propagator should be near one as well, hence $2n g^{-1}\sqrt{-{ {\rm i} }z}$ should be near $2\pi{ {\rm i} }$. Let us define $z_0$ by setting $2n g^{-1}\sqrt{-{ {\rm i} }z_0} = 2\pi{ {\rm i} }$, so $$z_0 = -{ {\rm i} }\pi^2 g^2 n^{-2}$$ and write $z = z_0 (1 + y) $ where $|y| \ll 1$ is another small complex parameter. However, since $z_0$ is purely imaginary, we need to compute a small but non-vanishing $y$ which will, in the leading order in $n$, solve (\[eq:sec\]) since the real part of the soft mode’s rapidity is determined as $$\re \beta = \re z_0 y = \pi^2 g^2 n^{-2} \im y \label{eq:y}$$ Now, writing $\sqrt{-{ {\rm i} }z} = \sqrt{-{ {\rm i} }z_0}\sqrt{1+y} = { {\rm i} }\pi g n^{-1} (1 + y/2 - y^2/8) + {\cal O}(y^3)$ in (\[eq:SZ\],\[eq:xiexp\]), plugging all that to eq. (\[eq:sec\]) and computing to order ${\cal O}(n^{-2})$, noting that ${\cal O}(|z|)={\cal O}(n^{-2})$, we arrive to a simple quadratic equation for $y$, whose solution, plugged to (\[eq:y\]), gives the final result, namely the sectral gap of Liouvillean $\Delta= 2\re \beta $ $$\begin{aligned} \Delta &=& \frac{(2\pi h J)^2}{(|h|+|J|)^2} \frac{\Delta_1}{\Delta_2} n^{-3} + {\cal O}(n^{-4}) \label{eq:delta} \\ \Delta_1 &:=& 64 (\GLp + \GRp) h^2 J^2 (2 h^2 + 2|h J| + J^2) \nonumber \\ &+& 16 ((\GLp)^3 + (\GRp)^3) h^2 J^2 \nonumber \\ &+& 16 \GLp \GRp (\GLp + \GRp) (2 h^2 + 2|hJ| + J^2)(4 h^2 + 2|hJ| + J^2) \nonumber \\ &+& 4 \GLp \GRp ((\GLp)^3 + (\GLp)^2 \GRp + \GLp (\GRp)^2 + (\GRp)^3) (2 h^2+ 2|h J| + J^2) \nonumber \\ &+& (\GLp \GRp)^3 (\GLp+\GRp) \nonumber \\ \Delta_2 &:=& ((\GLp)^4 + 4(\GLp)^2 (4 h^2 + 2|hJ| + J^2)+ 16 h^2 J^2 ) \nonumber \\ &\times& ((\GRp)^4 + 4(\GRp)^2 (4 h^2 + 2|hJ| + J^2)+ 16 h^2 J^2) \nonumber \end{aligned}$$ In fig. (\[fig:delta\]) we compare this analytical result to exact numerical calculations of the eigenvalue of ${{\mathbf{A}}}$ with minimal real part, confirming both, its precise numerical value and that the relative scaling of the next order correction is indeed ${\cal O}(n^{-1})$. Note that, interestingly, both main analytical results of this subsection, namely evanescent and soft mode rapidities [*do not depend*]{} on $\Gamma^{\rm L,R}_-$. Physically speaking, they only depend on the effective strengths of the bath couplings and not on the temperatures. ![ Spectral gap $\Delta$ times a third power of the chain length $n$ for a transverse Ising chain with $J=1.5,h=1$ and bath couplings $\Gamma^{\rm L}_1=1,\Gamma^{\rm L}_2=0.6$, $\Gamma^{\rm R}_1=1,\Gamma^{\rm R}_2=0.3$. Thin horizontal line indicates the theoretical asymptotic value (\[eq:delta\]). In the inset we show deviation from asymptotic constant value of $\Delta n^3$ in log-log scale and demonstrate that it decays as $\propto n^{-1}$ (thin line). \[fig:delta\]](deltafine.eps) ![ Spectral gap $\Delta$ times a third power of the chain length $n$ for a transverse Ising chain with $J=1.5,h=1$ and bath couplings $\Gamma^{\rm L}_1=1,\Gamma^{\rm L}_2=0.6$, $\Gamma^{\rm R}_1=1,\Gamma^{\rm R}_2=0.3$. Thin horizontal line indicates the theoretical asymptotic value (\[eq:delta\]). In the inset we show deviation from asymptotic constant value of $\Delta n^3$ in log-log scale and demonstrate that it decays as $\propto n^{-1}$ (thin line). \[fig:delta\]](delta.eps) ![ Complete spectrum of $2^{12}$ complex eigenvalues of Liouvillean for a transverse Ising chain with $n=6$ spins and $J=1.5,h=1$ and bath couplings $\Gamma^{\rm L}_1=1,\Gamma^{\rm L}_2=0.6$, $\Gamma^{\rm R}_1=1,\Gamma^{\rm R}_2=0.3$ (the case of the upper panel of fig. \[fig:rapid\]). \[fig:spc\]](spc.eps) ![ Energy current (upper/blue points), and average spin current (lower/red points), versus chain length $n$ for a transverse Ising chain with $J=1.5,h=1$ and bath couplings $\Gamma^{\rm L}_1=1,\Gamma^{\rm L}_2=0.6$, $\Gamma^{\rm R}_1=1,\Gamma^{\rm R}_2=0.3$. \[fig:current\]](current.eps) ![ Energy density profile (lower, blue points), and spin density profile (upper, red points), for a transverse Ising chain of $n=80$ spins with $J=1.5,h=1$ and bath couplings $\Gamma^{\rm L}_1=1,\Gamma^{\rm L}_2=0.6$, $\Gamma^{\rm R}_1=1,\Gamma^{\rm R}_2=0.3$. The insets display logarithm of the difference to the bulk values $\delta H_m := |{{\langle H_m\rangle}} - H_{\rm bulk}|$ (blue points), $\delta \sigma^{{\rm z}}_m := |{{\langle \sigma^{{\rm z}}_m\rangle}} - \sigma^{{\rm z}}_{\rm bulk}|$ (red points) in comparison with $\pm (4 \log \xi_- ) m + {\rm const}$ with quasi-momentum $\xi_- = 0.584692$ corresponding (\[eq:dispersion\]) to the leading evanescent rapidity $\beta_{\rm evan} = 0.438739$ (full lines). \[fig:profile\]](profile1.eps) ![ Energy density profile (lower, blue points), and spin density profile (upper, red points), for a transverse Ising chain of $n=80$ spins with $J=1.5,h=1$ and bath couplings $\Gamma^{\rm L}_1=1,\Gamma^{\rm L}_2=0.6$, $\Gamma^{\rm R}_1=1,\Gamma^{\rm R}_2=0.3$. The insets display logarithm of the difference to the bulk values $\delta H_m := |{{\langle H_m\rangle}} - H_{\rm bulk}|$ (blue points), $\delta \sigma^{{\rm z}}_m := |{{\langle \sigma^{{\rm z}}_m\rangle}} - \sigma^{{\rm z}}_{\rm bulk}|$ (red points) in comparison with $\pm (4 \log \xi_- ) m + {\rm const}$ with quasi-momentum $\xi_- = 0.584692$ corresponding (\[eq:dispersion\]) to the leading evanescent rapidity $\beta_{\rm evan} = 0.438739$ (full lines). \[fig:profile\]](profile2.eps "fig:")![ Energy density profile (lower, blue points), and spin density profile (upper, red points), for a transverse Ising chain of $n=80$ spins with $J=1.5,h=1$ and bath couplings $\Gamma^{\rm L}_1=1,\Gamma^{\rm L}_2=0.6$, $\Gamma^{\rm R}_1=1,\Gamma^{\rm R}_2=0.3$. The insets display logarithm of the difference to the bulk values $\delta H_m := |{{\langle H_m\rangle}} - H_{\rm bulk}|$ (blue points), $\delta \sigma^{{\rm z}}_m := |{{\langle \sigma^{{\rm z}}_m\rangle}} - \sigma^{{\rm z}}_{\rm bulk}|$ (red points) in comparison with $\pm (4 \log \xi_- ) m + {\rm const}$ with quasi-momentum $\xi_- = 0.584692$ corresponding (\[eq:dispersion\]) to the leading evanescent rapidity $\beta_{\rm evan} = 0.438739$ (full lines). \[fig:profile\]](profile3.eps "fig:") We end this subsection by presenting some further numerical results on heat transport in the open transverse Ising chain in the Lindblad form. In fig. \[fig:spc\] we demonstrate expression (\[eq:eval\]) for constructing the full spectrum of the Liouvillean in terms of a set of rapidities, for a short chain. In fig. \[fig:current\] we demonstrate eq. (\[eq:pairwise2\]) of Theorem 3 by computing the energy current $Q_m$ (\[eq:hcurr\]), and the average spin current $S=\frac{1}{n-1}\sum_{m=1}^{n-1} S_m$ (\[eq:scurr\]) in NESS of a typical transverse Ising chain. Numerical results give a clear indication of [*ballistic transport*]{} ${{\langle Q\rangle}} = {\cal O}(n^0), {{\langle S\rangle}}={\cal O}(n^0)$, however its rigorous proof and analytical calculation of the currents would require full control over the complete set of NMM which is at present not available. In fig. \[fig:profile\] we plot the energy density (\[eq:hdens\]) and spin density (\[eq:sdens\]) profiles in NESS. Again, we note flat profiles in the bulk of the chain, $m,n-m \gg 1$, with exponential falloff due to adjustment to the non-equilibrium bath values. Since the densities can be written, by means of (\[eq:pairwise2\]), as $4-$point functions in NMM components, the leading falloff exponents of the profile $|{{\langle H_m\rangle}} - H_{\rm bulk}| \sim |\xi_-|^{4m} $ is given by the quasi-momentum $\xi_-$ (\[eq:dispersion\]) corresponding to the maximal evanescent rapidity $\beta_{\rm evan}$ (\[eq:evan\]). Disordered XY chain {#sect:disord} ------------------- In this subsection we treat the opposite extreme, a disordered XY chain (\[eq:hamsc\]) where three sets of physical parameters are chosen as [*random uncorrelated*]{} variables from [*uniform*]{} distributions on the intervals, $J^{{\rm x}}_m \in [J^{{\rm x}}_{\rm min},J^{{\rm x}}_{\rm max}]$, $J^{{\rm y}}_m \in [J^{{\rm y}}_{\rm min},J^{{\rm y}}_{\rm max}]$, $h_m \in [h_{\rm min},h_{\rm max}]$. Clearly, the eigenvalue problem (\[eq:evA\]) for the matrix (\[eq:bigA\]) then becomes equivalent to the Anderson tight-binding problem in one dimension for a quantum particle with a $4-$level internal degree of freedom. We do not pursue any theoretical analysis of this problem here, but merely state that numerical investigations indicate existence of exponential localization of [*all*]{} eigenvectors (or normal master modes) for disorder of any strength in anyone of system’s parameters. ![ Average Liouvillean spectral gap ${{\langle \Delta\rangle}}$ versus the chain length $n$ for disordered XY models: (i) $J^{{\rm x}}_m = 0.5, J^{{\rm y}}_m = 0, h_m \in [1,2]$ (transverse Ising with field disorder, blue points), (ii) $J^{{\rm x}}_m \in [0.5,2], J^{{\rm y}}_m = 0, h_m = 1$ (transverse Ising with interaction disorder, red points), (iii) $J^{{\rm x}}_m \in [0.5,1],J^{{\rm y}}_m \in [0.5,1], h_m = 1$ (XY with interaction disorder, golden points), all for bath couplings $\Gamma^{\rm L}_1=1,\Gamma^{\rm L}_2=0.6$, $\Gamma^{\rm R}_1=1,\Gamma^{\rm R}_2=0.3$. Full lines indicate exponential fits to right halves of data. Averaging is performed over $2000$ disorder realizations. \[fig:disdelta\]](disdelta.eps) ![ The scaling of the energy current ${{\langle Q_m\rangle}}$ with chain length $n$ of the disordered XY model in the same regimes/parameters/plot styles as in fig. \[fig:disdelta\]. \[fig:discurrent\]](discurrent.eps) ![ Scaled energy density profile of interaction disordered XY chains (case (iii) of fig. \[fig:disdelta\]) for three chain sizes: $n=20$ (blue points), $n=40$ (red points), $n=60$ (golden points). Averages over 50000 disorder realizations have been performed. \[fig:disprofile\]](disprofile.eps) With the picture of localization of NMM in mind, the effect of the couplings to the heat baths at the chain’s ends on quantum transport can be predicted by theoretical arguments (see [@livi] for a review of related studies): The spectral gap of the Liouvillean should be exponentially small $\Delta \sim \exp(-n/\ell)$ where $\ell$ is the localization length of NMM which is expected to be proportional to the square of inverse disorder strength. This is demonstrated in fig.\[fig:disdelta\]. If all NMM are exponentially localized, the currents should decrease with the chain size $n$ faster than any power, perhaps exponentially, and the system should behave as an ideal insulator (at all temperatures). This is demonstrated by straightforward numerical calculations of the heat current (\[eq:hcurr\]) in fig. \[fig:discurrent\]. In the final figure \[fig:disprofile\] we plot the energy density profile ${{\langle H_m\rangle}}$ (\[eq:hdens\]) in a typical case of disordered XY chain, versus a scaled spatial coordinate $(m-1)/(n-1) \in [0,1]$, for several different chain lengths $n$, and demonstrate sharping up of energy density profiles with increasing $n$, which is again indicating insulating behaviour. Discussion and conclusions {#sect:conc} ========================== The main result of the paper is a general method of explicit solution of master equations describing dynamics of open quantum system, under the condition that the system’s Hamiltonian is [*quadratic*]{} and all Lindblad operators are [*linear*]{} in canonical fermionic operators (which can either represent real physical fermions or any abstract 2-level quantum systems (qubits) thru the Jordan-Wigner transformation). Using a novel concept of Fock space of physical operators (or density operators of physical states), and the adjoint structure of canonical creation and annihilation maps over this space, the problem can be treated in terms of a non-Hamiltonian generalization of the method of Lieb, Schultz and Mattis [@lieb] lifted to an operator space. We have explicitly constructed a non-canonical analog of Bogoliubov transformation of the quantum Liouville map to normal master modes. Related ideas in the Hamiltonian context have been used by the author [@ProsenPTPS; @prosen; @pizorn] in order to approach the problem of real time dynamics and ergodic properties of [*isolated*]{} interacting many-body quantum systems. As an illustration of the method we have solved far from equilibrium quantum heat and spin transport problem in Heisenberg XY spin 1/2 chains which are coupled to canonical heat baths only at the two ends. Irrespectively of the strength of the coupling to the baths and their temperatures, we have shown a ballistic transport in the spatially homogeneous (non-disordered) case, and an ideally insulating behaviour in the disordered case associated to localization of normal master modes of the quantum Liouville operator. In this context the method can be considered as a simple alternative to the solution of quantum Langevin equations [@dhar]. However, the method should easily be applicable to variety of other physical situations, for example if all fermions are coupled to the baths one could make a solvable model of genuine quantum diffusion, a many-body generalization of the tight-binding model [@piere]. We also expect the method to be applicable to the Redfield type of master equations (see e.g. [@piere]) - which do not conserve positivity for a short initial (slippage) time interval - provided only the system part of the Hamiltonian is [*quadratic*]{} and system-bath couplings are [*linear*]{} in fermionic variables. Furthermore, extension of the method to open [*many-boson*]{} systems should be straightforward, simply by replacing anticommutators by commutators throughout the exposition of section \[sect:method\]. Treating density operators of NESS as elements of a Hilbert space of operators one may also extend the concept of [*entanglement entropy*]{}, with respect to a bipartition of a system of many fermions [@latorre], to NESS which can in our approach be viewed as a kind of ground state of the Liouvillean. Saturation of such [*operator space entanglement entropy*]{} [@pizorn] (which is suggested by numerical experiments [@PZ08]) indicates [*efficient simulability*]{} of NESS by elaborate numerical methods such as [*density matrix renormalization group*]{} [@dmrg], perhaps even for more general, non-solvable quantum systems. As last we mention a more ambitious extension of the present work: Namely we propose to explore a question, whether more involved algebraic methods of solution of interacting many-body quantum systems, like e.g. Bethe Ansatz or quantum inverse scattering [@korepin], could be generalized to open quantum systems, e.g. by means of the proposed concept of Fock space of operators. Could one discuss completely integrable open quantum systems which go beyond quadratic Liouvilleans? Acknowledgements {#acknowledgements .unnumbered} ================ I gratefully acknowledge stimulating discussions with Pierre Gaspard, Keiji Saito and Walter Strunz, thank Carlos Mejia-Monasterio and Thomas H. Seligman for reading the manuscript and many useful comments, and Iztok Pižorn and Marko Žnidarič for collaboration on related projects. The work has been supported by the grants P1-0044 and J1-7347 of Slovenian research agency (ARRS). Explicit analytical calculations reported in subsection (\[sect:ti\]) were assisted by [*Mathematica*]{} software package. References {#references .unnumbered} ========== [10]{} W. H. Zurek, Rev. Mod. Phys. [**75**]{}, 715 (2003). E. Joos, H. D. Zeh, C. Kiefer, D. Giulini, J. Kupsch and I.-O. Stamatescu, [*Decoherence and the Appearance of a Classical World in Quantum Theory*]{}, (Springer, 2003). J. von Neumann, [*Mathematical Foundations of Quantum Mechanics*]{}, Trans. Robert T. Geyer. (Princeton University Press, Princeton 1955). M. 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[^2]: It is not known at present whether explict form (\[eq:explA\]) guarantees diagonalizability of any such ${{\mathbf{A}}}$. Note that one can construct certain types of complex antisymmetric matrices with degenerate eigenvalues which cannot be diagonalized [@semrl]. [^3]: For a non-degenerate rapidity spectrum $\{\beta_j\}$ the proof of this statement is a trivial consequence of antisymmetry ${{\mathbf{A}}}=-{{\mathbf{A}}}^T$, whereas in case of degeneracies it can be shown that one can always choose appropriate linear combinations of eigenvectors. [^4]: Trivial zero $\beta=0$ of course does not represent a physical solution since then the whole S-matrix (\[eq:Sexplicit\]) vanishes.
Q: how to 'inline' type cast in Groovy Maybe there is no way to do this, but I thought I would ask. Let me explain my question with an example. Imagine this as a groovy script: def myMap = [:] def myMap2 = ["Hello":'World'] myMap.put("example", myMap2) //now if I try to write this: myMap.get("example").get("Hello") //the get("Hello") comes up as an unrecognized method because groovy doesn't know what type of object it is dealing with until run time //To avoid this I can do this: def x = (Map) myMap.get("example") x.get("Hello") I was wondering if there was a way for me to typecast the return from myMap.get('example') without out making a new variable/new line A: If I understand your question correctly the issue is related to the parser syntax and the nature of dynamic behavior of Groovy language. I don't think this is related to IntelliJ since GGTS shows the same behavior. So right - as you said - you can access Map using the alternative syntax: println myMap["example"]["Hello"] Another possible way is to use direct access to object's properties: println myMap.example.Hello Hope this help.
#include "co/def.h" #include "co/time.h" #include "co/log.h" #define def_test(n) \ int N = n; \ int64 _us; \ Timer _t #define def_case(func) \ do { \ _t.restart(); \ for (int i = 0; i < N; ++i) { \ func; \ } \ _us = _t.us(); \ CLOG << #func << ":\t" << (_us * 1.0 / N) << " us"; \ } while (0)