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Portuguese lemonade: exploring the countryside
You know what they say: when life gives you lemons, make lemonade. And that’s what we did in our recent trip to Algarve. We flight to the South of Portugal looking for a sunny, lazy holiday but we found terrible thunderstorms and cold temperatures. Upset at first, we decided to look for alternative plans and ended up exploring the absolutely breathtaking Portuguese countryside.
Our first stop was the city of Silves, the former capital of the Algarve region. After a surprisingly beautiful ride aross fields of orange, almond and fig trees we spotted this magnificent town. Silves is located on a hill above the Arade River, so the first impression of the city, with its cathedrall and castle uphill was quite impressive.
We started our visit in the local market, which sadly was closed (lemons again…) However we were amazed by the little restaurants that surround the market. They all had grills outside where the cooks were preparing amazing Piri-piri chicken and the most lip-smacking sea food. At that moment we regretted the hearty breakfast we had had that morning, but the faces of the locals enjoying their meals were revealing: that was the best food in town for sure.
We made our way up to the top of the hill and were surprised by the lovely architecture. No wonder Silves was one of the most important towns in Portugal, even in the times it belonged to Al-Andalus. Decadent buildings, steep cobbled streets and huge stork nests have witnessed so many changes…
After a quick stop at the Town Hall square, with its lovely pink trees and its tiny cafe full of old men playing cards, we went through Porta de Loulé, part of the preserved Almohad town wall, and continued along the steep streets to the cathedral, which used to be the great mosque but now is a modest but charming church with a unique Manueline portico.
Finally and almost out of breath we arrived to the castle, where the views were absolutely breathtaking. Silves is a city of a big historical importance and the Muslim heritage, together with the typical portuguese tiles and Manueline style, makes it unique.
We took all in, breathing the orange scented air, and hit the road again to visit Caldas de Monchique, a tiny, tiny, tiny village perched in the mountains. The romantic setting, the luscious vegetation and the nineteenth-century buildings with Morish touches made us fall in love immediately. A bar serving the utterly delicious Pao com chouriço in the oven located in the pocket-size main square, a small shop selling almond and fig sweets and the renovated thermal spa is all you will find in Caldas de Monchique. However, this remote village exudes charm, peace and serenity.
A gem for everyone interested in photography, flowers and off the beaten track locations, Caldas de Monchique was one of the highlights of our trip. We realized that hadn’t been for the bad weather we would have never discovered this little village that surprised us so much. So, again, lemons and lemonade!
Well, to be honest we did find a wonderful little restaurant by the beach that was fantastic. But the oranges, almonds and figs of this region were amazing. I have to admit that I didn’t know that Portuguese oranges were so good!
The food is amazing, the architecture is stunning (those tiles!) and people are the nicest! This is our second time in Algarve and we will be back. I also loved Lisbon (I’ve been there a few times but I always want to come back) but I still have to visit Porto, which is supposed to be wonderful as well!
I really don’t know why Portugal isn’t more popular because it’s really lovely. However, this helps to keep its charm too! The food is amazing: lots of fresh fish and vegetables and amazing sweet treats :) I hope you can make it! | 2023-11-17T01:27:15.642919 | https://example.com/article/8595 |
People look at newspapers displayed at a news stand in Lahore, Pakistan AP India had twice told the U.S. that Osama Bin Laden was not in a cave somewhere but hiding in an urban area close to Islamabad, according to a report by The Times of India. The information is also likely to fuel speculation that Pakistan knew of the al-Qaeda leader's whereabouts.
The first lead came in mid-2007, soon after bin Laden's ally Ayman al-Zawahiri attended a Taliban meeting in Peshawar, that was also attended by leaders of Haqqani network, an insurgent group based in North Waziristan, and at least two ISI officials. Zawahiri is said to have rushed to Islamabad after the meeting and Indian operatives began receiving information that bin Laden's allies were working in the region.
The next lead came in 2008, when Indian officials were tipped off that bin Laden was ill and hiding out in a cantonment in the area. An official told The Times of India:
"This time we specifically mentioned about his presence in a cantonment area. It was because we had definite information that his movement was restricted owing to his illness and that it would have been impossible for him to go to an ordinary hospital. We told the Americans that only in a cantonment area could he be looked after by his ISI or other Pakistani benefactors."
The official said he believes Pakistani officials may finally have turn bin Laden in because he had become too much of a "liability".
It is unclear why American authorities didn't consider the information and raises more questions about Pakistan's alleged involvement in safe housing bin Laden. The news comes amidst reports in Pakistan that bin Laden was killed by his bodyguard. | 2024-06-03T01:27:15.642919 | https://example.com/article/1210 |
What Do Nonunions Do?
What Should We Do About Them?
by
Daphne Gottlieb Taras, University of Calgary and Bruce E. Kaufman, Georgia
State University
Task Force Working Paper #WP14
Prepared for the May 25-26, 1999, conference
Symposium on Changing Employment Relations and New Institutions of
Representation
September 1, 1999
I. Introduction
We have completed a major anthology Nonunion Employee
Representation (NY: ME Sharpe, 2000), which examines nonunion
representations history, contemporary practice, and policy implications.
In this paper we draw upon 32 chapters on all facets of the topic, both within
the United States and among other countries, including Canada, Japan, Germany,
Australia and the United Kingdom. We review the research findings, and offer
our own conclusions about the desirability of changing American labor laws to
permit employee representation to be practiced overtly by nonunion workers and
by nonunion companies.
We begin with brief descriptions of both the American and Canadian
contemporary public policy settings. The American situation is that the
National Labor Relations Act (NLRA), through Sections 8(a)(2) and 2(5),
places significant constraints on the structure and operation of employee
representation committees in nonunion companies. In particular, the law makes
it an unfair labor practice for a company to operate a dominated labor
organization, where dominated means that the labor organization is
in some way created, supported, or administered by management. The Act
defines a labor organization, in turn, quite broadly to include any
kind of employee representation group that deals with the employer over a term
or condition of employment. Considerable debate has ensued in recent years
whether these strictures in the NLRA impede employee collective voice
and constrain the operation of legitimate, productivity-enhancing employee
involvement programs in nonunion companies. This concern was heightened by the
NLRBs 1992 Electromation, Inc. decision that the company had
violated the NLRA when it established five employee action committees to
work with management on identifying and resolving sources of employee
dissatisfaction with various aspects of pay and working conditions.
Critics of the NLRA (and, to a lesser degree, the Railway
Labor Act) claim that its strictures inhibit the ability of American
companies to form and operate employee involvement and participation programs
in nonunion workplaces and thereby harm both national competitiveness and
cooperative employer-employee relations. For several years running, a coalition
of Republican and conservative Democrats in Congress have sought to enact
legislation, popularly known as "the TEAM Act," which would
weaken significantly the NLRA's Section 8(a)(2) restrictions on
"dominated" labor organizations. TEAM Act legislation was
passed by both houses of Congress in 1996, was vetoed by President Clinton, and
was reintroduced by its Congressional supporters. The ongoing debate engendered
by this proposed legislation, as well as that precipitated by the hearings and
final report of the Clinton-appointed Commission on the Future of
Worker-Management Relations (Dunlop Commission), have put the nonunion
representation on the front burner of the American labor policy debate.
Proponents of the law claim Sections 2(5) and 8(a)(2) are crucial to
protecting employee free choice in matters of union representation by
preventing employers from manipulating and coercing workers through
"sham" company unions. There also are those who agree that the
NLRA treatment is problematic, but are gravely concerned that a movement
to change the NLRA with respect to nonunion representation will merely
allow management to lawfully employ new techniques to defeat unions. Another
group would consider a change to the NLRA only if it was accompanied by
more sweeping reform to the Act in ways which would facilitate an easier
transition to unionization where it is desired by employees.
By contrast, Canadians are not engaged in a similar type of debate, and
so we draw upon the Canadian statutory framework for comparative purposes.
Canadian legislation, which observers would considered similar in most respects
to the Wagner Act, diverged in its treatment of nonunion representation.
Nonunion plans are legal in Canada provided they are not designed to thwart
union organizing. In Table 1 below, we blended a variety of Canadian statutes
to demonstrate the Canadian approach. At first glance, it appears that the
Canadian treatment is quite similar to the American. In Canada, it also is an
unfair labor practice for management to participate in, dominate, or interfere
with a union. A union which has been influenced by management cannot be
certified as a bona fide bargaining agent, and will not enjoy the protections
of any collective bargaining statutes. Where Canada deviates from the Wagner
Act is in the definition of a labor organization. A labor organization
means a union, or at the very least, a collective entity whose purpose includes
regulation of relations through collective bargaining. Management must not
interfere with a union, but management may deal openly with groups of nonunion
employees on any issue of concern, including the terms and conditions of
employment. It is not an unfair labor practice to run a nonunion employee
representation plan because Canadian labor boards do not have the reach given
to the U.S. NLRB through Section 2(5). The critical distinction between Canada
and the U.S. rests in the definitions sections of the statutes, and not in any
departure from the Section 8(a)(2).
Statutory Treatments of Nonunion Representation in the U.S. and
Canada [Text Version]
Statute
Definition
Prohibition
National Labor Relations Act
(Wagner Act, 1935)
Section 2(5). A labor organization is
any organization of any kind, or any agency or employee representation
committee or plan in which employees participate and which exists for the
purpose, in whole or in part, of dealing with employers concerning grievances,
labor disputes, wages, rates of pay, hours of employment, or conditions of
work.
Section 8(a)(2). It is an unfair labor
practice for an employer To dominate or interfere with the formation or
administration of any labor organization or contribute financial or other
support to it.
Railway Labor Act (1926)
Section 1.Representatives
means only persons or entities designated either by a carrier or group of
carriers or by its or their employees to act for it or them.
Section 2(2). Representatives for both
management and labor shall be designated by the respective parties and
without interference, influence, or coercion by either party over the
designation of representatives of the other; and neither party shall in any way
interfere with, influence, or coerce the other in its choice of
representatives.
Section 3(4). It shall be unlawful for any carrier to interfere in
any way with the organization of its employees, or to use the funds of the
carrier in maintaining or assisting or contributing to any labor organization,
labor representative, or other agency of collective bargaining.
Canadian Approach (blending 12
statutes: federal, public service, and 10 provincial labor codes) --
[information about each of these codes is found inAppendix 2 in this paper]
Definitions Sections: Trade
union, Bargaining agent, Union, Association
of employees, or labor organization means an entity that has
as one of its purposes the regulation of relations between employers and
employees through collective bargaining.
Unfair Labor Practice Sections: It is
an unfair labor practice for any employer or employer representative to
participate in or interfere with the formation or administration of a trade
union, or representation of employees in a trade union.
Prohibitions against Certification Sections: Labor boards (or in
Quebec, the commissioner-general) shall not certify a trade union if it is
employer dominated.
This Canadian-American difference motivated an intensive investigation
of nonunion employee representation (NER), including its contemporary features
and public policy treatment. We found that there are some elements of NER on
which there never will be consensus. These include whether nonunion employee
representation plans (NERPs) are substitutes to unions, complements to unions,
or make up a free-standing system of industrial relations occupying a different
domain of activities. The impact of NER on union organizing remains
speculative. These issues form the molten core of controversy that necessarily
ensues when any group of industrial relations scholars and practitioners
exchange their views on the desirability of nonunion representation.
There also are three major issues on which agreement virtually leaps off
the page, regardless of the perspective of the authors. These include (1) that
nonunion representation is not an easy human resource practice: it is costly
and creates dynamics that make it difficult to manage. In instances where NERPs
do indeed substitute for unions, they may well be more cumbersome and
challenging than the vehicle they are meant to displace. (2) Enduring nonunion
representation plans always match or exceed employment conditions in unionized
firms. Senator Wagners view that they result in a nibbling of the
meanest man, an inevitable deterioration of an industrys wage
contour, has no empirical support. (3) The contemporary American public policy
debate is misdirected. The controversy over loosening Wagner Act
restrictions has erroneously fixated around Section 8(a)(2), which details
employer interference with labor organizations as an unfair labor practice.
Section 8(a)(2) is not now, and never has been the problem. The opinion that
we, and a majority of authors in our book espouse, is that Section 2(5) - the
overly broad definition of a labor organization - is the crux of the perplexing
American statutory treatment.
The next (second) part of this paper reviews the empirical findings on
nonunion representation, and summarizes both the points of agreement and the
reasons for the American controversy about legalizing nonunion representation.
Despite the Wagner Acts ban on NERPs via Section 2(5) and
Section 8(a)(2), nonunion plans have made significant inroads into the American
industrial relations landscape. The third part of this paper demonstrates that
a number of American employers -- perhaps about 20% of all nonunion employers,
and about 50% of those nonunion employers implementing employee involvement and
participation programs, if we were pressed to put a raw figure to our
impressions and the available data -- are practicing forms of nonunion
representation that are contrary to the express language of the NLRA.
The fourth, and final, section of this paper addresses the public policy
changes that we recommend in order to allow for collective action by nonunion
employees without further jeopardizing the low levels of unionization. It is
noteworthy that neither Canada nor Japan banned nonunion representation. In the
fourth section we draw upon the Canadian statutes for a different approach to
the Section 8(a)(2) dilemma than has been previously proposed by
American employer lobby groups (e.g. the TEAM Act). Because we have
found from our research that nonunion systems operate best when they exist in
the shadow of a viable union threat, we believe it is vital that any softening
of the nonunion representation ban be accompanied by changes that increase the
ability of workers to join bona fide unions. | 2023-09-02T01:27:15.642919 | https://example.com/article/1621 |
Q:
Outgoing mail from linux not being delivered
I can't seem to send mail through my php scripts or through the linux console on my Centos 5.5 LAMP server, when the email is addressed to go to a domain that is hosted by my box.
I think it is something to do with the email routing internally, or the DNS servers that the box uses not reporting the correct MX records.
Basically my box doesn't host any mail, it's all hosted on google apps. My name servers are hosted by a 3rd party provider and I am using webmin. Webmin doesn't recognise the settings on the 3rd party provider.
I'm unsure how to fix this. Previously when I had this problem on a cpanel server, I would edit the remotedomains and localdomains files, moving domains from one file to another and it would fix the problem.
What information do I need to provide for anyone to work out what the issue is?
Thanks
A:
If you run sendmail -bt (test mode for sendmail) and then type $=w you will see that the domains that you have problem with are listed. This is because sendmail believes that the mail addressed to said domains must be delivered locally in the box, instead of sending it to Google. So what you have to do is to modify your sendmail.mc in two places (or add them if they do not exist).
First in the LOCAL_CONFIG section add a map that looks up the best MX for a domain:
LOCAL_CONFIG
Kbestmx bestmx -T.TMP
Next, in the LOCAL_RULE_0 section where sendmail selects a delivery agent use the map above to route mail to Google:
LOCAL_RULE_0
R $* < @ example.com. > $* $#esmtp $@ [$(bestmx example.com. $)] $: $1 < @ example.com. > $2
Note 1: replace example.com with the domain in question
Note 2: Do not copy paste the rules in your sendmail.mc. Type them for the left and the right hand side of the rules are not separated with spaces but with tab characters.
Note 3: After you've done editing sendmail.mc, you have to build sendmail.cf and then restart sendmail. I do not know how this is done in CentOS. I run Debian and execute sendmailconfig
You can read a more detailed explanation on the problem in my blog post here.
| 2024-01-12T01:27:15.642919 | https://example.com/article/2569 |
337 F.Supp. 947 (1972)
Michael James MOORE, Petitioner,
v.
STATE OF MISSOURI and D. J. McCarthy, Superintendent, California Correctional Institution, San Luis Obispo, California, Respondents.
No. 20071-4.
United States District Court, W. D. Missouri, W. D.
February 10, 1972.
*948 Michael James Moore, pro se.
Gene E. Voigts, First Asst. Atty. Gen., Jefferson City, Mo., for respondents.
MEMORANDUM AND ORDER DENYING PETITION FOR WRIT OF HABEAS CORPUS
ELMO B. HUNTER, District Judge.
Petitioner, a convicted state prisoner who is currently confined in the California Correctional Institution at San Luis Obispo, California, seeks leave to file in forma pauperis a petition for writ of habeas corpus challenging a detainer lodged by the State of Missouri against him. Leave to proceed in forma pauperis is hereby granted.
Petitioner states that in November or December of 1964 he was sentenced to a term of imprisonment by the Circuit Court of Jackson County, Missouri; that he does not know the period of imprisonment to which he was sentenced; that his sentence was to expire full term on November 11, 1971; that sometime after serving a part of his sentence in confinement he was released on parole by the Missouri Board of Parole; that while on parole he was declared an "absconder" by the Board and a parole violator's warrant was issued by the Board; that on August 18, 1969, he was taken into custody by Missouri authorities for revocation of his parole; that while he awaited the revocation of his parole a warrant was lodged against him by the State of California for the crimes of robbery and kidnapping; that the Missouri authorities promptly relinquished custody of petitioner to the State of California on the warrant; that on March 1, 1970, petitioner entered a plea of guilty to the California charges and began serving the sentence imposed upon him by the California court; that shortly thereafter, on April 15, 1971, the State of Missouri filed a detainer against petitioner based upon the revocation of his parole; that on May 29, 1971 petitioner wrote the Missouri Board of Parole inquiring into the status of his Missouri sentence; and that on June 4, 1971, the Missouri Board of Parole, by letter, advised petitioner that a detainer would remain in effect until the completion of petitioner's California sentence and that petitioner would not be given credit against his Missouri sentence for the time served on the California sentence. Based upon this factual recitation, it is petitioner's contention (1) that the State of Missouri waived jurisdiction over petitioner to execute the remainder of his Missouri sentence by relinquishing custody of him to the State of California, and (2) that he is entitled to credit against his Missouri sentence for the time spent in the service of his California sentence.
Initially, it should be noted that there is some question as to whether this Court has jurisdiction to entertain petitioner's application for habeas relief since petitioner was not in the territorial *949 jurisdiction of this Court at the time he filed his petition for writ of habeas corpus. Generally, when an applicant for habeas corpus relief under 28 U.S.C. § 2241 is not within the territorial jurisdiction of the District Court at the time the petition for writ of habeas corpus is filed, the court has no jurisdiction to issue the writ. Ahrens v. Clark, 335 U.S. 188, 68 S.Ct. 1443, 92 L.Ed. 1898 (1948); Booker v. State of Arkansas, 380 F.2d 240, 243 (8th Cir. 1967). However, it has been held that in situations such as this, where a person in custody outside the jurisdiction of the forum court is attacking a detainer lodged by the forum state, he is "in custody" in the demanding state for jurisdictional purposes in an action attacking the validity of the detainer. Word v. North Carolina, 406 F.2d 352, 359 (4th Cir. 1969); United States ex rel. Van Scoten v. Pennsylvania, 404 F.2d 767 (3rd Cir. 1968). And, although the Supreme Court in Nelson v. George, 399 U.S. 224, 90 S.Ct. 1963, 26 L.Ed.2d 578 (1970) expressly held that a state prisoner could challenge a detainer by means of a petition for writ of habeas corpus in the state of actual confinement, it reserved judgment as to whether a habeas proceeding could be maintained in the demanding state absent the petitioner's physical presence in that state. Id. at page 228, n. 5, 90 S.Ct. at page 1966. Further, it is also questionable whether petitioner has fully exhausted his available and adequate state remedies for attacking the detainer now in issue. Petitioner alleges that he has filed a petition for writ of habeas corpus in the Supreme Court of Missouri challenging the validity of the detainer and that his application for habeas relief was denied "for failure of petition to state a claim on which any relief can be granted." Whether this denial of habeas relief by the Supreme Court of Missouri is sufficient to exhaust petitioner's state remedies is also questionable. See: Wilwording v. Swenson, 404 U.S. 249, 92 S. Ct. 407, 30 L.Ed.2d 418 (1971); Picard v. Connor, 404 U.S. 270, 92 S.Ct. 509, 30 L.Ed.2d 438 (1971). For, it is entirely possible that petitioner may raise the issues herein in the state courts by means of an action for declaratory judgment in the Circuit Court of Cole County, Missouri, the state trial court having jurisdiction over the Missouri Board of Parole. See, for example: Boone v. Danforth, 463 S.W.2d 825 (Mo.1971).
Even assuming arguendo, however, that petitioner is entitled to maintain this habeas corpus proceeding in this Court and that he has overcome the jurisdictional and exhaustion problems mentioned above, it is clear that he is not entitled to relief upon the merits of his contentions. As stated in Bullock v. State of Mississippi, 404 F.2d 75 (5th Cir. 1968) at page 76:
"It is well established that where state authorities surrender a prisoner to [authorities of another sovereign] for trial, sentence, and execution of sentence before he is returned to state custody, the prisoner has no standing to contest the agreement between the sovereigns as to the order of prosecution and execution of sentences; that is, he may not challenge either his original removal from state custody, or his return thereto after the completion of [the sentence imposed by the other sovereign]. See Derengowski v. U. S. Marshal, 8th Cir. 1967, 377 F.2d 223; Hall v. Looney, 10th Cir. 1958, 256 F.2d 59; United States ex rel. Moses v. Kipp, 7th Cir. 1956, 232 F.2d 147; Gunton v. Squier, 9th Cir. 1950, 185 F.2d 470; United States ex rel. Lombardo v. McDonnell, 7th Cir. 1946, 153 F.2d 919; Stamphill v. Johnston, 9th Cir. 1943, 136 F.2d 291, cert. den. 320 U.S. 766, 64 S.Ct. 70, 88 L.Ed. 457."
Further, from the circumstances alleged by petitioner there is no indication that the State of Missouri "intentionally waived" jurisdiction over him. Rather, petitioner affirmatively sets forth that Missouri authorities lodged a detainer against petitioner immediately after he was convicted in the State of California. *950 Unlike the situation in Shields v. Beto, 370 F.2d 1003 (5th Cir. 1967), there is no indication from petitioner's averments that Missouri authorities have "lost interest in him." Thus, the State of Missouri has not "waived jurisdiction" over petitioner and is entitled to execute the remainder of his Missouri sentence after the completion of petitioner's California sentence. Williams v. Department of Corrections, 438 F.2d 78, 79 (9th Cir. 1971); Bilton v. Beto, 403 F. 2d 664 (5th Cir. 1968); Opheim v. Willingham, 364 F.2d 989 (10th Cir. 1966); Clifton v. Beto, 411 F.2d 1226 (5th Cir. 1969); Hanks v. Wideman, 434 F.2d 256 (5th Cir. 1970). Further, the State of Missouri is not obliged to credit petitioner for the time served on his California sentence. Williams v. Department of Corrections, supra.
Accordingly, for the reasons stated above, the petition for writ of habeas corpus is hereby denied.
It is so ordered.
| 2024-03-15T01:27:15.642919 | https://example.com/article/1927 |
A Litter Box With A Good Look
As you might have noticed from my “What Are We Wearing?” post last Friday, I am the proud owner of a monster cat named Colonel Mustard. I also have a less monster-ed but still epically large cat named Pony. They are both big-boned and, okay, eat quite a bit, and as such, they both poop — a lot. And the Colonel does not understand the concept of burying his poop; he’s a weirdo, I know. The sleek, well-designed and super efficient litter boxes from ModKat are heads and cat tails above your standard pet store box. And they come with a reusable inner liner! Sadly, I’m a bit too poor to be throwing $180 away on a litter box right now, but a girl can dream (of litter boxes) can’t she?
Comments
Simply Irresistible
Over the years, we've poked fun at a lot of "based on a true story" movies that turned out to be bullshit. But then we thought that maybe we should stop giving Hollywood shit for embellishing history a bit if it lets them tell a slightly better story. So instead, we decided to give Hollywood…
As you slog your way through the myriad not-yet-April Fools' Day pranks that plague this nation, revel in this: no one has ever pranked someone better than Michael Jackson pranked Russell Crowe, and he did it for years. In an interview with The Guardian, Crowe revealed that despite having never met Jackson,… | 2024-04-22T01:27:15.642919 | https://example.com/article/3413 |
Q:
JQuery: Hide children, show nth child?
This is really weird and should be simple.
I have an array of images within a tags within a div, eg:
<div id="images">
<a href="#"><img src="img1.jpg"/></a>
<a href="#"><img src="img2.jpg"/></a>
<a href="#"><img src="img3.jpg"/></a>
</div>
I want to hide all of them, but loop through and show the nth one, so I created this image slider style script:
var atags = $('#images').children().length;
$('#images').children().hide();
$('#images a:first').show();
var i=0
while (i <= atags){
$('#images').children().delay(4000).hide();
$("images:nth-child(" + i + ")").show();
i = i + 1;
}
The issue is that no other a tags, despite the first out side the loop, get displayed. They all remain hidden dispite the .show(). It appears the line $("images:nth-child(" + i + ")").show(); just doesnt work.
Can anyone point me in the right direction with this?
A:
images != #images plus you need to select the actual images not the container:
$("#images img:nth-child(" + i + ")").show();
But I would just use eq, not sure if the above will work given that the images are inside a tag:
$("#images img").eq(i).show();
In any case, you don't need that while loop, just use jQuery's each to loop the collection.
Also note that delay only works if there's an animation queue and this not your case.
| 2024-01-17T01:27:15.642919 | https://example.com/article/7682 |
Dad Hats
Dad Hats & Dad Caps
Dad hats are low profile, unstructured, 6 panel caps typically made from 100% cotton and has an adjustable strap. There are acrylic blends out there but those give the dad hat silhouette a more structured look. As a rule of thumb, the more acrylic in the material, the stiffer the material is going to be. So if you're looking for a relaxed fit, try the 'Clean Up' model from 47 right here at CraniumFitteds.com.
Dad hats became popular by the younger crowd in 2016 and has not slowed down since, as people scramble to build up their dad hat collection. The look has been adopted by countless celebrities and athletes. This phenomenon has spread to all four corners of the world with many foreigners adopting the look, including countries like Japan, Australia, Europe, and Latin America. At CraniumFitteds.com, we carry teams from MLB, NHL, NBA, MLS, NFL, and Collegiate from brands like 47, American Needle, and Mitchell and Ness.
Which Dad Hat To Choose
Our most popular dad hat model is hands down the 'Clean Up' model by 47. Again, it has a nice cotton crown with a cool, comfortable, and relaxed fit. This hat look pairs nicely with current men's streetwear fashion as it has a more toned down look because of the low profile and curved visor. Another brand that makes a similar dad hat, is American Needle. They also use 100% cotton giving their hat an unstructured relax fit as well.
How Clean & Maintain Your Dad Hat
To clean your dad hat from fabric fibers, dust, and lint, it's best practice to use a hat brush rather than trying to grab the dust and fibers with tape. The reason you don't want to use tape is because it leaves sticky residue on your dad hat which is like a magnet for more dust and fibers. You want to just use a brush and/or some compressed air to blow the dust off. This leaves your dad hat clean and free from tape residue, giving your hat a lasting clean look. In theory, you could throw it in the washing machine since it's unstructured, although we advise against it, but you don't need to go that route as there are cap cleaners out there for you to clean your dad hat with. | 2023-08-04T01:27:15.642919 | https://example.com/article/1272 |
Photo
Victorious British and Irish Lions players celebrate with the series trophy following the third test match against South Africa, the Lions won the series 2-1. South Africa v British and Irish Lions, Third Test, Ellis Park, July 5 1997. | 2023-08-10T01:27:15.642919 | https://example.com/article/1649 |
The ubiquitin-proteasome system in kidney physiology and disease.
Intracellular proteins continuously turn over by degradation and synthesis in all organ tissues. Owing to its irreversible nature, protein degradation is a highly selective process to avoid irreparable breakdown of cellular constituents, thereby disrupting cellular stability, integrity and signalling. The majority of intracellular proteins are degraded by the ubiquitin-proteasome system (UPS), a multi-enzyme process that involves the covalent conjugation of ubiquitin to a substrate protein and its recognition and degradation by the core multicomponent proteolytic complex of the UPS, the proteasome. In addition to labelling misfolded, damaged, aggregation-prone and intact but unneeded proteins for proteasomal degradation, ubiquitylation regulates a multitude of cellular processes, such as transcription, translation, endocytosis, and receptor activity and subcellular localization. In addition, the proteasome generates peptides for antigen presentation in the immune system and for further degradation by peptidases to provide amino acids for protein biosynthesis and gluconeogenesis. Alterations of the UPS or of protein substrates that render them more or less susceptible to degradation are responsible for disorders associated with renal cell dysfunction. In this Review, we provide insight into the elegant and complex nature of UPS-mediated proteostasis and focus on its established and potential roles in renal cell physiology and pathophysiology. | 2024-05-23T01:27:15.642919 | https://example.com/article/5519 |
Q:
GA-Z170X-Gaming 7 or GA-Z170X-Gaming G1 (2x M.2 NVMe) + SATA
I have been considering building a new system with dual Samsung 950 NVMe SSDs and I am slightly confused about how the firmware on GIGABYTE supports this setup.
Reading the manual for the Gaming 7(page 32), it states in a note that the second M.2 runs at 2X speed. However the document is 'talking about' SATAe (AFAIK) and not NVMe so I am curious about:
Will the GIGABYTE firmware support both M.2 NVMe drives as RAID0?
Will the 'second' 950 M.2 run only on two lanes (or 2x as the manual implies).
Because the drives are NVMe and not SATAe, will I still lose the ability to populate the SATA3 ports? (i.e. Is it because the M.2 controller needs the lanes or is it because the SATAe configuration requires this.)
What I would ~like~ to do is have a dual Samsung 950 NVMe setup with RAID0 as a primary (and given that the machine is likely going to be a Linux box eventually, this could be software). Then have the 8 SATA3 ports populated with a RAID6 array of 5TB drives (likely MDADM->LVM->EXT4).
I'd pick the Gaming G1 (http ://www.gigabyte.us/products/product-page.aspx?pid=5478) over the Gaming 7 (http ://www.gigabyte.us/products/product-page.aspx?pid=5481) if it supported this better, even if SOME of the other features are not required.
A:
Question 1:
Will the GIGABYTE firmware support both M.2 NVMe drives as RAID0?
The GIGABYTE Gaming 7 motherboard only has 2 x M.2 Socket 3 connectors on it. One appears to be a M.2 PCI-Express connector the other is a M.2 SATA connector. This is clear by the fact the chart in the manual, for each M2D_32G M.2 connector, is slightly different. If they were both M.2 PCI-Express connectors they would be identical. The "PCIe x4 SSD runs at x2 speed." comment is in reference to any device connected to the PCIe 3.0 x4 bus this includes NVMe devices. So if your goal is to use two Samsung 950 NVMe SSDs you won't acomplish your goals with that motherboard.
Directly from the manual:
The M.2 connectors support M.2 SATA SSDs and M.2 PCIe SSDs and support
RAID configuration through the Intel® Chipset. "The Intel® Chipset
supports RAID 0, RAID 1, RAID 5, and RAID 10.
You should take note of this though:
Please note that an M.2 PCIe SSD cannot be used to create a RAID set
either with an M.2 SATA SSD or a SATA hard drive. To create a RAID array with an M.2 PCIe SSD, you must set up the configuration in UEFI BIOS mode.
Question 2:
Because the drives are NVMe and not SATAe, will I still lose the
ability to populate the SATA3 ports? (i.e. Is it because the M.2
controller needs the lanes or is it because the SATAe configuration
requires this.)
The chart belows explains what SATA ports you will or will not lose based on the configuration you select.
Question 3:
Because the drives are NVMe and not SATAe, will I still lose the
ability to populate the SATA3 ports? (i.e. Is it because the M.2
controller needs the lanes or is it because the SATAe configuration
requires this.)
Your motherboard does not support the use of two NVMe devices based on the manual you provided.
My conclusion is also based on this statement.
1 x PCI Express x16 slot, running at x4 (PCIEX4)
* The PCIEX4 slot shares bandwidth with the M2H_32G connector. The PCIEX4 slot will become unavailable when an SSD is installed in the M2H_32G connector.
This statement by itself, indicates that only one of the M2H_32G connectors, is a M.2 PCI-Express connector. If the board supported two M.2 PCI-Express devices, the bandwidth to a second PCI-E slot would have to be shared, the amount of PCI-E bus is finite in the chipset being used.
A:
GA-Z170X-Gaming 7 does support two NVMe devices. I am currently using two Samsung 960 1TB PCIe NVMe M.2 SSDs successfully as RAID 0 equaling 2TB in storage.
From the chart, it says it operates as double the speed.
One of the issues I had is understanding the diagram in the motherboard for the disabling of SATA controllers. From what I've been able to figure out by trial-and-error is that when two of the aforementioned m.2s are installed, all SATA ports are disabled EXCEPT SATA 4,6,& 7.
| 2023-12-23T01:27:15.642919 | https://example.com/article/4069 |
What is Phenylethylamine?
PEA is derived from an amino acid which is known as Phenylalanine. This is actually found in a number of natural sources, including chocolate. This is one of the reasons why so many people tend to take such pleasure from eating chocolate, as it helps stimulate the release of dopamine and pleasure receptors. It is proving to be an incredibly beneficial supplement for elevating a person’s mood and reducing conditions such as: stress, anxiety, and depression. Not only is it great for improving our psychological health and well-being however, it is also very beneficial for when it comes to losing weight as well. So much so in fact, that if you were to read the ingredients label of most dietary and weight loss supplements, you would see that Phenylethylamine is one of the primary active ingredients.
How does it work?
PEA works in a number of different ways within the human body, which is actually one of the main reasons why experts have been so impressed with this supplement. In terms of improving mental health and mood in general, the main way in which this supplement works is that it helps to increase the amounts of natural dopamine being produced, and as dopamine is a chemical responsible for feelings of happiness and euphoria, you can see why this is beneficial. Not only that, but it also helps to block the action of other neurotransmitters such as cortisol, which can cause feelings of stress and depression. As mentioned, it also assists with weight loss as it contains compounds and active ingredients that have been found to increase the metabolism in a rested state. Obviously the stronger the metabolism becomes, the more calories the body can burn off, and so the more fat will be lost as a result.
What are the main benefits of using Phenylathylamine supplements?
Some of the primary benefits associated with Phenylethylamine supplements include the following:
Reduced risk of mental health issues
As mentioned, mental health issues are very common, and are far more common than most people realise. Conditions such as stress, and anxiety for example, can go on to manifest themselves in different ways and can lead to more serious conditions such as depression, or even clinical depression. Many people have sadly taken their own lives due to conditions of this nature, and the great thing about Phenylethylamine, is the fact that it can help to reduce the likelihood of people suffering from these conditions, and if they do, it can make dealing with them much easier.
Improved mood
Even if you aren’t suffering from mental health issues, improving your mood is still hugely beneficial because you will feel much better. If you feel better, you become happier, more driven, more motivated, and more productive.
Weight loss
As PEA contains compounds and ingredients that have been found to increase the metabolism, the great thing about this supplement is the fact that it can help individuals to lose weight easier. The faster the metabolism becomes, the more calories will be burnt off, the more fat will be lost, and the more energy will be produced. This increase in energy is especially useful as it can make workouts and physical exercise in general, a great deal more rewarding and productive.
Other benefits include:
Increased energy levels
Increased metabolism
Weight loss
Improved mental health
A stronger immune system
Better sleeping patterns
Better focus and concentration levels
And more…
How and when should it be consumed?
For optimal results, experts recommend around 300mg per day, although higher dosages can be taken. You should however, never exceed 1000mg per day, no matter why you’re using the supplement.
Phenylethylamine VS Phenylalanine
As mentioned, PEA is a derivative of Phenylalanine, and although similar, the two still have very unique differences. PEA for example, functions as a neuro-modulator, which basically means that it has an effect on how the brain deals with awareness and perception. Phenylalanine however, is actually an amino acid that is a precursor for PEA, as PEA is synthesized from Phenylalanine. Phenylalanine is chemically similar to dopamine, and provides similar benefits, usually which are less prominent.
What can it be stacked with?
PEA can be stacked with other natural supplements designed to improve mental health and well-being, with 5-HTP, and St John’s Wort, both proving beneficial. If using for weight loss purposes, it can be stacked with other supplements designed to assist with weight loss.
Potential side effects
As with all supplements, always consult your doctor before using any new products, and discontinue usage if you experience any adverse side effects. Pregnant and breastfeeding women should not use this supplement. Although considered safe in the correct dosages, potential side effects could include: | 2024-03-18T01:27:15.642919 | https://example.com/article/9057 |
Report Video Issue Issue: *
Broken Video Subtitle Issue Copyright Infringement Invalid Contents
Submit Report
Directed by: Beverly Sebastian and Ferd Sebastian
Actors: Claudia Jennings, Jean Marie Ingels, Cheri Howell and Joan Prather
Language: English
Country: USA
Also known as: Bloody Friday, Private School
Description: A group of men and girls travel to a Carribean resort to discover themselves sexually but unfortunately one of them has also discovered that they like to murder people too.
Review: Though originally promoted like low-grade sexploitation slop, this Dimension Pictures release from directors Ferd and Beverly Sebastian (best known for drive-in dreck such as THE HITCHHIKERS and GATOR BAIT) also mixes in a slasher subplot, trendy sex-therapy, and an overdose of butt-ugly ’70s-fashions. The fact that this El Cheapo production also co-stars 1970 Playboy Playmate of the Year Claudia Jennings, one of the undisputed queens of the drive-in, only adds to the film’s misguided allure. | 2024-01-04T01:27:15.642919 | https://example.com/article/1401 |
Set Warnings "-extraction-opaque-accessed,-extraction".
Set Warnings "-notation-overridden,-parsing".
Require Import ZArith.
Require Import mathcomp.ssreflect.ssreflect.
From mathcomp Require Import ssrfun ssrbool ssrnat eqtype seq.
From QuickChick Require Import
GenLow GenLowInterface
GenHighImpl GenHighInterface
RandomQC Tactics Sets.
Set Bullet Behavior "Strict Subproofs".
Import GenLow.
Module Import GenHigh := GenHighImpl.Impl GenLow.
Import QcDefaultNotation.
Lemma oneOf_freq {A} (g : G A) (gs : list (G A)) size :
semGenSize (oneOf (g ;; gs)) size <-->
semGenSize (freq ((1, g) ;; map (fun x => (1, x)) gs)) size.
Proof.
rewrite semOneofSize semFrequencySize /=.
elim : gs => [| g' gs IHgs ] /=.
- rewrite !cons_set_eq !nil_set_eq !setU_set0_neut !bigcup_set1.
now apply set_eq_refl.
- rewrite !cons_set_eq.
rewrite setU_assoc (setU_comm [set g] [set g']) -setU_assoc -cons_set_eq
bigcup_setU_l IHgs.
rewrite setU_assoc (setU_comm [set (1, g)] [set (1, g')])
-setU_assoc -cons_set_eq bigcup_setU_l.
eapply setU_set_eq_compat.
rewrite !bigcup_set1.
now apply set_eq_refl. now apply set_eq_refl.
Qed.
Lemma semFreq :
forall {A : Type} (ng : nat * G A) (l : seq (nat * G A)),
List.Forall (fun x => x.1 > 0) (ng :: l) ->
semGen (freq ((fst ng, snd ng) ;; l)) <-->
\bigcup_(x in (ng :: l)) semGen x.2.
Proof.
intros S ng l Hall.
rewrite semFrequency. simpl.
inversion Hall as [| x xs H1 H2 Heq1]; subst. clear Hall.
destruct ng as [n g]; simpl.
case : n H1 => [| n ] //= H1.
rewrite !cons_set_eq !bigcup_setU_l.
eapply setU_set_eq_compat.
now apply set_eq_refl.
elim : l H2 => [| x xs IHxs] H2.
- rewrite !nil_set_eq //=.
- unfold filter. inv H2.
destruct x as [xn xg].
case : xn H2 H3 => [| xn] //= H2 H3.
rewrite !cons_set_eq !bigcup_setU_l.
eapply setU_set_eq_compat.
now apply set_eq_refl.
eapply IHxs. eassumption.
Qed.
Lemma semFreqSize :
forall {A : Type} (ng : nat * G A) (l : seq (nat * G A)) (size : nat),
List.Forall (fun x => x.1 > 0) (ng :: l) ->
semGenSize (freq ((fst ng, snd ng) ;; l)) size <-->
\bigcup_(x in (ng :: l)) semGenSize x.2 size.
Proof.
intros S ng l s Hall.
rewrite semFrequencySize. simpl.
inversion Hall as [| x xs H1 H2 Heq1]; subst. clear Hall.
destruct ng as [n g]; simpl.
case : n H1 => [| n ] //= H1.
rewrite !cons_set_eq !bigcup_setU_l.
eapply setU_set_eq_compat.
now apply set_eq_refl.
elim : l H2 => [| x xs IHxs] H2.
- rewrite !nil_set_eq //=.
- unfold filter. inv H2.
destruct x as [xn xg].
case : xn H2 H3 => [| xn] //= H2 H3.
rewrite !cons_set_eq !bigcup_setU_l.
eapply setU_set_eq_compat.
now apply set_eq_refl.
eapply IHxs. eassumption.
Qed.
Lemma bigcup_cons_setI_subset_compat_backtrack_weak
{A} (n : nat) (g g' : G (option A)) (l l' : seq (nat * G (option A))) :
(forall s, isSome :&: semGenSize g s \subset isSome :&: semGenSize g' s) ->
(forall s, \bigcup_(x in (l :&: (fun x => x.1 <> 0))) (isSome :&: semGenSize x.2 s) \subset
\bigcup_(x in (l' :&: (fun x => x.1 <> 0))) (isSome :&: semGenSize x.2 s)) ->
(forall s, \bigcup_(x in (((n, g) :: l) :&: (fun x => x.1 <> 0))) (isSome :&: semGenSize x.2 s) \subset
\bigcup_(x in (((n, g') :: l') :&: (fun x => x.1 <> 0))) (isSome :&: semGenSize x.2 s)).
Proof.
intros. eapply bigcup_cons_setI_subset_compat_backtrack; eauto.
Qed.
Lemma bigcup_cons_setI_subset_pres_backtrack_weak
{A} (n : nat) (g : G (option A)) (l l' : seq (nat * G (option A))) :
(forall s, \bigcup_(x in (l :&: (fun x => x.1 <> 0))) (isSome :&: semGenSize x.2 s) \subset
\bigcup_(x in (l' :&: (fun x => x.1 <> 0))) (isSome :&: semGenSize x.2 s)) ->
(forall s, \bigcup_(x in (l :&: (fun x => x.1 <> 0))) (isSome :&: semGenSize x.2 s) \subset
\bigcup_(x in ((n, g) :: l') :&: (fun x => x.1 <> 0)) (isSome :&: semGenSize x.2 s)).
Proof.
intros. eapply bigcup_cons_setI_subset_pres_backtrack; eauto.
Qed.
| 2024-07-26T01:27:15.642919 | https://example.com/article/5901 |
/*
* Copyright (c) Mirth Corporation. All rights reserved.
*
* http://www.mirthcorp.com
*
* The software in this package is published under the terms of the MPL license a copy of which has
* been included with this distribution in the LICENSE.txt file.
*/
package com.mirth.connect.plugins.datatypes.xml;
import java.util.HashMap;
import java.util.LinkedHashMap;
import java.util.Map;
import org.apache.commons.lang3.StringUtils;
import com.mirth.connect.donkey.util.DonkeyElement;
import com.mirth.connect.donkey.util.purge.PurgeUtil;
import com.mirth.connect.model.datatype.BatchProperties;
import com.mirth.connect.model.datatype.DataTypePropertyDescriptor;
import com.mirth.connect.model.datatype.PropertyEditorType;
public class XMLBatchProperties extends BatchProperties {
public enum SplitType {
Element_Name, Level, XPath_Query, JavaScript;
@Override
public String toString() {
return super.toString().replace('_', ' ');
}
};
private SplitType splitType = SplitType.values()[0];
private String elementName = "";
private int level = 1;
private String query = "";
private String batchScript = "";
@Override
public Map<String, DataTypePropertyDescriptor> getPropertyDescriptors() {
Map<String, DataTypePropertyDescriptor> properties = new LinkedHashMap<String, DataTypePropertyDescriptor>();
properties.put("splitType", new DataTypePropertyDescriptor(splitType, "Split Batch By", "Select the method for splitting the batch message. This option has no effect unless Process Batch Files is enabled in the connector.\n\nElement Name: Use the element name to split messages. Does not work with namespaces.\n\nLevel: Use the element level to split messages.\n\nXPath Query: Use a custom XPath Query to split messages.\n\nJavaScript: Use JavaScript to split messages.", PropertyEditorType.OPTION, SplitType.values()));
properties.put("elementName", new DataTypePropertyDescriptor(elementName, "Element Name", "Each element with this name will split into its own message.", PropertyEditorType.STRING));
properties.put("level", new DataTypePropertyDescriptor(Integer.toString(level), "Level", "Each element at this level will be split into its own message. The root element is at level 0.", PropertyEditorType.STRING));
properties.put("query", new DataTypePropertyDescriptor(query, "XPath Query", "Each element found with the XPath Query will be split into its own message.", PropertyEditorType.STRING));
properties.put("batchScript", new DataTypePropertyDescriptor(batchScript, "JavaScript", "Enter JavaScript that splits the batch, and returns the next message. This script has access to 'reader', a Java BufferedReader, to read the incoming data stream. The script must return a string containing the next message, or a null/empty string to indicate end of input. This option has no effect unless Process Batch is enabled in the connector.", PropertyEditorType.JAVASCRIPT));
return properties;
}
@Override
public void setProperties(Map<String, Object> properties) {
if (properties != null) {
if (properties.get("splitType") != null) {
splitType = (SplitType) properties.get("splitType");
}
if (properties.get("elementName") != null) {
elementName = (String) properties.get("elementName");
}
if (StringUtils.isNotEmpty((String) properties.get("level"))) {
// Store an int
try {
int tempLevel = Integer.parseInt((String) properties.get("level"));
if (tempLevel >= 0) {
level = tempLevel;
}
} catch (NumberFormatException e) {
}
}
if (properties.get("query") != null) {
query = (String) properties.get("query");
}
if (properties.get("batchScript") != null) {
batchScript = (String) properties.get("batchScript");
}
}
}
public SplitType getSplitType() {
return splitType;
}
public void setSplitType(SplitType splitType) {
this.splitType = splitType;
}
public String getElementName() {
return elementName;
}
public void setElementName(String elementName) {
this.elementName = elementName;
}
public int getLevel() {
return level;
}
public void setLevel(int level) {
this.level = level;
}
public String getQuery() {
return query;
}
public void setQuery(String query) {
this.query = query;
}
public String getBatchScript() {
return batchScript;
}
public void setBatchScript(String batchScript) {
this.batchScript = batchScript;
}
// @formatter:off
@Override public void migrate3_0_1(DonkeyElement element) {}
@Override public void migrate3_0_2(DonkeyElement element) {}
@Override public void migrate3_1_0(DonkeyElement element) {}
@Override public void migrate3_2_0(DonkeyElement element) {}
@Override public void migrate3_3_0(DonkeyElement element) {}
@Override public void migrate3_4_0(DonkeyElement element) {}
@Override public void migrate3_5_0(DonkeyElement element) {}
@Override public void migrate3_6_0(DonkeyElement element) {}
@Override public void migrate3_7_0(DonkeyElement element) {}
@Override public void migrate3_9_0(DonkeyElement element) {} // @formatter:on
@Override
public Map<String, Object> getPurgedProperties() {
Map<String, Object> purgedProperties = new HashMap<String, Object>();
purgedProperties.put("splitType", splitType);
purgedProperties.put("batchScriptLines", PurgeUtil.countLines(batchScript));
return purgedProperties;
}
}
| 2024-04-25T01:27:15.642919 | https://example.com/article/7876 |
//
// This file was generated by the JavaTM Architecture for XML Binding(JAXB) Reference Implementation, v1.0.6-b27-fcs
// See <a href="http://java.sun.com/xml/jaxb">http://java.sun.com/xml/jaxb</a>
// Any modifications to this file will be lost upon recompilation of the source schema.
// Generated on: 2012.06.11 at 10:34:07 AM PDT
//
package com.sun.identity.saml2.jaxb.xmlenc.impl;
public class CipherDataTypeImpl implements com.sun.identity.saml2.jaxb.xmlenc.CipherDataType, com.sun.xml.bind.JAXBObject, com.sun.identity.saml2.jaxb.assertion.impl.runtime.UnmarshallableObject, com.sun.identity.saml2.jaxb.assertion.impl.runtime.XMLSerializable, com.sun.identity.saml2.jaxb.assertion.impl.runtime.ValidatableObject
{
protected com.sun.identity.saml2.jaxb.xmlenc.CipherReferenceType _CipherReference;
protected byte[] _CipherValue;
public final static java.lang.Class version = (com.sun.identity.saml2.jaxb.xmlenc.impl.JAXBVersion.class);
private static com.sun.msv.grammar.Grammar schemaFragment;
private final static java.lang.Class PRIMARY_INTERFACE_CLASS() {
return (com.sun.identity.saml2.jaxb.xmlenc.CipherDataType.class);
}
public com.sun.identity.saml2.jaxb.xmlenc.CipherReferenceType getCipherReference() {
return _CipherReference;
}
public void setCipherReference(com.sun.identity.saml2.jaxb.xmlenc.CipherReferenceType value) {
_CipherReference = value;
}
public byte[] getCipherValue() {
return _CipherValue;
}
public void setCipherValue(byte[] value) {
_CipherValue = value;
}
public com.sun.identity.saml2.jaxb.assertion.impl.runtime.UnmarshallingEventHandler createUnmarshaller(com.sun.identity.saml2.jaxb.assertion.impl.runtime.UnmarshallingContext context) {
return new com.sun.identity.saml2.jaxb.xmlenc.impl.CipherDataTypeImpl.Unmarshaller(context);
}
public void serializeBody(com.sun.identity.saml2.jaxb.assertion.impl.runtime.XMLSerializer context)
throws org.xml.sax.SAXException
{
if ((_CipherReference == null)&&(_CipherValue!= null)) {
context.startElement("http://www.w3.org/2001/04/xmlenc#", "CipherValue");
context.endNamespaceDecls();
context.endAttributes();
try {
context.text(com.sun.msv.datatype.xsd.Base64BinaryType.save(((byte[]) _CipherValue)), "CipherValue");
} catch (java.lang.Exception e) {
com.sun.identity.saml2.jaxb.assertion.impl.runtime.Util.handlePrintConversionException(this, e, context);
}
context.endElement();
} else {
if ((_CipherReference!= null)&&(_CipherValue == null)) {
if (_CipherReference instanceof javax.xml.bind.Element) {
context.childAsBody(((com.sun.xml.bind.JAXBObject) _CipherReference), "CipherReference");
} else {
context.startElement("http://www.w3.org/2001/04/xmlenc#", "CipherReference");
context.childAsURIs(((com.sun.xml.bind.JAXBObject) _CipherReference), "CipherReference");
context.endNamespaceDecls();
context.childAsAttributes(((com.sun.xml.bind.JAXBObject) _CipherReference), "CipherReference");
context.endAttributes();
context.childAsBody(((com.sun.xml.bind.JAXBObject) _CipherReference), "CipherReference");
context.endElement();
}
}
}
}
public void serializeAttributes(com.sun.identity.saml2.jaxb.assertion.impl.runtime.XMLSerializer context)
throws org.xml.sax.SAXException
{
if (!((_CipherReference == null)&&(_CipherValue!= null))) {
if ((_CipherReference!= null)&&(_CipherValue == null)) {
if (_CipherReference instanceof javax.xml.bind.Element) {
context.childAsAttributes(((com.sun.xml.bind.JAXBObject) _CipherReference), "CipherReference");
}
}
}
}
public void serializeURIs(com.sun.identity.saml2.jaxb.assertion.impl.runtime.XMLSerializer context)
throws org.xml.sax.SAXException
{
if (!((_CipherReference == null)&&(_CipherValue!= null))) {
if ((_CipherReference!= null)&&(_CipherValue == null)) {
if (_CipherReference instanceof javax.xml.bind.Element) {
context.childAsURIs(((com.sun.xml.bind.JAXBObject) _CipherReference), "CipherReference");
}
}
}
}
public java.lang.Class getPrimaryInterface() {
return (com.sun.identity.saml2.jaxb.xmlenc.CipherDataType.class);
}
public com.sun.msv.verifier.DocumentDeclaration createRawValidator() {
if (schemaFragment == null) {
schemaFragment = com.sun.xml.bind.validator.SchemaDeserializer.deserialize((
"\u00ac\u00ed\u0000\u0005sr\u0000\u001dcom.sun.msv.grammar.ChoiceExp\u0000\u0000\u0000\u0000\u0000\u0000\u0000\u0001\u0002\u0000\u0000xr\u0000\u001dcom.sun."
+"msv.grammar.BinaryExp\u0000\u0000\u0000\u0000\u0000\u0000\u0000\u0001\u0002\u0000\u0002L\u0000\u0004exp1t\u0000 Lcom/sun/msv/gramm"
+"ar/Expression;L\u0000\u0004exp2q\u0000~\u0000\u0002xr\u0000\u001ecom.sun.msv.grammar.Expression"
+"\u00f8\u0018\u0082\u00e8N5~O\u0002\u0000\u0002L\u0000\u0013epsilonReducibilityt\u0000\u0013Ljava/lang/Boolean;L\u0000\u000bex"
+"pandedExpq\u0000~\u0000\u0002xpppsq\u0000~\u0000\u0000ppsr\u0000\'com.sun.msv.grammar.trex.Eleme"
+"ntPattern\u0000\u0000\u0000\u0000\u0000\u0000\u0000\u0001\u0002\u0000\u0001L\u0000\tnameClasst\u0000\u001fLcom/sun/msv/grammar/Name"
+"Class;xr\u0000\u001ecom.sun.msv.grammar.ElementExp\u0000\u0000\u0000\u0000\u0000\u0000\u0000\u0001\u0002\u0000\u0002Z\u0000\u001aignore"
+"UndeclaredAttributesL\u0000\fcontentModelq\u0000~\u0000\u0002xq\u0000~\u0000\u0003pp\u0000sr\u0000\u001fcom.sun"
+".msv.grammar.SequenceExp\u0000\u0000\u0000\u0000\u0000\u0000\u0000\u0001\u0002\u0000\u0000xq\u0000~\u0000\u0001ppsr\u0000\u001bcom.sun.msv.g"
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+"atatype/xsd/WhiteSpaceProcessor;xpt\u0000 http://www.w3.org/2001/"
+"XMLSchemat\u0000\fbase64Binarysr\u00005com.sun.msv.datatype.xsd.WhiteSp"
+"aceProcessor$Collapse\u0000\u0000\u0000\u0000\u0000\u0000\u0000\u0001\u0002\u0000\u0000xr\u0000,com.sun.msv.datatype.xsd"
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+"ression$NullSetExpression\u0000\u0000\u0000\u0000\u0000\u0000\u0000\u0001\u0002\u0000\u0000xq\u0000~\u0000\u0003sr\u0000\u0011java.lang.Bool"
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+"type.xsd.QnameType\u0000\u0000\u0000\u0000\u0000\u0000\u0000\u0001\u0002\u0000\u0000xq\u0000~\u0000\u0013q\u0000~\u0000\u0019t\u0000\u0005QNameq\u0000~\u0000\u001dq\u0000~\u0000\u001fsq"
+"\u0000~\u0000\"q\u0000~\u0000*q\u0000~\u0000\u0019sr\u0000#com.sun.msv.grammar.SimpleNameClass\u0000\u0000\u0000\u0000\u0000\u0000\u0000"
+"\u0001\u0002\u0000\u0002L\u0000\tlocalNameq\u0000~\u0000\u0016L\u0000\fnamespaceURIq\u0000~\u0000\u0016xr\u0000\u001dcom.sun.msv.gra"
+"mmar.NameClass\u0000\u0000\u0000\u0000\u0000\u0000\u0000\u0001\u0002\u0000\u0000xpt\u0000\u0004typet\u0000)http://www.w3.org/2001/"
+"XMLSchema-instancesr\u00000com.sun.msv.grammar.Expression$Epsilon"
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+"\u0000!http://www.w3.org/2001/04/xmlenc#sq\u0000~\u0000\u0007pp\u0000sq\u0000~\u0000\u0000ppsr\u0000 com."
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+"ar.UnaryExp\u0000\u0000\u0000\u0000\u0000\u0000\u0000\u0001\u0002\u0000\u0001L\u0000\u0003expq\u0000~\u0000\u0002xq\u0000~\u0000\u0003q\u0000~\u0000!psq\u0000~\u0000%q\u0000~\u0000!psr\u0000"
+"2com.sun.msv.grammar.Expression$AnyStringExpression\u0000\u0000\u0000\u0000\u0000\u0000\u0000\u0001\u0002"
+"\u0000\u0000xq\u0000~\u0000\u0003q\u0000~\u00003q\u0000~\u0000>sr\u0000 com.sun.msv.grammar.AnyNameClass\u0000\u0000\u0000\u0000\u0000\u0000"
+"\u0000\u0001\u0002\u0000\u0000xq\u0000~\u0000-q\u0000~\u00002sq\u0000~\u0000,t\u00009com.sun.identity.saml2.jaxb.xmlenc."
+"CipherReferenceElementt\u0000+http://java.sun.com/jaxb/xjc/dummy-"
+"elementssq\u0000~\u0000\u0007pp\u0000sq\u0000~\u0000\u000bppsq\u0000~\u0000\u0007pp\u0000sq\u0000~\u0000\u0000ppsq\u0000~\u00009q\u0000~\u0000!psq\u0000~\u0000%"
+"q\u0000~\u0000!pq\u0000~\u0000>q\u0000~\u0000@q\u0000~\u00002sq\u0000~\u0000,t\u00006com.sun.identity.saml2.jaxb.xm"
+"lenc.CipherReferenceTypeq\u0000~\u0000Csq\u0000~\u0000\u0000ppsq\u0000~\u0000%q\u0000~\u0000!pq\u0000~\u0000\'q\u0000~\u0000.q"
+"\u0000~\u00002sq\u0000~\u0000,t\u0000\u000fCipherReferenceq\u0000~\u00006sr\u0000\"com.sun.msv.grammar.Exp"
+"ressionPool\u0000\u0000\u0000\u0000\u0000\u0000\u0000\u0001\u0002\u0000\u0001L\u0000\bexpTablet\u0000/Lcom/sun/msv/grammar/Exp"
+"ressionPool$ClosedHash;xpsr\u0000-com.sun.msv.grammar.ExpressionP"
+"ool$ClosedHash\u00d7j\u00d0N\u00ef\u00e8\u00ed\u001c\u0003\u0000\u0003I\u0000\u0005countB\u0000\rstreamVersionL\u0000\u0006parentt\u0000"
+"$Lcom/sun/msv/grammar/ExpressionPool;xp\u0000\u0000\u0000\n\u0001pq\u0000~\u00008q\u0000~\u0000Gq\u0000~\u0000E"
+"q\u0000~\u0000\u0006q\u0000~\u0000;q\u0000~\u0000Hq\u0000~\u0000\u0005q\u0000~\u0000$q\u0000~\u0000Lq\u0000~\u0000\fx"));
}
return new com.sun.msv.verifier.regexp.REDocumentDeclaration(schemaFragment);
}
public class Unmarshaller
extends com.sun.identity.saml2.jaxb.assertion.impl.runtime.AbstractUnmarshallingEventHandlerImpl
{
public Unmarshaller(com.sun.identity.saml2.jaxb.assertion.impl.runtime.UnmarshallingContext context) {
super(context, "------");
}
protected Unmarshaller(com.sun.identity.saml2.jaxb.assertion.impl.runtime.UnmarshallingContext context, int startState) {
this(context);
state = startState;
}
public java.lang.Object owner() {
return com.sun.identity.saml2.jaxb.xmlenc.impl.CipherDataTypeImpl.this;
}
public void enterElement(java.lang.String ___uri, java.lang.String ___local, java.lang.String ___qname, org.xml.sax.Attributes __atts)
throws org.xml.sax.SAXException
{
int attIdx;
outer:
while (true) {
switch (state) {
case 0 :
if (("CipherValue" == ___local)&&("http://www.w3.org/2001/04/xmlenc#" == ___uri)) {
context.pushAttributes(__atts, true);
state = 2;
return ;
}
if (("CipherReference" == ___local)&&("http://www.w3.org/2001/04/xmlenc#" == ___uri)) {
_CipherReference = ((com.sun.identity.saml2.jaxb.xmlenc.impl.CipherReferenceElementImpl) spawnChildFromEnterElement((com.sun.identity.saml2.jaxb.xmlenc.impl.CipherReferenceElementImpl.class), 1, ___uri, ___local, ___qname, __atts));
return ;
}
if (("CipherReference" == ___local)&&("http://www.w3.org/2001/04/xmlenc#" == ___uri)) {
context.pushAttributes(__atts, false);
state = 4;
return ;
}
break;
case 4 :
attIdx = context.getAttribute("", "URI");
if (attIdx >= 0) {
context.consumeAttribute(attIdx);
context.getCurrentHandler().enterElement(___uri, ___local, ___qname, __atts);
return ;
}
break;
case 1 :
revertToParentFromEnterElement(___uri, ___local, ___qname, __atts);
return ;
}
super.enterElement(___uri, ___local, ___qname, __atts);
break;
}
}
public void leaveElement(java.lang.String ___uri, java.lang.String ___local, java.lang.String ___qname)
throws org.xml.sax.SAXException
{
int attIdx;
outer:
while (true) {
switch (state) {
case 3 :
if (("CipherValue" == ___local)&&("http://www.w3.org/2001/04/xmlenc#" == ___uri)) {
context.popAttributes();
state = 1;
return ;
}
break;
case 4 :
attIdx = context.getAttribute("", "URI");
if (attIdx >= 0) {
context.consumeAttribute(attIdx);
context.getCurrentHandler().leaveElement(___uri, ___local, ___qname);
return ;
}
break;
case 5 :
if (("CipherReference" == ___local)&&("http://www.w3.org/2001/04/xmlenc#" == ___uri)) {
context.popAttributes();
state = 1;
return ;
}
break;
case 1 :
revertToParentFromLeaveElement(___uri, ___local, ___qname);
return ;
}
super.leaveElement(___uri, ___local, ___qname);
break;
}
}
public void enterAttribute(java.lang.String ___uri, java.lang.String ___local, java.lang.String ___qname)
throws org.xml.sax.SAXException
{
int attIdx;
outer:
while (true) {
switch (state) {
case 4 :
if (("URI" == ___local)&&("" == ___uri)) {
_CipherReference = ((com.sun.identity.saml2.jaxb.xmlenc.impl.CipherReferenceTypeImpl) spawnChildFromEnterAttribute((com.sun.identity.saml2.jaxb.xmlenc.impl.CipherReferenceTypeImpl.class), 5, ___uri, ___local, ___qname));
return ;
}
break;
case 1 :
revertToParentFromEnterAttribute(___uri, ___local, ___qname);
return ;
}
super.enterAttribute(___uri, ___local, ___qname);
break;
}
}
public void leaveAttribute(java.lang.String ___uri, java.lang.String ___local, java.lang.String ___qname)
throws org.xml.sax.SAXException
{
int attIdx;
outer:
while (true) {
switch (state) {
case 4 :
attIdx = context.getAttribute("", "URI");
if (attIdx >= 0) {
context.consumeAttribute(attIdx);
context.getCurrentHandler().leaveAttribute(___uri, ___local, ___qname);
return ;
}
break;
case 1 :
revertToParentFromLeaveAttribute(___uri, ___local, ___qname);
return ;
}
super.leaveAttribute(___uri, ___local, ___qname);
break;
}
}
public void handleText(final java.lang.String value)
throws org.xml.sax.SAXException
{
int attIdx;
outer:
while (true) {
try {
switch (state) {
case 4 :
attIdx = context.getAttribute("", "URI");
if (attIdx >= 0) {
context.consumeAttribute(attIdx);
context.getCurrentHandler().text(value);
return ;
}
break;
case 2 :
state = 3;
eatText1(value);
return ;
case 1 :
revertToParentFromText(value);
return ;
}
} catch (java.lang.RuntimeException e) {
handleUnexpectedTextException(value, e);
}
break;
}
}
private void eatText1(final java.lang.String value)
throws org.xml.sax.SAXException
{
try {
_CipherValue = com.sun.msv.datatype.xsd.Base64BinaryType.load(com.sun.xml.bind.WhiteSpaceProcessor.collapse(value));
} catch (java.lang.Exception e) {
handleParseConversionException(e);
}
}
}
}
| 2023-10-03T01:27:15.642919 | https://example.com/article/5939 |
PENSAMENTO BANTU A PARTIR DE ALEXIS KAGAME Mamadu Djalo, Cleber Daniel Lambert da Silva Resumo: Apresentaremos o resultado da pesquisa de iniciação científica intitulada "Cosmopolítica de alteridade a partir da cosmologia Bantu em Alexis Kagame", que integrou o projeto de pesquisa "Práticas Cosmopolíticas de um ponto de vista geofilosófico: identidade, alteridade, relação", coordenada pelo Prof. Cleber D. Lambert da Silva, desenvolvida no período de setembro de 2016 e agosto de 2017. Nossa pesquisa buscou, a partir de uma perspectiva decolonial e geofilosófica, contribuir para a compreensão de aspectos da natureza e da estrutura da noção de "cosmopolítica da alteridade" através da análise do livro "A Filosofia Bantu comparada", de A. Kagame (1976). Abordamos de uma maneira não exaustiva os principais fundamentos da cosmologia Bantu e a maneira como a sua compreensão implica um descentramento do pensamento filosófico em relação à narrativa filosófica ocidental e sua concepção de universalismo e, consequentemente, a sua abertura para novas possibilidades de pensar, tão legítimas quantas aquelas elaboradas pelas filosofias europeias. Exporemos, na ocasião, os principais pressupostos teóricos da pesquisa e seus resultados, bem como sua relevância para a nossa formação em Humanidades. Palavras-chave: Cosmologia, Alteridade, Muntu, Energia vital, Geofilosofia. | 2023-10-09T01:27:15.642919 | https://example.com/article/8546 |
The Phillies shopping list this Holiday season includes more than a legitimate middle of the order bat like a Bryce Harper or Manny Machado.
The club has needs at the back end of the bullpen and also aims to strengthen the starting rotation behind Aaron Nola and Jake Arrieta.
Jon Morosi of MLB.com reported on Monday the Phillies have been linked to veteran lefty-reliever Andrew Miller. The 33-year-old is coming off an injury-plagued campaign in 2018 but posted outstanding numbers during the four years prior and, if healthy, would be a noticeable upgrade in the setup role for the bullpen.
Another potential option for the setup role is righty Adam Ottavino who posted a career-best 2.43 ERA last season while pitching in Colorado. His 112 strikeouts set a franchise season high for a reliever.
Zach Britton, whom the Phillies have long fancied, is also a potential target. The lefty was traded from Baltimore to New York last year and could potentially slide into the role of closer if needed. The two-time All-Star has a career ERA+ of 153.
As for the starting rotation, multiple options have been linked to the Phillies over the last two weeks - including lefty Patrick Corbin. The Yankees were believed to be the favorites to land the 29-year-old entering the offseason, but things may have changed considering the club recently acquired James Paxton from the Mariners. Corbin tossed 200 innings last year, posting a 3.15 ERA.
Another potential option is righty Nathan Eovaldi. The 28-year-old is coming off a fantastic postseason with Boston and posted a 3.81 ERA in 21 starts last season. He may not make as much of a splash as Corbin, but he would be a welcome addition to the rotation.
The Winter Meetings open in Las Vegas in less than two weeks.
If you think the rumors are flying fast now, you haven't seen anything yet.
_____________________________________________ | 2024-01-07T01:27:15.642919 | https://example.com/article/6496 |
Comparison of frictional resistance among conventional, active and passive selfligating brackets with different combinations of arch wires: a finite elements study.
The aim of this study was to compare frictional resistance among conventional, passive and active selfligating brackets using Finite Elements Analysis (FEA). Seventynine (79) slide tests were performed by combining an upper first bicuspid conventional bracket, 0.018" stainless steel wires and 0.010" ligature by means of an INSTRON 3345 load system to obtain average maximum static frictional resistance (MSFR). This value was compared to the FR (frictional resistance) obtained by simulation of a slide of the same combination by FEA following conventional bracket modeling by means of Computer Aided Design (CAD). Once the FEA was validated, bracket CADs were designed (upper right first bicuspid conventional, active and passive selfligating bracket) and bracket properties calculated. MSFR was compared among conventional, active and passive selfligating brackets with different alloys and archwire cross sections such as 0.018", 0.019" x 0.025"and 0.020" x 0.020". Passive selfligating brackets had the lowest MSFR, followed by conventional brackets and active selfligating brackets. In conventional brackets, a 0.018" archwire produced a linear pattern of stress with maximum concentration at the center. Conversely, stress in 0.020 x 0.020" and 0.019 x 0.025" archwires was distributed across the width of the slot. The highest normal forces were 1.53 N for the 0.018" archwire, 4.85 N for the 0.020 x 0.020" archwire and 8.18 N for the 0.019 x 0.025" archwire. Passive selfligating brackets presented less frictional resistance than conventional and active selfligating brackets. Regardless of bracket type, greater contact area between the slot and the archwire and the spring clip increased frictional resistance. | 2024-04-08T01:27:15.642919 | https://example.com/article/4743 |
Former Wallabies star was arrested in November after he attached himself to a digger during a blockade of the coalmine site in New South Wales
The former Wallabies captain David Pocock, who was arrested during a coalmine protest in north-west New South Wales, has been excused from appearing in court.
Pocock joined several people in locking himself to a digger as part of a long-running blockade at the Maules Creek coalmine in the Leard state forest in November.
Pocock and a farmer, Rick Laird, were arrested and taken into custody by police 10 hours after occupying the digger .
Pocock, 26, was not in court when the matter came before Narrabri local court on Wednesday, but tweeted his thanks to supporters after the case was mentioned.
David Pocock (@pocockdavid) My court case has been adjourned until the 4th of Feb. Thanks for the all the support... #LeardBlockade http://t.co/WFRZJtQcJl
His barrister, Kenneth Averre, indicated representations had been made to the police about the three charges his client faces, which include entering enclosed land without lawful excuse and hindering the working of mining equipment.
His matter was adjourned to Gunnedah local court in February.
It comes after the Australian Rugby Union issued the 46-Test player with a written warning in December over his arrest.
Pocock, who has also been a vocal campaigner for marriage equality, has previously said his parents had always encouraged him to have the courage of his convictions.
After the protest, Pocock wrote on Tumblr: “While people may not agree with me being arrested, I hope they will see this as an opportunity to further the conversation about climate change and engage more people in helping to shape what is all of our futures,”
Pocock has returned to training with the ACT Brumbies as he continues his comeback from a second knee reconstruction.
The Brumbies said no further action would be taken against Pocock other than the written warning.
| 2023-11-27T01:27:15.642919 | https://example.com/article/6214 |
Valve updates the performance of SteamVR and virtual reality
Marvel shows an alternative scene of 'Iron Man' with plans for the X-Men and Spider-Man Quantic Dream thinks of to experiment with formats that are more brief in future projects
Motion Smoothing allows it to ask for less resources.
Valve remains committed to bring the technology of virtual reality to the greatest number of players. Taking into account the difficult barrier of entry of the device in the hardware required to move it, the company Gabe Newell has begun to investigate new ways to broaden the base of users with software engineering. Thus was born Motion Smoothing, something the company has announced official.
Upgrading the performance of SteamVR and the graphics less powerful
With this new technology, SteamVR detects when a game or experience a virtual reality is going to suffer a fall of frames, by developing a frame interpolated. That is to say, Motion Smoothing will be fixed in the last two frames delivered estimates the movement and animation and, finally, extrapolating a new frame, maintaining the application frame rate full and advancing the movement on the screen, avoiding vibrations or jumps in the image. Almost nothing.
This new technology is based on the environment of the glasses-HTC Live and Live Pro, solutions official Valve for virtual reality. With these two models, players can enjoy without any problems of titles VR and experiences 90 Hz even with graphics low yield or low-end, something that eliminates several integers one of the barriers to entry are more painful to level a monetary one.
Of time, and in the near future, solutions of virtual reality as an Oculus Rift and Windows Mixed Reality are not compatible. Valve has reported that this is because both systems use different technologies, as well as “display drivers underlying use other techniques when the application lost framerate“. In other words: Oculus and Microsoft use solutions so different in their systems that does not seem possible that the technology of Valve is applied to them.
it is Only compatible with HTC Live and Live Pro, as well as with NVIDIA graphics
it is Also noted that, for the moment, Motion Smoothing requiere a NVIDIA graphics so that you only bring virtual reality to the players who have a graph of mid-range/low of this brand. AMD is out of the equation, something that has not satisfied many. The technology Motion Smoothing will be launched in a beta during the next few days.
LEGAL NOTICE
This site uses cookies both own and third parties to offer a personalized experience and deliver related advertising to your interests. If you use our website you expressly agree the use of cookies on our part ... Read more | 2023-11-15T01:27:15.642919 | https://example.com/article/8749 |
Protein purification with novel porous sheets containing derivatized cellulose.
Novel porous sheets containing commercially available cellulosic ion exchange media of several different functionalities in a PVC matrix have been prepared and evaluated. The advantages of these materials are resistance to alkali, clean in place procedures and low nonspecific binding. These sheets thus provide well-known and well-characterized particulate chromatographic media in a porous sheet format. The porous sheet format permits use of short, squat geometries (stacked sheets) as well as tolerance of high pressure gradients. The net result is the ability to handle much higher flow rates (10-fold or greater) than achievable by comparable cellulosic packed columns of the neat particulate media. Chromatographic separation of natural egg white proteins by a linear salt gradient on a single sheet of 1.3-mm thickness was demonstrated. In addition, a very significant advantage of the porous sheet format is that it permits the fabrication of devices which are not possible with particulate media. An example of such a device is the Acti-Mod Spiral Module. In the spiral module a spiral flow channel is formed by wrapping the porous sheet material around a mandrel. Embossed ribbing in the porous sheet provides channel spacing. The small open channel accommodates high flow rates of biological suspensions while the porous sheet walls selectively remove components of the suspension. | 2023-12-24T01:27:15.642919 | https://example.com/article/7322 |
Q:
What is the difference between center of mass and center of gravity?
What is the difference between center of mass and center of gravity?
These terms seem to be used interchangeably.
Is there a difference between them for non-moving object on Earth, or moving objects for that matter?
A:
The difference is that the centre of mass is the weighted average of location with respect to mass, whereas the centre of gravity is the weighted average of location with respect to mass times local $g$. If $g$ cannot be assumed constant over the whole of the body (perhaps because the body is very tall), they might (and generally will) have different values.
I don't see an immediate connection with movement though.
| 2024-05-20T01:27:15.642919 | https://example.com/article/1287 |
Q:
Express js 4x :req.params returns empty object
Trying to get URl parameters in express js,but got empty object.
var password= require('./routes/password');
app.use('/reset/:token',password);
password.js
router.get('/', function(req, res, next) {
console.log(req.params);
res.send(req.params);
});
console.log(req.params) output is {}
Access url :http://localhost:3000/reset/CiVv6U9HUPlES3i0eUsNwK9zb7xVZpfHsQNuzMNWqLlGA4NJKoagwbcyiUZ8
A:
By default, nested routers do not get passed any parameters that are used in mountpaths from their parent routers.
In your case, app is the parent router, which uses /reset/:token as a mountpath, and router is the nested router.
If you want router to be able to access req.params.token, create it as follows:
let router = express.Router({ mergeParams : true });
Documented here.
| 2024-02-21T01:27:15.642919 | https://example.com/article/1803 |
{"text": ["$", "hsbc", "hsbc", "usa", "inc", ".", "declares", "divid", "URL"], "created_at": "Mon May 05 12:42:30 +0000 2014", "user_id_str": "2483745910"}
| 2023-11-12T01:27:15.642919 | https://example.com/article/6085 |
Sen. Durbin Wants Budget Showdown To End Quickly
All right. Let's talk more about that debate in Congress, which must pass a bill by Sept. 30 to keep the government running or see a partial shutdown. Republicans in the House passed a bill to fund the government but defund Obamacare; and now that bill is in the Senate, where Richard Durbin of Illinois is the Senate majority whip, the No. 2 Democrat in charge of counting votes. Senator, welcome back to the program.
SEN. RICHARD DURBIN: Good to be with you, Steve.
INSKEEP: OK. Republicans - many of them, anyway - seem to be backing away from this measure. They don't seem to think it's practical. But do you have any doubt that you have the votes to restore Obamacare to this bill - restore funding, anyway, and then just pass it through the Senate?
DURBIN: I can tell you that Sen. Cruz, of Texas, is leading the opposition on the Senate floor. He is a well-educated man. I'm confident, in the course of his education, he learned to count to 60. He doesn't have the votes. He doesn't have a handful of votes for his position. And most Republicans, Senate Republicans that I speak to, think this is not only hurtful to the economy and job creation, it's hurtful to their party.
I hope that we can get beyond this quickly, put the government back in business as it should be after Oct. 1, and start to solve some of the problems we need to face.
INSKEEP: OK. Let's work this through. So you think you've got 60 votes, which ends a filibuster. You change the bill so it's the way you want it to be. You send it back to the House, where Republicans did pass a bill that defunds Obamacare. Normally, you'd negotiate and end up somewhere in the middle. Are you willing to negotiate with the House?
DURBIN: Well, I can tell you at this point, Speaker Boehner has been enthralled by the Tea Party faction in his caucus and has said that they're going to get to run their play here. Well, their play is going nowhere. Shutting down the government to defund Obamacare is a non-starter. Obamacare is going to go into effect Oct. 1, at least in terms of offering the insurance exchanges, and actually in effect Jan. 1.
What we need to do is to fund the government as well as extend the debt ceiling; and sit down in a constructive fashion and say, well, there are aspects of Obamacare that we should address and we can address, and do it on a bipartisan basis.
INSKEEP: Well, let me ask about that, because Republicans are now suggesting, well, maybe in this negotiation they could cripple part of Obamacare or delay part of it. Are you willing to talk about that in the context of this possible shutdown?
DURBIN: Well, the crippling and delaying part I am not looking forward to do in any respect. What I think we need to do is to look to the practical aspects of this and accept the obvious. I was on the Bowles Simpson Commission. We looked at the long-term debt and deficit of the United States. Sixty percent of that is associated with the cost of healthcare.
We ought to sit down and find a bipartisan basis to reduce the increase growth rate of health care costs across America. That's something we can do and we should do.
INSKEEP: OK. You mentioned debt. That leads to the next thing. The middle of October it looks like there needs to be a vote to raise the federal debt ceiling. I understand the Democratic argument here - just pass it because the bills have already run up and you have to pay them and borrowing is part of that. And I know that the debt ceiling has been raised many times, Senator Durbin, but there's also been a lot of negotiation over the years as part of raising the debt ceiling.
Are you going to refuse to negotiate with Republicans who want some concessions here?
DURBIN: I stand with the president on this. We cannot afford, at this moment in our economic history, to negotiate over the debt ceiling. For the United States of America to default on its debt, for the full faith and credit of the United States to be questioned across the world, is as damaging to this economic growth as anything Congress can do.
We need to accept the reality that extending the debt ceiling is a must. There is no way around it. And then we need to talk about serious efforts to reduce the deficit. You know, I stuck my neck out. I voted for Bowles Simpson. It was a bipartisan approach to it. It put everything on the table. That is the only honest way to approach this.
INSKEEP: OK. One other thing, Senator Durbin. Amid all of this drama, I do hear signs of progress on immigration reform. Our correspondent Carrie Johnson was on the air here the other day saying it's the best time we've seen in decades for sentencing reform, changing the way people are sentenced. Do you think if you get past these crises, you could actually legislate something?
DURBIN: You put your finger on it here. We passed a bipartisan comprehensive immigration bill, 14 Republicans and 54 Democrats in the Senate. It's been sitting for over two months now in the House of Representatives. They've put nothing on the floor. The same thing is true on the farm bill. Twice now we've passed a bipartisan farm bill. If they called either of those measures in the House today, they would pass on a bipartisan roll call.
And then we need to move on to other important issues. It's time to put this game playing and this doomsday strategy of shutting down the government, damaging the economy, killing jobs, behind us. | 2024-03-13T01:27:15.642919 | https://example.com/article/2766 |
Rep. Peter King (R-N.Y.) says lawmakers should investigate leaks of U.S. intelligence to the media exposing Russian interference in the 2016 election.
“This is not a trivial matter,” he said on Fox News Friday. "This is supposed to be top secret, classified information, which they won’t even give to the [House] Intelligence Committee but they’re leaking to the press.
“That’s what’s really disgraceful about this,” King added, noting how most lawmakers had not seen a classified report on Russia’s election meddling. "I think there should be a federal investigation into how that was leaked out.”
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Reports emerged Thursday that U.S. intelligence agencies had intercepted top senior Russian officials celebrating President-elect Donald Trump Donald John TrumpBarr criticizes DOJ in speech declaring all agency power 'is invested in the attorney general' Military leaders asked about using heat ray on protesters outside White House: report Powell warns failure to reach COVID-19 deal could 'scar and damage' economy MORE win in November. Trump blasted the NBC report and urged the House and Senate to probe the U.S. intelligence leaks to the network.
King dismissed reports that top Russian officials celebrated Trump's win.
“That to me means absolutely nothing, other than the fact that they feel they contributed to the election,” he said. "They were going to claim a victory almost no matter what.
“I would think anything they showed that was different on Election Day from what people expected, the Russians would have been happy about it,” added King, who endorsed Trump’s presidential bid. “If that’s all they have to go on, that is a terrible way for the intelligence community or anyone in there to try to disparage the victory of Donald Trump.”
Intelligence community officials have said they concluded that Russian hacks during the election were intended to help Trump over Democrat Hillary Clinton Hillary Diane Rodham ClintonBarr criticizes DOJ in speech declaring all agency power 'is invested in the attorney general' Virginia Democrat blasts Trump's 'appalling' remark about COVID-19 deaths in 'blue states' The Hill's Campaign Report: Biden asks if public can trust vaccine from Trump ahead of Election Day | Oklahoma health officials raised red flags before Trump rally MORE.
But Trump has dismissed those claims, claiming the controversy over Russian hacking is a "political witch hunt."
President Obama received a classified report Thursday the role Russia played in influencing last year’s election contest. The report could be declassified as soon as Friday.
Trump also received a briefing from intelligence officials on Friday.
After the briefing he said the hacks had “absolutely no effect” on the 2016 race’s outcome. | 2024-04-10T01:27:15.642919 | https://example.com/article/1119 |
The cannabinoids have a long history as drugs of abuse, with profound effects at neurochemical, physiological and behavioral levels. Nevertheless, the molecular mechanisms of action of these drugs are still unknown. An important breakthrough in this field occurred with the discovery that Lambda 9-tetrahydrocannabinol (THC) and its analogs bind to brain membrane receptors which are coupled to G-proteins to inhibit adenylyl cyclase. While these THC receptors are probably not responsible for all CNS actions of cannabinoids, they may help explain some specific neuronal actions of these compounds. Moreover, since many other neurotransmitters and neuromodulators bind to G-protein-coupled receptors, these results suggest that cannabinoids may not simply be exogenous drugs of abuse but also be members of a novel class of neurotransmitters. The current study will explore components of the putative endogenous cannabinoid system in the brain by utilizing a novel class of compounds, the aminoalkylindoles (AAIs). The AAIs, originally synthesized as analgesics, are now known to bind to the same G-protein-coupled receptors as THC. These receptors can be studied by radioreceptor and cerebellar granule cells, and by inhibition of electrically-induced contractions of mouse vas deferens. Moreover, the AAIs contain a series of antagonists which competitively antagonize these receptor actions of THC. These compounds may be the first specific THC antagonists to be reported. This project will focus on THC and AAI actions in cultured cerebellar granule cells, which represent a novel, non-transformed cell culture system for the study of cannabinoid receptors. Other experiments will utilize these different methods of receptor assay, combined with specific AAI/THC antagonists, to isolate endogenous ligands binding to these receptor sites. | 2024-07-15T01:27:15.642919 | https://example.com/article/5794 |
The Dying Kiss: Gender and Intimacy in the Trenches of World War I
In the trenches of World War I, the norms of tactile contact between men changed profoundly. Mutilation and mortality, loneliness and boredom, the strain of constant bombardment, the breakdown of language and the sense of alienation from home led to a new level of intimacy and intensity under which the carefully constructed mores of civilian society broke down. As historian Joanna Bourke has documented in her exciting work on First World War and masculinity, men nursed and fed their friends when ill; they bathed together; they held each other as they danced, and during the long winter months, wrapped blankets around each other. These moments were often grounded in experiential reality, the nature of these encounters – men on the verge of death, under fire, or being ill – giving them an emotional nakedness and intensity that not only outlive their contingent nature but that continue to grow in emotional value and resonance. It is debatable whether these relationships were those of “comradeship” or personal “friendship” or trench “brotherhood”: each of these relationships had its particular nuance and value, though it is difficult to straitjacket human relationships and feelings, especially in times of physical and emotional extremity. Moreover, they were all forms of male intimacy during crisis with inevitable overlaps or continuity at times and touch seems to have cut across the range of these relationships. The conditions of trench life dictated that there could be moments of perilous intimacy between relative strangers: the trench journal Poil et Plume (October, 1916) records an incident where a severely wounded man fell on an unknown stretcher-bearer and said, “Embrace me. I want to die with you”. On the other hand, W. A. Quinton recalls how one night, as he lay shivering, “old Petch put his overcoat in addition to my own over me, taking care to tuck me in as a mother would a child.” A. F. B. notes, in The Third Battalion Magazine, that Smalley was the great favourite of the Third Battalion for “his heart was as big as his body – his strength like a lion’s – his touch to the wounded as a woman’s.” A new world of largely non-genital tactile tenderness was opening up in which pity, thrill, affection and eroticism are fused and confused depending on the circumstances, degrees of knowledge, normative practices, and sexual orientations, as well as the available models of male-male relationships.
Many returned soldiers carried with them photographs of their dead comrades or small items that belonged to them; men such as Ivor Gurney remembered the voices of the men in his company, the “roguish words by Welsh pit boys”. And yet, the most intimate moments with the comrades were those of actual body contact. These soldiers are often haunted by the feel of their comrades’ bodies as life ebbed out and the warm mutuality of the embrace was lost forever. The most immediate and yet the most evanescent of human senses, touch could only be preserved in memory and through language. Consequently, there is the urgent need within war writings to remember and re-present these moments, to evolve a literary language around touch. The writings of the soldier-poets may be regarded as a phantasmatic space where they would resurrect their dead comrades through language, infusing them with the warmth they had once known: “I clasp his hand”, “For a moment the touch/Of a warm hand” and “I had clasped warm, last night”. War literature is haunted by the sense of touch, from Rupert Brooke’s “linked beauty of bodies” to the “full-nerved, still-warm” limbs of Wilfred Owen’s dying boy and from Siegfried Sassoon’s “my fingers touch his face” to Robert Nichols’ more sentimental “My comrade, that you could rest / Your tired body on mine.” Remarque in All Quiet on the Western Front distils all the poignancy of Freundschaft into a single, silent gesture: “Kat’s hands are warm, I pass my hand under his shoulders in order to rub his temples with some tea. I feel my fingers becoming moist.” Sherriff’s Journey’s End, one of the most popular war plays, culminates in a similarly intense scene of tactile tenderness: “Stanhope […] lightly runs his fingers over Raleigh’s tousled hair.”
If shell shock had been the body language of masculine complaint, the poetic efflorescence of the 1920s was the celebration of what the Lawrentian hero Mellors famously describes as the “courage of physical tenderness” forged among men in the trenches: “I knew it with the men. I had to be in touch with them, physically and not go back on it. I had to be bodily aware of them and a bit tender to them.” Whether or not there is any conscious or unconscious erotic investment in these moments, they indicate a new level of intensity and intimacy in male-male relationships. Above all, these moments of physical bonding and tactile tenderness during trench warfare require us to reconceptualize masculinity, conventional gender roles, and notions of same-sex intimacy in postwar England in more nuanced ways than have been acknowledged in the criticism of war culture, studies of gender and sexuality, or the more general histories of the body, intimacy, and gesture.
In the trenches, the male body became an instrument of pain rather than of desire. World War I lasted over four years and claimed nine million lives; an average of 6,046 men were killed every day. In such a context, same-sex intimacy must also be understood in opposition to and as a triumph over death: it must be seen as a celebration of life, of young men huddled against long winter nights, rotting corpses, and falling shells. Physical contact was a transmission of the wonderful assurance of being alive, and more sex-specific eroticism, though concomitant, was subsidiary. In a world of visual squalor, little gestures – closing a dead comrade’s eyes, wiping his brow, or holding him in one’s arms – were felt as acts of supreme beauty that made life worth living. Although these acts may overlap with eroticism, such experiences should not simply be conflated with it – or, for that matter, with the repression or sublimation of sexual drives.
Consequently, in order to discuss intense same-sex relations during war, we must introduce a different and less distinctly sexualized array of emotional intensities and bodily sensations, a fresh category of nongenital tactile tenderness that goes beyond strict gender divisions and sexual binaries.The need for such an approach becomes particularly evident when examining representations of the dying kiss in World War I literature.
The Reverend Okeden writes to his wife: “I’ve got a little secret […] One dear lad very badly wounded […] said, ‘Hello Padre old sport’ and then ‘Come and kiss me Padre’ and he put his arms round me and kissed me.” Similarly, when his close friend Jim dies, a grief-stricken Lance-Corporal D. H. Fenton writes to his mother, Mrs Noone that ‘I held him in my arms to the end, and when his soul had departed I kissed him twice where I knew you would have kissed him – on the brow – once for his mother and once for myself’. The recurring, almost ritualistic phrase, “mother’s kiss”, suggests a powerful reconceptualization of both masculinity and male-male bonds through an assumed maternal impulse of security and tenderness, a moment of “perilous intimacy” to borrow a phrase from Lawrence.
It is a great irony that the world’s first industrial war, which brutalized the male body on such an unprecedented scale, also nurtured the most intense and intimate of male bonds. The myth of strong, invincible masculinity fostered through the works of Rudyard Kipling and Rider Haggard, later advocated by men such as Hulme, Lewis and Pound and finally embodied in the stolid figure of General Haig, exploded in the mud and blood of the Western Front. A very different order of male experience, one that accommodated fear, vulnerability, support and physical tenderness, sprang up in its place. What challenged heterosexuality in post-War England was not sexual dissidence but memories of such relationships. These were neither of romantic love nor blokish bonding nor homoerotic frisson: with each of these elements, there is a distinct overlap and, yet always, a distinct difference. Eroticism might occasionally have played a part, but it was not the founding impulse. Sexuality had not yet hijacked an intimate history of human emotions. “Frightful intimacy” is as far as language can go: the dying kiss was perhaps its true sign, the mouth filling the gap left by language.
———-
This is a revised extract from the chapter ‘Kiss me, Hardy: the dying kiss in the First World War Trenches’ in Santanu Das, Touch and Intimacy in First World War Literature (Cambridge University Press, 2005). An earlier version of the article appeared as ‘Kiss me, Hardy: Gender and Gesture in the First World War Trenches’ in Modernism/Modernity, 9.1 (Jan 2002).
Cite : The Dying Kiss: Gender and Intimacy in the Trenches of World War I
(http://ww1centenary.oucs.ox.ac.uk/?p=1695)
by Santanu Das (http://ww1centenary.oucs.ox.ac.uk/author/sdas/)
licensed as Creative Commons Attribution-Non-Commercial-Share Alike 2.0 UK: England & Wales (http://creativecommons.org/licenses/by-nc-sa/2.0/uk/)
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About Santanu Das
Educated in Calcutta and Cambridge, Santanu Das joined Queen Mary in 2005, initially as a British Academy Postdoctoral Fellow, from a research fellowship at St. John’s College, Cambridge. He is the author of Touch and Intimacy in First World War Literature (Cambridge, 2006, ppk 2008) which recovered and analysed the role of the senses, particularly touch, in First World War experience and literature, and for which he was awarded a Philip Leverhulme Prize in 2009. His work on war literature has appeared in journals such as Modernism/Modernity, Textual Practice and The American Scholar, and he has recently written on E.M.Forster for The Cambridge Companion to the English Novel (2010).
Recently he has been working on the international, particularly the colonial, aspects of First World War experience and writing. This has involved editing a volume of essays titled Race, Empire and the First World War and a monograph on India and First World War literature (in progress). | 2023-09-10T01:27:15.642919 | https://example.com/article/5556 |
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New rumours pertaining to Samsung’s first wearable system, the Galaxy Gear smart watch, indicate that the system could come in a number of colour choices. Could we create a extra efficient paradigm, a product that has much less influence on its surrounding surroundings and that permits the car to be constructed in a simpler method.
Compiled sketch are downloaded to the adapter by means of ICSP (SPI pins) with USBasp or simply Arduino as ISP. No last …
Before arrival – visitors need some basic information (e.g. how to get there, what are the costs, facilities and activities available). Before arrival the visitor would like to know what can be done and what cannot be done in the protected area he / she wants to visit. Protected Area Administration has the responsibility to create the right expectations for the visitors.
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During the visit – as their understanding of the protected area increases, the visitors have an increased interest in the natural environment, the culture
IPhoto 12 – iphoto 12 release date, iphoto12 rumours iPhoto is a software made by Apple Inc. And having apps mechanically change their structure is not the same as designing them for the pill from scratch, as is the case with the a whole lot of 1000’s of apps optimized for the iPad. By quantity, the 2 methods have a comparable number of apps.
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Onboard BLE (or Bluetooth 2.1) for wi-fi information communication with iOS and Android units. The new Nexus ships with a camera app, something last yr’s model didn’t really need because it had solely a entrance-going through camera, for videoconferencing.
Inc.’s $199 Kindle Fireplace HD is cheaper, nevertheless it doesn’t give you full entry to the rising library of Android apps for enjoying video games, checking the weather, tracking flights, reading the information and extra. For the reason that launch of its self-driving automotive challenge in 2010, Google has created self-driving systems … | 2024-05-21T01:27:15.642919 | https://example.com/article/6050 |
Introduction
============
The V1a/V2 receptor dual-agonist arginine vasopressin (AVP) is increasingly used in catecholamine-resistant septic shock \[[@B1]\]. While V1a receptor stimulation results in vasoconstriction, V2 receptor stimulation promotes coagulation, at least in part through an increase in plasma von Willebrand factor antigen (vWF:Ag) activity. We hypothesized that, at an intravenous infusion rate representative of the requirements for the treatment of sepsis-induced vasodilatory hypotension in sheep \[[@B2]\], AVP provides procoagulant activities. We tested this hypothesis by measuring vWF:Ag activity in unanesthetized healthy sheep during administration of AVP in comparison with the vWF:Ag activity increase induced by the selective V2 receptor agonist desmo-pressin (dDAVP).
Methods
=======
After two to four measurements of vWF:Ag activity and hemoglobin (Hb) over a 1-hour baseline (BL) period, 13 female sheep were randomly administered one of two treatments: an intravenous bolus of dDAVP (1 nmol/kg; n = 7) or a 2-hour intravenous infusion of AVP (3 pmol/kg/min; n = 6). vWF:Ag activity and Hb were measured every 30 minutes over 2 hours from the time of dDAVP administration or the initiation of AVP administration. For each sheep, vWF:Ag activity was corrected for plasma volume by calculating the vWF:Ag activity/Hb ratio and was expressed as percentage of the mean BL value. Data are expressed as the mean ± SEM.
Results
=======
Following dDAVP bolus injection and during AVP infusion, the vWF:Ag activity/Hb ratio increased to a maximum of 135 ± 4% (n = 7) and 135 ± 6% (n = 4) of mean BL value, respectively (*P*\< 0.001 and *P*= 0.002 vs. BL, respectively). The vWF:Ag activity/Hb ratio did not increase beyond the maximal fluctuation range of BL measurements in two out of the six sheep treated with AVP (maximum increases of 96% and 101%).
Conclusion
==========
At an intravenous infusion rate representative of the requirements for the treatment of sepsis-induced vasodilatory hypotension in sheep \[[@B2]\], the V1a/V2 receptor dual-agonist AVP increased vWF:Ag activity to the same extent as the selective V2 receptor agonist dDAVP. Because of its V2 receptor agonist activity, the use of AVP may potentially amplify the microcirculation impairment caused by sepsis-induced coagulopathy.
| 2023-08-17T01:27:15.642919 | https://example.com/article/7856 |
January 3, 2006
Review: Flava Pods Vanilla Hazelnut Coffee Pods
We recently discovered Flava Pods - a new coffee pod maker with a bunch of flavored coffee pod flavors for your Senseo, Krups KP1010 Home Cafe, Bunn My Cafe, and other single serve coffee brewers. Flava Pods come individually wrapped and weigh in at 10 grams per pod.
We decided to focus our first Flava Pod coffee pod review on their Vanilla Hazelnut coffee pods. We tend to drink a the more vanilla or hazel flavored coffees and we also like how they mix up with a little cream and sugar.
Other Current Flavors Include:
Cinnamon Sticky Bun
Hawaiian Macadamia Nut
Cinnamon Almond Macaroon
Mocha Cinnamon Swirl
Chocolate Cappuccino
French Vanilla
Supreme Hazelnut Delight
Vanilla Hazelnut
Caramel Nut Crunch
Swiss Chocolate Almond
Flava Pods boasts a a true, robust hazelnut flavor for their vanilla hazelnut coffee pods. What did we think?
We fired up our trusty Bunn My Cafe and decided on the 7 oz setting for testing. We find the best most coffee pods can do is 6.5-7 oz when brewing with the Bunn. We also like to run a good cup of hot water through the brewer to heat it up prior to tasting.
Flava Pods weigh in at 10 grams. This is a good sized coffee pod and has a nice thick feel to it. Flava Pods are packed with nitrogen and we could really sense the freshness when opening the pod.
Upon opening the Flava Pod, we got a nice scent of vanilla hazelnut. Now coffee nose and scent can be misleading. Sometimes a great smelling coffee pod can turn out to brew a very weak cup of coffee. Sometimes the brewed cup of coffee can have an even stronger scent but still produce weak coffee. So we are always a bit cautious with the scent as a big indicator of the type of coffee we may encounter in the end.
After brewing up a 7 oz cup of Vanilla Hazelnut from the Flava Pod coffee pod we like to add a little 2% milk and a teaspoon of sugar in the raw. We of course used our new Pavina double walled glass to sample the coffee in. We highly recommend a clear coffee mug when tasting. You can get a very "clear" read on how dark the coffee is and how your mix of milk goes over in the coffee.
The flavor of the Flava Pods Vanilla Hazelnut is subtle. This is not a knock your socks off with flavor cup of vanilla hazelnut, but does have a very good taste. We did sample some of the other flavors from Flava Pods and found them to also be more subtle than over the top. We do like the Flava Pods Vanilla Hazelnut coffee and think it has a very nice finish and also as the coffee cools maintains a nice flavor.
What we really like is the lack of any bitter bite. We really don't like a flavored coffee that in the end is also too dark and has an acid like finish. The Flava Pods Vanilla Hazelnut is much better with cream and sugar as well and we often find flavored coffees better with cream and sugar.
Overall we're going to give Flava Pods Vanilla Hazelnut a 3.5 out of 5 coffee pods. The smooth vanilla hazelnut flavor is very good and the freshness of the coffee produced is excellent.
You may want to try Flava Pods for yourself as they have a sampler pack available. We find the sampler pack of any pod etailer to be the best way to get an idea of what you'd like to order in any quantity.
Thanks again to Flava Pods for sending in the sample coffee pods to review.
Jim: I purchased a opus coffee maker and liked the sample read moreStephanie: I would like to know why grocery stores do not read moreNancy: I want to buy this lid read moreXelleld: I don't think they sell it nationwide. It only seems read moreBatman: I agree! The Junior Mints K cup is the best read more | 2023-10-14T01:27:15.642919 | https://example.com/article/8982 |
Blaine Gabbert will have a chance to close some ground on Cam Newton and show why he should be the first quarterback selected in the NFL draft when he throws at Missouri's pro day Thursday in Columbia, Mo.
Newton already has had three throwing workouts. He held one, mostly for media members, on Feb. 10 in San Diego, where he has been training. He threw during the NFL Scouting Combine in late February, and he threw a third time at Auburn's pro day last week.
At the urging of his agent, Tom Condon, Blaine Gabbert elected not to throw at the Combine. (AP Photo)
At the urging of his agent, Tom Condon, Gabbert elected to not throw at the Scouting Combine, so this will be his first opportunity to show off for NFL coaches and scouts in an individual workout.
Gabbert has a script of 60 passes that he will throw under the direction of former NFL quarterbacks coach Terry Shea, who has been working with Gabbert at the Athletes' Performance complex in Phoenix. Unfortunately for Gabbert, he will throw to some unfamiliar targets. Missouri doesn't have any draft prospects at receiver, and current NFL players are prohibited from participating in pro days because of the lockout. So Gabbert is expected to throw to receivers from Central Missouri State, Northwest Missouri State and Lindenwood University.
"Blaine's ready to go," said his father, Chuck Gabbert.
In addition to Gabbert's accuracy and arm strength, the NFL personnel on hand will evaluate his footwork. Missouri uses a spread offense, and Gabbert took most of his snaps from the shotgun formation.
Shea has been working with improving Gabbert's game in several areas: footwork, taking snaps from center, throwing on the run, and throwing short, intermediate and deep passes. NFL coaches and scouts are going to want to see how accurate Gabbert is when throwing from three- five- and seven-step drops.
"We expect to see a huge progression in his work," said an AFC scouting director. "Does his footwork look good? Along with that, how’s his accuracy? You’re going up against no pass rush and no defensive backs. You want to see a guy putting the ball in the places he’s supposed to put it."
Although some talent evaluators have first-round grades on Arkansas' Ryan Mallett and Washington's Jake Locker, it's largely believed that Gabbert and Newton are the only quarterbacks rated as top 10 draft prospects. It's possible that one of them could be selected No. 1 overall.
The Panthers, who have the first pick in the April 28-30 draft, are on the quarterback trail this week. They worked out Mallett on Tuesday, had a private session with Newton Wednesday at Auburn and will attend Gabbert's workout on Thursday. | 2024-07-05T01:27:15.642919 | https://example.com/article/2340 |
Likely invader busted on suspicion of dealing drugs
My Fox Boston
Police arrested a Lawrence man they say was dealing crack cocaine out of the false bottom of a Pringles can. — The Tewksbury Police Department say they conducted an undercover surveillance operation that led to the arrest of Joel Santiago-Vazquez, 28, of Lawrence, for trafficking cocaine and crack cocaine over 14 grams. — Tewksbury Detectives say they saw Santiago-Vazquez deal the drugs in the Woburn Street area. He was followed to Shoreline Drive in Tewksbury where he was observed dealing again…Read More | 2024-01-26T01:27:15.642919 | https://example.com/article/9379 |
The present invention concerns a loader boom arm, especially an arm for a front end loader wherein the arm is constructed so as to be in the form of a tube.
Loaders are installed, for example, on farm tractors and are moveable vertically for lifting loads. In the case of a front loader, the loader includes a loader boom having a forward end to which implements are attached, while the rear end is connected in an articulated manner to the farm tractor. Due to the length of the loader boom, and the forces involved, substantial bending moments arise in the loader arms constituting the boom. Various measures have been attempted in the known loader boom arms to make a basically square tube-like support that is more resistant to bending. For example, it is known to weld to U-channel sections together to form a rectangular tube or to insert two squared sections that are approximately 75% closed together and weld them in place to form a tube. According to another known design, two hollow sections partially; open on the broad side are placed on each other and welded together to form a closed tube resistant to bending.
The problem underlying the invention is that the known loader linkage arms are too expensive.
According to the present invention, there is provided a loader boom arm construction that represents a less expensive option to the aforementioned known designs.
An object of the invention is to provide a relatively inexpensive loader boom arm construction having a tubular configuration preferably defined by no more than two components with one of the components being simple bar.
A more specific object of the invention is to provide a loader boom arm formed of a first component bent from a sheet of material, so as to form a tube having a slot at one side defined by parallel edges of said sheet material, and a second component in the form of a rectangular bar received in the slot defined by the first component and welded to the first component at locations extending along the opposite sides of the slot.
These and other objects will become apparent from a reading of the ensuing description together with the appended drawings. | 2024-01-09T01:27:15.642919 | https://example.com/article/6424 |
Marijuana Moment is a wire service assembled by Tom Angell, a marijuana legalization activist and journalist covering marijuana reform nationwide. The views expressed by Angell or Marijuana Moment are neither endorsed by the Globe nor do they reflect the Globe’s views on any subject area.
Several studies have linked legal marijuana programs to lower rates of opioid overdoses, but most of that research has focused on broad, state-level data. Zoom in closer — to the county level — and the role of dispensaries where people can actually purchase cannabis becomes clear.
Looking at mortality records from 2009 to 2015, a team of researchers investigated whether the presence of dispensaries in counties with medical cannabis laws had an effect on deaths from prescription opioids, synthetic opioids, and heroin. The results supported previous research, indicating that access to marijuana can mitigate the opioid epidemic.
This study, published in October, was written by three researchers: Julio Garin at Claremont McKenna College, R. Vincent Pohl at the University of Georgia, and Rhet A. Smith at the University of Arkansas at Little Rock.
But not all counties in legal states allow dispensaries to operate. The study found that counties with dispensaries experience 6 to 8 percent fewer opioid overdose deaths overall and 10 percent fewer heroin overdose deaths.
“Importantly, these effects are limited to counties where dispensaries opened and do not apply to non-dispensary counties in states with that have legalized medical cannabis,” the researchers wrote. That is, “while legalizing medical cannabis is not associated with lower levels of opioid overdose mortality, the presence of dispensaries has a large negative impact on the number of opioid-related deaths.”
The study focused on non-Hispanic white men aged 15 to 54. Theoretically, the results indicate that for every 100,000 people in this demographic, 10 fewer people would have died from opioid overdoses between 1999 and 2015 if states that legalized medical cannabis had dispensaries in all counties from the start. | 2024-05-03T01:27:15.642919 | https://example.com/article/8917 |
Effects of discrete nuclear u.v-microbeam irradiation on herpes virus and SV40 infection.
The requirement for a nucleolus in the expression of structural genes of nuclear viruses was examined by means of experiments in which the nucleolus or other parts of the nucleus was inactivated by a microbean of unltraviolet light. These experiments showed that the expression of such genes is not dependent on cucleolar function. This conclusion is discussed in the light of previous experiments in which similar inactiviation of nucleolus was shown to prevent the expression of cellular structural genes. | 2024-04-07T01:27:15.642919 | https://example.com/article/8044 |
Suit filed in purge of Florida voter rolls
6/8/12 5:56 PM EDT
Good-government advocates have sued the state of Florida, alleging its purge of non-citizens from voter rolls has swept up too many legally-registered African American and Latino voters and is undermining laws that ensure fair access to the ballot box.
The state chapter of the American Civil Liberties Union, the Lawyers Committee for Civil Rights and the local office of the international law firm of Weil, Gotshal & Manges LLP filed a federal lawsuit in Tampa, claiming that the state Bureau of Elections is breaking the law in its ongoing purge, designed to scrub voter registration lists ahead of the state’s August congressional primary.
Florida officials, according to the suit, are using outdated information and a badly-flawed process to conduct the purge, according to the suit. And the procedure, the advocates contend, requires lawful citizens and already legally registered voters to prove their citizenship or lose their ability to vote.
“Florida is flouting federal laws designed to protect voters from precisely this kind of action,” Bob Kengle, co-director, Voting Rights Project, Lawyers’ Committee for Civil Rights Under Law, said in a statement issued Friday. “The right of every citizen to have their voice heard at the ballot box is being threatened. The Lawyers’ Committee will continue to tirelessly fight any effort to make full-fledged Americans second-class citizens.”
“The illegal program to purge eligible voters uses inaccurate information to remove eligible citizens from the voter rolls,” Howard Simon, executive director of ACLUFL, added in the statement. Governor Rick Scott and his administration, Simon added, “mislead Floridians by calling their illegal list purge ‘protecting citizen's voting rights.’ This is precisely why Congress has re-enacted, and why we continue to need, the Voting Rights Act – to prevent state officials from interfering with the constitutional rights of minorities. We now look to the courts to stop the Scott administration from assaulting democracy by denying American citizens the right to vote.”
The lawsuit adds to the drama surrounding Florida authorities' attempt to update the state's voting rolls -- a move activists say is intended to suppress the vote and comes too close to the primary to be legal. State officials say the scrub, launched under Scott, a Republican, is necessary to prevent fraud and keep foreign nationals from tainting the ballot.
Last week, The Justice Department last month formally asked Florida to justify the move, warning that it might violate provisions in the Voting Rights Act and the National Voter Registration Act. In their response earlier this week, Florida officials insist the scrub is legal under both statutes, and would have happened much earlier in the election cycle if the Department of Homeland Security had allowed them to use a more expansive federal database for the comparison. | 2024-06-09T01:27:15.642919 | https://example.com/article/6011 |
Q:
How to place responsively sizing text over images without breaking grid structure?
I created a responsive grid of 12 equal images (400px x 400px) on the basis of Bootstrap 3 and added a heading h2 with span over each image, which should only appear when hovering over the tile.
The problem is that on smaller screensizes (width smaller than 990px) the text is not responsively changing its size in line with the images and is breaking out of the grid structure. I created a JS Bin for demonstration purposes:
http://jsbin.com/OdAfUqE/2/
Would appreciate your help on this.
HTML
<div class="row" id="service-wrapper">
<div class="col-xs-6 col-sm-2 nopadding" >
<a href="http://stackoverflow.com/">
<h2><span>Lorem ipsum dolor</span></h2>
<div><img src="../img/service1.jpg" class="img-responsive" alt="Responsive image"></div>
</a>
</div>
<div class="col-xs-6 col-sm-2 nopadding">
<a href="http://stackoverflow.com/">
<h2><span>Lorem ipsum dolor</span></h2>
<div><img src="../img/service2.jpg" class="img-responsive" alt="Responsive image"></div>
</a>
</div>
<div class="col-xs-6 col-sm-2 nopadding">
<a href="http://stackoverflow.com/">
<h2><span>Lorem ipsum dolor</span></h2>
<div><img src="../img/service3.jpg" class="img-responsive" alt="Responsive image"></div>
</a>
</div>
<div class="col-xs-6 col-sm-2 nopadding">
<a href="http://stackoverflow.com/">
<h2><span>Lorem ipsum dolor</span></h2>
<div><img src="../img/service4.jpg" class="img-responsive" alt="Responsive image"></div>
</a>
</div>
<div class="col-xs-6 col-sm-2 nopadding">
<a href="http://stackoverflow.com/">
<h2><span>Lorem ipsum dolor</span></h2>
<div><img src="../img/service5.jpg" class="img-responsive" alt="Responsive image"></div>
</a>
</div>
<div class="col-xs-6 col-sm-2 nopadding">
<a href="http://stackoverflow.com/">
<h2><span>Lorem ipsum dolor</span></h2>
<div><img src="../img/service6.jpg" class="img-responsive" alt="Responsive image"></div>
</a>
</div>
</div>
<div class="row" id="service-wrapper">
<div class="col-xs-6 col-sm-2 nopadding" >
<a href="http://stackoverflow.com/">
<h2><span>Lorem ipsum dolor</span></h2>
<div><img src="../img/service7.jpg" class="img-responsive" alt="Responsive image"></div>
</a>
</div>
<div class="col-xs-6 col-sm-2 nopadding">
<a href="http://stackoverflow.com/">
<h2><span>Lorem ipsum dolor</span></h2>
<div><img src="../img/service8.jpg" class="img-responsive" alt="Responsive image"></div>
</a>
</div>
<div class="col-xs-6 col-sm-2 nopadding">
<a href="http://stackoverflow.com/">
<h2><span>Lorem ipsum dolor</span></h2>
<div><img src="../img/service9.jpg" class="img-responsive" alt="Responsive image"></div>
</a>
</div>
<div class="col-xs-6 col-sm-2 nopadding">
<a href="http://stackoverflow.com/">
<h2><span>Lorem ipsum dolor</span></h2>
<div><img src="../img/service10.jpg" class="img-responsive" alt="Responsive image"></div>
</a>
</div>
<div class="col-xs-6 col-sm-2 nopadding">
<a href="http://stackoverflow.com/">
<h2><span>Lorem ipsum dolor</span></h2>
<div><img src="../img/service11.jpg" class="img-responsive" alt="Responsive image"></div>
</a>
</div>
<div class="col-xs-6 col-sm-2 nopadding">
<a href="http://stackoverflow.com/">
<h2><span>Lorem ipsum dolor</span></h2>
<div><img src="../img/service12.jpg" class="img-responsive" alt="Responsive image"></div>
</a>
</div>
</div>
CSS:
.nopadding {
padding-left:0;
padding-right:0;
}
.row {
margin: 0;
}
#service-wrapper img {
width: 100%;
}
#service-wrapper {
position: relative;
/*display: block;*/
}
#service-wrapper h2 {
opacity: 0;
filter: alpha(opacity=0);
line-height: 1.2;
position: absolute;
font-weight: 400;
width: 100%;
height: 100%;
background: #0066FF;
color: #000;
padding: 0;
margin-top:0px;
text-align: center;
vertical-align: middle;
-webkit-transition: opacity .2s linear;
-moz-transition: opacity .2s linear;
-o-transition: opacity .2s linear;
transition: opacity .2s linear;
}
service-wrapper h2 span {
display: block;
padding: 10px;
color: white;
font: bold 24px/45px Helvetica, Sans-Serif;
letter-spacing: -1px;
background: rgb(0, 0, 0); /* fallback color */
background: rgba(0, 0, 0, 0.7);
}
#service-wrapper a:hover h2 {
opacity: 1;
filter: alpha(opacity=100);
cursor: pointer;
}
A:
To control the font-size use media queries: http://css-tricks.com/snippets/css/media-queries-for-standard-devices/. Set some break-points (320, 480, 540, 768, or whatever you want) and lower the font-size with each of these.
Also, use the em unit on font-size, and reset the line-height to normal.
| 2023-08-11T01:27:15.642919 | https://example.com/article/4939 |
MOSCOW, July 25. /TASS/. Moscow is investigating into the circumstances of Ukraine’s decision to detain a Russian tanker to take appropriate steps, the Russian Foreign Ministry told TASS on Thursday.
"We are studying the details of what has happened to take appropriate measures," the Russian diplomatic agency stressed. "If the Russians were taken hostage, this will be qualified as a brazen violation of the international law and consequences will ensue quickly."
As for media reports claiming that the crew of the Russian tanker detained in the Ukrainian port of Izmail are about to return home, the Russian embassy in Kiev could not confirm them in an interview with TASS.
"We can neither confirm nor deny these reports. The embassy and the consulate in Odessa are trying to figure out the circumstances of the incident and ways to resolve the situation," it stressed.
Interaction of the human rights advocates
Meanwhile Russian human rights ombudswoman Tatiana Moskalkova has asked her Ukrainian counterpart, Lyudmila Denisova, to clarify the circumstances of the detention of the Russian tanker at the port of Izmail and provide information about the Russian crew.
"On July 25, Russian human rights ombudswoman Tatiana Moskalkova had a telephone conversation with human rights ombudswoman of the Ukrainian Verkhovna Rada [parliament — TASS] Lyudmila Denisova. Moskalkova asked Denisova to find out the circumstances of the vessel’s detention and the composition of the crew: how many Russian nationals are aboard, whether they receive consular support and their rights are observed, whether they are provided with food and drinking water and whether some of them need medical assistance," Moskalkova’s office issued a press statement on its website on Thursday.
"Denisova, in turn, promised to clarify the situation with the SBU [Ukrainian Security Service — TASS]. The ombudswomen agreed to continue their humanitarian dialogue," the statement added.
Stance of senior Russian MPs
Chairman of the Russian State Duma (lower house) Foreign Affairs Committee Leonid Slutsky characterized Ukraine's actions as "state piracy." In his vision, the Ukrainian authorities are trying to exert pressure on the investigation into the case of Ukrainian sailors being arrested for illegally crossing Russia’s state border in the Kerch Strait.
"Ukraine responded to its own provocation [in the Kerch Strait area] with an act of state piracy. [That’s] illegal pressure on the investigation," he wrote in a Twitter post.
Later he told journalists that such Kiev’s actions give away its unpreparedness to normalize "relations with Russia, in particular, in what concerns navigation in the Kerch Strait."
"It gives an impression that the new Kiev authorities’ hints at establishing cooperation with Russia have nothing to do with their real plans. The anti-Russian hysteria that was whipped up under Pyotr Poroshenko keeps rolling on," he said.
"Nevertheless, we continue to call for the normalization of Russian-Ukrainian relations. We will work with those who are ready for a constructive dialogue with Moscow. Many in the Kiev 'establishment' want to resume relations as soon as possible. And in terms of history, our peoples are destined to be good neighbors," Slutsky stressed.
Another high-ranking MP, Chairman of the Russian Federation Council (upper house) Foreign Affairs Committee Konstantin Kosachev also issued a comment. In his view, Ukrainian President Vladimir Zelensky needs to clarify his position on the detention of the Russian tanker by Ukraine’s Security Service but such a provocation doesn’t bode well for relations between Moscow and Kiev. "The circumstances of the incident need to be clarified, as well as Zelensky’s position. When does Ukraine show its true face, when it rattles sabers or speaks about peace? The moment of truth has come," he wrote on Facebook on Thursday.
He supposed that the Ukrainian Security Service (SBU) might be acting upon the order of the country’s president, "then Vladimir Zelensky is actually picking up a provocation initiated by his predecessor Pyotr Poroshenko who sought to achieve his campaign goals." "It is a very bad thing for Ukraine, its relations with Russia and all of those people who expected Zelensky to determine a different policy course. Another possibility is that Ukraine’s SBU is acting on its own, seeking to drag the president into a provocation," the Russian senator noted.
Kosachev added that the second possibility meant nothing good "because in this case, Zelensky is only a tool in the hands of Ukrainian law enforcement agencies formed by the previous authorities."
The Russian ship's detention
Earlier on Thursday, the Ukrainian Security Service (SBU) detained Russia’s Nika Spirit tanker at the port of Izmail, claiming that it was the Neyma tanker that had blocked the movement of Ukrainian ships during the Kerch Strait incident of last November. According to the SBU, Ukrainian border guards identified the Russian-flagged Nika Spirit tanker that had entered the port of Izmail under its IMO number registered with the EQUASIS international database as the Neyma, the tanker that had been used to block Ukrainian warships in the Kerch Strait. The SBU reported it was issuing a motion with a court to arrest the vessel as a physical evidence. | 2023-10-02T01:27:15.642919 | https://example.com/article/3172 |
.49 acre of vacant land in the City of Summerville. Zoning B-3 allows for a variety of uses. Minutes to I-26 and major shopping.
DIRECTIONS: From I-26 take exit 199A towards Summerville, turn right onto W 9th North Street, take the 1st left... | 2023-10-24T01:27:15.642919 | https://example.com/article/9050 |
Louise: Thank you for inviting me, Mr. Molitor. I always look forward to reading these interviews in the Clarion. I never expected to be the subject of one. I'm afraid your readers might be a little bored this time.
Giving him a narrow-eyed look, Louise responds: Just who have you been talking to, young man?"
Reilly, holding up his hands: Sorry, ma'am, but a reporter never reveals his sources. Maybe we should start off with the easy questions. How long have you lived here in Snowberry Creek?
Louise: Pretty much my whole life. I left to attend nursing school. My parents expected me to return after I graduated, but I wanted to see a bit of the world before I settled down. I surprised everyone, myself included, by enlisting in the army. I was stationed overseas most of the time and got to see a bit of Europe while I was there. I met my husband when he was a patient on the ward where I worked. After we both left the service, we married and moved back here.
Reilly: Did you continue your work as a nurse once you returned to civilian life.
Louise: Yes, but only until our two children were born. I stayed home with them until they were both in school. After that, I worked as a nurse for the school district which let me be home when the kids were off school. You know, like summer vacations and holidays. Of course, I've been retired for some time now.
Reilly: Retired, maybe, but I know you keep busy with various committees here in town. Do you have a favorite?
Louise: Certainly I enjoy my circle at church, but my favorite is the quilting guild. I've been friends with some of the ladies my whole life. At the same time, we're happy to have quite a few younger members, too. We've come together through our mutual love of the artistry of quilting.
Reilly: I understand Abby McCree recently took over as president of the group. How did that come about?
Louise, looking a bit guilty: She did agree to step in and serve the remainder of her late aunt's term of office. You see, we convinced Abby that Sybil would have wanted her to assume her duties.
Reilly: But is that really true? It seems like a lot to ask of a relative newcomer to town like Ms. McCree.
Louise: She might be new to town, but she's proven herself to be up to the job. Her organizational skills are amazing and have made a real difference for our group. Largely thanks to her efforts, our annual garage sale was a huge success.
Louise pauses to give Reilly a sly look before continuing. But the real reason we wanted Abby to take over was to get her involved here in Snowberry Creek. You know, to help her make some strong personal connections in town. We wanted her to feel like she really belongs here. Of course, it helps that she's so friendly to everyone she meets.
Reilly looks up from his notes: Really? Because I've got to say that she seems pretty skittish to me. At least that's how she reacted when I tried to interview her.
Louise: Maybe because she knows the only reason you've come knocking was because you were hot on the trail of a story. Have you thought about interviewing her for this column?
Reilly: Yeah, I have, but she hangs up whenever I call her. If I go anywhere near her house, that huge dog of hers growls at me, and her tenant threatens to toss me out onto the road to see how high I would bounce.
Louise reaches out to pat Reilly on the arm. Well, I admit both Zeke and Tripp are pretty protective of her. Considering everything she's been through lately, I can's say as I blame them. I'll put in a good word for you, though. Especially if you mention that the quilting guild will be selling chances on another quilt this year. The proceeds go to buy fabric so we can make quilts for the local fire and police departments to give away to the children they meet while out on calls.
Reilly: I'll be sure to do that. Have Ms. McCree send me all the details, and I'll post the information periodically on the Clarion's social media throughout the year. Is there anything else you'd like to add?
Louise: No, but thank you for having me here today. My kids will be thrilled to see my picture in the paper!
Reilly: Well, that's it for this month's edition. If any of you out there know someone you think should be the subject of one of these interviews, you can contact me through the paper. | 2024-02-11T01:27:15.642919 | https://example.com/article/5048 |
Q:
Dynamically added directive is not interpolated
I have a call stack like below and problem is that directive template is not interpolated. So as a result of this I can see {{ data | json }} as a string and ng-repeat is not triggered. How to approach this?
Context of situation is that I have a Highchart's chart where I need to provide clickable plot lines. On line click I need to display popover with dynamic content.
Optional question to answer:
My play with events is working well but I'm not sure if it's also well done. I would welcome any criticism on that. Idea is to hide popover on all following clicks.
Code:
1.
series: {events: {click: function(e) {drillDownCall(e, dataGroups)}
2.
function drillDownCall (e, dataGroups) {
var elem = angular.element('#drilldown');
if (!elem[0]) {
elem = angular.element('<drilldown fancy-name="dataGroups"></drilldown>');
}
elem.css({
position: 'absolute',
top: e.pageY,
left: e.pageX,
width: '150px',
height: '250px',
zIndex: '2000',
background: 'red'
});
var body = angular.element(document).find('body').eq(0);
var scope = $rootScope.$new();
scope.dataGroups = dataGroups;
body.append($compile(elem)(scope));
}
3.
.directive('drilldown', [
'$compile',
'$window',
function (
$compile,
$window
) {
return {
restrict: 'E',
replace: true,
scope: {
data: '=fancyName'
},
template: '' +
'<div id="drilldown">{{ data | json }}' +
'<ul>' +
'<li ng-repeat="group in data">{{ group.name }}</li>' +
'</ul>' +
'</div>',
link: function (scope, element) {
var ele = $compile(element)(scope),
off;
angular.element($window).on('click', function(e) {
scope.$emit('drilldown::click');
});
off = scope.$on('drilldown::click', function() {
angular.element(ele).remove();
angular.element($window).off('click');
off();
});
}
};
}]
)
A:
I am unable test it myself but I think I know why.
Start of everything is drillDownCall and it is called by an event that is outside of Angular.js digest cycle. So Angular.js has no idea that there is a change in scope, and doesn't run a digest cycle, causing the new directive appear as non-compiled bunch of strings. (yes even you used $compile it works like that)
In summary, if I remember correct, you need at least one digest cycle to see that directive compiled. To trigger a digest cycle, you can add
$rootScope.$apply() or $rootScope.$applyAsync() or anything equivalent to it to the end of drillDownCall event handler.
Can you please try this?
| 2024-02-11T01:27:15.642919 | https://example.com/article/1155 |
Q:
How can I add a local drive to a Linux VM with Hyper-V that will stick around after I turn a VPN on inside the VM?
I have a Win 10 Pro host, running a Linux Mint VM.
I'd like the VM to always be connected to my VPN (Mullvad). I'd like it to be able to see a folder on my host machine, B:\ISOs. It will download stuff and place it here for me.
I can "share" a local drive while my VPN is off just fine.
Once I turn my VPN on, the drive is no longer accessible. My VPN has an option for "Local Sharing" that is turned on.
I was really hoping that I could just add a folder as a drive like I have with other VM solutions, without having to use the "share" route. But from my research there isn't a way to add a folder as a disk with Hyper-v (but if I'm wrong I'd be very happy).
Any advice would be awesome. Thanks.
A:
There is an workaround for Windows 10 - vhds
Create VHDS and mount it (as a folder) on host OS.
Copy required data to created disk.
Attach disk to Linux Mint
| 2024-06-05T01:27:15.642919 | https://example.com/article/1289 |
Oaking sauvignon blanc often overwhelms the fruit, but the combination of new and used French and Acacaia barrels adds complexity and structure. Less grassy than many California sauvignon blancs, with lemon zest, lemongrass, and even dried green herb flavors.
Less bitter and not quite as hoppy as many IPAs, but also richer and with more caramel and malt – this is a beer that needs food despite only 4.9 percent alcohol. Look for some lemon and floral aromas, with a full body and a longish finish.
A heavier, more red wine-like rose made in the post-modern style, and that includes 14 percent alcohol. More of a food wine than a porch sipper, with dark fruit flavors – dried strawberry, black cherry – and less crisp and more robust than many roses.
This dark rum is aged in used oak barrels used to make Colorado whiskey and gets a touch of local honey, which gives it an appealing, sugary aroma. The rum is deep and intriguing, with a variety of flavors – a hint of caramel, some spicy notes that pop up out of nowhere, and an almost tropical fruit finish.
About The Author
Jeff Siegel is a nationally known wine writer whose Wine Curmudgeon blog is one of the top 100 wine sites in the world. He’s co-founder and former president of Drink Local Wine, the first locavore wine movement, and his latest book is The Wine Curmudgeon's Guide to Cheap Wine. Leading the issue’s sustainability theme, Siegel tracks down producers using alternate energy sources for most (or all) operations, and finds the benefit isn’t just about cost savings. | 2024-04-21T01:27:15.642919 | https://example.com/article/4664 |
#!/bin/bash
set -eu
DOCKERFILE=Dockerfile
FROM=sail-base
IMAGE_NAME=codercom/ubuntu-dev
../buildfrom.sh $DOCKERFILE $FROM $IMAGE_NAME
../push.sh $IMAGE_NAME | 2024-01-14T01:27:15.642919 | https://example.com/article/4285 |
Belovski on the menu
A number of rabbis - Orthodox, Reform and Masorti - are down to speak at Gefiltefest, the food equivalent of Limmud, on Sunday week, including a leading home contender for the Chief Rabbinate, Rabbi Harvey Belovski of Golders Green (who has never been to Limmud).
He will be explaining why that troublesome fish, the turbot, even though once served to a Chief Rabbi at a communal banquet, is not considered kosher. | 2023-12-15T01:27:15.642919 | https://example.com/article/9164 |
Frequency of intracranial injury in cadavers with head trauma with and without scalp injury in Tehran.
Traumatic brain injury is a major cause of morbidity, disability and mortality in patients with head injury. The aim of this study was to elucidate the frequency of intracranial injury in cadavers with head trauma with and without scalp injury in Tehran. In this analytical cross-sectional study, we investigated 187 cadavers who died due to head trauma in motor vehicle accident or after falling in Tehran from November 2013 to February 2014. Age, sex, mechanism of trauma, scalp injury, sub-scalp bruising, skull fracture, hemorrhage including subdural hemorrhage (SDH), epidural hemorrhage (EDH), subarachnoid hemorrhage (SAH) and contusion were recorded from examination and autopsy. One hundred and eighty seven cadavers (165 (88.2%) male and 22 (11.8%) female) with head injury with the mean age of 36.14 years (SD = 15) were recruited in this study. Mechanism of trauma was motor vehicle accident in 147 (78.6%) cadavers and falling in 40 (21.4%) cadavers. One hundred and fifty eight (84.5%) had SDH, 44 (23.5%) had EDH, 162 (86.6%) had SAH and 139 (74.3%) had contusion. Hemorrhage was seen in 132 (93%) cadavers who had scalp injury and 36 (80%) cadavers who did not have scalp injury (p = 0.01). Overall, 168 (89.8%) cadavers had hemorrhage and 139 (74.3%) had contusion. There was a significant correlation between intracranial injuries and scalp injury (p < 0.05). There was not a significant correlation between EDH and scalp injury (p = 0.52). Consequently, in patients with head trauma, complete examination should be performed but absence of findings in examination cannot exclude intracranial injury. | 2024-07-31T01:27:15.642919 | https://example.com/article/7999 |
Hangash
The Hangash (), an acronym standing for Defence Security Agency, was a notorious secret police unit in Communist Somalia under Siad Barré until his overthrow in 1991.
Overview
Created in the aftermath of the 1978 coup attempt, the official purpose of the Hangash was to maintain surveillance over the Somali Armed Forces and the more widely known National Security Service (NSS). As the Barré government's crackdown on political activity became more severe, however, the Hangash acquired direct powers in civilian matters, overlapping with those of NSS. According to a 1993 Country Study published by the U.S. Library of Congress, "[e]ventually, the Hangash, which operated without legal authority, became more feared than the NSS".
When the NSS was formally dissolved in 1990, many of its activities were subsumed by the Hangash and other institutions comprising the security apparatus of the Barré regime, such as the Mobile Military Court (MMC), the Regional Security Council (RSC), and the Victory Pioneers.
References
Category:Defunct intelligence agencies
Category:Somali intelligence agencies
Category:Secret police
Category:Military history of Somalia
Category:Communism in Somalia
Category:Government agencies disestablished in 1991
Category:1991 disestablishments in Somalia | 2023-09-05T01:27:15.642919 | https://example.com/article/3373 |
Moment equations in spatial evolutionary ecology.
How should we model evolution in spatially structured populations? Here, I review an evolutionary ecology approach based on the technique of spatial moment equations. I first provide a mathematical underpinning to the derivation of equations for the densities of various spatial configurations in network-based models. I then show how this spatial ecological framework can be coupled with an adaptive dynamics approach to compute the invasion fitness of a rare mutant in a resident population at equilibrium. Under the additional assumption that mutations have small phenotypic effects, I show that the selection gradient can be expressed as a function of neutral measures of genetic and demographic structure. I discuss the connections between this approach and inclusive fitness theory, as well as the applicability and limits of this technique. My main message is that spatial moment equations can be used as a means to obtain compact qualitative arguments about the evolution of life-history traits for a variety of life cycles. | 2024-01-27T01:27:15.642919 | https://example.com/article/7929 |
Q:
Python list append to list "AttributeError: 'tuple' object has no attribute 'append'"
Alright so I know you cannot append a tuple to a list. However I am still receiving this error despite my best efforts. Can someone tell me what I am doing wrong or what is going on?
Traceback (most recent call last):
File "C:/Users/.py", line 31, in
listRow.append(convertedList)
AttributeError: 'tuple' object has no attribute 'append'
followedBy is a string that comes from a cursor and is split into a list form. Below is some sample data that the cursor would contain.
followedBy = "0| 1| 2| 40"
table = [] #contains all rows (table)
row = [] #contains row
listFollowedBy = [] #contains ids
for (var1, var2, var3, followedBy) in cursor:
row = var1, var2, var3
listFollowedBy = followedBy.split("| ") #Thought split always split the data into lists
convertedList = list(listFollowedBy) #Threw this in there just to insure it was converted to a list
row.append(convertedList)
table.append(row)
A:
Tuples are immutable meaning they can't be changed unless reassigned. You can however add tuples to a list because lists are mutable, meaning they can be changed. You need to edit the order of your append.
listFollowedBy.append(row)
As of now, your row is a tuple. Tuples don't have an append method, lists do. Why are you appending a list to a tuple instead of a tuple to a list? You've got the method call backwards.
| 2024-07-22T01:27:15.642919 | https://example.com/article/5083 |
Apparently Wolverine Turned Down James Bond and Other Actors Who've Walked Away from Blockbuster Roles
While out promoting his role in Les Miz leading up to this Sunday's Oscars, or maybe it was promoting the fact that everyone on the planet likes him, Hugh Jackman opened up about turning down the role of James Bond 007 when producers Barbara Broccoli and Michael G. Wilson were looking to erase Die Another Day from the minds of the public with a new, badder, bigger, Bourner Bond and offered it to the Wolverine-star.
Jackman told the Hollywood Reporter that at the time,'I thought it would box me in too much,' Jackman said. 'My natural instinct is to keep as many doors open as possible.' Jackman is probably one of the few people who can turn down an iconic role like that and live to tell the tale. Despite the fact that it was sh*ttier than a statue under a bird's nest in a public park, X-Men Origins: Wolverine garnered itself a sequel coming out later this year, The Wolverine, with early buzz looking much more positive than its predecessor. And Jackman is also confirmed to reprise the role in the time-travel themed X-Men Days of Future Past. So he's doing alright.
Hey, you never know how a movie will turn out. A movie is only as good as the sum of its parts and it may only work and be successful because a particular actor is in a particular role. Swap that out and the whole thing may crumble. Which is why we took a look at ten films and the actors that walked away from the famous roles in them. It's weird to imagine how things might have been. | 2024-07-02T01:27:15.642919 | https://example.com/article/1474 |
Introduction
============
Esophageal cancer (EC) is one of the most lethal types of digestive tract malignancy in the world.[@b1-ott-10-3095],[@b2-ott-10-3095] Esophageal squamous cell carcinoma (ESCC) is the predominant subtype of EC, with the highest incidence in People's Republic of China.[@b3-ott-10-3095] Although the diagnosis and treatment have been advanced during recent years, ESCC still ranks among the fourth leading cause of cancer-related death.[@b4-ott-10-3095] Because it is hard to detect at the early stage, and the tumor recurrence and metastasis after surgery are also very intractable, the long-term outcome of this malignancy is dismal, with an overall 5-year survival rate less than 10%.[@b5-ott-10-3095]--[@b7-ott-10-3095] A poor understanding of carcinogenic mechanism and a lack of biomarkers with desired sensitivity and specificity pose a major challenge in diagnosing ESCC. Therefore, comprehensive surveying of the molecular mechanism will facilitate parsing of the esophageal tumorigenesis progress and detection of efficient prognostic biomarkers.
Protein coding genes are usually regarded as tumor markers in ESCC pathology,[@b8-ott-10-3095] but only \~1.2% of the human genome encodes for protein-coding genes, and the large majority is transcribed into non-coding RNAs (ncRNAs).[@b9-ott-10-3095]--[@b11-ott-10-3095] Long non-coding RNAs (lncRNAs), which are longer than 200 nucleotides without protein coding capability, can regulate the expression of genes in various biological processes.[@b12-ott-10-3095],[@b13-ott-10-3095] Aberrant lncRNA expression participates in carcinogenesis by disrupting the major biological processes,[@b14-ott-10-3095] and could also serve as a potential diagnostic or prognostic biomarker for diverse human malignancies.[@b15-ott-10-3095]--[@b17-ott-10-3095] For example, HOTAIR is a well-known lncRNA, whose expression levels powerfully predict metastases and survival in different cancer types,[@b13-ott-10-3095],[@b18-ott-10-3095] including ESCC.[@b19-ott-10-3095],[@b20-ott-10-3095] However, the understanding of these lncRNAs is insufficient, and the functional implications of most lncRNAs remain to be explored.
Genome-wide gene expression profile has become an instrumental resource and been used pervasively in cancer research. Many of prognostic and diagnostic mRNAs and lncRNAs have been identified by the traditional differential expression approach. However, this method focuses on the differentially expressed individual genes and cannot present the changes in gene interconnection in response to different conditions.[@b21-ott-10-3095] Fortunately, differential co-expression analysis is not only emerging to complement the shortage, but also can hint the altered regulatory relationships and cancer-specific dysregulations.[@b22-ott-10-3095]--[@b24-ott-10-3095] Construction of differential co-expression models, which integrate mRNAs and lncRNAs, could uncover the underlying functional roles of lncRNAs in tumorigenesis progress. Therefore, it is reliable to study the molecular biological mechanism of cancerogenesis and identify cancer-related prognostic lncRNAs by using differential co-expression analysis.
Here, we used a differentially co-expressed method by integrating information of mRNAs and lncRNAs from 119 ESCC tissues and matched adjacent normal tissues to identify a set of differentially co-expressed genes (DCGs; mRNAs and lncRNAs) and links. To systemically explain the mechanism of transcriptome alteration in ESCC, we developed a differential regulatory network by harnessing these differentially co-expressed mRNAs (DCmRNAs). Furthermore, based on the differentially co-expressed lncRNAs (DClncRNAs), we found two novel lncRNAs, ADAMTS9-AS1 and AP000696.2, that could predict the survival of patients with ESCC and might be essential in the development of the ectoderm and epithelial cells. Our study demonstrates that the transcriptional dysregulation is the critical cause of ESCC tumorigenesis, and the two-lncRNA signature may be regarded as a novel prognostic molecular marker, which is better than traditional biomarkers. Furthermore, it will be helpful to further experimental studies on lncRNAs in ESCC.
Materials and methods
=====================
Expression profile dataset
--------------------------
The normalized gene expression datasets of ESCC (GSE53624[@b25-ott-10-3095] and GSE53622[@b25-ott-10-3095]) were downloaded from National Center for Biotechnology Information Gene Expression Omnibus database. The training dataset (GSE53624) included 119 ESCC and matched adjacent normal tissue samples. The independent testing dataset (GSE53622) contained 60 ESCC and matched adjacent normal tissue samples. All of patients in GSE53624 and GSE53622 were followed up for 5 years at least. The median follow-up time of patients in GSE53624 and GSE53622 was 32.2 and 39.5 months, respectively. The clinical characteristics of the two dataset populations are presented in [Supplementary materials, Table S1](http://pan.baidu.com/s/1pLBcaF5). The expression profile of ESCC was performed using Agilent-038314 CBC Homo sapiens lncRNA+mRNA array V2.0 platform. (Agilent Technologies, Santa Clara, CA, USA). Each array contained probes interrogating 32,000 human mRNAs and 39,000 human lncRNAs. The probes with the same sequence were merged, resulting in 35,025 unique probes. GENCODE database was taken as reference to annotate mRNAs and lncRNAs. Then, we employed the Basic Local Alignment Search Tool (BLAST) program to map the unique probes to the reference; 17,245 mRNAs and 5,760 lncRNAs with at least one unique probe were retrieved.
Differential co-expression analysis
-----------------------------------
Differential co-expression analysis for the expression profile of the training dataset was conducted in R environment (V3.2.3) using differentially co-expressed genes and links (DCGL) package (V2.0).[@b22-ott-10-3095]--[@b24-ott-10-3095] First, the genes were filtered by the method of gene variance with default options, which resulted in a total of 12,426 genes preserved. Next, differential co-expression profile and differential co-expression enrichment (DCe) methods were adopted to identify DCGs, while differentially co-expressed links (DCLs) were identified by the modified limit fold change model incorporated in the DCe method. In summary, 4,632 DCGs and about 6,384,526 DCLs were obtained, with each DCL containing at least one DCG. The DCGs consisted of 3,709 DCmRNAs and 923 DClncRNAs. In order to remove the low correlation DCLs, the correlation coefficients of gene pairs less than 0.2, 0.3 and 0.4 in both normal and tumor conditions were used as cutoffs. As similar results could be observed under the three criteria (see "Results" section), we selected 0.3 to be the final cutoff for removing low correlation DCLs, and the remaining DCLs were used for further analysis.
Functional analysis of ESCC-associated DCGs
-------------------------------------------
The gene ontology (GO) and pathway enrichment analysis were performed using DAVID software[@b26-ott-10-3095] to investigate the functional roles of DCmRNAs in the development of ESCC (Benjamin adjust *P*-value \<0.01). In addition, priori knowledge was incorporated to verify the association of DCGs with the disease. Gene enrichment analysis was also performed for the DCmRNAs based on 572 cancer genes from Cancer Gene Census,[@b27-ott-10-3095] 1,601 human drug targets from DrugBank,[@b28-ott-10-3095] as well as 363 ESCC-related genes from seven high-quality literatures (Fisher test, *P*-value \<0.05).[@b29-ott-10-3095]--[@b35-ott-10-3095] Meanwhile, gene enrichment analysis was performed for the DClncRNAs based on 253 cancer-related lncRNAs from Lnc2Cancer (Fisher test, *P*-value \<0.05).[@b36-ott-10-3095]
DCmRNAs: construction of regulatory network
-------------------------------------------
The regulatory networks were constructed to reveal the molecular mechanism of transcriptional alteration in ESCC. The transcription factor (TF)-target relationships predicted in our previous study were treated as the reference network of transcriptional regulation.[@b37-ott-10-3095] The gene set of 3,709 DCmRNAs was used for the construction of ESCC-related TF-target networks in the normal and tumor conditions by using linear regression model.[@b37-ott-10-3095] The important differentially regulated genes (DRGs) were identified by calculating the differential regulation (DR) value of genes between the two regulatory networks.[@b37-ott-10-3095] The DR value could measure whether a DRG was highly relevant to the tumorigenesis. According to the changes of the regulation efficacy between a TF and its target, the differentially regulated links (DRLs) were identified, which were equal or greater than the average value across all TF-target pairs.
DClncRNAs: the identification of novel prognostic lncRNAs
---------------------------------------------------------
The 923 DClncRNAs were taken as the initial gene set for screening prognostic biomarkers. To choose the cancer-related candidates, only the lncRNAs differentially co-expressed with cancer genes, drug targets or *ESCC* genes were considered. To shrink the DClncRNAs, we considered the differential expression between the normal and tumor tissues (Paired Student's *t*-test, Benjamin-Hochberg adjust *P*-value \<0.05), and the top 10 lncRNAs with the highest fold changes were selected as the prognostic candidates.
To obtain an optimal combination from the top 10 lncRNAs, 5-fold cross-validation was used. There are 1,023 combinations (2[@b10-ott-10-3095]−1) for the 10 lncRNAs. For each combination, prognostic accuracy was calculated by the K-means algorithm based on their expression profile to stratify ESCC samples into high-risk and low-risk groups. Kaplan--Meier survival analysis was performed for the two groups, and statistical significance was assessed using the log-rank test by using the R survival package.[@b38-ott-10-3095] The optimum lncRNA combination was determined by the most significant average *P*-value in the 5-fold cross-validation.
To explore the function of the identified prognostic lncRNAs, functional enrichment analysis was performed for mRNAs, which were differentially co-expressed with them. By doing this, 675 DCmRNAs were used to predict their prognostic capacities. The hazard ratio (HR) of genes were evaluated by using the SurvComp package in R, and a univariate Cox regression model was implemented to analyze the relationship between the gene expression and survival time. The genes with *P*-value \<0.05 were selected for the survival analysis[@b39-ott-10-3095],[@b40-ott-10-3095] as we did for lncRNAs.
Results
=======
Identified DCGs and DCLs
------------------------
A total of 17,245 mRNAs and 5,760 lncRNAs across 119 ESCC and matched adjacent healthy tissue samples were retrieved from the training dataset. After being filtered by variance, 9,078 mRNAs and 3,348 lncRNAs were preserved for differential co-expression analysis by the DCGL package (see "Materials and methods" section). As a result, DCLs containing 4,632 DCGs were yielded for further analysis, including 3,709 DCmRNAs and 923 DClncRNAs.
To investigate the functions of the ESCC DCGs, functional enrichment analysis was carried out for the DCmR-NAs, and significant GO terms are listed in [Supplementary materials, Figure S1](http://pan.baidu.com/s/1pLBcaF5). These DCmRNAs might take part in ESCC cell growth (such as development, differentiation and proliferation of cells), in agreement with the fact that cancer is a disease involving dysregulation of multiple fundamental cell processes such as development, proliferation, differentiation, migration and apoptosis.[@b41-ott-10-3095] The DCmRNAs were also enriched in two Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of extracellular matrix (ECM)-receptor interaction and arachidonic acid metabolism, which were reported to contribute to esophageal squamous cell carcinogenesis.[@b42-ott-10-3095]--[@b44-ott-10-3095] Gene enrichment analysis proved that the DCGs were also significantly enriched in drug targets (*P*-value =9.85E-6), *ESCC* genes (*P*-value =1.15E-14) and cancer related lncRNAs (*P*-value =3.04E-5), except cancer genes (*P*-value =0.34). We purposed that there would be some novel and important cancer-related genes in the DCGs.
After removing the DCLs with the absolute correlation coefficient less than 0.3 in both normal and tumor conditions, the rest of DCLs included 939,936 mRNA-lncRNA associations; 2,192,442 mRNA-mRNA associations and 112,005 lncRNA-lncRNA associations. We divided the DCLs into three types, "loss-of-association", "gain-of-association" and "reverse-of-association". If the absolute correlation coefficient of a DCL was equal or greater than 0.3 in the normal, but smaller than 0.3 in the ESCC, it would be grouped into the "loss-of-association" type. On the contrary, it belonged to the "gain-of-association" type. The "reverse-of-association" was the case wherein the absolute correlation coefficient was larger than 0.3 in both normal and tumor conditions, but the direction of association was reversed during tumorigenesis ([Figure 1A](#f1-ott-10-3095){ref-type="fig"}). Our results showed that almost 80% DCLs lost associations, 20% gained new associations and only few of DCLs reversed associations ([Figure 1B](#f1-ott-10-3095){ref-type="fig"}). We also tested other cutoffs of 0.2 and 0.4, and similar results were obtained ([Supplementary materials, Figure S2](http://pan.baidu.com/s/1pLBcaF5)). When DCLs were classified into three types, mRNA-lncRNA, mRNA-mRNA and lncRNA-lncRNA, this result still held, suggesting a widespread alteration of gene relationships in the transcriptome of ESCC.
Comparison of regulatory network
--------------------------------
We hypothesized that the dysfunctional regulation of TFs may be one of the important causes for transcriptome alteration. To prove the hypothesis, we used the 3,709 DCmRNAs to build normal and ESCC regulatory networks (see "Materials and methods" section). The regulated links could represent the causal influences in the network. By comparing the difference of the two regulatory networks, 4,442 and 3,492 regulated links were observed in the normal and ESCC conditions. The changes of the regulation efficacy were employed to screen the TF-target pairs, and 2,208 DRLs contributed by 37 TFs were identified. We found that seven of top 10 DRmRNAs that had the largest DR values ([Supplementary materials, Table S2](http://pan.baidu.com/s/1pLBcaF5)) were TFs, and these TFs regulated nearly half of DRLs. Among them, *TCF3*, *TP53*, *MYB* and *JUN* were cancer-related genes in the database of Cancer Gene Census.[@b27-ott-10-3095] Next, DRLs were divided into five types according to the changes of the regulation efficacy in the tumor compared with the normal cells, "loss-of-regulation" (42.66%), "gain-of-regulation" (24%), "reverse-of-regulation" (20.11%), "weaken-of-regulation" (9.15%) and "strengthen-of-regulation" (4.08%) ([Figure 2A](#f2-ott-10-3095){ref-type="fig"}). This result was consistent with our differential co-expression analysis that most DCLs belonged to the loss-of-association type.
Then, the GO term functional enrichment analysis was separately performed for TF-target pairs in the five types of DRLs. We found that the five types were all significantly enriched in positive regulation of biosynthetic and metabolic processes and transcription ([Supplementary materials, Table S3](http://pan.baidu.com/s/1pLBcaF5)), and some biological functions were specific to each type ([Figure 2B](#f2-ott-10-3095){ref-type="fig"}). Interestingly, 20.11% of reverse-of-regulation DRLs had the most significant GO terms, and they were enriched in both positive and negative regulation of bio-synthetic and metabolic process and transcription, suggesting their capacity of bi-directional regulation. The KEGG pathway enrichment analysis revealed that the reverse-of-regulation DRLs significantly enriched in Wnt signaling pathway, which was proved to be associated with the ESCC progression and metastasis.[@b33-ott-10-3095],[@b45-ott-10-3095]--[@b47-ott-10-3095] Our results demonstrated that the alterations of gene-to-gene relationships in the ESCC may be mediated by the dysregulation of TFs to some extent.
Identified novel lncRNAs associated with the overall survival of ESCC patients
------------------------------------------------------------------------------
lncRNAs carry out the regulatory functions base on their complex structures which are convenient for binding proteins, RNA, DNA, and closely associate with the progression of disease that have been widely regarded as biomarkers. In order to investigate whether the DClncRNAs could become prognostic indicators for the survival of ESCC patients, differential co-expression method identified 923 DClncRNAs, which served as the initial prognostic candidates. In order to narrow down the DClncRNAs, a total of 820 cancer-related lncRNAs were found through differential co-expression with cancer genes, drug targets and *ESCC* genes, simultaneously ([Figure 3](#f3-ott-10-3095){ref-type="fig"}). The differential expression analysis was adopted to narrow down the candidates (see "Materials and methods" section). The top 10 lncRNAs in terms of their fold change were selected for the cross-validation analysis. A two-lncRNA combination, ADAMTS9-AS1 (ENSG00000241158.5) and AP000696.2 (ENSG00000231324.1), was identified as the optimal combination for predicting the survival of ESCC patients ([Figure 3](#f3-ott-10-3095){ref-type="fig"}).
The expression of the two lncRNAs categorized 119 ESCC patients into high-risk and low-risk groups (log rank test, *P*-value =1.28E-2) ([Figure 4A](#f4-ott-10-3095){ref-type="fig"}). Among them, 42 patients were identified as belonging to the "high-risk" group, in which less than 24% living people were observed and the median of overall survival time was 22.92 months. By contrast, 77 patients were grouped as belonging to the "low-risk" group, in which 47% living people were observed and the median of overall survival time was 48.77 months. Next, we verified the prediction power of the two lncRNAs in an independent dataset of 60 patients. The patients were classified into the high-risk (19) and low-risk groups (41) with significantly different survival time (log rank test, *P*-value =2.56E-2) ([Figure 4B](#f4-ott-10-3095){ref-type="fig"}). With a similar result, there were 26% living patients in the high-risk group and the median survival time was 16 months, and 54% living patients in the low-risk group and the median survival time was 48 months. CYFRA21-1 and CEA, two traditional tumor markers, have been used for diagnosis of ESCC.[@b48-ott-10-3095] High CYFRA21-1 level in patients is associated with poor prognosis. CEA is significantly associated with overall 5-year survival in ESCC.[@b49-ott-10-3095]--[@b51-ott-10-3095] Then, we compared our lncRNA biomarkers with the traditional tumor markers CYFRA21-1 and CEA. The result showed that our lncRNA markers had a higher power to predict the survival of human ESCC patients ([Figure 5](#f5-ott-10-3095){ref-type="fig"}).
mRNAs differentially co-expressed with the two-lncRNA biomarker
---------------------------------------------------------------
ADAMTS9-AS1 and AP000696.2 were two novel lncR-NAs without any functional annotations, except another ADAMTS9 antisense transcript. ADAMTS9-AS2 could regulate the expression level of tumor suppressor ADAMTS9, and its overexpression resulted in significant inhibition of glioma cell migration.[@b52-ott-10-3095] Furthermore, the starBase[@b53-ott-10-3095] showed that ADAMTS9-AS1 interacted with two RNA-binding protein genes, *DCGR8* and *FUS*. lncRNAs exert regulatory function in cancer biology mainly through their relationships with RNA-binding proteins. H19, HOTAIR, MALAT1 and HOTTIP are essential in many biological events for cell proliferation and differentiation, apoptosis and tumorigenesis via their impact on RNA-binding protein in HCC.[@b54-ott-10-3095] Therefore, we proposed that ADAMTS9-AS1 might be functional in the development of cancer. To investigate the potential function of ADAMTS9-AS1 and AP000696.2 in ESCC, GO enrichment was performed to analyze the mRNAs that were differentially co-expressed with them. We got 1,139 mRNAs that were differentially co-expressed with ADAMTS9-AS1 or AP000696.2, in which 1,056 mRNAs lost associations and 86 mRNAs gained associations with the two lncRNAs. First, we performed the GO enrichment analysis for these mRNAs. The result indicated that they were significantly enriched in the biological process of ectoderm development and epidermis development (adjust *P*-value \<0.01). The epidermis, which is formed by ectoderm, is the outermost layer of the skin, and protects the body from environmental insults.[@b55-ott-10-3095] The development of the ectoderm and epidermis are two crucial functions in the progression of ESCC and hence the two novel lncRNAs might be very important in the development of the ESCC.
Second, we constructed the regulatory network for the high-risk and low-risk groups, which were classified by our two identified novel prognostic lncRNAs, respectively, and then compared with the normal regulatory network one by one. The results revealed that the changes of TF-target pairs between the normal and the low-risk group were smaller than those between the normal and the high-risk group (Wilcoxon test, *P*-value =2.15E-2) ([Supplementary materials, Figure S3](http://pan.baidu.com/s/1pLBcaF5)). This large number of dysregulation might contribute to the poor prognosis of the high-risk group.
Third, we wondered that if the mRNAs differentially co-expressed with the two prognostic lncRNAs also had the capacity of predicting the survival outcome of ESCC patients. To test this, we used the HR and survival analysis to screen the DCmRNAs from the 1,139 mRNAs (see "Materials and methods" section). Finally we identified four mRNAs, *ERBB3*, *ENSA*, *KCNK7* and *MFSD5*, that could significantly divide the patients into high-risk and low-risk groups both in the training and testing datasets ([Supplementary materials, Figure S4](http://pan.baidu.com/s/1pLBcaF5) and [Supplementary materials, Table S4](http://pan.baidu.com/s/1pLBcaF5)). These four mRNAs were all signal transduction-related genes.
Discussion
==========
In this study, differential co-expression analysis of ESCC expression profiles was applied to analyze the mechanism of transcriptome alteration and identify the novel prognostic lncRNAs. We firstly proposed three different types of DCLs among the DCGs, "loss-of-association", "gain-of-association" and "reverse-of-association", and found that most DCLs belonged to the loss-of-association type. Considering the importance of DCmRNAs in ESCC, we constructed the normal and ESCC regulatory networks for the DCmRNAs to explore the alteration of gene co-expression caused by dysfunctional regulation of TFs. By comparison of two networks, we found that 37 TFs contributed to the all DRLs, in which the predominant type was the "loss-of-regulation".
Nearly half of the DRLs were concerned by seven TFs in the top 10 DRGs, in which *TCF3* and *TP53* were very meaningful and worthy to notice as they contributed to more than a quarter of loss-of-regulation DRLs. *TCF3* was the TF that had the highest DR value and the most DRLs in all DCmRNAs, and most of the DRLs regulated by *TCF3* were loss-of-regulation type. It has been reported that *TCF3* is a transcriptional repressor and plays the key role in cell fate, and its overexpression could block epithelial differentiation.[@b56-ott-10-3095],[@b57-ott-10-3095] *TP53* was ranked the third one among the DRGs. In all, 76.92% of *TP53*-DRLs belonged to the loss-of-regulation, and none of the other TFs showed such obvious preference. The multifunctional TF *TP53* was involved in the carcinogenesis of various malignancies, and is frequently mutated in \>50% of human cancers.[@b58-ott-10-3095]--[@b60-ott-10-3095] A lot of *TP53* mutants can lead to the loss of its DNA-binding activity and affect its role as a TF.[@b58-ott-10-3095]--[@b61-ott-10-3095]
lncRNAs can be dysregulated in tumor progression[@b62-ott-10-3095],[@b63-ott-10-3095] and involved in tumorigenesis, invasion and metastasis.[@b12-ott-10-3095],[@b14-ott-10-3095] However, their potential as diagnostic and prognostic markers is less explored. In our study, we found and validated that a two-lncRNA combination (ADAMTS9-AS1 or AP000696.2) was the most optimal predictor of survival in ESCC, which significantly classified 42 and 77 patients into high-risk and low-risk groups with totally different survival times. The variance of TF-target regulation between the high- and low-risk groups indicated that transcriptional regulation might be altered with the deterioration of cancer. In addition, we found that our two-lncRNA combination had stronger predictive power than the known clinical markers, CYFRA21-1 and CEA, suggesting that it might be a potential clinical indicator. Functional enrichment analysis of the mRNAs differentially co-expressed with them suggested that they might be associated with the biological process of the development of the ectoderm and epithelial cells. Moreover, the four mRNAs (*ERBB3*,[@b64-ott-10-3095],[@b65-ott-10-3095] *ENSA*,[@b66-ott-10-3095] *KCNK7*,[@b67-ott-10-3095] *MFSD5*[@b68-ott-10-3095],[@b69-ott-10-3095]), involved in signal transductions and differentially co-expressed with ADAMTS9-AS1 or AP000696.2, could be regarded as predictors of survival outcomes in ESCC. This result provided another evidence for the rationality of the two novel lncR-NAs. The original study of GSE53624 revealed a prognosis-related three-lncRNA signature, which classified the patients into two groups with significantly different overall survival. However, the machine learning method they used could not fully explain the underlying biological regulation mechanism, whereas our differential co-expression analysis method not only identified a more economical biomarker (a two-lncRNA combination) with similar prognostic capacity, but also provided an opportunity to investigate the possible functional role of the identified lncRNAs through the DCmRNAs.
Limitations
===========
In summary, our study comprehensively analyzed the transcriptomes of ESCC. By using the differential co-expression method, we investigated the mechanism of abnormal regulation of mRNAs and lncRNAs, and identified a novel combination of two lncRNAs for predicting the survival of ESCC patients. There are limitations in our study. First, the functions of the two lncRNAs in tumorigenesis were still unknown, even though the potential biological processes had been inferred. Second, although the predictive ability of the two-lncRNAs signature was verified in the independent dataset, the sample size was limited. And it still needs experimental studies like RT-PCR, clinical trials and functional verification in the future. But computational investigation of functional lncRNAs is helpful to guide further experimental studies on lncRNAs. Our results may provide important resources for the future ESCC researches.
This work was supported by the National High Technology Research and Development Program of China (2015AA020104, 2015AA020108), the National Key Research and Development Program on Precision Medicine (2016YFC0901700, 2016YFC0901900, 2016YFC0901600), the National Key Technology Support Program (2013BAI101B09), the National Grand Program on Key Infectious Diseases (2015ZX10004801) and the Youth Innovation Promotion Association CAS.
**Author contributions**
ZL, ZW and YXL conceived the concept for this work; ZL performed the analyses and wrote the manuscript; ZL, QLY and ZW discussed the analyses; and ZW, SJZ and YW carried out the review. All authors contributed toward data analysis, drafting and revising the paper and agree to be accountable for all aspects of the work.
**Disclosure**
The authors report no conflicts of interest in this work.
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{#f5-ott-10-3095}
| 2023-11-17T01:27:15.642919 | https://example.com/article/4195 |
Brand: Shake Shack x Allbirds
Model: Tree Runner
Key Features: Made from eucalyptus trees, this unisex silhouette features the Shake Shack burger logo on a green and white color palette.
Release Date: May 24
Price: $100
Buy: Exclusive to Shake Shack’s Madison Square Park location.
Editor’s Notes: After Shake Shack collaborated with Highsnobiety on our Art Basel Miami photo walk in 2015, we know that fashion loves a fast food fix. Now, the burger joint’s latest fashion foray comes in the shape of this super-limited edition drop, pictured above.
Reimagining Allbirds’ Tree Runner silhouette, the collab comes in white and Shake Shack green, and features the restaurant chain’s burger logo on the shoe’s tongue. But here’s the rub: They’re only available to cop at Shake Shack’s Madison Square Park location on Thursday, May 24 from 10 a.m. to 8 p.m. — after that, they’re done. Should you get a pair, you’ll get a free three-pack lace kit and special edition Hokey Pokey shake thrown in with the deal, too.
Super comfortable — Business Insider claims Allbirds shoes are “pretty much the most comfortable shoes out there."
You can cop the Allbirds x Shake Shack collab on May 24, but be fast.
Do you want some Shake Shack shoes? Let us know in the comments.
Next up, A$AP Rocky officially unveils his signature Under Armour sneaker. | 2024-03-25T01:27:15.642919 | https://example.com/article/7214 |
[A study on the etiology and epidemiology of familial aggregation in arteriosclerotic cerebral infarction].
A case-control study including 214 pedigrees (109 cases and 105 controls) was carried out to explore the etiology of family aggregation of arteriosclerotic cerebral infarction in Yi-Xing city, March 1997. The results showed that the family member in both cases and control groups were comparable. The total prevalence rate of the first-degree relatives in cases was 5.12%, significantly higher than (1.63%) that noticed in controls, with chi 2 = 16.40 (P < 0.01). The same results was also found in their parents and siblings. Results from binominal distribution analysis showed that the number of cases in the families of arteriosclerotic cerebral infarction was significantly higher than the theortical range which indicated that there was significant familial aggregation in the occurance of arteriosclerotic cerebral infarction. Logistic regression model also showed that genetic factor was one of the most important risk factors in Xi-xing, Jiangsu. Dose-response was observed in this model. The heritability and the segregation ratio of arteriosclerotic cerebral infarction were the same as seen in other chronic diseases, such as coronary heart disease and esophageal cancer. | 2023-09-28T01:27:15.642919 | https://example.com/article/8900 |
agriculture search result
agriculture search result
A country’s development doesn’t lie solely in developing urban areas. Rural areas, their women and people are as much a part of any country as the urban. There are various methods for helping rural women and people.
Agnihotra is a Yagnya to be performed throughout your life, everyday regularly at sunrise and sunset. All other Yagnyas are time bound and are performed for achieving a certain purpose. Not so with Agnihotra which is to be performed every morning and evening without a break all
Pakistan has unveiled its first-ever National Water Policy (NWP). The 45-page document addresses a wide range of issues currently plaguing the Pakistani water sector. While it provides valuable lessons and insights for South Asian countries, notably India, it falls short of prioritising
K Chandrashekar Rao's Rythu Bandhu scheme of providing Rs 8,000 per acre per year as cash support amounts to providing a Rs 1,000 crore-bonanza for absentee landlords like real estate developers, urban rich etc. The actual tiller is ignored, while the landowner is
New Delhi: After Firstpost's expose on Uttar Pradesh Co-operative Bank Limited (UPCBL) for financing tainted Simbhaoli Group and converting the non performing assets (NPAs) of Kesar Sugar Mills into a long-term loan, a rattled top bank management
At the fourth meetingof NITI Aayog's Governing Council on Sunday, Prime Minister Narendra Modi strongly defended the NDA's 'cooperative federalism-based' approach to governance, asserting that under his rule, the states had received Rs 11 lakh crore, which
Mumbai: Exports of merchandise – from industrial to agricultural goods – to African countries, Latin America and Japan dropped over the four years of Prime Minister Narendra Modi’s government and grew at single digits to other regions, according to
This is a subject that often goes unnoticed when reported by the Pakistani press — major dams like the Tarbela and Mangla have both reached the point of dead storage, at a time when farmers desperately need their water for the newly-sown Kharif crops. The Indus River Systems
Addressing industrialists at Lucknow on 29 July 2018, Prime Minister Narender Modi made no bones about his good relationship with Indian industrialists who he said contribute as much to nation building as farmers. Drawing a parallel with Mahatma Gandhi’s worldview of industrialists, he
Worker-farmer rally LIVE: The demands of the protesters are effective implementation of labour laws, minimum wage, more employment, and recognition of one crore Anganwadi and ASHA workers as a workforce. | 2024-04-08T01:27:15.642919 | https://example.com/article/7568 |
Glasgow Rangers on the up: Glasgow Celtic in trouble
The new Glasgow Rangers side created by rookie manager Steven Gerrard is starting to show their true potential, despite the poor refereeing decisions that continue to haunt them.
Rangers players booed by the so called, ‘Tartan Army’, and the SFA and BBC firmly against the Ibrox club, provide the ‘Blue Brigade’ with reasons to be wary of much of the Scottish media.
Rangers fans have been forced to listen to BT Sports pundits Chris Sutton and John Hartson promoting their views that the Light Blues are miles behind Celtic and will do well to get second in the league over Aberdeen.
Next, Neil Lennon, the Hibernian manager opined, “Don’t believe the hype about Rangers”. All three of these people are ex-Celtic players with biased views.
Several prominent journalists wrote that to hire Gerrard was a reckless route for the Ibrox club to go down. Shows you what they know.
Without rhyme nor reason they said Gerrard had an impossible challenge ahead. They insisted Brendan Rodgers and his wonderful Celtic would walk the title and go on to win 10 in a row.
What are they saying now – nothing.
Actions speak louder than words, so the Rangers fans are not shouting about winning the league.
Rangers are playing attractive football and scoring goals for fun. The team are still to gel even further together in the next few months.
Once Gerrard and his talented backroom staff get more time to work with this squad, just watch them go.
Gerrard is the first to say there is still a lot to be done. Eros Grezda has still to find his match fitness and will be a first team pick when he is fit enough to start games.
When will Scottish football admit that Rangers are back in the big time, and start to give them some credit?
I am an avid, mature Rangers supporter who has been a season ticket holder for over 40 years. My hobby is writing articles and giving my predictions of team selections and commenting on all interesting information regarding Rangers.
Ninety Minutes Online aims to be objective in assessing the current trends in the sport, sparking debate and invoking thought. The site aims to provide a mix of breaking news, opinion-based articles and analytical pieces that are interesting and enjoyable for the reader.Please read our Privacy Policy | 2024-03-15T01:27:15.642919 | https://example.com/article/1731 |
Introduction {#Sec1}
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The normal mammary gland is composed of multiple cell types including luminal and myoepithelial cells^[@CR1]--[@CR3]^. Myoepithelial cells produce and are in direct contact with the basement membrane (BM). Together, these cells outline the inner luminal epithelial cells in both ducts and alveoli, serving as a structural barrier, and they regulate luminal epithelial cell differentiation and polarity^[@CR1]--[@CR3]^. Upon lactation and breastfeeding, myoepithelial cells contract hence propelling milk out of the lumens in response to oxytocin. Normal myoepithelial cell differentiation is still poorly understood, although Notch, TGFβ, Hh, and HER1-ERK1/2-RSK signaling pathways, and the p63 transcription factor (TF) have been implicated^[@CR4]--[@CR9]^.
Myoepithelial cells also inhibit neoplastic phenotypes including tumor cell growth, invasion, and angiogenesis^[@CR10]--[@CR13]^. The presence or absence of an intact myoepithelial cell layer and BM, assessed based on histology and by immunohistochemical analyses for myoepithelial markers including CD10, p63, and SMA, differentiat in situ from invasive breast carcinomas^[@CR14]^. Immunohistochemical analyses of normal breast tissue, and in situ and invasive breast carcinomas aiming to identify markers of tumor progression have identified several genes that are differentially expressed between normal and DCIS-associated myoepithelial cells including SMMHC, CK5/6, CD10, calponin, and integrin αvβ6^[@CR15]--[@CR21]^. Decreased expression of CD10 (*MME*) was also reported to predict recurrence in patients with DCIS, but the number of cases analyzed was small and the patients received variable treatments^[@CR22]^. Similarly, loss of myoepithelial CD10 expression by immunohistochemical staining was associated with stromal invasion^[@CR23]^. Myoepithelial CD10 expression may have functional relevance, since it is a membrane-associated zinc-dependent neutral endopeptidase that can cleave glucagon, enkephalins, and oxytocin^[@CR24]^. In normal mouse mammary gland oxytocin enhances myoepithelial cell proliferation and differentiation^[@CR25]^, while in cell culture CD10 inhibition decreases proliferation^[@CR26]^. Thus, the decreased CD10 expression in DCIS-associated myoepithelial cells may contribute to their progressive loss^[@CR27]^.
We previously purified myoepithelial cells using the CD10 cell surface marker from normal reduction mammoplasties and DCIS, and determined that their DNA methylation and gene expression patterns are distinct implying malignancy-associated changes in DCIS^[@CR28],[@CR29]^. We also showed that myoepithelial cells prevent tumor growth and invasive progression in experimental models of DCIS^[@CR6],[@CR30]^, suggesting that perturbed myoepithelial cell function in DCIS may be permissive for tumor progression. DCIS-associated myoepithelial cells also overexpress immune-regulatory proteins (e.g., CXCL12, CXCL14, and PD-L1)^[@CR28],[@CR31]^ suggesting a role in immune evasion. Thus, loss of normal myoepithelial cells in DCIS might be key for in situ to invasive breast carcinoma transition and it may identify patients with high risk of progression. However, the regulators of normal myoepithelial differentiation programs and how these may be altered in DCIS are not well understood.
Here we used a combination of genomic profiling of human normal and DCIS breast tissues and functional assays in the MCF10DCIS experimental model of DCIS^[@CR32]^ to investigate determinants of normal myoepithelial cell differentiation and perturbations of these in *BRCA1* and *BRCA2* germline mutation carriers and in DCIS. Luminal differentiation was shown to be perturbed in *BRCA1* mutation carriers^[@CR33]--[@CR35]^, but myoepithelial cells and *BRCA2* mutation carriers have not been investigated. We defined the genomic targets of p63 and TCF7, two TFs we identified as co-expressed in the majority of myoepithelial cells in normal breast tissue of non-carrier women but not in *BRCA1/2* mutation carriers and in DCIS, and the enhancer landscape in normal myoepithelial cells. We also characterized the functional relevance of p63 and TCF7 co-expression and their targets in MCF10DCIS cells. Our results suggest that a transcriptional program orchestrated by p63 and TCF7 is required for a normal differentiated myoepithelial cell phenotype and perturbations of this may contribute to the increased breast cancer risk of *BRCA* mutation carriers, and it may lead to the loss of myoepithelial cells in DCIS promoting progression to invasion.
Results {#Sec2}
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Heterogeneity of normal CD10^+^ myoepithelial cell population {#Sec3}
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CD10 is a myoepithelial cell surface marker and its expression level may vary depending on differentiation state^[@CR22],[@CR23],[@CR26]^, thus we explored CD10^+^ cell population heterogeneity in normal human breast tissues by multicolor FACS for CD10 and markers known to be associated with basal/progenitor features including CD44, ITGA3, ITGB6, and ITGA6^[@CR6],[@CR28],[@CR36]--[@CR39]^. We analyzed normal breast tissues of nulliparous and parous women, as pregnancy and lactation may impact cellular phenotypes^[@CR40]^, from reduction mammoplasties and from prophylactic mastectomy tissues of *BRCA1* and *BRCA2* mutation carriers (Supplementary Data [1](#MOESM3){ref-type="media"}). Women were as closely matched as possible for menopausal status, ethnicity, and age. We identified two distinct CD10^+^ cell populations distinguished by the expression of CD44 that were both CK14^+^, but CD10^+^CD44^+^ cells were more mesenchymal and CD10^+^CD44^−^ cells more epithelial (Fig. [1a](#Fig1){ref-type="fig"} and Supplementary Fig. [1a](#MOESM1){ref-type="media"}). We also assessed ALDH activity, a feature of stem/progenitor cells^[@CR41]^, in three distinct CD10^+^ cell subpopulations (i.e., CD10^high^CD44^−^, CD10^low^CD44^−^, and CD10^+^CD44^+^). ALDH^+^ cells were mainly present in the CD10^+^CD44^+^ subset, where \~37% of the cells displayed ALDH activity suggesting the presence of progenitors (Supplementary Fig. [1b](#MOESM1){ref-type="media"}).Fig. 1Heterogeneity of the CD10^+^ cell population. **a** FACS analysis of CD10^+^ cells according to expression of CD44 in normal breast tissues of nulliparous (NP) and parous (P) control women and *BRCA1* and *BRCA2* mutation carriers. **b** Quantification of percentage of CD10^+^CD44^−^ and CD10^+^CD44^+^ in total epithelial cells (*n* = 6/group). *p*-values indicate statistical significance of difference in total CD10^+^ cells between groups by *t*-test. **c** viSNE maps from CyTOF analysis of normal breast tissues colored for expression of SMA, CD10, CD44, and CD49f (control *n* = 6, *BRCA1* *n* = 6, *BRCA2* *n* = 7). Color scale indicates minimum and maximum values of expression. **d** Pathways enriched in genes differentially expressed between CD10^+^CD44^−^ and CD10^+^CD44^+^ cells. Color scale corresponds to −log(*p*-value) of significance of enrichment, calculated by MetaCore Enrichment Analysis test. **e** 3D Principal component analysis plots of CD10^+^ gene expression data from the indicated samples. **f** Transcription factors differentially expressed between CD10^+^CD44^−^ and CD10^+^CD44^+^ cells. Red highlight indicates genes selected for further analyses. **g** Multicolor immunofluorescence analysis of p63, TCF7, and CD10 expression in normal breast tissues. Images are a montage of nine fields captured from one area of the tissue. Scale bar 50 μm. **h** Relative quantification of CD10^+^ myoepithelial cells positive for p63 or TCF7 or both proteins. *p*-value indicates the significant association of the p63/TCF7 positive/negative status of CD10^+^ myoepithelial cells with condition (Control, *BRCA1*, or *BRCA2*), as assessed by Pearson's chi-squared test among averages of estimated cell counts across replicates (total population size was conservatively estimated to 100 cells). Source data are provided as a Source Data file
Quantification of the relative fraction of total CD10^+^ cells and CD10^+^CD44^−^ and CD10^+^CD44^+^ subpopulations demonstrated a significant decrease in CD10^+^ cells in *BRCA1* mutation carriers (Fig. [1b](#Fig1){ref-type="fig"} and Supplementary Fig. [1c](#MOESM1){ref-type="media"}). CyTOF analysis of non-carrier (*n* = 6), *BRCA1* (*n* = 6), and *BRCA2* (*n* = 7) samples using myoepithelial, luminal, basal, and progenitor markers also demonstrated significant differences with a decrease in SMA^+^CD10^+^ myoepithelial cells and diminished expression of SMA, CD10, CD44, and CD49f in *BRCA1* mutation carriers (Fig. [1c](#Fig1){ref-type="fig"} and Supplementary Fig. [1d, e](#MOESM1){ref-type="media"}). To minimize individual or age-related differences, all samples for a respective mutation status (i.e., control, *BRCA1*, *BRCA2*) were concatenated and used as a single file for analysis. These data suggest that the phenotype of myoepithelial cells is distinct between normal tissues of non-carrier and *BRCA* mutation-carrier women.
Gene expression profiles of CD10^+^ cell populations {#Sec4}
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Next, we analyzed CD10^+^CD44^−^ and CD10^+^CD44^+^ cell gene expression profiles from reduction mammoplasty samples (*n* = 3 each, from nulliparous and parous women). Known myoepithelial cell markers (e.g., *ACTG2*, *SFN*, and *OXTR*) had higher expression in CD10^+^CD44^−^ cells, while stem/progenitor cell markers (e.g., *ALDH1A1*, *WNT2*, and *KLF4*), and epithelial-to-mesenchymal transition (EMT)-related genes (e.g., *TWIST1* and *ZEB1*) were more abundantly expressed in CD10^+^CD44^+^ cells (Supplementary Fig. [1f](#MOESM1){ref-type="media"} and Supplementary Data [2](#MOESM4){ref-type="media"}). Pathway analysis using Metacore^[@CR42]^ revealed enrichment for extracellular matrix (ECM) remodeling and TGFβ signaling in CD10^+^CD44^+^ cells, whereas keratin, chemokines, and adhesion pathways were more enriched in genes highly expressed in CD10^+^CD44^−^ cells (Fig. [1d](#Fig1){ref-type="fig"}). Parity-related differences were limited and enriched in ECM remodeling pathways (Supplementary Fig. [1g](#MOESM1){ref-type="media"}).
Next, we profiled CD10^+^ cells from *BRCA1* and *BRCA2* mutation carriers and compared them to non-carriers. Principal component analysis (PCA) depicted three distinct groups reflecting germline mutation status (Fig. [1e](#Fig1){ref-type="fig"}). Genes highly expressed in *BRCA1*-mutant CD10^+^ cells were enriched in DNA replication-related functions, whereas *BRCA2*-mutant CD10^+^ cells showed a decrease in keratins and an increase in immune-related genes (Supplementary Fig. [1g](#MOESM1){ref-type="media"} and Supplementary Data [3](#MOESM5){ref-type="media"}).
TFs play key roles in cellular differentiation. Thus, we identified TFs differentially expressed between CD10^+^CD44^−^ and CD10^+^CD44^+^ cells including many homeobox genes (e.g., *IRX1*, *IRX4*, and *IRX2*) and genes with known roles in epithelial differentiation (e.g., *GATA3* and *TFAP2A*) and in myoepithelial cells (e.g., *TP63*) (Fig. [1f](#Fig1){ref-type="fig"}). Among these TFs, *TP63* and *TCF7* were particularly interesting, since p63 plays key roles in epithelial progenitors^[@CR43],[@CR44]^, whereas TCF7 regulates WNT signaling and its deletion in mice leads to mammary gland adenomas^[@CR45]^. Both *TP63* and *TCF7* have multiple functionally distinct isoforms^[@CR46],[@CR47]^. Based on RNA-seq we detected ΔNp63 and the long isoform of TCF7 in normal myoepithelial cells (Supplementary Fig. [1h, i](#MOESM1){ref-type="media"}).
We further analyzed the expression of p63 and TCF7 in normal breast tissues by multicolor immunofluorescence in a larger cohort. We found that in control non-carrier women and in *BRCA2* mutation carriers the majority of CD10^+^ myoepithelial cells were p63^+^TCF7^+^, but in *BRCA1* mutation carriers the expression of p63 and TCF7 decreased, and co-localization was less frequent (Fig. [1g, h](#Fig1){ref-type="fig"}). These data indicate altered myoepithelial cell phenotypes in *BRCA1* mutation carriers and suggest key roles for p63 and TCF7 in normal myoepithelial cell differentiation.
Myoepithelial cells in DCIS {#Sec5}
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In DCIS, cancer cells are growing within normal mammary ducts, thus, tumor epithelial and surrounding myoepithelial cells thought to be clonally unrelated. To investigate CD10^+^ myoepithelial cells in DCIS we first analyzed the ratios of CD10^+^CD44^−^ and CD10^+^CD44^+^ cells by FACS. We found that in DCIS the majority of CD10^+^ cells were also CD44^+^ (Fig. [2a, b](#Fig2){ref-type="fig"}) and the gene expression profiles of CD10^+^ cells from DCIS were distinct from CD10^+^ cells in normal breast tissues (Fig. [2c](#Fig2){ref-type="fig"}, Supplementary Fig. [2a](#MOESM1){ref-type="media"}, and Supplementary Data [4](#MOESM6){ref-type="media"}). Pathway analysis showed enrichment for several immune-related signaling pathways in both DCIS-high and normal-high genes (Fig. [2d](#Fig2){ref-type="fig"}), implying a role in immune regulation.Fig. 2CD10, p63, and TCF7 expression in DCIS and in invasive breast tumors. **a** FACS analysis of CD10 and CD44 expression in DCIS and in normal breast tissue. **b** Relative quantification of CD10^+^CD44^−^ and CD10^+^CD44^+^ in total epithelial cells. *p*-value indicates the significant association of the CD44 positive/negative status of CD10^+^ cells with condition (Normal, DCIS), as assessed by Pearson's chi-squared test among averages of estimated cell counts across replicates (total population size was conservatively estimated to 100 cells). **c** 3D principal component analysis plot of gene expression data. **d** Pathways enriched in genes differentially expressed between CD10^+^ cells in DCIS and in normal breast. Color scale corresponds to −log(*p*-value) of significance of enrichment, calculated by MetaCore Enrichment Analysis test. **e** Multicolor immunofluorescence analysis of p63, TCF7, and CD10 expression in low grade (LG) and high grade (HG) DCIS and DCIS-IDC. Left panels are a montage of nine fields captured from one area of the tissue, while right panels are high magnification of selected areas. Scale bar 50 μm. **f** Relative quantification of CD10^+^ cells positive for p63 or TCF7 or both proteins in low (LG) and high (HG) grade pure DCIS and DCIS adjacent to IDC (DCIS-IDC). *p*-value indicates the significant association of the p63/TCF7 positive/negative status of CD10^+^ cells with condition (LG-DCIS, HG-DCIS, and DCIS-IDC), as assessed by Pearson's chi-squared test among averages of estimated cell counts across replicates (total population size was conservatively estimated to 100 cells). **g** Multicolor immunofluorescence analysis of PanCK, p63, and TCF7 in luminal, basal-like, and metaplastic invasive breast tumors. Images are a montage of nine fields captured from one area of the tissue. Scale bar 50 μm. **h** Scoring the expression and co-localization of p63 and TCF7 in different subtypes of metaplastic breast tumors. Source data are provided as a Source Data file
We also performed immunofluorescence analysis of p63 and TCF7 expression in pure DCIS, DCIS adjacent to IDC, and IDC. There was a striking loss of TCF7 levels in CD10^+^ cells in DCIS, especially in high-grade lesions, leading to a significant decrease in p63^+^TCF7^+^ cells compared to normal breast (Fig. [2e, f](#Fig2){ref-type="fig"}). Instead, a subset of DCIS tumor epithelial cells was TCF7^+^. To assess if this tumor epithelial expression of TCF7 is maintained during invasive progression, we also analyzed invasive tumors of different subtypes. Luminal and basal-like tumors had a nearly complete lack of p63 and TCF7 expression, although a subset of leukocytes was TCF7^+^ (Fig. [2g](#Fig2){ref-type="fig"}). In contrast, in metaplastic breast cancer a variable fraction of cancer cells expressed p63 or TCF7 or both proteins with squamous tumors having the highest frequency of p63^+^TCF7^+^ cells (Fig. [2g, h](#Fig2){ref-type="fig"}). Metaplastic breast tumors are the only breast cancer subset that relatively commonly have mutations in the APC/β-catenin pathway^[@CR48]^ and the expression of TCF7 could be due to its induction by WNT/β-catenin signaling^[@CR45]^. Overall, these data demonstrate perturbed myoepithelial cell differentiation in DCIS associated with altered cellular expression of TCF7.
Targets of p63 and TCF7 and normal myoepithelial enhancers {#Sec6}
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Next, we investigated the genomic targets of p63 and TCF7 and potential differences due to *BRCA* mutation status in normal myoepithelial cells by ChIP-seq. We identified significant differences in both p63 and TCF7 genomic binding between control and *BRCA* mutation carriers (Fig. [3a, b](#Fig3){ref-type="fig"}, Supplementary Fig. [2b](#MOESM1){ref-type="media"}, and Supplementary Data [5](#MOESM7){ref-type="media"}). We detected significant overlap between p63 and TCF7 peaks only in non-carrier tissues and not in *BRCA1/2* mutation carriers consistent with the decreased frequencies of p63^+^TCF7^+^ cells in these tissues (Fig. [3c](#Fig3){ref-type="fig"}). Interestingly, normal myoepithelial cell-specific genes including *ACTA2*, *SFN*, and *OXR1* were associated with overlapping p63 and TCF7 peaks suggesting that the co-localization of these two TFs may regulate their expression (Fig. [3d](#Fig3){ref-type="fig"}). Metacore analysis of p63 and TCF7 targets revealed that most of the top pathways were commonly enriched in all three tissue types including WNT, Hh, and NOTCH, cell adhesion, and cell--matrix interaction signaling (Fig. [3e](#Fig3){ref-type="fig"}), consistent with the role of p63 in epithelial stem cells and cell adhesion^[@CR49]^. Mitosis and DNA damage checkpoint pathways were more significantly enriched in *BRCA1* mutation carriers potentially due to DNA repair defects even in *BRCA1*^*+/−*^ cells (Fig. [3e](#Fig3){ref-type="fig"}). TCF7 peaks were enriched in the same process networks as p63, while p63 and TCF7 overlapping peaks showed less significant enrichment and in fewer networks.Fig. 3p63 genomic targets of and enhancer landscape in myoepithelial cells. **a**, **b** Heatmap depicting p63 (**a**) and TCF7 (**b**) peaks which are unique in normal breast tissue of control women (C only), and *BRCA1* (B1 only), and *BRCA2* (B2 only) mutation carriers, and overlap between groups. The color key is the score of ChIP-seq signal over selected genomic region, the signals across different genomic regions have scaled to the same length. **c** Overlap between p63 peaks and TCF7 peaks in control women, *BRCA1* and *BRCA2* mutation carriers. **d** Gene tracks depicting p63 and TCF7 signal at selected genomic loci. The *x*-axis shows position along the chromosome with gene structures drawn below, whereas *y*-axis shows genomic occupancy in units of rpm/bp. **e** Pathway-enrichment analysis of genes associated with p63 or TCF7 peaks in normal, *BRCA1*, or *BRCA2* myoepithelial cells or differentially expressed between the indicated cell types. Color scale corresponds to −log(*p*-value) of significance of enrichment, calculated by MetaCore enrichment analysis test. **f** Plot depicting super-enhancers in normal myoepithelial cells from control women. **g** Predicted protein interaction network of TFs identified as core transcriptional regulatory circuits in myoepithelial cells. Legend indicates the source of data used to determine interactions. TFs that are not part of the network were removed
Integration of p63 ChIP-seq data with differentially expressed gene lists in CD10^+^ cells showed enrichment for NOTCH and WNT signaling in p63 targets with higher expression in *BRCA1* tissues implying more progenitor-like features (Fig. [3e](#Fig3){ref-type="fig"}). The majority of genes with higher expression in CD10^+^CD44^−^ cells were also direct p63 targets, and many were related to cell adhesion, cytoskeleton, and neurogenesis-axonal guidance confirming a central role for p63 in these cells (Fig. [3e](#Fig3){ref-type="fig"}).
Enhancers and super-enhancers (SE) play important roles in establishing cellular identity^[@CR50]^. Thus, we also characterized the enhancer landscape of normal CD10^+^ myoepithelial cells by ChIP-seq for histone H3 lysine 27 acetyl (H3K27ac). We identified 671 myoepithelial cell SEs that included several TFs (e.g., *TCF7L2*, *TRPS1*, *GLI3*), genes encoding axonal guidance (e.g., *SEMA3C, SEMA5A*) and cytoskeletal proteins (e.g., *PALLD, TNS1*), TGFβ-signaling pathway components (e.g., *TGFBR3, SMAD3*), and genes involved in muscle differentiation (e.g., *BOC, MYLK, CALD1*) (Fig. [3f](#Fig3){ref-type="fig"} and Supplementary Data [6](#MOESM8){ref-type="media"}). We also subject the SE data to core transcriptional circuitry (CRC) analysis^[@CR51]^ and identified 14 TFs predicted to be core regulators of myoepithelial cell state. To analyze interaction networks among these 14 TFs, we performed protein--protein interactome analysis using the STRING database^[@CR52]^ as described in Supplementary Methods. 13 out of 14 TFs formed a tight interaction network with SMAD3 and TCF7L2 as major hubs (Fig. [3g](#Fig3){ref-type="fig"}), suggesting that these TFs are the master regulators of the myoepithelial cell SE landscape and phenotype.
Functional relevance of p63 in MCF10DCIS cells {#Sec7}
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To address the functional relevance of p63 and TCF7 in regulating myoepithelial cell features, we used the MCF10DCIS human xenograft model^[@CR6],[@CR32]^ as we were not able to grow and manipulate normal CD10^+^ myoepithelial cells. MCF10DCIS cells form DCIS-like lesions with a myoepithelial cell layer at early time points after injection that progress to invasive tumors^[@CR6],[@CR32]^. Thus, while MCF10DCIS cells are tumorigenic, they have the ability to differentiate into cells with myoepithelial features making them useful for the analysis of this process. We previously showed that MCF10DCIS cells express ΔNp63 and in cell culture virtually all cells are p63^+[@CR6]^, while in DCIS-like xenografts only the myoepithelial cells remain p63^+^. We downregulated p63 using TET-inducible shRNAs (Supplementary Fig. [3a](#MOESM1){ref-type="media"}) and analyzed myoepithelial cell differentiation in xenograft assays. We performed subcutaneous, mammary fat pad, and intraductal injections to test if the microenvironment affects the phenotype of the tumors and p63 expression. MCF10DCIS cells expressing TET-inducible sh*TP63* efficiently formed tumors in NSG mice regardless of the injection site, although there were significant differences in tumor size with mammary fat pad tumors being the largest (Fig. [4a](#Fig4){ref-type="fig"}). Based on our prior studies, the establishment of DCIS-like histology requires 7--10 days after tumor initiation^[@CR6]^, thus, sh*TP63* was induced 1 day or 10 days after injection and tumors were harvested 3 weeks after injection. Downregulation of p63 significantly reduced tumor weight regardless of injection site and time of sh*TP63* induction (Fig. [4a](#Fig4){ref-type="fig"}). However, while most tumors in the fat pad and intraductal groups were invasive, subcutaneous tumors were mostly DCIS-like (Fig. [4b](#Fig4){ref-type="fig"}). Based on immunofluorescence there was a nearly complete absence of SMA in myoepithelial cells in the subcutaneous tumors, while in fat pad and intraductal tumors there were many SMA^+^ myofibroblasts (Fig. [4b](#Fig4){ref-type="fig"}). Unexpectedly, myoepithelial cells of DCIS-like tumors were weakly p63^+^ in all cases except in intraductal tumors implying escape from shRNA effect (Fig. [4b](#Fig4){ref-type="fig"}). These data demonstrate that the microenvironment has a pronounced effect on p63 expression and tumor histology.Fig. 4Functional relevance of p63 in myoepithelial cells. **a** Xenograft tumor weight of sh*TP63*-expressing MCF10DCIS cells with or without doxycycline following mammary fat pad, intraductal, or subcutaneous injection. *p*-value indicates statistical significance of difference in tumor weight between groups based on *t*-test. Mean ± SD shown. **b** Hematoxylin--eosin (H&E) staining and immunofluorescence analysis of SMA and p63 expression. Scale bar 100 μm. **c** Pathway enrichment analysis of genes up-regulated or down-regulated following sh*TP63* expression in MCF10DCIS cells. Color scale corresponds to −log(*p*-value) of significance of enrichment, calculated by MetaCore enrichment analysis test. **d**--**f** Immunoblot analysis of p63 expression levels in MCF10DCIS cells following detachment from matrix **d**, detachment and concomitant treatment with MG132 (10 µM), Staurosporin (STS, 10 µM), and Bafilomycin A1 (BAF 100 nM) **e**, and treatment with inhibitors of various signaling pathways \[Rapamycin (mTOR), Y15 (FAK) 5 µM; Sonidegib (Hh), XAV393 (WNT), LY2157299 (TGFβ), Verteporfin (YAP), PD0325901 (MEK) 10 µM; Dasatinib (SRC) 2 µM\] in adherent conditions **f**. GAPDH serves as loading control. **g** Heatmap depicting unique and H3K27ac overlapping p63 peaks. The color key is the score of ChIP-seq signal over selected genomic region, the signals across different genomic regions have scaled to the same length. **h** Hockey stick plot depicting super-enhancers in MCF10DCIS cells. **i** Predicted protein interaction network of TFs identified as core transcriptional regulatory circuits in MCF10DCIS cells. Legend indicates the source of data used to determine interactions. TFs that are not part of the network were removed. **j** Integration of differential gene expression and p63 targets by BETA analysis. The *p*-value listed in the top left represents the significance of the UP or DOWN group relative to the NON group as determined by the Kolmogorov--Smirnov test. Source data are provided as a Source Data file
To investigate transcriptional changes after p63 downregulation, we analyzed the gene expression profiles by RNA-seq at days 3 and 5 following sh*TP63* induction (time points chosen based on assessment of p63 protein levels) (Supplementary Data [7](#MOESM9){ref-type="media"}). Pathway analysis showed an enrichment for cell cycle G2-M (e.g., cyclin B, BUB1), S phase, WNT signaling (e.g., TCF7L1, TCF3) in genes downregulated following p63 loss, whereas upregulated genes were enriched for factors involved in G1-S phase transition (Fig. [4c](#Fig4){ref-type="fig"}).
To explore the relevance of cell adhesion and other signaling pathways in regulating p63 function, we analyzed p63 protein levels at different time points after detachment from ECM. We found that p63 protein level is rapidly decreased after detachment, consistent with our prior data^[@CR6]^ (Fig. [4d](#Fig4){ref-type="fig"}). To determine if the detachment-induced decline in p63 protein levels is due to increased degradation, we treated cells with proteosomal (MG132), protein kinase (Staurosporine, STS), and lysosomal (Bafilomycin A1, BAF) inhibitors. MG132 and BAF treatment significantly inhibited p63 loss, implicating proteosomal and lysosomal degradation as potential underlying mechanisms (Fig. [4e](#Fig4){ref-type="fig"}). To further investigate the regulation of p63 protein stability, we explored if inhibition of certain signaling pathways could induce a decrease in p63 protein levels even in attached cells. We found that mTOR (rapamycin), Hh (sonidegib), and WNT (XAV939) inhibitors had no effect on p63 protein levels, while treatment with TGFBR (LY2157299), MEK/ERK (PD0325901), SRC (dasatinib), FAK (Y15), and Hippo (verteporfin) inhibitors lead to a significant decrease (Fig. [4f](#Fig4){ref-type="fig"}). These data suggest that p63 regulates the expression of ECM and cell adhesion proteins and p63 protein stability is regulated by ECM attachment via SRC, FAK, and HIPPO signaling creating a positive feedback loop. However, since we generated these data in the MCF10DCIS model, these findings need to be validated in normal myoepithelial cells.
p63 targets and enhancer landscape in MCF10DCIS cells {#Sec8}
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To investigate the genomic targets of p63 and the enhancer landscape in MCF10DCIS cells and to compare these with normal myoepithelium, we performed ChIP-seq for p63 and H3K27ac (Fig. [4g](#Fig4){ref-type="fig"}). Pathway analysis of genes nearest to p63 and H3K27ac overlapping peaks demonstrated enrichment in G1-S regulation, cadherin-mediated and integrin-mediated cell adhesion, NOTCH, and WNT signaling (Supplementary Fig. [3b](#MOESM1){ref-type="media"}). Normal myoepithelial-specific genes including *ACTA2* and several TFs highly expressed in CD10^+^CD44^−^ cells (e.g., *TCF7*, *IRF6*, *TRIM29*) were also direct targets of p63 in MCF10DCIS cells. Overall, we identified 1,233 p63 targets that were common between MCF10DCIS cells and normal myoepithelium suggesting that this model reproduces at least some aspects of normal myoepithelial cell differentiation.
Next, we performed SE analysis of the H3K27ac ChIP-seq data and identified 1,178 SEs. Top SEs included genes encoding cell adhesions proteins (e.g., *ITGA6*, *ITGB4*, *ITGB1*, *ITGB6*), keratins (e.g., *KRT5*), TFs co-expressed with p63 in normal myoepithelial cells (e.g., *GATA3*, *IRX2*, *IRX4*), and TGFβ pathway components (e.g., *TGFBR2*) (Fig. [4h](#Fig4){ref-type="fig"} and Supplementary Data [6](#MOESM8){ref-type="media"}). As expected, genes nearest to SEs showed higher gene expression levels, and we also observed a significant enrichment of p63 peaks in higher ranking SEs (Supplementary Fig. [3c](#MOESM1){ref-type="media"}), highlighting its importance in regulating basal cell-specific transcription programs. CRC^[@CR51]^ analysis of SEs identified 29 top TFs that formed a tight interaction network with MYC and SMAD3, as major hubs based on the STRING database^[@CR52]^ (Fig. [4i](#Fig4){ref-type="fig"}). SMAD3 was also a major hub in normal myoepithelial cells highlighting its importance in these cell types.
To further define associations between p63 chromatin binding and transcription, we integrated p63 ChIP-seq with genes differentially expressed after sh*TP63* induction and performed binding and expression target analysis (BETA)^[@CR53]^. We found that genes downregulated after p63 loss were significantly enriched in p63 peaks (Fig. [4j](#Fig4){ref-type="fig"}), thus, p63 functions as a transcriptional activator in MCF10DCIS cells. Pathways analysis of downregulated genes that are direct p63 targets demonstrated enrichment in blood vessel morphogenesis, mitosis, cell cycle G2-M, NOTCH and WNT signaling, and neurogenesis-related pathways (Supplementary Fig. [3d](#MOESM1){ref-type="media"}), which is consistent with the apparent decrease in cell proliferation after sh*TP63* expression (Supplementary Fig. [4a, b](#MOESM1){ref-type="media"}). These data demonstrate that p63 is required for myoepithelial cell features and is a major regulator of the enhancer landscape in the MCF10DCIS model.
Targets and functional relevance of TCF7 in MCF10DCIS cells {#Sec9}
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Although TCF7 and p63 are co-expressed in normal myoepithelial cells, we were not able to detect TCF7 expression in MCF10DCIS cells neither in cell culture nor in xenografts suggesting that MCF10DCIS cells do not fully recapitulate the normal differentiated myoepithelial cell phenotype (Fig. [5a](#Fig5){ref-type="fig"}). However, to analyze the effects of p63 and TCF7 co-expression on myoepithelial cell features in the MCF10DCIS model, we expressed HA-tagged TCF7 (long isoform) using a TET-ON expression vector. Induction of TCF7 expression led to a decrease in p63 implying cross-regulation (Fig. [5a](#Fig5){ref-type="fig"}). Due to the leakiness of the TET-ON vector we detected TCF7 protein even in unstimulated controls, exhibiting minimal repression of p63 (Fig. [5a](#Fig5){ref-type="fig"}), thus, reproducing the TCF7-p63 co-expression observed in normal myoepithelium.Fig. 5Functional relevance of TCF7 in myoepithelial cells. **a** Immunoblot analysis of p63 and TCF7 expression in parental MCF10DCIS cell line and TCF7 overexpressing TET-inducible derivatives. Jurkat and DU4475 cells were used as positive control for TCF7. ACTB is loading control. **b** Xenograft tumor weight of parental and TCF7 expressing MCF10DCIS cells by mammary fat pad, intraductal or subcutaneous injection. *p*-values indicate statistical significance of difference in tumor weight between groups based on *T*-test. Mean ± SD shown. **c** Hematoxylin--eosin (H&E) staining and immunohistochemical analysis of SMA and p63 expression. Scale bar 100 μm. **d** Immunofluorescence analysis of TCF7 and SMA expression in xenograft tumors of parental and TCF7 expressing MCF10DCIS cells. Scale bar 100 μm. **e** Pathway-enrichment analysis of genes upregulated and downregulated following TCF7 expression in MCF10DCIS cells. Color scale corresponds to −log(*p*-value) of significance of enrichment, calculated by MetaCore enrichment analysis test. **f** Heatmap depicting TCF7 unique and H3K27ac overlapping peaks. The color key is the score of ChIP-seq signal over selected genomic region, the signals across different genomic regions have scaled to the same length. **g** Gene tracks of TCF7 and H3K27ac signals at selected genomic loci. The *x*-axis shows position along the chromosome with gene structures drawn below, whereas *y*-axis shows genomic occupancy in units of rpm/bp. **h** Hockey stick plot depicting changes in super-enhancers in MCF10DCIS cells after TCF7 expression. **i** Integration of differential gene expression and TCF7 targets by BETA analysis. The *p*-value listed in the top left represents the significance of the UP or DOWN group relative to the NON group as determined by the Kolmogorov--Smirnov test. **j** Immunoblot analysis of total cell lysates and TCF7 immunoprecipitates. **k** Immunoblot analysis of MCF10DCIS-TCF7 cells with or without doxycycline (dox) (24 h) for phospho-FAK^Y397^, FAK, phospho-SRC^Y416^, and SRC. GAPDH serves as loading control. Source data are provided as a Source Data file
To investigate the effects of TCF7 expression on tumor growth and histology, we performed xenograft assays. Similar to sh*TP63*, we tested mammary fat pad, intraductal, and subcutaneous injections to see how the microenvironment influences tumor growth and histology, and we induced TCF7 at day 1 or day 10 after injection. Expression of TCF7 decreased tumor size regardless of injection site and time of induction, although again, there was a significant difference in tumors size with fat pad tumors being the largest and intraductal the smallest (Fig. [5b](#Fig5){ref-type="fig"}). There were significant differences in histology as well, with mixed DCIS-IDC histology in the fat pad, invasive histology in the intraductal group, and DCIS in subcutaneous tumors (Fig. [5c](#Fig5){ref-type="fig"}). Interestingly, in the xenografts TCF7 expression was heterogeneous and SMA^+^ myoepithelial cells were largely TCF7 negative (Fig. [5d](#Fig5){ref-type="fig"}). In tumors with mixed IDC histology, both p63 and SMA expression were much lower in myoepithelial cells than in more DCIS-resembling areas with nearly complete absence of these cells in intraductal tumors (Fig. [5c](#Fig5){ref-type="fig"}). These data suggest that the microenvironment has the most pronounced effect on tumor histology and myoepithelial cell features possibly via regulating p63 and TCF7.
To investigate the genomic targets of TCF7 and the enhancer landscape of MCF10DCIS-TCF7 cells, we analyzed the gene expression profiles of cells at different time points following TCF7 induction and performed ChIP-seq for TCF7 and H3K27ac (Supplementary Data [8](#MOESM10){ref-type="media"}). Pathway analysis showed an enrichment of genes upregulated following TCF7 overexpression for cell cycle S phase and G2-M, antigen presentation, proteolysis, DBS repair, mRNA processing, and regulation of angiogenesis, whereas downregulated genes were enriched for translational regulation, cytoskeleton rearrangement, cell adhesion, and FSH-signaling pathways (Fig. [5e](#Fig5){ref-type="fig"}). These gene expression changes are consistent with the apparent increase in cell proliferation after TCF7 expression (Supplementary Fig. [4b](#MOESM1){ref-type="media"}).
TCF7 ChIP-seq demonstrated 68,592 TCF7-binding sites in MCF10DCIS cells and one-third of these (23,034) overlapped with H3K27ac peaks (Fig. [5f](#Fig5){ref-type="fig"} and Supplementary Data [8](#MOESM10){ref-type="media"}). Pathway analysis of genes nearest to TCF7 and H3K27ac overlapping peaks demonstrated enrichment in EMT, integrin-mediated cell adhesion, angiogenesis, and NOTCH, WNT, and Hedgehog signaling (Fig. [5e](#Fig5){ref-type="fig"}). TCF7 direct targets include *TP63*, *CDH1, CCND1*, and *CCND2* (Fig. [5g](#Fig5){ref-type="fig"}). Interestingly, TCF7 is also a direct target of p63, thus, these two TFs cross-regulate each other's expression.
Analysis of H3K27ac data identified 1,178 SEs in TCF7-HA-expressing cells and most of these were also SEs in MCF10DCIS cells (Fig. [5h](#Fig5){ref-type="fig"} and Supplementary Data [6](#MOESM8){ref-type="media"}). However, we also identified 135 SEs that were gained after TCF7 expression and many of these were associated with TCF7-binding sites. The TCF7 locus itself was associated with a gained SE, demonstrating that TCF7 self-regulates its own expression, as well as several other TFs (e.g., *FOXO3*, *SMAD2*, *TEAD1*, *IRF2*), and cell cycle regulators (e.g., *CDK6*). The gain of these SEs was coupled with the increased expression of the associated genes, which could contribute to the increase in cell proliferation after TCF7 expression in vitro (Supplementary Fig. [4b](#MOESM1){ref-type="media"}). Analysis for CRCs^[@CR51]^ identified 25 top TFs, mostly overlapping with top CRC-forming TFs in MCF10DCIS cells, but we also observed some differences including gain of *ELF3*, *ETS2*, *IRF2*, and loss of *TP63*. Analysis of interaction networks among these 25 TFs identified a well-connected network with SMAD3, MYC, and SP1 as major hubs (Supplementary Fig. [4c](#MOESM1){ref-type="media"}).
To further investigate the effect of TCF7 on transcription, we integrated TCF7 ChIP-seq and RNA-seq data and found that genes upregulated after TCF7 expression were significantly predicted to be TCF7 targets indicating that TCF7 functions as a transcriptional activator in MCF10DCIS cells (Fig. [5i](#Fig5){ref-type="fig"}). Pathway analysis of direct TCF7 targets that are upregulated after TCF7 expression showed enrichment in proteolysis, antigen presentation, cell cycle S phase, ESR1 pathway, mitosis, regulation of angiogenesis, and EMT (Fig. [5e](#Fig5){ref-type="fig"}).
We also analyzed potential overlap between TCF7 and p63 peaks in MCF10DCIS cells and found that \~25% of p63 peaks overlap with TCF7-binding sites (Supplementary Fig. [4d, e](#MOESM1){ref-type="media"}). Most genes associated with these overlapping peaks are stem cell-related, such as WNT, NOTCH, and Hh signaling (Fig. [5e](#Fig5){ref-type="fig"}) implying that TCF7 and p63 may cooperate to regulate the proliferation and differentiation of epithelial stem cells. To test if p63 and TCF7 are in the same chromatin complex in MCF10DCIS cells, we performed TCF7 immunoprecipitation followed by p63 immunoblot. We found that a significant fraction of p63 is associated with TCF7, which could explain the significant overlap between p63 and TCF7 peaks (Fig. [5j](#Fig5){ref-type="fig"}).
Our xenograft and gene expression data implied that downregulation of *TP63* and overexpression of *TCF7* may have similar functional consequences and that both TFs regulate the expression of ECM and cell adhesion proteins, which in turn regulate p63 protein levels. To determine if the apparent decrease in p63 protein levels after TCF7 overexpression in MCF10DCIS cells could be due to indirect effects through the ECM, we performed immunoblot analysis for FAK and SRC activity. We found that TCF7 expression results in decreased phospho-FAK^Y397^ and phospho-SRC^Y416^ levels (Fig. [5k](#Fig5){ref-type="fig"}), which could explain the decrease in p63 protein levels, since inhibition of these pathways had the same effect (Fig. [4f](#Fig4){ref-type="fig"}). We also evaluated if decrease in FAK and SRC activity influences cellular migration, invasion, or adhesion to different substrates. We found that while cell migration and invasion were not significantly different between control and sh*TP63* or TCF7-expressing cells, although migration and invasion is very low in MCF10DCIS cells making it difficult to see a decrease, cell adhesion to fibronectin and collagens significantly decreased (Supplementary Fig. [4f, g](#MOESM1){ref-type="media"}). These results suggest that p63 and TCF7 cooperate to regulate ECM and cell adhesion, and these reciprocatively regulate the levels and activity of these two TFs (Supplementary Fig. [4h](#MOESM1){ref-type="media"}).
Discussion {#Sec10}
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*BRCA1* and *BRCA2* germline mutation carriers have an increased risk of breast cancer, but the cellular and molecular basis of this increased risk is still poorly defined. Prior studies described perturbed luminal differentiation and expansion of luminal progenitors in *BRCA1* mutation carriers^[@CR33],[@CR34],[@CR39]^. However, the potential impact of *BRCA1/2* germline mutation on myoepithelial cells has not been investigated in detail. In this study, we describe the molecular characterization of CD10^+^ myoepithelial cell population from normal breast tissue of healthy control nulliparous and parous women with no family history of breast cancer, and *BRCA1*/*2* mutation carriers, as well as from DCIS. Based on our integrated analyses of gene expression, enhancer, and p63 and TCF7 genomic target profiles, we determined that normal myoepithelial cell programs are maintained by an interactive TF network orchestrated by p63 and TCF7 in part via their regulation of ECM proteins and cell adhesion.
p63 plays key roles in the formation of epithelia during embryonic development and germline mutations in *TP63* are responsible for multiple syndromes that involve malformations of various epithelial structures, limb deformations, and cleft palate^[@CR54]^. Some of these individuals also have other abnormalities including hypoplastic mammary glands and/or nipples highlighting the importance of p63 in mammary gland development. Interestingly, several other genes that we identified as co-expressed and/or targets of p63 in myoepithelial cells are also linked to congenital syndromes with skin and facial abnormalities. *IRF6* is co-expressed with p63 in normal CD10^+^CD44^−^ cells and it is the target of both p63 and TCF7 in MCF10DCIS cells. Germline mutations in *IRF6* cause van der Woude syndrome^[@CR55]^, while its deletion in mice results in skin and limb abnormalities^[@CR56]^. Germline mutations in *TFAP2A* and *TFAP2B*, TFs also co-expressed with p63 in myoepithelium, cause branchio-oculo-facial and Char syndrome^[@CR57]^, respectively. Abnormal epithelial cell differentiation, and disorganized cell adhesion and ECM pathways are features of all these syndromes implying that perturbation of the interactive TF network orchestrated by p63 at different points can have similar effects.
TCF7 (a.k.a. TCF1) is a member of the TCF/LEF TF family that are nuclear-binding partners of β-catenin and downstream mediators of WNT signaling^[@CR47],[@CR58]^. APC/WNT/β-catenin signaling is a key regulator of stem/progenitor cell proliferation and survival, and germline mutations of APC predispose to colorectal and, at lower penetrance, breast carcinomas^[@CR59]^. In animal models, mammary-specific deletion of *Apc* leads to delayed ductal development and metaplastic outgrowths, but these do not progress to neoplasia^[@CR60]^. However, combined deletion of *Apc* and *Tcf1* (Tcf7) completely abrogates mammary gland development and leads to acanthomas^[@CR45]^. In our study, we identified TCF7 as a TF co-expressed with p63 in normal myoepithelial cells in control women. Furthermore, p63 and TCF7 also colocalize on the chromatin near genes required for normal myoepithelial cell function including *ACTA2* (smooth muscle actin) and *OXR1* (oxytocin receptor 1). In contrast, in *BRCA1* mutation carriers and in DCIS TCF7 and p63 are expressed in distinct cell types and almost no overlap is detected in their genomic binding. These data suggest that changes in the cellular expression pattern of TCF7 play important roles in breast tumor initiation and progression.
We identified an extensive cross-talk between p63 and TCF7/WNT signaling both in normal myoepithelial cells and also in the MCF10DCIS model, as well as a crosstalk of these pathways with ECM, Hh, and TGFβ signaling (Supplementary Fig. [4h](#MOESM1){ref-type="media"}). TCF7 and p63 are direct genomic targets of each other and p63 protein levels decrease with an increase in TCF7 in MCF10DCIS cells due to changes in cell--matrix interaction and pathways regulated by these including FAK and SRC signaling. GLI3, a transcriptional mediator of Hh signaling, is also a direct target of p63, while SMADs, transcriptional mediators of TGFβ signaling are direct targets of TCF7. At the same time, each one of these TFs regulate numerous cell adhesion and ECM proteins, which in turn regulate p63 protein levels. In normal myoepithelial cells p63 and TCF7 are co-expressed in non-carrier women, but the fraction of these cells is decreased in *BRCA1* mutation carriers. Based on the phenotype of the *Tcf1*^*−/−*^ mice demonstrating mammary adenomas in the absence of *Tcf1*, it is possible that the decrease of TCF7 in basal/myoepithelial cells of *BRCA1* mutation carriers may play a role in their higher risk of breast cancer, especially predisposing them to basal/triple-negative tumors. However, functional data obtained in animal models and in the MCF10DCIS model we utilized in this study should be interpreted with caution as neither mice nor the MCF10DCIS model fully recapitulate the expression patterns of p63 and TCF7 observed in normal human breast tissues. Thus, mechanistic studies focusing on myoepithelial cell differentiation would require the development and testing of more faithful models in the future. Mammary organoid cultures^[@CR61]^ or certain strains of rats that can be manipulated experimentally may potentially be useful in this regard.
DCIS is a precursor of invasive breast cancer, but currently we lack molecular markers to predict the likelihood of progression. We and others have analyzed the gene expression and genetic profiles of DCIS and IDC with the aim of identifying histologic stage-specific markers and drivers of invasive progression^[@CR62]--[@CR65]^, but none of the cancer cell-specific markers had shown consistent differences. In contrast, the lack of myoepithelial cells differentiates invasive from in situ disease and DCIS-associated myoepithelial cells show consistent differences compared to normal. Interestingly, many genes differentially expressed between tumor epithelial cells in DCIS and IDC encode cell adhesion and ECM proteins, and the downregulation of one of these (DST) in an intraductal model increased invasive progression^[@CR62]^ implying that perturbed cell--ECM interactions play an important role in tumor progression. Since normal myoepithelial cells prevent invasive progression by multiple different mechanisms, perturbed myoepithelial cell differentiation, such as changes in TCF7 expression patterns, could potentially be used as longitudinal biomarkers for patient risk stratification.
Methods {#Sec11}
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Cell lines and breast tissue specimens {#Sec12}
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MCF10ADCIS.com cells were generously provided by Fred Miller (Karmanos Cancer Institute, Detroit, MI, USA) and cultured following the provider's recommendations. Jurkat (TIB-152) and DU4475 (HTB123) cell lines were purchased from ATCC. Cell line identity was confirmed by short tandem repeats (STR) analysis and the cells were regularly tested for mycoplasma (Venor GeM Mycoplasma Detection Kit, Sigma). Fresh normal and neoplastic breast tissue specimens were collected at Harvard-affiliated hospitals, at John Hopkins University School of Medicine, Baylor-Charles A. Sammons Cancer Center, Hellen Diller Family Comprehensive Cancer Center, Washington University School of Medicine, University of Michigan, Sutter Roseville Medical Center, Seoul National University using protocols approved by the Institutional Review Board at each institution. Tissue samples at Dana-Farber Cancer Institute were collected under Dana-Farber Harvard Cancer Center (DF/HCC) Institutional Review Board (IRB) protocol \#93-085 following written informed consent and used in the lab in compliance with DF/HCC IRB protocol \#14-400 approved for the use of de-identified tissue samples. The study is compliant with all relevant ethical regulations regarding research involving human participants. Samples were de-identified prior to transport to the laboratory.
FACS, immunofluorescence, and immunohistochemical analyses {#Sec13}
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For FACS, single-cell suspensions of human breast epithelial cells were obtained by collagenase IV (1 mg/ml, Worthington, LS004l89bar) hyaluronidase (1 mg/ml, Sigma cat\#H3506) digestion in DMEM/F12 followed by trypsinization. Cells were stained with DAPI, and the following antibodies at 1:100 dilution in PBS + 2% BSA solution: CD10-FITC (Fisher Scientific cat\#F082601F) or CD10-RPE (DAKO, clone SS2/36, cat\#R084801), or CD10 (Biolegend, clone HI10A, cat\#312202), CD10-FITC (BD Biosciences; clone HI10a, cat\#340925), CD24-Alexa 647 (Biolegend; clone ML5, cat\#311110) and CD44-PE (BD Biosciences; clone 515, cat\#550989). The analysis was performed on a BD FACS Canto system (BD Biosciences). Gating and subpopulation analysis were performed using FlowJo software.
Immunofluorescence and immunohistochemical analyses were performed following standard protocols for formalin-fixed paraffin-embedded tissues using antibodies CD10 (DAKO, clone 56C6, cat\#M0727), TCF7 (Cell Signaling, C63D9, cat\#2203S), pan-cytokeratin (DAKO, Clone AE1/AE3, cat\#M3515), SMA (Thermo Scientific, Clone 1A4, cat\#MS113B), and p63 (Santa Cruz, clone 4A4, cat\#sc-8431) at 1:100 dilution in PBS 10% goat serum. Images from multiple areas of each sample were acquired using a Nikon Ti microscope attached to a Yokogawa spinning-disk confocal unit using a 603 plain apo objective, and OrcaER camera controlled by Andor iQ software; or a Leica SP5 confocal scanning microscope or slides were scanned by Servicebio (<http://www.servicebio.com>). Expression of TCF7 and p63 in metaplastic tumors was scored as follows 0 (negative), 1 (weak), and 2 (strong), whereas the co-expression of the two proteins were scored as 0 (no co-staining), 1 (\<50% overlap), and 2 (\>50% overlap).
SAGE-seq, RNA-seq, ChIP-seq sample preparation, and data analysis {#Sec14}
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A subset of the RNA-seq and ChIP-seq libraries were generated by the Center for Cancer Computational Biology (CCCB), Center for Functional Cancer Epigenetics (CFCE), and Molecular Biology Core (MBC) at Dana-Farber Cancer Institute (DFCI) following manufacturer's protocols. ChIP for p63, H3K27ac, TCF7, and TCF7-HA was performed using antibodies p63 (abcam, ab735), H3K27ac (abcam, ab4729), TCF7 (Sigma, WH0006932M1), and HA (abcam, ab9110)^[@CR66]^. For TCF7 and TCF7-HA ChIP-seq, 1 × 10^7^ cells were fixed with 2 mM DSG (Thermo Fisher Scientific cat\#20593) for 30 min at room temperature. DSG was then removed and replaced with fixing buffer (50 mM HEPES--NaOH (pH 7.5), 100 mM NaCl, 1 mM EDTA) containing 1% paraformaldehyde (Electron Microscopy Sciences, 15714) and crosslinked for 10 min at 37 °C. For histone modification ChIP-seq, 5 × 10^6^ cells were fixed with 1% paraformaldehyde for 10 min at room temperature. For ER ChIP-seq, 1 × 10^7^ cells were fixed with 1% paraformaldehyde for 10 min at 37 °C. Crosslinking was quenched by adding glycine to a final concentration of 0.125 M. Cells were washed with ice-cold PBS and harvested in PBS. The nuclear fraction was extracted by first resuspending the pellet in 1 ml of lysis buffer (50 mM HEPES--NaOH (pH 8.0), 140 mM NaCl, 1 mM EDTA, 10% glycerol, 0.5% NP-40, and 0.25% Triton X-100) for 10 min at 4 °C. Cells were pelleted, and washed in 1 ml of wash buffer (10 mM Tris--HCl (pH 8.0), 200 mM NaCl, 1 mM EDTA) for 10 min at 4 °C. Cells were then pelleted and resuspended in 1 ml of shearing buffer (10 mM Tris--HCl (pH 8), 1 mM EDTA, 0.1% SDS) and sonicated in a Covaris sonicator. Lysate was centrifuged for 5 min at 14,000 rpm to purify the debris. Then 100 µl of 10% Triton X-100 and 30 µl of 5 M NaCl were added. The sample was then incubated with 20 µl of Dynabeads Protein G (LifeTechnologies,10003D) for 1 h at 4 °C. Primary antibodies were added to each tube and immunoprecipitation (IP) was conducted overnight in the cold room. Cross-linked complexes were precipitated with Dynabeads Protein G for 2 h at 4 °C. The beads were then washed in low salt wash buffer (20 mM Tris--HCl pH 8, 150 mM NaCl, 10 mM EDTA, and 1% SDS) for 5 min at 4 °C, high salt wash buffer (50 mM Tris--HCl pH 8, 10 mM EDTA, and 1% SDS) for 5 min at 4 °C and LiCl wash buffer (50 mM Tris--HCl pH 8, 10 mM EDTA, and 1% SDS) for 5 min at 4 °C. DNA was eluted in elution buffer (100 mM sodium bicarbonate and 1% SDS). Cross-links were reversed overnight at 65 °C. RNA and protein were digested with 0.2 mg/ml RNase A for 30 min at 37 °C followed by 0.2 mg/ml Proteinase K for 1 h at 55 °C. DNA was purified with phenol--chloroform extraction and isopropanol precipitation. ChIP-seq libraries were prepared using the ThruPLEX DNA-seq Kit (Rubicon, cat\#R400427) from 1 ng of purified ChIP DNA or input DNA according to the manufacturer's protocol. ChiLin pipeline 2.0.0^[@CR67]^ was used for QC and preprocess of the ChIP-seq. We used Burrows--Wheeler Aligner (BWA)^[@CR68]^ as a read mapping tool, and Model-based Analysis of ChIP-Seq (MACS2)^[@CR69]^ as a peak caller. Peak annotation was performed using annotatePeaks.pl of the HOMER package v4.9.1 with version hg19 of the human genome^[@CR70]^. Based on a dynamic Poisson distribution MACS2 can effectively capture local biases in the genome sequence, allowing for more sensitive and robust prediction of binding sites. Unique read for a position for peak calling was used to reduce false-positive peaks, statically significant peaks were finally selected by calculated false discovery rate of reported peaks. The following QC methods were applied to the ChIP-seq data: (1) sequence quality QC, we calculated these scores using the FastQC software (FastQC. <http://www.bioinformatics.babraham.ac.uk/projects/fastqc/>). A good sequence quality score is ≥ 25; (2) PCR bottleneck coefficient---PBC score ≥ 0.90; (3) percentage overlap with known DHSs derived from the ENCODE project (the minimum required was 70%); (4) peak conservations; (5) number of total peaks (the minimum required was 1000). Deeptools^[@CR71]^ was used for the heatmap plots. BETA^[@CR53]^ was used in integrates ChIP-seq of TFs or chromatin regulators with differential gene expression data to infer direct target genes. Super enhancers were called by ROSE^[@CR50]^ using H3K27ac ChIP-seq data. Core regulator circuits were identified using the superenhancers data using the algorithm developed by the Young lab^[@CR51]^ and interactions among TFs were visualized using an online tool STRING^[@CR52]^. Specifically, we identified TFs predicted to form CRCs and selected TFs in the two top scoring CRCs for further analyses. These included 14 TFs in normal myoepithelial cells (ETV5, ETV6, FOXO1, GLI3, MAF, PBX1, RFX2, RUNX1, SMAD3, TCF7L2, TEAD1, TFAP2B, TFAP2C, THRB), 29 TFs in MCF10DCIS cells (RUNX1, SMAD3, RREB1, BHLHE40, TCF7L2, MYC, KLF13, ETV6, SOX9, VDR, ZNF217, GATA3, STAT4, EHF, FOS, TGIF1, FOSL2, RXRA, GLI3, SREBF1, HES1, RARA, TFCP2L1, KLF5, ERF, NFIB, FOS, OSR1, TGIF1), and 25 TFs in MCF10DCIS-TCF7 cells (SMAD3, TEAD1, RREB1, KLF13, BHLHE40, EGR1, MYC, RUNX1, IRF2, TCF7L2, ELF3, RARA, SP1, STAT4, EHF, ETS2, FOS, RXRA, RFX3, FOSL2, FOXO3, TFCP2L1, DLX2, SREBF1, GATA3). These TFs were then loaded into the STRING online tool to assess interactions using default settings: network edges based on evidence, use all active interaction sources (indicated in legend), medium confidence interaction score (0.004), and use only query proteins.
SAGE-seq library construction and sequencing were performed using long iSAGE kit (Invitrogen, cat\#T500003) and following the manufacturer's instructions^[@CR39]^. SAGE-seq tags were mapped to genes according to the best tag file for long SAGE (available from SAGE genie website at ftp://ftp1.nci.nih.gov/pub/SAGE/HUMAN). Tag counts mapped to the same genes were combined and total counts were normalized to counts per 10 million reads. For human patient samples, SAGE-seq and RNA-seq results were combined, first quantile normalized and then subjected to batch effect removal using the R software comBat package. Cluster analysis was done using the Cluster and TreeView software (available at <http://rana.lbl.gov/EisenSoftware.htm>) on top 1000 most variedly expressed genes. PCA analysis was performed using the R software pca function and rgl package. Differential gene expression was done using the R software samr and limma packages. The significance of overlap between gene signatures was performed by a hypergeometric test using the R function phyper. For MCF10DCIS cell line raw RNA-seq datasets read alignment, quality control, and data analysis were performed using STAR^[@CR72]^. Differential expression is called by DEseq2^[@CR73]^, significant genes were selected based on cutoff of *P*-value \< 0.05 and log~2~fold change \> 1.
Cell adhesion, migration, and invasion assays {#Sec15}
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Cell adhesion assay was performed using CytoSelect^TM^ 48-Well Cell Adhesion Assay (ECM Array, Colorimetric Format) (Cell Biolabs, Inc., cat\#CBA-070) according to the manufacturer's instruction. In brief, MCF10DCIS-TCF7 and MCF10DCIS-sh*TP63* cells were incubated with doxycycline (1 µg/ml) for 24 and 72 h, respectively. 7.5 × 10^4^ cells in serum-free medium supplemented with 0.5% BSA, 2 mM CaCl~2~, 2 mM MgCl~2~, and with or without doxycycline were plated on ECM Adhesion plate and incubated for 1 h in a cell culture incubator. Migration and invasion assays were performed using CytoSelect^TM^ 24-Well Cell Migration and Invasion Assay (8 µm, Colorimetric Format) (Cell Biolabs, Inc., cat\#CBA-100-C) according to the manufacturer's instructions. In brief, MCF10DCIS-TCF7 and MCF10DCIS-sh*TP63* cells were incubated with doxycycline (1 µg/ml) for 24 and 72 h, respectively. 4 × 10^4^ cells in serum-free medium supplemented with 0.5% BSA, 2 mM CaCl~2~, 2 mM MgCl~2~ and with or without doxycycline were plated on invasion or migration insert. Insert was placed on full media. Migration assay was incubated for 24 h and invasion assay for 48 h in a cell culture incubator.
Immunoblot analyses {#Sec16}
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Cell lysates were prepared in ice-cold RIPA lysis buffer (50 mM Tris pH 8, 150 mM NaCl, 1% NP40, 0.5% Na-deoxycholate, 0.1% SDS) supplemented with HALTTM Protease and Phosphatase Inhibitor Cocktail (Thermo Fisher Scientific) and sonicated using a Bioruptor^®^ Pico sonication device (diagenode). Protein content was determined with the BCA Protein Assay Kit (Pierce). 20 µg of protein were resolved by SDS--PAGE, transferred to Nitrocellulose membrane (Thermo Fisher Scientific) and blocked in 5% Milk/TBST for 1 h at RT. Primary antibodies were used as follows: anti-p63 (ab735; 1:500; abcam), anti-phospho FAK-Y397 (\#8556; 1:500; Cell Signaling Technology), anti-FAK (\#3285; 1:1000; Cell Signaling Technology), anti-phospho Src-Y416 (\#6943; 1:1000; Cell Signaling Technology), anti-Src (\#2109; 1:1000; Cell Signaling Technology), TCF7 (\#2203; 1:1000; Cell Signaling Technology), anti-GAPDH (\#5174; 1:5000; Cell Signaling Technology), and anti-ACTB (\#A2228; 1:1000, Sigma-Aldrich).
Proliferation assay {#Sec17}
-------------------
1.5 × 10^5^ cells were seeded in 6 cm tissue culture plates in duplicate. Cells were pulsed with BrdU (10 µM) for 1 h next day and stained with FITC-conjugated-anti-BrdU antibody and 7-AAD using the BD BrdU Flow kit (BD, Biosciences, cat\#552598) according to the manufacturer's instructions and analyzed by flow cytometry. Data acquisition was performed on a BD LSR Fortessa Flow Cytometry Analyzer, data analysis was done with Cytobank.
Mass cytometry (CyTOF) {#Sec18}
----------------------
For CyTOF, antibodies were purchased in carrier-free buffers and conjugated with the respective lanthanide metals by the CyTOF Antibody Resource and Core at Brigham Women's Hospital, Boston, MA, USA. Single cell suspensions of normal breast tissue from non-carrier and *BRCA1* and *BRCA2* mutation carriers were treated with 50 µM IdU-127 (Fluidigm, cat\#201127) for 30 min and 100 µM of the intercalator-103Rh (Fluidigm, cat\#201103A) for 15 min at 37 °C in DMEM/F12 medium. Next, 1 × 10^6^ cells of each sample were barcoded using the Cell-ID 20-Plex Pd Barcoding Kit (Fluidigm, cat\#201060) according to the manufacturer's instructions. Barcoded samples were pooled and stained simultaneously. Cells were fixed for 10 min with paraformaldehyde (Electron Microscopy Sciences, cat\#50-980-494) at a final concentration of 1.6% followed by Fc-receptor block Human TruStain FcX (Biolegend, cat\#422302) for 10 min and surface antibody staining for 30 min at room temperature. Subsequently, cells were permeabilized with methanol for 10 min on ice and incubated with the antibody cocktail for intracellular epitopes for 30 min. Cells were kept at 4 °C overnight in Fix and Perm Buffer (Fluidigm, cat\#201067) supplemented with Intercalator-IR (Fluidigm, cat\#201192A) 1:2000. Prior to analysis cells were washed with water, resuspended in water containing EQ™ Four Element Calibration Beads (Fluidigm, cat\#201078) (1:10) and filtered through a 35 µm strainer. Samples were acquired at a CyTOF Helios instrument (Fluidigm), normalized as previously described^[@CR74]^ and analyzed with Cytobank (Cytobank, Inc., Mountain View, CA). For all washes during staining Cell Staining Media (PBS with 0.5% BSA, 0.02% NaN3) was used. For analysis all files for normal (*n* = 6), *BRCA1* (*n* = 6), and *BRCA2* *(n* = 7) samples have been concatenated to create a single normal, *BRCA1* and *BRCA2* file, respectively. Files have been gated for singlets, viable (defined as Rh-103 negative) and non-apoptotic (cleaved PARP negative). To exclude contaminating immune cells (defined as CD45^+^), files have further been gated for CD45^−^ population. viSNE analysis has been performed using this population or the myoepithelial population defined as CK8/18 negative, E-Cadherin^+^ and SMA^+^. For all viSNE analysis the following markers were used for clustering: PR, CD10, CD44, MUC1, CD24, Vimentin, Epcam, CK8/18, SMA, GATA-3, ER, AR, HER2, CK5, E-Cadherin, CD49f. Antibodies used for CYTOF (metal): Rabbit monoclonal anti-PR a/b (141Pr), Cell Signaling Technology Cat\#8757; Mouse monoclonal anti-CD10 (142Nd) BD Biosciences Cat\#555373; Rat monoclonal anti-CD44 (143Nd) Biolegend Cat\#103002; Mouse monoclonal anti-cyclin D3 (144Nd) Abcam Cat\#ab28283; Mouse monoclonal anti-MUC1 (145Nd) Biolegend Cat\#355602; Mouse monoclonal anti-LAMP2 (146Nd) Biolegend Cat\#354302; Mouse monoclonal anti-CDK4 (147Sm) BD Biosciences Cat\#559677; Rabbit monoclonal anti-PTEN (148Nd) Cell Signaling Technology Cat\#9559; Rabbit monoclonal anti-E-Cadherin (149Sm) Cell Signaling Technology Cat\#3195; Mouse monoclonal anti-EpCAM (150Nd) Biolegend Cat\#324202; Mouse monoclonal anti-HER2 (151Eu) BD Biosciences Cat\#554299; Rabbit polyclonal anti-CK5 (152Sm) Abcam Cat\#ab53121; Mouse monoclonal anti-CD24 (153Eu) Biolegend Cat\#311102; Mouse monoclonal anti-CDK1 (154Sm) Biolegend Cat\#626901; Rabbit monoclonal anti-CDK6 (155Gd)
Cell Signaling TechnologyCat\#13331; Rabbit monoclonal anti-p63 (158Gd) Abcam Cat\#ab124762; Rabbit monoclonal anti-TCF7 (159Tb) Cell Signaling Technology Cat\#2203; Rabbit monoclonal anti-AR (160Gd) Cell Signaling Technology Cat\#5153; Mouse monoclonal anti-Cyclin A (161Dy) BD Biosciences Cat\#554175; Mouse monoclonal anti-Ki-67 (162Dy) BD Biosciences Cat\#550609; Mouse monoclonal anti-SMA (163Dy) Thermo Fisher Scientific Cat\#14-9760-82; Mouse monoclonal anti-cPARP (164Dy) BD Biosciences Cat\#552596; Rabbit monoclonal anti-Vimentin (165Ho) Cell Signaling Technology Cat\#5741; Rat monoclonal anti-GATA3 (166Er) eBioscience Cat\#14-9966-80; Rabbit monoclonal anti-p21 (167Er) Cell Signaling Technology Cat\#2947; Rabbit monoclonal anti-phospho-AKT Ser473 (168Er) Cell Signaling Technology Cat\#4060; Rabbit monoclonal anti-phospho-STAT3 Tyr705 (169Tm) Cell Signaling Technology Cat\#9145; Rabbit monoclonal anti-EGFR (170Er) Cell Signaling Technology Cat\#4267; Rabbit monoclonal anti-phospho-SMAD2 Ser465/467/Smad3 Ser423/425 (171Yb) Cell Signaling Technology Cat\#8828; Rabbit monoclonal anti-ERα (172Yb) Cell Signaling Technology Cat\#13258; Rat monoclonal anti-CD49f (173Yb) Biolegend Cat\#313602; Rabbit monoclonal anti-phospho-STAT5 Tyr694 (174Yb) Cell Signaling Technology Cat\#4322; Rabbit monoclonal anti-phospho-S6 Ser235/236 (175Lu) Cell Signaling Technology Cat\#4858; Mouse monoclonal anti-CK8/18 (176Yb) Cell Signaling Technology Cat\#4546; Mouse monoclonal anti-CD45 (156Gd) BD Biosciences Cat\#555480.
shRNA plasmids and lentivirus production {#Sec19}
----------------------------------------
pLKO shRNA vectors for control GFP (clone 437) and *TP63* (clones 6502, 6504, and 6506) were obtained from the Broad Institute RNAi consortium (TRC). To express doxycycline-inducible shRNAs, annealed oligos (LacZ and TP63) were cloned into pLKO-tet-on lentiviral vector (kindly provided by Dr. Alex Toker, Beth-Israel Deaconess Medical Center, Boston, MA). For expression of TCF7, HA tagged full-length TCF7 cDNA was obtained from pcDNA-HA-TCF1 plasmid purchased from Addgene^[@CR75]^. cDNA was inserted into pLenti6.3 Gateway compatible lentiviral vector (Life Technologies, cat\#V53306). To produce lentiviral supernatants, HEK293T cells were co-transfected with shRNA or expression vectors, VSVG, and pDG8.91 using Fugene 6 (Roche, cat\#11988387001). The targeting cells were infected with the viral supernatant containing 8 µg/ml polybrene. 48 h post-infection, the target cells were exposed to puromycin (2 µg/ml) to select for infected cells.
Mouse xenograft assays {#Sec20}
----------------------
Female NSG mice (8 weeks old) were purchased from The Jackson Laboratory and maintained in pathogen-free conditions. Tumors were induced by mammary fat pad, intraductal and subcutaneous bi-lateral injections of MCF10DCIS-sh*TP63* (45 mice, 5 mice per treatment group) or MCF10DCIS-TCF7 (45 mice, 5 mice per treatment group) cells (2 × 10e5 in 50 µL, 1 × 10e5 in 20 µL, and 2 × 10e5 in 100 µL, respectively) resuspended in DMEM-F12 medium/Matrigel Growth Factor Reduced Basement Membrane Matrix, Phenol Red-Free (Fisher Scientific, cat\#CB356238) in a 1:1 ratio. Treatment groups received doxycycline rodent chow (2000 ppm). Animal experiments were performed by the Lurie Family Imaging Center following protocols approved by the Dana--Farber Cancer Institute Animal Care and Use Committee. The study is compliant with all relevant ethical regulations regarding animal research. Mice were euthanized and tumors collected 21 days after injection.
Statistical analyses {#Sec21}
--------------------
Statistical significance of differences in tumor weight and cell adhesion were determined by based on *T*-test. For assessing the association among cell subtype (Figs. [1h](#Fig1){ref-type="fig"} and [2f](#Fig2){ref-type="fig"}: p63^−^TCF7^-^, p63^+^TCF7^+^, TCF7^+^p63^−^, p63^+^TCF7^−^; Fig. [2b](#Fig2){ref-type="fig"}: CD10^+^CD44^−^, CD10^+^CD44^+^) and condition Fig. [1i](#Fig1){ref-type="fig"}: Control, *BRCA1*, *BRCA2*; Fig. [2b](#Fig2){ref-type="fig"}: Normal and DCIS; Fig. [2f](#Fig2){ref-type="fig"}: DCIS-HG, DCIS-LG, DCIS-IDC), we first conducted Pearson's chi-squared tests among averages of estimated cell counts across replicates. For computing the *P*-values in the main figures, we used a conservative estimate of 100 cells. With increasing population size, the power of identifying associations also increases: for 150 cells, *p*-values of 1.485e−07 (Fig. [1h](#Fig1){ref-type="fig"}) and 8.998e−06 (Fig. [2f](#Fig2){ref-type="fig"}); for 200 cells: 1.864e−10 (Fig. [1h](#Fig1){ref-type="fig"}) and 8.713e−08 (Fig. [2f](#Fig2){ref-type="fig"}). For Fig. [1h](#Fig1){ref-type="fig"} and population size of 100, we simulated the *p*-value, since the count for Control p63-TCF7- was only 2. Next, in order to take into account the variation among replicates (which is not considered by the chi-squared test), we employed methods specific to Compositional Data Analysis^[@CR76]^. These methods are needed because of the negative correlations artificially introduced by the structure of these data: since the amount of every cell subtype is limited to the whole, if the percentage of one subtype of cells increases, the amounts of other subtypes must decrease. Therefore, we first evaluated whether the cell subtype composition can be accurately predicted given the condition, by using Dirichlet regression^[@CR77]^. The Dirichlet distribution is a multivariate generalization of the beta distribution and is commonly employed for modeling compositional data^[@CR78]^. However, likely because of the low number of replicates, as well as the large variation among replicates, in all cases (data from Figs. [1h](#Fig1){ref-type="fig"} and [2b, f](#Fig2){ref-type="fig"}) the effect sizes were small, and the large majority of predictors were not significant. We further evaluated whether the condition can be accurately predicted given the cell subtype composition, by using Multinomial logistic regression. Prior to this, the cell subtype compositions were transformed to a *D*−1 dimensional space (where *D* is the dimension of the original data), by using the isometric log transform^[@CR79]^, commonly applied to compositional data. Likely from the same reasons described above, in almost all cases the predictors were not significant, with the sole exception of the ratio of CD10^+^CD44^+^ cells in separating DCIS from Normal, for which the effect size was 1.01, and the *p*-value 0.063.
Reporting summary {#Sec22}
-----------------
Further information on research design is available in the [Nature Research Reporting Summary](#MOESM11){ref-type="media"} linked to this article.
Supplementary information
=========================
{#Sec23}
Supplementary Information Description of Additional Supplementary Files Supplementary Data 1 Supplementary Data 2 Supplementary Data 3 Supplementary Data 4 Supplementary Data 5 Supplementary Data 6 Supplementary Data 7 Supplementary Data 8 Reporting Summary
Source Data
**Peer review information** *Nature Communications* thanks Vessela Kristensen and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
**Publisher's note** Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
These authors contributed equally: Lina Ding, Ying Su, Anne Fassl, Kunihiko Hinohara.
Supplementary information
=========================
**Supplementary Information** accompanies this paper at 10.1038/s41467-019-12125-5.
We thank members of our laboratories for their critical reading of this manuscript and useful discussions. This research was supported by the National Cancer Institute U01 CA143233 (K.P. and M.B.), P01 CA080111 (P.S. and K.P.), R01 CA202634 (P.S.), SPORE P50 C CA202634 (J.E.G., A.L.R., K.P.), R35CA197623 (K.P.), R01 CA 107469 (C.G.K.), R01 CA125577 (C.G.K.), and the Susan G. Komen Foundation (Y.S. and K.P.).
L.D. performed immunofluorescence, cell culture, FACS, cell purification, ChIP-seq, and RNA-seq experiments. Y.S. performed FACS, cell purification, ChIP-seq, SAGE-seq, immunofluorescence, cell culture, and xenograft experiments. A.F. performed CyTOF, cell proliferation, migration, invasion, adhesion assays, and detachment/inhibitor treatment experiments. K.H. performed ChIP-seq, immunofluorescence analyses, and xenograft experiments. N.B.-Q. performed FACS, cell purification, SAGE-seq, cell culture, and ALDH activity assays. S.J.H. and S.Ch. helped with FACS and cell purification. B.J. helped with ChIP-seq experiments. R.J.C., D.M.B., and Q.-D.N performed xenograft studies. X.Z. generated CD10^+^ cell RNA-Seq libraries. M.A. and C.G.D.A. helped with image analyses. V.F.M., A.L.R., G.E., L.P., M.G., G.D.R., W.H., A.A., P.A., E.S.H., D.C.A., K.Ba., E.M.H.K., C.H.M.III., J.W., R.R., K.Bo., S.Y.P., C.G.K., J.L.B., S.S., D.D., and J.E.G. facilitated human tissue sample collection. L.D., Y.S., X.Q., N.W.H., M.E., J.Y., and S.Cr. performed genomic data and statistical analyses. W.C.H. and R.F. provided detailed protocols, technical help, and advice. K.P. supervised the overall study with help from P.S., H.W.L., and M.B. K.P. wrote the manuscript with input from all authors.
All raw genomic data was deposited to GEO under accession number [GSE113909](https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE113909). The source data underlying Figs. [1](#MOESM12){ref-type="media"}b, h, [2](#MOESM12){ref-type="media"}b, f, h, [4](#MOESM12){ref-type="media"}b, [5b](#MOESM12){ref-type="media"} and Supplementary Figs. [4b, f, g](#MOESM1){ref-type="media"} and the full-size images of immunoblots depicted in Figs. [4d, e, f](#Fig4){ref-type="fig"}, [5a, j, k](#Fig5){ref-type="fig"} and Supplementary Fig. [3a](#MOESM1){ref-type="media"} are included in the Source Data file. Detailed protocols and reagents described in this manuscript are available from the corresponding author upon request.
K.P. currently serves on the Scientific Advisory Board of Mitra Biotech and Acrivon Therapeutics and used to be a consultant to Novartis. D.D. is a consultant for Novartis and serves on the Academic Advisory Board of Oncology Analytics, Inc. J.L.B. is a consultant for Pfizer, Medivation, and Amgen. P.S. has been a consultant to Novartis, Genovis, Guidepoint, The Planning Shop, ORIC Pharmaceuticals, and Exo Therapeutics; P.S. also receives research funding from Novartis. R.F. served on the Scientific Advisory Boards of IsoPlexis, BioTechne, and Singleron Biotechnologies. L.P. is a current employee of Ambry Genetics. Y.S. is a current employee of Deciphera Pharmaceuticals; S.J.H. is a current employee of ImmunoGen, Inc.; M.E. is a current employee of WuXi NextCODE; S.C. is a current employee of Metamark Genetics Inc. The remaining authors declare no competing interests.
| 2024-07-22T01:27:15.642919 | https://example.com/article/9203 |
Question of the Day
Should Trump keep Pence on the ticket in 2020?
Story TOpics
Staff at the VA’s Cleveland medical center destroyed records into the death of a patient to avoid unwanted publicity, then punished a whistleblower and put her under surveillance after she revealed lapses in the patient’s care, the woman charged in ... more >
Staff at the VA’s Cleveland medical center destroyed records into the death of a patient to avoid unwanted publicity, then punished a whistleblower and put her under surveillance after she revealed lapses in the patient’s care, the woman charged in a recent complaint.
Patricia Leligdon said superiors began retaliating against her in 2010 after she reported that VA medical staff could have done more to prevent the death of a veteran who died after an “altercation” with another veteran at a VA outpatient mental health clinic, according to a federal whistleblower lawsuit she recently filed against the Department of Veterans Affairs.
The accusations come as the VA tries to assure its own employees and Congress that whistleblowers won’t be retaliated against for reporting on patient safety and management problems.
The VA’s previous secretary, Eric K. Shinseki, was ousted last year after a scandal into the falsification of wait time data, which surfaced because of complaints from whistleblowers.
Ms. Leligdon, whose attorney could not be immediately reached for comment, says in her complaint that the retaliation occurred before and after the VA’s change in leadership. And the complaint says she wasn’t the only employee at the VA’s Cleveland Medical Center subject to retaliation for voicing concerns about the workplace, according to the complaint.
“This cultural attribute is part of a broader culture of suppressing criticism by engaging in reprisals against those who engage in criticism or otherwise associated with such critics,” the complaint states.
VA officials declined to comment on the accusations or the extent to which the agency utilizes surveillance to monitor its own employees in and out of the workplace.
“The case is being handled by the US Attorney’s office and is ongoing so I am unable to comment,” VA spokeswoman Ashley Trimble wrote in an email.
Ms. Leligdon, who supervised a staff of about a dozen social workers, said she was told not to go public with her belief that the VA could have done more for the patient in 2010, according to her complaint.
She also said that during a February 2011 VA ethics panel meeting, which she attended through a conference call, an unnamed caller referred to information that another employee was going to disclose through social media sites that “would have destroyed” the Cleveland VA medical center’s reputation.
According to Ms. Leligdon, the caller said a VA privacy official destroyed the evidence the other person would have disclosed, and the privacy official later issued a memo cautioning employees about a prohibition against sharing information about “personal activities occurring within the medical center” on social media.
The name of the veteran who died is not disclosed in the complaint, but the lawsuit says Ms. Leligdon and other VA personnel received subpoenas to testify in a hearing that never took place because the case was settled.
She said she was passed over for promotions, blackballed by staff and subject to increasing surveillance, and she sent letters to Mr. Shinseki, Attorney General Eric H. Holder Jr. and Ohio Attorney General Mike DeWine about the “coverup of unlawful activity,” evidence destruction and the ongoing surveillance.
In March 2014 the VA medical center “stepped up its attacks” by issuing one disciplinary action after another and “escalating its unlawful surveillance” of Ms. Leligdon, she said in her complaint.
She said the retaliation continued even after the ouster of Mr. Shinseki and a June 13 memo by then-Acting VA Secretary Sloan Gibson hailing the VA’s “unwavering” commitment to employee protections under the federal whistleblower statute.
Earlier this month, Rep. Jeff Miller, Florida Republican and chairman of the House Committee on Veterans’ Affairs, told new VA Secretary Robert McDonald that his committee was investigating the agency’s treatment of whistleblowers.
He also called on the agency to turn over disciplinary records in the case of a VA credentialing official in Puerto Rico who says he was suspended after notifying the VA about the late-night drug arrest of a high-ranking official, who was ultimately cleared of the charges. | 2024-04-14T01:27:15.642919 | https://example.com/article/2059 |
Q:
Strategy for implementing a complex curve editor with XAML/WPF
I want to implement a rather complex CurveEditor that has to support the usual requirements like:
freely scalable and moveable axis
different interpolation types per curve point (Linear, Cubic, Spline)
Tangents (joined and broken)
Selecting one or several points to edit (move, scale, delete) via Fence or Click
Only show handles and highlights for selected curve points
I don't want to manipulate actual WPF curves but an existing model with key/value/tangents sets and sample the precise shape of the curve from our implementation.
I already gathered some experience on implementing custom UserControls and Templates. But I want to make sure, I don't miss any apparent solution. I planned to have this general XAML-tree:
CurveEditor - Window holding all content
MainThumb : Enable dragging and scaling the editor range
XAxis : UserControl rending some scale on the left side
YAxis : UserControl rending some scale on the bottom
Curves : Canvas holding the curves
Curve : UserControl for a single curve
CurveName - Label of the curve
CurveLine - DrawingVisual that will render the actual curve by sampling the internal implementation of the spline function.
CurveEditPoints - Canvas that holds all edit points
CurveEditPoint - UserControl for a single edit point
LeftTangent - UserControl for the left tangent handle
LeftTangentThumb - For modifying the handle
RightTangent - UserControl for the right tangent handle
RightTangentThumb - For modifying the handle
CurvePointCenter - Visualisation of the actual point, select state and interpolation type.
CurvePointThumb - Thumb to select and drag point around
I know, this is quite a complex question and I am not asking for an actual implementation. I am interested in the following questions:
Can you recommend any tutorials or books that might help me (I already got Illustrated WPF, WPF Control Development Unleashed, and a couple of other)
Should minor elements like the Tangents be individual UserControls?
What container is best suited for hosting the individual "Curves", "EditPoints" and "Tangents". Right now, I use Canvas and Canvas.SetLeft/SetTop to position the children, but that feels "strange".
Should I use "Shapes" like Path or DrawingVisual-Classes to implement actual representation. Path is straight forward, but I am concerned about performance with hundreds of CurvePoints.
Should I use Transforms to rotate the tangents or is just fine to do some triangulation math in the code behind files?
Does the structure roughly make sense, or do you suggest a completely different approach?
A:
you seem to have the right tools at hand, WPF Unleashed is excellent, but I guess you have that one already.
make individual UserControls in one of these cases:
you are using the same xaml all over the place (DRY)
you xaml file gets too big (get some components out)
you need to inherit from some class
this depends on how much codebehind you want.
you can, as you suggested in your comment, use an ItemsControl as a container for wherever you need selection between multiple items. so this could also be done on the level of Curves, not just on the level of points on the curve. Depending on how you want to handle drawing of the actual lines and curves you can even have an ItemsControl for those. (on a side note: you will not have virtualization out of the box though, as your items won't have a constant height)
Path is OK with hundreds of CurvePoints. If you have 10.000, I'd say you could get problems.
can't imagine how a transform should be used here, maybe inside an Adorner.
your structure looks good. you will be able to implement all of this. I will suggest though how I would do it:
first of all use MVVM.
CurveEditor
ListBox(Panel=Canvas)(ItemsSource=Curves)(ItemTemplate=CurveControl)
CurveControl
Canvas(Background=Transparent) <= I'm not sure if standard is white, but you don't want to overlap other Curves...
CurveName
ListBox(Panel=Canvas(Background=Transparent))(ItemsSource=CurveParts)
ListBox(Panel=Canvas(Background=Transparent))(ItemsSource=CurvePoints)(ItemTemplate=>EditPointControl)
EditPointControl
Canvas
Thumb(Template = Ellipse) (Name=CenterHandle) (with some Visualstates for Selection and hiding of Tangents)
Thumb(Template = Ellipse) (Name=LeftHandle)
Thumb(Template = Ellipse) (Name=RightHandle)
Line (Binding X/Y to Centerpoint and LeftHandlePoint)
Line (Binding X/Y to Centerpoint and RightHandlePoint)
I have stated to set ItemTemplate for the ListBox. You can however style the listbox however you want (I think the standard style includes a border, you might want to remove that or set bordersize=0) and set instead of ItemTemplate the ItemContainerStyle and bind to IsSelected so you have control over IsSelected from your ViewModel (look here for what I mean).
So the viewmodel looks like this:
- CurveEditorViewModel
- ObservableCollection<CurveViewModel> Curves
- CurveViewModel
- string Label
- (Point LabelPlacement)
- bool IsSelected
- ObservableCollection<CurvePointViewModel> CurvePoints
- ObservableCollection<CurvePartViewModel> CurveParts
- CurvePointViewModel
- Point Position
- bool IsSelected
- Point LeftHandle
- Point RightHandle
- CurvePartViewModel
- CurvePointViewModel StartPoint
- CurvePointViewModel EndPoint
- Path CurvePath
in here you can subscribe to CurvePointViewModel's PropertyChanged and recalculate the Path you're exposing.
I'd probably improve on it as I go but that'd be my first guess.
There are some details you might want to watch out for. eg: the style for the thumbs might be a visible circle in the middle and an invisible bigger one around that with background=transparent. that way you can have your visible circle small, but have the user use the tumb in an area around the small circle.
EDIT:
here is an Example for the Thumb:
<Thumb Width="8" Height="8" Cursor="Hand" Margin="-4">
<Thumb.Template>
<ControlTemplate TargetType="Thumb">
<Grid>
<Ellipse Fill="Transparent" Margin="-6"/>
<Ellipse Stroke="Red" StrokeThickness="2"/>
</Grid>
</ControlTemplate>
</Thumb.Template>
</Thumb>
as you want to position this at a specific point on a canvas setting the Margin to minus half the width and height will place the center of the circle on that point. Furthermore, having that inner ellipse with a transparent fill and Margin of -6 you will get a 6px bigger radius around the inner (smaller) circle where you can drag the thumb.
| 2024-04-25T01:27:15.642919 | https://example.com/article/7525 |
Franklin Advisers, Inc., is a wholly owned subsidiary of Franklin Resources, Inc. [NYSE:BEN], a global investment organization operating as Franklin Templeton Investments.Franklin Templeton Investments provides global and domestic investment management solutions managed by its Franklin, Templeton, Mutual Series and Fiduciary Trust investment teams. The San Mateo, CA-based company has more than 50 years of investment experience and over $351 billion in assets under management as of March 31, 2004. For more information, please call 1-800/DIAL BEN® or visit franklintempleton.com.
FRANKLIN UNIVERSAL TRUST (002) ASSET ALLOCATION @ 3/31/04
SECURITY
MARKET VALUE
PERCENTAGE OF FUND
Corporate Bonds
$157,470,582
66.79%
Convertible Bonds
$2,473,291
1.05%
Utilities Stocks
$51,241,987
21.73%
Natural Resources Equities & Preferred Stocks
$2,355,939
1.00%
Misc. Equities & Preferred Stocks
$5,557,315
2.36%
Foreign Denominated Corporate Bonds
$0
0.00%
Foreign Gov't U.S. Dollar Denominated Bonds
$9,158,050
3.88%
Foreign Government Agencies
$714,359
0.30%
Cash & Other Net Assets
$6,811,256
2.89%
=========================
============
============
Total Assets1
$235,782,779
100.00%
10 LARGEST HOLDINGS BY ISSUER
MARKET VALUE
PERCENTAGE OF FUND
Southern Co.
$5,185,000
2.20%
FPL Group
$4,679,500
1.98%
Dominion Resources
$4,501,000
1.91%
Mexico Government
$4,077,563
1.73%
IMC Global
$3,772,500
1.60%
Republic of Bulgaria
$3,708,300
1.57%
Legrand S.A.
$3,585,000
1.52%
Exelon Corp.
$3,581,240
1.52%
D.R. Horton
$3,502,500
1.49%
Nicor Inc.
$3,452,540
1.46%
=========================
============
============
Total
$40,045,143
16.98%
% OF GROSS ASSETS IN DEFAULT:ISSUER
MARKET VALUE
PERCENTAGE OF FUND
Atherton Franchise
$267,876
0.11%
Century Communications
$3,106,250
1.32%
Fibermark Inc.
$1,710,000
0.73%
Key3Media
$62,500
0.03%
Pindo Deli
$795,000
0.34%
Poland Telecom
$300
0.00%
PSINet
$222,398
0.09%
=========================
============
============
Total
$6,164,324
2.62%
Note: The value of these defaulted securities is reflected in the fund's net asset value.
All percentages are rounded to two decimal places.
==============================
==============================
Number of Positions
130
NAV per share
$6.47 2
Market price per share
$5.87 2
Number of shares outstanding
27,924,294
Asset coverage (Investment Company Act)
428.70%
Total net assets
$180,782,780
1 Percentage of total assets of the fund (total net assets plus long-term debt issued by the fund). | 2023-10-28T01:27:15.642919 | https://example.com/article/8701 |
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</head>
<body onload="init()">
<div id="topics">
<div id="toolDescription" class="smallsize">
<h2>버퍼 생성 (Create Buffers)</h2><p/>
<h2><img src="../images/GUID-6E648C49-37F9-4673-82D5-DB646921A828-web.png" alt="버퍼 생성"></h2>
<hr/>
<p>버퍼는 포인트, 라인 또는 영역 피처에서 지정된 거리를 포함하는 영역입니다.
</p>
<p>버퍼는 일반적으로 다른 도구를 사용하여 추가 분석할 수 있는 영역을 생성하는 데 사용됩니다. 예를 들어 질문이 "학교에서 1.6Km 이내에 있는 건물은 무엇입니까?"인 경우 학교를 중심으로 1.6Km 버퍼를 생성한 후 건물 풋프린트가 포함된 레이어로 버퍼를 중첩하여 답을 찾을 수 있습니다. 이 과정을 통해 학교에서 1.6Km 이내에 있는 건물의 레이어가 최종 결과로 생성됩니다.
</p>
</div>
<!--Parameter divs for each param-->
<div id="inputLayer">
<div><h2>버퍼를 적용할 레이어 선택</h2></div>
<hr/>
<div>
<p>버퍼할 포인트, 라인 또는 영역 피처입니다. 입력 레이어가 투영 좌표체계에 있거나 <b>분석 환경</b>을 사용하여 처리 공간 참조가 투영 좌표체계로 설정되어 있어야 합니다.
</p>
<p>맵에서 레이어를 선택하는 것 이외에, 드롭다운 목록의 하단에 있는 <b>분석 레이어 선택</b>을 선택하여 빅데이터 파일 공유 데이터셋 또는 피처 레이어의 콘텐츠를 찾아볼 수 있습니다. 필요에 따라 입력 레이어에 필터를 적용하거나 맵에 추가된 호스팅 레이어에 선택 항목을 적용할 수 있습니다. 필터와 선택 항목은 분석에만 적용됩니다.
</p>
</div>
</div>
<div id="bufferType">
<div><h2>적용할 버퍼의 유형 선택</h2></div>
<hr/>
<div>
<p>다음과 같은 3가지 방법으로 입력 피처의 버퍼 크기를 지정할 수 있습니다.
<ul>
<li>모든 피처에 적용되는 거리를 지정합니다.
</li>
<li>거리 값을 포함하는 입력 레이어의 필드를 지정합니다. 문자열 필드나 숫자 필드를 사용할 수 있습니다. 선형 단위가 정의되지 않은 경우 공간 참조의 단위가 사용됩니다. 지리 좌표체계를 사용하는 경우 단위가 없는 필드는 미터로 간주됩니다.
</li>
<li>여러 필드와 산술 연산자로 식을 만듭니다. 예를 들어 이름이 <i>wind_speed</i>인 필드 값을 10배 버퍼하려면 <i>$feature["wind_speed"] x 10</i> 식을 추가합니다.
</li>
</ul>
</p>
</div>
</div>
<div id="method">
<div><h2>버퍼 방법 선택</h2></div>
<hr/>
<div>
<p> <b>평면</b> 방법 또는 <b>측지선</b> 방법을 사용하도록 선택할 수 있습니다. <b>평면</b> 방법이 더 빠르며 투영된 데이터의 로컬 분석에 적합합니다. <b>측지선</b> 방법은 대형 영역 및 지리 좌표체계에 적합합니다.
</p>
</div>
</div>
<div id="dissolveOption">
<div><h2>디졸브 방법의 유형 선택</h2></div>
<hr/>
<div>
<p>디졸브 방법을 지정하는 옵션입니다. 디졸브 방법을 선택하고 나면 멀티파트 또는 싱글파트 영역을 생성하는 옵션을 선택할 수 있으며 제공된 필드를 기반으로 통계를 계산할 수 있습니다.
<ul>
<li> <b>모두</b> - 모든 피처가 디졸브됩니다. 멀티파트 피처가 허용된 경우 모든 피처는 단일 피처로 디졸브됩니다. 멀티파트 피처가 허용되지 않은 경우에는 겹치거나 인접한 피처가 디졸브됩니다.
</li>
<li> <b>필드</b> - 동일한 지정 필드 또는 지정 필드 조합을 공유하는 피처가 디졸브됩니다. 멀티파트 피처가 허용된 경우 동일한 필드를 가진 모든 피처는 단일 피처로 디졸브됩니다. 멀티파트 피처가 허용되지 않은 경우에는 겹치거나 인접하며 동일한 필드 값을 갖는 피처가 디졸브됩니다.
</li>
<li> <b>없음</b> - 피처가 디졸브되지 않습니다. 이 방법이 기본값입니다.
</li>
</ul>
</p>
</div>
</div>
<div id="multipart">
<div><h2>멀티파트 피처 허용</h2></div>
<hr/>
<div>
<p>결과를 구성하는 피처가 싱글파트 피처인지 멀티파트 피처인지를 지정하는 옵션입니다.
</p>
<p>
<ul>
<li>이 옵션을 선택하면 분석 결과에 멀티파트 피처가 포함됩니다.
</li>
<li>이 옵션을 선택하지 않으면 분석 결과에 싱글파트 피처가 포함됩니다. 이 상태가 기본 설정입니다.
</li>
</ul>
</p>
</div>
</div>
<div id="summaryFields">
<div><h2>통계 추가(선택)</h2></div>
<hr/>
<div>
<p>요약된 피처에 대한 통계를 계산할 수 있습니다. 숫자 필드에서 다음을 계산할 수 있습니다.
<ul>
<li>개수 - null이 아닌 값의 개수를 계산합니다. 숫자 필드나 문자열에 사용할 수 있습니다. [null, 0, 2]의 개수는 2입니다.
</li>
<li>합계 - 필드에 있는 숫자 값의 합계입니다. [null, null, 3]의 합계는 3입니다.
</li>
<li>평균 - 숫자 값의 평균입니다. [0, 2, null]의 평균은 1입니다.
</li>
<li>최소 - 숫자 필드의 최소 값입니다. [0, 2, null]의 최소는 0입니다.
</li>
<li>최대 - 숫자 필드의 최대 값입니다. [0, 2, null]의 최대는 2입니다.
</li>
<li>범위 - 숫자 필드의 범위입니다. 이 값은 최대 값에서 최소 값을 뺀 값입니다. [0, null, 1]의 범위는 1입니다. [null, 4]의 범위는 0입니다.
</li>
<li>분산 - 트랙 내 숫자 필드의 분산입니다. [1]의 분산은 null입니다. [null, 1,0,1,1]의 분산은 0.25입니다.
</li>
<li>표준편차 - 숫자 필드의 표준편차입니다. [1]의 표준편차는 null입니다. [null, 1,0,1,1]의 표준편차는 0.5입니다.
</li>
</ul>
</p>
<p>문자열 필드에서 다음을 계산할 수 있습니다.
<ul>
<li>개수 - null이 아닌 문자열의 개수입니다.
</li>
<li>임의 - 이 통계는 지정된 필드에 있는 문자열 값에 대한 랜덤 샘플입니다.
</li>
</ul>
모든 통계는 null이 아닌 값에 대해 계산됩니다. 결과 레이어에는 계산된 각 통계에 대한 새 필드가 포함됩니다. 속성과 통계를 선택하여 원하는 개수의 통계를 추가할 수 있습니다.
</p>
</div>
</div>
<div id="dataStore">
<div><h2>결과를 저장할 ArcGIS 데이터 저장소 선택</h2></div>
<hr/>
<div>
<p>GeoAnalytics 결과는 데이터 저장소에 저장되며 Portal for ArcGIS에서 피처 레이어로 나타납니다. 대부분의 경우 결과는 기본 설정에 따라 시공간적 데이터 저장소에 저장되어야 합니다. 관계형 데이터 저장소에 결과를 저장하는 것이 좋은 경우도 있습니다. 결과를 관계형 데이터 저장소에 저장하려는 이유는 다음과 같습니다.
<ul>
<li>결과를 포털 간 컬래버레이션에 사용할 수 있습니다.
</li>
<li>기능을 결과와 동기화할 수 있습니다.
</li>
</ul>
</p>
<p>GeoAnalytics 결과가 늘어날 것으로 예상되며 시공간 빅데이터 저장소의 기능을 활용하여 대용량 데이터를 처리하려는 경우에는 관계형 데이터 저장소를 사용하지 마세요.
</p>
</div>
</div>
<div id="outputName">
<div><h2>결과 레이어 이름</h2></div>
<hr/>
<div>
<p> 생성될 레이어의 이름입니다. ArcGIS Data Store에 작성하는 경우 결과는 <b>내 콘텐츠</b>에 저장되고 맵에 추가됩니다. 빅데이터 파일 공유에 작성하는 경우 결과는 빅데이터 파일 공유에 저장되고 해당 매니페스트에 추가됩니다. 이러한 결과는 맵에 추가되지 않습니다. 기본 이름은 도구 이름과 입력 레이어 이름을 기반으로 합니다. 레이어가 이미 있으면 도구를 사용할 수 없습니다.
</p>
<p> ArcGIS Data Store(관계형 또는 시공간 빅데이터 저장소)에 작성하는 경우 <b>결과 저장:</b> 드롭다운 상자를 사용하여 <b>내 콘텐츠</b>에서 결과를 저장할 폴더의 이름을 지정할 수 있습니다.
</p>
</div>
</div>
</div>
</html>
| 2023-09-10T01:27:15.642919 | https://example.com/article/7277 |
California Central Valley Map v3.0 for FS 17
Description about California Central Valley Map v3.0 for FS 17:
California Central Valley Map v3.0 for Farming Simulator 17 game.
After 3 months of construction, as well as full-time work and evening studies, my map is not yet finished but has reached the beta test status. So I would be very glad that you test the map and give me your feedback on what I should improve in the V2.
For questions I am available.
Version 3- new courtyards and buildings
Version 2.1
- remove the blocking element at the Ingleside Dairy.
- Add 2 gasstaition trigger
Changes in v2.0:.
delete flying objects and finish the emty parts of the map
. Better integrate forestry
. New industries such as mining and construction
. And of course your opinions
The map is based as in the FS15 in California, but was rebuilt from the ground up. As in real California, one of the main focal points is dairy farming. | 2023-11-12T01:27:15.642919 | https://example.com/article/3280 |
Further 2998 Hand Observations
There seems to be considerable variations in the actual layout these hands, and it is important to determine which are original. One of the reasons, apart form value preservation, is that having original, old, correct Omega hands adds to the attraction and desirability of the watch, while a watch fitted with service hands, especially the flat ones, will be less and less attractive as the owner becomes more and more aware.
These are my conclusions.
First if I see flat hands, with sharp edges, and sharp lume openings all through (on all four ends) then I treat them as service replacements.
There are new service replacements, “old” service replacements with tritium, and new hands with replaced lume.
These hands I consider modern replacements, with aged lume. Therefore when buying, I reduce the valuation. It is almost impossible to find old replacements, so it does not stop me from buying.
Thin lume with square ends. Flat metal. The minute hand is also a little short.
Here is an example of what I think might be early service hands – because of the shape of the hands and the lume openings. I have seen this on numerous watches, but the colour does not strike me as truly vintage – but it is just a feeling. Perhaps these are early service hands from 60’s/70’s? Who knows, all I know is that I do not appreciate the colour.
Thin, blueish lume, with curved ends on each end of the opening. The metal of the hands is slightly curved.
So are all thin lume hands replacements? I do not think so. Are there any original thin lume hands for 2998’s? I think so. Note on the following examples the lume openings have ends that while are not always curved, they are not the “laser cut” sharp of the modern hands. Note also the minute hands reach the minute track.
Thin lume, curved metal. Not all the ends of the lume are curved, but they are not sharp either. I also know the history of the watch and it is unlikely the hands were ever changed – although as always, it is possible.
Another set of thin lume originals:
So when I look at thin lume hands, I want to see:
curved metal (not mirror flat)
Minute hand to the minute track
Curved or uneven lume opening ends. NOT sharp.
On now to the triangle lume hour hand sets. These are more desired by me, and also have different characteristics, including a shorter minute hand, and lume openings in the minute hands that can be sharp, or at least straight. Often we look immediately at the minute hand length, but I have seen some of these original sets do not have a minute hand that extends all the way to the track – but very close.
There are some service hands with the triangle lume but these hands are flat and super luminova. It would be possible to relume these but the flat would be harder to deal with.
Here are what I think are good sets. Note that some of the minute hands are not as long as the thin lume sets, and that some of the lume openings are squarer. However they are not sharp.
So the triangle lume set seems to date to be much easier to accept as original, as there does not seem to be any reproductions or service items that can come close to looking like them.
So that is why I will always value a watch with correct triangle lume alpha hands over the straight lume. | 2024-03-02T01:27:15.642919 | https://example.com/article/2384 |
/*
*
* * ******************************************************************************
* * Copyright (C) 2014-2019 Dennis Sheirer
* *
* * 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 io.github.dsheirer.module.decode.p25.identifier.talkgroup;
import io.github.dsheirer.identifier.Role;
import io.github.dsheirer.identifier.talkgroup.FullyQualifiedTalkgroupIdentifier;
import io.github.dsheirer.protocol.Protocol;
/**
* Fully Qualified Radio Identifier (talkgroup) that includes WACN, System, and Radio Address.
*/
public class APCO25FullyQualifiedTalkgroupIdentifier extends FullyQualifiedTalkgroupIdentifier
{
public APCO25FullyQualifiedTalkgroupIdentifier(int wacn, int system, int id, Role role)
{
super(wacn, system, id, role);
}
@Override
public Protocol getProtocol()
{
return Protocol.APCO25;
}
public static APCO25FullyQualifiedTalkgroupIdentifier createFrom(int wacn, int system, int id)
{
return new APCO25FullyQualifiedTalkgroupIdentifier(wacn, system, id, Role.FROM);
}
public static APCO25FullyQualifiedTalkgroupIdentifier createTo(int wacn, int system, int id)
{
return new APCO25FullyQualifiedTalkgroupIdentifier(wacn, system, id, Role.TO);
}
public static APCO25FullyQualifiedTalkgroupIdentifier createAny(int wacn, int system, int id)
{
return new APCO25FullyQualifiedTalkgroupIdentifier(wacn, system, id, Role.ANY);
}
}
| 2024-05-31T01:27:15.642919 | https://example.com/article/2295 |
What Good Can a Roth IRA Do for Me?
In today’s blog we are in the area of retirement planning, and we’re going to go through some of the advantages of having a Roth IRA as part of your retirement plan and how it can benefit you.
First, just a quick refresher; in general Roth IRAs are tax free as long as you are age 59 ½ and have had the Roth opened for a minimum of 5 years. Traditional IRAs are tax deferred, so you are putting the IRS on hold and income taxes will be due later. To change (or convert) a Traditional IRA to a Roth IRA, you must pay income taxes on the converted amount. This conversion is taxed as ordinary income, NOT capital gains tax, there’s a big difference. Sorry, as nice as it would be, you cannot offset the conversion tax using long term capital losses.
Also, if you pay the conversion tax from a non-IRA source, you keep more tax‐free returns since you took money from a taxable asset to pay the taxes, and kept all the money in a tax‐free asset, the Roth IRA.
One very unique feature is that you can recharacterize a conversion if you change your mind and wish you hadn’t done it. Think about that. You can “undo” the conversion for any reason – like it never happened. How many times in life have you wished you could redo something?! For example, what if the market nose-dives after your conversion? Although you had terrible timing, you can undo it, if you want. You have until October of the following year to recharacterize. Again, this is a one of a kind and convenient feature.
Did you know there are NO Required Minimum Distributions (RMDs) at age 70½ for Roth IRAs like there are for Traditional IRAs? It’s true! This is a big advantage for the Roth IRA holder because it allows you to keep more of your money growing tax‐free. For example, let’s say Harold has a Traditional IRA with a $100,000 balance on December 31, 2015 and is 70 ½. Harold must begin RMDs at age 70 ½ and do so every year. Harold’s RMD would be $3650 for 2015. The $3650 is taxable income and revenue to the IRS. “Revenue” indeed is the IRS’s middle name!! If instead Harold had the $100,000 balance in a Roth IRA, Harold would not be required to take that $3650 RMD at age 70 ½ or any other age, he can just keep it in the Roth and let it grow tax free.
Conversions to a Roth IRA reduces the value of your estate, which can lower the effect of higher estate tax rates if you’re in danger of paying estate taxes.
Roth IRAs take it easy tax wise on a surviving spouse. If a Roth IRA owner passes away, income taken from a Roth IRA by a surviving spouse won’t send them into a higher tax bracket because the distributions are tax free. A surviving spouse will probably file as a single filer, and single filers reach higher marginal tax rates quicker than married filing joint couples do. Beneficiaries of a Roth IRA can take income tax‐free. This may be the mightiest advantage of a Roth IRA or converting to one. It’s not just tax free to you or a surviving spouse, but can be to children and grandchildren as well. Wouldn’t this be a nice asset to pass on to a child in a high tax bracket? Now that’s planning!
Another factor to consider is if future marginal tax brackets go up, you will pay more tax on income from a traditional IRA. However, if future tax brackets go up, it might be cheaper to pay the tax on a Roth conversion now before tax rates go up.
Lastly, converting funds to a Roth IRA may help you avoid that annoying new 3.8% Net Investment Income Tax. It’s a process, but it can help. If you would like more details in this area, please don’t hesitate to contact us. Thanks so much for reading!
The content is developed from sources believed to be providing accurate information. The information in this material is not intended as tax or legal advice. It may not be used for the purpose of avoiding any federal tax penalties. Please consult legal or tax professionals for specific information regarding your individual situation. The opinions expressed and material provided are for general information, and should not be considered a solicitation for the purchase or sale of any security.
Recognized Media Resource
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The content is developed from sources believed to be providing accurate information.
The information in this material is not intended as tax or legal advice. Please consult legal or tax professionals
for specific information regarding your individual situation. Some of this material was developed and produced by
FMG Suite to provide information on a topic that may be of interest. FMG Suite is not affiliated with the named
representative, broker - dealer, state - or SEC - registered investment advisory firm. The opinions expressed and
material provided are for general information, and should not be considered a solicitation for the purchase or
sale of any security.
Copyright 2019 FMG Suite.
Piershale Financial Group and Charles Schwab & Company, Inc. are not affiliated companies and our advisory personnel are not affiliated with Charles Schwab & Company, Inc. However, we participate in the Charles Schwab Advisor Services platform. Charles Schwab serves as the independent broker/dealer and independent qualified custodian for individual client accounts managed by Piershale Financial Group.
Piershale Financial Group uses links to other web sites for purposes such as to provide clients access to their online accounts held directly by the independent qualified custodian and to assist users in locating information on topics that might be of interest to them. We cannot attest to the accuracy of information provided by linked sites. Linking to a web site does not constitute an endorsement by Piershale Financial Group, its President Michael D Piershale or any of its employees of the sponsors of the site or the products presented on the site. Technical problems with outside links, other than a link that has been moved or changed, should be reported to the entity that maintains the site. | 2023-08-23T01:27:15.642919 | https://example.com/article/6308 |
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abstract: 'Tidal disruption events occur rarely in any individual galaxy. Over the last decade, however, time-domain surveys have begun to accumulate statistical samples of these flares. What dynamical processes are responsible for feeding stars to supermassive black holes? At what rate are stars tidally disrupted in realistic galactic nuclei? What may we learn about supermassive black holes and broader astrophysical questions by estimating tidal disruption event rates from observational samples of flares? These are the questions we aim to address in this Chapter, which summarizes current theoretical knowledge about rates of stellar tidal disruption, and compares theoretical predictions to the current state of observations.'
author:
- 'N.C. Stone'
- 'E. Vasiliev'
- 'M. Kesden'
- 'E.M. Rossi'
- 'H.B. Perets'
- 'P. Amaro-Seoane'
bibliography:
- 'main.bib'
date: 'Received: date / Accepted: date'
title: Rates of Stellar Tidal Disruption
---
Introduction {#sec:intro}
============
The discovery and characterization of quasars in the 1960s [@Schmidt63] was rapidly recognized as evidence for the existence of supermassive black holes (SMBHs) [@Salpeter64]. Shortly thereafter, the possibility of tidal disruption events (TDEs) was proposed by @Wheeler71, who hypothesized that the tidal disruption of a star by a massive black hole could create a high energy transient by means of the disintegrational Penrose process. If stars were consumed frequently enough by massive black holes, the resulting accretion of their gas could, perhaps, explain the observed properties of quasars and active galactic nuclei [@Hills75].
By the mid-1970s, the importance of [*TDE rates*]{} was evident, and rapid theoretical progress was made on understanding the dynamical processes that feed stars to SMBHs. Early work envisaged this as a diffusive process in the space of orbital energy: an isotropic distribution of stars living around a SMBH might be depleted by diffusion of stars onto more tightly bound orbits . In reality, however, the process of diffusion through energy space is slow and self-limiting; subsequent analytic and numerical works quickly demonstrated the greater importance of velocity-space [*anisotropies*]{} in determining TDE rates. More precisely, the rate of tidal disruptions in a dense star cluster is set by diffusion through angular momentum, rather than energy, space. The stellar distribution function (DF) drains into the black hole through a “loss cone,” named after the analogous phase space region in magnetic mirror fusion reactors .
In this Chapter, we survey the dynamical physics of dense stellar systems containing massive black holes, focusing particularly on the collisional evolution of stellar DFs in the presence of a loss cone. Our presentation will, by necessity, be rather terse and without proofs. A more detailed treatment of stellar orbits and kinetic theory can be found in several textbooks. The reader interested in going beyond this chapter may wish to consult chapter 7 of or chapters 5 and 6 of @Merritt13.
We begin in §\[sec:TDEBasics\], by overviewing the basic physics of stellar tidal disruption. In §\[sec:losscone\], we present the theoretical picture of the loss cone, describing both the orbital dynamics of individual stars near supermassive black holes, and the ways in which two-body relaxation and collisionless effects cause stellar populations to evolve over time. We provide both Newtonian and general relativistic treatments of loss cone dynamics, and examine more exotic types of tidal disruptions (e.g. disruption of evolved or binary stars). Next, we apply these theoretical tools to realistic astrophysical environments. In §\[sec:applied\], we examine past efforts to estimate TDE rates by building dynamical models of nearby galactic nuclei, emphasizing both the empirically-calibrated event rate predictions and the distributions of event properties. In §\[sec:comparison\], we compare these estimates to observational inferences of the volumetric stellar disruption rate. Finally, in §\[sec:implications\], we examine the broader importance of nuclear stellar dynamics, and describe how well-measured TDE rates may determine the uncertain bottom end of the supermassive black hole mass function, probe basic predictions of general relativity, and calibrate rate estimates for extragalactic phenomena such as mHz gravitational wave sources.
On the Proper Care and Feeding of Supermassive Black Holes {#sec:TDEBasics}
==========================================================
Modern observations demonstrate that SMBHs are ubiquitous in the nuclei of sufficiently large galaxies (e.g. ). While a minority of SMBHs live in active galactic nuclei (AGN), where they accrete steadily from long-lived and large-scale discs of interstellar gas, the majority of SMBHs are quiescient: accreting at very low rates [@Heckman+04]. In these quiescent galactic nuclei, it is only in the aftermath of a TDE that the SMBH may shine brightly. But what variables determine the rate of stellar tidal disruption? We can break down the controlling variables into two categories: those relevant to the [*hydrodynamic*]{} process of tidal disruption, and those related to the [*orbital dynamics*]{} of stars in galactic nuclei.
The first set of variables – those governing hydrodynamic stellar disruption – are explored in greater detail in the [Disruption Chapter]{}, whereas in this Chapter, we focus on the latter set, with the following philosophy. In quiescent galactic nuclei, hydrodynamic forces are negligible and the orbits of stars will be shaped by (i) the smooth background gravitational potential of the SMBH and the stellar population; (ii) discrete, pair-wise scatterings with other stellar-mass objects; (iii) coherent secular effects arising from correlations between the orbits of multiple stars[^1]. In the continuum limit, the DF of a population of identical stars can be written in position space as $f(\vec{r}, \vec{v})$. In a sufficiently old galactic nucleus, the DF will exist in a quasi-steady state, but two-body scatterings and collisionless effects will cause it to evolve adiabatically. We call such an old nucleus “relaxed,” in contrast to a nucleus with a younger stellar population that was born far from a quasi-steady state configuration; such a young nucleus would be “unrelaxed.”
A full knowledge of the DF $f(\vec{r}, \vec{v})$ and the gravitational potential $\Phi(\vec{r})$ would allow us to compute osculating stellar orbits, their temporal evolution, and the rate at which stars pass near the SMBH. But in order to understand which orbits are doomed to disruption, we must first introduce at least approximate hydrodynamic criteria for the disruption process. Fortunately, these approximations are reasonably accurate.
Tidal forces increase as one approaches a black hole. The strength of the tidal field diverges as distance from the singularity $r\to0$, so interior to some critical distance $R_\mathrm{t}$ (the tidal radius, Eq. \[eq:rtidal\]), any macroscopic object will be torn apart. By equating the Newtonian tidal field to the victim star’s surface self-gravity, we find that a star of mass $M_\star$ and radius $R_\star$ will be torn apart by tides if its pericentre $R_{\rm p}$ is roughly[^2] within a tidal radius, $$\label{eq:rtidal}
R_{\rm t} = R_\star \left( \frac{M_\bullet}{M_\star} \right)^{1/3},$$ of an SMBH with mass $M_\bullet$. This Newtonian expression is reasonably accurate when $R_{\rm t} \gg R_{\rm g}$, where the latter is the gravitational radius $R_{\rm g} \equiv G M_\bullet / c^2$. But, as we shall see in §\[sec:GR\], when $R_{\rm t} \sim R_{\rm g}$, the tidal radius will depend significantly on SMBH spin $\chi_\bullet$, and the orbital inclination $\iota$.
Until §\[sec:GR\], however, we will treat Eq. \[eq:rtidal\] as exact. With this approximation, we can immediately note one (slightly counter-intuitive) feature of tidal disruption. Any SMBH will have an event horizon comparable in size to its gravitational radius, $R_{\rm g}$. We may note that $R_{\rm t} \propto M_\bullet^{1/3}$, while $R_{\rm g} \propto M_\bullet^1$. The weak power-law dependence of $R_{\rm t}$ on $M_\bullet$ means that, for any given stellar type, there is a [*maximum black hole mass*]{} capable of producing a TDE outside the event horizon. TDEs from SMBHs above this critical mass, often called the Hills mass [@Hills75], will produce debris wholly swallowed by the horizon, and will fail to produce an electromagnetically luminous flare. Approximating the event horizon size as $2R_{\rm g}$, we find that the Hills mass is $$M_{\rm H} = M_\star^{-1/2}\left(\frac{c^2R_\star}{2G} \right)^{3/2} \approx 1\times 10^8 M_\odot \left(\frac{R_\star}{R_\odot}\right)^{3/2}\left(\frac{M_\star}{M_\odot}\right)^{-1/2}. \label{eq:MHills}$$ Eqs. \[eq:rtidal\] and \[eq:MHills\] are fundamentally Newtonian expressions that we generalize to a relativistic context in §\[sec:GR\]. A relativistic treatment is necessary to account for the effects of SMBH spin, which can sizeably alter $M_{\rm H}$ [@Beloborodov+92; @Kesden12].
In both the Newtonian and relativistic regimes, it is clear that, so long as TDE rates depend on $R_{\rm t}$ (the exact dependence is non-trivial and will be quantified in §\[sec:losscone\]), they will depend on the mass, radius, and (to a weaker extent) internal structure of the star. These quantities evolve over the lifetime of a star, so that the tidal radius ultimately depends on the star’s zero-age main sequence (ZAMS) mass, its metallicity, its age, its spin, and even its binarity (see §\[sec:types\]). In the general relativistic context (appropriate when $R_{\rm p}\sim R_{\rm g}$), SMBH spin $\chi_\bullet$ and spin-orbit misalignment $\iota$ may affect disruption rates as well.
If we care not only about [*intrinsic*]{} rates of tidal disruption (e.g. per-galaxy rates, volumetric rates, etc.), but rates of TDE detection in current or planned surveys, then we must consider additional properties of these events. For example, we may define the strength of the TDE with a dimensionless penetration parameter $$\label{eq:beta}
\beta = R_{\rm t} / R_{\rm p}.$$ When $\beta \approx 1$, we have a relatively mild, grazing disruption; if $\beta \gg 1$, we have a more violent, deeply plunging disruption; if $\beta \lesssim 1$, a partial disruption may ensue. The observational properties of a TDE flare may depend in various ways on $\beta$ , meaning that distributions of this parameter are an important prediction for event rate calculations.
As this discussion illustrates, TDE rates depend on a large number of variables related to the participating stars and SMBHs themselves. Fortunately (for the sake of minimizing astrophysical uncertainty), intrinsic TDE rates depend only weakly on stellar properties, through $R_{\rm t}$. However, the properties of host galaxies, and their SMBHs, matter a great deal more in setting TDE rates. In the next section, we will compute first-principles rates of tidal disruption in idealized galactic nuclei, providing the theoretical framework to understand how TDE rates vary with host galaxy properties.
Loss-Cone Theory {#sec:losscone}
================
In this section, we overview, from a theoretical perspective, the many ways in which stars can be fed to massive black holes. As we shall see, the dynamical evolution of stellar orbits from “safe” to “unsafe” trajectories is most easily visualized and quantified with the concept of a loss cone, which we define in §\[sec:LCBasics\]. We present the physics of loss cones in spherical galactic nuclei, as well as their connections to TDE rates, in §\[sec:relaxation\] and §\[sec:aniso\]. The first of these sections is focused on steady-state loss-cone physics, while the second focuses on the time-dependent problem. We consider more general (aspherical) geometries in §\[sec:aspherical\], which opens up new avenues for loss-cone repopulation. In §\[sec:GR\], we generalize our treatment of the loss cone from Newtonian to general relativistic gravity. Finally, in §\[sec:types\], we briefly survey other types of SMBH loss cones, relevant for processes beyond main-sequence stellar disruption.
The Loss Cone {#sec:LCBasics}
-------------
In Newtonian gravity, a star on a nearly parabolic orbit (eccentricity $e \approx 1$) with pericentre $R_{\rm p}$ will have specific orbital angular momentum $L \approx \sqrt{2 G M_\bullet R_\mathrm{p}}$. This implies that stars with specific orbital angular momentum below the critical value (or, equivalently, with $\beta > 1$), $$L_\mathrm{\rm t} = \sqrt{2 G M_\bullet R_\mathrm{t}},$$ will be disrupted when passing within $R_\mathrm{t}$ of the SMBH. One can define analogous “loss regions” in angular momentum space for destructive processes other than tidal disruption, and we will explore these later on, in §\[sec:types\].
We are generally interested in the evolution of the stellar DF in phase space on timescales much longer than the orbital time $T_\mathrm{orb}$, and will therefore describe populations of stars in the space of integrals of motion (“integral space”), rather than the phase space of $\vec{r}$ and $\vec{v}$. It is convenient to define a new variable $\mathcal R \equiv \big[ L / L_\mathrm{circ}(E) \big]^2 \in [0,1]$, where $L_\mathrm{circ}(E)$ is the specific angular momentum of a circular orbit with the given specific energy $E$; in a Keplerian potential, $\mathcal R = 1-e^2$. The number $N(E, \mathcal R)$ of stars per unit interval of $E$ and $\mathcal R$ is related to the DF $f(E, \mathcal{R})$ as [@Merritt13 Equation 5.166] $$N(E, \mathcal R) = 4\pi^2\, T_\mathrm{orb}(E, \mathcal R)\, L_\mathrm{circ}^2(E)\; f(E, \mathcal R).$$ Since we are interested mainly in the low-$\mathcal R$ region, it is convenient to ignore the dependence of orbital time on $\mathcal R$ (which is usually weak) and write $N(E, \mathcal R) \approx g(E)\, f(E, \mathcal R)$, where $g(E)$ is the density of states, defined more generally as: $$\label{eq:g_of_E}
g(E) \equiv 4\pi^2\,L_\mathrm{circ}^2(E) \int_0^1 T_\mathrm{orb}(E, \mathcal R)\, \mathrm{d} \mathcal R.$$ The number of stars per unit energy is $\overline N(E) \equiv \int_0^1 N(E, \mathcal R) \; \mathrm d \mathcal R$. An isotropic distribution of stars in velocity corresponds to a uniform distribution in $\mathcal R$: $N(E, \mathcal R) \approx \overline N(E)$.
![Schematic representations of the loss cone in a spherical galactic nucleus. On the left (panel a, taken with permission from @AmaroSeoane18), we see the conical velocity-space loss region at an instantaneous point along a star’s elliptical orbit around a supermassive black hole. The tidal radius (denoted $r_\mathrm{tid}$ in this image) will overlap with the star’s pericentre if its instantaneous velocity vector $\vec{v}$ falls into the loss cone. On the right (panel b, taken with permission from ), an orbit-averaged loss cone is depicted in the space of (negative) specific orbital energy $\mathcal E \equiv -E$ and angular momentum $j=\mathcal{R}^{1/2} = L/L_{\rm circ} \le 1$. The loss cone becomes larger and larger in the space of dimensionless angular momentum as one moves to more tightly bound orbits (larger $|E|$).[]{data-label="fig:lossConeCartoons"}](Cartoon.pdf){width="120mm"}
The region of phase space with $L\le L_{\rm t}$ is colloquially called the loss cone (a term borrowed from plasma physics), which we illustrate in Figure \[fig:lossConeCartoons\]. If angular momentum were conserved for every stellar orbit, the number of stars inside the loss cone would drop to zero within one orbital period. However, $L$ changes with time due to various processes: classical two-body and resonant relaxation, and torques induced by an aspherical stellar potential. Therefore, the time-averaged number of stars inside the loss cone is nonzero, and the tidal disruption rate per unit energy is $$\begin{aligned}
\mathcal F_\mathrm{t}(E) &\equiv& \frac{1}{T_\mathrm{orb}(E)}
\int_0^{\mathcal R_\mathrm{t}(E)} N(E, \mathcal R)\, \mathrm d \mathcal R, \\
T_\mathrm{orb}(E) &\equiv& T_\mathrm{orb}(E, \mathcal R=0), \qquad
\mathcal R_\mathrm{t} \equiv \left( \frac{L_\mathrm{t}}{L_\mathrm{circ}(E)} \right)^2 . \nonumber\end{aligned}$$ Much of the remaining story revolves around estimating the equilibrium loss cone population, which is set by the efficiency of those processes that change the angular momenta of stars. As a useful benchmark, consider a situation where these processes are extremely rapid, so that the angular momentum distribution is nearly uniform (isotropic). The corresponding rate of disruptions is called the (isotropic) full loss cone flux: $$\label{eq:flux_full_iso}
\mathcal F_\mathrm{iso}(E) = \frac{\overline N(E)\, \mathcal R_\mathrm{t}(E)}{T_\mathrm{orb}(E)}.$$ In a more complicated situation, the loss-cone population may be either smaller or larger than this reference value, depending on both the initial conditions and the efficiency of angular momentum mixing.
Two-Body Relaxation {#sec:relaxation}
-------------------
A mechanism that operates in all stellar systems is two-body (or collisional) relaxation, caused by the discreteness of the stellar distribution. In the classical, “Chandrasekhar,” theory of two-body relaxation, the evolution of the stellar DF is driven by uncorrelated two-body encounters. We will begin, for simplicity, with a spherically symmetric nuclear star cluster surrounding a SMBH. The star cluster has local three-dimensional density $n(r)$ and velocity dispersion $\sigma(r)$ in coordinate space (here $r$ is the distance from the SMBH), but its time evolution is most simply described by the Fokker–Planck equation in integral space, i.e. for $N(E, L, t)$. We may define a local relaxation time as $$T_{\rm rel} \equiv \frac{\sigma^3}{G^2 n \langle m_\star^2 \rangle \ln\Lambda},$$ where $\ln\Lambda \approx 10$ is the Coulomb logarithm [@Chandrasekhar42; @SpitzerHart71]. This expression assumes a present-day mass function (PDMF) of stars, ${\rm d}N/{\rm d}m_\star$, defined over the interval $[m_{\rm min}, m_{\rm max} ].$ The first and second moments of the PDMF are defined as $$\begin{aligned}
\langle m_\star \rangle =& \int_{m_{\rm min}}^{m_{\rm max}} m_\star \frac{{\rm d}N}{{\rm d}m_\star} {\rm d}m_\star \notag \\
\langle m_\star^2 \rangle =& \int_{m_{\rm min}}^{m_{\rm max}} m_\star^2 \frac{{\rm d}N}{{\rm d}m_\star} {\rm d}m_\star. \label{eq:PDMF}\end{aligned}$$ Notably, the rate of two-body relaxation is controlled by the second moment, $\langle m_\star^2\rangle$, of the PDMF, indicating that for realistic stellar mass functions, it is typically the heaviest surviving species (often stellar-mass black holes) which dominate relaxation rates, especially at small radii where their relative fraction is higher due to mass segregation. For example, if one adds a population of stellar-mass black holes to a truncated Kroupa PDMF, the TDE rate can increase by up to a factor of $\approx 5$ [@StoneMetzger16], depending on the assumed metallicity (which determines the relation between zero-age main sequence masses and compact remnant masses, e.g. @Belczynski+10).
Over the characteristic relaxation timescale $T_\mathrm{rel} \gg T_\mathrm{orb}$, the typical change in energy is $\mathcal O\big(E\big)$ and in angular momentum is $\mathcal O\big(L_\mathrm{circ}(E)\big)$. However, far smaller changes in angular momentum $\mathcal O\big(L_\mathrm{t}\big)$ are needed to move stars on nearly radial orbits into or out of the loss cone: the time needed to produce characteristic changes in dimensionless angular momentum $\sim \mathcal{R}$ is $\sim \mathcal{R} T_{\rm rel}$. Because the relaxation of stars in angular momentum *near the loss-cone boundary* occurs much faster than relaxation in energy , in the first approximation these types of relaxation can be considered separately. As we will discuss shortly, this two-timescale decoupling establishes a (quasi-)steady-state distribution of stars in $L$ (or $\mathcal R$) at fixed $E$, which remains quasi-isotropic even in the presence of a loss cone .
Over longer timescales, stellar diffusion in energy space gradually drives the stellar distribution towards a quasi-steady-state $\overline N(E)$ profile. If the gravitational potential is dominated by the $\Phi \propto 1/r$ potential of the SMBH, this steady-state solution is known as the Bahcall–Wolf cusp, with $f(E) \propto |E|^{1/4}$. In coordinate space, the distribution translates to a spherically symmetric density profile[^3] $n(r) \propto r^{-7/4}$, extending out to some fraction of the SMBH influence radius $r_{\rm inf}$, which we define to be the radius enclosing a total stellar mass equal to $M_\bullet$. Notably, this is a [*zero-flux solution*]{} in energy space: in the limit as $R_{\rm t}/r_{\rm inf} \to 0$, the energy-space flux to the SMBH also goes to zero.
Accordingly, we will focus for now on the angular momentum diffusion[^4], by considering the one-dimensional, orbit-averaged Fokker–Planck equation for the evolution of the stellar distribution $N(\mathcal R,t)$ in the space of dimensionless angular momentum $\mathcal R$, at a fixed energy $E$ (the dependence of various quantities on $E$ is implied in the rest of this section, but is not explicitly marked): $$\label{eq:diffusion_in_R}
\frac{\partial}{\partial t} N(\mathcal R,t) = \frac{\partial \mathcal F}{\partial \mathcal R}, \qquad
\mathcal F \equiv \mathscr D(E, \mathcal R)\,\frac{\partial N}{\partial \mathcal R}, \qquad
\mathscr D(E, \mathcal R) \approx \mathcal{D}(E)\, \mathcal R.$$ As before, $\mathcal F$ is the flux of stars through integral space in the direction of the inner boundary[^5] $\mathcal R_\mathrm{t}$, and the orbit-averaged diffusion coefficient $\mathcal D(E) \sim T_\mathrm{rel}^{-1}$ depends on various moments of the stellar DF [@Merritt13 Equation 6.31] $$\begin{aligned}
\label{eq:diffusion_coefficient}
\mathcal D(E) &= \frac{64\pi^2 \,G^2\; \ln\Lambda\; \langle m_\star^2\rangle}{3\, L_\mathrm{circ}^2(E)\,T_\mathrm{orb}(E)}\,
\int_0^{r_\mathrm{max}(E)} \!\!\!\!\!\mathrm{d} r\, \frac{r^2}{\sqrt{2[E-\Phi(r)]}}
\big( 2 I_0 + 3 J_{1/2} - J_{3/2} \big) , \nonumber \\
I_0(E) &= \int_E^0 f(E')\, \mathrm{d} E' ,\\
J_n(E, r) &= \int_{\Phi(r)}^{E} \left[\frac{E'-\Phi(r)}{E-\Phi(r)} \right]^n f(E')\, \mathrm{d} E'. \nonumber\end{aligned}$$ Here $r_\mathrm{max}(E)$, the apocentre of a radial orbit with given specific energy, is the root of $\Phi(r_\mathrm{max})=E$. In a relatively shallow stellar density profile, or at high binding energies, $I_0(E)$ is the dominant moment of the stellar DF, and diffusion is a quasi-local process in energy space. In a relatively steep stellar density profile, or at large radii, $J_n(E, r)$ will become of greater importance, and diffusion may become strongly non-local in energy space, with very tightly bound stars playing an important role in the evolution of more loosely bound bins of $E$. Over long timescales, the 1D Fokker–Planck approach of Eq. (\[eq:diffusion\_in\_R\]) may break down due to changes in the energy-space distribution of stars, $\bar{N}(E)$, and this breakdown will be hastened in bins of energy whose diffusion coefficients $\mathcal{D}(E)$ are dominated by contributions from distant regions of energy-space with shorter relaxation times. In general, however, the 1D approach is a self-consistent way to determine quasi-steady state conditions near the loss cone boundary, since the time for orbits to experience a change in $\mathcal{R} \sim \mathcal{R}_{\rm t}$ is $\sim T_{\rm rel}(E)\mathcal{R}_{\rm t}$.
These equations are complemented with a no-flux, $\partial N / \partial \mathcal{R} = 0$ outer boundary condition (at $\mathcal R=1$), and an inner boundary condition (at $\mathcal R_\mathrm{t}$) of the Robin type (a linear combination of the function and its derivative): $$\label{eq:boundary_condition}
N(\mathcal R_\mathrm{t}, t) - \alpha\, \mathcal R_\mathrm{t}\,
\frac{\partial N}{\partial \mathcal R}\Big|_{\mathcal R=\mathcal R_\mathrm{t}} = 0, \qquad
\alpha\approx (q^2+q^4)^{1/4}, \qquad
q\equiv \frac{\mathcal D\; T_\mathrm{orb}}{R_\mathrm{t}}.$$ The dimensionless quantity $q(E)$ describes the diffusivity of relaxational loss cone refilling. If the typical change of angular momentum per orbital time is larger than the size of the loss cone ($q\gg 1,\, \alpha\approx q$), the distribution of stars near and inside the loss cone is close to uniform (its gradient is small; $\partial N / \partial \mathcal R \ll N / \mathcal R$). In this case, we speak of a “full loss cone” or a “pinhole” regime where the flux through the loss-cone boundary is $$\label{eq:flux_full}
\mathcal F \approx \mathcal F_\mathrm{full} \equiv
\frac{N(\mathcal R_\mathrm{t}) \, \mathcal R_\mathrm{t}}{T_\mathrm{orb}}.$$ This flux is proportional to the size of the loss cone but independent of the relaxation rate. Note that, unlike Eq. (\[eq:flux\_full\_iso\]) for the isotropic full loss cone flux, the above expression assumes only that the DF is *locally* well-mixed near the loss-cone boundary. In the opposite limit ($q\ll 1, \alpha \approx q^{1/2}$), we are in an “empty loss cone” or “diffusive” regime, where $N(\mathcal R_\mathrm{t})\approx 0$ and the flux is limited by the relaxation.
We may consider a quasi-steady-state solution of Eq. (\[eq:diffusion\_in\_R\]) in which the shape of the DF $N(\mathcal R, t)$ stays the same, but its overall normalization $\overline N \equiv \int_0^1 N(\mathcal R)\,\mathrm{d}\mathcal R$ changes with time. This solution has a nearly logarithmic profile : $$\label{eq:logarithmic_profile}
N(\mathcal R) \approx \overline N\, \frac
{\alpha + \ln(\mathcal R / \mathcal R_\mathrm{t})}
{(\alpha-1)(1-\mathcal R_\mathrm{t}) + \ln(1 / \mathcal R_\mathrm{t})},$$ and the corresponding flux is $$\label{eq:flux_general}
\mathcal F =
\frac{\mathcal D\;\overline N}{(\alpha-1)(1-\mathcal R_\mathrm{t}) + \ln(1 / \mathcal R_\mathrm{t})} =
\frac{q\; \mathcal F_\mathrm{full}}{(\alpha-1)(1-\mathcal R_\mathrm{t}) + \ln(1 / \mathcal R_\mathrm{t})}.$$ As expected, in the full-loss cone limit the DF is nearly uniform ($N(\mathcal R) \approx \overline N$), and the flux approaches the isotropic full-loss-cone value (Eq. \[eq:flux\_full\_iso\]), which coincides with Eq. (\[eq:flux\_full\]) for a steady-state solution (however, this is no longer true for a time-dependent solution with strongly anisotropic initial conditions, as we will discuss in Section \[sec:aniso\]). In the opposite, empty-loss cone limit, the DF falls sharply to zero for $\mathcal R \lesssim \mathcal R_\mathrm{t}$, and the flux is $$\label{eq:flux_empty}
\mathcal F_\mathrm{empty} \equiv \frac{\mathcal D\;\overline N}{\ln(1 / \mathcal R_\mathrm{t}) + R_\mathrm{t} - 1}.$$ This empty loss cone flux is proportional to the relaxation rate but only weakly dependent on the size of the loss cone. The steep drop in the DF below $R_\mathrm{t}$ implies that the TDE rate will be dominated by grazing encounters with $\beta \approx 1$ in the empty loss-cone regime (see Section \[sec:synthetic\]).
The transition between empty and full loss cone regimes corresponds to $\mathcal F \approx \frac{1}{2}\mathcal F_\mathrm{full}$, or $q \approx \ln(1/\mathcal R_\mathrm{t}) \sim \mathcal O(10)$. This occurs at the “critical” energy $E_{\rm crit}$, or the corresponding radius $r_{\rm crit}$. The total TDE rate[^6] $$\dot{N} \equiv \int_{-\infty}^0 \mathcal{F}(E){\rm d}E \label{eq:total_rate}$$ will contain contributions from both empty- and full-loss cone regimes. If $r_{\rm crit} \ll r_{\rm infl}$, then most of the total loss cone flux arises from $E \sim E_{\rm crit}$, and both the empty- and full-loss cone regimes contribute an $\mathcal{O}(1)$ fraction of the TDE rate[^7]. Conversely, if $r_{\rm crit} \gg r_{\rm infl}$, then most of the integrated loss cone flux comes from $E \sim -G M_\bullet / (2r_{\rm infl})$, and is predominantly in the empty loss cone regime [@SyerUlmer98]. Astrophysical galactic nuclei typically possess $r_{\rm crit} \sim r_{\rm infl}$ [@WangMerritt04], as we will discuss later in §\[sec:empirical\].
Anisotropic and Time-Dependent Loss Cones {#sec:aniso}
-----------------------------------------
So far, we have estimated the loss cone flux $\mathcal{F}(E)$ and TDE rate $\dot{N}$ in a relatively old galactic nucleus, one which has reached a quasi-steady state, quasi-isotropic distribution of orbital angular momentum in each bin of orbital energy (i.e. Eq. \[eq:logarithmic\_profile\]). This quasi-steady state solution is attained on a timescale $\sim T_\mathrm{rel}$. At earlier times, the angular momentum distribution may be quite anisotropic, and in this regime, the capture rate depends sensitively on the initial conditions. In certain types of galactic nuclei, where phenomena other than two-body relaxation are at work, it is not even clear that we can expect the angular momentum distribution to converge to Eq. \[eq:logarithmic\_profile\]. For example, a galactic nucleus with a long-lived SMBH [*binary*]{} will preferentially eject stars on radial orbits, continually pumping up the tangential anisotropy of the star cluster . The presence of a massive gas disc (i.e. an [*active*]{} galactic nucleus) will affect stellar orbits in a more complicated way . The evolution of the nuclear stellar cusp and its build-up through star formation and/or cluster infall will also affect TDE rates [@Aharonetal2016]. In this section, we will ignore these complications, and focus on DFs $f(E, \mathcal{R}, t)$ for spherical galactic nuclei evolving only due to two-body relaxation. We consider more general loss-cone physics in aspherical potentials in §\[sec:aspherical\].
In the limit of spherical symmetry and arbitrary initial conditions $f(E, \mathcal{R}, 0)$, it is possible to use Fourier-Bessel synthesis techniques to derive exact, time-dependent solutions to the Fokker–Planck equation in angular momentum space. These solutions can then be converted into TDE rates via Eq. \[eq:diffusion\_in\_R\] ($\mathcal{F} \propto \partial N / \partial \mathcal{R}$). The semi-analytic Fourier-Bessel solutions were first derived in the empty loss cone limit , but can also be applied for more general inner boundary conditions . While these solutions are useful, they are too lengthy to reproduce and explore in this review, so we will focus instead on results from the numerical solution of the time-dependent Fokker–Planck equation (Eq. \[eq:diffusion\_in\_R\]).
The anisotropy of a stellar distribution can be quantified with the parameter (usually called $\beta$, but here we use $b$ to avoid confusion with Eq. \[eq:beta\]) $$b(E) = 1-\frac{T_\perp(E)}{2T_\parallel(E)},$$ which is a function of the total radial ($T_\parallel$) and tangential ($T_\perp$) kinetic energies of stellar orbits. This definition can be related to the DF as $f(E, \mathcal{R}) = f_E(E)\mathcal{R}^{- b(E)}$, where $f_E(E)$ is a function independent of angular momentum, although more complicated (non-separable) DFs can have the same level of anisotropy. When $b=0$, orbital velocities and angular momenta are distributed isotropically; when $b>0$, there is a radial orbit bias; when $b<0$, there is a tangential orbit bias. In the case of a purely isotropic initial distribution ($b=0$; flat in $\mathcal{R}$), the initial TDE rates $\mathcal{F}(E) \approx \mathcal{F}_{\rm iso}(E)$ (Eq. \[eq:flux\_full\_iso\]), even at high binding energy where $q(E)\ll 1$. In these energy bins, stars at $\mathcal R < \mathcal R_\mathrm{t}$ are removed on a timescale $T_\mathrm{orb}$, creating a steep gradient near the loss-cone boundary. As the angular momentum distribution is progressively depleted at small but increasing $\mathcal R$ and approaches the Cohn–Kulsrud quasi-steady state profile (Eq. \[eq:logarithmic\_profile\]), the gradient $(\partial N / \partial \mathcal R)_{\mathcal R = \mathcal R_\mathrm{t}}$ will soften, and the rates will decline and approach the steady-state value (Eq. \[eq:flux\_general\]). Because the Cohn–Kulsrud quasi-steady state is nearly isotropic (more specifically, a logarithmic function of $\mathcal{R}$), isotropic initial conditions produce time-dependent TDE rates that are not far from the steady-state expectation of Eq. \[eq:flux\_general\].
Larger deviations from Eq. \[eq:flux\_general\] will occur if the initial conditions are strongly anisotropic. For example, a galactic nucleus may inherit a strong tangential anisotropy in the aftermath of a SMBH binary merger. As two SMBHs inspiral, they eject those stars which pass within the orbit of the binary, scouring out a cavity in angular momentum space and depleting radial orbits . This creates a gap in the initial distribution $N(\mathcal R, t=0)$ for $\mathcal R \le \mathcal R_\mathrm{gap} \gg \mathcal R_\mathrm{t}$. After the SMBHs have merged, the TDE rate will be suppressed until the angular momentum gap is refilled, typically over a timescale $\sim 10^{-2} - 10^{-1}\,T_\mathrm{rel}$ .
The opposite situation occurs when the initial distribution has an excess of stars with low angular momentum (a radially-biased velocity distribution). This may occur naturally[^8] as a result of nuclear cluster buildup through infalling globular clusters (@Hartmann+11, although many clusters are likely to disrupt far from the SMBH; ). In the case of eccentric cluster infall, stars will be left behind on preferentially radial orbits. If we assume an idealized, initial radial anisotropy of $b$ across all bins of energy, then the TDE rate will initially be elevated and then decline with time roughly as $\mathcal F(E) \approx \mathcal F_\mathrm{full}(E) \times [ t / T_\mathrm{rel}(E) ]^{-b}$ [@Stone+18]. Despite the initially high rates of this scenario, this formula demonstrates (since $b \le 1$ definitionally) that the integrated total number of TDEs will be dominated by late times, once the distribution has become quasi-isotropic.
Asphericity and Collisionless Loss Cone Refilling {#sec:aspherical}
-------------------------------------------------
The classical loss-cone theory of Sections \[sec:relaxation\] and \[sec:aniso\] was developed in the 1970s for globular clusters, which are nearly spherical systems. However, galactic nuclei are, to some extent, non-spherical (see e.g. @Lauer+05), and stellar orbital angular momentum is, therefore, not conserved even in the absence of two-body relaxation. Thus, even if the time-averaged angular momentum $\overline L$ of a star on a given orbit is large, the minimum value of angular momentum $L_\mathrm{min}$ reachable by this orbit may be smaller than $L_\mathrm{t}$, potentially bringing a much larger reservoir of stars into the loss cone.
In perfectly axisymmetric systems, one component of angular momentum ($L_z$) is still conserved, so $L_\mathrm{min} \ge L_z$; however, in triaxial or even less symmetric potentials, $L_\mathrm{min}$ may be zero for a significant fraction of orbits; specifically, those in “centrophilic” orbit families, such as box, pyramid or chaotic orbits . More generally, we refer to all orbits with $L_\mathrm{min} \le L_\mathrm{t}$ as the “drain region[^9],” and denote the fraction of phase space occupied by these orbits at a given energy as $\mathcal R_\mathrm{drain}(E)$. Most of these orbits have low average angular momentum, i.e. $\overline L \ll L_\mathrm{circ}(E)$, although not all orbits with $\overline L \ll L_\mathrm{circ}(E)$ are centrophilic. Nevertheless, for the sake of simplicity, we assume that the drain region is simply $\mathcal R < \mathcal R_\mathrm{drain}$.
There are two separate effects associated with the existence of a drain region. First, the scalar angular momentum changes significantly (by $\mathcal O(\epsilon\,L_\mathrm{circ}))$ on a timescale $T_\mathrm{ang}\simeq \epsilon^{-1}\,T_\mathrm{prec}$, where $\epsilon$ is the (dimensionless) degree of non-sphericity (the relative difference between the three principal axes). Here the period of pericentre precession $T_\mathrm{prec}\equiv 2\pi(\Omega_r-\Omega_\phi)^{-1}$ is given by the difference between the frequencies of the radial and azimuthal motion: it is comparable to the orbital period $T_\mathrm{orb}\equiv 2\pi\Omega_r^{-1}$ outside the SMBH radius of influence, but is much longer than $T_\mathrm{orb}$ in a nearly Keplerian potential (see Equation 4.88 in @Merritt13). In the drain region, the timescale for the scalar angular momentum to change by $\mathcal O(L_\mathrm{t})$ is typically shorter than $T_\mathrm{orb}$. Therefore, stars on drain orbits are in the full loss cone regime , and their capture rate is given by Eq. (\[eq:flux\_full\]). Note that this does not imply that the capture rate is equal to the isotropic full loss cone rate of Eq. (\[eq:flux\_full\_iso\]), because the density of stars in the drain region $N(E, \mathcal R < \mathcal R_\mathrm{drain})$ may be different from the angular momentum-averaged density of stars $\overline N(E)$. We may now define the “drain timescale” needed to remove the stars from this region: $T_\mathrm{drain} \equiv T_\mathrm{orb}\, \mathcal R_\mathrm{drain} / \mathcal R_\mathrm{t}$. It turns out that in axisymmetric systems, this time is still much shorter than the Hubble time, at least in those galactic nuclei with $M_\bullet \lesssim 10^8\,M_\odot$ that are the main sources of TDEs. However, in triaxial systems, the fraction of centrophilic orbits, $\mathcal R_\mathrm{drain}$, could be $\gtrsim 0.1$ (it is proportional to the degree of non-sphericity $\epsilon$), making the draining time longer than the Hubble time for most orbits (see Equations 6, 7 and Figure 4 in @Vasiliev14). During this time, the capture rate is determined by the initial conditions. In the “most neutral” case of a (nearly-)isotropic distribution in angular momentum, the TDE rate is of order the isotropic full loss cone rate of Eq. (\[eq:flux\_full\_iso\]), which could be much higher than the relaxation-limited capture rate in purely spherical nuclei .
![ Illustration of the quasi-steady-state DF in spherical (solid blue) and non-spherical (dotted red) galactic nuclei, for the case of an empty loss cone ($q=0$ in Eq. \[eq:boundary\_condition\]) with a fairly large loss-cone size ($\mathcal R_\mathrm{t}=3\times10^{-4}$). In the spherical case, the DF has a logarithmic profile (Eq. \[eq:logarithmic\_profile\]), and the slope of this profile in the semi-log-scaled coordinates determines the flux. In the non-spherical case, the profile flattens out at $\mathcal R \lesssim \mathcal R_\mathrm{drain}$ (${}=0.1$ in this example), because the angular momenta of stars are shuffled by non-spherical torques. At the same time, the profile at $\mathcal R \gtrsim \mathcal R_\mathrm{drain}$ remains nearly logarithmic, as it is still determined by relaxation-driven diffusion, but it has a steeper slope (roughly a factor of two in this example), producing a correspondingly larger flux. Adapted from Figure 5 of . []{data-label="fig:losscone_nonsph"}](fig_losscone_nonsph.pdf)
After the initial population of stars in the drain region has been depleted, two-body relaxation again becomes the rate-limiting step. However, relaxation will still be aided by the existence of the drain region, which acts as an “extended” loss cone: one with a much larger surface area in phase space. After a star has diffused into the drain region via collisional relaxation, it will collisionlessly wander into the actual loss cone in a time $\lesssim T_\mathrm{drain}$ (unless it is scattered back into the higher-$\overline L$ region of phase space). The TDE rate from the loss wedge is technically still set by the full loss-cone rate of Eq. (\[eq:flux\_full\]), but the phase-space density of stars in this region, $N(\mathcal R_\mathrm{t}) \simeq N(\mathcal R_\mathrm{drain})$, may be much lower than $\overline N$, if the supply rate is diffusion-limited. In this case, the steady-state flux is given by the expression for the empty-loss cone regime of Eq. (\[eq:flux\_empty\]), but replacing $\ln(1/\mathcal R_\mathrm{t})$ with $\ln(1/\mathcal R_\mathrm{drain})$. Because of this logarithmic dependence, the actual enhancement of capture rate is at most a factor of few, as is illustrated by Figure \[fig:losscone\_nonsph\].
A different type of transient asphericity can occur in special, “degenerate” potentials where frequencies of motion are rationally commensurate with each other and orbits close. For example, in the Kepler potential of the SMBH, all three frequencies of motion are exactly equal for an individual star (so long as we neglect precession from the background stellar potential and relativistic effects). Because the stellar cusp is made of a finite number of stars, the combination of discreteness and closed orbits will create a statistical excess of time-averaged stellar mass in one direction: a temporary asphericity. An alternative view of this process is that pairwise encounters between nearby stars will be [*correlated*]{} over time, and therefore may coherently torque stellar orbits much more efficiently than do the [*uncorrelated*]{} effects from two-body relaxation. The resulting orbital evolution, known as [*resonant relaxation*]{} , has been proposed as a way to more efficiently refill empty loss cones . However, general relativistic precession often prevents resonant relaxation from exciting stars to the high eccentricities needed to enter the loss cone [@Merritt+11; @Brem+14], and recent calculations suggest that its impact on the loss-cone flux is fairly minor in realistic galactic nuclei (e.g., @Merritt15, or Fig. 17 in ).
To summarize, the TDE rate in non-spherical systems is larger than in spherical ones, if most of the flux in the latter is delivered in the diffusion-limited (empty loss cone) regime. In Section \[sec:empirical\], we will see that in denser galactic nuclei, with $M_\bullet \lesssim 10^6\,M_\odot$, this enhancement is small, while for $M_\bullet\gtrsim 10^8\,M_\odot$ it could be more than an order of magnitude. However, these larger galaxies are (i) rarer and (ii) have difficulty producing luminous TDEs ($M_\bullet \sim M_{\rm H}$), and so do not dominate the cosmic TDE rate of main-sequence stars.
General Relativistic Loss Cone Theory {#sec:GR}
-------------------------------------
Einstein’s theory of general relativity (GR) differs from Newtonian gravity in several respects that may carry important observational consequences for TDEs. The first of these differences concerns the nature of gravity itself in the two theories. In Newtonian gravity, the SMBH exerts an inverse-square-law force on the star, pulling more strongly on the side of the star facing the SMBH than on the stellar centre of mass. Equating the difference in the acceleration experienced by the stellar centre of mass and surface (i.e. the tidal acceleration) to the star’s self gravity and solving for the distance from the SMBH yields the Newtonian tidal radius $R_{\rm t}$ (Eq. \[eq:rtidal\]).
General relativistic gravity is interpreted instead as a non-vanishing spacetime curvature that determines the geodesics along which test particles travel. This spacetime curvature can cause initially parallel geodesics to deviate, leading to tidal disruption if the rate of geodesic deviation exceeds the star’s self-gravity. The relativistic geodesic-deviation equation is most conveniently expressed in Fermi normal coordinates $\{ \tau, X^{(i)}\}$ . Here $\tau$ is the proper time along the central timelike geodesic on which the star’s centre of mass travels, and $X^{(i)}$ are Cartesian spatial coordinates in a spatial hypersurface orthogonal to this central geodesic. In these coordinates, the geodesic-deviation equation becomes $$\label{E:geoDFNC}
\frac{d^2X^{(i)}}{d\tau^2} = -C^{(i)}_{\quad(j)} X^{(j)}.$$ where $$\label{E:TidalTens}
C^{(i)}_{\quad(j)} = R^\beta_{~\mu\alpha\nu} \lambda_\beta^{~(i)} \lambda^\mu_{~(0)} \lambda^\alpha_{~(j)} \lambda^\nu_{~(0)}$$ is the tidal tensor, $R^\beta_{~\mu\alpha\nu}$ is the Riemann curvature tensor, and $\{ \lambda^\mu_{~(0)}, \lambda^\mu_{~(i)}\}$ is the orthonormal tetrad of 4-vectors with respect to which the Fermi normal coordinates $\{ \tau, X^{(i)}\}$ are defined. The symmetries of the Riemann tensor imply that the tidal tensor is a real, symmetric $3\times 3$ matrix with three real eigenvalues and orthogonal eigenvectors. Eq. \[E:geoDFNC\] implies that the star will be stretched along the eigenvector corresponding to the tidal tensor’s sole negative eigenvalue, $V_-$ ; equating the tidal acceleration in this direction at pericentre to the star’s self-gravity yields the relativistic generalization of the tidal radius [@Kesden12] $$\label{E:GRrtidal}
R_{\rm t,GR} = \left[ \left( \frac{|V_-|}{2GM_\bullet/r^3} \right) \left( \frac{M_\bullet}{M_\star} \right) \right]^{1/3} R_\star.$$ As in the Newtonian case (Eq. \[eq:rtidal\]), the exact criterion for tidal disruption is $R_{\rm p} < R_{\rm t,GR}/\beta_{\rm crit}$, where $\beta_{\rm crit} \approx 1 - 2$ depends on the internal structure of the star. In the non-relativistic limit ($v \ll c, r \gg R_{\rm g}$), $R_{\rm t,GR}$ reduces to $R_{\rm t}$.
Although there is a superficial similarity between the Newtonian and relativistic tidal radii of Eqs. \[eq:rtidal\] and \[E:GRrtidal\], there are also important differences. Because the tidal tensor $C^{(i)}_{(j)}$ and thus its negative eigenvalue $V_-$ depend on both the Riemann tensor and the stellar geodesic, the relativistic tidal radius depends on both the spacetime metric of the SMBH and the stellar 4-position and 4-velocity at pericentre, not just the distance from the SMBH. The spacetime near SMBHs is described in GR by the Kerr metric [@1963PhRvL..11..237K], which depends not just on the SMBH mass $M_\bullet$, but also on its dimensionless spin, $0 \leq \chi_\bullet \leq 1$ [@1971PhRvL..26..331C].
The spin dependence of the SMBH’s gravity is the second important difference between Newtonian gravity and GR. The SMBH spin breaks the spherical symmetry present in Newtonian point potentials, implying that, in the commonly used Boyer-Lindquist coordinate system [@1967JMP.....8..265B], the Riemann tensor depends on both the radial coordinate $r$ and the polar coordinate $\theta$. The Kerr metric is stationary and axisymmetric, implying the existence of a specific energy $E$ and angular momentum $L_z$ that are conserved along geodesics. In addition, the Kerr metric has a Killing tensor that provides a conserved Carter constant $Q$ [@1968PhRv..174.1559C; @1970CMaPh..18..265W]. In the non-relativistic limit, the Carter constant corresponds to the square of the magnitude of the component of the orbital angular momentum in the equatorial plane of the SMBH. This allows us to define an (effective) specific orbital angular momentum $L \equiv \sqrt{L_z^2 + Q}$, and an (effective) inclination $\iota = \cos^{-1}(L_z/\sqrt{L_z^2 + Q})$ that are conserved along all Kerr geodesics. These considerations indicate that the relativistic tidal radius $R_{\rm t,GR}$ can, in principle, depend on the SMBH mass $M_\bullet$ and spin $\chi_\bullet$, but also on the stellar orbital energy $E$, inclination $\iota$, and argument of pericentre $\omega$. In practice, the dependence on $E$ and $\omega$ can be neglected to high accuracy, allowing us to define the threshold for tidal disruption $L_{\rm t,GR}(\chi_\bullet, \iota)$ as the value of $L$ for which $$\label{E:LtGR}
V_-(M_\bullet, \chi_\bullet, L, \iota) = -\frac{2GM_\star}{R_\star^3}$$ when evaluated at pericentre[^10].
A third significant difference between Newtonian gravity and GR is that, in the latter theory, a black hole is defined as an object possessing an event horizon, a hypersurface from within which even light cannot escape [@1984ucp..book.....W]. The tidal force exerted by a Newtonian point mass scales $\propto r^{-3}$ and can therefore become arbitrarily large. This implies that any Newtonian point mass is capable of tidal disruption, given a small enough pericentre. However, to produce an observable TDE in GR, a SMBH’s tides must overcome the star’s self gravity while avoiding direct capture of the tidal debris by the event horizon. Stars on parabolic orbits (and their resulting debris) will be captured when their specific orbital angular momentum $L$ falls below a threshold $L_{\rm cap}(\chi_\bullet, \iota)$ that depends on both the SMBH spin and orbital inclination. The rate of observable TDEs in GR will therefore be given by the rate at which two-body relaxation or other processes described above drive stars onto orbits with $L_{\rm cap}(\chi_\bullet, \iota) < L < L_{\rm t,GR}(\chi_\bullet, \iota)$. The hierarchy of distance scales, $R_{\rm g} \ll r_{\rm infl}$, between the gravitational radius and the radius of influence (from which most tidally disrupted stars are scattered into the loss cone) ensures that GR only modifies the boundaries of the loss cone, but does not otherwise affect the process responsible for refilling it.
The capture threshold $L_{\rm cap}(\chi_\bullet, \iota)$ scales linearly with $M_\bullet$ on dimensional grounds, while to lowest order in $M_\star/M_\bullet \ll 1$, the threshold for tidal disruption $L_{\rm t,GR}(\chi_\bullet, \iota) \propto M_\bullet^{2/3}$, like its Newtonian counterpart $\sqrt{2GM_\bullet R_{\rm t}}$. This implies that SMBHs more massive than the relativistic Hills mass $M_{\rm H,GR}(\chi_\bullet)$, defined such that $L_{\rm cap}(\chi_\bullet, \iota) > L_{\rm t,GR}(\chi_\bullet, \iota)$ for all inclinations $\iota$, will be incapable of producing observable TDEs. For Schwarzschild SMBHs ($\chi_\bullet = 0$), spherical symmetry is restored and the disruption and capture thresholds are inclination-independent. The relativistic Hills mass for a Schwarzschild SMBH is $$\label{E:relHills}
M_{\rm H,GR} = \left( \frac{5c^6R_\star^3}{128\beta_{\rm crit}^3G^3M_\star} \right)^{1/2} = \left( \frac{5}{16\beta_{\rm crit}^3} \right)^{1/2} M_{\rm H} = 10^{7.8}\beta_{\rm crit}^{-3/2}M_\odot,$$ where $\beta_{\rm crit}$ is the minimum penetration factor for tidal disruption and $M_{\rm H}$ is the Newtonian Hills mass given by Eq. (\[eq:MHills\]). For high-mass stars like our Sun whose equation of state can be approximated by a polytropic index $\gamma = 4/3$, Newtonian hydrodynamic simulations suggest that $\beta_{\rm crit} \simeq 1.85$ implying $M_{\rm H,GR} \simeq 10^{7.4} M_\odot$ [@2017PhRvD..95h3001S]. For Kerr SMBHs ($\chi_\bullet > 0$), both $L_{\rm t,GR}(\chi_\bullet, \iota)$ and $L_{\rm cap}(\chi_\bullet, \iota)$ are monotonically increasing functions of inclination $\iota$, but the direct capture threshold has a steeper dependence. This implies that the Hills mass $M_{\rm H,GR}(\chi_\bullet)$ will be determined by the condition $L_{\rm cap}(\chi_\bullet, \iota = 0^\circ) = L_{\rm t,GR}(\chi_\bullet, \iota = 0^\circ)$. For maximally spinning SMBHs ($\chi_\bullet = 1$), this limit can be as large as $\sim 10^9 M_\odot$ .
![The TDE rate $\Gamma$ in an idealized singular isothermal sphere ($\rho \propto r^{-2}$) galactic nucleus, shown as a function of SMBH mass $M$. The black dashed line shows the analytic estimate from @WangMerritt04 which neglects direct capture of stars by the event horizon. Colored lines show TDE rate curves corrected for this general relativistic effect, with the red, orange, green, blue and purple curves corresponding to SMBH spin magnitudes $\chi_\bullet$ with values of $0.0$, $0.5$, $0.9$, $0.99$, and $0.999$, respectively. These calculations average over an isotropic distribution of incoming stellar orbits and assume all disrupted stars are of solar mass and radius with $\beta_{\rm crit} = 2^{-1/3}$. Taken with permission from @Kesden12.[]{data-label="fig:spinSuppression"}](spinSuppression.pdf){width="120mm"}
We show the reduction in the observable TDE rate due to direct capture by the event horizon in Fig. \[fig:spinSuppression\] [@Kesden12]. The dashed black curve shows the TDE rate as a function of SMBH mass $M_\bullet$ for galaxies with a singular isothermal sphere ($\rho \propto r^{-2}$) stellar density profile and velocity dispersions $\sigma$ set by the $M_\bullet-\sigma$ relation [@2000ApJ...539L...9F; @2000ApJ...539L..13G]. These rates were calculated with a Newtonian loss cone refilled by two-body relaxation as described in Sec. \[sec:relaxation\] [@WangMerritt04]. The solid colored curves (corresponding to different SMBH spins as indicated in the caption) show the suppression of this TDE rate from the fraction of stars in the tidal disruption loss cone, $L < L_{\rm t,GR}(\chi_\bullet, \iota)$, that also lie within the direct capture loss cone[^11], $L < L_{\rm cap}(\chi_\bullet, \iota)$. We see that the event horizon has a negligible effect for $M_\bullet \lesssim 10^6 M_\odot$, and that SMBHs with $M_\bullet \approx 5\times 10^{8} M_\odot$ can still produce observable TDEs provided their spins are large enough. The predicted suppression of the TDE rate by direct capture for $M_\bullet \gtrsim 10^{7.5} M_\odot$ shown in Fig. \[fig:spinSuppression\] is consistent with the super-exponential cutoff in the TDE rate observed in a limited sample of twelve optically-selected TDE candidates [@vanVelzen18].
Calculating observable TDE rates in a fully self-consistent manner with the asymmetric, relativistic loss cones described above remains an open problem, but we can anticipate several qualitative features of the results. For Schwarzschild SMBHs, the tidal acceleration is stronger in GR than on Newtonian orbits with the same angular momentum $L$ [@2017PhRvD..95h3001S]. Eq. \[eq:flux\_full\] thus implies that, in the full loss-cone regime, the TDE rate will be enhanced by a factor of $(L_{\rm t,GR}/L_{\rm t})^2$ in the absence of direct capture by the event horizon. This factor is a monotonically increasing function of SMBH mass that reaches $\approx 2.7$ for $M_\bullet = M_{\rm H,GR}(\chi_\bullet = 0)$, though by definition direct capture cannot be neglected for SMBHs near the Hills mass. In the [*empty*]{} loss cone regime, direct capture can be generally neglected so long as $L_{\rm t, GR}(\chi_\bullet, \iota) > L_{\rm cap, GR}(\chi_\bullet, \iota)$, but in this case the TDE rate enhancement is only by a factor $\approx \ln(L_{\rm t,GR}/L_{\rm t})$, as in Eq. \[eq:flux\_empty\]. However, according to Eq. \[eq:boundary\_condition\], the dimensionless factor $q(E)$ will be suppressed in GR by the same factor $(L_{\rm t,GR}/L_{\rm t})^2$, pushing more of the phase space into the empty loss-cone regime where the TDE rate is suppressed with respect to the full loss-cone regime by this factor. In either loss cone regime, these effects will be small when $M_\bullet \ll M_{\rm H,GR}$.
SMBH spin further complicates TDE rate predictions. The thresholds $L_{\rm t,GR}(\chi_\bullet, \iota)$ and $L_{\rm cap}(\chi_\bullet, \iota)$ are smaller for Kerr SMBHs than their Schwarzschild values when orbits are prograde ($\iota < 90^\circ$), and are larger when orbits are retrograde ($\iota > 90^\circ$). For isotropic distributions (flat in $\cos\iota$), even large spins have a modest $\lesssim 10\%$ effect on the $M_\bullet$-integrated TDE and capture rates in the full loss-cone regime [@Young+77]. However, we have already seen that spin can have [*dramatic*]{} effects on rates of observable TDEs from individual bins of SMBH mass when $M_\bullet \sim 10^8 M_\odot$ (Fig. \[fig:spinSuppression\]). Furthermore, spin can have a significant effect on the inclination distributions of tidally disrupted and captured stars, with important observational consequences that we discuss further in Section \[sec:synthetic\], and in greater detail in the [Formation of the Accretion Flow Chapter]{}.
Other Loss Cones {#sec:types}
----------------
So far, we have focused our attention on the loss cone relevant for standard TDEs: one centered on a massive black hole, with a boundary defined by the complete tidal disruption of a main sequence star. But the concept of a loss cone can be applied more generally to compute rates of other types of tidal disruptions. Some, such as the disruptions of binary or giant-branch stars by SMBHs, have event rates set by loss cone considerations not too dissimilar from those discussed already. More exotic types of tidal disruptions, such as “micro-TDEs” involving hyperbolic flybys of stars and stellar-mass black holes [@Peretsetal2016], or the short gamma-ray bursts produced by the quasi-circular inspiral of a neutron star into a stellar-mass black hole, are produced by quite different dynamical processes, and are therefore outside the purview of this Chapter. In this section, we briefly overview how loss cone physics is altered for different types of tidal disruptions: partial rather than full (§\[sec:partials\]), giant-branch rather than main sequence (§\[sec:giants\]), and binary rather than single (§\[sec:binaries\]). Stars may also be tidally disrupted by [*binary*]{} SMBHs, but the underlying dynamics here are sufficiently complicated that they are left to the [Binaries Chapter]{}.
### Partial Disruptions {#sec:partials}
Partial disruptions will occur when stars approach the central SMBH with $\beta < \beta_{\rm crit}$. As discussed previously, the exact value of $\beta_{\rm crit}$ is a number $\mathcal{O}(1)$ that depends on the internal structure of the victim star. For simple polytropic models, $\beta_{\rm crit}$ ranges from $\approx 0.92$ (for a relatively fluffy, $n=3/2$ polytrope, representative of lower main sequence stars) to $2.01$ (for a more centrally concentrated $n=3$ polytrope, representative of Sun-like stars). While these thresholds for full disruption are well-established for polytropic stellar models , the corresponding $\beta_{\rm crit}$ values for more realistic stellar structures have yet to be determined. The exact threshold below which [*no*]{} mass loss occurs is also a function of stellar structure; for polytropic models, mass loss typically requires $\beta > \beta_{\rm min} \approx 0.5$ .
Because the cross-section for partial disruption is substantially larger than that for full disruption, partial disruptions should be more common. This is clearly true in the empty loss-cone limit; when $q(E) \ll 1$, higher $\beta$ values are exponentially suppressed[^12]. In the full loss-cone regime, the number of stars $N(\mathcal{R})$ is roughly independent of $\mathcal{R}$ deep into the loss cone, meaning that the differential rate of disruptions ${\rm d}\dot{N}/ {\rm d}\mathcal{R} \propto {\rm d}\dot{N}/ {\rm d}r_{\rm p} \propto \mathrm{const}$. By a change of variables, this gives the differential rate ${\rm d}\dot{N}/ {\rm d}\beta \propto \beta^{-2}$. The ratio of partial to full tidal disruptions will, in the $q(E)\gg 1$ limit, be $$\label{eq:Ndot_partial}
\frac{\dot{N}_{\rm partial}}{\dot{N}_{\rm full}} = \frac{\beta_{\rm min}^{-1} - \beta_{\rm crit}^{-1}}{\beta_{\rm crit}^{-1} - \beta_{\rm max}^{-1}},$$ where $\beta_{\rm max}$ is the maximum penetration parameter that can avoid direct capture by the horizon. In Newtonian gravity, where the horizon may be approximated as an absorbing boundary at $2R_{\rm g}$, $$\beta_{\rm max}^{\rm N} = \frac{R_\star c^2}{2GM_\bullet^{2/3}M_\star^{1/3}}.$$ In GR, $\beta_{\rm max} = \beta_{\rm max}^{\rm GR}(\chi_\bullet, \iota)$, and can be computed by determining both $L_{\rm t, GR}$ and $L_{\rm cap}$, although it is important to note that the definition of $\beta$ becomes more ambiguous in relativistic gravity [@2017PhRvD..95h3001S]. For simplicity, we have so far discussed differential rates ${\rm d}\dot{N}/{\rm d}\beta$ in the two extreme limits of loss cone repopulation; a more sophisticated treatment of the intermediate, $q \sim 1$ case can be found in @Strubbe11.
### Giant Stars {#sec:giants}
After a sufficient fraction of their hydrogen has been burnt, most stars will evolve off the main sequence and become giants, increasing their radial size by at least one order of magnitude. Stars with initial mass $M_\star \sim 1-8 M_\odot$ will spend most of their post-main sequence evolution on the red giant branch (RGB), with $R_{\rm RG} \sim 10R_\odot$, and a smaller but dynamically important portion on the AGB branch with $R_{\rm AGB} \sim 100R_\odot$.
Giant-branch stars are, consequently, much more vulnerable to partial tidal disruption: while their cores are no less dense than those of main sequence stars, their envelopes are distended and only weakly bound. If we reapply the results of §\[sec:relaxation\], we therefore expect that per-star TDE rates of giants should be larger by a factor $\sim R_{\rm G} / R_\star$ in the full loss cone regime, but by a more modest factor $\sim \ln(R_{\rm G} / R_\star)$ in the empty loss cone regime. Because the total TDE rate $\dot{N}$ is an integral across these two regimes, it will typically follow a sublinear power law as shallow as $\dot{N} \propto (R_{\rm G} / R_\star)^{1/4}$ [@MacLeod+12]. While these arguments show that the per-star rate of giant disruption is higher than that for main sequence stars, this enhancement competes unsuccessfully with the much smaller number of giant-branch stars. As a result, the ratio between giant-branch and main sequence TDE rates is $\dot{N}_{\rm G} / \dot{N}_{\rm MS} \sim 0.1$ . This ratio holds across a wide range of SMBH masses but breaks down above the main sequence Hills mass, when $M_\bullet \gtrsim M_{\rm H}$. Schwarzschild SMBHs with $10^8 M_\odot \lesssim M_\bullet \lesssim 10^9 M_\odot$ are generally unable to disrupt main sequence stars, and only produce luminous flares from giant disruptions. When $M_\bullet \gtrsim 10^9 M_\odot$, Schwarzschild SMBHs will become incapable of disrupting most giant-branch stars as well, and their only luminous flares will come from the small population of stars at the tips of the RGB and AGB [@MacLeod+12].
The time-dependent radii of giants gives these stars a non-diffusive way to enter the loss cone, one that is inaccessible to main sequence stars: expanding in size until their loss cone grows to intersect their current orbit. “Growth into the loss cone” was first investigated by @SyerUlmer98, who argued that this will be the dominant source of TDEs from evolved stars. However, this early work assumed that every giant disruption would be a full and highly luminous one. In reality, stars that grow onto the loss cone will, very likely, be “spoon-fed” to the SMBH in a series of tens to hundreds of very weak partial disruptions [@MacLeod+13], making these events quite challenging to detect.
We note, however, that various dynamical processes can shorten relaxation times outside the influence radius [@Perets+07a; @Hamers:2017]. At these regions MS stars are typically already in the full loss cone regime and are not significantly affected by such processes. However, the empty loss cone for objects with larger tidal radii such as binary stars and giant stars extend to larger distances (as we discuss in the next section). Such processes can therefore increase the TDE rates of giants, and change the above-mentioned ratio, leading to a greater contribution of TDEs from giant stars.
### Binary Stars {#sec:binaries}
Binary stars – especially massive ones – can be as common as single stars. Their fate, when plunging along highly eccentric orbits towards a SMBH, can be richer than that of single stars. A binary star passing near a SMBH can be tidally separated with no tidal disruption of the single-star components. In this case, the individual stars may either recombine to reform a binary after pericentre passage, or undergo a three-body exchange interaction, with one star being captured around the black hole and the other being ejected with velocity in excess of the bulge escape speed [@hills88; @hills91; @SKR10]. These escapers may have already been observed as hypervelocity stars (HVSs) in the halo of our Galaxy [e.g. @brownw18]. Such outcomes most likely occur for binaries with internal semimajor axes $a_{\rm bin}\gg R_\star$, with a centre-of-mass orbit just grazing the tidal separation radius $R_{\rm sep} = a (M_\bullet/m _{\rm bin})^{1/3}$ (here $m_{\rm bin}$ is the binary mass). Tidal disruption, or tidally-induced mergers, may result from either deeper encounters that cross the stellar tidal radius, $R_{\rm t} \approx (R_\star/a_{\rm bin}) R_{\rm sep}$, or near-contact binaries for which $a_{\rm bin} \sim R_\star$ . For details on how the disruption and accretion processes are altered by binarity, we refer the reader to the [Disruption Chapter]{} and the [Formation of the Accretion Flow Chapter]{}. Here we will discuss properties of the stellar binaries’ loss cone, the ensuing event rates, and their connections with HVSs.
As discussed in §\[sec:relaxation\], the critical radius measures the size of the region that is in the empty loss cone regime, and it depends on the tidal radius of the system under consideration (and, strictly speaking, can be more precisely defined in energy space, a detail we neglect in this section). When the critical radius is smaller than the sphere of influence radius, $r_{\rm crit} \propto R_{\rm t}$, but in the opposite case, when $r_{\rm crit} > r_{\rm inf}$, $r_{\rm crit} \propto R_{\rm t}^{1/(4-\gamma)}$, where $\gamma$ is the power-law slope of the nuclear stellar density profile [e.g. Eqs. 9-10 in @SyerUlmer98]. Empirically, observed nuclear density profiles typically have $0\lesssim \gamma \lesssim 2$ [@Lauer+05]; in the Milky Way specifically, the central cusp appears shallower than a Bahcall–Wolf steady-state , and recent measurements indicate $\gamma \approx 1.13$ [@schoedel+18]. The typical tidal separation radius of stellar binaries is larger than the single-star disruption radius by a factor $a_{\rm bin}/R_\star \sim \mathcal{O}(10)$, so we expect the critical radius for binary separation in the Milky Way to exist at several tens of parsecs (instead of the few parsecs expected for tidal disruption by Sgr A\* in our Galactic Centre).
![A schematic representation of the local contribution to the loss-cone flux, for both binary and single stars. [*Top*]{}: the loss-cone flux for binary stars due to 2-body stellar relaxation (bottom dashed line) and due to massive perturbers (MP, top dashed line). Empty and full loss-cone regimes are denoted by “E” and “F”, respectively. The radius $r_{\rm mp}$ corresponds to the region where such perturbers exist, likely just outside the innermost region of the nucleus. The critical radius for binaries and the sphere of influence radius are denoted respectively $r_{\rm c}^{\rm b}$ and $r_{\rm h}$. [*Bottom*]{}: the disruption rate of single stars. Here the presence of MPs coincides with the full loss cone regime and therefore little flux increase is expected. The critical radius for single stars is $r_{\rm c}^{\rm s} \sim r_{\rm h}$. Taken with permission from @Perets+07a, Fig. 3.[]{data-label="fig:empty-full-lc"}](full-empty-lc-mps.pdf){width="120mm"}
As sketched in Fig. \[fig:empty-full-lc\], when two-body stellar relaxation is dominant and $\gamma < 9/4$, the [*empty*]{} loss cone (for binary separation) flux per unit bin of logarithmic radius increases outwards within the sphere of influence of the SMBH ($r_\mathrm{infl}$). On the other hand, it decreases outwards when $r>r_{\rm infl}$ . This implies that the loss cone flux for stellar binaries may peak around $r_\mathrm{\rm infl}$, with a long tail out to $\sim 100$ pc. As described earlier, the peak of the loss cone flux for single-star disruption comes from $\min(r_{\rm crit},r_{\rm infl})$, where typically $r_{\rm crit} \sim r_\mathrm{infl}$. Moreover, the empty loss cone flux is only logarithmically dependent on the loss cone size. These facts together might suggest that observational measurements of the rate of Galactic HVSs could be directly translated into constraints on TDE rates here[^13]. This moment in time is especially propitious because of the ongoing data releases by the astrometric Galactic survey Gaia that have intensified searches for HVSs [e.g. @marchetti+17; @marchetti+19; @boubert+18; @bromley18]. Likewise, a comparison between rates of single and double TDE in other galaxies could provide an extra consistency check on the relationship between single and binary star loss cones. This comparison, however, requires more theoretical work in order to observationally distinguish these two types of transients . In general, both comparisons need to account for the fraction of binaries being separated versus disrupted [@bradnick+17].
In principle, this is very exciting, but there are other physical ingredients – irrelevant for single-star disruption – that complicate the loss cone dynamics of binary stars. The high stellar density inside the sphere of influence means that most soft binaries will not survive “ionization” (or “evaporation”) from continuous gravitational interactions with field stars around them [@Perets+07a; @hopman09; @perets09; @generozov18]. Hard binaries (progenitors of the fastest HVSs) can instead be driven to merger by magnetic braking. The overall result is a binary to single ratio of less than $10\%$ at $1$ pc for low mass stars ($\leq 1 M_{\odot}$). For more massive (but typically more rare) stars, the main sequence lifetime can be shorter than the evaporation timescale and the binary fraction would remain close to its birth value. Evaporation might therefore drastically suppress the HVS rate from $r\lesssim r_{\rm infl}$, limiting our ability to directly calibrate TDE rates from HVS or double disruption rates, with the partial exception of massive stars. On the other hand, outside the sphere of influence, dynamical relaxation can be dominated by “massive perturbers", such as giant molecular clouds, greatly shortening the relaxation timescale over that from two-body scatterings off stars. Since binary stars on loss cone orbits come from distances as far as $\sim 100 \times r_{\rm infl}$ and, unlike single stars, are in the empty loss cone regime (i.e. their flux [*can*]{} be increased), the presence of giant molecular clouds would enhance the HVS rate by a few orders of magnitude while leaving unaffected the predictions for TDEs [@Perets+07a; @Hamers:2017]. In summary, constraining the TDE rate by observing HVSs in our Galaxy or double TDEs in external galaxies is in principle possible, but not straightforward.
Applied Loss Cone Theory {#sec:applied}
========================
By changing the underlying density profile $\rho(r)$ or DF $f(\epsilon)$ in a spherical, isotropic galactic nucleus, a motivated theorist can tune the TDE rate to any desired value. Asphericities and anisotropies offer further levers with which to change TDE rates. In order to produce astrophysically realistic TDE rate estimates, the underlying galaxy model must, in some way, be calibrated off observations. In this section, we will outline approximate but practical procedures for doing so. More specifically, we review how the theoretical loss cone physics of §\[sec:losscone\] may be combined with observations to make [*empirically-calibrated*]{} TDE rate estimates in nearby galaxies (§\[sec:empirical\]). We will then examine the implications that past rate estimates along these lines have for distributions of TDE observables (§\[sec:synthetic\]).
Simple Phase Space Modeling {#sec:empirical}
---------------------------
In this subsection, we present a simple procedure for estimating TDE rates in individual galactic nuclei. The key assumptions of this procedure, which was first developed by and @WangMerritt04, are (i) spherical symmetry and (ii) nearly isotropic velocities, and this will be our starting point. Later on, we will also discuss more general prescriptions to account for geometrical asphericities or velocity anisotropies[^14]. We begin with the observed 2D surface brightness profile, $I(R)$, which can be deprojected into a 3D luminosity density profile $j(r)$ using an Abel integral: $$j(r) = \frac{-1}{\pi} \int_r^\infty \frac{{\rm d}I}{{\rm d} R} \frac{{\rm d} R}{\sqrt{R^2-r^2}}.$$ Note that $R$ is a projected 2D radius and $r$ a 3D radius. We then use a mass-to-light ratio, $\Upsilon$, to compute the 3D mass density $\rho(r) = \Upsilon j(r)$.
This mass density profile can be used to compute other quantities of relevance to us, such as the period of a radial orbit, $T_{\rm orb}(E)$, the stellar mass enclosed $M_\star(r)$, and the gravitational potential $\Phi(r)$: $$\begin{aligned}
M_\star(r)=& \int_0^{r} 4\pi (r')^2 \rho(r'){\rm d}r' \\
\Phi(r)=& -\frac{GM_\bullet}{r} - \frac{GM_\star(r)}{r} - 4\pi G \int_r^\infty \rho(r')r'{\rm d}r' \\
T_{\rm orb}(E)=& 2\int_0^{r_\mathrm{max}} \frac{{\rm d}r}{\sqrt{2\big(E - \Phi(r)\big)}}.\end{aligned}$$ Here we have also used the apocentre of a radial orbit, $r_\mathrm{max}(E)$. Next, under the assumption of (nearly) isotropic velocities[^15], we use Eddington’s formula to compute a one-integral DF: $$f(E) = \frac{-1}{\pi^2 \sqrt{8}} \frac{{\rm d}}{{\rm d}E} \int^0_E \frac{{\rm d} n}{{\rm d}\Phi} \frac{{\rm d}\Phi}{\sqrt{\Phi - E}}. \label{eq:Eddington}$$ In this integral, we convert stellar mass density to stellar number density $n(r)\equiv \rho(r) / \langle m_\star \rangle$. The difference between these two mass functions is merely the average stellar mass $\langle m_\star \rangle$, which is determined by the stellar PDMF as in Eq. \[eq:PDMF\].
With the isotropic DF $f(E)$ in hand, we may now apply the formalism of §\[sec:relaxation\] to obtain the TDE rate, $\dot{N}$, of the galaxy in question. More specifically, we calculate the orbit-averaged diffusion coefficient $\mathcal{D}(E)$ using Eq. \[eq:diffusion\_coefficient\], use this to calculate the diffusivity parameter $q(E)$ using Eq. \[eq:boundary\_condition\], and then compute the loss cone flux $\mathcal{F}(E)$ as in Eq. \[eq:flux\_general\]. Integrating $\mathcal{F}(E)$ across all energies $E$ gives the total TDE rate $\dot{N}$ (Eq. \[eq:total\_rate\]).
In order to apply the above formalism to photometric observations of real galactic nuclei, we must consider a number of astrophysical uncertainties, including:
- The functional form of $I(R)$: ideally, one would operate with nonparametric data, although some smoothing may be necessary to ensure positivity of $f(E)$. However, in low-mass galaxies ($M_\bullet \sim 10^6 M_\odot$), the influence and critical radii are at best marginally resolved, so some degree of inward extrapolation in $I(R)$ is often necessary. Past works have typically employed power-law fits to the innermost isophotes [@WangMerritt04; @StoneMetzger16], and the uncertainty produced by this extrapolation is in need of greater quantification.
- Choice of mass-to-light ratio $\Upsilon$: past efforts to predict TDE rates through dynamical modeling of large samples of galaxies have made crude estimates for $\Upsilon$. For example, employed the scaling relationship for V-band luminosities $\Upsilon_{\rm V} = 4.9 (M_\odot / L_\odot)(L_{\rm V} / 10^{10}L_\odot)^{0.18}$ [@Magorrian+98]. Later works made virial estimates, starting with a galaxy’s velocity dispersion $\sigma$, effective radius $R_{\rm eff}$, and luminosity $L$, then computing $\Upsilon_{\rm vir} = 2\sigma^2R_{\rm eff} / (GL)$ [@WangMerritt04; @StoneMetzger16]. Both of these methods make the large assumption that $\Upsilon$ is constant throughout the galaxy; a more self-consistent method would apply simple stellar population models to multiband photometry of the galactic nucleus to estimate $\Upsilon(R)$, as was done by @StonevanVelzen16.
- Choice of PDMF, ${\rm d}N/{\rm d}m_\star$: as we have seen, both the first and second moments of the PDMF enter into TDE rate calculations. Since the diffusion coefficients $\langle (\Delta \mathcal{R})^2 \rangle \propto \langle m_\star^2 \rangle$, the heaviest surviving stellar species will generally dominate rates of two-body relaxation. For very young stellar populations this may be O stars, but for more typical stellar populations, it will be stellar-mass black holes. Depending on the mass function of stellar-mass black holes considered [@Belczynski+10], their inclusion in ${\rm d}N/{\rm d}m_\star$ will enhance TDE rates by factors of $\approx 1.3-4.9$ [@StoneMetzger16].
- Determination of SMBH mass $M_\bullet$: all the studies described so far relied on galaxy scaling relations to estimate $M_\bullet$, due to scarcity of direct SMBH mass determinations. As such, they may be biased to various extents, depending on the assumed form of these relations, for which numerous and often incompatible versions have been produced over the last two decades. See, for example, the comparison between different calibrations of the $M_\bullet-\sigma$ relation in the rate estimates of @WangMerritt04.
Aside from these astrophysical uncertainties, the simplifying assumptions introduce more fundamental limitations to the validity of this formalism. So far, we have outlined a procedure for computing a one-integral, isotropic DF given only photometric information (i.e. the galaxy’s surface brightness profile). If additional kinematic information is available, a two-integral DF $f(E, L_{\rm z})$ may be computed instead , which will self-consistently account for the impact of flattening and orbital anisotropy on TDE rates.
The simple procedure outlined above has repeatedly been used to compute TDE rates in large galaxy samples, and at this point can be performed with the publicly available Fokker–Planck code <span style="font-variant:small-caps;">PhaseFlow</span> [@Vasiliev17], as was done in, e.g. @Pfister19. This basic procedure was first used, however, by @SyerUlmer98, who employed an even simpler formalism (one operating in coordinate space, not integral space) to a sample of 25 galaxies with surface brightness profiles $I(R)$ taken from @Byun+96 and SMBH masses taken from @Magorrian+98. The computed TDE rates were very low, with $10^{-7}~{\rm yr}^{-1} \lesssim \dot{N} \lesssim 10^{-4}~{\rm yr}^{-1}$ across most of the sample, although only 6 out of the 25 galaxies had SMBHs smaller than the Newtonian Hills mass. Almost simultaneously, used a more sophisticated, two-integral version of the loss cone formalism to analyze a sample of 29 galaxies, taking into account multiple sources of loss cone flux: standard two-body relaxation, the draining of a loss wedge region in an axisymmetric potential, and two-body repopulation of the loss wedge. Two-integral DFs $f(E, L_{\rm z})$ were taken from @Magorrian+98. This work found relatively low rates of disruption from two-body relaxation (albeit a factor of a few higher than what was found in @SyerUlmer98), but once again, focused primarily on the largest galactic nuclei, with only 3 out of the 29 galaxies possessing SMBHs below the Schwarzschild Hills mass. This study was the first to point out that the observed dichotomy in nuclear density profiles $n(r)$ – between steeply declining “cusp” galaxies and relatively shallow “core” galaxies [@Lauer+95] – implies that the highest TDE rates will occur in lower-mass, “cuspy” galaxies. We reproduce many of the derived quantities, such as $q(E)$ and $\mathcal{F}(E)$, from in Fig. \[fig:modeledLW\].
![Dynamically modeled photometry of two nearby galaxies, M32 (left) and M87 (right). Figures show intermediate quantities and the final product of the modeling prescription described in §\[sec:applied\], plotted in bins of (negative) specific orbital energy $\mathcal E \equiv -E > 0$. The top two rows show apocentric radius $r_{\rm apo}(\mathcal E)$ and orbital period $P(\mathcal E)$ for radial orbits. The next two rows show the one-integral DF $f(\mathcal E)$ (computed with an Eddington integral under the assumption of isotropic velocities) and the dimensionless size of the loss cone in angular momentum space, $\mathcal R_{\rm t}$ (labeled here as $\mathcal{R}_\mathrm{lc}$). The second-to-last row shows the diffusivity parameter $q(\mathcal E)$ (for two-body loss cone repopulation), and the final row shows several different estimates for differential loss cone flux $\mathcal{F}(\mathcal E)$. In the final row, the full loss cone flux is shown with a dotted line, the loss cone flux due to (spherical) two-body relaxation is a light solid line, the rate of draining of a full (axisymmetric) loss wedge is shown as a dot-dashed line, and the flux from a (axisymmetric) loss wedge being repopulated by two-body relaxation is shown as a dashed line. The thick solid line represents the total TDE rate. Taken with permission from .[]{data-label="fig:modeledLW"}](modeledLossWedge.pdf){width="120mm"}
A larger sample of 41 galaxies was modeled using one-integral DFs $f(E)$ by @WangMerritt04, following almost exactly the procedure of this subsection. These authors estimated SMBH masses using the $M_\bullet -\sigma$ relationship of @MerrittFerrarese01. This scaling relationship predicts systematically lower $M_\bullet$ values than that of @Magorrian+98, and as a result this study found much higher TDE rates, with typical $\dot{N} \sim 10^{-4}~{\rm yr}^{-1}$ in sub-Hills mass nuclei. This sample, which took $I(R)$ profiles from @Faber+97, was more applicable to realistic TDE hosts than past studies, with 21 out of 41 galaxies possessing SMBHs below the Schwarzschild Hills mass. @WangMerritt04 established much more firmly that the volumetric rate of TDEs, $\dot{n}$, should be dominated by the lowest-mass galaxy bin with a high SMBH occupation fraction. The reasons for this are (i) the greater abundance of low-mass galaxies in the Universe, (ii) the empirical preference of low-mass galaxies to have steep central stellar density cusps, which produce higher per-galaxy TDE rates $\dot{N}$, and (iii) the anticorrelation between $\dot{N}$ and SMBH mass $M_\bullet$ in a cuspy profile (see Fig. \[fig:coreCusp\] for the identification of this trend in @WangMerritt04).
![The dependence of stellar consumption rates $\dot{N}$ on assumed SMBH mass $M_\bullet$ in a sample of 41 galaxies modeled with [*HST*]{} photometry (note that main-sequence stars will not produce TDEs for $M_\bullet > M_{\rm H}\sim 10^8\,M_\odot$). The rates were computed assuming spherical symmetry and two-body relaxation, using the prescriptions of §\[sec:applied\], but allowing SMBH mass to float. An interesting dichotomy emerges: for cusp (“power-law”) stellar distributions, TDE rates increase with decreasing $M_\bullet$, while TDE rates are roughly independent of $M_\bullet$ in flatter, core-like nuclei. Taken with permission from @WangMerritt04.[]{data-label="fig:coreCusp"}](coreCuspDependencies.pdf){width="120mm"}
More recently, empirically calibrated TDE rates were re-examined by @StoneMetzger16, who used the one-integral formalism of this section to model a sample of 144 galaxies [@Lauer+07a; @Lauer+07b], of which 42 contain SMBHs with $M_\bullet$ below the Schwarzschild Hills mass. This work was the first to estimate the fraction, $f_{\rm pin}$, of TDEs from a given galaxy in the $q(E)>1$ (pinhole) regime of disruption. Empirically, $f_{\rm pin}$ is $\mathcal{O}(1)$ in galaxies with $M_\bullet \lesssim 10^7 M_\odot$, but exhibits broad scatter ($10^{-2} < f_{\rm pin} < 1$) at higher SMBH masses. In any given bin of $M_\bullet$, the pinhole fraction is much higher in core galaxies than in cusp galaxies. @StoneMetzger16 reproduced earlier findings that per-galaxy TDE rates $\dot{N}$ are highest in smaller galaxies, and fit power-laws to their sample of dynamically modeled nuclei: $$\dot{N} = \dot{N}_8 \left(\frac{M_\bullet}{10^8 M_\odot} \right)^B. \label{eq:empiricalRate}$$ Here $\dot{N}_8 = 2.9 \times 10^{-5}~{\rm yr}$ and $B=-0.404$ when considering the entire sample of 144 modeled galaxies. For a subsample of exclusively core (cusp) galactic nuclei, $\dot{N}_8 = 1.2 \times 10^{-5}~{\rm yr}$ and $B=-0.247$ ($\dot{N}_8 = 6.5 \times 10^{-5}~{\rm yr}$ and $B=-0.223$). These results were combined with a Schechter function, the Faber–Jackson law, a recent calibration of the $M_\bullet - \sigma$ relation , and various parametrizations of the SMBH occuption fraction to estimate the volumetric TDE rate, $\dot{n}(M_\bullet)$, which is presented here in Fig. \[fig:modeledRate\]. These results indicate that a volume-complete sample of TDEs will be a powerful probe of the unknown bottom end of the SMBH mass function.
![The volumetric TDE rate per dex, ${\rm d}\dot{n} / {\rm d}\ln M_\bullet$, plotted as a function of SMBH mass $M_\bullet$. Per-galaxy TDE rates are estimated by power-law fits to the results of a large, dynamically modeled galaxy sample, and are then coupled to a Schechter function that is populated with SMBHs using the $M_\bullet-\sigma$ relation and five different models for the SMBH occupation fraction in low-mass nuclei. Specifically, the SMBH occupation fraction is assumed to resemble a step function, with SMBHs largely absent below a cutoff host stellar mass $M_{\rm cut}/M_\odot$ of $10^9$ (grey solid), $10^{8.5}$ (brown dashed), $10^8$ (green dot-dashed), $10^{7.5}$ (blue dot-dot-dashed), and a final scenario in which every dwarf galaxy has massive black holes down to a limiting mass of $M_\bullet=10^4 M_\odot$ (purple dotted). Volumetric TDE rates are dominated by the smallest galaxies that typically host SMBHs. Mass-integrated rates $\dot{n}$ are labeled for each of these five models. Taken with permission from @StoneMetzger16.[]{data-label="fig:modeledRate"}](modeledVolumetricRate.pdf){width="120mm"}
Several astrophysical uncertainties apply to existing empirically-calibrated TDE rate estimates, as we have listed above. Aside from these caveats, it is notable that no loss cone calculations have yet been performed using the richer dynamical information available from Jeans or Schwarzschild modeling of a large sample of galaxies with (i) resolved kinematics and (ii) $M_\bullet < M_{\rm H}$. The pioneering work of established the basic theoretical framework for this effort, but was applied almost exclusively to SMBHs too large to produce luminous TDEs. Applying loss cone theory to galaxies with directly measured SMBH masses and anisotropy profiles would enhance the precision of TDE rate estimates substantially, and is a logical next step forward.
Synthetic Observables {#sec:synthetic}
---------------------
In the previous subsection, we surveyed existing efforts to empirically calibrate volumetric ($\dot{n}$) and per-galaxy ($\dot{N}$) TDE rates. However, the observable properties of TDE flares are not uniform, and can depend strongly on event parameters such as SMBH mass $M_\bullet$ or penetration parameter $\beta$. If one knows the differential distribution of TDE rates with respect to controlling parameters such as these, then it is straightforward to compute distributions of observable parameters of interest. Some of these parameters, such as the peak mass fallback rate $\dot{M}_{\rm peak}$ (or its Eddington ratio, $\dot{M}_{\rm peak}/\dot{M}_{\rm Edd}$), are very well-understood theoretically. Others, such as peak optical luminosity, are much less well-understood. Much more detailed theoretical treatments of TDE observables are offered in later Chapters of this Volume. In this section, we do not provide detailed models for TDE observables, but advise the interested reader to consult the [Disruption Chapter]{}, [Formation of the Accretion Flow Chapter]{}, [Accretion Disc Chapter]{}, and [Emission Mechanisms Chapter]{}.
Dynamical modeling of nearby galactic nuclei has already allowed us to estimate the $M_\bullet$-dependence of TDE rates, ${\rm d}\dot{n}/{\rm d}M_\bullet$ (e.g. Fig. \[fig:modeledRate\]). The $\beta$-dependence, ${\rm d}\dot{n}/{\rm d}\beta$, is a little more complicated, but at least in the limit of spherical loss cone repopulation, it can be estimated approximately. In the pinhole regime ($q \gg 1$), the differential distribution of penetration parameters goes as ${\rm d}\dot{n}/{\rm d}\beta \propto \beta^{-2}$, while in the diffusive regime ($q \ll 1$), $\beta \approx 1$, and higher $\beta$ values are exponentially suppressed (see also the discussion surrounding Eq. \[eq:Ndot\_partial\]). @StoneMetzger16 find that low-mass galactic nuclei ($M_\bullet \lesssim 10^7 M_\odot$) typically produce most of their TDEs from the pinhole regime, while there is much more scatter in the “pinhole fraction” of high-mass galactic nuclei (although it is rarely less than $10\%$, for $M_\bullet < M_{\rm H}$). For any given bin of $M_\bullet$, the pinhole fraction is lower in cusp and higher in core nuclei.
The distribution of fallback times $t_{\rm fall}$ and the closely related peak fallback rate $\dot{M}_{\rm peak}$ may be estimated using the approximate analytic formulae [@Rees88; @Stone+13]: $$\begin{aligned}
t_{\rm fall} \approx& 3.5\times 10^6~{\rm s}~\left( \frac{M_\bullet}{10^6 M_\odot} \right)^{1/2} \left( \frac{M_\star}{ M_\odot} \right)^{-1} \left( \frac{R_\star}{R_\odot} \right)^{3/2} \\
\frac{\dot{M}_{\rm peak}}{\dot{M}_{\rm Edd}} \approx & 130 \left( \frac{\eta}{0.1} \right) \left( \frac{M_\bullet}{10^6 M_\odot} \right)^{-3/2} \left( \frac{M_\star}{ M_\odot} \right)^{2} \left( \frac{R_\star}{R_\odot} \right)^{-3/2}.\end{aligned}$$ Here we have defined the Eddington-limited mass accretion rate, $\dot{M}_{\rm Edd} \equiv L_{\rm Edd}/(\eta c^2)$, in terms of a radiative efficiency $\eta<1$ and the Eddington luminosity $L_{\rm Edd} \approx 1.5 \times 10^{46}~{\rm erg~s}^{-1}~(M_\bullet / 10^8 M_\odot)$. While these observables can be computed more precisely using hydrodynamical disruption simulations , these analytic expressions were combined with TDE rate computations to predict distributions of peak fallback rates and rise times in @StoneMetzger16 and @Kochanek16. We present the results of the latter paper in Fig. \[fig:modeledDemographics\], which plots ${\rm d}\dot{n}/{\rm d}\ln M_\bullet$ in different bins of peak Eddington ratio $\dot{M}_{\rm peak}/\dot{M}_{\rm Edd}$. These distributions (which are integrated over different stellar PDMFs, corresponding to different star formation histories) highlight that for $M_\bullet \lesssim 10^7 M_\odot$, the large majority of TDEs have initially super-Eddington fallback rates, while the reverse is true for $M_\bullet \gtrsim 10^{7.5}M_\odot$.
Fig. \[fig:modeledDemographics\] also presents the TDE rates that will be [*observed*]{} in a flux-limited survey, $\dot{\mathcal{N}}(M_\bullet)$. These results assume a simple model relating peak luminosity to $M_\bullet$; more complicated models are explored in @StoneMetzger16 and . Generally, if super-Eddington fallback rates can be translated linearly into super-Eddington luminosities, then $\dot{\mathcal{N}}(M_\bullet)$ is dominated by the smallest values of $M_\bullet$ that exist with a high occupation fraction. Conversely, if TDE emission mechanisms are Eddington-limited, then $\dot{\mathcal{N}}(M_\bullet)$ is dominated by $M_\bullet \sim 10^7 M_\odot$, the characteristic SMBH mass where $\dot{M}_{\rm peak}/\dot{M}_{\rm Edd} \sim 1$. A more recent estimate of the volumetric detection rate, using a simple phenomenological model for TDE luminosities, is available in @Thorp+18, which also compares standard TDE rates to those from binary SMBHs.
Other notable conclusions of efforts to produce synthetic observable distributions include: (i) regardless of star formation history, both intrinsic and observed TDE rates are dominated by the bottom end of the stellar IMF, except when $M_\bullet \sim M_{\rm H}$ [@StoneMetzger16; @Kochanek16]; (ii) under the assumption that galactic nuclei have similar dynamical properties at all redshifts[^16], comoving volumetric TDE rates will decline by a factor $\approx 10$ from their $z=0$ value as one moves to $z=2$ [@Kochanek16], largely due to the decreasing volume density of SMBHs at high $z$ [@Shankar+09]; (iii) k-corrections generally aid the detectability of TDEs at cosmological distances [@StrubbeQuataert09]. Unfortunately, the current lack of accurate, first-principles models for TDE emission mechanisms has, at the time of writing, hampered the calculation of more specific distributions of observables (e.g. emission line strengths, X-ray to optical ratios, etc.).
So far we have only discussed the observable properties of main sequence TDEs, but detailed distributions of red giant disruption properties (such as stage of post-main sequence evolution) are available in @MacLeod+12. Synthetic distributions of fallback times for helium white dwarf and brown dwarf disruptions were, likewise, computed in @LawSmith+17b.
![The differential distribution of volumetric TDE rates (top panels) ${\rm d}\dot{n}/{\rm d}\ln M_\bullet$ and observed rates per dex ${\rm d}\dot{\mathcal{N}}/{\rm d} \ln M_\bullet$ (bottom panels). Because these TDE rates are integrated over PDMFs, they depend on assumed star formation histories; the left panels assume a single burst of star formation 10 Gyr ago, while the right panels assume a constant star formation rate over a Hubble time. Dashed black lines show total TDE rates ${\rm d}\dot{n}/{\rm d}\ln M_\bullet$ and ${\rm d}\dot{\mathcal{N}}/{\rm d} \ln M_\bullet$, while the other lines break up the rates into bins of $\dot{m}_{\rm peak} \equiv \dot{M}_{\rm peak}/\dot{M}_{\rm Edd}$. The red dotted lines correspond to super-Eddington peak fallback rate regimes of $10^{0.0}<\dot{m}_{\rm peak} <10^{0.5}$, $10^{0.5}< \dot{m}_{\rm peak} <10^{1.0}$, and $10^{1.0}> \dot{m}_{\rm peak}$, while the black solid lines correspond to sub-Eddington peak fallback rate regimes of $10^{-0.5}< \dot{m}_{\rm peak} <10^{0.0}$, $10^{-1.0}< \dot{m}_{\rm peak} <10^{-0.5}$, $10^{-1.5}< \dot{m}_{\rm peak} <10^{-1.0}$, and $ \dot{m}_{\rm peak} <10^{-1.5}$. In translating from intrinsic rates to observed rates, the calculation assumes a flux-limited survey and that TDE peak luminosities are determined by either the peak mass fallback rate or the Eddington-limited accretion rate, whichever is smaller. Taken with permission from @Kochanek16.[]{data-label="fig:modeledDemographics"}](modeledDemographics2.pdf){width="120mm"}
Comparing to Observed Rates of Tidal Disruption {#sec:comparison}
===============================================
For over two decades, tidal disruptions were studied from purely theoretical grounds. This situation changed in the 1990s with the discovery, in soft X-ray energies, of the first strong TDE candidates . Later, wide-field ultraviolet [@Gezari+06] and optical [@vanVelzen+11 see also the [Optical Chapter]{}] surveys discovered other classes of TDE candidates. At the time of writing, the current rate of TDE discovery stands at $\approx 1-3$ new TDE candidates per year, and a few dozen TDE candidates are known (see e.g. the compilations of @Auchettl+17 [@Hung+17]). New and upcoming time domain surveys are poised to expand our sample by orders of magnitude . Clearly, it is important to assess what scientific goals can be achieved with the statistical analysis of large near-future TDE samples. A key component of any such analysis is understanding the rate of tidal disruption.
In this section, we compare the theoretical rate estimates of §\[sec:applied\] to those inferred from the existing sample of tidal disruption flares. This type of comparison has, so far, found two interesting puzzles, which we outline in §\[sec:observationalRates\]. First, there may be a broad rate discrepancy, with fewer TDEs detected than are predicted by stellar dynamics [@StoneMetzger16]. Second, there is a more specific and definitive discrepancy related to the [*overproduction*]{} of observed TDEs in a rare galaxy subclass: so-called “E+A,” or post-starburst, galaxies [@Arcavi+14]. We discuss these puzzles in §\[sec:discrepancies\].
Observationally Inferred Rates {#sec:observationalRates}
------------------------------
The first TDE candidates were discovered via soft X-ray emission [@Bade+96], and the first observational rate inferences were based off of these events. The pioneering work of @Donley+02 analyzed three TDE candidates from the [*ROSAT*]{} All-Sky Survey and inferred a per-galaxy disruption rate $\dot{N} \approx 9 \times 10^{-6}~{\rm yr}^{-1}$. Subsequent analysis of two TDE candidates from the [*XMM-Newton*]{} slew survey inferred a volumetric TDE rate $\dot{n} \approx 5.4\times 10^{-6}~{\rm yr}^{-1}~{\rm Mpc}^{-3}$, and a per-galaxy rate $\dot{N} \approx 2.3 \times 10^{-4}~{\rm yr}^{-1}$ [@Esquej+08]. Later, one soft X-ray TDE candidate was found by reanalysis of archival [*Chandra*]{} and [*XMM-Newton*]{} observations of galaxy clusters [@Maksym+10]; three more were discovered by cross-correlating [*ROSAT*]{} archives with serendipitous [*XMM-Newton*]{} pointings [@KhabibullinSazonov14]. The per-galaxy event rates computed from these samples were $\dot{N} \approx 1.2 \times 10^{-4}~{\rm yr}^{-1}$ and $\dot{N} \approx 3 \times 10^{-5}~{\rm yr}^{-1}$, respectively. The sample of @KhabibullinSazonov14 implies a volumetric event rate $\dot{n} \approx 4-8\times 10^{-7}~{\rm yr}^{-1}~{\rm Mpc}^{-3}$.
The range of inferred X-ray TDE rates spans roughly 1.5 orders of magnitude. This spread can be attributed to a number of factors. Obviously, small-number statistics play a role. Due to the poor temporal resolution of all wide-field soft X-ray surveys to date, these samples are both flux- and cadence-limited, and rate inference therefore requires assumptions about (i) the X-ray luminosity function of TDEs, and (ii) the characteristic decay time of TDEs. With these assumptions, one may estimate survey completeness as a function of source distance, and therefore infer a volumetric event rate $\dot{n}$. As a simplified but illustrative example, consider a high-cadence survey operating at low redshifts for a duration $T$, covering an angular area $\Delta \Omega$. In this limit, the number of detected TDEs $$N_{\rm TDE} = \int \frac{{\rm d}\dot{n}}{{\rm d}L} \times \frac{4\pi}{3}D_{\rm max}^3(L) \times \frac{\Delta \Omega}{4\pi} \times T {\rm d}L.$$ Here $D_{\rm max}(L)$ is the maximum distance out to which a TDE can be detected in a flux-limited survey, and ${\rm d}\dot{n}/{\rm d}L$ is the volumetric TDE luminosity function [@Hung+18]. By assuming approximate functional forms for the luminosity function, one may use a measured $N_{\rm TDE}$ to estimate $\dot{n}\equiv \int({\rm d}\dot{n}/{\rm d}L){\rm d}L$. Translating this $\dot{n}$ into a per-galaxy rate $\dot{N}$ requires further assumptions about [*which*]{} galaxies may produce TDEs (e.g. down to what limiting mass do dwarf galaxies still possess SMBHs?). Given these many uncertainties, it is perhaps unsurprising to see substantial scatter in observationally inferred X-ray event rates.
More recently, the discovery rate of TDEs has been dominated by wide-field optical/UV surveys. The first TDE candidates discovered from their thermal UV emission were found with the [*GALEX*]{} satellite [@Gezari+06]. The rate of TDE discovery by [*GALEX*]{} was found to be consistent [@Gezari+08] with the empirical predictions of @WangMerritt04. Soon afterwards, TDE candidates began to be discovered through their thermal optical emission – at first archivally [@vanVelzen+11], and soon afterwards in real-time surveys [@Gezari+12]. As the optically-selected TDE sample has grown, several groups have attempted to infer the TDE rates $\dot{N}$ and $\dot{n}$ associated with optically-bright flares. One advantage that rate inferences from optically-selected TDEs have over those from X-ray-selected TDEs is the much higher cadence of optical time-domain surveys. This means that rate estimates will be less sensitive to assumptions about the temporal evolution of TDE light curves.
Initially, rates estimated from optically-selected TDEs were low. For example, the discovery of two TDE candidates in SDSS archival data was used to compute a per-galaxy rate $\dot{N} \approx (1.5-2.0)^{+2.7}_{-1.3}\times 10^{-5}~{\rm yr}^{-1}$, and a volumetric rate $\dot{n} \approx (4-8) \times 10^{-8\pm 0.4}~{\rm yr}^{-1}~{\rm Mpc}^{-3}$ [@vanVelzenFarrar14][^17]. The later discovery of two TDE candidates by the ASAS-SN survey implied a somewhat higher per-galaxy rate of $\dot{N} \approx 4.1_{-1.9}^{+12.9} \times 10^{-5}~{\rm yr}^{-1}$ [@Holoien+16]. More recent calculations that use an [*empirical*]{} TDE luminosity function find higher event rates. For example, @vanVelzen18 analyze a sample of thirteen TDE candidates found in optical/UV surveys and find $\dot{n} = (8 \pm 4) \times 10^{-7}~{\rm Mpc}^{-3}~{\rm yr}^{-1}$, consistent with a per-galaxy rate $\dot{N} \approx 1\times 10^{-4}~{\rm yr}^{-1}$. Comparably high-per galaxy rates are also inferred from two TDE candidates found by iPTF ($\dot{N} \approx 1.7^{+2.9}_{-1.3}\times 10^{-4}~{\rm yr}^{-1}$; @Hung+18).
One particularly intriguing observational finding is an apparent overabundance of TDE candidates in quiescent galaxies with no ongoing star formation and prominent Balmer absorption features. These absorption features are generally produced by a large population of young A stars, indicating that this type of galaxy (in its extreme form, sometimes known as an “E+A” or “K+A” galaxy) recently underwent a major star formation episode, that has since ceased. Although this post-starburst preference was first noted among optically-selected TDEs [@Arcavi+14], it appears to be generic across most classes of candidate TDE flares [@Graur+18]. While the [*absolute*]{} rate density of TDEs in post-starburst galaxies, $\dot{n}_{\rm PS}$, is subject to the same uncertainties discussed above, the relative rate enhancement factor $\mathscr{R} \equiv \dot{n}_{\rm PS} / \dot{n}$, may be computed with much less uncertainty (provided that the TDE luminosity function is nearly the same in normal and post-starburst galaxies).
Interestingly, the rate enhancement seems to depend strongly on the strength of the Balmer absorption features. The first detailed analysis of post-starburst TDE hosts found that, in the most Balmer-strong post-starbursts (classical E+As), $\mathscr{R} = 190_{-100}^{+191}$, while in less extreme Balmer-strong post-starbursts, $\mathscr{R} = 33_{-11}^{+7}$ [@French+16 for a sample of 8 TDE hosts]. The strength of the Balmer absorption feature represents a weighted combination of post-starburst age, fraction of the galaxy starlight produced in the starburst, and the detailed shape of star formation history during and after the starburst [@French+17]. A subsequent analysis [@Graur+18] of a larger TDE host sample found somewhat smaller but still significant rate enhancements ($\mathscr{R} = 35_{-17}^{+21}$ and $\mathscr{R} = 18_{-7}^{+8}$ for the same categories of Balmer-line strength). The @Graur+18 rate enhancements were computed from a larger but more heterogeneous sample of 33 TDE host galaxies, and vary significantly if one examines different sub-samples. TDE host galaxies display some other peculiarities as well, such as an unusually high surface brightness on $\sim \rm kpc$ scales [@LawSmith+17]. The properties of TDE hosts are not yet fully understood, and our empirical knowledge of this subject is evolving rapidly. The interested reader is advised to consult the [Host Galaxies Chapter]{} for a more comprehensive picture.
As TDE samples grow, it will become possible to make more refined comparisons between theory and observation. For example, in Fig. \[fig:modeledRate\], we can see that the predicted, volumetric TDE rate is expected to significantly depend on $M_\bullet$. Observational evidence testing this prediction is mixed, although still limited by small-number statistics. Early work by @StoneMetzger16 used galaxy scaling relations to find that an optical/UV selected TDE sample (consisting of 11) had a mass distribution sharply peaked near $10^{6.8}M_\odot$, with little evidence for optical/UV TDE hosts possessing SMBHs below $10^6 M_\odot$. Subsequent work by @Wevers+19 improved on this by using a larger TDE sample (15 flares) and also using a more homogenous set of SMBH mass estimates. The @Wevers+19 histogram shows a more broadly peaked distribution centered on somewhat lower masses ($\approx 10^{6.2}M_\odot$), but with a qualitatively similar shape. In contrast, both of these analyses find a much broader distribution of host masses for TDEs selected through soft X-ray emission. In comparison to the optical/UV selected sample, the distribution of inferred SMBH masses in X-ray TDEs is less sharply peaked, with a greater fraction of these events occurring in galaxies with very high-mass ($M_\bullet \gtrsim 10^{7.5}M_\odot$) or very low-mass ($M_\bullet \lesssim 10^{5}M_\odot$) SMBHs.
Neither of these analyses, however, accounted for survey selection effects, such as volume-correcting flux-limited samples. To date, the most thorough effort to back out volumetric rates $\dot{n}(M_\bullet)$ from observations comes from @vanVelzen18, who find an effectively constant TDE rate for bins of SMBH mass between $10^6 M_\odot$ and $10^{7.5}M_\odot$. At present, the two biggest obstacles to drawing inferences about the bottom end of the SMBH mass function from observed TDEs are (i) small, inhomogenous TDE samples and (ii) the uncertain luminosity function of TDEs, particularly those from smaller SMBHs where Eddington considerations may be more important.
Rate Discrepancies {#sec:discrepancies}
------------------
As we saw in §\[sec:applied\], there are many uncertainties associated with dynamical modeling of nearby galactic nuclei. However, a few general conclusions stand out:
1. TDE rates $\dot{N}$ are generally higher in smaller galaxies, if we consider only two-body relaxation in spherical potentials[^18]. This is primarily due to the higher central densities and steeper density profiles associated with low-mass galactic nuclei.
2. The differential volumetric TDE rate ${\rm d} \dot{n}/{\rm d}\ln M_\bullet$ varies across host galaxy mass, but the integrated rate $\dot{n}$ is likely dominated by the lowest-mass range galaxies that have a high SMBH occupation fraction.
3. Averaged over the set of galaxies with a high black hole occupation fraction, per-galaxy TDE rates are $\dot{N} \gtrsim 1\times 10^{-4}~{\rm yr}^{-1}$.
4. Main sequence TDE rates should robustly cut off at the main sequence Hills mass, which, depending on the SMBH spin distribution, lies in a range $10^8 \lesssim M_\bullet/M_\odot \lesssim 10^9$.
Conclusion (3) exists in tension with a number of the lower empirical TDE rate estimates discussed in §\[sec:observationalRates\], such as those of @Donley+02, @KhabibullinSazonov14, and @vanVelzenFarrar14. Another interesting, observationally motivated puzzle is the large rate enhancement seen in post-starburst galaxies (§\[sec:observationalRates\]), which was not directly predicted by any pre-existing dynamical studies.
It seems, therefore, that potential tensions exist between the inferred TDE rates and those predicted from (empirically calibrated) dynamical theory. These tensions can be divided into two types: too many TDEs observed in post-starburst galaxies, and too few observed in “normal” galaxies. In the following subsections, we discuss both of these tensions. First, however, we must note one important caveat in the comparison of theory to observation: the necessity of having observed TDE samples that are both flux-complete and pure (i.e. not contaminated by a significant number of TDE impostors, such as nuclear supernovae, AGN variability, or more exotic transients). A large presence of TDE impostors in an observed sample will skew inferred event rates upwards, while a flux-incomplete TDE sample will skew inferred rates downwards. The first of these issues is discussed at length in the [Imposters Chapter]{}, while we cover the latter in some detail below.
### Elevated TDE rates in Post-Starburst Galaxies {#sec:poststarburst}
The post-starburst preference of optical [@Arcavi+14] and X-ray [@Graur+18] TDEs is an interesting observational puzzle that was not predicted by theory. The tension between dynamically predicted rates and the higher rates inferred from observations is a problem that has many possible solutions. The simple (spherically symmetric, quasi-isotropic) models of §\[sec:applied\] neglect many proposed dynamical mechanisms for increasing per-galaxy TDE rates above $\dot{N} \sim 10^{-4}~{\rm yr}^{-1}$, such as binary SMBHs [@Ivanov+05; @Chen+11], radial anisotropies [$b>0$; @Stone+18], nuclear triaxiality , secular instabilities in stellar discs [@Madigan+18], overdense central star clusters [@StoneMetzger16; @StonevanVelzen16], and rate enhancements from massive perturbers [@Perets+07a; @Perets:2008; @Mastrobuono+2014] and/or nuclear spiral arms [@Hamers:2017]. In this subsection, we discuss each of these potential solutions to the discrepancy.
The first proposed explanation for the post-starburst preference invoked the correlation between starbursts and galaxy mergers [@Arcavi+14]. If many post-starburst galaxies are also post-merger galaxies, their nuclei may contain SMBH binaries which can increase TDE rates by many orders of magnitude (relative to galactic nuclei with solitary SMBHs) through a combination of Kozai cycles [@Ivanov+05] and chaotic three-body scatterings . However, even though SMBH binaries may temporarily enhance TDE rates by multiple orders of magnitude, the short timescales for such enhancements (typically $\sim 10^5~{\rm yr}$, e.g. ) may make it challenging for this mechanism to explain the global fraction of all TDEs seen in post-starburst galaxies (see also discussions in @StoneMetzger16 [@Saxton+18]).
Prior to the discovery of the post-starburst preference, @Perets+07a [@Perets:2008] suggested that massive perturbers, such as giant molecular clouds, can greatly shorten the two-body relaxation times (since $T_{\rm rel} \propto \langle M_\star^2 \rangle^{-1}$) and enhance TDE rates as a result. Nuclear spiral arms would have a similar effect [@Hamers:2017]. Such enhanced rates would occur preferentially in gas-rich galaxies and, in particular, in post-merger galaxies, and would last for long timescales. However, because massive perturbers are unlikely to exist at radial scales $r \lesssim r_{\rm crit}$, these processes could possibly enhance TDE rates by a factor of two or less, and are thus unlikely explanations for the extreme, $1-2$ orders of magnitude enhancements inferred for post-starburst galaxies.
Nuclear starbursts sometimes produce eccentric stellar discs in which secular effects can dramatically increase TDE rates [@Madigan+18; @WernkeMadigan18]. However, for such secular processes to operate, the nuclear cluster mass should be relatively small, so as not to give rise to mass precession that quenches coherent secular evolution. This may be problematic for this explanation of the post-starburst preference, as most low-mass SMBHs coexist with a sizeable nuclear star cluster. The more favorable environment of a disc-dominated nuclear stellar population likely exists only for more massive galaxies, which host SMBHs with $M_\bullet \gtrsim 10^8$ M$_\odot$ [@Antonini+15] above the Hills mass $M_{\rm H}$ that are unable to tidally disrupt main sequence stars.
If star formation in starbursts is centrally concentrated[^19], then post-starbursts may have unusually overdense galactic nuclei. Such overdensities would result in short two-body relaxation times and high TDE rates [@StoneMetzger16]. Nevertheless, it is not yet clear whether such extreme density nuclear clusters form in most post-starbursts (most nuclei can not be spatially resolved to assess the stellar density there, although the results of @StonevanVelzen16 lend tentative support to this hypothesis in one nearby, highly overdense E+A).
A final class of dynamical explanations relies on asymmetries in stellar position and/or velocity fields. If nuclear star formation produces highly triaxial potentials or radially anisotropic velocity distributions [@Stone+18], these effects can increase TDE rates by an order of magnitude. However, both of these types of asymmetries tend to “wash out” over time due to the effects of two-body relaxation, which may pose a problem in the low-mass galaxies with short relaxation times that host most TDEs.
With so many theoretical explanations to choose from, it is important to find observational tests that can discriminate between different mechanisms. The total TDE rates from the mechanisms suggested above are sensitive to a wide variety of assumptions regarding the host galaxies and their nuclei. The statistical properties of post-starburst TDE hosts might therefore be a more useful diagnostic. For example, the observed distribution of post-starburst host masses is biased towards smaller galaxies, in agreement with the overdensity and radial orbit hypotheses, but in notable disagreement with the top-heavy distribution of host masses expected for SMBH binary-triggered TDEs [@Stone+18]. Likewise, the delay time distribution of TDEs in post-starbursts is highly discrepant with that of the SMBH binary explanation, generally compatible with the overdensity hypothesis, and compatible with the radial orbit hypothesis provided fairly extreme[^20] ($b \gtrsim 0.5$) anisotropy parameters are chosen [@Stone+18]. Dynamical modeling of [*HST*]{} photometry of the nearby E+A galaxy NGC 3156 lends further support to the overdensity explanation, as this galaxy appears to have both an unusually steep central density profile ($\rho(r) \propto r^{-2.25}$, formally in the “ultrasteep” regime) with an unusually small SMBH influence radius [@StonevanVelzen16].
Finally, many of the suggested scenarios – such as SMBH binaries, eccentric nuclear discs, radial anisotropies and nuclear triaxiality – produce TDEs predominantly in the full loss-cone regime (or at the very least, with a $\beta$ distribution matching that of the full loss-cone regime). TDE flares produced via these channels[^21] should preferentially have a lower fraction of grazing TDEs than will TDEs arising from stellar two-body relaxation processes.
While the true explanation of the post-starburst preference remains an open question, it seems likely that (i) larger statistical samples of TDE hosts and (ii) dynamical modeling of more nearby post-starburst nuclei will allow rapid progress on this question in the near future.
![Theoretical delay time distributions as functions of time $t$ since a burst of nuclear star formation. [*Top panel*]{}: the average rate enhancement $\langle \mathscr{R}_\rho \rangle$ in [*overdense*]{} galactic nuclei, in comparison to TDE rates from a population of “normal” galaxies. The enhancement factor $\langle \mathscr{R}_\rho \rangle$ is computed by integrating across an empirical SMBH mass function (the boundaries of the shaded error regions correspond to assuming that astrophysical SMBH masses cut off either at $10^5 M_\odot$ or $10^6 M_\odot$). Theoretical models assume a range of different post-starburst density profiles $\rho(r) \propto r^{-\gamma}$, and circular data points are taken from a sample of eight TDE candidates with well-characterized host galaxies [@French+16; @French+17]. [*Bottom panel*]{}: same as before, but now considering the average rate enhancement $\langle \mathscr{R}_\beta \rangle$ in [*radially biased*]{} galactic nuclei, with a range of different initial anisotropy parameters $\beta_0$. Taken with permission from @Stone+18.[]{data-label="fig:DTD"}](DTD.pdf){width="120mm"}
### A Possible Dearth of TDEs in “Normal” Galaxies
Very few dynamical mechanisms exist to [*lower*]{} TDE rates below the conservative floor set by two-body relaxation in a spherical and isotropic nucleus. The only mechanism that seems clearly able to do this is the presence of a strong tangential anisotropy in the stellar velocity field, which is capable of producing arbitrarily large reductions in $\dot{N}$ . However, such tangential anisotropies will wash out due to two-body relaxation on a small fraction of the energy relaxation time . The small galaxies that dominate the volumetric TDE rate (and whose relaxation times are less than $t_{\rm H}$), are therefore unlikley to have large tangential anisotropies in their nuclei unless an exotic dynamical mechanism exists to pump $b<0$ in small galactic nuclei. Long-lived SMBH binaries are expected to produce this type of tangential anisotropy , but as small galactic nuclei are the environments most favorable for solving the final parsec problem through collisional mechanisms [@Begelman+80], this does not seem promising.
![Observationally inferred TDE rates from six different (but, in some cases, overlapping) TDE samples: @Donley+02 [brown], @Esquej+08 [pink], @vanVelzenFarrar14 [blue], @Holoien+16 [red], @vanVelzen18 [purple], and @Hung+18 [green]. Rate estimates using TDEs selected by their soft X-ray emission are indicated with “X” symbols, while rate estimates using optically-selected TDEs are shown with circles. The x-axis indicates the maximum redshift $z$ out to which the underlying surveys would detect flares with peak g-band luminosities of $L_{\rm g}=10^{43}~{\rm erg~s}^{-1}$ (for the X-ray samples, the equivalent condition is a 0.2-2.4 keV luminosity $L_{\rm X}=10^{43}~{\rm erg~s}^{-1}$). The dotted black line shows an approximate theoretical lower limit on per-galaxy TDE rates due to 2-body relaxation in isotropic galactic nuclei [@WangMerritt04]. Taken with permission from @Hung+18.[]{data-label="fig:HungComparison"}](HungComparison.pdf){width="120mm"}
The lack of clear mechanisms available to decrease [*dynamically-predicted*]{} TDE rates led @StoneMetzger16 to identify a “rate discrepancy” between (empirically-calibrated) theory and observation[^22]. Subsequent analysis of observed TDEs has identified a plausible resolution to this discrepancy: a very steep TDE luminosity function. In particular, @vanVelzen18 find that, for optically-selected TDE candidates, ${\rm d}\dot{N}/{\rm d}L \propto L^{-2.5}$, with an uncertain lower luminosity limit. This suggests that current, flux-limited TDE samples are seeing only “the tip of the iceberg,” in comparison to the much larger number of very dim TDEs that exist in the local Universe. While it is important to test the shape of the TDE luminosity function further, both with larger near-future TDE samples [*and*]{} with better first-principles modeling of flare emission mechanisms, this seems like a promising resolution of tensions between theoretical and observational rate estimates. The origin of the luminosity function is theoretically uncertain, and depends on the complicated physics of debris circularization ([Formation of the Accretion Flow Chapter]{}) and optical emission ([Emission Mechanisms Chapter]{}). Specific hypotheses could be tested with larger TDE samples; for example, rapid disc formation is probably disfavored for $\beta\approx 1$ TDEs around small SMBHs [@Dai+15], so the smaller SMBHs that dominate volumetric event rates $\dot{n}$ might preferentially be associated with lower peak luminosities. We illustrate the current state of this rate discrepancy in Fig. \[fig:HungComparison\], which shows that the most recent rate inferences from optically-selected TDE samples appear compatible with the conservative side of theoretical rate estimates.
Broader Implications {#sec:implications}
====================
In the final section of this Chapter, we focus on the broader scientific importance of TDE rates. We have already explored one major astrophysical motivation for studying statistical samples of TDEs: SMBH demographic measurements. In §\[sec:GR\], we saw that the statistical distribution of SMBH spins is imprinted into the mass distribution of TDE host galaxies (at least for $10^{7.5} \lesssim M_\bullet / M_\odot \lesssim 10^{8.5}$). Likewise, in §\[sec:empirical\], we saw that the volumetric TDE rate contains information on the uncertain bottom end of the SMBH mass function. Because these motivations have already been described in depth, we will not belabor them in this section, but instead focus on alternative applications and implications of TDE rates. In §\[sec:demographics\], we discuss the potential importance of TDEs for SMBH mass, spin, and luminosity evolution. Next, in §\[sec:Hills\], we draw on the general relativistic analysis of \[sec:GR\] to explore how SMBH spin distributions may be encoded in volumetric disruption rates. In §\[sec:EMRIs\], we explore how TDE rates and inferences may be used to calibrate our understanding of extreme mass ratio inspirals, a related byproduct of loss cone physics in galactic nuclei. Finally, in §\[sec:future\], we offer a few speculations for what the future may hold for tidal disruption science.
Black Hole Demographics and Growth {#sec:demographics}
----------------------------------
As SMBHs feast on debris from tidally disrupted stars, they accrete both mass and angular momentum. Over a Hubble time, $t_{\rm H}\approx 1.4\times 10^{10}~{\rm yr}$, the cumulative effect of many TDEs is to increase the SMBH mass, $M_\bullet$. The net effect on SMBH angular momentum, $\chi_\bullet$, is less obvious, as individual TDEs may either spin it up or spin it down. Because TDEs usually produce transient accretion flares, the stochastic background of TDEs in otherwise quiescent (inactive) galactic nuclei produces a baseline level of accretion luminosity that may contribute in an interesting way to the bottom end of the AGN luminosity function.
The importance of all three of these effects – SMBH mass growth, SMBH spin evolution, and accretion luminosity in quiescent galaxies – depends strongly on TDE rates. These effects will be of little importance in galaxies with very low TDE rates, but can be of crucial importance in galaxies, or classes of galaxies, with higher TDE rates. Indeed, it is possible that some types of galaxies may accumulate most of their SMBH mass and/or spin angular momentum through stellar tidal disruption.
In the simplest picture, where loss cone repopulation is governed by two-body relaxation, TDE rates are decreasing functions of SMBH mass (§\[sec:applied\]), indicating that TDEs will be of the greatest importance for the growth of low-mass SMBHs [@Milosavljevic+06]. We may compute the typical SMBH mass below which TDEs are important for growth[^23] by equating $M_\bullet = \frac{1}{2}\langle M_\star \rangle \dot{N}(M_\bullet) t_{\rm H}$. We solve this equation using the empirically calibrated scaling of Eq. \[eq:empiricalRate\], and find $M_{\rm TDE} \approx 5\times 10^5 M_\odot$ to be the characteristic mass below which SMBH growth should be dominated by TDEs. Larger SMBHs acquire most of their mass from other sources, primarily radiatively efficient gas accretion [@Soltan82].
Because two-body relaxation delivers stars to the SMBH from a quasi-isotropic distribution of directions[^24], the net effect of mass growth through TDEs is to spin the SMBH down, in analogy to “chaotic accretion” of gas clouds by AGN , and small SMBHs that have grown primarily through tidal disruption should be spinning slowly. Interestingly, even if TDEs are a subdominant contributor to SMBH mass growth, they may still play an important role in the evolution of SMBH spin. SMBHs that grow through prolonged AGN episodes, or through short episodes with the same direction of disc angular momentum will, over a handful of mass-doubling times, spin up to very high values of $\chi_\bullet$ [@2008ApJ...684..822B]. If it is only these AGN episodes that supply angular momentum to the SMBH, $\chi_\bullet$ will saturate at a value dictated by accretion physics - for example, growth through standard thin disc accretion saturates at $\chi_\bullet=0.998$ [@Thorne74]. Because this dimensionless spin is so large, even a very small fraction of mass growth from (isotropically distributed) TDEs will place a lower cap on SMBH spin .
Even though TDEs are rare events, they occur in all galaxies with $M_\bullet < M_{\rm H}$, and therefore produce a minimum time-averaged accretion rate onto SMBHs in quiescent galactic nuclei. While the peak luminosity of a TDE (up to $\sim 10^{44-45}~{\rm erg~s}^{-1}$) is typically maintained for a period of weeks to months, there is a long, slow decay period in which the galactic nucleus may resemble a low-luminosity AGN. Recent UV observations indicate that most TDEs continue to radiate at $\sim 10^{42}~{\rm erg~s}^{-1}$ at times $\sim 10~{\rm yr}$ post-peak [@vanVelzen+18]. Based on simple models for TDE light curves, @Milosavljevic+06 estimated that main sequence TDEs could be responsible for a majority of the lowest-luminosity X-ray AGN (although it is important to note that the “AGN” produced by late stages of TDEs would probably lack standard narrow-line regions). More recent work suggests that episodic partial disruptions of giant-branch stars may be the most important type of tidal disruption for setting a floor on accretion rates in galactic nuclei [@MacLeod+13]. The actual luminosity floor set by the late stages of tidal disruption flares remains somewhat ambiguous, as it depends on (i) the still uncertain volumetric TDE rate, (ii) the presence or absence [@vanVelzen+18] of thermal instability in late-time TDE discs, and (iii) the ability of TDE debris from red giant disruptions to efficiently accrete onto the SMBH [@Bonnerot+16].
The Shadow of the Horizon {#sec:Hills}
-------------------------
As we have seen in §\[sec:GR\], the Hills mass depends sensitively on SMBH spin, and can vary by almost an order of magnitude (for prograde equatorial orbits) as one varies $\chi_\bullet$ from $0$ to $1$. While this has exciting astrophysical applications for measuring the distribution of SMBH spins in a mass range $10^{7.5} \lesssim M_\bullet/M_\odot \lesssim 10^{8.5}$, the hard upper limit on $M_{\rm H}$ (for lower main sequence stars) imposed by the Kerr bound ($\chi_\bullet \le 1$) raises the prospect of using TDE distributions as probes of general relativity. For example, @Lu+17 demonstrate that samples of TDEs may rule out exotic alternatives to Kerr black holes, such as boson stars, which possess hard surfaces and would therefore be capable of producing limited electromagnetic emission from stellar impacts onto central massive objects with super-Hills masses. More generally, we may say that the hypothetical discovery of TDE flares from galaxies with SMBH masses $M_\bullet \gtrsim 10^9 M_\odot$ by future time-domain surveys would strongly motivate consideration of exotic SMBH alternatives.
It is interesting to note that even in a limited sample of twelve optically-selected TDE candidates, there is already statistical evidence for a super-exponential cutoff in the TDE rate near $M_\bullet \sim 10^8 M_\odot$ [@vanVelzen18] as discussed in Sec. \[sec:GR\]. This tentative evidence for the Hills mass may provide support for the the identification of observed TDE candidates as bona-fide stellar tidal disruption events; it likewise demonstrates how much larger near-future TDE samples may statistically test the existence of event horizons.
EMRI Rates {#sec:EMRIs}
----------
If a star approaching the SMBH is compact enough, the differential gravitational pull exerted on points which are diametrically separated will not lead to dangerously large tidal stresses. A compact object such as a neutron star, a white dwarf, or a stellar-mass black hole can therefore safely pass through pericentres with $R_{\rm p} \gtrsim R_{\rm mb}$[^25] many times until it plunges through the SMBH event horizon due to energy loss via gravitational radiation. This chain of events is referred to as an “extreme mass-ratio inspiral” (EMRI, see the review of @2018LRR....21....4A and references therein). The number of passages is roughly proportional to the mass ratio, so that for a $10\,M_{\odot}$ stellar-mass black hole and a SMBH of mass $10^6\,M_{\odot}$, the EMRI will complete some $\sim 10^5$ orbits before plunging.
This source of gravitational waves represents a unique probe of gravity in the strong-field regime. Generic EMRI orbits are both eccentric and inclined, and apsidal and nodal precession imply that the compact object explores the full torus between the radial and polar turning points as it inspirals towards the black hole. At every pericentre passage there is a strong burst of radiation, and with a typical total of $\sim 10^5$ such bursts, an EMRI can be used to map spacetime around SMBHs. With EMRIs one can probe the geometry of SMBHs in a regime of non-linear, strong-field and dynamical gravity. This means that one can test GR and alternative theories of gravity, but also test different questions related to stellar dynamics in galactic nuclei. The gravitational-wave radiation from these systems allows one to extract qualitative information from a regime which is inaccessible to the photon, the surface of the central supermassive dark object, and to investigate if spacetime around it differs from Kerr. In particular, in GR the Kerr solution is the unique end state of gravitational collapse. The Kerr metric depends on the mass and spin of the object only, and all higher multiple moments are related to the gravitational radiation emitted by the compact object on its orbits towards the SMBH. This can be used to test the no-hair theorem, as first put forward by [@1995PhRvD..52.5707R]. Moreover, they can be used as standard sirens to measure the luminosity of the source and to test the cosmological expansion history of the Universe [@1986Natur.323..310S]. See [@2007CQGra..24R.113A; @2015JPhCS.610a2002A] for a general description of the implications of EMRIs on cosmology and fundamental physics.
EMRIs are formed via two-body relaxation in dense stellar systems, and the theory that allows us to derive their event rate is heavily based on the concept of a loss cone. This is so because of the many similarities of the two problems. However, as we mentioned before, the compact object needs to revolve for tens or hundreds of thousands of orbits around the SMBH before disappearing into the horizon, not just one orbit, as is the case for TDEs. When an orbit’s pericentre approaches $R_{\rm p}\sim {\rm few}\times R_{\rm g}$, even if its semimajor axis is $a\gg R_{\rm g}$, it starts to rapidly lose energy and progress towards smaller $a$ while remaining at a nearly constant $R_{\rm p}$, until it is finally captured at $a\sim {\rm few}\times R_{\rm g}$ (see e.g. Fig. 43 of @2018LRR....21....4A). However, for this process to be successful, the inspiralling object should not be disturbed by the two-body relaxation. This places an upper limit on the initial values of $a$ for EMRIs at around $10^{-2}$ pc, meaning that EMRIs constitute a small fraction of all compact object capture events ($\lesssim 1\%$, see Fig. 17 in ). The accumulation of a long number of orbits means that relativistic effects at pericentre must be taken into account.
Analogous but even stricter considerations limit the parameter space for “stellar EMRIs,” which are main-sequence stars inspiraling on quasi-circular orbits. These systems are potentially interesting because of their long lives: stable Roche lobe overflow can last for millions of years, and power a weak accretion disk , though the arrival of a second stellar EMRI during the lifetime of the first may lead to a TDE impostor due to mass loss in a hypersonic stellar collision . However, such systems require fairly fine-tuned initial conditions in order to circularize through gravitational wave emission (as opposed to tidal circularization, which would destroy the star), and the most promising formation scenario may use the bound star left over after the Hills mechanism breaks up a pre-existing binary [@AmaroSeoane+12].
Unless the SMBH is Schwarzschild, the spin plays a fundamental role in the fate of a compact object EMRI [@2013MNRAS.429.3155A], controlling the required number of pericentre passages before crossing the event horizon. Resonant relaxation can also allow EMRIs to form closer to the SMBH, where the stellar density decreases, and two-body relaxation is not efficient enough [@2006ApJ...645.1152H]. While the dynamics of resonant relaxation are much more complicated than that of two-body relaxation, recent studies indicate that its ultimate contribution to steady-state EMRI rates is modest .
Even though a consensus about the cusp at the Galactic Centre has recently emerged in which theory, numerical calculations and observations agree on the existence of the sub-pc stellar cusp, , the dynamics of distant galactic nuclei on sub-pc scales are less clear, making it challenging to predict generic EMRI rates. The first major astrophysical uncertainty concerns the massive black hole occupation fraction. If many intermediate-mass black holes exist in the nuclei of dwarf galaxies, their contribution to the volumetric EMRI rate could dominate over larger SMBHs [@Babak+17]. A second major uncertainty comes from the unknown distribution of stellar profiles; if cored galactic nuclei are more common than is expected, volumetric EMRI rates will be low. Finally, as noted before, the magnitude of SMBH spin is crucial in the derivation of EMRI rates [@2013MNRAS.429.3155A], as rapidly spinning Kerr SMBHs will convert many “direct plunges” into observable EMRIs. Upcoming observations of TDEs in nuclei which harbour SMBHs in the mass range of $10^5-10^7\,M_{\odot}$ may help to at least partially clear up these uncertainties; using large samples of TDEs to constrain the low-mass black hole occupation fraction will be particularly valuable.
Future Prospects {#sec:future}
----------------
Over the next five years, our sample of TDEs will expand by multiple orders of magnitude. At the time of writing, a few dozen strong TDE candidates have been discovered, primarily through thermal emission in either the soft X-ray (e.g. the compilations of @Komossa15 and @Auchettl+17, and the [X-ray Chapter]{}) or optical/UV (e.g. the compilation of @Hung+17 and the [Optical Chapter]{}) bands[^26]. For most of the last decade, the time-averaged TDE detection rate has been a handful of strong candidate flares per year. This situation is already starting to change in 2019, as the wide-field optical survey ZTF [@Bellm+19] has begun harvesting TDE candidates, with an expected detection rate of $32^{+41}_{-25}$ TDEs per year [@Hung+18].
While the ongoing ZTF survey is expected to increase today’s TDE sample by one order of magnitude, near-future optical and X-ray time domain surveys may increase our TDE inventory even further, into the thousands and possibly tens of thousands. Two upcoming space-based X-ray surveys, [*eROSITA*]{} [@Merloni+12 launched during the writing of this Chapter] and [*Einstein Probe*]{} [@Yuan+15 launch date note yet determined], hold particular promise. The [*Einstein Probe*]{} is expected to detect tens to hundreds of X-ray bright TDEs per year [@Yuan+15], while [*eROSITA*]{} predictions give a per-year detection rate $\approx 1000$ [@Khabibullin+14]. On the ground, the wide-field LSST optical survey [@Abell+09] has long been recognized for its ability to detect thousands of TDEs per year [@StrubbeQuataert09; @vanVelzen+11]; the true detection rate depends on survey strategy, but one recent estimate predicted $\approx 3-6 \times 10^3$ TDEs per year.
It is important to consider the many science goals that can be accomplished with such large, near-future samples of TDEs. Advance planning is important both (i) to develop relevant theoretical predictions that can be tested and falsified by statistical samples of TDEs, and (ii) to aid future observers in prioritizing scarce spectroscopic or multiwavelength followup resources, which will certainly be inadequate to fully characterize [*every*]{} TDE candidate found by the surveys described above. In the list below, we offer a brief (and, unavoidably, subjective) selection of important questions in physics and astrophysics that may be partially addressed by large samples of TDEs. In assembling this list, we have purposefully avoided questions focused entirely on the process and consequences of stellar tidal disruption. While this arena features many interesting open questions, they are discussed in much greater detail in the other Chapters of this Volume, and here our aim is to examine the utility of TDEs [*as a tool*]{} for answering broader questions.
- What is the distribution of SMBH masses in the Universe?
- How did SMBH seeds form at high redshift?
- What is the distribution of SMBH spins in the Universe?
- Are the “SMBHs” observed in galactic nuclei true Kerr metric black holes, or more exotic, horizonless compact objects?
- What is the rate of other processes involving loss cone physics in galactic nuclei (e.g. hypervelocity star and EMRI production)?
- What fraction of galactic nuclei host unresolved binary SMBHs?
- What exotic dynamical processes are common to post-starburst galactic nuclei?
- Are there other subclasses of galaxies with anomalous nuclear stellar dynamics?
In this Chapter, we have discussed how each of these questions may be probed – at least to some extent – with a statistical sample of TDEs. But in almost all cases, directly answering these questions with TDEs will require a firmer grasp on rates of tidal disruption, and how they depend on astrophysical variables like SMBH mass, host galaxy mass, redshift, and so on. Over the next few years, we expect progress on TDE rates to arise from three parallel channels. Better theoretical models for non-standard loss cone repopulation mechanisms (e.g. nuclear triaxiality, eccentric stellar discs) will help solidify our understanding of underlying dynamical theory. Better dynamical modeling of nearby galactic nuclei will improve our understanding of TDE rates in astrophysically realistic galaxies. And better samples of observed TDE flares – samples that are both larger and more homogeneously selected – will provide firmer observational estimates of the real volumetric TDE rate in the Universe.
N.C.S. received financial support from the NASA Astrophysics Theory Research Program (Grant NNX17AK43G; PI B. Metzger). M. K. acknowledges support from NSF Grant No. PHY-1607031 and NASA Award No. 80NSSC18K0639. E.M.R. acknowledges support from NWO TOP grant Module 2, project number 614.001.401. P.A.S. acknowledges support from the Ram[ó]{}n y Cajal Programme of the Ministry of Economy, Industry and Competitiveness of Spain, the COST Action GWverse CA16104, and the National Key R&D Program of China (2016YFA0400702) and the National Science Foundation of China (11721303).
[^1]: As we see later in §\[sec:aspherical\], factor (iii) is generally unimportant for determining TDE rates.
[^2]: In reality, the exact criterion for tidal disruption of a main sequence star is that $R_{\rm p} < R_{\rm t}/\beta_{\rm crit}$, where $\beta_{\rm crit}\approx 0.95-1.85$ is a dimensionless constant dependent on the central concentration of the star, and can be measured precisely with numerical hydrodynamics simulations (; see also the [Disruption Chapter]{}).
[^3]: If a broad spectrum of stellar masses exist, it is generally the heaviest species that relaxes to the $n(r) \propto r^{-7/4}$ profile, while lighter species will achieve shallower, $n(r) \propto r^{-3/2}$ distributions . However, strong mass-segregation can give rise to steeper distributions, as in .
[^4]: For a less rigorous – but in some respects more intuitive – approach operating entirely in coordinate space, see the work of @SyerUlmer98, which obtains qualitatively similar results to those presented here.
[^5]: With this definition, the flux is positive if the stars diffuse towards the loss cone, as they usually do. Note that the sign convention is the opposite in some studies.
[^6]: In general, closed-form expressions for the variables in this section do not exist. However, for the special case of a singular isothermal sphere density profile, with $n(r) \propto r^{-2}$, @WangMerritt04 provide analytic expressions for $q(E)$, $\mathcal{F}(E)$, and $\dot{N}$.
[^7]: An interesting caveat to this discussion concerns extremely steep stellar cusps, i.e. those with density profiles falling off faster than $n(r) \propto r^{-9/4}$. Such density profiles are not self-consistent, because they predict that, as $E\to -\infty$, $\mathcal{F}_{\rm empty}\to \infty$ [@SyerUlmer98]. Density profiles of this steepness are rarely seen in nature, with the possible exception of post-starburst galaxies, which we discuss later §\[sec:poststarburst\].
[^8]: But see also for counterexample simulations, where star cluster infall leads to a tangential bias. Ultimately, the final $b(E)$ profile is likely sensitive to the orbital properties of infalling star clusters.
[^9]: The drain region is often called the “loss wedge” in the axisymmetric case – e.g. .
[^10]: The right-hand side of Eq. \[E:LtGR\] should be multiplied by $\beta_{\rm crit}^3$ to account for stellar structure.
[^11]: This calculation assumes the full loss-cone limit, in computing the relativistic correction factor, although the per-galaxy TDE rates shown in Fig. 3 are based on loss-cone calculations using contributions from both the full and empty regions.
[^12]: Although we note that a power-law tail of high-$\beta$ TDEs will occur, even when $q \ll 1$, due to the effects of strong scattering .
[^13]: We note that since the counterparts of HVSs can be captured around the MBH, the distribution of such stars could also reflect the processes leading to, and the rates of, TDEs .
[^14]: The assumptions of spherical symmetry and quasi-isotropy are relaxed in , but for brevity we focus primarily on the simplest case.
[^15]: If the stellar density profile $n(r)$ is too shallow, the DF $f(E)$ obtained from Eq. \[eq:Eddington\] will have negative values, which is an unphysical outcome. In the limit of a Kepler potential, the shallowest self-consistently isotropic power-law density profile is $n(r) \propto r^{-1/2}$; shallower density profiles require some degree of tangential anisotropy to remain positive-definite in $f(E,\mathcal R)$.
[^16]: This assumption is unlikely to be generically true. The clearest caveat here concerns the strong preference among observed TDE flares to reside in rare E+A and, more generally, post-starburst galaxies (see discussion in §\[sec:poststarburst\]). Because E+A and post-starburst galaxies make up very small fractions of the low-$z$ galaxy population ($\sim 0.2\%$ and $2.3\%$, respectively [@French+16], this implies the presence of unusual stellar dynamics enhancing TDE rates in these galaxies by at least an order of magnitude. However, the fraction of all galaxies that have a post-starburst nature increases steeply as a function of redshift. For example, going from $z\approx 0.5$ to $z\approx 2$ increases the fraction of post-starburst galaxies by a factor of $\approx 5$ [@Wild+16], suggesting that at high $z$, the decline in $\dot{n}$ due to the decreasing volume density of SMBHs may be overwhelmed by the growing abundance of this rare galaxy type.
[^17]: Note that in the results of @vanVelzenFarrar14, statistical uncertainties are denoted in superscript/subscript error ranges, while systematic uncertainties (associated with the uncertain choice of model light curve used to back out true rates from flux-limited samples) are denoted in prefactor error ranges.
[^18]: The situation becomes more complicated if galactic nuclei are significantly triaxial, in which case larger galaxies may have larger individual TDE rates $\dot{N}$. From an observational point of view, the prevalence of nuclear triaxiality remains uncertain.
[^19]: This seems to be indicated by resolved color gradients in nearby E+A galaxies, see e.g. @Pracy+12.
[^20]: Such large anisotropies may be vulnerable to the radial orbit instability .
[^21]: A notable exception to this trend is the overdensity scenario; ultrasteep density cusps will produce almost all their TDEs in the empty loss cone regime.
[^22]: Although it is worth noting that some observational rate inferences, such as @Esquej+08, would not be in tension with conservative theoretical rate estimates.
[^23]: In this calculation, we have assumed that half of the disrupted star accretes onto the SMBH. For nearly-parabolic stellar orbits, precisely half of the disrupted star is dynamically bound to the SMBH, although we caution that hydrodynamic shocks and radiation pressure in super-Eddington accretion may unbind a portion of this dynamically bound half (see the [Formation of the Accretion Flow Chapter]{} and the [Accretion Disc Chapter]{} for more discussion of these uncertainties).
[^24]: In principle, if TDE rates are dominated by mechanisms (such as nuclear triaxiality, or eccentric stellar discs) that preferentially supply stars from a specific orbital orientation, TDEs may act to spin up SMBHs.
[^25]: The marginally bound radius $R_{\rm mb}$ is the minimum pericentre that avoids capture by the event horizon and is of order $R_{\rm g}$ [@1972ApJ...178..347B].
[^26]: The online “Open TDE Catalog” https://tde.space/ is a useful resource for the observationally-curious reader.
| 2023-10-28T01:27:15.642919 | https://example.com/article/4745 |
Helga Aradóttir
Helga Aradóttir (1538–1614) was an Icelandic woman famous for her stormy love story, divorce and following feud with the poet Staðarhóls-Páll, who dedicated many of his poems to her. She was the daughter of Ari Jónsson, a lawyer, and his wife Halldora Þorleifsdóttir.
References
Illa konu eiga hlaut. Fálkinn, 4. tbl. 1963.“,
„Staðarhóls-Páll. Sunnudagsblað Tímans, 19. apríl 1964.“,
„Staðarhóls-Páll. Þjóðviljinn, 24. desember 1954.“,
Category:16th-century Icelandic people
Category:17th-century Icelandic people
Category:1538 births
Category:1614 deaths
Category:16th-century Icelandic women
Category:17th-century Icelandic women | 2024-05-19T01:27:15.642919 | https://example.com/article/1061 |
Efficiently determining if the identifier of a message received at a network node could be equivalent to one of a set of predetermined identifiers is useful in numerous networking applications. One such application is verifying that the sender of a message received at a peer on the network is authorized to receive a service requested in the message. For example, a first peer that is a proxy server receives a message from a user over a first network. The message requests service from a second peer, a resource that provides the requested service, on a second network. The first peer (the proxy server) sends the message to the second peer (the resource), and the resource provides the requested service to the user. This simple scenario is most likely to occur when the service provided by the resource is freely available to all users.
However, when the service is not freely available, the user request must be checked to determine if the resource is authorized to provide service in response to the request. For example, a service is sold by subscription. When a request is received, it must be determined if the request correspond to a valid subscription. If it does, then the resource provides the service. If it does not so correspond, then the resource denies the service.
One known method for checking if a resource is authorized to provide service based upon a request is to receive all requests for service at the resource, and determine the authorization of each request before responding. This can disadvantageously overburden the resource, particularly when a large number of requests are received and have to be checked. Another known method is to check the requests at an intermediate point between the requesting user (the requester) and the resource, such as the proxy server. A request is only forwarded to a resource if the proxy server determines that the request is authorized, thereby mitigating the burden on the resource by appropriately routing each message based upon its authorization. This, however, introduces the problems of distributing and maintaining the accuracy of authorization data (such as subscriber lists) to several proxy servers, which can disadvantageously generate a substantial amount of network traffic. Further, having to check every request for authorization against a list can be time consuming and burdensome. These problems are especially severe for services with large, dynamic (rapidly changing) subscriber bases. These problems are further exacerbated if a proxy server is configured to receive requests for many different services, each with its own subscriber list. When there are several proxy servers in a large network that are so configured, maintaining the accuracy of authorization criteria (such as subscriber lists) for all services across all proxy servers can be impractical.
In certain known systems, a user sends a request to a peer, which forwards the request to a proxy server, which in turn forwards the request to a resource. Such a system is shown in FIG. 1. Users U1 101, U2 102 and U3 103 send messages through network alpha 104 to peer A 105 requesting service from a resource B 106 on network beta 107. Only U2 102 and U3 103 are subscribers to resource B 106. Proxy server C 108 is connected to both network alpha 104 and network beta 107, and processes requests for service directed to resource B from users on network alpha 104. One known method provides authorization criteria (e.g., subscriber lists) to Peer A 105, which carries out the authorization routing function rather than the proxy server C 108.
Peer A first registers (or logs on) to resource B 106 through peer C 108. Resource B provides peer A 105 with a sorted list of subscriber entries that comprise network addresses of subscribing users U2 and U3. A request for service from resource B is sent from a user to peer A. The request includes a user identifier, such as the user's network address. The user's address is checked against the list of subscriber addresses at Peer A. If the user's network address matches a subscriber address, the user's request is forwarded to proxy server C 108 as an authorized request for service. Proxy server C 108 then forwards the request to resource B 106. If no match is found, the message is not forwarded to proxy server B, and a return message sent to the user indicating a denial of service. Devolving the authorization routing function to the peer advantageously reduces the burden on the proxy server, and can be more efficient when the peer serves a homogeneous and relatively small community of user subscribers. In other words, this method can be efficient when the number of users from which the peer receives requests for service is relatively small, and the number of different services the peer must authorize is also small. However, this known method does not scale well as the number of peers and users increases. The sizes of subscriber table in peer A 105 grows with the number of subscribers to resource B 106. Maintaining the accuracy of such subscriber tables for a large number of peers can be impractical, especially when the subscriber base is dynamic. A substantial amount of message traffic is disadvantageously generated between proxy server B and peer A as the subscriber table in Peer A is sent and/or updated frequently to reflect changes in the authorizations of various users. Larger subscriber tables are also more computationally expensive to search, burdening the peer and taking up resources needed for other tasks.
Another known system uses specialized authorization servers known as "membership servers" to carry out the authorization function, as shown in FIG. 2. Membership server 201 stores subscriber lists 208 and is connected to network alpha 202. When peer A 203 receives a request from a user 204 for service from resource B 205 connected to network beta 206, peer A 203 queries the membership server 201. Membership sever 201 consults the appropriate subscriber list 208 stored in computer readable memory to determine if the requesting user 204 is authorized to access resource B 205 for the requested service. Membership server 201 sends a message to peer A 203 indicating whether the requesting user 204 is authorized. Peer A 203 then caches the user's identifier and authorization for future reference. If the user is authorized, peer A 203 forwards the user request to resource B 205 through proxy server C 207. This method can be more efficient than maintaining current subscriber lists on each peer that receives requests from users. However, this known system also disadvantageously fails to scale well in large networks. A substantial amount of network traffic is disadvantageously generated between peer and membership server in determining authorization, and in maintaining the accuracy of subscriber lists when more than one membership server is needed.
Another disadvantage of known systems is that extensive memory resources are required to maintain subscriber lists, especially in large systems with many users. In certain known systems, users are identified by their user identifiers. For example, an Internet Protocol (IP) network address is represented by a string of 32 bits. A bit string of this length may be necessary for a network to distinguish users, but is unnecessarily long for the purpose of determining if a user is authorized to access a resource. On the other hand, a resource needs only enough information to distinguish the predefined, limited number of authorized users from the rest of all users. Relying upon an unnecessarily long bit string (such as a IP network address) to distinguish authorized users is expensive both in memory usage and in the processing time needed to search lists of such bit strings. This problem is particularly severe when a relatively large number of users subscribe to a given resource. A better system would be able to distinguish authorized users from unauthorized users while using substantially fewer bits per user that are easier to search than long lists of long bit strings.
A known partial solution to this is to represent a user identifier with an integer by using a hash function. A hash function maps a string (such as a network address) to an integer. Although hash functions realize some savings in memory resources and processor search time, they still impose a substantial overhead for large systems with many users.
Thus, known systems that distinguish authorized users from unauthorized users disadvantageously require substantial memory resources and processor time to establish, maintain and search subscriber lists. Further, they can generate substantial amounts of network traffic to distribute and maintain the coherence and/or accuracy of authorization databases.
A better system would distinguish authorized users from unauthorized users while requiring less memory and processor search time. Further, such a system when implemented for a large network would not concentrate the authorization function at the resource. At least part of the authorization function would be distributed over the network. In spite of being distributed, the accuracy of authorization criteria such as subscriber lists would be easy to maintain because such lists would be represented in a compact form, rather than as searchable lists of authorized users. A better system would also be tolerant of authorization errors. By relaxing the requirement of making a completely accurate authorization decision at a single point, less accuracy could be tolerated in the distributed authorization criteria, thereby advantageously decreasing the network traffic needed to keep it sufficiently accurate. The better system would scale well as the network size increased, and provide a more efficient way to handle requests for service based upon their authorization. | 2024-05-16T01:27:15.642919 | https://example.com/article/8486 |
5-Aza-2'-deoxycytidine: cell differentiation and DNA methylation.
5-Azacytidine (5-aza-CR) and 5-aza-2'-deoxycytidine (5-aza-CdR), analogs of cytidine modified in position 5, were originally developed as antitumor agents, and have been useful in the treatment of both childhood and adult leukemias. These agents are cytotoxic per se, but also induce differentiation in several experimental systems, most notably the induction of muscle, adipocytes, and chondrocytes in cultures of drug-treated mouse embryo fibroblasts. The mechanisms underlying this drug-induced differentiation have been difficult to unravel, a fact which limits the rational design of differentiation therapy as a modulator of cancer using these agents. Induction of new developmental pathways in cultured cells involves stable, heritable changes, presumably of an epigenetic nature. Our early studies demonstrated that changes in methylation of cytosine in DNA occurred concurrently with changes in developmental potential, and that the presence of 5-azacytosine in DNA interfered with the action of DNA methyltransferase. Since DNA methylation is believed to be involved at some level in the regulation of gene expression, the hypothesis was developed that changes in methylation allowed the expression of new genes whose activity initiated new pathways of differentiation. The characterization of this drug-induced system of differentiation has therefore opened the way to identifying genes directly involved in the initiation or modification of pathways of differentiation. The first of these was MyoD, a member of a family of myogenic determination genes. Expression of MyoD in myogenic cell lines has been correlated with loss of methylation at specific sites in the genome, but the critical events leading to expression of MyoD and muscle differentiation are poorly understood. Recent developments in understanding this mechanism are discussed. | 2023-11-21T01:27:15.642919 | https://example.com/article/7088 |
In the aftermath of Russia’s annexation of the Crimea region of Ukraine in 2014, Democrats and Republicans in Congress overwhelmingly rallied around measures to condemn the Kremlin’s actions and provide military and economic aid to Ukraine’s government.
In that era of divided government, pushing back on Russia was a rare area of bipartisan consensus. But a small group of lawmakers—usually a dozen or fewer—routinely opposed those bills. One of them was Beto O’Rourke, then a first-term Democratic congressman from Texas.
Since jumping into presidential politics, O’Rourke has been forced to answer for his past positions on a range of subjects, from his early advocacy of “means testing” government benefits to his endorsement of single-payer health care during his 2018 Senate run.
Little, however, has been made of the former congressman’s record on Russia policy.
Following Russia’s February 2014 incursion in Crimea, O’Rourke was one of just two Democrats to vote down several Ukraine-related measures, including a broad aid package—which included $1 billion in loan guarantees to Ukraine and support for the country’s defenses—that passed overwhelmingly. O’Rourke was also one of 12 lawmakers to vote against promoting U.S. media like Radio Free Europe and Voice of America in the region.
In December 2014, O’Rourke was one of 10 House members to vote against a symbolic resolution that called out Russian President Vladimir Putin for “carry[ing] out a policy of aggression against neighboring countries aimed at political and economic domination.”
The lone Democrat usually joining O’Rourke in voting against these measures, then-Rep. Alan Grayson of Florida, praised Russia’s internationally condemned annexation as a “a virtually bloodless transfer of power." They were often joined, too, by then-Rep. Dana Rohrabacher (R-CA), who was so close to the Kremlin that his ties warranted investigation by the FBI and the Senate Intelligence Committee.
O’Rourke, the Washington Post reported at the time, was unavailable for comment on his vote against the Ukraine aid package. His campaign did not respond to request for comment on the votes from The Daily Beast.
Recently, O’Rourke has gone further than some of his rivals on the issue of Russian election-meddling. He has claimed it is clear “beyond a shadow of a doubt” that President Trump attempted to collude with Russia during the 2016 election. In 2017, he joined several other Democratic lawmakers in pressuring Trump to affirm U.S. commitment to NATO’s foundational principle of mutual defense, as the president questioned the transatlantic defense pact.
Still, according to Rachel Ellehuus, deputy director of the Europe program at the Center for Strategic and International Studies think tank, some of O’Rourke’s votes were just plain weird for the time.
“It was a little unusual for a Democrat to be skeptical even of something that is clearly just defensive security assistance,” she said. “Part of it could come from limited foreign policy experience, part of it could come from a junior congressman wanting to keep the door open for future relations with Russia.”
Ellehuus mentioned a candidate O’Rourke may be trying to emulate now, by way of understanding his early congressional votes. “You saw this with Obama, this idea we could confront the Russians when we had to but cooperate with them on certain areas,” she said.
From his perch in the House Armed Services Committee, O’Rourke also repeatedly asked Pentagon officials if they were thinking about how U.S. assistance to Ukraine—and U.S. arming of rebels fighting the regime of Syrian dictator Bashar al-Assad, a Putin ally—might lead to unintended consequences.
“How,” O’Rourke asked Army Lt. Gen William Mayville in February 2015, “are you approaching those second and third order consequences in arming moderate opposition forces in Syria potentially sending weapons and aid to Ukraine?”
Mayville, a top Pentagon official, defended arming of Syrian rebels and the military support of countries in Eastern Europe, like Ukraine.
“ I'm out of time,” O’Rourke responded, “but what I'm really interested in knowing for the future is what potential threats are we generating by interventions in these two areas, Syria and Ukraine.”
These questions could easily be interpreted as a skeptical legislator simply doing due diligence about a significant foreign policy issue. But they were considered notable enough to draw the attention of Sputnik News, the Kremlin-linked news organization, which interviewed O’Rourke afterward. “What are the potential unintended consequences of arming Ukraine? I don’t know the answer,” O’Rourke said to Sputnik.
O’Rourke noted some interventions “make a lot of sense at the time,” bringing up the Islamist militants that the U.S. backed to fight the Soviet Union. “We didn’t look at… The second or third order consequences,” he said.
Within the Democratic primary field, O’Rourke is hardly the only candidate to have challenged consensus U.S. foreign policy. Rep. Tulsi Gabbard (D-HI), who is running as a peacenik non-interventionist, has defended Syria’s Assad and vocally opposed U.S. involvement in the civil war there. She has emerged as the Kremlin’s favored candidate and has received warm write-ups in associated media outlets like Sputnik and RT.
O’Rourke, meanwhile, has taken some potshots from Russian media. “ A few days into his campaign,” RT wrote in one recent article, “O'Rourke seems to be making headlines mainly for apologizing for past lapses.” | 2024-04-03T01:27:15.642919 | https://example.com/article/4988 |
Features (1)High Quality (1)I'd Buy It Again (1)Durable (1)Reliable (1)
Cons
None to display.
75% of respondents would recommend this product to a friend
4 Reviews
Sort by
Bruce R.West Grove, PA
28 Helpful Votes
REVIEWED
JUL.
15
2014
Great Chainsaw
I have used chainsaws a lot over the years having grown up in Oregon, and I have cut my own firewood for many years too. This is one of the best saws I have ever used. It starts up on the first or second pull each time. It is light and cuts very fast. It is a little loud, but all saws are a little that way. I would recommend this saw to just about anyone.
Pros:Easy To Use, Light Weight, Fast, Reliable
Bruce Recommends This Husqvarna Product
Was this review helpful?
280
Gregory H.Churubusco, IN
Purchased 5/17/14
30 Helpful Votes
REVIEWED
JUL.
01
2014
Amateur Saw Owner
Didn't have much experience with chainsaws so asked around, read reviews and checked websites. Chainsaw Direct had good selection of saws to pick from and good info on features. I think they helped me pick a great saw. Saw arrived on time as promised. Have used the saw a few days now and saw starts good when I followed the directions and cuts great even though I have dulled the chain from use (my fault).
With the chain resharpened it cuts like butter. Good saw good price thank you Chainsaws Direct.
Didn't have much experience with chainsaws so asked around, read reviews and checked websites. Chainsaw Direct had good selection of saws to pick from and good info on features. I think they helped me pick a great saw. Saw arrived on time as promised. Have used the saw a few days now and saw starts good when I followed the directions and cuts great even though I have dulled the chain from use (my fault).
With the chain resharpened it cuts like butter. Good saw good price thank you Chainsaws... more
Pros:Durable, Features, High Quality, I'd Buy It Again
Gregory Recommends This Husqvarna Product
Was this review helpful?
304
Florence D.Readfield, ME
Purchased 8/9/15
REVIEWED
SEP.
07
2015
No Support For What Csd Sells
Unpacked and assembled saw per instructions. Fueled and oiled and would not run. Totally dead on arrival. Contacted seller and told could not return it because it had gas and oil in it and that I had to take it to manufacturer's shop for warranty repairs to get it to work. That fixed problem (whatever it was) and cost additional $$. It is very much a buyer beware with this seller. You may pay a little more at Amazon but you don't have this kind of hassle.
Florence Does Not Recommend This Product
Product Expert
Florence,
The manufacturers support their products with their own warranties. This saw is covered by Husqvarna with a 2 year warranty. Any defect in material or workmanship would be covered by Husqvarna. If you feel you were charged for something which should have been covered by the warranty, please let us know and we would be happy to review this further. | 2023-12-10T01:27:15.642919 | https://example.com/article/2168 |
My Dancing Mermaid is now out and on the cover of the latest issue of Just Cross Stitch magazine. Here’s what they have to say about it:
This “glittering and glamorous mermaid emerges from the mist in Joan Elliott’s superb cross-stitch creation. Hand-dyed Caribbean blue Joblean fabric, almost three dozen floss colors, metallic braid and three colors of beads are the ingredients for making this deliciously dazzling wall decoration.” | 2024-02-21T01:27:15.642919 | https://example.com/article/4445 |
Tuesday, September 17, 1996
Administrators check MEChA riot complaint
By Glenn Hurowitz
Contributing Reporter
Administrators are investigating a police complaint filed early Monday morning by MEChA
after students in Lanman-Wright Hall sprayed water on their Mexican Independence Day
gathering from a fourth-floor window.
Leaders of the Mexican-American campus group
Movimiento Estudiantil Chicano de Atzlan have notified the Saybrook College Master's
Office in the wake of the incident, which may result in disciplinary action against
the students involved.
"We called the police because it was very important to MEChA
members not to let this get pushed under the rug," MEChA Chairman Norma Copado '97 said.
"The incident was symptomatic of a trend of little communication across the campus."
Wright Hall residents Joseph Mouallem '00 and Karna Basu '00 said the raucous celebration,
which included drinking, dancing, and loud music, provoked them to hose down the nighttime
revelers.
"I was sitting in our common room trying to study," Basu said. "Joe came in and
we saw a loud party with people drinking and screaming."
They decided to spray the crowd outside their window with lukewarm water "to quiet them
down and add an element of excitement. We did not know who they were," Basu added.
Dean of Student Affairs Betty Trachtenberg said she is unaware of the incident.
MEChA members said there was no excuse for the freshpeople's actions.
"There's never a reason to do this. This is Yale. There's a [proper] forum for expression
of grievances," MEChA member Alfonso Maldonado '97 said.
Following an initial spraying, the crowd erupted into a clamor. Basu and Mouallem said
they took the noise as encouragement, and continued to spray the crowd below until
several MEChA members went to their room to complain.
An argument ensued, with Copado accusing the students of ignorance and insensitivity.
"I believe and all of us believe that what just happened now was an act of disrespect.
Instead of hosing us with water, they could have come down and asked us to quiet down,"
Copado said. "We understand that people have to study and would have turned the volume down."
Rahul Rajkumar '00, who lives with Basu and Mouallem, blamed Copado for making the incident
into something it was not.
"The incident was not directed at Mexican-Americans.
Norma Copado escalated what was just an adolescent prank into a racial incident," he
said.
According to Itzolin Garcia '98, a MEChA member who witnessed the altercation, Basu and
Mouallem "were shocked and surprised because they didn't know what they were getting into.
They sort of stumbled into a really compromising situation."
Mouallem said Copado assumed
the prank was racially motivated.
"She insulted me by even insinuating that our actions were racially motivated. We had no
idea who they were when we hosed them.," added Mouallem.
Both he and Basu apologized
for the incident. "We sincerely regret our actions. We did not know how special this
occasion was and if we had been aware of the importance of it, we would not have
sprayed them," Basu said.
Witnesses like Zachary Kaufman '00 said they did not
believe the incident was driven by prejudice.
"I don't think it was targeted at
anyone. I think it was a practical joke that was a little overreacted to," Kaufman
said.
Both parties expressed their desire to foster further communication and prevent future
incidents. Garcia reported that MEChA will try to publicize their activities more and
invite people of all backgrounds to join them. | 2024-01-17T01:27:15.642919 | https://example.com/article/6327 |
Resolution of massive technetium-99m methylene diphosphonate uptake in the stomach in vitamin D intoxication.
Vitamin D intoxication, which may result from zealous intake of health food supplements, may cause metastatic calcification. This is the first reported case of a patient with vitamin D intoxication who had massive gastric uptake of [99mTc]MDP, but no lung uptake, with histologic documentation of the metastatic calcification by gastric biopsy. It is probable that the metastatic calcification was a highly metabolic process in this patient since the gastric uptake resolved within 3 wk when serum calcium and phosphate had returned to normal. | 2023-10-21T01:27:15.642919 | https://example.com/article/5812 |
Hot! Dovpo Topside Dual Squonker Box Mod 200W Presale @ Vapesourcing
New Arrival Alert! You can now pre-order the new Dovpo Topside Dual Squonker Box Mod 200W fromVapesourcing.comfor only $73.90. Hurry up, limited time offer!
Dovpo Topside Dual Mod is an updated version of the Topside. It has all the innovation from its predecessor but now offers more power and extended battery life. Powered by dual 18650 batteries, the Topside Dual can fire up to 200W with switchable power, bypass, and temperature control modes. On the control face, you have a 0.96″ OLED display with a vertical menu that adopts blue font for easy viewing. Meanwhile, the Topside Dual offers a large 10ml squonk bottle e-liquid capacity (backward compatible with original topside bottle and sled), simple top filling and an easy-to-use interface which makes it the perfect addition to those who want more power and extended battery life. Powerful and simple squonking is waiting for you! 8 colors are available.
About Vapesourcing.comWe are the top authorized agent for electronic cigarettes and e-liquid in China and dedicated to create the No.1 Brand Mall of vape online store in the world . Supplying the goods and service for e-commerce of Business to Business, Business to Small Business, and Business to Customer . We aim to enable all customers to enjoy the competitive price with best service of global electronic cigarette & e-liquid products, and focus on offering convenient and efficient service to keep us moving.
Did this article help you? If so, please tell me in a comment what do you think about it. | 2023-10-30T01:27:15.642919 | https://example.com/article/7389 |
Learn more about homes in Bentley, Farnham, United Kingdom
Bentley, Farnham Home inventory breakdown by property type
Of the 1 homes for sale in Bentley, Farnham, the breakdown of property types
is as follows:100% Single Family.
100% Single Family
Area details, home facts and figures
Homes for sale
1
Average Home Size
2,343 ft² / 218 m²
Price Range
($960,000 - $960,000)
Information from in and around Bentley, Farnham...
You are Viewing 1 to 1 of 1 homes for sale in Bentley, Farnham. These homes are comprised of Single Family. The average list price of these property results is 960,000. Prices are shown as US Dollar. For more information on these homes for sale in Bentley, Farnham please contact our member brokerages to schedule a showing or view an open house.
The 1 homes for sale in Bentley, Farnham, United Kingdom are represented by 1 member brokerages serving the Bentley, Farnham area. Member brokerages representing the 1 homes include Strutt & Parker. | 2023-10-15T01:27:15.642919 | https://example.com/article/4828 |
Sri Lankans seek $1M to free captured crewmen
COLOMBO, Sri Lanka – Sri Lankan religious leaders have joined with the families of seven crewmen held by Somali pirates to launch a fundraising drive to pay a ransom of more than $1 million for their release.
Buddhist, Catholic and Muslim clergy and the families made a joint appeal to Sri Lankans on Monday to contribute to the fund.
The Malaysian-owned MV Albedo was hijacked in November 2010 in the Gulf of Aden as it was sailing to Kenya. The pirates released seven Pakistani crew members last week after their families and other groups paid $1.1 million for their release. The pirates had earlier agreed to free all 22 crew for $2.85 million.
The crew members still held by pirates consist of seven Sri Lankans, six Bangladeshis, one Iranian and one Indian. | 2024-05-12T01:27:15.642919 | https://example.com/article/3337 |
passTimeChange=true
licenseTypeChange=false
deptId=true
insert_time = true
kafka_licenseType=license_type
kafka_passingTime=passing_time
kafka_deptId=dept_id
kafka_insertTime=insert_time | 2023-11-20T01:27:15.642919 | https://example.com/article/5312 |
Pulse compression and multimegawatt optical solitons in hollow photonic-crystal fibers.
Solitonic phenomena in hollow photonic-crystal fibers are shown to offer new solutions for the control, transmission, and spectral-temporal transformation of ultrashort high-power laser pulses. With the initial parameters of laser radiation accurately matched with fiber dispersion and nonlinearity, submicrojoule laser pulses are shown to exhibit a self-compression and soliton dynamics in the regime of anomalous dispersion. Regimes of solitonic pulse evolution giving rise to few-cycle field waveforms are demonstrated. Based on simple arguments of soliton theory, we derive semiempirical relations providing interesting insights into the minimum pulse width of the laser field in a hollow photonic-crystal fiber as a function of the input laser energy. | 2024-02-17T01:27:15.642919 | https://example.com/article/4492 |
Senate Republicans ask Moore to withdraw as new accuser steps forward
WASHINGTON (Reuters) - U.S. Senate Majority Leader Mitch McConnell led a chorus of establishment Republicans on Monday urging Roy Moore, the party’s Senate candidate in Alabama, to quit the race as a fifth woman came forward with allegations Moore had sexual contact with teenage girls decades ago.
Beverly Young Nelson said Moore sexually assaulted her when she was 16 and he was a prosecuting attorney in his 30s. At a New York news conference, the tearful Nelson said Moore groped her, tried to pull her shirt off and shove her head in his lap, then warned that “no one will believe you” if she told anyone.
“I was twisting and struggling and begging him to stop,” said Nelson, a waitress at an Alabama restaurant where Moore often ate when the incident occurred. “I had tears running down my face.”
Moore, a Christian conservative and former chief justice of the Alabama Supreme Court, has refused to withdraw from the race. His campaign released a statement denying “any sexual misconduct with anyone” and saying the new allegations were part of a “witch hunt.”
At a news conference in Gallant, Alabama on Monday night, Moore told reporters that Nelson’s accusations are “absolutely false,” the Birmingham News reported.
“I never did what she said I did,” the newspaper quoted Moore as saying. “I don’t even know the woman. I don’t know anything about her.”
McConnell told reporters in his home state of Kentucky that party officials were considering whether a Republican write-in candidate could be found to challenge Moore in the Dec. 12 special election.
“I think he should step aside,” said McConnell, who previously said Moore should leave the race if the allegations were true. “I believe the women.”
Republican Senators Orrin Hatch, Susan Collins, Lindsey Graham, Todd Young and Cory Gardner joined McConnell in calling for Moore to drop out - a move that could open the door for Democrats to cut into Republicans’ narrow two-seat Senate majority.
Gardner, the head of the Senate Republican campaign arm, said Moore was unfit to serve in the Senate.
“If he refuses to withdraw and wins, the Senate should vote to expel him, because he does not meet the ethical and moral requirements of the United States Senate,” Gardner said in a statement.
Senator John Cornyn, the Senate’s No. 2 Republican, withdrew his endorsement but said Alabama voters should make the final judgment on Moore.
Another prominent conservative who had endorsed Moore, Senator Ted Cruz, said Moore should either clearly refute the allegations or if they are true, drop out. “I am not able to urge the people of Alabama to support his candidacy so long as these allegations remain unrefuted,” Cruz told reporters in the Capitol.
Moore, 70, had been a heavy favorite to win the election against Democrat Doug Jones. He has denied the allegations first raised in a Washington Post story about his relationships with four women when they were teenagers, including a charge he initiated sexual contact with a 14-year-old girl when he was in his 30s.
He said on Twitter that McConnell was the person who should step down.
“He has failed conservatives and must be replaced,” Moore said.
MANY SUPPORTERS STEADFAST
The state party and many other Alabama Republicans have not wavered in their support of Moore, who scored a decisive Republican primary victory in September over Luther Strange. Strange, who drew the support of President Donald Trump in the primary, had been appointed to fill the seat vacated by Jeff Sessions when he became U.S. attorney general earlier this year.
Slideshow (11 Images)
The growing furor over Moore sets up a confrontation between establishment Republicans and Moore’s supporters in the party’s populist movement led by former White House chief strategist Steve Bannon.
A Democratic win in Alabama would be a blow to Trump’s agenda and shift the political outlook for next year’s congressional elections, giving Democrats a stronger shot at recapturing control of the Senate.
It is too late to remove Moore’s name from the ballot, but McConnell told reporters he was “looking at” potential write-in candidates who could mount a successful campaign. Asked if Strange might be a candidate again, he said: “We’ll see.”
But Strange told reporters it was “highly unlikely” he would mount a write-in campaign. “Now it’s going to really be up to the people of our state to sort this out,” he said.
A special-election victory had been a long shot for Democrats in Alabama, which has not elected a Democratic senator in a quarter century. Jones, a former federal prosecutor, was trailing by double digits in some opinion polls.
Moore, who is prone to incendiary comments on social and cultural issues, has survived controversy before. He was twice forced out of his position as chief justice, once for refusing to remove a Ten Commandments monument from the courthouse and once for defying the U.S. Supreme Court decision legalizing same-sex marriage.
He threatened over the weekend to sue the Post and said the allegations were a smear campaign by his political opponents. Reuters has been unable to independently confirm any of the allegations.
While making the new allegations, Nelson showed reporters Moore’s signature in her high school yearbook. She said he had offered to give her a ride home one night, then pulled the car behind the restaurant and assaulted her.
“I was terrified,” she said. “I thought he was going to rape me.”
Nelson said she told her sister about the attack two years afterward, and eventually told her mother and husband. She said she backed Trump for president and was not coming forward because of politics but because she was inspired by the women who talked to the Post.
Additional reporting by Susan Cornwell and David Alexander in Washington and Peter Szekely in New York; Editing by Bill Trott and Peter Cooney | 2024-03-30T01:27:15.642919 | https://example.com/article/2954 |
Q:
Phusion Passenger 2.2.2 crashes often
I deployed an rails(2.3.2) app on Passenger 2.2.2.
It crashes sometimes.
There's the error message.
Passenger encountered the following error:
The application spawner server exited unexpectedly: Broken pipe
Exception class:
PhusionPassenger::Railz::ApplicationSpawner::Error
Backtrace:
# File Line Location
0 /dh/passenger/lib/phusion_passenger/railz/application_spawner.rb 117 in `spawn_application'
1 /dh/passenger/lib/phusion_passenger/spawn_manager.rb 265 in `spawn_rails_application'
2 /dh/passenger/lib/phusion_passenger/abstract_server_collection.rb 80 in `synchronize'
3 /dh/passenger/lib/phusion_passenger/abstract_server_collection.rb 79 in `synchronize'
4 /dh/passenger/lib/phusion_passenger/spawn_manager.rb 250 in `spawn_rails_application'
5 /dh/passenger/lib/phusion_passenger/spawn_manager.rb 153 in `spawn_application'
6 /dh/passenger/lib/phusion_passenger/spawn_manager.rb 282 in `handle_spawn_application'
7 /dh/passenger/lib/phusion_passenger/abstract_server.rb 337 in `__send__'
8 /dh/passenger/lib/phusion_passenger/abstract_server.rb 337 in `main_loop'
9 /dh/passenger/lib/phusion_passenger/abstract_server.rb 187 in `start_synchronously'
10 /dh/passenger/bin/passenger-spawn-server 61
Can somebody help me please?
A:
According to the answer to this question, you can run into this if you're hitting your memory limit on Dreamhost. If you're in a shared hosting environment I'd bet that's your issue.
| 2024-01-23T01:27:15.642919 | https://example.com/article/5339 |
Nonfarm payrolls grew far more than expected in February as companies continued to hire leading into a growing coronavirus scare. The Labor Department reported Friday that the U.S. economy added 273,000 new jobs during the month, while the unemployment rate was 3.5%, matching its lowest level in more than 50 years. An alternative measure of joblessness that counts those not looking for work and holding part-time jobs for economic reasons edged higher to 7%. The January and February gains tied for best month since May 2018. Economists surveyed by Dow Jones had been looking for payroll growth of 175,000 and a 3.5% jobless level. Average hourly earnings grew by 3% over the past year, in line with estimates, while the average work week, considered a key measure of productivity, nudged up to 34.4 hours. There was more good news for the jobs market: The previous two months' estimates were revised higher by a total of 85,000. December moved up from 147,000 to 184,000, while January went from 225,000 to 273,000. Those revisions brought the three-month average up to a robust 243,000 while the average monthly gain in 2019 was 178,000.
Despite the strong numbers, Wall Street was heading for more losses stemming from worries over the effects of the coronoavirus outbreak, though Friday's futures were off their bottom after the report. "This could be the last perfect employment report the market gets for some time," said Chris Rupkey, chief financial economist at MUFG Union Bank. Gains were spread across a multitude of sectors as the total employment level hit 158.8 million, near its December 2019 record. Health care and social assistance led the way in job creation with 57,000 new positions. Food services and drinking places both added 53,000 while government employment grew by 45,000 due to Census hiring and state government education. Construction added 42,000 thanks to continued mild weather, while professional and technical services contributed 32,000 and finance rose by 26,000, part of a 160,000 gain over the past 12 months. In the survey of households, employment rose by 126,000 while the ranks of the unemployed decreased by 105,000. "While it's too early to see the impact of the coronavirus on the labor market, we can say the labor market was in a good place before the virus began to spread," said Nick Bunker, economic research director at job placement firm Indeed. "But the next few months will be a test of just how resilient this labor market is."
Jobs market still looks strong | 2024-07-05T01:27:15.642919 | https://example.com/article/7782 |
Top Social
Sailor Tokiwa-Matsu (Evergreen Pine)
7/6/14
Hi folks,
This is the first of the "new" Sailor inks that just became available in the US this summer. Lisa and Brian Anderson kindly provided samples of each of the new inks (free of charge!), and I'm excited to be able to show them to you. (Previews available here.)
Tokiwa-Matsu is a light-medium green with just a touch of a sheen to it where the ink pools. I tried to catch that sheen in my pictures of the ink smear, but It's kind of hard to see. Present, but not the focal point of this ink.
You'll notice that I misspelled the ink's name every time I wrote it. I don't know why I did that.
As I say in the written review, this is a really smooth ink. It tended to skate just a bit in this nib, but that might be due to the Custom 74's really smooth nib. Its' a nice green with lots of shading.
This ink is also really well behaved. In fact, all of the new Sailor inks that I've tried are real well behaved. They don't seem to bleed, feather, or spread on any kind of decent paper. I have a couple of pads of really bad paper, and it will feather some on that paper, but it doesn't do any of that on common office copy paper (Staples 20lb paper is my tester paper.)
This isn't quite a replacement for Sailor's Jentle Epinard. It's not quite dark enough to replace that ink for a lot of people, I'd guess. It's still a pretty nice green. | 2024-03-01T01:27:15.642919 | https://example.com/article/2797 |
/*
* Copyright 1995-2016 The OpenSSL Project Authors. All Rights Reserved.
*
* Licensed under the OpenSSL license (the "License"). You may not use
* this file except in compliance with the License. You can obtain a copy
* in the file LICENSE in the source distribution or at
* https://www.openssl.org/source/license.html
*/
#include "internal/cryptlib.h"
#ifdef OPENSSL_NO_RSA
NON_EMPTY_TRANSLATION_UNIT
#else
# include <stdio.h>
# include <openssl/evp.h>
# include <openssl/objects.h>
# include <openssl/x509.h>
# include <openssl/rsa.h>
int EVP_OpenInit(EVP_CIPHER_CTX *ctx, const EVP_CIPHER *type,
const unsigned char *ek, int ekl, const unsigned char *iv,
EVP_PKEY *priv)
{
unsigned char *key = NULL;
int i, size = 0, ret = 0;
if (type) {
EVP_CIPHER_CTX_reset(ctx);
if (!EVP_DecryptInit_ex(ctx, type, NULL, NULL, NULL))
return 0;
}
if (!priv)
return 1;
if (EVP_PKEY_id(priv) != EVP_PKEY_RSA) {
EVPerr(EVP_F_EVP_OPENINIT, EVP_R_PUBLIC_KEY_NOT_RSA);
goto err;
}
size = EVP_PKEY_size(priv);
key = OPENSSL_malloc(size + 2);
if (key == NULL) {
/* ERROR */
EVPerr(EVP_F_EVP_OPENINIT, ERR_R_MALLOC_FAILURE);
goto err;
}
i = EVP_PKEY_decrypt_old(key, ek, ekl, priv);
if ((i <= 0) || !EVP_CIPHER_CTX_set_key_length(ctx, i)) {
/* ERROR */
goto err;
}
if (!EVP_DecryptInit_ex(ctx, NULL, NULL, key, iv))
goto err;
ret = 1;
err:
OPENSSL_clear_free(key, size);
return ret;
}
int EVP_OpenFinal(EVP_CIPHER_CTX *ctx, unsigned char *out, int *outl)
{
int i;
i = EVP_DecryptFinal_ex(ctx, out, outl);
if (i)
i = EVP_DecryptInit_ex(ctx, NULL, NULL, NULL, NULL);
return i;
}
#endif
| 2023-09-16T01:27:15.642919 | https://example.com/article/3920 |
861 So.2d 851 (2003)
STATE of Louisiana
v.
William Odell CASH.
No. 03-853.
Court of Appeal of Louisiana, Third Circuit.
December 10, 2003.
*852 Michael Cade Cassidy, District Attorney, Thirty-first Judicial District, Bennett R. Lapoint, Asst. District Attorney, Jennings, LA, for Plaintiff/Appellee, State of Louisiana.
Jack Derrick Miller, Crowley, LA, for Defendant/Appellant, William Odell Cash.
William Odell Cash, In Proper Person.
Court composed of BILLIE COLOMBARO WOODARD, GLENN B. GREMILLION, and ELIZABETH A. PICKETT, Judges.
GREMILLION, Judge.
The defendant, William Odell Cash, was convicted by a jury of possession of marijuana with intent to distribute, a violation of La.R.S. 40:966, and possession of methamphetamine, a violation of La.R.S. 40:967, and was sentenced to ten years at hard labor. He now appeals his conviction. For the following reasons, we affirm.
ERRORS PATENT
We review all appeals for errors patent on the face of the record in accordance with La.Code Crim.P. art. 920. After reviewing the record, we find that there is one error patent.
*853 Defendant and a co-defendant were charged by bill of information with two offensesone count of possession with the intent to distribute marijuana and one count of possession of methamphetamine. Defendant and co-defendant were not tried together and the bill of information read at Defendant's trial cited only one of the offenses charged on the billpossession of marijuana with the intent to distribute. Consequently, the jury returned a verdict as to that charge alone, and no verdict was returned on count twopossession of methamphetamine. We sent an information request to the Jefferson Davis Clerk of Court's Office for any minute entry, motion, order, or other pleading showing the disposition of count two, possession of methamphetamine. The clerk's office responded with an affidavit stating, "that there is no minute entry, motion, order or other pleading showing the disposition" of that charge in the docket number that is before this court. We also conducted an examination of the transcripts included in the record, but found no mention of the disposition of count two. Thus, it appears that count two is an outstanding charge against Defendant, for which no verdict was returned by the jury.
Louisiana Code of Criminal Procedure Article 819 requires a verdict to be returned on each count charged in an indictment: If there is more than one count in an indictment, the jury must find a verdict as to each count, unless it cannot agree on a verdict as to a count.
In two previous cases, when faced with a similar error patent, we remanded for a proper disposition of the outstanding charge. State v. Davis, 614 So.2d 270 (La.App. 3 Cir.1993), reversed on other grounds, 93-0599 (La.4/11/94), 634 So.2d 1168, and State v. James, 99-1858 (La.App. 3 Cir. 5/3/00), 761 So.2d 125, writ denied, 00-1595 (La.3/23/01), 787 So.2d 1010. Likewise, we remand this matter for a proper disposition of the possession of methamphetamine charge.
SUFFICIENCY OF EVIDENCE
In this assignment, Defendant attacks the sufficiency of the evidence. Because a ruling that the evidence was insufficient would necessitate an acquittal, we will address this argument before the others. State v. Hearold, 603 So.2d 731, 734 (La. 1992).
When the issue of sufficiency of evidence is raised on appeal, the critical inquiry of the reviewing court is whether, after viewing the evidence in the light most favorable to the prosecution, any rational trier of fact could have found the essential elements of the crime proven beyond a reasonable doubt. Jackson v. Virginia, 443 U.S. 307, 99 S.Ct. 2781, 61 L.Ed.2d 560, rehearing denied, 444 U.S. 890, 100 S.Ct. 195, 62 L.Ed.2d 126 (1979); State ex rel. Graffagnino v. King, 436 So.2d 559 (La.1983); State v. Duncan, 420 So.2d 1105 (La.1982); State v. Moody, 393 So.2d 1212 (La. 1981). It is the role of the fact finder to weigh the respective credibility of the witnesses, and therefore, the appellate court should not second guess the credibility determinations of the triers of fact beyond the sufficiency evaluations under the Jackson standard of review. See State ex rel. Graffagnino, 436 So.2d 559 (citing State v. Richardson, 425 So.2d 1228 (La.1983)). In order for this Court to affirm a conviction, however, the record must reflect that the state has satisfied its burden of proving the elements of the crime beyond a reasonable doubt.
State v. Kennerson, 96-1518, p. 5 (La.App. 3 Cir. 5/7/97), 695 So.2d 1367, 1371.
Defendant was convicted of possession of marijuana with intent to distribute, *854 a violation of La.R.S. 40:966. The statute states, in pertinent part:
A. Manufacture; distribution. Except as authorized by this Part, it shall be unlawful for any person knowingly or intentionally:
(1) To produce, manufacture, distribute or dispense or possess with intent to produce, manufacture, distribute, or dispense, a controlled dangerous substance or controlled substance analogue classified in Schedule I[.]
We have stated:
The State was required to prove two essential elements: possession of the controlled dangerous substance and the intent to distribute it.
The prosecution is not required to show actual possession in order to convict. The State need only show that the defendant exercised dominion and control over the illegal substance. State v. Trahan, 425 So.2d 1222 (La.1983); State v. Rexrode, 536 So.2d 671 (La.[App.3rd Cir.]1988). The mere presence of the defendant in the area where narcotics are discovered is insufficient to support a finding of possession. State v. Matthews, 552 So.2d 590 (La.App. 2nd Cir. 1989). What must be shown is that the defendant had a direct right and ability to exercise control. State v. Segura, 546 So.2d 1347 (La.App. 3rd Cir.1989). Additionally, the prosecution must show guilty knowledge. Trahan, supra; Matthews, supra.
State v. Newberry, 560 So.2d 121, 123 (La. App. 3 Cir.1990).
We have also explained constructive possession as follows:
The following factors should be considered in determining whether defendant exercised dominion and control so as to constitute constructive possession: defendant's knowledge that illegal drugs were in the area; the defendant's relationship with the person in actual possession; the defendant's access to the area where the drugs were found; evidence of recent drug use; the defendant's proximity to the drugs; and any evidence that the area was frequented by drug users.
State v. Laws, 95-593, p. 4 (La.App. 3 Cir. 12/6/95), 666 So.2d 1118, 1121, writ denied, 96-0089 (La.9/13/96), 679 So.2d 102 (citation omitted).
On appeal, Defendant claims the State's case was circumstantial, thus requiring it to produce evidence that excluded "every reasonable hypothesis of innocence," as required by La.R.S. 15:438. At trial, the State relied mainly upon the testimony of Louisiana State Trooper Richard Elliot, a motor carrier safety inspector. Elliot testified that on July 19, 2000, in Jefferson Davis Parish, he stopped a tractor-trailer rig driven by Defendant. There was also a passenger, Karen Kayla. The purpose of the stop was a routine safety inspection. After Defendant produced his log book, Elliot checked its entries and noticed discrepancies. We note that Defendant stipulated there were falsified entries in the log book.
Elliot testified Defendant "seemed extremely nervous." He explained that people are often nervous when they encounter police, but usually relax after the initial contact. However, he testified that Defendant did not relax. He further testified that Defendant's demeanor made him suspicious, as did the presence of a number of locks on the trailer section of the rig. Defendant was hauling produce, which Elliot testified is not normally a high-security load. Thus, Elliot obtained Defendant's written permission to search the vehicle. After a backup officer arrived, Elliot commenced his search. He began in the cab area of the truck, which included a sleeper *855 compartment. Behind the driver's seat, he found a bag containing a full bottle of wine. Elliot testified that drivers may not possess alcohol in commercial vehicles. About three feet away from the wine, he found a dog-food box in plain view. Elliot observed there was no dog in the truck, and Defendant admitted he did not have a dog. Also, Elliot could tell the box had been opened and then re-sealed with packing tape. He opened the box and discovered several bricks of a substance he believed to be marijuana. He said there were "little perfume things" packed in with the marijuana. Subsequent laboratory testing confirmed the substance was marijuana and that its weight was 9,579.9 grams.
Elliot immediately arrested Defendant and Kayla, advised them of their rights, and separated them. He then resumed the search. He found possible drug paraphernalia, i.e., clips and pipes, but no other drugs in the cab area. He then checked the utility boxes on the outside of the truck and found one or two more bricks of marijuana in a shopping bag, packaged in a manner similar to those found in the dog-food box. Elliot then searched the trailer. He found more bottles of alcoholic beverages, but no other contraband.
The State also presented the testimony of Trooper Martin Zaunbrecher, who participated in the follow-up investigation of Defendant. Zaunbrecher testified that the lower section of Texas, along the Mexican border, is an area of high drug-trafficking. Elliot's testimony had already indicated Defendant had been in the Corpus Christi, Texas area on the same date as the traffic stop and arrest. Subsequently, another state trooper, Sergeant Christopher Ivey, testified regarding the prevalence of drug trafficking in lower Texas. Ivey also testified the marijuana in this case was packaged in a manner meant to conceal its odor, as it was wrapped in dryer sheets and vacuum-sealed. Further, he explained the manner of packaging was consistent with distribution rather than personal consumption. On cross-examination, Ivey acknowledged the truck apparently belonged to a company, rather than to Defendant. Ivey also testified that he photographed and processed the evidence; like Elliot, he observed an item in the truck that he believed to be drug paraphernalia, i.e., a smoking pipe. He photographed it, but the pipe itself was not preserved.
In addition to the above evidence, the State also adduced testimony from Detective William Gary of South Carolina. Gary testified that on January 25, 2002, he arrested Defendant for possession of marijuana. The detective further testified that he came into contact with Defendant pursuant to a search warrant that covered his residence and vehicle. As Gary arrived, Defendant was leaving in the vehicle; the officer stopped him, and found a substance that appeared to be marijuana in plain view in a clear plastic bag. The weight of the substance was approximately twenty-one grams. The lab test of the substance was not introduced, because it was excluded as hearsay.
We have reviewed the entire record, particularly addressing specific portions of the evidence highlighted by Defendant and the State in their appellate arguments. We note that the majority of the arguments set forth by Defendant involve alleged "failures" to produce or preserve various types of evidence. It is well-established that the State has discretion regarding how to make out its case. Presence or absence of evidence, and weight of the evidence produced, are matters to be assessed by the factfinder. For example, there is no legal requirement for the State to test for fingerprints, produce fingerprint evidence, test certain evidence, or call certain witnesses to satisfy the elements *856 of the offense at issue. See State v. Green, 94-986 (La.App. 3 Cir. 3/1/95), 651 So.2d 435. State v. Sweeney, 443 So.2d 522 (La.1983) cited by Defendant, merely contains general statements of law; and State v. Penson, 351 So.2d 1181 (La.1977), which he also cites, is a pre-Jackson sufficiency case.
In State v. Odle, 02-226, p. 11 (La.App. 3 Cir. 11/13/02), 834 So.2d 483, 492, writ denied, 03-0625 (La.6/20/03), 847 So.2d 1219, in which the defendant was found to be in constructive possession of cocaine hidden in his gas tank, we wrote:
Considering the evidence, particularly the fact that Shaw was acting abnormally, gave information to the police that was inconsistent with that given by Odle, was surrounded by a gasoline smell as well as an air freshener smell while in the vehicle, along with the fact that rags containing gasoline were found in the cargo area of the vehicle and his explanation for them was lacking, the fact that the gas tank had recently been tampered with, was geared to always read full, and there were several cans of cocaine hidden in the gas tank, we find that sufficient evidence was presented to the jury for it to find that Shaw constructively possessed the cocaine.
The present case is even stronger than Odle as the box of marijuana was in an open area that was within Defendant's dominion and control. The evidence is sufficient to support the conviction. Therefore, this assignment is without merit.
MOTION TO SUPPRESS
In his first assignment of error, Defendant argues the lower court erred by denying his Motion to Suppress, which alleged Trooper Elliott did not have probable cause to stop him. However, as the State observes, Defendant raised this same argument in a pre-trial writ application. In an unpublished opinion bearing docket number 02-0293, this court denied the application on May 15, 2002. Subsequently, the supreme court also denied the writ. State v. Cash, 02-1667 (La.8/30/02), 823 So.2d 932.
Our previous review of the issue does not preclude review on appeal. State v. Wessinger, 98-1234 (La.5/28/99), 736 So.2d 162, cert. denied, 528 U.S. 1050, 120 S.Ct. 589 (1999).[1] However, our review of the prior file reveals Defendant's current appeal is raising no new issues for analysis. As the Louisiana Supreme Court has explained:
When this court considers questions of admissibility of evidence in advance of trial by granting a pretrial application for supervisory writs (rather than deferring judgment until an appeal in the event of conviction), the determination of admissibility does not absolutely preclude a different decision on appeal, at which time the issues may have been more clearly framed by the evidence adduced at trial. Nevertheless, judicial efficiency demands that this court accord great deference to its pretrial decisions on admissibility, unless it is apparent, in light of the subsequent trial record, that the determination was patently erroneous and produced an unjust result.
State v. Humphrey, 412 So.2d 507, 523 (La.1981) (on rehearing).
We find that the trial record does not reveal new evidence on this issue, nor does Defendant's brief point to any such evidence. Further, neither our review nor *857 Defendant's argument suggests our earlier ruling was patently erroneous or unjust. Thus, this assignment of error shall not be considered.
OTHER CRIMES EVIDENCE
Defendant's assignments of error two and three relate to the State's introduction of "other crimes evidence." First, he contends that the other crimes evidence, evidence that police in South Carolina arrested him on suspicion of possession of marijuana on January 25, 2002, was irrelevant. Second, he argues that the prejudicial impact of the other crimes evidence outweighed its probative value.
The relevant law is set forth in La. Code Evid. art. 404(B), which states, in pertinent part:
[E]vidence of other crimes, wrongs, or acts is not admissible to prove the character of a person in order to show that he acted in conformity therewith. It may, however, be admissible for other purposes, such as proof of motive, opportunity, intent, preparation, plan, knowledge, identity, absence of mistake or accident, provided that upon request by the accused, the prosecution in a criminal case shall provide reasonable notice in advance of trial, of the nature of any such evidence it intends to introduce at trial for such purposes, or when it relates to conduct that constitutes an integral part of the act or transaction that is the subject of the present proceeding.
Our supreme court has explained:
La.C.E. art. 404(B)(1) incorporates a fundamental evidentiary rule that "[m]atters which are logically relevant to issues before the jury should not be excluded merely because they show the accused has committed other offenses." State v. Moore, 278 So.2d 781, 788 (La. 1972) (on reh'g). Such evidence may be admissible to prove "motive, opportunity, intent, preparation, plan, knowledge, identity, absence of mistake or accident...." La.C.E. art. 404(B)(1). However, La.C.E. art. 404(B)(1) also incorporates Louisiana's traditional rule, see former La.R.S. 15:446, that evidence of other crimes, wrongs, or acts "is not admissible to prove the character of a person in order to show that he acted in conformity therewith." The state therefore must show "that the evidence is necessary to prove a matter genuinely at issue ... and that the probative value of the evidence of the other crime outweighs the prejudicial effect." State v. Martin, 93-0285, p. 12 (La.10/17/94), 645 So.2d 190, 197 (citation omitted). For purposes of the balancing test provided by La.C.E. art. 403, Louisiana's analogue of Fed.R.Evid. 403, "[t]he term `unfair prejudice,' as to a criminal defendant, speaks to the capacity of some concededly relevant evidence to lure the fact-finder into declaring guilt on a ground different from proof specific to the offense charged.... Such improper grounds certainly include ... generalizing a defendant's earlier bad act into bad character and taking that as raising the odds that he did the later bad act now charged...." Old Chief v. United States, 519 U.S. 172, 180, 117 S.Ct. 644, 650, 136 L.Ed.2d 574 (1997); see also State v. Hatcher, 372 So.2d 1024, 1036 (La.1979) (Tate, J., concurring) ("Other-crime evidence may not be used to prove that the offender committed this crime simply because he had committed similar crimes in the past.").
State v. Morgan, 99-1895, pp. 2-3 (La.6/29/01), 791 So.2d 100, 102-03.
According to Defendant, the arrest for possession was irrelevant because it did not relate to the current charge of possession with intent to distribute. For *858 support, he cites State v. Quest, 00-205, p. 19 (La.App. 5 Cir. 10/18/00), 772 So.2d 772, writ denied, 00-3137 (La.11/2/01), 800 So.2d 866:
Intent is an essential element of the crime of possession with intent to distribute heroin. Previous attempts to distribute may be considered in establishing intent. State v. White, 98-91 (La.App. 5th Cir.6/30/98), 715 So.2d 714, 717, writ denied, 98-2043 (La.11/25/98), 729 So.2d 577.
In [State v.] Johnson, [98-604 (La. App. 5th Cir.1999), 728 So.2d 901, writ denied, 99-0624 (La.6/25/99), 745 So.2d 1187,] we held that evidence of a defendant's prior conviction for distribution of cocaine had independent relevance because it satisfied an element of the crime of unlawful possession of a firearm. In this case, the Defendant's admission that he sold drugs in the past has independent relevance in satisfying the intent element of the crime of possession with intent to distribute heroin.
The part of the Defendant's statement in which he admitted to using heroin does not appear to have any relevance other than to show his "bad character." The actual use of heroin does not satisfy or relate to any element of the crime of possession with intent to distribute heroin. Therefore, that portion of the Defendant's statement should have been excised. However, the admission is subject to the harmless error rule. State v. Johnson, 728 So.2d at 911. The analysis for determining harmless error is whether the verdict actually rendered in this case was surely unattributable to the error. Id.
The State argues the other crimes evidence was relevant to help prove guilty knowledge, as Defendant argued in the case sub judice that the State failed to prove he knew the marijuana was in the truck. The lower court reasoned:
I think this particular case is distinguishable from the State versus Quest case that defense counsel has cited andandto the extent that the Quest case was an attempt to use an admission by the defendant that he was a drug user or user of heroin.
In this particular case, that is not the evidence. The evidence is that the defendant possessed marijuana at a time closely in proximity to the arrest that that is the subject of this particular case before us today.
To accept the defense argument would essentially exclude any evidence of a prior possession of a drug by a person who subsequently is arrested and on trial for possession of that drug with intent to distribute. And I don't believe that that was the intent of the Quest case to go that far. I think it wasin my reading, itit intended simply to avoid the evidence of use by the defendant because use had no other relevance other than to show that the defendant was a bad person; whereas, in this particular case, the relevance is to show knowledge ofon the part of the defendant that he knew what marijuana was.
So the Court is going to allow the introduction of the other crimes evidence, and that being the arrest on January 25 of 2002 of the defendant, William Cash, in South Carolina for the charge of possession of marijuana.
The Court is going to, however, restrict any testimony by the State's witnesses to that particular crime or other act and will not allow testimony of the of any other crimes or any other acts by the defendant. And I'm particularly addressing the defense's concern that there may be some evidence of the purpose for execution or having the search *859 warrant and that is not going to be admitted. It will not be allowed.
We agree with the lower court and its points are well-founded. Also, Defendant in the present case contested the possession element of the crime at issue; thus, the evidence regarding the South Carolina arrest had clear relevance in showing "knowledge" of marijuana and how it may be packed and shipped, as well as "absence of mistake or accident" in transporting the marijuana.
Next, we will examine Defendant's separately-captioned fifth and sixth issues, which both relate to the notice the State provided regarding the other crimes evidence. First, Defendant argues the State did not provide a sufficient description of the evidence to be introduced. He cites State v. McArthur, 97-2918, pp. 1-2 (La.10/20/98), 719 So.2d 1037, 1039-40, (emphasis added):
Finally, the requirements set forth in State v. Prieur, 277 So.2d 126 (La. 1973) must be met. Thereunder, the state must, within a reasonable time before trial, provide written notice of its intent to use other acts or crimes evidence and describe these acts in sufficient detail. The state must show the evidence is neither repetitive nor cumulative, and is not being introduced to show the defendant is of bad character. Further, the court must, at the request of the defendant, offer a limiting instruction to the jury at the time the evidence is introduced. The court must also charge the jury at the close of the trial that the other crimes evidence serves a limited purpose and that the defendant cannot be convicted for any crime other than the one charged or any offense responsive to it.
Regarding Defendant's contention that the State's notice was insufficient, we observe the following language from the State's notice:
1.
The State anticipates that the following individual will testify against William Cash in his trial, namely Officer William Gary, a police officer from South Carolina.
2.
State intends to introduce evidence through the testimony of said witnesses [sic] that on or about January of 2002, the defendant William Cash was arrested and charged in South Carolina with possession of marijuana.
3.
The State asserts that this other crimes evidence is admissible pursuant to law to show motive, opportunity, intent, preparation, plan, knowledge, identity, and/or absence of mistake or accident pursuant to Louisiana Code of Evidence Article 404(B).
WHEREFORE, the State of Louisiana prays that a prieur [sic] hearing be held on this matter prior to the defendant's trial to determine the admissibility of this other crimes evidence.
The trial court conducted a Prieur hearing, and, after taking testimony, made the following observations:
Well, the language in 404(B) of the evidence code requires reasonable notice, and after reviewing the motion of the State, I-I find that they have provided reasonable notice of the particularity of the crime that they wish toto introduce.
And then subsequently, the trial court stated:
All right. The Court has listened to the evidence and the argument of counsel. I've reviewed the memorandums *860 that's been submitted as well as the motion for the hearing. As I've indicated earlier, I found thethe notice or the motion did provide adequate notice of theother crimes or other acts that the State intended to introduce, and I also find that thethe motion sets forth with sufficient specificity the purpose for which the State intends to introduce those items....
At trial, the State limited its introduction of other crimes evidence to the fact of the arrest. Thus, the pretrial notice provided by the State specified exactly the evidence that was eventually introduced at trial. Therefore, Defendant's argument on this issue fails on its facts.
The other notice-related issue raised by Defendant is his contention that the State's notice did not properly particularize the reason why the other crimes evidence was admissible. In its written notice, the State listed all the statutory exceptions that apply under La.Code Evid. art. 404 (motive, opportunity, intent, preparation, plan, knowledge, identity, and/or absence of mistake or accident). We have found no case on point, as prior reported cases that include similar arguments have been disposed of on other grounds. However, we note that even when Prieur-related error occurs, reversal is not automatic. If a defendant is not prejudiced by the error, then reversal is not required. In other words, the error may be harmless, although some cases focus upon prejudice and do not use harmless-error language.
In the present case, the trial court conducted a Prieur hearing before trial. The present argument was asserted by Defendant at that hearing, discussed and ruled upon by the trial court, although our review indicates the State never specified which exception it was applying. However, because we have found that the South Carolina arrest was relevant for the reasons stated above, Defendant cannot claim undue prejudice from the admission of the evidence at trial. Any error committed by the trial court in failing to require and name a specific exception would, therefore, be harmless. Because we have found that the Quest case is distinguishable from the case at bar for the reasons expressed by the trial court, we hold that the other crimes evidence was properly admitted, and that this assignment of error lacks merit.
OTHER CRIMES-JURY INSTRUCTIONS
In this assignment of error, Defendant argues that the trial court erred by instructing the jury that the standard of proof for "other crimes evidence" is preponderance of the evidence. Defendant contends the clear and convincing standard should apply. We disagree. The trial court's instruction regarding the standard of proof was correct in regard to admissibility, pursuant to La.Code Evid. art. 1104 and State v. Crawford, 95-1352 (La.App. 3 Cir. 4/3/96), 672 So.2d 197, writ denied, 96-1126 (La.10/4/96), 679 So.2d 1379, insofar as the standard of proof requirement for Prieur hearings. How ever, it is not clear if the standard for admissibility of other crimes evidence at trial is the same as the standard for the Prieur hearing.
Accordingly, we shall begin our analysis of this issue with Judge Katz's dissent in State v. Pollard, 98-1376 (La.App. 4 Cir. 2/9/00), 760 So.2d 362, 373 (emphasis added), where he observed:
The court in State v. Pardon, 97-248 (La.App. 5 Cir. 10/15/97), 703 So.2d 50, 57, writ denied, 97-2892 (La.3/20/98, 715 So.2d 1207), stated:
La.Code Evid. Art. 1104, added by Acts 1994, 3rd Ex.Sess. No. 51, § 2, changed the burden of proof. It provides: *861 "The burden of proof in a pretrial hearing held in accordance with State v. Prieur, 277 So.2d 126 (La. 1973), shall be identical to the burden of proof required by Federal Rules of Evidence Article IV, Rule 404." That burden of proof was enunciated in Huddleston v. U.S., 485 U.S. 681, 108 S.Ct. 1496, 99 L.Ed.2d 771 (1988), as follows:
"We conclude that [Rule 404(b) ] evidence should be admitted if there is sufficient evidence to support a finding by the jury that the defendant committed the similar act.* * * The court simply examines all the evidence in the case and decides whether the jury could reasonably find the conditional fact ... by a preponderance of the evidence. (citations omitted)" [sic]
The court in Pardon then concluded:
"... we find the State carried its burden of proving the prior bad acts by a preponderance of the evidence." Pardon, supra, at p. 58. However, footnote # 1 in Pardon states: "Because La.Code Evid. Art. 1104 refers to the burden of proof at a hearing only, the impact of this article on the burden of proof at trial is unknown at this point." See Pugh, Force, Rault & Triche, "Handbook on Louisiana Evidence Law".
Our review of the jurisprudence since Pollard reveals the impact of Article 1104 on the burden of proof at trial remains unresolved in Louisiana. For this reason, and because the relevant state law apparently requires that we follow federal law in determining the burden of proof, we shall refer to the Supreme Court of the United States. We have noted that the Supreme Court, in discussing the standard for admissibility of other crimes evidence in Huddleston v. U.S., 485 U.S. 681, 690, 108 S.Ct. 1496, 1501, 99 L.Ed.2d 771, (1988) (emphasis added), stated that the court should decide "whether the jury could reasonably find the conditional fact ... by a preponderance of the evidence."
This language suggests the Huddleston court contemplated that juries would employ the preponderance standard in their assessments of other crimes evidence. Further, the Supreme Court's language in Dowling v. U.S., 493 U.S. 342, 110 S.Ct. 668, 107 L.Ed.2d 708 (1990), a collateral estoppel case, appears to take the same view. In explaining why collateral estoppel did not apply, the Supreme Court noted:
'[S]imilar act evidence is relevant only if the jury can reasonably conclude that the act occurred and that the defendant was the actor.' Because a jury might reasonably conclude that [defendant] was the masked man who entered [victim's] home, even if it did not believe beyond a reasonable doubt that [defendant] committed the crimes charged at the first trial ... the Double Jeopardy Clause is inapposite.
Dowling, 493 U.S. at 348-49, 110 S.Ct. at 672, citing Huddleston, 485 U.S. at 689, 108 S.Ct. at 1501 (emphasis added).
Therefore, following the Huddleston and Dowling cases, we find that the preponderance of evidence standard, rather than a clear and convincing standard of proof, shall apply to both pretrial and trial admissibility involving other crimes evidence. Thus, the trial court did not err in its instruction. Defendant's fourth assignment of error lacks merit.
CONCLUSION
Defendant's conviction and sentence are affirmed. However, we remand the case to the trial court for a proper disposition of count two, possession of methamphetamine, of the bill of information.
*862 AFFIRMED WITH INSTRUCTIONS.
NOTES
[1] An unrelated portion of Wessinger has been suspended by statute. State v. Gomez, 00-0566 (La.1/17/01), 778 So.2d 549.
| 2024-02-04T01:27:15.642919 | https://example.com/article/9122 |
What Kids Need to Learn to Succeed in 2050
The art of reinvention will be the most critical skill of this century
Humankind is facing unprecedented revolutions, all our old stories are crumbling, and no new story has so far emerged to replace them. How can we prepare ourselves and our children for a world of such unprecedented transformations and radical uncertainties? A baby born today will be thirtysomething in 2050. If all goes well, that baby will still be around in 2100 and might even be an active citizen of the 22nd century. What should we teach that baby that will help them survive and flourish in the world of 2050 or the 22nd century? What kind of skills will they need in order to get a job, understand what is happening around them, and navigate the maze of life?
Unfortunately, since nobody knows what the world will look like in 2050 — not to mention 2100 — we don’t know the answer to these questions. Of course, humans have never been able to predict the future with accuracy. But today it is more difficult than ever before because once technology enables us to engineer bodies, brains, and minds, we will no longer be able to be certain about anything — including things that previously seemed fixed and eternal.
A thousand years ago, in 1018, there were many things people didn’t know about the future, but they were nevertheless convinced that the basic features of human society were not going to change. If you lived in China in 1018, you knew that by 1050 the Song Empire might collapse, the Khitans might invade from the north, and plagues might kill millions. However, it was clear to you that even in 1050 most people would still work as farmers and weavers, rulers would still rely on humans to staff their armies and bureaucracies, men would still dominate women, life expectancy would still be about 40, and the human body would remain exactly the same. For that reason, in 1018 poor Chinese parents taught their children how to plant rice or weave silk; wealthier parents taught their boys how to read the Confucian classics, write calligraphy, or fight on horseback, and they taught their girls to be modest and obedient housewives. It was obvious that these skills would still be needed in 1050.
To keep up with the world of 2050, you will need to do more than merely invent new ideas and products, but above all, reinvent yourself again and again.
In contrast, today we have no idea how China or the rest of the world will look in 2050. We don’t know what people will do for a living, we don’t know how armies or bureaucracies will function, and we don’t know what gender relations will be like. Some people will probably live much longer than today, and the human body itself might undergo an unprecedented revolution, thanks to bioengineering and direct brain-to-computer interfaces. Much of what kids learn today will likely be irrelevant by 2050.
At present, too many schools focus on cramming information into kids’ brains. In the past, this made sense, because information was scarce and even the slow trickle of existing information was repeatedly blocked by censorship. If you lived, say, in a small provincial town in Mexico in 1800, it was difficult for you to know much about the wider world. There was no radio, television, daily newspaper, or public library. Even if you were literate and had access to a private library, there was not much to read other than novels and religious tracts. The Spanish empire heavily censored all texts printed locally and allowed only a dribble of vetted publications to be imported from the outside. Much the same was true if you lived in some provincial town in Russia, India, Turkey, or China. When modern schools came along, teaching every child to read and write and imparting the basic facts of geography, history, and biology, they represented an immense improvement.
In contrast, in the 21st century, we are flooded with enormous amounts of information, and the censors don’t even try to block it. Instead, they are busy spreading misinformation or distracting us with irrelevancies. If you live in some provincial Mexican town and have a smartphone, you can spend many lifetimes just reading Wikipedia, watching TED Talks, and taking free online courses. No government can hope to conceal all the information it doesn’t like. On the other hand, it is alarmingly easy to inundate the public with conflicting reports and red herrings. People all over the world are but a click away from the latest accounts of the bombardment of Aleppo or melting ice caps in the Arctic, but there are so many contradictory accounts that it is hard to know what to believe. Besides, countless other things are just a click away as well, making it difficult to focus, and when politics or science look too complicated, it is tempting to switch to some funny cat videos, celebrity gossip, or porn.
In such a world, the last thing a teacher needs to give her pupils is more information. They already have far too much of it. Instead, people need the ability to make sense of information, to tell the difference between what is important and what is unimportant, and, above all, to combine many bits of information into a broad picture of the world.
In truth, this has been the ideal of Western liberal education for centuries, but up until, now even many Western schools have been rather slack in fulfilling it. Teachers allowed themselves to focus on imparting data while encouraging students “to think for themselves.” Due to their fear of authoritarianism, liberal schools have had a particular horror of grand narratives. They’ve assumed that as long as we give students lots of data and a modicum of freedom, the students will create their own picture of the world, and even if this generation fails to synthesize all the data into a coherent and meaningful story about the world, there will be plenty of time to construct a better synthesis in the future.
We have now run out of time. The decisions we will make in the next few decades will shape the future of life itself, and we can make these decisions based only on our present worldview. If this generation lacks a comprehensive view of the cosmos, the future of life will be decided at random.
The Heat Is On
Besides information, most schools also focus too much on providing students with a set of predetermined skills, such as solving differential equations, writing computer code in C++, identifying chemicals in a test tube, or conversing in Chinese. Yet since we have no idea what the world and the job market will look like in 2050, we don’t really know what particular skills people will need. We might invest a lot of effort teaching kids how to write in C++ or speak Chinese, only to discover that by 2050, artificial intelligence can code software far better than humans and a new Google Translate app will enable you to conduct a conversation in almost flawless Mandarin, Cantonese, or Hakka, even though you only know how to say “Ni hao.”
So, what should we be teaching? Many pedagogical experts argue that schools should switch to teaching “the four Cs” — critical thinking, communication, collaboration, and creativity. More broadly, they believe, schools should downplay technical skills and emphasize general-purpose life skills. Most important of all will be the ability to deal with change, learn new things, and preserve your mental balance in unfamiliar situations. To keep up with the world of 2050, you will need to do more than merely invent new ideas and products, but above all, reinvent yourself again and again.
If somebody describes the world of the mid-21st century to you and it doesn’t sound like science fiction, it is certainly false.
For as the pace of change increases, not just the economy, but the very meaning of “being human” is likely to mutate. Already in 1848, the Communist Manifesto declared that “all that is solid melts into air.” Marx and Engels, however, were thinking mainly about social and economic structures. By 2048, physical and cognitive structures will also melt into air, or into a cloud of data bits.
In 1848, millions of people were losing their jobs on village farms and going to the big cities to work in factories. But upon reaching the big city, they were unlikely to change their gender or add a sixth sense. And if they found a job in some textile factory, they could expect to remain in that profession for the rest of their working lives.
By 2048, people might have to cope with migrations to cyberspace, fluid gender identities, and new sensory experiences generated by computer implants. If they find both work and meaning in designing up-to-the-minute fashions for a 3D virtual reality game, within a decade, not just this particular profession, but all jobs demanding this level of artistic creation might be taken over by A.I. So, at age 25, you might introduce yourself on a dating site as “a 25-year-old heterosexual woman who lives in London and works in a fashion shop.” At 35, you might say you are “a gender-nonspecific person undergoing age adjustment, whose neocortical activity takes place mainly in the NewCosmos virtual world, and whose life mission is to go where no fashion designer has gone before.” At 45, both dating and self-definitions are passé. You just wait for an algorithm to find (or create) the perfect match for you. As for drawing meaning from the art of fashion design, you are so irrevocably outclassed by the algorithms that looking at your crowning achievements from the previous decade fills you with embarrassment rather than pride. And you still have many decades of radical change ahead of you.
Please don’t take this scenario literally. Nobody can predict the specific changes we will witness in the future. Any particular scenario is likely to be far from the truth. If somebody describes the world of the mid-21st century to you and it sounds like science fiction, it is probably false. But then again, if somebody describes the world of the mid-21st century to you and it doesn’t sound like science fiction, it is certainly false. We cannot be sure of the specifics; change itself is the only certainty.
Such profound change may well transform the basic structure of life, making discontinuity its most salient feature. From time immemorial, life was divided into two complementary parts: a period of learning followed by a period of working. In the first part of life, you accumulated information, developed skills, constructed a worldview, and built a stable identity. Even if at 15 you spent most of your day working in your family’s rice field (rather than in a formal school), the most important thing you were doing was learning: how to cultivate rice, how to conduct negotiations with the greedy rice merchants from the big city, and how to resolve conflicts over land and water with the other villagers. In the second part of life, you relied on your accumulated skills to navigate the world, earn a living, and contribute to society. Of course, even at 50, you continued to learn new things about rice, merchants, and conflicts, but these were just small tweaks to your well-honed abilities.
By the middle of the 21st century, accelerating change plus longer lifespans will make this traditional model obsolete. Life will come apart at the seams, and there will be less and less continuity between different periods of life. “Who am I?” will be a more urgent and complicated question than ever before.
This is likely to involve immense levels of stress. Change is almost always stressful, and after a certain age most people just don’t like to do it. When you are 15, your entire life is change. Your body is growing, your mind is developing, your relationships are deepening. Everything is in flux, and everything is new. You are busy inventing yourself. Most teenagers find it frightening, but at the same time, it is also exciting. New vistas are opening before you, and you have an entire world to conquer.
By the time you are 50, you don’t want change, and most people have given up on conquering the world. Been there, done that, got the T-shirt. You prefer stability. You have invested so much in your skills, your career, your identity, and your worldview that you don’t want to start all over again. The harder you’ve worked on building something, the more difficult it is to let go of it and make room for something new. You might still cherish new experiences and minor adjustments, but most people in their 50s aren’t ready to overhaul the deep structures of their identity and personality.
There are neurological reasons for this. Though the adult brain is more flexible and volatile than was once thought, it is still less malleable than the teenage brain. Reconnecting neurons and rewiring synapses is hard work. But in the 21st century, you can’t afford stability. If you try to hold on to some stable identity, job, or worldview, you risk being left behind as the world flies by you with a whoosh. Given that life expectancy is likely to increase, you might subsequently have to spend many decades as a clueless fossil. To stay relevant — not just economically but above all socially — you will need the ability to constantly learn and to reinvent yourself, certainly at a young age like 50.
The best advice I can give a 15-year-old is: don’t rely on the adults too much. Most of them mean well, but they just don’t understand the world.
As strangeness becomes the new normal, your past experiences, as well as the past experiences of the whole of humanity, will become less reliable guides. Humans as individuals and humankind as a whole will increasingly have to deal with things nobody ever encountered before, such as super-intelligent machines, engineered bodies, algorithms that can manipulate emotions with uncanny precision, rapid man-made climate cataclysms, and the need to change your profession every decade. What is the right thing to do when confronting a completely unprecedented situation? How should you act when you are flooded by enormous amounts of information and there is absolutely no way you can absorb and analyze it all? How do you live in a world where profound uncertainty is not a bug but a feature?
To survive and flourish in such a world, you will need a lot of mental flexibility and great reserves of emotional balance. You will have to repeatedly let go of some of what you know best, and learn to feel at home with the unknown. Unfortunately, teaching kids to embrace the unknown while maintaining their mental balance is far more difficult than teaching them an equation in physics or the causes of the First World War. You cannot learn resilience by reading a book or listening to a lecture. Teachers themselves usually lack the mental flexibility that the 21st century demands since they themselves are the product of the old educational system.
The Industrial Revolution has bequeathed us the production-line theory of education. In the middle of town, there is a large concrete building divided into many identical rooms, each room equipped with rows of desks and chairs. At the sound of a bell, you go to one of these rooms together with 30 other kids who were all born the same year as you. Every hour a different grown-up walks in and starts talking. The grown-ups are all paid to do so by the government. One of them tells you about the shape of the earth, another tells you about the human past, and a third tells you about the human body. It is easy to laugh at this model, and almost everybody agrees that no matter its past achievements, it is now bankrupt. But so far we haven’t created a viable alternative. Certainly not a scalable alternative that can be implemented in rural Mexico rather than just in wealthy California suburbs.
Hacking Humans
So the best advice I can give a 15-year-old stuck in an outdated school somewhere in Mexico, India, or Alabama is: don’t rely on the adults too much. Most of them mean well, but they just don’t understand the world. In the past, it was a relatively safe bet to follow the adults, because they knew the world quite well, and the world changed slowly. But the 21st century is going to be different. Because of the increasing pace of change, you can never be certain whether what the adults are telling you is timeless wisdom or outdated bias.
So on what can you rely instead? Perhaps on technology? That’s an even riskier gamble. Technology can help you a lot, but if technology gains too much power over your life, you might become a hostage to its agenda. Thousands of years ago humans invented agriculture, but this technology enriched just a tiny elite while enslaving the majority of humans. Most people found themselves working from sunrise till sunset plucking weeds, carrying water buckets, and harvesting corn under a blazing sun. It could happen to you too.
Technology isn’t bad. If you know what you want in life, technology can help you get it. But if you don’t know what you want in life, it will be all too easy for technology to shape your aims for you and take control of your life. Especially as technology gets better at understanding humans, you might increasingly find yourself serving it, instead of it serving you. Have you seen those zombies who roam the streets with their faces glued to their smartphones? Do you think they control the technology, or does the technology control them?
Should you rely on yourself, then? That sounds great on Sesame Street or in an old-fashioned Disney film, but in real life, it doesn’t work so well. Even Disney is coming to realize it. Just like Riley Andersen, most people barely know themselves, and when they try to “listen to themselves” they easily become prey to external manipulations. The voice we hear inside our heads is never trustworthy because it always reflects state propaganda, ideological brainwashing, and commercial advertisements, not to mention biochemical bugs.
As biotechnology and machine learning improve, it will become easier to manipulate people’s deepest emotions and desires, and it will become more dangerous than ever to just follow your heart. When Coca-Cola, Amazon, Baidu, or the government knows how to pull the strings of your heart and press the buttons of your brain, will you still be able to tell the difference between your self and their marketing experts?
If you don’t know what you want in life, it will be all too easy for technology to shape your aims for you and take control of your life.
To succeed at such a daunting task, you will need to work very hard at getting to know your operating system better — to know what you are and what you want from life. This is, of course, the oldest advice in the book: know thyself. For thousands of years, philosophers and prophets have urged people to know themselves. But this advice was never more urgent than in the 21st century, because unlike in the days of Laozi or Socrates, now you have serious competition. Coca-Cola, Amazon, Baidu, and the government are all racing to hack you. Not your smartphone, not your computer, and not your bank account; they are in a race to hack you and your organic operating system. You might have heard that we are living in the era of hacking computers, but that’s not even half the truth. In fact, we are living in the era of hacking humans.
The algorithms are watching you right now. They are watching where you go, what you buy, who you meet. Soon they will monitor all your steps, all your breaths, all your heartbeats. They are relying on Big Data and machine learning to get to know you better and better. And once these algorithms know you better than you know yourself, they can control and manipulate you, and you won’t be able to do much about it. You will live in the matrix, or in The Truman Show. In the end, it’s a simple empirical matter: if the algorithms indeed understand what’s happening within you better than you understand it yourself, authority will shift to them.
Of course, you might be perfectly happy ceding all authority to the algorithms and trusting them to decide things for you and for the rest of the world. If so, just relax and enjoy the ride. You don’t need to do anything about it. The algorithms will take care of everything. If, however, you want to retain some control over your personal existence and the future of life, you have to run faster than the algorithms, faster than Amazon and the government, and get to know yourself before they do. To run fast, don’t take much baggage with you. Leave all your illusions behind. They are very heavy. | 2024-02-24T01:27:15.642919 | https://example.com/article/3836 |
Walter Murton
Walter Murton was a British art director, who worked from the 1920s until the 1940s. During his early career in the 1920s Murton was the regular set designer on the silent film series The Further Adventures of Sherlock Holmes and The Mystery of Dr. Fu Manchu.
Along with Clifford Pember, Murton was identified as part of an "old guard" resisting change in British set design sought by younger set designers and by German immigrants. During his later career Murton worked for Gainsborough Pictures. His final film was the influential Gainsborough Melodrama The Man in Grey (1943). His son Peter Murton was also an art director.
Selected filmography
Open Country (1922)
The Truants (1922)
Petticoat Loose (1922)
The Glorious Adventure (1922)
The Indian Love Lyrics (1923)
The Kensington Mystery (1924)
The Conspirators (1924)
Huntingtower (1928)
A Warm Corner (1930)
The Sport of Kings (1931)
Third Time Lucky (1931)
The Ghost Train (1931)
The Great Barrier (1937)
Second Best Bed (1938)
Strange Boarders (1938)
Climbing High (1938)
Hi Gang! (1941)
We Dive at Dawn (1943)
The Man in Grey (1943)
References
Bibliography
Bergfelder, Tim & Cargnelli, Christian. Destination London: German-speaking emigrés and British cinema, 1925-1950. Berghahn Books, 2008.
External links
Category:1892 births
Category:Year of death unknown
Category:British art directors
Category:People from Norwich | 2023-12-10T01:27:15.642919 | https://example.com/article/1805 |
Hive has launched a bitcoin and litecoin wallet app for iOS devices, including the iPhone, iPad and iPod Touch.
Called Hive Wallet, the app is free, takes up just 2MB of users’ precious memory and requires iOS 7.0 or later to run properly. The company says the app is optimised for the iPhone 5, which will also apply to the subsequent 5S and 5C models.
The company announced its new product with a simple tweet:
The Hive app for iOS was listed on iTunes on 13th August and it is available in German and English language user interfaces. The company already has wallets available for Mac OS X and Android devices, as well as an online version.
Feature set
Following Apple’s controversial ban on cryptocurrency wallets in early 2014, Hive was busy developing a browser-run HTML 5 web wallet that would have circumvented the ruling. However, the change of policy at Apple in June allowed the company to develop this, its first app for iOS.
The new iOS wallet looks rather like a hybrid of the HTML5 app and Hive’s Android equivalent, providing a clean user interface, but with a number of features neatly included without adding clutter.
Notably, the wallet features support for both bitcoin and litecoin, with more cryptocurrencies said to be coming soon.
Like other Hive wallets, it also offers a geo-location feature called ‘Waggle’, which allows users to exchange funds with other nearby Hive users with ease. A native QR code scanner is on board, too.
The new app is a hierarchical deterministic (HD) wallet and Hive says each transaction generates a new address in the BIP32 tree, “ensuring maximum privacy”. With HD wallets, a passphrase is used to generate the wallet, making it recoverable in the event of a lost PIN or corrupted hard drive, and which can be used across devices.
App Store rivals
Since Apple lifted its ban on wallet apps three months ago, we have witnessed an upsurge in mobile wallet development for the platform.
Several familiar apps have now appeared in Apple’s walled garden, including the Blockchain wallet – the most popular wallet out there, with over two million downloads so far (across all platforms). Blockchain saw its original iOS wallet taken down by Apple in February.
Coinbase still has not returned to the App Store, but has approved an unofficial app that launched late in June. | 2023-11-19T01:27:15.642919 | https://example.com/article/7788 |
Bring water and sugar to a boil, stirring with a wooden spoon until sugar is dissolved. Add cranberries and lower flame to a simmer, stirring occasionally. Cook until most of the berries just pop, about 10 minutes. Allow to cool. Taste for sweetness and add more sugar if necessary (dissolved in 2x the amount of water and brought to a boil briefly.) Can be made ahead of time, cover and store in the refrigerator for up to a week. | 2023-08-13T01:27:15.642919 | https://example.com/article/4628 |
Vespa Tour San Zeno - Malcesine
The classic ride that every Holiday-Vespista should have done at least once when visiting Lake Garda. Coming around the tip of San Punto di Vigilio the long stretched part of the lake opens up to you while riding into Torri del Benaco. From there you can take the main road up to Albisano and San Zeno, where you already enjoy beautiful views onto the Lake. The highlight comes when you ride down from San Zeno to Castelletto on the Via Panoramica - incredible views on the Lake which are unparalleled on any other Vespa ride.
Coming to Malcesine you can also ride up to the middle station of the lift, saving you a lot of time and a bit of money because you skip the long waiting line for the lift from Malcesine to the middle station. | 2024-04-19T01:27:15.642919 | https://example.com/article/9788 |
Fuelling social conversation and community through content generation and curation is incredibly important today for brands looking to drive conversion and loyalty around their products and services. But responding to and acting on these interactions presents significant management challenges around IT infrastructure, bandwidth, and tailoring real-time content through analysis to keep the community thriving.
This was the problem facing Australian media company, MMGN, which generates and curates professional and user-generated content to encourage better interaction between individuals in the gaming community. Since its launch, the company has built one of the biggest gaming communities in Australia, with more than 6 million conversations per month, and has 60 moderators working on interaction globally.
More recently, MMGN has also begun providing its community management know-how to corporate clients, helping to improve user engagement for a range of enterprises including DMG Radio, Australia Post and Sensis, and hopes to continue growing this side of its business.
“The idea behind our business is that when users are interacting, lots of interesting things start to happen,” MMGN founder, Roy Hui, told CMO. “People talk about the things they are passionate about and involved in.
“User discussion, user generated content, social discovery and private messaging all increase the amount of time a consumer interacts with a brand. For example, when you read an article about a game, we often provide those consumers with a way to interact with the game and that content, as well as connect with other people that share their passion and interest. That generally increases engagement and with it, business metrics.
“As an innovative and smaller business, we are more agile and can interact more quickly than larger businesses. We can share our success and technology built along the way.”
Hui claimed client-business engagement for organisations that have applied its technology and services to existing communities have increased by up to 250 per cent.
One of the challenges MMGN faced was controlling the costs of IT infrastructure and bandwidth usage in the face of traffic spikes generated by particularly popular content. The company was using a managed services provider in Australia to host its websites and technology services, but struggled under the weight of unpredictable bandwidth charges.
“We were being heavily penalised for growth,”Hui said. “For example, if we had a social uplift from an article that went viral on Reddit, for example, you get a huge spike in global traffic from it, and we were getting punished.”
MMGN opted to switch Amazon Web Services (AWS) in 2009, starting with its storage and content delivery networking capabilities. When the company launched its data centre in Sydney last year, MMGN opted to run its entire infrastructure in an Australian-hosted AWS environment.
Hui claimed AWS offers almost infinite storage and bandwidth capabilities with no penalty for exceeding the monthly quota. He highlighted having its own independent services and full control of its data locally as another welcome improvement.
In addition, combining AWS DynamoDB, a database for fast performance and seamless scalability with ElastiCache, an in-memory caching system solution, has allowed MMGN to store millions of conversations and provide real-time analysis on big data.
Hui said the decision to switch completely to AWS has reduced total operating costs for MMGN by 50 per cent.
Another benefit is that AWS makes all its own infrastructure accessible via APIs, giving the team at MMGN the opportunities to delve into the technical details and really understand new products and usage before having to commit, he said.
Access to enterprise-grade solutions architects is another plus. For example, MMGN had been interested in switching from a traditional MySQL data to a NoSQL non-relational database solution, but was unsure of its effectiveness versus the amount of effort to transition. By escalating the problem, MMGN was able to talk to AWS advisors about the pros and cons and advised to stick with the traditional relational database solution.
“That validation from someone who understands the industry and technology was a nice surprise,” Hui added.
Blog Posts
Ginni Rometty, the CEO of IBM, announced the death of customer segmentation five years ago saying, "The shift is to go from the segment to the individual. She might have been a bit premature for most marketers, but if customer segmentation isn't dead yet, it's definitely on life support.
Andrew Ehrenberg was a giant in the field of marketing science. He believed scientific methods could reveal law-like patterns of how people buy. In this post, I summarise one of Ehrenberg’s most important discoveries and its implications on how people buy brands.
The purpose of Artificial Intelligence (AI) has always been to replace the menial and repetitive tasks we do each day in every sector, so that we can concentrate on doing what we do best. Saving time and money has certainly been a decent outcome as AI infiltrates the business landscape, however, now we are starting to see problems that cause major issues in practice.
Latest Podcast
In this bonus last episode of this new podcast series, BrandHook MD, Pip Stocks, talks with former ANZ group general manager of marketing, Louise Eyres, talks about the importance of thinking like a customer and using intuition to solve customer painpoints.
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Reproduction in whole or in part in any form or medium without express written permission of IDG Communications is prohibited. | 2024-07-04T01:27:15.642919 | https://example.com/article/2134 |
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<meta charset="UTF-8" />
<title>Phaser-Kinetic-Scrolling-Plugin</title>
<script src="js/phaser.min.js" type="text/javascript"></script>
<script src="js/phaser-kinetic-scrolling-plugin.js" type="text/javascript"></script>
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| 2024-01-01T01:27:15.642919 | https://example.com/article/8286 |
2008-07-13
apsrTable
I have needed to do this for a very long time: apsrtable is now completely rewritten. It is temporarily called apsrTable to avoid much confusion with the old one, does things that the old one didn't, and is on its way to being more extensible. It handles lm and glm objects for now. Documentation and formal packaging I will wrap up in the next week.
Its latex code is now much readable, still uses dcolumn, still handles user-supplied standard errors, and it adds a host of features like omitting some rows of like controls, and model naming is flexible. Most importantly it matches variable names across models and leaves holes where they belong. Here's a snippet of sample output:apsrTable(m1,m2,m3,omitcoef=4:17,lev=.1,align="c",model.counter=6,se="robust") | 2024-03-29T01:27:15.642919 | https://example.com/article/5418 |
;;; userlock.el --- handle file access contention between multiple users
;; Copyright (C) 1985-1986, 2001-2017 Free Software Foundation, Inc.
;; Author: Richard King
;; (according to authors.el)
;; Maintainer: emacs-devel@gnu.org
;; Keywords: internal
;; Package: emacs
;; This file is part of GNU Emacs.
;; GNU Emacs 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.
;; GNU Emacs 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 GNU Emacs. If not, see <http://www.gnu.org/licenses/>.
;;; Commentary:
;; This file is autoloaded to handle certain conditions
;; detected by the file-locking code within Emacs.
;; The two entry points are `ask-user-about-lock' and
;; `ask-user-about-supersession-threat'.
;;; Code:
(define-error 'file-locked "File is locked" 'file-error)
;;;###autoload
(defun ask-user-about-lock (file opponent)
"Ask user what to do when he wants to edit FILE but it is locked by OPPONENT.
This function has a choice of three things to do:
do (signal \\='file-locked (list FILE OPPONENT))
to refrain from editing the file
return t (grab the lock on the file)
return nil (edit the file even though it is locked).
You can redefine this function to choose among those three alternatives
in any way you like."
(discard-input)
(save-window-excursion
(let (answer short-opponent short-file)
(setq short-file
(if (> (length file) 22)
(concat "..." (substring file (- (length file) 22)))
file))
(setq short-opponent
(if (> (length opponent) 25)
(save-match-data
(string-match " (pid [0-9]+)" opponent)
(concat (substring opponent 0 13) "..."
(match-string 0 opponent)))
opponent))
(while (null answer)
(message "%s locked by %s: (s, q, p, ?)? "
short-file short-opponent)
(let ((tem (let ((inhibit-quit t)
(cursor-in-echo-area t))
(prog1 (downcase (read-char))
(setq quit-flag nil)))))
(if (= tem help-char)
(ask-user-about-lock-help)
(setq answer (assoc tem '((?s . t)
(?q . yield)
(?\C-g . yield)
(?p . nil)
(?? . help))))
(cond ((null answer)
(beep)
(message "Please type q, s, or p; or ? for help")
(sit-for 3))
((eq (cdr answer) 'help)
(ask-user-about-lock-help)
(setq answer nil))
((eq (cdr answer) 'yield)
(signal 'file-locked (list file opponent)))))))
(cdr answer))))
(defun ask-user-about-lock-help ()
(with-output-to-temp-buffer "*Help*"
(princ "It has been detected that you want to modify a file that someone else has
already started modifying in Emacs.
You can <s>teal the file; the other user becomes the
intruder if (s)he ever unmodifies the file and then changes it again.
You can <p>roceed; you edit at your own (and the other user's) risk.
You can <q>uit; don't modify this file.")
(with-current-buffer standard-output
(help-mode))))
(define-error 'file-supersession nil 'file-error)
;;;###autoload
(defun ask-user-about-supersession-threat (fn)
"Ask a user who is about to modify an obsolete buffer what to do.
This function has two choices: it can return, in which case the modification
of the buffer will proceed, or it can (signal \\='file-supersession (file)),
in which case the proposed buffer modification will not be made.
You can rewrite this to use any criterion you like to choose which one to do.
The buffer in question is current when this function is called."
(discard-input)
(save-window-excursion
(let ((prompt
(format "%s changed on disk; \
really edit the buffer? (y, n, r or C-h) "
(file-name-nondirectory fn)))
(choices '(?y ?n ?r ?? ?\C-h))
answer)
(while (null answer)
(setq answer (read-char-choice prompt choices))
(cond ((memq answer '(?? ?\C-h))
(ask-user-about-supersession-help)
(setq answer nil))
((eq answer ?r)
;; Ask for confirmation if buffer modified
(revert-buffer nil (not (buffer-modified-p)))
(signal 'file-supersession
(list "File reverted" fn)))
((eq answer ?n)
(signal 'file-supersession
(list "File changed on disk" fn)))))
(message
"File on disk now will become a backup file if you save these changes.")
(setq buffer-backed-up nil))))
(defun ask-user-about-supersession-help ()
(with-output-to-temp-buffer "*Help*"
(princ "You want to modify a buffer whose disk file has changed
since you last read it in or saved it with this buffer.
If you say `y' to go ahead and modify this buffer,
you risk ruining the work of whoever rewrote the file.
If you say `r' to revert, the contents of the buffer are refreshed
from the file on disk.
If you say `n', the change you started to make will be aborted.
Usually, you should type `n' and then `\\[revert-buffer]',
to get the latest version of the file, then make the change again.")
(with-current-buffer standard-output
(help-mode))))
;;; userlock.el ends here
| 2023-08-01T01:27:15.642919 | https://example.com/article/7358 |
Our custom design service allows you to maximise the energy saving benefits of using energy efficient materials while still maintaining the visual appeal and integrity of your project.
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Thermally broken windows also offer a high degree of acoustic insulation. Noise infiltration is minimised through the use of the highest standard of sealing possible.
With over 25 years experience in the building industry, Creative Windows have wide ranging experience in both the domestic and commercial building markets.
Creative Windows routinely work with many prominent and award winning architects and builders to offer creative solutions to your window and door design concepts.
This custom design service sets Creative Windows apart from so many of our competitors.
Creative Windows work in the specialist market of architect designed and custom made aluminium windows, doors and skylights.
Through our use of commercial grade materials, fixtures and fittings, we offer a competitive alternative to those customers for whom quality, workmanship, service and distinctive good looks are all important features. | 2024-05-19T01:27:15.642919 | https://example.com/article/5497 |
1984 Fischer-Grand Prix
The 1984 Fischer-Grand Prix was a men's tennis tournament played on indoor hard courts at the Wiener Stadthalle in Vienna, Austria that was part of the 1984 Volvo Grand Prix. It was the tenth edition of the tournament and was held from 22 October until 29 October 1984. Eighth-seeded Tim Wilkison won the singes title.
Finals
Singles
Tim Wilkison defeated Pavel Složil 6–1, 6–1, 6–2
It was Wilkison's 1st title of the year and the 8th of his career.
Doubles
Wojciech Fibak / Sandy Mayer defeated Heinz Günthardt / Balázs Taróczy 6–4, 6–4
It was Fibak's 4th title of the year and the 61st of his career. It was Mayer's 4th title of the year and the 34th of his career.
References
External links
ATP tournament profile
ITF tournament edition details
Fischer-Grand Prix
Category:Vienna Open | 2024-05-28T01:27:15.642919 | https://example.com/article/3023 |
| Palestine | Brazilians workers support Palestinian teacher strikers
Workers’ organizations affiliated to the CSP-Conlutas express their solidarity with the historical strike of Palestinian teachers, which began on 10 February.
The strike has being held for ensuring labor rights and against the Palestinian Authority policies (ANP), which maintains security cooperation with Israel. Despite the repression, which resulted in temporary prisons, the strike strengthens and gets support. Several demonstrations have gathered thousands in the occupied Palestinian streets. The representation of the CSP-Conlutas was present at one of them, on last 23th.
The mobilization requires implementation of a labor agreement signed in 2013 and also faces with the labor union, which failed to defend the rights and interests of teachers, losing legitimacy with the people they represent. The average salary of a Palestinian teacher does not exceed 3000 shekels (equivalent to R $ 3,040.00) per month. To get an idea, the average monthly expenditure on rent in Ramallah is around 1,370 shekels, almost half the salary of a teacher.
The arrests denounce the unfortunate role of ANP in repressing struggle of workers and Palestinian youth, either by their basic rights such as better wages and benefits, either against the State of Israel. This has been the center of the ANP role, which intensifies while intifada (popular uprising) is on the way.
These workers keep on fighting. In solidarity, we demand dignity to Palestinian teachers and the end of the agreements between PA and Israel. | 2024-02-15T01:27:15.642919 | https://example.com/article/8474 |
1. Introduction {#sec1-molecules-22-01650}
===============
Disaccharide nucleosides, which contain an external sugar moiety linked to one of the hydroxyl groups of the nucleoside via an *O*-glycoside bond, constitute an important class of natural compounds \[[@B1-molecules-22-01650],[@B2-molecules-22-01650],[@B3-molecules-22-01650],[@B4-molecules-22-01650],[@B5-molecules-22-01650],[@B6-molecules-22-01650],[@B7-molecules-22-01650]\]. They are found in biopolymers, such as tRNA and poly(ADP-ribose), as well as antibiotics and other biologically-active compounds \[[@B5-molecules-22-01650],[@B6-molecules-22-01650],[@B8-molecules-22-01650],[@B9-molecules-22-01650],[@B10-molecules-22-01650],[@B11-molecules-22-01650]\]. Adenophostins \[[@B12-molecules-22-01650],[@B13-molecules-22-01650],[@B14-molecules-22-01650],[@B15-molecules-22-01650]\], HF-7 \[[@B16-molecules-22-01650]\], amicetin analogs \[[@B6-molecules-22-01650],[@B17-molecules-22-01650]\], ezomycin \[[@B18-molecules-22-01650]\] and some candidates for inhibitors of chitin synthase \[[@B19-molecules-22-01650]\] are typical examples of disaccharide nucleosides that contain adenine, guanine, cytosine and uracil moieties, respectively. Therefore, disaccharide nucleosides and their analogs would be expected to be good drug candidates.
Several strategies for the synthesis of disaccharide nucleosides such as enzymatic *O*-glycosylation \[[@B20-molecules-22-01650],[@B21-molecules-22-01650]\], chemical *N*-glycosylation \[[@B5-molecules-22-01650],[@B9-molecules-22-01650],[@B16-molecules-22-01650],[@B22-molecules-22-01650],[@B23-molecules-22-01650],[@B24-molecules-22-01650]\] and chemical *O*-glycosylation \[[@B7-molecules-22-01650],[@B9-molecules-22-01650],[@B14-molecules-22-01650],[@B16-molecules-22-01650],[@B18-molecules-22-01650],[@B19-molecules-22-01650],[@B24-molecules-22-01650],[@B25-molecules-22-01650],[@B26-molecules-22-01650],[@B27-molecules-22-01650],[@B28-molecules-22-01650],[@B29-molecules-22-01650],[@B30-molecules-22-01650],[@B31-molecules-22-01650],[@B32-molecules-22-01650],[@B33-molecules-22-01650],[@B34-molecules-22-01650],[@B35-molecules-22-01650],[@B36-molecules-22-01650],[@B37-molecules-22-01650]\] have been reported to date. Chemical *O*-glycosylation is often useful for the large-scale synthesis of the desired disaccharide nucleosides in higher chemical yields compared to chemical *N*-glycosylation. However, the neutralization of promoters, which are generally Lewis or Brønsted acids, by the nucleobase moieties would be a possible drawback. Moreover, it is reported that an excess amount of the glycosyl donor is required for glycosylation at the hydroxyl site to be complete, because it is likely that glycosylation preferentially proceeds on the nucleobase or other Lewis basic site \[[@B18-molecules-22-01650],[@B32-molecules-22-01650],[@B34-molecules-22-01650],[@B36-molecules-22-01650]\]. Side reactions such as depurination (cleavage of the anomeric C--N bond of nucleosides), anomerization reaction and trans-purinylation have also been reported \[[@B35-molecules-22-01650],[@B38-molecules-22-01650],[@B39-molecules-22-01650]\].
We previously reported on the synthesis of disaccharide nucleosides **3** by the direct *O*-glycosylation of 2'-deoxyribonucleoside **2** with the thioglycosyl donor **1** (PG: protecting group) ([Figure 1](#molecules-22-01650-f001){ref-type="fig"}a) \[[@B40-molecules-22-01650]\]. Among the glycosyl promoters tested, a combination of *p*-toluenesulfenyl chloride (*p*-TolSCl) and silver triflate (AgOTf) was found to give the corresponding products in moderate to high chemical yields. These results prompted us to investigate the synthesis of disaccharide nucleosides via the *O*-glycosylation of ribonucleosides. The synthesis of disaccharide nucleosides using protected ribonucleosides as glycosyl acceptors, which requires tedious protecting group manipulations, has been reported in previous studies \[[@B7-molecules-22-01650],[@B9-molecules-22-01650],[@B14-molecules-22-01650],[@B16-molecules-22-01650],[@B18-molecules-22-01650],[@B19-molecules-22-01650],[@B24-molecules-22-01650],[@B32-molecules-22-01650],[@B33-molecules-22-01650],[@B34-molecules-22-01650],[@B35-molecules-22-01650],[@B36-molecules-22-01650],[@B37-molecules-22-01650]\]. The development of direct and regioselective *O*-glycosylation using unprotected or temporarily-protected ribonucleosides would afford a more convenient synthetic route to prepare various biologically-active derivatives.
In this manuscript, we report on the *O*-glycosylation of unprotected ribonucleosides **4** at the 5′-hydroxyl group via the temporary protection of the 2′,3′-*cis*-diol by a boronic ester **6**. It has been reported that boronic and borinic acids are capable of forming the cyclic esters with carbohydrate derivatives \[[@B41-molecules-22-01650],[@B42-molecules-22-01650]\], and such derivatives have been utilized for regio- and/or stereo-selective alkylation, acylation, silylation and glycosylation \[[@B43-molecules-22-01650],[@B44-molecules-22-01650],[@B45-molecules-22-01650],[@B46-molecules-22-01650],[@B47-molecules-22-01650],[@B48-molecules-22-01650],[@B49-molecules-22-01650],[@B50-molecules-22-01650],[@B51-molecules-22-01650],[@B52-molecules-22-01650],[@B53-molecules-22-01650]\]. In our strategy, the ribonucleoside **4** is treated with the boronic acid **5** to temporarily protect the 2′,3′-*cis*-diol of **4** to prepare **6** in situ, which is then *O*-glycosylated at the 5'-hydroxyl group with the glycosyl donor **7** to afford the disaccharide nucleosides **8** in a regioselective manner ([Figure 1](#molecules-22-01650-f001){ref-type="fig"}b) (in this manuscript, "disaccharide nucleosides" include the glycosylated deoxyribonucleosides and ribonucleosides, due to the generally-used terminology).
2. Results and Discussion {#sec2-molecules-22-01650}
=========================
2.1. O-Glycosylation of Nucleosides with Thioglycosyl Donors {#sec2dot1-molecules-22-01650}
------------------------------------------------------------
We first examined the *O*-glycosylation of uridine **10** with the thiomannoside **9** \[[@B54-molecules-22-01650]\] using 3.0 equivalents of *p*-TolSCl and 6.0 equivalents of AgOTf \[[@B55-molecules-22-01650],[@B56-molecules-22-01650]\] against **10** (i.e., 2.0 equivalents of *p*-TolSCl and 4.0 equivalents of AgOTf against **9** according to our previous paper \[[@B40-molecules-22-01650]\]). Thioglycosides are one of the most popular glycosyl donor due to their ease of preparation and modification, high stability and the many available activation methods \[[@B25-molecules-22-01650],[@B26-molecules-22-01650],[@B27-molecules-22-01650],[@B28-molecules-22-01650],[@B29-molecules-22-01650],[@B57-molecules-22-01650]\]. After the glycosylation and crude purification, the resulting compounds were acetylated to permit the desired products to be purified more easily.
The results for the glycosylation reactions are summarized in [Table 1](#molecules-22-01650-t001){ref-type="table"}. In Entry 1, the glycosylation of **10** with **9** without boronic acid derivatives gave a complex mixture. In Entry 2, a mixture of **10** and phenylboronic acid **11a** was co-evaporated with pyridine and 1,4-dioxane followed by stirring in 1,4-dioxane under reflux conditions \[[@B44-molecules-22-01650]\] to prepare the temporary 2′,3′-*cis*-diol-protected intermediate **6** (in [Figure 1](#molecules-22-01650-f001){ref-type="fig"}), to which **9** (corresponding to **7** in [Figure 1](#molecules-22-01650-f001){ref-type="fig"}) was added. The glycosylation of **6** proceeded at its 5′-OH to afford **12** (corresponding to **8** in [Figure 1](#molecules-22-01650-f001){ref-type="fig"}) in 41% (α/β = 1.6/1) in a regioselective manner. The formation of a 1′′,5′-glycosidic linkage of **12** was confirmed by comparing its ^1^H NMR spectrum with that of the authentic sample prepared by another synthetic route, in which the chemical yield was 20% for four steps from **10** to **12** (excluding the steps required for the preparation of **9**; see [Scheme S1](#app1-molecules-22-01650){ref-type="app"} in the [Supplementary Materials](#app1-molecules-22-01650){ref-type="app"}). In Entry 3, a mixture of **9**, **10** and **11a** was co-evaporated with pyridine and 1,4-dioxane, and the resulting mixture was treated with promoters to give **12** in a yield nearly similar to that for Entry 2. In the following Entries 4--10, therefore, glycosylation reactions were conducted using a procedure similar to that used in Entry 3 for easy manipulation.
The electrostatic effect of the substituents of the boronic acid was studied in Entries 4--6. Glycosylations using 4-methoxyphenylboronic acid (4-MeOPhB(OH)~2~) **11b**, 4-(trifluoromethyl)phenylboronic acid (4-CF~3~PhB(OH)~2~) **11c** and 2,4-difluorophenylboronic acid (2,4-F~2~PhB(OH)~2~) **11d** were conducted to give **12** in 39%, 51% and 46%, respectively, suggesting the positive effect of electron-withdrawing moieties such as -CF~3~ and -F on the aromatic ring of the boronic acid.
The solvent effect was also examined in Entries 7--9. It is well known that glycosylation in an ether-type solvent such as Et~2~O, THF and 1,4-dioxane enhances α-stereoselectivity \[[@B58-molecules-22-01650],[@B59-molecules-22-01650]\]. As shown in Entry 7, 1,4-dioxane improved the α-stereoselectivity of the reaction, while the chemical yield was unsatisfactory. In Entry 8, CH~2~Cl~2~ gave a negligible amount of **12**, due to the low solubility of the substrates. Glycosylation using EtCN gave **12** in higher chemical yield (Entry 9) than those for 1,4-dioxane (Entry 7) and MeCN (Entry 3), and the stereoselectivity was nearly the same as that in MeCN (Entry 3).
In Entry 10, glycosylation using lower equivalents of promoters (1.8 equivalents of *p*-TolSCl and 3.6 equivalents of AgOTf against **10**) than those in Entry 9 gave similar results. Therefore, 3.0 equivalents and 6.0 equivalents of *p*-TolSCl and AgOTf were used in the following *O*-glycosylations to complete the reactions. In Entry 11, phenylboronic acid having a C6 alkyl chain **11e** was used to improve the solubility of the boronic ester, albeit the chemical yield was not improved.
The *O*-glycosylation of adenosine **13** with **9** was examined next. As shown in Entry 1 of [Table 2](#molecules-22-01650-t002){ref-type="table"}, *O*-glycosylation in the absence of boronic acid derivatives gave a complex mixture, as in the case of uridine (Entry 1 in [Table 1](#molecules-22-01650-t001){ref-type="table"}). In Entries 2 and 3, in which PhB(OH)~2~ **11a** and 4-CF~3~PhB(OH)~2~ **11c** were used, **14** was produced, but the yields were lower (14% and 11%, respectively) than those of **10** in Entries 3 and 9 of [Table 1](#molecules-22-01650-t001){ref-type="table"}, which can be attributed to the trans-purinylation of **13** and/or **14** (*N*-mannosyl adenine **15** was isolated in 6--27%) \[[@B36-molecules-22-01650]\].
We attempted the *O*-glycosylations of various nucleosides **10**, **13** and **16**--**22** with the thiogalactoside **23**, in which the hydroxyl groups were protected by benzoyl groups to achieve β-selective *O*-glycosylation by neighboring group participation at the O2 benzoyl group ([Table 3](#molecules-22-01650-t003){ref-type="table"}). The formation of a β-1′′,5′-glycosidic linkage between the galactose moiety and ribonucleoside in the products **24**--**32** was confirmed by NNR measurements (^1^H NMR, ^13^C NMR, ^1^H-^1^H COSY, HMQC and HMBC). As listed in [Table 3](#molecules-22-01650-t003){ref-type="table"}, the reaction of the unprotected and *N*-protected adenosine, **13** and **16** \[[@B60-molecules-22-01650]\], afforded the desired products β-**24** and β-**25** in 42% and 30%, respectively (Entries 1 and 2). Note that the use of unprotected adenosine **13** gave a better yield than that for the protected **16**, phenomena similar to the *O*-glycosylation of 2'-deoxyadenosine reported by us in a previous study ([Figure 1](#molecules-22-01650-f001){ref-type="fig"}a) \[[@B40-molecules-22-01650]\]. It should also be noted that the reaction of **13** with **23** (Entry 1) gave negligible amounts of *N*-galactosyl adenine as a byproduct unlike the use of the mannosyl donor **9** in an *O*-glycosylation reaction (Entries 2 and 3 in [Table 2](#molecules-22-01650-t002){ref-type="table"}). In Entries 3 and 4, the reaction of the unprotected and *N*-protected guanosine, **17** and **18** \[[@B61-molecules-22-01650]\], afforded the corresponding products β-**26** and β-**27** in 12% and 44%, respectively. The higher yield of β-**27** is possibly due to better solubility of the boronic ester intermediate prepared from the *N*-protected **18** in EtCN than that from the unprotected **17**. In Entry 5, the *O*-glycosylation of uridine **10** with **23** gave the desired product β-**28** in 42% yield, and the electrophilic substitution reaction at the 5-position of the uracil moiety of **10** and/or β-**28** with the *p*-toluenesulfenyl cation was observed (*ca.* 15%) \[[@B62-molecules-22-01650]\]. In Entries 6 and 7, the *O*-glycosylation of 5-metyluridine **19** and 5-fluorouridine **20** afforded the corresponding products β-**29** and β-**30** in 53% and 61%, respectively. In Entries 8 and 9, the reaction of the unprotected and *N*-protected cytidine, **21** and **22** \[[@B63-molecules-22-01650]\], afforded β-**31** and β-**32** in 55% and 40%, respectively. It should be noted that the use of the unprotected **21** gave β-**31** in slightly higher yield than β-**32** from the protected **22**.
The *O*-glycosylation of 5-fluorouridine **20** with glucosyl, galactosyl and mannosyl donors was also examined. As summarized in [Table 4](#molecules-22-01650-t004){ref-type="table"}, the glucosyl donor **33** \[[@B64-molecules-22-01650]\] and the galactosyl donor **23** afforded the corresponding products β-**35** and β-**30** in reasonably acceptable yields, while the use of the mannosyl donor **34** \[[@B65-molecules-22-01650]\] gave a mixture.
2.2. O-Glycosylation of Nucleosides with Thioglycosyl Donors Containing the Boronic Acid Moiety on the Leaving Group {#sec2dot2-molecules-22-01650}
--------------------------------------------------------------------------------------------------------------------
Shen and co-workers recently reported on the 1,2-*cis* glycosylation of some simple alcohols using glucosyl donors containing a boronic acid moiety on the leaving group, which is referred to leaving group-based aglycon delivery \[[@B48-molecules-22-01650]\]. These results prompted us to examine the use of the thioglycosyl donor **37** containing a boronic acid moiety on the leaving group, which was expected to form a boronic ester with the 2′,3′-*cis*-diol of ribonucleoside **38** to give the intermediate **39** ([Figure 2](#molecules-22-01650-f002){ref-type="fig"}). It was expected that the *O*-glycosylation of **39** would produce **40** in a pseudo-intramolecular manner.
In [Table 5](#molecules-22-01650-t005){ref-type="table"}, the results for the *O*-glycosylation of uridine **10** and adenosine **13** with the glycosyl donors **41** and **42** ([Schemes S2 and S3 in the Supplementary Materials](#app1-molecules-22-01650){ref-type="app"}) are summarized. In Entries 1 and 2, the reactions of **10** and **13** with **41** afforded the corresponding products **12** and **14** in 44% (α/β = 1.9/1) and 16% (α/β = 1.3/1), respectively. In Entries 3 and 4, **42** gave the almost the same chemical yields and stereoselectivities as those in Entries 1 and 2. These results are similar to Entry 3 in [Table 1](#molecules-22-01650-t001){ref-type="table"} and Entry 2 in [Table 2](#molecules-22-01650-t002){ref-type="table"}, in which **10** or **13** was reacted with **9** and phenylboronic acid **11a** under the same conditions in [Table 5](#molecules-22-01650-t005){ref-type="table"}, indicating that the introduction of a boronic acid on the thiophenyl leaving group in our reactions has a negligible effect on the overall reaction.
2.3. Deprotection of the Glycosylation Products {#sec2dot3-molecules-22-01650}
-----------------------------------------------
The deprotection of the glycosylation product **12** (α/β = 1.6/1) involved a treatment with aqueous LiOH to afford α-**43** and β-**43**, which were separated by silica gel column chromatography. The deprotection of the benzyl groups of α-**43** and β-**43** under traditional reaction conditions (10% Pd/C with H~2~ gas) gave α-**44** and β-**44**, respectively ([Scheme 1](#molecules-22-01650-sch001){ref-type="scheme"}a) \[[@B66-molecules-22-01650]\]. The deprotection of β-**30** by treatment with MeNH~2~ \[[@B67-molecules-22-01650]\] afforded β-**45** \[[@B68-molecules-22-01650]\] in 62% ([Scheme 1](#molecules-22-01650-sch001){ref-type="scheme"}b).
2.4. Interaction of Uridine and 4-(Trifluoromethyl)phenylboronic Acid Studied by ^1^H, ^11^B and ^19^F NMR Spectroscopy {#sec2dot4-molecules-22-01650}
-----------------------------------------------------------------------------------------------------------------------
The temporary protection of the 2'3'-*cis*-diol of ribonucleoside with a boronic acid was checked by NMR spectroscopy. The ^1^H, ^11^B and ^19^F NMR measurements of uridine **10**, 4-(trifluoromethyl)phenylboronic acid **11c** and a mixture of **10** and **11c** were undertaken in CD~3~CN ([Figure 3](#molecules-22-01650-f003){ref-type="fig"}). For the preparation of the third sample, a mixture of **10** and **11c** was azeotroped with pyridine and 1,4-dioxane, followed by stirring in 1,4-dioxane under the reflux conditions for 1 h. For comparison, **11c** was azeotroped in a similar manner, and the ^11^B and ^19^F NMR spectra of the resulting mixture were obtained. As shown in [Figure 3](#molecules-22-01650-f003){ref-type="fig"}a,b, the peaks for the 2′ and 3′ hydroxyl groups disappeared, and the 2′ and 3′ proton signals were shifted considerably upfield upon the addition of **11c**. In [Figure 3](#molecules-22-01650-f003){ref-type="fig"}c--e, it was assumed that the peaks at 21 ppm, 28 ppm and 32 ppm correspond to a 2,4,6-tris\[4-(trifluorometyl)phenyl\]boroxine pyridine complex, the proposed structure of which is **49** (some NMR spectra of boroxine pyridine complexes were reported \[[@B69-molecules-22-01650],[@B70-molecules-22-01650],[@B71-molecules-22-01650]\]), **11c** or 2,4,6-tris\[4-(trifluorometyl)phenyl\]boroxine and the desired boronic ester **47**, respectively. In [Figure 3](#molecules-22-01650-f003){ref-type="fig"}f--h, we assumed that the peaks at −63.3 ppm, −63.2 ppm and −62.8 ppm correspond to **47**, **11c** or 2,4,6-tris\[4-(trifluorometyl)phenyl\]boroxine and **49**, respectively.
3. Materials and Methods {#sec3-molecules-22-01650}
========================
3.1. General Information {#sec3dot1-molecules-22-01650}
------------------------
Reagents and solvents were commercially purchased, were the highest commercial quality available and were used without further purification. Anhydrous CH~2~Cl~2~ was prepared by distillation from calcium hydride. Acetonitrile and propionitrile were prepared by distillation from calcium hydride and the successive distillation from phosphorus (V) oxide. Anhydrous 1,4-dioxane was prepared by distillation from sodium. All aqueous solutions were prepared using deionized water.
^1^H (300 and 400 MHz), ^11^B (128 MHz), ^13^C (75 and 100 MHz) and ^19^F (376 MHz) NMR spectra were recorded on a JEOL Always 300 (JEOL, Tokyo, Japan) and a JEOL Lamda 400 (JEOL, Tokyo, Japan) spectrometer. Tetramethylsilane (TMS) was used as an internal reference for ^1^H and ^13^C NMR measurements in CDCl~3~, CD~3~OD, CD~3~CN, acetone-*d*~6~ and DMSO-*d*~6~. 3-(Trimethylsilyl)propionic-2,2,3,3-*d*~4~ acid sodium (TSP) was used as an internal reference for ^1^H NMR measurements in D~2~O. 1,4-Dioxane was used as an internal reference for ^13^C NMR measurements in D~2~O. ^11^B and ^19^F NMR spectra were measured in a quartz NMR tube. The boron trifluoride-diethyl ether complex (BF~3~·OEt~2~) in CDCl~3~ was used as an external reference (0 ppm) for ^11^B NMR, and trifluoroacetic acid (TFA) in CDCl~3~ was used as an external reference (−76.5 ppm) for ^19^F NMR. IR spectra were recorded on a Perkin-Elmer FTIR Spectrum 100 (ATR) (PerkinElmer, Massachusetts, USA). MS measurements were performed on a JEOL JMS-700 (JEOL, Tokyo, Japan) and Varian 910-MS (Varian Medical Systems, California, USA) spectrometer. Elemental analyses were performed on a Perkin-Elmer CHN 2400 analyzer (PerkinElmer, Massachusetts, USA). Optical rotations were measured with a JASCO P-1030 digital polarimeter (JASCO, Tokyo, Japan) in 50-mm cells using the D line of sodium (589 nm). Thin-layer chromatography (TLC) and silica gel column chromatography were performed using Merck Silica gel 60 F~254~ plate (Merck KGaA, Darmstadt, Germany) and Fuji Silica Chemical FL-100D (Fuji Silysia Chemical, Aichi, Japan), respectively. HPLC experiments were carried out using a system consisting of a PU-2089 Plus intelligent HPLC pump (JASCO, Tokyo, Japan), a UV-2075 Plus intelligent UV-visible detector (JASCO, Tokyo, Japan), a Rheodine injector (Model No. 7125) and a Chromatopak C-R8A (Shimadzu, Kyōto, Japan). For preparative HPLC, a SenshuPak Pegasil ODS column (Senshu Scientific Co., Ltd., Tokyo, Japan) (20φ × 250 mm, No. 0509271H) was used. GPC experiments were carried out using a system consisting of a POMP P-50 (Japan Analytical Industry Co., Ltd., Tokyo, Japan), a UV/VIS DETECTOR S-3740 (Soma, Tokyo, Japan), a Manual Sample Injector 7725i (Rheodyne, Bensheim, Germany) and an MDL-101 1 PEN RECORDER (Japan Analyrical Industry Co., Ltd., Tokyo, Japan), equipped with two GPC columns, JAIGEL-1H and JAIGEL-2H (Japan Analyrical Industry Co., Ltd., Tokyo, Japan) (20φ × 600 mm, No. A605201 and A605204).
3.2. Synthesis of Compounds {#sec3dot2-molecules-22-01650}
---------------------------
*2′,3′-Di-O-acetyl-5′-O-(6′′-O-acetyl-2′′,3′′,4′′-tri-O-benzyl-α/β-[d]{.smallcaps}-mannopyranosyl)uridine* (**12**) (Entry 9 in [Table 1](#molecules-22-01650-t001){ref-type="table"}): A mixture of **9** (28.4 mg, 48.6 µmol), **10** (7.9 mg, 32.4 µmol) and **11c** (9.3 mg, 49.0 µmol) was co-evaporated with anhydrous pyridine (three times) and anhydrous 1,4-dioxane (three times) and dissolved in anhydrous 1,4-dioxane (320 µL). This reaction mixture was stirred under reflux conditions for 1 h and concentrated under reduced pressure. The resulting mixture was stirred with activated 4 Å molecular sieves (64 mg) in anhydrous EtCN (640 µL) at room temperature for 30 min and then cooled to −40 °C, to which *p*-TolSCl (12.8 µL, 96.8 µmol) and AgOTf (49.9 mg, 194 µmol) were added at the same temperature. After stirring for 1.5 h at −40 °C, the reaction mixture was quenched with saturated aqueous NaHCO~3~, diluted with CHCl~3~ and filtered through Celite. The organic layer was washed with saturated aqueous NaHCO~3~ and brine, dried over Na~2~SO~4~, filtered and concentrated under reduced pressure. The remaining residue was purified by silica gel column chromatography (CHCl~3~/MeOH = 1/0--50/1) to give 5′-*O*-(6′′-*O*-acetyl-2′′,3′′,4′′-tri-*O*-benzyl-α/β-[d]{.smallcaps}-mannopyranosyl)uridine including a small amount of byproducts as a colorless syrup (15.2 mg). To the resulting crude compound in anhydrous pyridine (200 µL), Ac~2~O (20.4 µL, 21.6 µmol, 10.0 equiv. based on the crude compound) and DMAP (catalytic amount) were added at 0 °C. The reaction mixture was stirred at the same temperature for 30 min and then allowed to warm to room temperature. After stirring overnight, the reaction mixture was diluted with CHCl~3~, washed with 1 M aqueous HCl, saturated aqueous NaHCO~3~ and brine, dried over Na~2~SO~4~, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl~3~/MeOH = 1/0--90/1) to give **12** as a colorless amorphous solid (15.8 mg, 61% yield for 3 steps, α/β = 1.6/1): ^1^H NMR (300 MHz, CDCl~3~, TMS): δ = 8.56 (s, 0.6H), 8.29 (s, 0.4H), 7.89 (d, *J* = 8.1 Hz, 0.4H), 7.41--7.19 (m, 15.6H), 6.29 (d, *J* = 7.2 Hz, 0.4H), 6.15--6.05 (m, 0.6H), 5.55 (dd, *J* = 5.1, 1.2 Hz, 0.4H), 5.39 (dd, *J* = 8.1, 1.8 Hz, 0.6H), 5.33--5.23 (m, 2H), 5.01--4.86 (m, 2H), 4.80--4.55 (m, 4.6H), 4.46 (s, 0.4H), 4.39--4.21 (m, 3H), 4.13 (dd, *J* = 10.5, 1.8 Hz, 0.4H), 4.05 (d, *J* = 2.7 Hz, 0.4H), 3.99--3.84 (m, 2.2H), 3.84--3.68 (m, 1.6H), 3.68--3.57 (m, 1H), 3.44 (dt, *J* = 9.9, 6.9 Hz, 0.4H), 2.15 (s, 1.2H), 2.12 (s, 1.8H), 2.09 (s, 1.2H), 2.09 (s, 1.8H), 2.06 (s, 1.8H), 2.00 (s, 1.2H) ppm; ^13^C NMR (100 MHz, CDCl~3~, TMS): δ = 170.9, 170.8, 170.1, 169.8, 169.7, 169.6, 162.8, 162.6, 150.8, 150.4, 141.0, 138.8, 138.2, 137.9, 137.8, 137.7, 128.5, 128.5, 128.4, 128.4, 128.1, 128.1, 128.0, 127.9, 127.8, 127.7, 127.6, 103.3, 103.2, 100.0 (C~1′′~, ^1^*J*~CH~ = 153.6 Hz, β form), 98.5 (C~1′′~, ^1^*J*~CH~ = 171.0 Hz, α form), 86.3, 85.2, 82.8, 82.1, 81.4, 80.1, 77.3, 75.2, 75.2, 75.0, 74.8, 74.7, 74.3, 73.9, 73.7, 73.5, 72.9, 72.8, 72.5, 72.2, 71.9, 71.2, 71.0, 68.6, 66.8, 63.3, 63.2, 20.9, 20.9, 20.7, 20.6, 20.4 ppm; IR (ATR): *ν* = 3200, 3065, 3032, 2930, 2877, 1742, 1691, 1498, 1455, 1373, 1310, 1231, 1073, 1042, 1029, 925, 901, 811, 737, 697, 635, 597 cm^−1^; HRMS (FAB+): calcd. for \[M + H\]^+^, C~42~H~47~N~2~O~14~, 803.3027; found, 803.3028.
*2′,3′-Di-O-acetyl-5′-O-(6′′-O-acetyl-2′′,3′′,4′′-tri-O-benzyl-α/β-[d]{.smallcaps}-mannopyranosyl)adenosine* (**14**) and *7-N-(6′-O-acetyl-2′,3′,4′-tri-O-benzyl-α-[d]{.smallcaps}-mannopyranosyl)adenine* (**15**) (Entry 2 in [Table 2](#molecules-22-01650-t002){ref-type="table"}): A mixture of **9** (28.4 mg, 48.6 µmol), **13** (8.6 mg, 32.2 µmol) and **11a** (5.9 mg, 48.4 µmol) was co-evaporated with anhydrous pyridine (three times) and anhydrous 1,4-dioxane (three times) and dissolved in anhydrous 1,4-dioxane (320 µL). This reaction mixture was stirred under reflux conditions for 1 h and concentrated under reduced pressure. The resulting mixture was stirred with activated 3 Å molecular sieves (64 mg) in anhydrous MeCN (640 µL) at room temperature for 30 min and then cooled to −20 °C, to which *p*-TolSCl (12.8 µL, 96.8 µmol) and AgOTf (49.9 mg, 194 µmol) were added at the same temperature. After stirring for 1.5 h at −20 °C, the reaction mixture was quenched with saturated aqueous NaHCO~3~, diluted with CHCl~3~ and filtered through Celite. The organic layer was washed with saturated aqueous NaHCO~3~ and brine, dried over Na~2~SO~4~, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (CHCl~3~/MeOH = 1/0--10/1) to give 5′-*O*-(6′′-*O*-acetyl-2′′,3′′,4′′-tri-*O*-benzyl-α/β-[d]{.smallcaps}-mannopyranosyl)adenosine including a small amount of byproducts as a colorless syrup (6.3 mg). To the resulting crude compound in anhydrous pyridine (200 µL), Ac~2~O (8.0 µL, 84.9 µmol, 10.0 equiv. based on the crude compound) and DMAP (catalytic amount) were added at 0 °C. The reaction mixture was stirred at the same temperature for 30 min and then allowed to warm to room temperature. After stirring overnight, the reaction mixture was diluted with CHCl~3~, washed with aqueous NaHCO~3~ and brine, dried over Na~2~SO~4~, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl~3~/MeOH = 1/0--5/1) to give **14** as a colorless amorphous solid (3.8 mg, 14% yield for 3 steps, α/β = 1/1.0) and **15** as a colorless syrup (1.1 mg, 6% yield for 3 steps): **14** (α/β = 1/1.0); ^1^H NMR (300 MHz, CDCl~3~, TMS): δ = 8.36 (s, 1H), 8.35 (s, 0.5H), 7.93 (s, 0.5H), 7.42--7.27 (m, 13.5H), 7.16 (t, *J* = 2.7 Hz, 1.5H), 6.31 (d, *J* = 6.0 Hz, 0.5H), 6.20 (d, *J* = 5.7 Hz,0.5H), 5.92 (t, *J* = 5.7 Hz, 0.5H), 5.78--5.67 (m, 1H), 5.67--5.52 (m, 2.5H), 4.97--4.83 (m, 3H), 4.77--4.45 (m, 5H), 4.45--4.16 (m, 3H), 4.05--3.82 (m, 3H), 3.82--3.62 (m, 1H), 3.58--3.41 (m, 1H), 2.15 (s, 1.5H), 2.13 (s, 1.5H), 2.07 (s, 1.5H), 2.06 (s, 1.5H), 2.03 (s, 1.5H), 2.01 (s, 1.5H) ppm; ^13^C NMR (100 MHz, CDCl~3~, TMS): δ = 171.1, 170.9, 169.9, 169.6, 169.4, 169.3, 155.5, 155.4, 153.4, 153.1, 150.0, 150.0, 139.7, 138.7, 138.4, 138.2, 138.1, 138.0, 137.9, 128.4, 128.4, 128.4, 128.4, 128.4, 128.2, 128.1, 127.9, 127.9, 127.8, 127.7, 127.7, 127.6, 127.6, 127.3, 120.1, 119.8, 100.9 (C~1′′~, ^1^*J*~CH~ = 156.9 Hz, β form), 98.6 (C~1′′~, ^1^*J*~CH~ = 168.5 Hz, α form), 85.7, 85.2, 82.3, 82.2, 81.4, 80.2, 75.3, 75.1, 75.0, 74.5, 74.4, 74.3, 74.1, 73.9, 73.1, 73.0, 72.4, 71.7, 71.1, 70.7, 69.3, 66.6, 63.5, 63.4, 21.0, 20.9, 20.7, 20.6, 20.4, 20.4 ppm; IR (ATR): *ν* = 3332, 3171, 3066, 3032, 2927, 2875, 1742, 1635, 1595, 1498, 1473, 1455, 1424, 1366, 1332, 1293, 1234, 1213, 1071, 1042, 1027, 903, 825, 799, 736, 697, 667, 649, 602 cm^−1^; HRMS (FAB+): calcd. for \[M + H\]^+^, C~43~H~48~N~5~O~12~, 826.3299; found, 826.3294; **15**; ^1^H NMR (300 MHz, CDCl~3~, TMS): δ = 8.44 (s, 1H), 7.90 (s, 1H), 7.41--7.28 (m, 10H), 7.23--7.19 (m, 1H), 7.18--7.08 (m, 2H), 6.86--6.74 (m, 2H), 5.88 (s, 2H), 5.61 (s, 1H), 4.97 (d, *J* = 10.8 Hz, 1H), 4.77 (s, 2H), 4.70 (d, *J* = 6.3 Hz, 1H), 4.66 (d, *J* = 6.6 Hz, 1H), 4.45 (dd, *J* = 12.0, 3.3 Hz, 1H), 4.26 (dd, *J* = 12.0, 2.4 Hz, 1H), 4.25 (d, *J* = 11.1 Hz, 1H), 4.11 (t, *J* = 9.6 Hz, 1H), 3.96 (s, 1H), 3.88 (dd, *J* = 9.3, 2.7 Hz, 1H), 3.76 (dt, *J* = 9.6, 3.0 Hz, 1H), 1.98 (s, 3H) ppm; ^13^C NMR (75 MHz, CDCl~3~, TMS): δ = 170.0, 160.7, 153.2, 151.6, 143.0, 137.3, 135.9, 128.7, 128.6, 128.5, 128.5, 128.4, 128.3, 128.3, 128.2, 127.7, 111.8, 85.7, 82.8, 76.7, 76.1, 75.4, 75.1, 73.0, 72.5, 62.2, 20.7 ppm; IR (ATR): *ν* = 3449, 3371, 3167, 3089, 3064, 3031, 2927, 2873, 1742, 1627, 1587, 1551, 1497, 1475, 1455, 1425, 1389, 1365, 1340, 1296, 1228, 1094, 1019, 966, 909, 887, 825, 736, 695, 602 cm^−1^; HRMS (FAB+): calcd. for \[M + H\]^+^, C~34~H~36~N~5~O~6~, 610.2666; found, 610.2668; $\left\lbrack \mathsf{\alpha} \right\rbrack_{D}^{25}$ = −20.6 (*c* = 1.0, CHCl~3~).
*5′-O-(2′′,3′′,4′′,6′′-Tetra-O-benzoyl-β-[d]{.smallcaps}-galactopyranosyl)adenosine* (β-**24**) (Entry 1 in [Table 3](#molecules-22-01650-t003){ref-type="table"}): A mixture of **23** (80.4 mg, 114 µmol), **13** (20.4 mg, 76.3 µmol) and **11c** (21.7 mg, 114 µmol) was co-evaporated with anhydrous pyridine (three times) and anhydrous 1,4-dioxane (three times) and dissolved in anhydrous 1,4-dioxane (760 µL). This reaction mixture was stirred under reflux conditions for 1 h and concentrated under reduced pressure. The resulting mixture was stirred with activated 4 Å molecular sieves (150 mg) in anhydrous EtCN (1.50 mL) at room temperature for 30 min and then cooled to −40 °C, to which *p*-TolSCl (30.3 µL, 229 µmol) and AgOTf (117.6 mg, 458 µmol) were added at the same temperature. After stirring for 1.5 h at −40 °C, the reaction mixture was quenched with saturated aqueous NaHCO~3~, diluted with CHCl~3~ and filtered through Celite. The organic layer was washed with saturated aqueous NaHCO~3~ and brine, dried over Na~2~SO~4~, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (CHCl~3~/MeOH = 1/0--30/1) to give β-**24** as a colorless solid (27.4 mg, 42% yield): ^1^H NMR (400 MHz, CDCl~3~, TMS): δ = 8.46 (s, 1H), 8.07 (dd, *J* = 7.6, 2.0 Hz, 2H), 8.02--7.98 (m, 3H), 7.97--7.93 (m, 2H), 7.83--7.79 (m, 2H), 7.57--7.51 (m, 1H), 7.49 (t, *J* = 7.6 Hz, 1H), 7.45--7.32 (m, 8H), 7.20 (t, *J* = 8.0 Hz, 2H), 6.47 (brs, 2H), 6.13 (d, *J* = 6.4 Hz, 1H), 6.04 (d, *J* = 3.2 Hz, 1H), 5.90 (dd, *J* = 10.4, 8.0 Hz, 1H), 5.73 (dd, *J* = 10.4, 3.2 Hz, 1H), 4.92 (d, *J* = 8.0 Hz, 1H), 4.70 (dd, *J* = 11.2, 6.4 Hz, 1H), 4.63 (t, *J* = 5.6 Hz, 1H), 4.47--4.33 (m, 4H), 4.20 (d, *J* = 4.8 Hz, 1H), 3.77 (d, *J* = 8.4 Hz, 1H) ppm; ^13^C NMR (100 MHz, CDCl~3~, TMS): δ = 166.1, 166.1, 165.6, 165.5, 155.3, 152.0, 148.8, 139.0, 133.8, 133.5, 133.4, 133.4, 130.0, 129.8, 129.8, 129.7, 129.3, 128.7, 128.7, 128.6, 128.5, 128.4, 119.0, 101.5, 88.3, 83.9, 76.3, 72.5, 71.6, 71.2, 70.1, 70.0, 68.0, 61.8 ppm; IR (ATR): *ν* = 3345, 3203, 3070, 2929, 1721, 1639, 1602, 1585, 1475, 1452, 1421, 1316, 1259, 1177, 1092, 1066, 1025, 1002, 938, 906, 857, 799, 753, 705, 685, 649, 617 cm^−1^; HRMS (FAB+): calcd. for \[M + H\]^+^, C~44~H~40~N~5~O~13~, 846.2623; found, 846.2626; Anal. Calcd. for C~44~H~39~N~5~O~13~·1.5H~2~O: C, 60.55; H, 4.85; N, 8.02; found: C, 60.47; H, 4.61; N, 7.98; $\left\lbrack \mathsf{\alpha} \right\rbrack_{D}^{25}$ = +13.9 (*c* = 1.0, CHCl~3~).
*6-N-Benzoyl-5′-O-(2′′,3′′,4′′,6′′-tetra-O-benzoyl-β-[d]{.smallcaps}-galactopyranosyl)adenosine* (β-**25**) (Entry 2 in [Table 3](#molecules-22-01650-t003){ref-type="table"}): *O*-Glycosylation using **23** (80.5 mg, 115 µmol), **16** (28.4 mg, 76.5 µmol), **11c** (21.8 mg, 115 µmol), anhydrous 1,4-dioxane (760 µL), *p*-TolSCl (30.3 µL, 229 µmol), AgOTf (117.8 mg, 458 µmol), 4 Å molecular sieves (150 mg) and anhydrous EtCN (1.50 mL) was conducted according to the procedure used for the synthesis of β-**24**. The residue was purified by silica gel column chromatography (CHCl~3~/MeOH = 1/0--50/1) to give β-**25** as a colorless solid (21.9 mg, 30% yield for 2 steps): ^1^H NMR (300 MHz, CDCl~3~, TMS): δ = 9.21 (brs, 1H), 8.66 (s, 1H), 8.57 (s, 1H), 8.17-8.08 (m, 2H), 7.90--7.81 (m, 4H), 7.90--7.81 (m, 2H), 7.76 (d, *J* = 7.5 Hz, 2H), 7.62--7.36 (m, 11H), 7.30 (t, *J* = 7.8 Hz, 2H), 7.22 (t, *J* = 7.8 Hz, 2H), 6.15 (d, *J* = 5.1 Hz, 1H), 6.01 (d, *J* = 3.0 Hz, 1H), 5.78 (dd, *J* = 10.2, 7.5 Hz, 1H), 5.65 (dd, *J* = 10.5, 3.3 Hz, 1H), 5.49 (brs, 1H), 4.88 (d, *J* = 7.8 Hz, 1H), 4.76--4.59 (m, 2H), 4.43 (dd, *J* = 11.1, 6.3 Hz, 1H), 4.38--4.21 (m, 4H), 3.81 (dd, *J* = 10.5, 2.7 Hz, 1H), 3.51 (s, 1H) ppm; ^13^C NMR (75 MHz, CDCl~3~, TMS): δ = 166.1, 165.5, 165.5, 164.6, 152.2, 151.0, 149.4, 141.7, 133.7, 133.5, 133.4, 132.8, 130.2, 129.8, 129.6, 129.3, 128.9, 128.8, 128.8, 128.7, 128.6, 128.5, 128.3, 127.9, 122.8, 101.5, 89.4, 84.2, 75.8, 71.8, 71.6, 71.2, 69.9, 69.3, 68.0, 61.9 ppm; IR (ATR): *ν* = 3336, 3066, 2938, 1721, 1612, 1603, 1584, 1510, 1489, 1452, 1406, 1316, 1250, 1177, 1092, 1066, 1025, 1002, 938, 901, 858, 824, 798, 755, 704, 685, 644, 616 cm^−1^; HRMS (FAB+): calcd. for \[M + H\]^+^, C~51~H~44~N~5~O~14~, 950.2885; found, 950.2885; Anal. Calcd. for C~51~H~43~N~5~O~14~·1.5H~2~O: C, 62.70; H, 4.75; N, 7.17; found: C, 62.80; H, 4.57; N, 7.22; $\left\lbrack \mathsf{\alpha} \right\rbrack_{D}^{25}$ = +4.88 (*c* = 1.0, CHCl~3~).
*5′-O-(2′′,3′′,4′′,6′′-Tetra-O-benzoyl-β-[d]{.smallcaps}-galactopyranosyl)guanosine* (β-**26**) (Entry 3 in [Table 3](#molecules-22-01650-t003){ref-type="table"}): *O*-Glycosylation using **23** (80.5 mg, 115 µmol), **17** (21.6 mg, 76.3 µmol), **11c** (21.8 mg, 115 µmol), anhydrous 1,4-dioxane (760 µL), *p*-TolSCl (30.3 µL, 229 µmol), AgOTf (117.6 mg, 458 µmol), 4 Å molecular sieves (150 mg) and anhydrous EtCN (1.50 mL) was conducted according to the procedure used for the synthesis of β-**24**. The residue was purified by silica gel column chromatography (CHCl~3~/MeOH = 1/0--8/1) to give β-**26** as a colorless solid (8.1 mg, 12% yield for 2 steps): ^1^H NMR (400 MHz, DMSO-*d*~6~, TMS): δ = 10.68 (s, 1H), 8.11-8.07 (m, 2H), 8.05 (s, 1H), 7.94 (d, *J* = 8.4 Hz, 2H), 7.85 (d, *J* = 8.4 Hz, 2H), 7.76--7.69 (m, 3H), 7.69--7.63 (m, 3H), 7.62--7.48 (m, 4H), 7.43 (t, *J* = 7.6 Hz, 2H), 7.35 (t, *J* = 7.6 Hz, 2H), 6.51 (s, 2H), 5.91 (d, *J* = 3.2 Hz, 1H), 5.86 (dd, *J* = 10.4, 3.2 Hz, 1H), 5.70 (d, *J* = 6.0 Hz, 1H), 5.60 (t, *J* = 10.0 Hz, 1H), 5.39 (d, *J* = 6.4 Hz, 1H), 5.22 (d, *J* = 7.6 Hz, 1H), 5.19 (d, *J* = 3.6 Hz, 1H), 4.69 (t, *J* = 6.4 Hz, 1H), 4.52 (dd, *J* = 11.2, 2.8 Hz, 1H), 4.42 (dd, *J* = 11.2, 6.8 Hz, 1H), 4.37 (dd, *J* = 11.2, 6.0 Hz, 1H), 4.10 (d, *J* = 8.8, 1H), 4.03 (d, *J* = 2.8 Hz, 1H), 3.92 (d, *J* = 2.8 Hz, 1H), 3.82 (dd, *J* = 10.8, 4.0 Hz, 1H) ppm; ^13^C NMR (100 MHz, DMSO-*d*~6~, TMS): δ = 165.1, 165.1, 165.1, 164.4, 156.8, 153.6, 151.4, 135.1, 133.8, 133.7, 133.5, 133.5, 129.4, 129.2, 129.1, 129.0, 129.0, 128.8, 128.7, 128.7, 128.7, 128.6, 128.6, 128.4, 116.6, 99.9, 86.4, 83.1, 73.8, 71.2, 70.7, 70.0, 69.6, 68.4, 61.7 ppm; IR (ATR): *ν* = 3332, 3128, 3065, 2935, 1724, 1673, 1638, 1602, 1584, 1572, 1538, 1491, 1452, 1350, 1316, 1261, 1177, 1092, 1067, 1025, 1002, 938, 904, 857, 801, 781, 755, 706, 686, 638, 617 cm^−1^; HRMS (FAB+): calcd. for \[M + H\]^+^, C~44~H~40~N~5~O~14~, 862.2572; found, 862.2573; Anal. Calcd. for C~44~H~39~N~5~O~14~·1.5H~2~O: C, 59.46; H, 4.76; N, 7.88; found: C, 59.52; H, 4.62; N, 7.87; $\left\lbrack \mathsf{\alpha} \right\rbrack_{D}^{24}$ = +11.3 (*c* = 1.0, DMSO).
*2-N-Isobutyryl-5′-O-(2′′,3′′,4′′,6′′-tetra-O-benzoyl-β-[d]{.smallcaps}-galactopyranosyl) guanosine* (β-**27**) (Entry 4 in [Table 3](#molecules-22-01650-t003){ref-type="table"}): Glycosylation using **23** (80.5 mg, 115 µmol), **18** (27.0 mg, 76.4 µmol), **11c** (21.8 mg, 115 µmol), anhydrous 1,4-dioxane (760 µL), *p*-TolSCl (30.3 µL, 229 µmol), AgOTf (117.8 mg, 458 µmol), 4 Å molecular sieves (150 mg) and anhydrous EtCN (1.50 mL) was conducted according to the procedure used for the synthesis of β-**24**. The residue was purified by silica gel column chromatography (CHCl~3~/MeOH = 1/0--20/1) to give β-**27** as a colorless solid (31.4 mg, 44% yield for 2 steps): ^1^H NMR (300 MHz, CDCl~3~, TMS): δ = 12.11 (s, 1H), 10.33 (s, 1H), 8.09--7.90 (m, 6H), 7.88 (s, 1H), 7.79--7.67 (m, 2H), 7.58--7.31 (m, 10H), 7.24 (t, *J* = 7.8 Hz, 2H), 6.20 (brs, 1H), 6.00 (d, *J* = 3.3 Hz, 1H), 5.79 (dd, *J* = 10.5, 7.5 Hz, 1H), 5.72--5.60 (m, 2H), 4.98 (d, *J* = 5.1 Hz, 1H), 4.84 (d, *J* = 8.1 Hz, 1H), 4.67 (dd, *J* = 10.5, 5.1 Hz, 1H), 4.42--4.24 (m, 3H), 4.16 (d, *J* = 2.7 Hz, 1H), 4.05 (brs, 2H), 3.72 (d, *J* = 8.1 Hz, 1H), 2.62--2.49 (m, 1H), 1.13 (d, *J* = 6.9 Hz, 3H), 0.94 (d, *J* = 6.6 Hz, 3H) ppm; ^13^C NMR (75 MHz, CDCl~3~, TMS): δ = 179.6, 166.5, 166.0, 165.5, 165.4, 155.6, 148.7, 147.8, 139.4, 133.8, 133.4, 129.9, 129.7, 129.6, 129.2, 128.8, 128.6, 128.5, 128.3, 120.6, 101.8, 89.4, 83.7, 72.5, 71.4, 71.2, 70.1, 69.4, 67.9, 61.6, 36.1, 18.8, 18.5 ppm; IR (ATR): *ν* = 3201, 3067, 2974, 2936, 1720, 1677, 1602, 1560, 1475, 1452, 1404, 1376, 1350, 1316, 1258, 1178, 1156, 1092, 1066, 1026, 1002, 949, 908, 856, 802, 784, 752, 706, 687, 642, 617 cm^−1^; HRMS (FAB+): calcd. for \[M + H\]^+^, C~48~H~46~N~5~O~15~, 932.2990; found, 932.2990; Anal. Calcd. for C~48~H~45~N~5~O~15~·1.5H~2~O: C, 60.12; H, 5.05; N, 7.30; found: C, 60.29; H, 4.86; N, 7.34; $\left\lbrack \mathsf{\alpha} \right\rbrack_{D}^{25}$ = +25.9 (*c* = 1.0, CHCl~3~).
*5′-O-(2′′,3′′,4′′,6′′-Tetra-O-benzoyl-β-[d]{.smallcaps}-galactopyranosyl)uridine* (β-**28**) (Entry 5 in [Table 3](#molecules-22-01650-t003){ref-type="table"}): *O*-Glycosylation using **23** (80.4 mg, 114 µmol), **10** (18.6 mg, 76.2 µmol), **11c** (21.7 mg, 114 µmol), anhydrous 1,4-dioxane (760 µL), *p*-TolSCl (30.3 µL, 229 µmol), AgOTf (117.6 mg, 458 µmol), 4 Å molecular sieves (150 mg) and anhydrous EtCN (1.50 mL) was conducted according to the procedure used for the synthesis of β-**24**. The residue was purified by silica gel column chromatography (CHCl~3~/MeOH = 1/0--40/1) to give β-**28** as a colorless solid (26.1 mg, 42% yield for 2 steps): ^1^H NMR (400 MHz, CDCl~3~, TMS): δ = 9.91 (s, 1H), 8.10--8.05 (m, 2H), 8.04--7.99 (m, 2H), 7.95--7.86 (m, 3H), 7.79--7.75 (m, 2H), 7.63 (t, *J* = 7.6 Hz, 1H), 7.59--7.49 (m, 3H), 7.50--7.38 (m, 4H), 7.33 (t, *J* = 7.6 Hz, 2H), 7.23 (t, *J* = 7.6 Hz, 2H), 6.02 (d, *J* = 2.8 Hz, 1H), 5.92--5.84 (m, 2H), 5.77 (dd, *J* = 10.4, 8.0 Hz, 1H), 5.67 (dd, *J* = 10.8, 3.6 Hz, 1H), 5.03 (d, *J* = 4.0 Hz, 1H), 4.91 (d, *J* = 7.6 Hz, 1H), 4.71 (dd, *J* = 10.8, 6.0 Hz, 1H), 4.49--4.39 (m, 3H), 4.23 (d, *J* = 4.4 Hz, 1H), 4.13--4.02 (m, 2H), 3.79 (d, *J* = 10.0 Hz, 1H), 3.39 (d, *J* = 5.6 Hz, 1H) ppm; ^13^C NMR (100 MHz, CDCl~3~, TMS): δ = 166.1, 165.5, 165.5, 165.5, 163.6, 151.3, 140.2, 133.9, 133.6, 133.4, 129.8, 129.8, 129.7, 129.3, 128.9, 128.7, 128.6, 128.6, 128.5, 128.4, 102.6, 101.5, 90.6, 83.4, 75.2, 71.7, 71.2, 70.0, 69.8, 68.2, 68.1, 61.9 ppm; IR (ATR): *ν* = 3356, 3069, 2972, 1720, 1687, 1602, 1585, 1492, 1452, 1383, 1316, 1261, 1178, 1093, 1067, 1027, 1002, 907, 858, 806, 763, 706, 686, 617 cm^−1^; HRMS (FAB+): calcd. for \[M + H\]^+^, C~43~H~39~N~2~O~15~, 823.2350; found, 823.2352; Anal. Calcd. for C~43~H~38~N~2~O~15~·H~2~O: C, 61.43; H, 4.80; N, 3.33; found: C, 61.45; H, 4.70; N, 3.38; $\left\lbrack \mathsf{\alpha} \right\rbrack_{D}^{25}$ = +50.7 (*c* = 1.0, CHCl~3~).
*5-Metyl-5′-O-(2′′,3′′,4′′,6′′-tetra-O-benzoyl-β-[d]{.smallcaps}-galactopyranosyl)uridine* (β-**29**) (Entry 6 in [Table 3](#molecules-22-01650-t003){ref-type="table"}): *O*-Glycosylation using **23** (80.5 mg, 115 µmol), **19** (19.7 mg, 76.3 µmol), **11c** (21.8 mg, 115 µmol), anhydrous 1,4-dioxane (760 µL), *p*-TolSCl (30.3 µL, 229 µmol), AgOTf (117.6 mg, 458 µmol), 4 Å molecular sieves (150 mg) and anhydrous EtCN (1.50 mL) was conducted according to the procedure used for the synthesis of β-**24**. The residue was purified by silica gel column chromatography (CHCl~3~/MeOH = 1/0--40/1) to give β-**29** as a colorless solid (33.8 mg, 53% yield for 2 steps): ^1^H NMR (400 MHz, CDCl~3~, TMS): δ = 10.04 (s, 1H), 8.09--8.05 (m, 2H), 8.04--8.00 (m, 2H), 7.97--7.93 (m, 2H), 7.79--7.74 (m, 2H), 7.67 (s, 1H), 7.61--7.52 (m, 2H), 7.50--7.37 (m, 6H), 7.34 (t, *J* = 7.6 Hz, 2H), 7.20 (t, *J* = 7.6 Hz, 2H), 6.03 (d, *J* = 3.6 Hz, 1H), 5.88 (d, *J* = 4.4 Hz, 1H), 5.81 (dd, *J* = 10.4, 7.6 Hz, 1H), 5.71 (dd, *J* = 10.4, 3.2 Hz, 1H), 5.08 (s, 1H), 4.90 (d, *J* = 7.6 Hz, 1H), 4.70 (dd, *J* = 11.2, 6.4 Hz, 1H), 4.50--4.37 (m, 3H), 4.21 (d, *J* = 4.4 Hz, 1H), 4.09 (dd, *J* = 10.0, 4.4 Hz, 1H), 4.01 (dd, *J* = 10.0, 4.8 Hz, 1H), 3.77 (d, *J* = 9.2 Hz, 1H), 3.41 (d, *J* = 4.8 Hz, 1H), 2.06 (s, 3H) ppm; ^13^C NMR (100 MHz, CDCl~3~, TMS): δ = 166.1, 165.6, 165.6, 165.5, 164.2, 151.3, 136.1, 133.8, 133.6, 133.4, 129.9, 129.8, 129.7, 129.7, 129.3, 128.9, 128.7, 128.6, 128.5, 128.5, 128.3, 111.3, 102.2, 89.8, 83.3, 74.6, 71.8, 71.2, 70.2, 69.8, 69.3, 68.1, 61.9, 12.8 ppm; IR (ATR): *ν* = 3385, 3067, 2930, 1720, 1686, 1602, 1585, 1492, 1468, 1452, 1386, 1349, 1316, 1259, 1177, 1092, 1066, 1025, 1002, 937, 909, 858, 802, 793, 755, 705, 685, 616 cm^−1^; HRMS (FAB+): calcd. for \[M + H\]^+^, C~44~H~41~N~2~O~15~, 837.2507; found, 837.2510; Anal. Calcd. for C~44~H~40~N~2~O~15~·H~2~O: C, 61.82; H, 4.95; N, 3.28; found: C, 61.70; H, 4.85; N, 3.30; $\left\lbrack \mathsf{\alpha} \right\rbrack_{D}^{25}$ = +28.1 (*c* = 1.0, CHCl~3~).
*5-Fluoro-5′-O-(2′′,3′′,4′′,6′′-tetra-O-benzoyl-β-[d]{.smallcaps}-galactopyranosyl)uridine* (β-**30**) (Entry 7 in [Table 3](#molecules-22-01650-t003){ref-type="table"}): *O*-Glycosylation using **23** (80.4 mg, 114 µmol), **20** (20.0 mg, 76.3 µmol), **11c** (21.7 mg, 114 µmol), anhydrous 1,4-dioxane (760 µL), *p*-TolSCl (30.3 µL, 229 µmol), AgOTf (117.6 mg, 458 µmol), 4 Å molecular sieves (150 mg) and anhydrous EtCN (1.50 mL) was conducted according to the procedure used for the synthesis of β-**24**. The residue was purified by silica gel column chromatography (CHCl~3~ then AcOEt/CHCl~3~ = 1/1) to give β-**30** as a colorless solid (38.8 mg, 61% yield for 2 steps): ^1^H NMR (300 MHz, CDCl~3~, TMS): δ = 9.81 (brs, 1H), 8.10 (t, *J* = 7.2 Hz, 3H), 8.04--7.99 (m, 2H), 7.94--7.89 (m, 2H), 7.78--7.73 (m, 2H), 7.64--7.48 (m, 4H), 7.47--7.37 (m, 4H), 7.33 (t, *J* = 7.5 Hz, 2H), 7.21 (t, *J* = 7.2 Hz, 2H), 6.03 (d, *J* = 3.0 Hz, 1H), 5.88 (d, *J* = 3.9 Hz, 1H), 5.78 (dd, *J* = 10.2, 7.5 Hz, 1H), 5.71 (dd, *J* = 10.2, 3.3 Hz, 1H), 4.86 (d, *J* = 7.2 Hz, 1H), 4.72 (dd, *J* = 11.1, 6.3 Hz, 1H), 4.51 (brs, 1H), 4.52--4.33 (m, 3H), 4.27 (d, *J* = 3.3 Hz, 1H), 4.19 (t, *J* = 4.8 Hz, 1H), 4.02 (s, 1H), 3.74 (d, *J* = 9.6 Hz, 1H), 3.32 (brs, 1H) ppm; ^13^C NMR (100 MHz, CDCl~3~, TMS): δ = 166.1, 165.8, 165.7, 165.5, 157.0 (d, ^2^*J*~CF~ = 26.4 Hz), 149.9, 140.8 (d, ^1^*J*~CF~ = 237.0 Hz), 133.9, 133.7, 133.4, 130.0, 129.8, 129.7, 129.3, 128.8, 128.7, 128.6, 128.5, 128.4, 124.9 (d, ^2^*J*~CF~ = 35.5 Hz), 101.7, 90.5, 84.0, 75.3, 71.8, 71.0, 70.9, 69.9, 69.0, 67.9, 61.8 ppm; ^19^F NMR (376 MHz, CDCl~3~, TFA): δ = −164.57 (s) ppm; IR (ATR): *ν* = 3447, 3074, 2941, 1715, 1602, 1585, 1493,1452, 1351, 1317, 1258, 1178, 1092, 1066, 1026, 1002, 936, 894, 858, 800, 753, 706, 687, 617 cm^−1^; HRMS (FAB+): calcd. for \[M + Na\]^+^, C~43~H~37~FN~2~O~15~Na, 863.2076; found, 863.2072; Anal. Calcd. for C~43~H~37~FN~2~O~15~·H~2~O: C, 60.14; H, 4.58; N, 3.26; found: C, 60.02; H, 4.41; N, 3.32; $\left\lbrack \mathsf{\alpha} \right\rbrack_{D}^{25}$ = +37.2 (*c* = 1.0, CHCl~3~).
*5′-O-(2′′,3′′,4′′,6′′-Tetra-O-benzoyl-β-[d]{.smallcaps}-galactopyranosyl)cytidine* (β-**31**) (Entry 8 in [Table 3](#molecules-22-01650-t003){ref-type="table"}): *O*-Glycosylation using **23** (80.4 mg, 114 µmol), **21** (18.5 mg, 76.1 µmol), **11c** (21.7 mg, 114 µmol), anhydrous 1,4-dioxane (760 µL), *p*-TolSCl (30.3 µL, 229 µmol), AgOTf (117.6 mg, 458 µmol), 4 Å molecular sieves (150 mg) and anhydrous EtCN (1.50 mL) was conducted according to the procedure used for the synthesis of β-**24**. The residue was purified by silica gel column chromatography (CHCl~3~/MeOH = 1/0--10/1) to give β-**31** as a colorless solid (34.1 mg, 55% yield for 2 steps): ^1^H NMR (300 MHz, acetone-*d*~6~, TMS): δ = 8.13-8.08 (m, 2H), 8.06--8.01 (m, 2H), 7.97--7.92 (m, 2H), 7.88 (d, *J* = 7.5 Hz, 1H), 7.76 (dd, *J* = 8.4, 1.1 Hz, 2H), 7.73-7.65 (m, 1H), 7.65-7.56 (m, 3H), 7.56-7.44 (m, 4H), 7.39 (t, *J* = 7.2 Hz, 2H), 7.32 (t, *J* = 7.5 Hz, 2H), 6.90 (brs, 2H), 6.10 (dd, *J* = 3.0, 0.9 Hz, 1H), 5.97 (d, *J* = 7.8 Hz, 1H), 5.90 (d, *J* = 7.8 Hz, 1H), 5.87--5.77 (m, 2H), 5.33 (d, *J* = 7.8 Hz, 1H), 4.78 (t, *J* = 6.3 Hz, 1H), 4.70 (dd, *J* = 10.8, 6.0 Hz, 1H), 4.54 (dd, *J* = 10.8, 6.6 Hz, 1H), 4.38 (dd, *J* = 11.1, 1.8 Hz, 1H), 4.19--4.12 (m, 1H), 4.06 (t, *J* = 4.5 Hz, 1H), 4.02--3.93 (m, 2H) ppm; ^13^C NMR (100 MHz, acetone-*d*~6~, TMS): δ = 166.9, 166.4, 166.3, 166.2, 165.8, 157.0, 142.1, 134.6, 134.3, 134.3, 134.2, 130.7, 130.5, 130.4, 130.3, 130.2, 130.2, 130.1, 129.8, 129.5, 129.4, 129.3, 102.2, 95.4, 91.6, 84.0, 76.4, 72.8, 72.0, 71.1, 70.9, 69.8, 69.7, 62.8 ppm; IR (ATR): *ν* = 3350, 3208, 3072, 2935, 1723, 1642, 1602, 1529, 1486, 1452, 1349, 1316, 1259, 1178, 1092, 1065, 1025, 1002, 940, 909, 857, 788, 753, 705, 685, 616 cm^−1^; HRMS (FAB+): calcd. for \[M + H\]^+^, C~43~H~40~N~3~O~14~, 822.2510; found, 822.2507; Anal. Calcd. for C~43~H~39~N~3~O~14~·1.5H~2~O: C, 60.85; H, 4.99; N, 4.95; found: C, 60.87; H, 4.72; N, 4.97; $\left\lbrack \mathsf{\alpha} \right\rbrack_{D}^{25}$ = +62.4 (*c* = 1.0, CHCl~3~).
*4-N-Benzoyl-5′-O-(2′′,3′′,4′′,6′′-tetra-O-benzoyl-β-[d]{.smallcaps}-galactopyranosyl)cytidine* (β-**32**) (Entry 9 in [Table 3](#molecules-22-01650-t003){ref-type="table"}): *O*-glycosylation using **23** (80.6 mg, 115 µmol), **22** (26.6 mg, 76.6 µmol), **11c** (21.8 mg, 115 µmol), anhydrous 1,4-dioxane (760 µL), *p*-TolSCl (30.3 µL, 229 µmol), AgOTf (117.8 mg, 458 µmol), 4 Å molecular sieves (150 mg) and anhydrous EtCN (1.50 mL) was conducted according to the procedure used for the synthesis of β-**24**. The residue was purified by silica gel column chromatography (CHCl~3~/MeOH = 1/0--50/1) to give β-**32** as a colorless solid (28.0 mg, 40% yield for 2 steps): ^1^H NMR (400 MHz, CDCl~3~, TMS): δ = 8.93 (brs, 1H), 8.28 (d, *J* = 7.6 Hz, 1H), 8.06--8.01 (m, 4H), 7.91 (dd, *J* = 8.4, 1.6 Hz, 2H), 7.87 (d, *J* = 7.2 Hz, 2H), 7.73 (dd, *J* = 8.0, 1.6 Hz, 2H), 7.68 (brs, 1H), 7.60--7.53 (m, 2H), 7.53--7.37 (m, 9H), 7.32 (t, *J* = 8.0 Hz, 2H), 7.19 (t, *J* = 8.0 Hz, 2H), 6.03 (d, *J* = 3.2 Hz, 1H), 5.86 (d, *J* = 3.6 Hz, 1H), 5.76 (dd, *J* = 10.4, 8.0 Hz, 1H), 5.69 (dd, *J* = 10.4, 3.6 Hz, 1H), 5.54 (brs, 1H), 4.92 (d, *J* = 7.6 Hz, 1H), 4.78 (dd, *J* = 11.6, 6.4 Hz, 1H), 4.48 (dd, *J* = 11.2, 6.4 Hz, 1H), 4.43--4.35 (m, 3H), 4.14 (t, *J* = 4.4 Hz, 1H), 4.10 (d, *J* = 3.6 Hz, 1H), 3.81 (dd, *J* = 11.6, 2.4 Hz, 1H), 3.66 (brs, 1H) ppm; ^13^C NMR (100 MHz, CDCl~3~, TMS): δ = 166.1, 165.6, 165.5, 165.3, 162.6, 144.7, 133.6, 133.4, 133.4, 133.1, 132.9, 129.9, 129.8, 129.8, 129.7, 129.4, 128.9, 128.8, 128.6, 128.5, 128.4, 128.3, 127.7, 101.7, 97.1, 93.1, 84.8, 76.4, 71.8, 71.3, 71.2, 69.6, 68.7, 68.1, 61.9 ppm; IR (ATR): *ν* = 3320, 3066, 2930, 1724, 1645, 1603, 1556, 1481, 1452, 1379, 1315, 1248, 1177, 1092, 1066, 1025, 1002, 938, 899, 859, 802, 787, 756, 704, 685, 616 cm^−1^; HRMS (FAB+): calcd. for \[M + H\]^+^, C~50~H~44~N~3~O~15~, 926.2772; found, 926.2773; Anal. Calcd. for C~50~H~43~N~3~O~15~·H~2~O: C, 63.62; H, 4.81; N, 4.45; found: C, 63.34; H, 4.71; N, 4.56; $\left\lbrack \mathsf{\alpha} \right\rbrack_{D}^{25}$ = +46.6 (*c* = 1.0, CHCl~3~).
*5-Fluoro-5′-O-(2′′,3′′,4′′,6′′-tetra-O-benzoyl-β-[d]{.smallcaps}-glucopyranosyl)uridine* (β-**35**) (Entry 1 in [Table 4](#molecules-22-01650-t004){ref-type="table"}): *O*-Glycosylation using **33** (80.4 mg, 114 µmol), **20** (20.0 mg, 76.2 µmol), **11c** (21.7 mg, 114 µmol), anhydrous 1,4-dioxane (760 µL), *p*-TolSCl (30.3 µL, 229 µmol), AgOTf (117.6 mg, 458 µmol), 4 Å molecular sieves (150 mg) and anhydrous EtCN (1.50 mL) was conducted according to the procedure used for the synthesis of β-**24**. The residue was purified by silica gel column chromatography (CHCl~3~/MeOH = 1/0--30/1) to give β-**35** as a colorless solid (34.5 mg, 54% yield for 2 steps): ^1^H NMR (300 MHz, CDCl~3~, TMS): δ = 9.66 (brs, 1H), 8.09 (d, *J* = 6.6 Hz, 1H), 8.04-7.98 (m, 2H), 7.91 (d, *J* = 8.1 Hz, 4H), 7.87--7.82 (m, 2H), 7.56--7.24 (m, 12H), 5.97 (t, *J* = 9.9 Hz, 1H), 5.82 (d, *J* = 3.0 Hz, 1H), 5.69 (t, *J* = 9.9 Hz, 1H), 5.48 (dd, *J* = 10.2, 7.8 Hz, 1H), 4.90 (d, *J* = 8.1 Hz, 1H), 4.70 (dd, *J* = 12.0, 3.0 Hz, 1H), 4.55 (brs, 1H), 4.52 (dd, *J* = 12.0, 4.8 Hz, 1H), 4.33 (dd, *J* = 10.8, 2.1 Hz, 1H), 4.28--4.15 (m, 3H), 4.06 (s, 1H), 3.76 (d, *J* = 9.6 Hz, 1H), 3.31 (s, 1H) ppm; ^13^C NMR (100 MHz, CDCl~3~, TMS): δ = 166.2, 165.8, 165.5, 165.0, 157.1 (d, ^2^*J*~CF~ = 26.4 Hz), 149.8, 140.7 (d, ^1^*J*~CF~ = 236.2 Hz), 133.7, 133.5, 133.4, 133.3, 129.9, 129.8, 129.7, 129.4, 128.7, 128.6, 128.5, 128.4, 128.4, 124.8 (d, ^2^*J*~CF~ = 34.6 Hz), 100.8, 90.6, 83.9, 75.4, 72.7, 72.3, 71.9, 70.6, 69.6, 68.0, 62.8 ppm; ^19^F NMR (376 MHz, CDCl~3~, TFA): δ = −165.00 (s) ppm; IR (ATR): *ν* = 3426, 3072, 2953, 1716, 1602, 1585, 1493,1452, 1369, 1317, 1260, 1178, 1091, 1068, 1027, 1003, 936, 895, 855, 800, 758, 708, 687, 618 cm^−1^; HRMS (FAB+): calcd. for \[M + H\]^+^, C~43~H~38~FN~2~O~15~, 841.2256; found, 841.2261; Anal. Calcd. for C~43~H~37~FN~2~O~15~·1.5H~2~O: C, 59.52; H, 4.65; N, 3.23; found: C, 59.51; H, 4.47; N, 3.26; $\left\lbrack \mathsf{\alpha} \right\rbrack_{D}^{25}$ = +8.39 (*c* = 1.0, CHCl~3~).
*O*-Glycosylation using glycosyl donors containing boronic acid on leaving group (Entries 1--4 in [Table 5](#molecules-22-01650-t005){ref-type="table"}): A mixture of **41** or **42** (30.2 mg, 48.0 µmol) and **10** (7.8 mg, 31.9 µmol) or **13** (8.6 mg, 32.2 µmol) was co-evaporated with anhydrous pyridine (three times) and anhydrous 1,4-dioxane (three times) and dissolved in anhydrous 1,4-dioxane (320 µL). This reaction mixture was stirred under reflux conditions for 1 h and concentrated under reduced pressure. *O*-glycosylation and acetylation were conducted according to the procedure used for the synthesis of **12** or **14** using *p*-TolSCl (12.7 µL, 96.1 µmol), AgOTf (49.5 mg, 193 µmol), 3 Å molecular sieves (64 mg), anhydrous MeCN (640 µL), anhydrous pyridine (200 µL), Ac~2~O (10.0 equiv. based on the crude compound) and DMAP (catalytic amount).
*5′-O-(2′′,3′′,4′′-Tri-O-benzyl-α/β-[d]{.smallcaps}-mannopyranosyl)uridine* (**43**) ([Scheme 1](#molecules-22-01650-sch001){ref-type="scheme"}a): To a solution of **12** (25.2 mg, 31.4 µmol, α/β = 1.6/1) in THF (400 µL), 1 M aqueous LiOH was added at room temperature. After stirring for 2 h, the reaction mixture was neutralized with 0.1 M aqueous HCl, extracted with CHCl~3~, washed with brine, dried over Na~2~SO~4~, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl~3~/MeOH = 20/1) to give α-**43** as a colorless solid (12.1 mg, 57% yield) and β-**43** as a colorless solid (7.5 mg, 35% yield): α-**43**; ^1^H NMR (300 MHz, CDCl~3~, TMS): δ = 10.11 (s, 1H), 7.39 (d, *J* = 8.4 Hz, 1H), 7.36--7.17 (m, 15H), 5.74 (d, *J* = 2.1 Hz, 1H), 5.43 (d, *J* = 8.4 Hz, 1H), 4.91 (s, 1H), 4.87 (t, *J* = 6.3 Hz, 2H), 4.75 (d, *J* = 12.0 Hz, 1H), 4.67 (d, *J* = 9.0 Hz, 1H), 4.64--4.51 (m, 3H), 4.20 (s, 1H), 4.13 (s, 1H), 4.02 (s, 2H), 3.90--3.74 (m, 4H), 3.73--3.56 (m, 4H), 3.00 (s, 1H) ppm; ^13^C NMR (100 MHz, CDCl~3~, TMS): δ = 163.7, 151.1, 139.7, 138.0, 137.8, 128.5, 128.4, 128.4, 128.3, 127.9, 127.8, 127.7, 127.6, 102.3, 98.3 (C~1"~, ^1^*J*~CH~ = 169.4 Hz), 90.1, 82.6, 79.7, 75.1, 75.0, 74.8, 74.7, 73.1, 73.0, 72.4, 69.9, 66.6, 62.3 ppm; IR (ATR): *ν* = 3384, 3064, 3032, 2924, 2879, 1683, 1497, 1455, 1389, 1364, 1321, 1269, 1210, 1068, 1027, 909, 864, 845, 810, 735, 697 cm^−1^; HRMS (FAB+): calcd. for \[M + H\]^+^, C~36~H~41~N~2~O~11~, 677.2710; found, 677.2709; Anal. Calcd. for C~36~H~40~N~2~O~11~·H~2~O: C, 62.24; H, 6.09; N, 4.03; found: C, 62.36; H, 6.01; N, 4.13; $\left\lbrack \mathsf{\alpha} \right\rbrack_{D}^{25}$ = +42.7 (*c* = 0.2, CHCl~3~); β-**43**; ^1^H NMR (300 MHz, CD~3~OD, TMS): δ = 7.96 (d, *J* = 8.1 Hz, 1H), 7.41--7.20 (m, 15H), 5.96 (d, *J* = 5.4 Hz, 1H), 5.34 (d, *J* = 8.1 Hz, 1H), 4.92--4.84 (m, 2H), 4.75--4.55 (m, 5H), 4.28 (t, *J* = 5.7 Hz, 1H), 4.22 (dd, *J* = 5.1, 3.3 Hz, 1H), 4.18--4.10 (m, 2H), 4.08 (d, *J* = 2.1 Hz, 1H), 3.86--3.73 (m, 3H), 3.67 (dd, *J* = 9.6, 2.7 Hz, 1H), 3.60 (dd, *J* = 11.7, 6.3 Hz, 1H), 3.35--3.26 (m, 1H) ppm; ^13^C NMR (100 MHz, CD~3~OD, TMS): δ = 166.1, 152.6, 143.4, 139.8, 139.7, 129.7, 129.4, 129.3, 129.3, 128.9, 128.8, 128.7, 103.0, 101.8 (C~1"~, ^1^*J*~CH~ = 156.1 Hz), 89.9, 85.2, 84.1, 77.9, 76.9, 76.2, 76.0, 75.8, 75.6, 73.0, 72.2, 70.0, 62.8 ppm; IR (ATR): *ν* = 3387, 3063, 3032, 2926, 2874, 1673, 1498, 1456, 1401, 1364, 1316, 1274, 1249, 1211, 1179, 1072, 1027, 906, 866, 811, 786, 736, 696 cm^−1^; HRMS (FAB+): calcd. for \[M + H\]^+^, C~36~H~41~N~2~O~11~, 677.2710; found, 677.2709; Anal. Calcd. for C~36~H~40~N~2~O~11~·H~2~O: C, 62.24; H, 6.09; N, 4.03; found: C, 62.29; H, 5.86; N, 4.20; $\left\lbrack \mathsf{\alpha} \right\rbrack_{D}^{23}$ = −67.6 (*c* = 0.5, CH~3~OH).
*5′-O-α/β-[d]{.smallcaps}-Mannopyranosyl)uridine* (**44**) ([Scheme 1](#molecules-22-01650-sch001){ref-type="scheme"}a): A mixture of α-**43** (19.2 mg, 28.4 µmol), 10% Pd/C (19.0 mg) in MeOH (540 µL) was vigorously stirred for 22 h at room temperature under a H~2~ atmosphere. The mixture was filtered through Celite with MeOH and H~2~O, and then, the filtrate was concentrated under reduced pressure to give α-**44** as a colorless solid (11.4 mg, 99% yield): α-**44**; ^1^H NMR (300 MHz, D~2~O, TSP): δ = 7.89 (d, *J* = 8.1 Hz, 1H), 5.96--5.87 (m, 2H), 4.96 (s, 1H), 4.33 (s, 3H), 4.06--3.96 (m, 2H), 3.90 (t, *J* = 10.5 Hz, 2H), 3.57--3.84 (m, 4H) ppm; ^13^C NMR (75 MHz, D~2~O, 1,4-dioxane): δ = 166.8, 152.1, 142.0, 102.5, 100.3, 90.4, 82.9, 74.6, 73.6, 71.2, 70.6, 69.8, 67.2, 66.3, 61.5 ppm; IR (ATR): *ν* = 3289, 2935, 2502, 1666, 1466, 1397, 1273, 1199, 1129, 1104, 1050, 1025, 912, 868, 810, 801, 765, 720, 676, 622 cm^−1^; HRMS (FAB+): calcd. for \[M + Na\]^+^, C~15~H~22~N~2~O~11~Na, 429.1121; found, 429.1118; Anal. Calcd. for C~15~H~22~N~2~O~11~·2.75H~2~O: C, 39.52; H, 6.08; N, 6.14; found: C, 39.58; H, 5.93; N, 5.81; $\left\lbrack \mathsf{\alpha} \right\rbrack_{D}^{24}$ = +29.3 (*c* = 0.8, H~2~O).
Cleavage of benzyl groups using β-**43** (17.8 mg, 26.3 µmol), 10% Pd/C (18.0 mg) and MeOH (500 µL) was conducted according to the procedure for synthesis of α-**44** to give the β-**44** as a colorless solid (10.5 mg, 98% yield): β-**44**; ^1^H NMR (300 MHz, D~2~O, TSP): δ = 8.05 (d, *J* = 8.1 Hz, 1H), 5.96 (d, *J* = 4.2 Hz, 1H), 5.89 (d, *J* = 8.1 Hz, 1H), 4.74 (s, 1H), 4.49--4.12 (m, 4H), 4.05 (s, 1H), 3.95 (d, *J* = 12.3 Hz, 1H), 3.88 (d, *J* = 11.7 Hz, 1H), 3.75 (dd, *J* = 11.7, 6.6 Hz, 1H), 3.70--3.52 (m, 2H), 3.40 (t, *J* = 6.6 Hz, 1H) ppm; ^13^C NMR (75 MHz, D~2~O, 1,4-dioxane): δ = 167.8, 153.0, 142.7, 103.0, 100.9, 89.7, 83.6, 76.9, 74.4, 73.5, 70.9, 70.4, 69.0, 67.5, 61.7 ppm; IR (ATR): *ν* = 3288, 2933, 2503, 1670, 1510, 1465, 1390, 1266, 1133, 1053, 1023, 879, 815, 790, 764, 714, 632, 616 cm^−1^; HRMS (FAB+): calcd. for \[M + Na\]^+^, C~15~H~22~N~2~O~11~Na, 429.1121; found, 429.1119; Anal. Calcd. for C~15~H~22~N~2~O~11~·2.6H~2~O: C, 39.76; H, 6.05; N, 6.18; found: C, 40.15; H, 6.00; N, 5.80; $\left\lbrack \mathsf{\alpha} \right\rbrack_{D}^{25}$ = −10.6 (*c* = 0.8, H~2~O).
*5-Fluoro-5′-O-(β-[d]{.smallcaps}-galactopyranosyl)uridine* (β-**45**) ([Scheme 1](#molecules-22-01650-sch001){ref-type="scheme"}b): A mixture of β-**30** (25.2 mg, 30.0 µmol) and 10 M MeNH~2~ in MeOH was stirred at 0 °C for 2 h and then allowed to warm to room temperature. After stirring for 13 h, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in H~2~O, and the *N*-methylbenzamide was removed by successive washing of the aqueous phase with CH~2~Cl~2~. The aqueous layer was concentrated under reduced pressure. The residue was purified by preparative HPLC (H~2~O (0.1%TFA)) to give β-**45** as a colorless amorphous solid (7.9 mg, 62% yield): ^1^H NMR (300 MHz, D~2~O, TSP): δ = 8.18 (d, *J* = 6.6 Hz, 1H), 5.94 (d, *J* = 1.8 Hz, 1H), 4.51 (d, *J* = 7.2 Hz, 1H), 4.48--4.24 (m, 4H), 3.98--3.86 (m, 2H), 3.86--3.77 (m, 2H), 3.77--3.69 (m, 1H), 3.69--3.58 (m, 2H) ppm; ^13^C NMR (100 MHz, D~2~O, 1,4-dioxane): δ = 160.1 (d, ^2^*J*~CF~ = 26.4 Hz), 150.8, 141.4 (d, ^1^*J*~CF~ = 232.1 Hz), 126.3 (d, ^2^*J*~CF~ = 38.1 Hz), 103.7, 89.9, 83.6, 75.9, 74.4, 73.4, 71.5, 69.9, 69.2, 68.9, 61.6 ppm; ^19^F NMR (376 MHz, D~2~O, TFA): δ = −166.73 (s) ppm; IR (ATR): *ν* = 3357, 3075, 2935, 2827, 1661, 1477, 1398, 1365, 1258, 1202, 1035, 952, 921, 890, 843, 793, 750, 722, 697 cm^−1^; HRMS (FAB+): calcd. for \[M + Na\]^+^, C~15~H~21~FN~2~O~11~Na, 447.1027; found, 447.1030; $\left\lbrack \mathsf{\alpha} \right\rbrack_{D}^{25}$ = +17.6 (*c* = 0.3, H~2~O).
^1^H, ^11^B and ^19^F NMR measurements of mixtures of uridine (**10**) and boronic acid (**11c**) ([Figure 3](#molecules-22-01650-f003){ref-type="fig"}): A mixture of **10** (34.3 mg, 140 µmol) and **11c** (40.0 mg, 211 µmol) was co-evaporated with anhydrous pyridine (three times) and anhydrous 1,4-dioxane (three times). The resulting residue was dissolved in anhydrous 1,4-dioxane (1.40 mL) and then stirred under reflux conditions for 1 h. The reaction mixture (140 µL) was separated and concentrated under reduced pressure. The residue **46** dissolved in CD~3~CN (640 µL) was measured by a ^1^H, ^11^B and ^19^F NMR spectrometers. **11c** was treated under the same conditions as were used to prepare **48** for the ^11^B and ^19^F NMR measurements.
4. Conclusions {#sec4-molecules-22-01650}
==============
We report herein on the synthesis of disaccharide nucleosides utilizing the temporary protection of the 2′,3′-*cis*-diol of ribonucleosides by a boronic ester. The glycosylation of the uridine **10**, which is temporarily protected by a boronic acid, with the thioglycoside **9** using a *p*-TolSCl/AgOTf promoter system followed by acetylation gave the disaccharide nucleoside **12** containing a 1′′,5′-glycosidic linkage in reasonable chemical yield. This synthetic method was applied to the glycosylation of protected or unprotected adenosine, guanosine, uridine or cytidine, **10**, **13**, **16**--**22**, with the galactosyl donor **23** to afford the desired products in moderate chemical yields. *O*-glycosylations of 5-fluorouridine **20** with the glucosyl donor **33**, the galactosyl donor **23** and the mannosyl donor **34** were also conducted. The introduction of a boronic acid on the phenylthio leaving group had only a negligible effect on the reactivity and stereoselectivity of the system. The deprotection of compounds **12** and β-**30** was also demonstrated to give the corresponding deprotected compounds α-**44** and β-**44** from **12** and β-**45** from β-**30**. Because 5-fluorouridine and 5-fluorouracil have been reported to have anticancer, antivirus and antibacterial activities \[[@B24-molecules-22-01650],[@B68-molecules-22-01650],[@B72-molecules-22-01650],[@B73-molecules-22-01650],[@B74-molecules-22-01650],[@B75-molecules-22-01650],[@B76-molecules-22-01650],[@B77-molecules-22-01650],[@B78-molecules-22-01650]\], β-**45** and its analogs represent potentially new drug candidates.
Finally, ^1^H, ^11^B and ^19^F NMR measurements of a mixture of uridine **10** and 4-(trifluoromethyl)phenylboronic acid **11c** suggest that the 2' and 3' hydroxyl groups of **10** react with **11c** to form the cyclic boronic ester intermediate **47**, as expected, resulting in selective *O*-glycosylation of the ribonucleoside acceptors at the 5'-position.
These results afford important and useful information regarding the concise and short-step synthesis of various biologically-active disaccharide nucleoside derivatives via the *O*-glycosylation of temporarily-protected nucleosides and related compounds.
This work was supported by grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan (Nos. 22390005, 245900425, 24659011, 24640156 and 15K00408 for S.A.) and a grant from the Tokyo Biochemical Research Foundation, Tokyo, Japan. We appreciate the assistance of Fukiko Hasegawa (Faculty of Pharmaceutical Sciences, Tokyo University of Science) for collecting and interpreting the mass spectral data, Noriko Sawabe for the NMR measurement and Tomoko Matsuo (Research Institute for Science and Technology, Tokyo University of Science) for the elemental analyses.
**Sample Availability:** Sample of the compounds are not available from the authors.
Supplementary Materials are available online.
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Click here for additional data file.
Hidehisa Someya carried out the synthesis of the glycosyl donors and acceptors, *O*-glycosylation reactions, deprotection of **12** and ^1^H, ^11^B and ^19^F NMR measurements and prepared the manuscript. Taiki Itoh synthesized some glycosyl donors and carried out the deprotection of β-**30**. Shin Aoki supervised all experiments and the preparation of the manuscript. All of the authors have read and approved the final version of the manuscript.
The authors declare no conflict of interest.
Figures, Scheme and Tables
==========================
{#molecules-22-01650-f001}
{#molecules-22-01650-f002}
{#molecules-22-01650-sch001}
######
Possible assignment of intermediates from the reaction of uridine **10** and 4-CF~3~PhB(OH)~2~ **11c** in ^1^H, ^11^B and ^19^F NMR spectra (in CD~3~CN at 25 °C). (**a**) ^1^H NMR of **10**; (**b**) ^1^H NMR of a mixture **46**; (**c**) ^11^B NMR of **11c**; (**d**) ^11^B NMR of a mixture **48**; (**e**) ^11^B NMR of a mixture **46**; (**f**) ^19^F NMR of **11c**; (**g**) ^19^F NMR of a mixture **48**; (**h**) ^19^F NMR of a mixture **46**.
molecules-22-01650-t001_Table 1
######
*O*-glycosylation of uridine **10** with the thiomannoside **9** in the absence and presence of boronic acid.
Entry Boronic Acid *^b^* Solvent Condition Yield (for 3 Steps) *^c^*
------------------ --------------------------------------- ------------- --------------- ---------------------------
1 ***^a^*** \- MeCN −20 °C, 1.5 h \<16% (complex mixture)
2 *^**a,**d^* PhB(OH)~2~ (**11a**) MeCN −20 °C, 1.5 h 41% (α/β = 1.6/1)
3 *^**a,**e^* **11a** MeCN −20 °C, 1.5 h 45% (α/β = 1.6/1)
4 *^**a,**e^* 4-MeOPhB(OH)~2~ (**11b**) MeCN −20 °C, 1.5 h 39% (α/β = 1.8/1)
5 *^**a,**e^* 4-CF~3~PhB(OH)~2~ (**11c**) MeCN −20 °C, 1.5 h 51% (α/β = 1.8/1)
6 *^**a,**e^* 2,4-F~2~PhB(OH)~2~ (**11d**) MeCN −20 °C, 1.5 h 46% (α/β = 1.8/1)
7 *^**a,**e^* **11c** 1,4-Dioxane r.t., 1.5 h 27% (α/β = 3.3/1)
8 *^**a,**e^* **11c** CH~2~Cl~2~ −40 °C, 1.5 h trace
9 *^**a,**e^* **11c** EtCN −40 °C, 1.5 h 61% (α/β = 1.6/1)
10 ***^e,f^*** **11c** EtCN −40 °C, 1.5 h 57% (α/β = 1.5/1)
11 *^**a,**e^* 4-CH~3~(CH~2~)~5~PhB(OH)~2~ (**11e**) EtCN −40 °C, 1.5 h 30% (α/β = 1.6/1)
*^a^* Glycosylation reactions were carried out in the presence of 1.5 equivalents of **9**, 3.0 equivalents of *p*-TolSCl and 6.0 equivalents of AgOTf against **10**. Acetylation reactions were carried out in the presence of *ca.* 10 equivalents of Ac~2~O (acetic anhydride) and catalytic amount of DMAP. *^b^* Stoichiometry of **11** was 1.5 equivalents against **10**. *^c^* The α/β ratio was determined by ^1^H NMR. *^d^* A mixture of **10** and **11a** was co-evaporated with pyridine and 1,4-dioxane, and then, a solution of **9** in MeCN was added. *^e^* A mixture of **9**, **10** and **11** was co-evaporated with pyridine and 1,4-dioxane and treated with promoters. *^f^* Glycosylation reactions were carried out in the presence of 1.5 equivalents of **9**, 1.8 equivalents of *p*-TolSCl and 3.6 equivalents of AgOTf against **10** as followed by acetylation with Ac~2~O (*ca.* 10 equivalents) and DMAP (catalytic amount).
molecules-22-01650-t002_Table 2
######
*O*-glycosylation of adenosine **13** with thiomannoside **9** in the absence and presence of boronic acid.
Entry *^a^* Boronic Acid *^b^* Solvent Condition Yield of 14 (for 3 Steps) *^c^* Yield of 15 (for 3 Steps)
------------- ----------------------------- --------- --------------- --------------------------------- ---------------------------
1 \- MeCN −20 °C, 1.5 h \<10% (complex mixture) not isolated
2 *^d^* PhB(OH)~2~ (**11a**) MeCN −20 °C, 1.5 h 14% (α/β = 1/1.0) 6%
3 *^d^* 4-CF~3~PhB(OH)~2~ (**11c**) EtCN −40 °C, 1.5 h 11% (α/β = 1/1.2) 27%
*^a^* Glycosylation reactions were carried out in the presence of 1.5 equivalents of **9**, 3.0 equivalents of *p*-TolSCl and 6.0 equivalents of AgOTf against **13**. Acetylation reactions were carried out in the presence of *ca.* 10 equivalents of Ac~2~O and the catalytic amount of DMAP. *^b^* Stoichiometry of **11** was 1.5 equivalents against **13**. *^c^* The α/β ratio was determined by ^1^H NMR. *^d^* A mixture of **9**, **13** and **11** was co-evaporated with pyridine and 1,4-dioxane and treated with promoters.
molecules-22-01650-t003_Table 3
######
*O*-glycosylation of nucleosides **10**, **13** and **16**--**22** with the thiogalactoside **23**.
Entry *^a^* Acceptor Product Yield (for 2 Steps)
------------- ----------------------- ---------- ------------------------------------------
1 **13** (Ade) β-**24** 42%
2 **16** (Ade^Bz^) β-**25** 30%
3 **17** (Gua) β-**26** 12%
4 **18** (Gua*^i^*^Bu^) β-**27** 44%
5 **10** (Uri) β-**28** 42% (*ca.* 15%: nucleobase = 5-STol-Uri)
6 **19** (5-Me-Uri) β-**29** 53%
7 **20** (5-F-Uri) β-**30** 61%
8 **21** (Cyt) β-**31** 55%
9 **22** (Cyt^Bz^) β-**32** 40%
*^a^* Glycosylation reactions were carried out in the presence of 1.5 equivalents of **23**, 3.0 equivalents of *p*-TolSCl and 6.0 equivalents of AgOTf against the acceptor (**10**, **13** or **16**--**22**). Stoichiometry of **11c** was 1.5 equivalents against acceptor (**10**, **13** or **16**--**22**). A mixture of **23**, acceptor (**10**, **13**, or **16**--**22**) and **11c** was co-evaporated with pyridine and 1,4-dioxane and treated with promoters.
molecules-22-01650-t004_Table 4
######
*O*-Glycosylation of 5-fluorouridine **20** with thioglycosides **23**, **33** and **34**.
Entry *^a^* Donor Product Yield (for 2 Steps)
------------- ---------------- ---------- ---------------------
1 **33** (β-Glc) β-**35** 54%
2 *^b^* **23** (β-Gal) β-**30** 61%
3 **34** (α-Man) α-**36** \<39% (mixture)
*^a^* Glycosylation reactions were carried out in the presence of 1.5 equivalents of donor (**23**, **33** or **34**), 3.0 equivalents of *p*-TolSCl and 6.0 equivalents of AgOTf against **20**. Stoichiometry of **11c** was 1.5 equivalents against **20**. A mixture of donor (**23**, **33** or **34**), **20** and **11c** was co-evaporated with pyridine and 1,4-dioxane and treated with promoters. *^b^* Taken from Entry 7 of [Table 3](#molecules-22-01650-t003){ref-type="table"} in this manuscript.
molecules-22-01650-t005_Table 5
######
*O*-glycosylation of uridine **10** and adenosine **13** with thioglycosides **41** and **42**.
Entry *^a^* Donor Acceptor Product Yield (for 3 Steps) *^b^*
------------- ------------------------------------------ --------------------------- --------- ---------------------------
1 **41** (Ar = 2-PhB(OH)~2~) (α form) **10** (Nucleobase = Uri) **12** 44% (α/β = 1.9/1)
2 **41** (Ar = 2-PhB(OH)~2~) (α form) **13** (Nucleobase = Ade) **14** 16% (α/β = 1.3/1)
3 **42** (Ar = 4-PhB(OH)~2~) (α/β = 1/1.0) **10** (Nucleobase = Uri) **12** 36% (α/β = 2.1/1)
4 **42** (Ar = 4-PhB(OH)~2~) (α/β = 1/1.0) **13** (Nucleobase = Ade) **14** 14% (α/β = 1.1/1)
*^a^* Glycosylation reactions were carried out in the presence of 1.5 equivalents of donor (**41** or **42**), 3.0 equivalents of *p*-TolSCl and 6.0 equivalents of AgOTf against the acceptor (**10** or **13**). A mixture of donor (**41** or **42**) and acceptor (**10** or **13**) was co-evaporated with pyridine and 1,4-dioxane and treated with promoters. Acetylation reactions were carried out in the presence of *ca.* 10 equivalents of Ac~2~O and a catalytic amount of DMAP. *^b^* The α/β ratio was determined by ^1^H NMR.
| 2023-10-05T01:27:15.642919 | https://example.com/article/9132 |
President Barack Obama followed tradition at the opening session of the U.N. General Assembly this week by engaging in perhaps the most intense diplomacy this year, juggling everything from the Syria crisis to development aid. At his side were mainly politically appointed aides, including National Security Adviser Susan Rice, her deputy Benjamin Rhodes, and U.N. Ambassador Samantha Power. But most of the people working behind the scenes to make it all happen are career diplomats, also known as Foreign Service officers — a group of about 8,000 Americans who, along with about 5,000 technical staff, serve in 275 embassies, consulates, and other missions around the world.
Over the years, the Obama White House has been criticized as being too controlling on foreign policy, running an overly tight ship, and keeping these professionals at the State Department — the Foreign Service’s home agency in Washington — at arm’s length when it comes to the issues the administration most cares about. Critics cite the Iran nuclear negotiations and the secret talks with Cuba as recent examples of diplomacy where more professionals could have been included at earlier stages. Does that suggest a lack of trust?
This question typically rises during Republican administrations, which tend to view the diplomatic service as liberally inclined and excessively internationalist. During President George W. Bush’s first term, former House Speaker Newt Gingrich famously accused it of deliberately undermining Bush’s policies, while Christian Coalition founder Pat Robertson suggested “nuking” the State Department. “There is always a bias in Washington against the State Department, and when you have a very conservative Republican administration, it’s worse,” said former Secretary of State Colin Powell. “The perception is that diplomats are bad — they want to talk people into things, while soldiers fight or get ready to fight.”
Democrats — and many Republicans — reject accusations that the Foreign Service is disobedient or pursues its own agenda, and commend its members’ professionalism, expertise, and sacrifices. After all, these public servants take an oath of office to implement the president’s foreign policy, no matter which party is in power. At the same time, however, when asked privately whether the president has full confidence in the institution — regardless of the administration in office — White House aides tend to avoid a yes or no answer, saying instead that the president highly respects the most senior career diplomats he interacts with and values their counsel. Former Deputy Secretary of State William Burns and former Undersecretary of State Thomas Pickering are among the most frequently cited examples of such officers in recent years.
What does the Foreign Service think? I asked hundreds of its members that question while researching my book, America’s Other Army. Their responses: Presidents trust some senior officers, but not necessarily the institution itself. They trust the service to keep embassies running. But on policy, it typically depends on the issue — on the most important and consequential matters, such as Syria and climate change, probably not.
These answers are based on presidents’ actions, rather than their words. Perhaps the most significant action has been the huge increase in the number of political appointees at the State Department over several administrations. Some of these individuals are selected not because they are the best-qualified, but because of their political connections or campaign fundraising efforts. According to the American Academy of Diplomacy, an organization of retired career ambassadors and other senior diplomats, the number of political appointees in assistant secretary and higher-ranking position at the department has increased from 37 percent in 1975 to 51 percent in 2014.
Another major reason for the above responses is the immense expansion of the National Security Council (NSC), which has nearly quadrupled in the last two decades, gradually neutering the State Department’s decision-making power.
In a report earlier this year entitled “American Diplomacy At Risk,” the Academy of Diplomacy lamented “the politicization of and reduction in the role of the professional Foreign Service in diplomacy,” a shift that it said “weakens the nation” and has caused a decline in “America’s diplomatic ability to lead.” The Foreign Service Act, passed by Congress in 1980, is “under assault from a variety of actors who seek to dilute the commitment to career precepts and service norms to the point of nullifying the act,” the Academy added.
The main reason the White House does not seem to fully trust the Foreign Service, many career and political appointees say, is that the institution is poorly equipped and ill-prepared to deal with today’s thorniest challenges. The Academy of Diplomacy said the State Department is “neither educating its staff to the professional level of our allies and competitors nor systematically preparing its future ‘bench’ to assume senior roles.”
Eliot Cohen, a John Hopkins University professor who served under President George W. Bush as State Department counselor, a senior position equivalent to undersecretary, put it more specifically. “If you come across good leaders, they just happened to be born that way,” he said. “The institution doesn’t do enough to develop good leadership, as far as I can tell. There are leaders like Bill Burns, but that’s because of whatever magic was in his DNA.” Cohen hastened to add that he was “quite taken” by the “dedication, hard work and intelligence” of the Foreign Service. “I was impressed by the professionalism and discipline, and in some cases self-sacrifice. There were some people who were downright heroic.”
When career diplomats rise to levels that put them in contact with the president, what the White House primarily looks for are formidable policy advisers, strategists, and implementers. On that score, few Foreign Service officers make the cut, said James Jeffrey, a former career ambassador to Iraq and Turkey, who also served as a deputy national security adviser in the Bush administration.
That is because “we don’t formally acknowledge or institutionalize the seemingly self-evident truth” that the goal of the Foreign Service should be to produce first-rate experts and advisers capable of “shaping and executing policy” at the highest levels of power, Jeffrey said. Such a formal acknowledgement, he suggested, would risk “slighting the work” of management and consular officers, who are usually not involved in policy. “Thus, career patterns, training, promotions, and assignments cannot flow from and support that reality,” he added.
Kurt Volker, a former career ambassador to NATO, said a major reform of the diplomatic service is long overdue. “The law that defines the current Foreign Service was passed in 1980 — before the fall of the Berlin Wall, the Internet, globalization, 9/11, Iraq and Afghanistan, China’s rise and the Arab Spring,” Volker said. “We have adapted by pushing the people we have into new roles, without really thinking through what we are doing, and what we as a country need. But are we hiring the right people to do this? Is there a long-term cost to pay when Foreign Service officers are neither expected nor challenged to become top foreign policy strategists and thinkers, [and] figuring we can just bring in political appointees for that?”
So, why has no president or secretary of state since the end of the Cold War even attempted to reform a system the White House evidently does not fully trust to produce the type of officers it wants in key high-level positions?
The prevailing view among both career and political appointees is that it is unrealistic, amid all the problems in the world, to expect the president or the secretary of state to spend political capital on such a difficult and long-term effort, the impact of which would not be felt until after he or she leaves office. Many Foreign Service officers also said that the White House does not seem to mind the wealth of opportunities it sees for political appointees in the current system. For that reason, those officers added, the service should not wait for the country’s top leadership to seize the initiative.
“The drive for this change must come from within the Foreign Service,” Tamir Waser, a senior officer, wrote in a paper during a recent stint at the National Defense University.
The service “cannot expect that others will care more for the institution than its members do. They shouldn’t wait for yet another study to tell them what they already know: that the Foreign Service needs reform,” Waser said. “And they must not hope that the energy to do the tough work of changing the institution and its culture will come from outside their ranks. Moreover, as an institution, we adopted a defensive mentality. All our problems were the results of pernicious outside forces — not enough support from Congress, too many political appointees, civil servants stealing our jobs. I felt we were only looking outside without considering what we, as members of the Foreign Service, could do to strengthen it.”
Any sweeping reforms of the service should begin with a rethinking of what the profession of diplomacy and its practice mean in the 21st century, what new skills may be required, and how to identify and train diplomats who can rise to the expectations of even the most demanding White House, many officers said. Since 9/11, the service has recruited people from diverse backgrounds in order to look more like the United States, but a large number of them come in with no experience in foreign affairs. That demands much more solid training than officers currently receive, as well as professional development throughout their careers, which is almost nonexistent, the Academy of Diplomacy said. It went as far as to state that U.S. diplomacy “functions on a highly amateur basis.”
“The [current] strategy seemed to be to hope that [officers] would pick things up as they went along, with the best officers rising to the top,” Waser said. “This is no way to run a railroad.”
This article is adapted from America’s Other Army: The U.S. Foreign Service and 21st-Century Diplomacy, the second updated edition of which is out this week.
About Me
A Princeton PhD, was a US diplomat for over 20 years, mostly in Eastern Europe, and was promoted to the Senior Foreign Service in 1997. For the Open World Leadership Center, he speaks with
its delegates from Europe/Eurasia on the topic, "E Pluribus Unum? What Keeps the United States United" (http://johnbrownnotesandessays.blogspot.com/2017/03/notes-and-references-for-discussion-e.html). Affiliated with Georgetown University (http://explore.georgetown.edu/people/jhb7/) for over ten years, he still shares ideas with students about public diplomacy.
The papers of his deceased father -- poet and diplomat John L. Brown -- are stored at Georgetown University Special Collections at the Lauinger Library. They are manuscript materials valuable to scholars interested in post-WWII U.S.-European cultural relations.
This blog is dedicated to him, Dr. John L. Brown, a remarkable linguist/humanist who wrote in the Foreign Service Journal (1964) -- years before "soft power" was ever coined -- that "The CAO [Cultural Affairs Officer] soon comes to realize that his job is really a form of love-making and that making love is never really successful unless both partners are participating." | 2023-12-04T01:27:15.642919 | https://example.com/article/5308 |
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