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/* * GDevelop Core * Copyright 2008-present Florian Rival (Florian.Rival@gmail.com). All rights * reserved. This project is released under the MIT License. / #ifndef GDCORE_PROPERTYDESCRIPTOR #define GDCORE_PROPERTYDESCRIPTOR #include <vector> #include "GDCore/String.h" namespace gd { class SerializerElement; } namespace gd { /* * \brief Used to describe a property shown in a property grid. * \see gd::Object * \see gd::EffectMetadata / class GD_CORE_API PropertyDescriptor { public: /* * \brief Create a property being a simple gd::String with the specified * value. * * \param propertyValue The value of the property. / PropertyDescriptor(gd::String propertyValue) : currentValue(propertyValue), type("string"), label(""), hidden(false) {} /* * \brief Empty constructor creating an empty property to be displayed. / PropertyDescriptor() : hidden(false){}; /* * \brief Destructor / virtual ~PropertyDescriptor(); /* * \brief Change the value displayed in the property grid / PropertyDescriptor& SetValue(gd::String value) { currentValue = value; return this; } /** * \brief Change the type of the value displayed in the property grid. * \note The type is arbitrary and is interpreted by the class updating the * property grid: Refer to it or to the documentation of the class which is * returning the PropertyDescriptor to learn more about valid values for the * type. / PropertyDescriptor& SetType(gd::String type_) { type = type_; return this; } /** * \brief Change the label displayed in the property grid. / PropertyDescriptor& SetLabel(gd::String label_) { label = label_; return this; } /** * \brief Change the description displayed to the user, if any. / PropertyDescriptor& SetDescription(gd::String description_) { description = description_; return this; } /** * \brief Add an information about the property. * \note The information are arbitrary and are interpreted by the class * updating the property grid: Refer to it or to the documentation of the * class which is returning the PropertyDescriptor to learn more about valid * values for the extra information. / PropertyDescriptor& AddExtraInfo(const gd::String& info) { extraInformation.push_back(info); return this; } const gd::String& GetValue() const { return currentValue; } const gd::String& GetType() const { return type; } const gd::String& GetLabel() const { return label; } const gd::String& GetDescription() const { return description; } const std::vector<gd::String>& GetExtraInfo() const { return extraInformation; } /** * \brief Set if the property should be shown or hidden in the editor. / PropertyDescriptor& SetHidden(bool enable = true) { hidden = enable; return this; } /** * \brief Check if the property should be shown or hidden in the editor. / bool IsHidden() const { return hidden; } /* \name Serialization / ///@{ /* * \brief Serialize the PropertyDescriptor. / virtual void SerializeTo(SerializerElement& element) const; /* * \brief Unserialize the PropertyDescriptor. / virtual void UnserializeFrom(const SerializerElement& element); /* * \brief Serialize only the value and extra informations. / virtual void SerializeValuesTo(SerializerElement& element) const; /* * \brief Unserialize only the value and extra informations. */ virtual void UnserializeValuesFrom(const SerializerElement& element); ///@} private: gd::String currentValue; ///< The current value to be shown. gd::String type; ///< The type of the property. This is arbitrary and interpreted by ///< the class responsible for updating the property grid. gd::String label; //< The user-friendly property name gd::String description; //< The user-friendly property description std::vector<gd::String> extraInformation; ///< Can be used to store for example the available ///< choices, if a property is a displayed as a combo ///< box. bool hidden; }; } // namespace gd #endif	{ "pile_set_name": "Github" }
sat	{ "pile_set_name": "Github" }
Organic Light Emitting Diode (OLED) display technology has advantages such as low energy consumption. However, The OLED has a short lifespan as luminance of the emitted light is frequently changed according to displayed contents in operation. For this, there is a technology combining OLED display and Liquid Crystal Display (LCD). In a display device of such display device, an OLED substrate is provided, which comprises a plurality of OLEDs configured to emit light of different colors, a LCD panel which comprises a plurality of sub-pixels configured to filter light is disposed outside of the OLED substrate, light emitted from the respective OLED is filtered by the sub-pixels so as to have a desired luminance and to perform display. In such a display device, the luminance is controlled by filtering light through the sub-pixels of the LCD panel. Thus, the luminance of light emitted from the OLEDs is not required to be changed frequently, and the lifespan of OLEDs will be elongated. Obviously, in order for normal operation, both the OLED substrate and the LCD panel require a driving circuit for supplying driving signal (for example, gate scanning signals, data voltage signals, common voltage signals, and the like) thereto. Conventional driving circuits are integrated in a Driver IC which is disposed on a printed circuit board (PCB) and is electrically connected to the OLED substrate and the LCD panel through a flexible printed circuit (FPC). Clearly, in such a display device, the OLED substrate and the LCD panel are respectively controlled by different driving circuits, and two different driver IC and two flexible printed circuits are required, thereby causing a large amount of elements, a complex structure and high cost.	{ "pile_set_name": "USPTO Backgrounds" }
JAPANESE researchers have implanted a small camera inside a mouse's brain to see how memory is formed, in an experiment they hope to some day apply to humans to treat illnesses such as Parkinson's disease. The study, published in the Journal ofNeuroscience Methods and Sensors and Actuators, used a camera 3 mm long, 2.3 mm wide and 2.4 mm in depth, Jun Ohta, professor at Nara Institute of Science and Technology in western Japan, said. Working with researchers at Kinki University, Mr Ohta implanted the special semiconductor camera inside the hippocampus of the mouse's brain, designing the devise so that a screen showed blue light whenever the camera captured memory being recorded by the brain. The researchers injected the mouse with a substance that lights up whenever there is brain activity. The camera then captures that light and the visuals come up on a screen. The team now plans to use the camera while the mouse is walking. "We are thinking about how to apply this to humans, though we must be very careful, as it involves implanting something into the brain,'' Mr Ohta said. "It would take 10 years at the earliest.'' The researchers hope the study will lead to new ways to treat Parkinson's disease, as they aim to have the camera track brain activity that trigger symptoms such as tremours. Member Hmm.. my FIL died of complications of Parkinson's, and I have a brother who's mentally and phyiscally disabled due to birth defects. I'm a HUGE animal lover, but I think this is for the greater good, you know? I mean, come on! We buy leaather goods all the time and don't think of the cow/deer/alligator/ostrich/ect it came from!! Hehehe... you know, if that mouse was running loose in your kitchen, I bet you'd grab a broom and try to smack him, or at the very least freak a little bit? This mouse is giving his all for science! Addicted to Tiffany's Member I feel terrible for the mouse, and am personally against animal testing for any reason. Click to expand... But do you wear leather? Eat meat? Use chemicals to clean? Animals were all involved in those things. Actually, the growth of man is the worse thing that ever happened to animals, becuase we are the only species that kills for revenge, sport and greed, as well as fashion. I'm not condeming what you said either, I'm just pointing out different sides. nyan nyan percent But do you wear leather? Eat meat? Use chemicals to clean? Animals were all involved in those things. Actually, the growth of man is the worse thing that ever happened to animals, becuase we are the only species that kills for revenge, sport and greed, as well as fashion. I'm not condeming what you said either, I'm just pointing out different sides. Click to expand... I feel really badly about animal testing, and I try to live my life the most ethically as I can (no excessive leather products - thank you LV !, vegetarian, natural cleaning products, carpooling as much as possible etc).. with that being said, I understand that animal research is often done in order to gain further understanding, I just hope that it's being done in the most ethical way possible in order to minimize the suffering. I'm possibly coming off as a hypocrite, since any intrusion in an animal's life may cause it unnecessary suffering.. this is just how I feel about it. I wish we could all just sing song and hold hands/paws ! Member I feel really badly about animal testing, and I try to live my life the most ethically as I can (no excessive leather products - thank you LV !, vegetarian, natural cleaning products, carpooling as much as possible etc).. with that being said, I understand that animal research is often done in order to gain further understanding, I just hope that it's being done in the most ethical way possible in order to minimize the suffering. I'm possibly coming off as a hypocrite, since any intrusion in an animal's life may cause it unnecessary suffering.. this is just how I feel about it. I wish we could all just sing song and hold hands/paws ! Click to expand... LOL! Kumbaya is a great song!! I would have to think that yes, they treat the mouse as ethically and carefully as they can, since they are recording brain waves, and pain will make the tests useless if the animal is in pain. I abhor animal testing, especially when it's totally unnessary. One study I read about was testing lipsticks in the eyes of rabbits! I was so ticked off when I read that, WHY did they have to test it in an animals eyes... don't they know what they put in it? I mean, it's stupid... if the ingrediants are known, then the reaction should also been known. Besides, how many women do you know who miss their mouths completely and hit themselves in the eye? I am pleased Ayla, you do make a concentrated effort to refrain from using animal parts and the like, but we depend on many animals for many things... got leather seats in your car? Leather furniture in your house? Leather in your shoes? Yes, I think we can minimize how much of animal products we use, but we can't completely stop from using some. New Member though I do think that it's not too fair for animal testing , but can be there any other way to prove the efficiency of a method of treatment. Though now there're many people are voluntary for human testing, but it'd take such a long time and cost.	{ "pile_set_name": "Pile-CC" }
Ibbi-Sin Ibbi-Sin (, ), son of Shu-Sin, was king of Sumer and Akkad and last king of the Ur III dynasty, and reigned c. 1963–1940 BCE (Short chronology). During his reign, the Sumerian empire was attacked repeatedly by Amorites. As faith in Ibbi-Sin's leadership failed, Elam declared its independence and began to raid as well. Ibbi-Sin ordered fortifications built at the important cities of Ur and Nippur, but these efforts were not enough to stop the raids or keep the empire unified. Cities throughout Ibbi-Sin's empire fell away from a king who could not protect them, notably Isin under the Amorite ruler Ishbi-Erra. Ibbi-Sin was, by the end of his kingship, left with only the city of Ur. In 1940 BCE, the Elamites, along with "tribesmen from the region of Shimashki in the Zagros Mountains" sacked Ur and took Ibbi-Sin captive; he was taken to the city of Elam where he was imprisoned and, at an unknown date, died. The success of the Amorite invasion The Amorites were considered a backward people by Mesopotamian standards; Ibbi-Sin's 17th year was officially named "Year the Amorites, the powerful south wind who, from the remote past, have not known cities, submitted to Ibbi-Sin the king of Ur." However, despite his father Shu-Sin having built a "wall of Martu" across Mesopotamia against Amorite incursions, these were penetrated early in Ibbi-Sin's reign. Scholars have suggested that, by the reign of Ibbi-Sin, the empire was already in decline due to long-term drought – in fact, the same drought that helped to take down the Akkadian Empire c. 2193 BCE may have been responsible for the fall of Ur III. Studies of Persian Gulf sediments indicate that the stream flow of the Tigris and Euphrates was very low around 2100–2000 BCE. [...] Any damage to the agricultural system by enemy raids, bureaucratic mismanagement, or an inattentive ruler would result in food shortages In years seven and eight of Ibbi-Sin's kingship, the price of grain increased to 60 times the norm, which means that the success of the Amorites in disrupting the Ur III empire is, at least in part, a product of attacks on the agricultural and irrigation systems; these attacks brought famine and caused an economic collapse in the empire, paving the way for the Elamites under Kindattu to strike into Ur and capture the king. References Category:Sumerian rulers Category:20th-century BC rulers	{ "pile_set_name": "Wikipedia (en)" }
Tumorigenic effects of endocrine-disrupting chemicals are alleviated by licorice (Glycyrrhiza glabra) root extract through suppression of AhR expression in mammalian cells. Endocrine-disrupting chemicals (EDCs) have been reported to interfere with estrogen signaling. Exposure to these chemicals decreases the immune response and causes a wide range of diseases in animals and humans. Recently, many studies showed that licorice (Glycyrrhiza glabra) root extract (LRE) commonly called "gamcho" in Korea exhibits antioxidative, chemoprotective, and detoxifying properties. This study aimed to investigate the mechanism of action of LRE and to determine if and how LRE can alleviate the toxicity of EDCs. LRE was prepared by vacuum evaporation and freeze-drying after homogenization of licorice root powder that was soaked in 80% ethanol for 72 h. We used 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as a representative EDC, which is known to induce tumors or cancers; MCF-7 breast cancer cells, used as a tumor model, were treated with TCDD and various concentrations of LRE (0, 50, 100, 200, 400 μg/mL) for 24, 48, and 72 h. As a result, TCDD stimulated MCF-7 cell proliferation, but LRE significantly inhibited TCDD-induced MCF-7 cell proliferation in a dose- and time-dependent manner. The expression of TCDD toxicity-related genes, i.e., aryl hydrocarbon receptor (AhR), AhR nuclear translocator, and cytochrome P450 1A1, was also down-regulated by LRE in a dose-dependent manner. Analysis of cell cycle distribution after treatment of MCF-7 cells with TCDD showed that LRE inhibited the proliferation of MCF-7 cells via G2/M phase arrest. Reverse transcription-polymerase chain reaction and Western blot analysis also revealed that LRE dose-dependently increased the expression of the tumor suppressor genes p53 and p27 and down-regulated the expression of cell cycle-related genes. These data suggest that LRE can mitigate the tumorigenic effects of TCDD in breast cancer cells by suppression of AhR expression and cell cycle arrest. Thus, LRE can be used as a potential toxicity-alleviating agent against EDC-mediated diseases.	{ "pile_set_name": "PubMed Abstracts" }
Handled by Yu Xue Introduction {#s0005} ============ Cancer somatic mutations and viral oncogenes can generate tumor-specific protein sequences that are entirely absent from normal human cells. These novel proteins may result in the formation of tumor-specific antigens (TSAs) [@b0005]. As an important type of TSAs, neoantigens are generated by tumor-specific proteins, and presented by major histocompatibility complexes (MHCs) on cell surfaces through antigen presentation, where they can be recognized by T-cell receptors (TCRs) [@b0010], [@b0015]. Recently, neoantigens have attracted a large amount of attention, because they are potential biomarkers to distinguish tumor cells from normal cells. Neoantigens are of critical importance for cancer immunotherapy in the following two aspects. First, the neoantigen burden and quality can be used to predict therapeutic effects for immune checkpoint blockade therapy, such as blockage of programmed death-1 (PD-1) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) [@b0020], [@b0025], [@b0030]. Second, neoantigens can be used as potential targets for cancer immunotherapy, such as personalized cancer vaccines [@b0035], [@b0040] and adoptive cell therapy (ACT) [@b0045]. Therefore, there is an urgent need to identify neoantigens accurately for cancer patients. With the progress of cancer immunogenomics, several kinds of integrated software have been developed for tumor-specific neoantigen detection, such as TSNAD [@b0050] and pVAC-seq [@b0055]. The most critical function of such software is to predict the binding affinities between mutant peptides and human leukocyte antigen (HLA) alleles. To achieve this, a lot of well-acknowledged and popular tools, such as NetMHC [@b0060], NetMHCpan [@b0065], sNebula [@b0070], and HLA-CNN [@b0075], can be used. In addition, several databases can provide necessary information for the development of tools to predict the affinities between peptides and HLA alleles. For example, the Immune Epitope Database (IEDB) is an important immune-related database, providing a large amount of valuable and experimentally-validated information of immune epitopes [@b0080]. The International Immunogenetics Information System (IMGT) offers information about antibodies, TCRs, MHCs, and so on [@b0085]. Taking advantage of existing neoantigen prediction software, several neoantigen-related databases have been built. For example, TRON Cell Line Portal (TCLP) presents potential neoantigens of 1082 cancer cell lines [@b0090]. The Cancer Immunome Atlas (TCIA) presents the relationship between tumor genotypes and immunophenotypes based on 20 solid cancers, and provides a quantitative index for immunotherapy response [@b0095]. With the rapid growth of cancer genomics data, researchers are able to discover potential shared neoantigens across tumor patient populations [@b0100], [@b0105]. In this study, we developed a tumor-specific neoantigen database (TSNAdb v1.0) from pan-cancer immunogenomic analyses. Based on the 7748 tumor samples of 16 tumor types from The Cancer Genome Atlas (TCGA), we predicted the binding affinities between mutant/wild-type peptides and HLA class I molecules. Datasets we used include somatic mutation data of tumor samples from TCGA and the corresponding HLA allele data from TCIA. Two different versions of NetMHCpan, v2.8 [@b0065], and v4.0 [@b0110], were used for prediction. Furthermore, we also conducted extensive analyses and presented detailed information of potential neoantigens generated by somatic mutations, utilizing the related filtering tools embedded in TSNAD [@b0050]. In addition, we employed the recurrent missense mutations in combination with the highly frequent HLA alleles to predict and analyze potential shared neoantigens. Our study would provide a platform to discover putative targets for neoantigen-based cancer immunotherapy. Database content and usage {#s0010} ========================== Data source {#s0015} ----------- We collected somatic mutations and HLA alleles of 7748 tumor samples across 16 tumor types from TCGA (Release7.0, <https://portal.gdc.cancer.gov>) and TCIA (<https://tcia.at/home>), respectively. These tumor samples carry 972,187 missense mutations, among which 18,897 were found recurrently (at least three occurrences in all tumor samples). We selected the top 100 HLA alleles (frequency \>0.5%) of 7748 tumor samples and combined them with the recurrent missense mutations to predict potential shared neoantigens. Moreover, we also extracted 13,459 recurrent missense mutations from 9155 samples derived from the International Cancer Genome Consortium (ICGC) (Release20, <https://icgc.org/>) and 16 highly frequent HLA alleles (frequencies \>5%) from the 1000 Genome Project [@b0115] for the prediction of potential shared neoantigens. Neoantigen prediction {#s0020} --------------------- We took the information on somatic mutations and HLA alleles of each tumor sample and employed NetMHCpan v2.8 [@b0065] and NetMHCpan v4.0 [@b0110] for neoantigen prediction, using the filtering tools embedded in our previously-developed software TSNAD [@b0050]. All the peptides with 8--11 amino acids that contain missense mutations were extracted as mutant peptides, and the corresponding wild-type peptides were extracted as references. We collected the mutant peptides and HLA alleles with binding affinity IC~50~ \< 500 nM (including strong binding with IC~50~ \< 150 nM and weak binding with 150 nM \< IC~50~ \< 500 nM), without consideration of the binding level between their corresponding wild-type peptides and HLA alleles. We then clustered prediction results based on tumor types and calculated the frequencies of shared neoantigens. Compared with NetMHCpan v2.8, NetMHCpan v4.0 is trained based on both binding affinity data and mass spectrometry data, thus adopting stricter criteria for binding prediction. Consequently, 3,707,562 and 1,146,961 neoantigens were predicted by NetMHCpan v2.8 and v4.0, respectively, among which, 716,876 neoantigens were found in both predictions. The potential shared neoantigens based on recurrent mutations and highly frequent HLA alleles were predicted in the similar way. Web interface {#s0025} ------------- To facilitate the utilization of TSNAdb, we have established a web interface to browse and analyze neoantigens. The web interface comprises five main pages ([Figure 1](#f0005){ref-type="fig"}A): (i) Home, (ii) Browse, (iii) Search, (iv) Validation, and (v) Download. In the following context, we exemplify the usage of TSNAdb with the results predicted by NetMHCpan v2.8.Figure 1An overview of the TSNAdb web interfaceA. TSNAdb comprises five main components: (i) Home; (ii) Browse; (iii) Search; (iv) Validation, and (v) Download. The distribution of HLA alleles (B) and somatic missense mutations (C) extracted from TCGA and TCIA are listed. D. The average neoantigen loads across different tissues. E. Top 20 genes with predicted neoantigens in 7748 samples. F. The result of 'Search' page under the selection of "NetMHCpan2.8, KRAS, and TCGA". G. The result of 'Search' page under the selection of "NetMHCpan2.8, KRAS, and ICGC". H. Example of validation data from IEDB in 'Validation' page (top) and partial information on 'Download' page (bottom). The predicted binding level 'Strong' indicates strong binding with IC~50~ \< 150 nM. TCGA, The Cancer Genome Atlas; TCIA, The Cancer Immunome Atlas; HLA, human leukocyte antigen; TSNAD, tumor-specific neoantigen detector; ICGC: International Cancer Genome Consortium; IEDB, Immune Epitope Database; WT, wild type. In the 'Home' page, TSNAdb provides a statistical table about the database, including the number of projects, samples, HLA alleles ([Figure 1](#f0005){ref-type="fig"}B), mutations ([Figure 1](#f0005){ref-type="fig"}C), and predicted neoantigens of each tumor type. The table presents 3,707,562 potential neoantigens from the 7748 tumor samples across 16 tumor types. The average predicted neoantigen loads vary across different tumor types ([Figure 1](#f0005){ref-type="fig"}D). For instance, the average predicted neoantigen load for uterus cancer is 1957, which is 21 for thyroid cancer. Besides, users can get the detailed information about the predicted neoantigens of each tumor type by clicking on the tissue name in the table. The content of each tumor type includes top 20 HLA alleles and top 20 genes with predicted neoantigens in this tumor type, which are shown as two figures. All predicted neoantigens in this tumor type would be displayed below figures. To further understand the distribution of neoantigens at gene level, users can retrieve neoantigens by feeding in a gene name in the 'Browse' page ([Figure 1](#f0005){ref-type="fig"}E). The retrieval results provide more functions than that indicated in each tumor type, such as sorting and searching within results, making it easier to search the most frequent neoantigens generated by each gene. For instance, the potential neoantigen based on BRAF V600E mutation and HLA-A03:01 exists in 117 tumor samples, and corresponding neoantigens based on several mutations of KRAS and PIK3CA are also shared in more than 40 tumor samples ([Table 1](#t0005){ref-type="table"}).Table 1Top 10 shared neoantigens of 7748 tumor samples from TCGAGeneMutationHLA alleleWT peptideWT affinity (nM)MT peptideMT affinity (nM)FrequencyBRAFV600EA03:01KIGDFGLATVK94.09KIGDFGLATEK125.24117/7748KRASG12DA02:01KLVVVGAGGV520.08KLVVVGADGV213.8282/7748KRASG12VA02:01KLVVVGAGGV520.08KLVVVGAVGV111.8771/7748KRASG12VA02:01KLVVVGAG17,690.28KLVVVGAV162.9771/7748BRAFV600EA11:01KIGDFGLATVK53.27KIGDFGLATEK45.2068/7748PIK3CAH1047RC07:01AHHGGWTTKM6742.50ARHGGWTTKM248.5762/7748PIK3CAH1047RC07:02AHHGGWTTKM2596.23ARHGGWTTKM217.7656/7748PIK3CAE545KA03:01STRDPLSEITE28,265.76STRDPLSEITK321.1954/7748BRAFV600EB57:01FGLATVKSRW128.34FGLATEKSRW246.2341/7748BRAFV600EB57:01LATVKSRW73.82LATEKSRW124.6141/7748[^8] There would always be some newly discovered tumor patients with combinations of somatic mutations and HLA alleles absent from 'Browse' page. We thus provide neoantigen prediction results of all possible combinations (Cartesian product) of recurrent mutations (occurring at least three times in all samples) and highly frequent HLA alleles in 'Search' page. The data used for neoantigen prediction include 18,897 recurrent missense mutations and the top 100 HLA alleles (frequency \>0.5%) of 7748 tumors from TCGA. Furthermore, we also employed the 13,459 recurrent missense mutations from ICGC and 16 HLA alleles with frequency \>5% in the population collected in the 1000 Genome Project [@b0115], for the prediction of potential shared neoantigens. Compared with the prediction results from real tumor samples, the frequencies of shared neoantigens predicted on recurrent mutations and highly frequent HLA alleles are similar ([Table 2](#t0010){ref-type="table"}). The distribution of predicted shared neoantigens is displayed as shown in [Figure 1](#f0005){ref-type="fig"}F and G.Table 2Frequency of the top 10 shared neoantigens predicted by recurrent mutations in combination with highly frequent HLA alleles from TCGAGeneMutationHLA alleleExpected frequencyObserved frequencyBRAFV600EA03:011.55%1.51%KRASG12DA02:011.01%1.06%PIK3CAH1047RC07:010.73%0.80%PIK3CAE545KA03:010.68%0.70%PIK3CAE542KA03:010.44%0.44%TP53R248WA02:010.33%0.34%TP53R273CA02:010.29%0.31%TP53R248QC07:020.25%0.23%TP53Y220CA02:010.24%0.19%PIK3CAR88QC07:020.16%0.17%[^9] Besides, we present experimentally-validated data for the predicted neoantigens in the 'Validation' page ([Figure 1](#f0005){ref-type="fig"}H), according to the binding level between peptides and HLA alleles. Limited by the availability of binding data between mutant peptides and HLA alleles, all the validation data derived from IEDB is for wild-type peptides and HLA alleles [@b0080]. TSNAdb v1.0 (<http://biopharm.zju.edu.cn/tsnadb/>) is freely available for all academic users. Users can download data from the 'Download' page ([Figure 1](#f0005){ref-type="fig"}H), according to tumor types and the prediction tools chosen. Case study {#s0030} ---------- The major function of our database is to provide potential neoantigens of various tumor types and shared neoantigens across tumor patient populations. Therefore, we further provide statistical analyses of neoantigen prediction results in each tumor type. Here, we take the results of bladder cancer predicted by NetMHCpan v2.8 as an example to demonstrate the utilization of TSNAdb. There are 408 tumor samples for bladder cancer, with 106 different HLA alleles and 49,537 missense mutations. From these tumor samples, we obtain 182,756 predicted neoantigens. We present the top 20 HLA alleles, top 20 genes, and detailed neoantigen information in the web page ([Figure 2](#f0010){ref-type="fig"}A--C). According to the number of predicted neoantigens presented by each HLA allele, the top three HLA alleles are A02:01, A11:01, and C03:04, which account for 19.5%, 5.6%, and 4.7% of the total HLA alleles, respectively. These three HLA alleles also show \>5% frequency in the 1000 Genome Project [@b0115]. According to the number of predicted neoantigens generated by each gene, top three genes are TTN, MUC16, and TP53, which have 584, 318, and 270 neoantigens, respectively. In these genes, TTN and MUC16 encode large proteins with numerous random mutations, whereas TP53 is the most famous tumor suppressor gene with lots of recurrent mutations. The most recurrent mutation of TP53 is R248Q, which exists in 17 out of 408 bladder cancer patients. The mutant peptide arising as a consequence of TP53 R248Q mutation could bind to HLA-C07:02 and be presented as a potential neoantigen in four patients, which is the most frequent neoantigen in bladder cancer. If a bladder cancer patient carries the same mutation and HLA allele with existing patients, such as TP53 R248W and HLA-A02:01, the corresponding neoantigen can be retrieved from the 'Browse' page directly. And the potential neoantigens can be used for experimental validation, which would facilitate the following cancer immunotherapy. If the combination of HLA allele and TP53 mutation of this patient is absent in the existing samples, users can try to retrieve it in the 'Search' page. For instance, the combination of TP53 R273H and HLA-A02:01 is absent in existing bladder cancer patients but can be retrieved in the 'Search' page, which provides the predicted neoantigens generated by all combinations of recurrent TP53 mutations and highly frequent HLA alleles ([Figure 2](#f0010){ref-type="fig"}D). There are 155 types of recurrent TP53 mutations that can generate at least one potential neoantigen presented by highly frequent HLA alleles, and 130 of these mutations could be presented by at least ten highly frequent HLA alleles. For instance, peptides generated by TP53 G105C mutation are predicted to bind to 47 different HLA alleles. The most frequent potential neoantigen is generated by TP53 R273H (0.86%) and HLA-A02:01 (41.4%), which shows the frequency of 0.36%.Figure 2*Example applications of predicted neoantigens for bladder cancer and the gene TP53*Top 20 HLA alleles (A) and genes (B) with predicted neoantigens are displayed in the page using bladder cancer as an example, with the detailed neoantigen information listed (C). The binding level 'Strong' indicates strong binding with IC~50~ \< 150 nM, 'Weak' indicates weak binding with 150 nM \< IC~50~ \< 500 nM, '-' indicates non-binding with IC~50~ \> 500 nM. D.** Distribution of the predicted neoantigens for all combinations of recurrent mutations of TP53 and the highly frequent HLA alleles according to the TCGA dataset. The color gradient indicates the frequencies of potential shared neoantigens for the specific combinations of somatic mutations and HLA alleles. All the data shown are predicted by NetMHCpan v2.8. HLA, human leukocyte antigen; TCGA, The Cancer Genome Atlas; WT, wild type; MT, mutant. Perspectives and concluding remarks {#s0035} =================================== In this study, we developed a comprehensive database named TSNAdb for tumor-specific neoantigens based on 7748 tumor samples of 16 tumor types from TCGA. This database provides detailed affinity information between mutant/wild-type peptides and HLA alleles, and the frequencies of neoantigens shared by tumor samples of each tumor type and pan-cancer. Furthermore, this database also provides potential shared neoantigens generated from all possible combinations of recurrent mutations and highly frequent HLA alleles. The information provided by the database could facilitate the subsequent experimental design and validation and the discovery of potential targets for cancer immunotherapy. Compared with other existing neoantigen-related databases, such as TCIA, TSNADB provides the HLA binding information of both mutant peptides and wild-type peptides, which could be used for evaluating the differential agretopicity index (DAI), the difference of HLA binding affinity between mutant and wild-type peptides [@b0120]. Besides, users could search neoantigens at the gene level and obtain the potential shared neoantigens generated from all possible combinations of recurrent mutations and highly frequent HLA alleles from TSNAdb, which makes the database more user-friendly and comprehensive. In the future, we would expand our work from the following three aspects. In terms of the data, we would collect more samples from not only TCGA, but also other cancer databases such as ICGC or published literatures, for more comprehensive combination of HLA alleles and somatic mutations. In terms of the methods, we would apply more state-of-the-art methods on the neoantigen prediction and update our prediction software to improve the accuracy. In terms of the evaluation metrics, we would employ more well-acknowledged metrics to evaluate predicted neoantigens, e.g., neoantigen quality indicating the probability for TCR recognition [@b0125], as well as DAI [@b0120]. Authors' contributions {#s0040} ====================== ZZ and SC conceived of the idea and supervised the study. ZS and XG participated in the design of the study. JW constructed and maintained the database and web interface, performed the data analysis. ZZ wrote the program and WZ designed the system architecture. WZ participated in the data analysis; ZS participated in the data acquisition; BZ participated in the statistical analysis. JW, BZ, and ZZ wrote the manuscript. All authors have read and approved the final manuscript. Competing interests {#s0045} =================== The authors have declared no competing interests. This work was supported by the National Key Research and Development Program of China (Grant No. 2017YFC0908600), the National Natural Science Foundation of China (Grant No. 31501021), and the Fundamental Research Funds for the Central Universities of China. The authors gratefully acknowledge the clinical contributors and data producers from the TCGA Research Network for referencing the TCGA datasets and the TCIA for referencing HLA-type data of TCGA samples. Peer review under responsibility of Beijing Institute of Genomics, Chinese Academy of Sciences and Genetics Society of China. [^1]: ORCID: 0000-0003-4554-9155. [^2]: ORCID: 0000-0003-1834-0348. [^3]: ORCID: 0000-0002-9141-8474. [^4]: ORCID: 0000-0002-4881-1238. [^5]: ORCID: 0000-0001-9845-6986. [^6]: ORCID: 0000-0002-2730-5483. [^7]: ORCID: 0000-0002-0792-3735. [^8]: Note: WT, wild type; MT, mutant. Amino acid residue changes caused by somatic mutations are indicated in red. [^9]: Note: Expected frequency indicates the frequency of shared neoantigens predicted by recurrent mutations in combination with highly frequent HLA alleles. Observed frequency, the frequency of shared neoantigens in 7748 tumor samples.	{ "pile_set_name": "PubMed Central" }
Q: Proving $n!n^s=o(n^n)$ I want to prove that for any $s\geq0$, and $n\to\infty$, $n!n^s=o(n^n)$ or $$\lim_\limits{n\to\infty}\frac{n!n^s}{n^n}=0.$$ As a hint, the inequality $$\sum\limits_{k=1}^{n}\log k\leq n\log\frac{n+1}2$$ is given. I thought that instead of proving $\lim_\limits{n\to\infty}n!n^{s-n}=0$, one could also show $\lim_\limits{n\to\infty}\log\left(n!n^{s-n}\right)=-\infty$. This would be equivalent to $\lim_\limits{n\to\infty}\log\left(n!\right)+\log\left(n^{s-n}\right)=-\infty$. Using the given inequality, it would be sufficient to prove $$\lim_\limits{n\to\infty}n\log\frac{n+1}2+\log\left(n^{s-n}\right)=-\infty\Leftrightarrow\lim_\limits{n\to\infty}n\log\frac{n+1}{2n}+s\log n=-\infty\\\Leftrightarrow\lim_\limits{n\to\infty}n\log\frac12+s\log n=-\infty.$$ What should I do now? A: The series $$\sum_\limits{n=1}^\infty\frac{n!n^s}{n^n}$$ is convergent by the ratio test (easy exercise). Therefore $$\lim_\limits{n\to\infty}\frac{n!n^s}{n^n}=0.$$	{ "pile_set_name": "StackExchange" }
Q: PHP Xpath simple search I'm trying to add two conditions to a search on my XML. Consider this XML: <?xml version="1.0"?> <votes> <vote> <url>http://www.mydoamin.com</url> <ip>xxx.xxx.xxx.xxx</ip> </vote> </votes> Then I use: $xml->xpath("(//votes/vote/[url='Admin' and ip='Group']"); But that give an invalid expression error: For a single condition this works: $xml->xpath("(//votes/vote/ip[contains(text(), '$ip')])"); Logic would suggest an AND would worK: $xml->xpath("(//votes/vote/ip[contains(text(), '$ip')]) & (//votes/vote/url[contains(text(), '$ip')])"); But this fails - Warning: SimpleXMLElement::xpath(): Invalid expression What am I doing wrong? A. A: Remove / between vote and [. XPath should look like //votes/vote[url='Admin' and ip='Group']	{ "pile_set_name": "StackExchange" }
576 So.2d 666 (1991) Jimmy R. HASTINGS v. Bobby HANCOCK d/b/a B & P Used Motors. Civ. 7845. Court of Civil Appeals of Alabama. February 6, 1991. 667 Clyde D. Baker, Guntersville, for appellant. No brief for appellee. ROBERTSON, Presiding Judge. Following a hearing in which the employee, Jimmy Hastings, was awarded workmen's compensation benefits, he moved for an amended judgment, requesting double compensation pursuant to § 25-5-8(e), Code 1975. That code section provides: "Penalties for failure to secure payment of compensation; injunctions. Any employer required to secure ... compensation shall be guilty of a misdemeanor and, upon conviction thereof, shall be subject to a fine of not less than $25 nor more than $1,000. In addition thereto, any employer required to secure the payment of compensation under this section who fails to secure such compensation shall be liable for two times the amount of compensation which would have otherwise been payable for injury or death to an employee." § 25-5-8(e), Code 1975 (emphasis added). The trial court's order in this case that awarded the employee benefits made no finding concerning whether the employer had failed to secure workmen's compensation insurance. However, upon the employee's motion to amend the final judgment, the court entered the following order: "The claim for the penalty under the aforesaid code section [§ 25-5-8(e)] was not made a part of the plaintiff's complaint and was not litigated on trial of this cause. Further, there is no evidence before the court of whether the defendants have opted to be self-insurers, under sub-paragraph (b) of the aforesaid code section, as they have the right to do." This court has previously determined that the double award penalty provision of § 25-5-8(e), Code 1975, is mandatory. Rush v. Heflin, 411 So.2d 1295 (Ala.Civ. App.1982). In fact, this court specifically noted in Rush that "there is no legal right to relief from a penalty which is required to be imposed by law." Further, because the code section was found to be valid, this court held that "it had to be applied by the trial court." Rush at 1296. However, the trial court in this case refused to impose the penalty for two reasons. First, the trial court determined that no claim for the penalty was made as a part of the employee's complaint and that the issue was not litigated. Second, the trial court found that no evidence was presented concerning whether the employer had elected to be a self-insurer. (Such an election, if proven, would have removed the employer from the application of the penalty provision. § 25-5-8(b), Code 1975.) Concerning the trial court's finding that no claim for the penalty was made or litigated, we note the following. The employee's complaint requested such benefits as he was entitled to pursuant to the workmen's compensation laws of Alabama. Further, the court is bound to grant whatever relief is appropriate in a case based on 668 the facts proved, regardless of whether the complaint specifically demanded such relief. Rule 54(c), A.R.Civ.P.; Johnson v. City of Mobile, 475 So.2d 517 (Ala.1985). The following testimony was given by Pat Hancock, the employer's wife, who worked as a clerical employee of the employer: "MR. BAKER: When Mr. Hastings was hurt, you went to the hospital in Fort Payne and guaranteed his hospital bill, did you not? "MRS. HANCOCK: Yes, sir. "MR. BAKER: Did you tell them it was workmen's compensation? "MRS. HANCOCK: No, sir, because we didn't have workmen's comp. "MR. BAKER: You did not have any workmen's comp. coverage at the time of this injury? "MRS. HANCOCK: No, sir." ". . . "MR. MCGEE (employer's lawyer): Did you, in fact, make arrangements at the hospital for the medical bills? "MRS. HANCOCK: Yes, sir. ". . . "MR. MCGEE: Why did you do that? "MRS. HANCOCK: Well, I knew he had gotten hurt on our property and I just figured that it was because he had got hurt on our property, it was our responsibility." From this testimony, we find that the employee proved such facts as would entitle him to recover the double penalty, regardless of the fact that the employee failed to specifically request this relief in his complaint. Johnson. In short, because the employer had no workmen's compensation insurance as required by law, the penalty was due to be imposed. Rush. However, we must now examine whether the trial court's second legal conclusion correctly prevented the employee from recovering the double benefits penalty. We recognize that the provisions of § 25-5-8 do not set out who has the burden of establishing whether an employer is self insured, and, further, we note that this issue has not been previously addressed by the appellate courts of this state. However, because proof of self-insurance would prevent an employer from having to pay the double penalty provision, we find that establishing such proof should properly be the employer's burden. In Mobile Liners, Inc. v. McConnell, 220 Ala. 562, 126 So. 626 (1930), our supreme court was confronted with the question of who had the burden of proof with regard to establishing the number of employees regularly employed by an employer. In that situation, the court noted that because the code section concerning the number of employees operated to remove the employer from having to comply with workmen's compensation laws, "the burden is upon the employer to bring itself within the terms of that exception." Mobile Liners, 220 Ala. at 566, 126 So. at 629 (citation omitted). Similarly, proof of self-insurance in this case would remove the employer from having to comply with the workmen's compensation laws, and we find that "the burden is upon the employer to bring itself within the terms of that exception." Mobile Liners. Our examination of the record discloses that the employer in this case failed to offer any evidence tending to establish that he was self-insured. In fact, all of the testimony previously referred to indicates just the opposite. Likewise, we note that at the outset of the case, the employer contended he was not subject to the requirements of the workmen's compensation act because he did not have enough employees; however, the court found otherwise. The employer made no contention that he was exempt from the workmen's compensation laws due to his having been authorized by the director of industrial relations to operate as a self-insurer. Consequently, we find that the trial court erred in not applying the mandatory penalty provision of § 25-5-8(e). This case is reversed and remanded with directions that the trial court enter a judgment consistent with this opinion. *669 REVERSED AND REMANDED WITH DIRECTIONS. THIGPEN and RUSSELL, JJ., concur.	{ "pile_set_name": "FreeLaw" }
In recent years, non-volatile static random access memory has been widely used. Non-volatile static random access memory (nvSRAM) does not lose data stored therein, even when the power to the nvSRAM is interrupted. A unit memory cell of an nvSRAM is described in U.S. Pat. No. 5,914,895. That unit memory cell includes a non-volatile circuit configured as a non-volatile memory element for maintaining non-volatile data. It also includes an SRAM configured as a volatile memory element for performing read and write operations of volatile data. FIG. 1 is a schematic equivalent circuit illustrating a unit memory cell 10 of the nvSRAM described in U.S. Pat. No. 5,914,895. Referring to FIG. 1, the memory cell 10 includes an SRAM 12 and a pair of non-volatile memory circuits (hereinafter, referred to as NVM) 14. The SRAM 12 includes a pair of access transistors 30, 32 and a latch circuit 33. The latch circuit 33 includes two NMOS transistors and two PMOS transistors which are cross-coupled to each other. A data true level signal and a data complement level signal are output to data nodes 20 and 22, respectively. The data nodes 20, 22 are located within the latch circuit 33. The data true level signal and the data complement level signal are opposite to each other. The access transistor 30 is coupled between the data node 20 and a signal line BT. The access transistor 32 is coupled between the data node 22 and a signal line BC. The signal line BT is a bit line for the data true level. The signal line BC is a bit line for the data complement level. The bit lines BT and BC extend to all the stacked cells in a single vertical column in a memory cell array. Each vertical column of cells has a common pair of bit lines. The access transistors 30, 32 are controlled by a signal applied to a signal line WL. The signal line WL is a word line connected in common to the gate terminals of the access transistors 30, 32 and to the gate terminals of all the other access transistors in all the stacked cells in a single low. The NVM 14 is a circuit connected to each of the data nodes 20, 22 for storing data at the data nodes 20, 22 such that the stored data is not volatile. The NVM 14 of FIG. 1 is configured as a pair of tri-gate transistors 41, 42 including recall transistors 41a and 42a, SONOS (silicon/oxide/nitride/oxide/silicon) transistors 41b and 42b, and pass transistors 41c and 42c. The SONOS transistors 41b, 42b, which are described in U.S. Pat. No. 5,914,895 and U.S. Pat. No. 6,770,950, have an ONO (oxide/nitride/oxide) structure. The SONOS transistors 41b, 42b store the data levels of the data nodes 20, 22 such that the data levels stored in the latch circuit 33 are not volatile. The data levels stored in the SONOS transistors 41b, 42b are removed when a control signal Vse is applied thereto. The recall transistors 41a, 42a recall the data levels stored in the SONOS transistors 41b, 42b and write the data levels stored in the SONOS transistors 41b, 42b into the latch circuit 33 when a control signal Vrcl is applied to the recall transistors 41a, 42a. The pass transistors 41c, 42c read the state of the data true level signal and the complement level signal in the latch circuit 33, or write the data levels stored in the SONOS transistors 41b, 42b into the latch circuit 33 when a control signal Vpas is applied to the pass transistors 41c, 42c. The operation of the conventional nvSRAM 10 will now be described. When a power source is on and the nvSRAM operates normally, all of the voltages of the control signals Vrcl, Vpas and Vse are set to 0[V] so that all of the transistors of the tri-gate transistors 41, 42 are turned off. As a result, the SONOS transistors 41b and 42b are isolated from the latch circuit 33 and, thus, are not affected by state variations of the levels at the data nodes 20, 22 of the latch circuit 33. However, when the power source is turned off, the nvSRAM 10 stores the levels at the data nodes 20, 22 of the latch circuit 33 in the SONOS transistor 41b, 42b, or erases the levels while passing through an erase mode and a program mode. In the erase mode, a voltage of −10 to −15 [V] (depending on erase speed, erase time, the ONO structure, etc) is applied to the gate electrodes of the SONOS transistors 41b, 42b. Also, a voltage of 0 [V] is applied to the control signal line Vrcl and to the control signal line Vpas for a predetermined time. In general, the bias voltage is usually applied for less than 10 [msec] in the erase mode. Under the bias conditions of the erase mode, the recall transistors 41a, 42a and the pass transistors 41c, 42c are held in an off state, and the SONOS transistors 41b, 42b are placed in an accumulation mode. Most of the electric field associated with the voltage applied to the gate electrodes of the SONOS transistors 41b, 42b is concentrated on the ONO layer. As a result of the intensive electric field concentrated on the ONO layer, holes accumulated on a silicon substrate surface on which the gate electrodes of the SONOS transistors 41b, 42b are placed tunnel through the tunnel oxide film of the SONOS transistors 41b, 42b, and are trapped in traps which are present in the nitride film of the SONOS transistors 41b, 42b. Then, the electrons which have been trapped in the nitride films tunnel the tunnel oxide and escape into the silicon substrate, thereby resulting in erasure whereby a threshold voltage of the SONOS transistors 41b, 42b is lowered. Next, in the program mode, a voltage of +10 to +15 [V] (depending on program speed, program time, the ONO stack structure, etc) is applied to the gate electrodes of the SONOS transistors 41b, 42b. Also, 0 [V] is applied to the control signal line Vrcl, and a voltage “H” (herein, “H” refers to a voltage representing a high logic state; typically 2.5 [V]) is applied to the control signal line Vpas for a predetermined time. In general, the bias voltage is usually applied for less than 10 [msec] in the program mode. Under the bias conditions of the program mode, the recall transistors 41a, 42a are held in an off state, and accordingly, do not conduct current from the Vcc voltage. The conducting states of the pass transistors 41c, 42c are determined by the logic levels (“H” and “L”) stored in the data nodes 20, 22 of the latch circuit 33. For example, if we assume that a high voltage level “H” is stored in the data node 20 and a low voltage level “L” is stored in the data node 22, since a high level Vpas is applied to the gate electrode of the pass transistor 41c connected to the data node 20 and the data node 20 is connected to the source electrode of the pass transistor 41c, the voltage difference between the gate electrode and the source electrode becomes nearly 0 [V]. Accordingly, the pass transistor 41c does not conduct current. As a result, the silicon substrate below the gate electrode of the SONOS transistor 41b goes into a deep depletion state due to the positive voltage applied to the gate electrode of the SONOS transistor 41b. During this deep depletion, since the electric field caused by the positive voltage Vse applied to the gate electrode of the SONOS transistor 41b is mostly applied to a depletion region of the silicon substrate and, thus, is only slightly applied to the ONO layer, the program mode (where electrons tunnel the tunnel oxide film and are trapped into the traps of the nitride film) does not occur. This phenomenon is called a dynamic write inhibition (DWI). Since this deep depletion occurs in a non-equilibrium state, it disappears over time as the non-equilibrium state turns to an equilibrium state. When the deep depletion condition disappears, DWI does not occur any longer. In other words, although programming is not conducted due to the DWI phenomenon occurring at the beginning of the program mode, programming is conducted as the DWI phenomenon disappears after a predetermined period of time elapses. The characteristic of the DWI phenomenon depends on the device structure. The DWI phenomenon typically lasts for 1 to 100 [msec]. On the other hand, since the voltage Vpas applied to the gate electrode of the pass transistor 42c has a high level “H, a low voltage level “L” is stored in the data node 22, and since the data node 22 is connected to the source electrode of the pass transistor 42c, a voltage difference between the gate electrode and the source electrode becomes nearly “H” [V]. Consequently, the pass transistor 42c is turned on. As a result, the voltage applied to the silicon substrate below the gate electrode of the SONOS transistor 42b becomes nearly an “L” [V]. Thus, most of the program voltage applied to the gate electrode of the SONOS transistor 42b is applied to the ONO layer. Accordingly, electrons accumulated on the surface of the silicon substrate tunnel the tunnel oxide film, and the program mode is conducted to trap the electrons in the traps of the nitride film. The trapped electrons increase the threshold voltage of the SONOS transistor 42b. In other words, the SONOS transistor 41b maintains an erase state at the beginning of the program mode and, thus, has a low threshold voltage because the program mode is suppressed due to the DWI phenomenon. However, the SONOS transistor 42b has a high threshold voltage as the program mode is conducted. When the power source is on, a recall mode for recalling data stored in the SONOS transistors 41b, 42b to the latch circuit 33 is performed. In the recall mode, a low voltage 0 [V] is applied to the control signal line Vse, and a high voltage “H” is applied to the control signal line Vrcl and to the control signal line Vpas. Under the bias conditions of the recall mode, since the control signal line Vrcl and the control signal line Vpas are set to a logic high voltage “H”, the recall transistors 41a, 42a and the pass transistors 41c, 42c go into an on state. Since the SONOS transistor 41b is in an on state, current flows therethrough and the data node 20 goes into a logic high state “H”. Since the programmed SONOS transistor 42b is in an off state, it does not flow current therethrough and the data node 22 goes into a logic low state “L”. Accordingly, even though a memory element configured by the nvSRAM is powered off while passing through the erase mode, the program mode and the recall mode, the data of SRAM can be securely stored in the NVM 14. However, in an nvSRAM using conventional SONOS transistors 41b, 42b, due to the DWI phenomenon when data is stored, one data node is programmed and the other data node is not programmed depending on the states of the data nodes 20, 22 of the latch circuit 33. In such a selective program mode, it is important to improve the DWI characteristic and the programming speed. However, it is very difficult to improve the DWI characteristic. Although programming time is prolonged when the selective program mode is conducted by a DWI mechanism, a threshold voltage window (i.e., a difference between a threshold voltage of a SONOS transistor to be programmed and a threshold voltage of a SONOS transistor in which the DWI phenomenon occurs) cannot be increased beyond a certain voltage. In addition, since the thickness of the tunnel oxide film of the SONOS transistor is very small (typically about 20 Å), the retention characteristic of the SONOS transistor is very poor. Furthermore, since the programming speed of the SONOS transistor is relatively low, a significantly large capacitance is required to maintain a constant voltage required to store the data of the SRAM for a predetermined time when the power is off. In the drawings and the following detailed description, the same or similar elements are denoted by the same reference.	{ "pile_set_name": "USPTO Backgrounds" }
Trumai language Trumai is an endangered language isolate of Brazil. Most Trumai are fluent in languages of wider communication, and children are not learning it well. Background Trumai is a language spoken by the indigenous community of the same name located in the Xingu reserve along the Upper Xingu River in central Brazil. Murphy and Quain reported that there were only 25 people remaining in the Trumai community. Fortunately, this has since increased to 94 as of 1997, of which 51 people spoke the Trumai language. In the International Encyclopedia of Linguistics, Grimes observes that there are 78 speakers as of 2003. Due to the popularity of speaking Portuguese among the local population, Trumai is considered an extremely endangered language because the children are not learning to speak it as a first language. The Trumai people first entered the Upper Xingu region sometime in the early 19th century after being driven away from southeastern Brazil by the Xavante people. The first contact the Trumai had with a white person was in 1884 when Karl von den Steinen explored the Upper Xingu region. He observed the differences between Trumai culture and other Xingu cultures due to the Trumai’s relocation. In the fifty years or so that followed Von den Steinem’s first visit to the Trumai, there is little documentation of the community because researchers who visited the Xingu region preferred visiting and studying other indigenous cultures instead. In the time between the Trumai’s first arrival in the upper Xingu and Von den Steinen’s first contact with them, they were continuously being attacked by the native communities in the region, including the Suyá and Ikpeng. Following a period of contacts from researchers, including Buell Quain in 1938, the Trumai moved to a new territory again, this time because of a flu and measles epidemic. After recovering from this, the subsequent population increase led to the emergence of more Trumai villages in the Upper Xingu region, while their former territories have since become occupied by other communities. Despite being surrounded by a variety of different languages that belong to the four major stocks of Brazilian indigenous languages (Tupi, Arawak, Cariban, and Ge), Trumai is an isolated language. There is speculation that Trumai belongs to the Equatorial language stock, in which case it is still very far removed from other languages and families belonging here. Initial research done on the Trumai was included in an overall study of the cultures of the Xingu region, which was performed through surveys focussing on “material culture”. Quain was the first researcher to focus on the Trumai culture specifically, however, this was an anthropological study, not linguistic. In the preface to her thesis “A Reference Grammar of Trumaí”, Guirardello states that Monod-Becquelin was the first person to conduct descriptive studies on the Trumai language, in which she focused on aspects of the language such as ergativity and phonological transcriptions. Monod-Becquelin’s early work was followed by Greenberg’s research, which includes his aforementioned proposal that Trumai, instead of being a completely isolated language, belongs to the Equatorial stock. Guirardello’s “A Reference Grammar of Trumai” is the first proper description of Trumai grammar, which Guirardello composed with the intention of it becoming an aid for future research papers on the language. Since then, research on the Trumai language has increased, leading to studies of various aspects of the language. Monod-Becquelin has continued her research by investigating the use of transitive verbs in Trumai. Guirardello’s work has also included studies into Trumai’s ergativity, focussing on the ergative-absolutive patterns in its morphology and the complexity of its syntax due to the nominative-accusative patterns also present. Trumai was one of the 24 indigenous languages studied in South America as part of a series of documentation projects conducted by DoBeS (Documenting Endangered Languages). DoBeS is one of the many language documentation organizations operating in Brazil, and is funded by the Volkswagen Foundation. The Trumai culture has also been the topic of anthropological studies. The first was done by Buell Quain, who spent four months with the Trumai and gathered information on many aspects of the culture and community. More recently, De Vienne has conducted ethnographic studies on Trumai focussing on language and communication in the community, such as joking and ritual singing traditions. Grammar Phonology This inventory is atypical of Amazonian languages (Trumai is a recent immigrant to the Xingu basin) in its ejective consonants, the lateral fricative , and the alveolar–dental distinction. Guirardello, who specializes on Trumai, has presented varied inventories of these phonemes: Guirardello (1999a) lists /t̪ t̪' ts ts' s/ as dental, and /t t' d n l ɬ ɾ/ as alveolar; whereas Guirardello (1999b) lists only /t/ and /t'/ as alveolar. Younger speakers do not make the ejective distinction. The vocalic inventory is /, , , , / and . Syllable structure is maximally CVC, and stress always falls on the final syllable of a word. Morphology The morphological aspects of Trumai as covered in Guirardello’s grammar of the language include the parts of speech: nouns, verbs, and auxiliaries. Under nouns, she investigates the effect of adjectives, plurality in the language, and count versus mass nouns, among others. Under verbs, she focuses on causality, negation, intensity, and imperativity in verb particles. And under auxiliaries, she discusses body posture, mood and aspect, and directional auxiliaries. Chapter 5 explores further analyses of each of these aspects of the parts of speech in terms of “Simple Declarative Clauses”. Pronouns in Trumai are distinguished by person, gender, number, and listener inclusion/exclusion in the first-person plural pronoun. Like in English, gender is only seen in the third-person singular pronoun, while number is categorized as singular, dual, and plural (whereas English only has singular and plural). They are also affected by the type of Noun Phrase (henceforth “NP”) they appear in (absolutive, ergative, or dative), which are distinguished by suffix insertion. The following are tables of the Trumai personal pronouns with examples included for the absolutive case: Absolutive: ha hu’tsa chï(_in) [huksitukuk yi]-ki [yayanke tam] 1 see Foc/Tens capivara YI-Dat deer Com “I saw a capivara and a deer.” Ergative: [Karu], [Kumaru], [Atawaka] hai-ts amidoxos ke. Karu Kumaru Atawaka 1-Erg call KE ‘I called Karu, Kumaru, and Atawaka.’ Dative: kiki-k atlat-ø kï̡tï ha wan-ki. man-Erg pan-Abs give 1-Dat ‘The man gave it to us.’ 1st-person/exclusive pronouns are formed in ha, inclusive with ka, 2nd person with hi, and 3rd with in. Dual number is indicated by the suffix -a, and plural by -wan. Masculine and feminine are distinguished in the 3rd person. Alienable possession is indicated by the suffix -kte or -kate on the possessor (Kumaru-kte tahu "Kumaru's spoon"), and inalienable possession by juxtaposition (dinoxo kuʃ "the girl's head", ha kuʃ "my head"). Suffixes are used to mark ergative (-ts for 1sg, otherwise -ek/-ak), dative, locative, allative, comitative, and instrumental case. One interesting phenomena in Trumai morphology is the use of particles in the language. Guirardello first discusses them as a form of identifying tense in lieu of the tense-aspect-mood affixes used in English. These word formations are ‘ka in’, used for present or the recent past, and ‘chï in’, for past tense, but they are only used when the tense is not indicated via context. In a sentence, these particles appear as so: ka_in: [[Yaka] chumuchu] ka_in tehnene-n. Yaka lie.down Foc/Tens floor-Loc ‘Yaka lay.down on the floor.’ chï_in: [ha ayen]-atl chï_in [hai]-ts [oke yi] kï̡tï. 1 grandfather-Dat Foc/Tens 1-Erg medicine YI give ‘I gave medicine to my grandfather (emphasis).’ As a whole, particles in Trumai are defined as a verb modifier that is not an adverb or auxiliary instead of being placed in a class of its own. There are four classes of particles in Trumai: Intensity, Negation, Causative, and Intensity. These modifiers fall under the ‘particle’ label because of their characteristics which differentiate them from auxiliaries. For example, while auxiliaries can only modify verbs, Intensity and Negation particles can also modify adverbs and quantifiers. The use of auxiliaries in Trumai is also very fascinating. In the language, they are defined as verb modifiers “associated with the domain of aspect, mood, and spatial orientation (this last domain is subdivided into body posture of the entity performing the event and directionality of the event being performed)”. Here are some examples of each of these auxiliaries used in sentences: Aspect/Mood: iyi sone-kma-n de. IYI drink-Perf-3Abs already ‘He already finished drinking.’ OR ‘He already drank all.’ Body Posture: iyi ma chumuchu-n. IYI eat lie-3Abs ‘He is eating lying (on the floor).’ Directionals: ha ka’chï lako. 1 walk Dir(down hill) ‘I go down walking.' Guirardello makes a point of noting the significant differences between auxiliaries and verbs in Trumai: there is no independent argument structure, no lexical content, some experience phonological reduction, and they form a closed class. Their syntactic position is restricted to following a verb in the VP, which distinguishes them from adverbs, which hold a more flexible position in sentences. Apart from appearing inside the VP following the Verb, a property of some auxiliaries is that “they can bear the 3Abs enclitic –n/-e”. Syntax Ergative-Absolutive Language Structure Trumai is a language with ergative-absolutive case assignment and therefore has three argument types: absolutive, ergative, and dative. The ergative-absolutive language system is described as that “in which a subject in an intransitive construction is realized in the same way as a patient or object in a transitive construction, and is thus distinguished from the subject or agent in the transitive”. It is “manifested through case-marking, verb-marking, and word order”. Dative case is used for verbs such as 'eat', 'see', and 'talk with'. There are two verbs 'kill', one, -fa, which takes a dative, and one, disi, which takes the ergative. Constituent order is basically ergative-absolutive-verb-dative (SV, SVB, AOV, AOVB). Ergative and dative arguments, which are marked by postpositions, may occur on the other side of the verb, but for an absolutive to do this, it needs to be marked with ke. In noun phrases (including pronouns), the grammatical case is marked by an enclitic. For example, an ergative NP would end in either –ek or –k. Case marking using enclitics also occurs for Dative, Locative, and Genitive cases. In the case of personal pronouns, the first person singular pronoun also allows the enclitic –ts. The first person singular pronoun is also changed from ha in Absolutive case to hai for Ergative and Dative cases. An interesting phenomenon in Trumai syntax is the NP morpheme iyi/yi because of its lack of a clear function. It always appears phrase-final, as iyi when only the noun itself is included in the phrase, but as yi when pluralizers or other lexical items are also included. However, despite this rule, there are still occasions where iyi appears in an NP with a lexical item. When it is present in Ergative and Dative sentences, the enclitics for each case are still added to the end of the NP: Reduced form: [inatl yi] pech ka_in. 3Pr(Fem) run Foc/Tens ‘She is running.’ No lexical item: [iyi] pech-e ka_in. run-3Abs Foc/Tens ‘She/he is running.’ Ergative/Dative: [ni’dak wan yi]-k chï_in ha disi. that.one PL -Erg Foc/Tens 1 beat ‘They (these ones) beat me.’ For verb phrases in Trumai, case marking provides four verb categories: Intransitive, Transitive, Extended Intransitive, and Extended Transitive, where Intransitive verbs can have Absolutive case, Transtive verbs have Absolutive and Ergative case, and the Extended categories also have Dative case on top of this. Guirardello labels arguments as S, A, O, and DAT for case-marking instead of terms such as “agent” and “patient”. Guirardello observed three types of clauses in Trumai sentences. Intransitive clauses attach the case marking /-ø/ to the S noun phrase or attach the third person enclitic –n/-e to the end of the verb phrase. Transitive clauses have A marked by –(V)k and O marked by –ø. Similarly to Intransitive clauses, the third person enclitic is added to the VP when A is absent. In Ditransitive clauses, the same marking occurs for A and O that we see in Transitive clauses. The DAT argument is marked by either –(V)tl, -ki, or –(V)s “depending on the characteristics of the head of the NP”. No marking is attached to the VP when DAT is absent from the sentence. These clauses are proof of the Ergative-Absolutive argument of Trumai, as we see S and O undergo the same marking, while A is treated differently. In sentences, they would appear as follows: Intransitive: S V pet’ew-ø achïkida frog-Abs jump ‘The frog jumps.’ (256) Transitive: A V ine-k Ø mapa-n 3-Erg break-3Abs ‘He broke it (a valuable pan).' Ditransitive: A O V DAT kiki-k atlat-ø kï̡tï kasoro-s 1-Erg rice-Abs give dog-Dat ‘I gave rice to the dogs.' The Absolutive argument is obligatory and therefore occurs in all clause types. Its case-marking is –ø or it has none at all and its syntactic placement is within the VP, before the verb (Guirardello is not clear as to whether it appears immediately before the verb or if other lexical items can be placed between them). The Ergative argument is marked by –(V)k and only occurs in Transitive clauses, where it is the main argument of the verb and is therefore always required. Its syntactic placement is preceding the VP. While there are certain scenarios where it can be absent from a sentence that mainly occurs when there is discourse continuity. If it occurs without this, then the sentence has passive or middle voice. The Dative argument is marked by –(V)tl, -ki, or –(V)s. Like the Ergative argument, it occurs before and outside of the VP. It is only obligatory in Extended clauses, where it is the main argument of the verb. Trumai’s causative construction uses the particle ka, which appears after the verb and can modify it. For Intransitive and Extended Transitive verbs, the causee is marked as Absolutive, while the causer is marked as Ergative. While this makes it similar to a simple Transitive clause, the difference is that the Absolutive enclitic is marked on the particle instead of the verb. For Transitive verbs, both the causee and causer are marked Ergative: a. hai-ts Yakairu-ø sa ka. 1-Erg Yakairu-Abs dance Caus ‘I made Yakairu dance.’ [Intransitive verb] b. hai-ts sa ka-n. 1-Erg dance Caus-3Abs. ‘I made her dance.' Semantics Quantifiers In Trumai, quantifiers appear before the noun they modify. For numerals, while the language includes the names for 1-10, most often only numbers 1-5 are spoken: ‘1’ mihin ‘2’ huch ‘3’ huch tahme ‘4’ pine pine-kte len ‘5’ ine k’ad kel-an Friend friend-Gen group 3Masc hand finger-Loc Other quantifier words (ex. ‘few’, ‘many’, etc.) change depending on whether they appear before count or mass nouns. They also vary from speaker to speaker, as in the case of “few” versus “a little”, some speakers can distinguish the two based on how they appear before count vs. non-count words, while others cannot except for “high quantities”. When they are distinguished, the quantifiers used by some speakers are: While most speakers, who cannot distinguish between count and mass nouns for small quantities, say: Aside from the above forms, there is an alternate form to describe small quantities: pa̡t “few”, which is meant to describe a small portion of an object. Here are some examples for each type of the above quantifiers: Many/a lot: a’di ka_in k’ate yi. (count) many Foc/Tens fish YI ‘There are many fish.’ (or: ‘The fish are many/big in quantity.’) Many/a lot: pïx ka_in misu yi. (mass) a.lot Foc/Tens water YI ‘There is a lot of water.’ (or: ‘The water is big in quantity.’) Few/a little: a’di tak ka_in k’ate yi. (some speakers) many Neg Foc/Tens fish YI ‘There are a few fish.’ (or: ‘The fish are not many.’) Few/a little: pïx tak ka_in k’ate yi. (most speakers) a.lot Neg Foc/Tens fish YI ‘There are a few fish.’ (or: ‘The fish are not many.’) Few: atlat pa̡t. clay.pan small ‘small clay.pan.’ Just as is seen above where “few/a little” are formed as “many/a lot” plus a negation, there is no word for “none”, so negation is added in its place as well: katnon take tak [kiki wan yi]. work Desid Neg man PL YI ‘No man wants to work.’ (lit: ‘The men do not want to work.’) Quantifiers (numeral and otherwise) can also appear as a clause predicate or a focussed unit, in which they appear at the beginning of a sentence and are followed by a Focus/Tense particle. Person plays a crucial role in what NP a quantifier is assigned to. Guirardello explains that in a sentence where there is both first- and third-person nouns/pronouns, it is clear that the quantifier is attached to the third-person. This is not as clear when there are two third-person NPs in a sentence. In order to understand which NP the quantifier is modifying in this scenario, one must look at what kinds of NPs are in the clause with the quantifier and if it is also being modified by a pluralizer. Vocabulary Loukotka (1968) lists the following basic vocabulary items for Trumai. {\| class="wikitable sortable" ! gloss !! Trumai \|- \| one \|\| mihin \|- \| two \|\| hursh \|- \| three \|\| hurstame \|- \| head \|\| yau-kut \|- \| ear \|\| yau-haptü \|- \| tooth \|\| yau-i \|- \| hand \|\| yau-kenap \|- \| woman \|\| ipae \|- \| water \|\| misu \|- \| fire \|\| só \|- \| stone \|\| liki \|- \| maize \|\| hotet \|- \| tapir \|\| monotó \|} References External links Trumai (Intercontinental Dictionary Series) Category:Language isolates of South America Category:Endangered indigenous languages of the Americas Category:Endangered language isolates Category:Languages of Brazil	{ "pile_set_name": "Wikipedia (en)" }
An acquaintance who once went to overboard annoying lengths with their Seahawks fandom said it best yesterday: “I’m just not into football anymore. I’m over it.” This was someone who routinely blasted me during 49ers games, posted on my Facebook after they lost the 2013 NFC Championship Game and mocked me with a post saying “We gonna wiiiiiiin” during the 49ers Thanksgiving debacle. That final post was the last straw and I unfriended them until about a week ago. It wasn’t a punishment, I just never got around to re-adding them. I don’t know if her statements echo the sentiments of the 12th Man, but Seattle has made it very difficult to get excited for their team in 2018. Their roster has been gutted, their coaching staff has been reorganized, and their once devastating secondary has been dismantled. And yet, they might yet finish above .500. The Seahawks still have Russell Wilson, Bobby Wagner, and Earl Thomas, and while that patchwork offensive line grows worse, not better, Wilson’s mobility keeps it as a problem and not a serious one. One thing is certain, the Seahawks are entering a rebuild, and their window for a championship may have already been shut. The Los Angeles Rams are on the rise and the 49ers managed to go toe-to-toe with the Seahawks on their home turf — with Brian Hoyer as their quarterback. And while I don’t want to speak about the blowout handed to the 49ers at Levi’s Stadium, it ushered in the era of Jimmy Garoppolo. When he hit the field, the Seahawks had no answer for him. Too bad he was on the field for only four or so plays before the game ended. But it’s the principle of the thing. When Garoppolo was on the field, the 49ers scored a touchdown in just over a minute. Draft picks Round 1: Rashaad Penny (RB) Round 3: Rasheem Green (DE) Round 4: Will Dissly (TE) Round 5: Shaquem Griffin (LB) Round 5: Tre Flowers (DB) Round 5: Michael Dickson (P) Round 5: Jamarco Jones (OT) Round 6: Jacob Martin (DE) Round 7: Alex McGough (QB) Notable free agents Brandon Marshall (WR) Sebastian Janikowski (K) Dontae Johnson (CB) Jaron Brown (WR) Maurice Alexander (S) Notable Departures Richard Sherman (CB) Michael Bennett (DE) Jimmy Graham (TE) Luke Wilson (TE) Paul Richardson (WR) Thomas Rawls (RB) The Seahawks glaring problem has been their offensive line and lack of running game since Marshawn Lynch departed. Both could be linked together. Rather than address the line as-is the Seahawks decided to draft a running back in the 1st round and put them behind the same line that helped Rawls to 157 yards in 58 carries. Penny isn’t getting any favors done with that line. Beyond that, the drafting of Shaquem Griffin should help the linebacker group. The secondary is fractured with the release of Richard Sherman and the defense lost a playmaker in Bennett. On the other side of the ball, all of Wilsons weapon’s not named Bobby Wagner Doug Baldwin are gone. Graham, RIchardson, and Wilson all did something in 2017 and it will be interesting to see how the replacements work. Way too early gambling line 49ers at Seahawks: Seahawks (-1) Seahawks at 49ers: 49ers (-3.5) The matchups The 49ers rival during the Jim Harbaugh era was the Seattle Seahawks. This was brought mostly due to the relationship between Harbaugh and Seahawks head coach Pete Carroll. When Harbaugh left, the difference in ability grew and the 49ers sank into mediocrity while the Seahawks continued to stay atop the NFC West. But now the scales are tipping the other way. The Seahawks have suffered a talent exit not unlike the 49ers talent purge of 2015. Brian Schottenheimer will helm the Seahawks offense for a fired Darrell Bevell which will bring all sorts of questions for Wilson and company with a new offense. Beyond the questions, Wilson doesn’t have much to rely on anymore either, besides Doug Baldwin. While I laughed about Brandon Marshall being signed, it’s actually very smart, especially with how cheap they got him for. Marshall has something left in the tank, but it’s going to take a lot more than him to turn this offense around. On the other side of the ball, the defense has some of it’s glue, but the loss of Sherman and Bennett will hurt—make no mistake about it. While not outside the realm of possibility to see the Seahawks go over .500, especially with that stadium they play in, I don’t see it. My 2018 predictions are having an awful, awful year, but I predicted the 49ers would beat the Seahawks in Seattle by two touchdowns, and I stand by that one. In San Francisco, I see a win coming as well. That game will get ugly and I don’t see the Seahawks hanging on. The 49ers have the Rams to worry about in the NFC West, the Seahawks are just an annoying insect. But one that can definitely sting hard with lingering effects if given the chance.	{ "pile_set_name": "OpenWebText2" }
When Carlos Rivas’ slingshot curled into the net and Kaká jumped into the arms of fans after scoring a goal in his first game back from injury, Orlando City was in the midst of arguably its best performance of the year. The Lions held Colorado to one shot on goal, tying a league record, controlled possession and kept a clean sheet. There was little time to celebrate, however, with two days of rest and one training session before the team hopped on a plane to Canada. Orlando City (6-1-0, 18 points) hopes to continue its win streak despite less-than-ideal preparation time when it plays Toronto FC (3-1-4, 13 points) at 7:30 p.m. Wednesday at BMO Field. Lions coach Jason Kreis didn’t blink calling the game “the most difficult challenge we could face in the league at this moment.” “To go to an away match against Toronto, in their form right now with Jozy Altidore and Sebastian Giovinco in particular, presents us some real problems,” Kreis said. “Our team is very familiar with them, having played them in preseason. “I think our team is very aware of what we’re going into and I think we’re ready. From a physical stand point, of course I’d like to have a few more days to rest. I’d like to have a few more days to tactically prepare, but I think our group is ready.” Altidore, a U.S. men’s national team standout, and his Italian teammate Giovinco, who was the 2015 league MVP, have combined for four goals in the last two games, helping Toronto out of a stagnant stretch of opening matches that included four draws, a win and a loss. Kreis drew comparisons between Altidore and Orlando City striker Cyle Larin, saying they’re alike in size and stature and in the way they are perceived by many as “typical box strikers,” though Kreis believes both contribute far more to their teams than just goals inside the box. In addition to a preseason match, which Toronto dominated, to help the Lions get to know their opponent, midfielder Will Johnson and goalkeeper Joe Bendik both previously played for the Reds. Bendik was able to provide more insight on Toronto for his teammates and said it’s not just Altidore and Giovinco they need to watch. “It’s those two and their wing backs and then whoever is playing in the middle, whether it’s [Armando] Cooper, [Jonathan] Osorio,” Bendik said. “When [forward Tosaint] Ricketts comes on, he kind of makes everything turn for them. You can see that with their combinations. “Confident team, especially at home. They like to get their wingbacks really high and really try to batter down on teams. For us, we have to stay compact, be able to weather what they have for the first half.” Toronto also plays a 3-5-2 formation, which can be difficult to defend. With three at the back instead of four, it also means TFC can be vulnerable on the counterattack if Orlando City is able to force turnovers. Team captain Kaká is now firmly back in the game-day roster and likely will start in Toronto to supplement the attack and the Lions' defense is being touted as one of the best in the league, though it will need to perform after getting little time to recover, study and train. “They’re a good team,” Lions left back Donny Toia said. “They’ve shown that the past couple of years. They move the ball nice and they like to find their forwards. If we keep them in front of us the whole time, I think we’ll be OK.” ardelgallo@orlandosentinel.com	{ "pile_set_name": "OpenWebText2" }
695 S.W.2d 954 (1985) STATE of Tennessee, Appellee, v. Ricky Goldie SMITH, Appellant. Supreme Court of Tennessee, at Jackson. August 12, 1985. 956 James V. Ball, Arch B. Boyd, III, Memphis, for appellant. W.J. Michael Cody, Atty. Gen. & Reporter, Ann Lacy Johns, Asst. Atty. Gen., for appellee. OPINION HARBISON, Justice. Appellant was convicted of murder in the first degree and sentenced to death by electrocution. We affirm the judgment and the sentence. In the late afternoon of April 21, 1982, appellant twice shot and killed 71-year-old Walter Allen while attempting to rob him. Appellant was at that time not quite 23 years of age. He and two other youths had been "cruising" in an automobile belonging to appellant's aunt after having taken appellant's sister to a bus stop. Thereafter they saw the victim walking along the street near his home, carrying a sack of groceries, as he did almost daily. Appellant was armed and decided to rob the victim, who was previously unknown to any of the three youths and who had not offered them any provocation whatever. Leaving his aunt's parked automobile, which was being driven by one of his cousins, appellant accosted the victim and demanded his money. The victim apparently resisted and sought to grapple with appellant or to apprehend him. Appellant shot the victim twice, either of the wounds being sufficient to cause death. Mr. Allen died a little over four hours later. Appellant did not pause to render aid, but fled, leaving his elderly victim lying helpless and bleeding on the sidewalk. Appellant returned to the automobile as did the only one of his companions who had left it. The other had remained in the driver's seat. The three were seen leaving the area at a high speed. A witness was able to furnish some description of appellant and the 15-year-old companion who had stepped out of the automobile with him. She was also able partially to describe the numbering on 957 the license plate. The automobile was discovered by police the next day and identified as belonging to appellant's aunt. It was not until November, some seven months later, in connection with an unrelated criminal incident, that police received definite information that appellant had been involved in the murder of Mr. Allen. According to testimony at a suppression hearing, one of appellant's cousins who was in custody called appellant from the police station and was assured by appellant that he, not the cousin, was responsible for the homicide. The police contacted appellant a few days later. When he returned their telephone call they took him into custody. He later gave a statement admitting that he shot and killed Mr. Allen but contending that the shooting was accidental, rather than intentional. The 15-year-old companion of appellant, Darrell Lipscomb (also known as Chuck Williams) testified at the trial. In his confession appellant stated that Lipscomb suggested the robbery and was with him when it was attempted. He later indicated to another relative that Lipscomb could have prevented the shooting but did not do so. Lipscomb, however, testified that the attempted robbery was appellant's own idea. He also testified that he had left the automobile after appellant, and that appellant accosted Mr. Allen some distance away. Lipscomb denied being present at the shooting, but testified that he heard two shots. He said that appellant then came running back to the automobile, and the three youths sped away. He stated that appellant told him that the victim had "tussled" with appellant and that appellant had then shot him twice. Appellant was taller than Lipscomb and his hair style matched the description given by the witness, Mrs. Settle, who saw the youths running from the area where Mr. Allen had fallen. Appellant did not testify at the trial or at the sentencing hearing, other than to take the stand in a jury-out hearing to confirm that he had been advised of his legal rights. In addition to admitting to Lipscomb and to the police that he had shot Mr. Allen, he also admitted doing so to his aunt, Mrs. Ella Mae McClain, who visited him at the jail. Although there were discrepancies between the testimony of Lipscomb and appellant's statement, and although strenuous efforts were made to impeach Mrs. McClain, these were issues which were submitted to and resolved by the jury. There is abundant material evidence in the record to support their verdict, and appellant's attack upon the sufficiency of the convicting evidence is without merit. Similarly without substance is the contention of appellant that the State's evidence fails to show premeditation and malice. Murder in the first degree is defined in T.C.A. § 39-2-202(a) as premeditated, willful, deliberate and malicious homicide, but it is also defined as including any murder committed in the perpetration of certain specified felonies, including robbery. Murder in the first degree is sufficiently shown by proof of a killing committed during one of these specified felonies. State v. Johnson, 661 S.W.2d 854, 860-861 (Tenn. 1983); Tosh v. State, 527 S.W.2d 146, 148 (Tenn. Crim. App. 1975). In this and in other cases it has been suggested that a change in the wording of the first degree murder statutes from "killing" to "murder" by 1977 Tenn. Pub. Acts ch. 51, § 1, had the effect of abolishing the felony-murder rule. We do not so construe the statute and did not do so in Johnson, supra, in which the homicide occurred in 1980. Appellant attacks the admissibility of his confession upon the ground that it was not voluntarily given. The trial judge, however, held a full pre-trial suppression hearing and resolved the factual issues against appellant. The record fully supports his conclusion that appellant was clearly advised of his legal rights with respect to the statement, and that the statement was voluntarily given. As previously 958 indicated, appellant had already seriously incriminated himself in a telephone conversation, monitored by the police, in which he advised his cousin that he was responsible for Mr. Allen's death and would so inform the police. At the time the investigation in this case was initiated, immediately after the shooting, the victim had not died. Initial police documents indicated that an aggravated assault had occurred, and the caption to appellant's statement contains the words "aggravated assault" rather than referring to a homicide. The context of the questioning itself, however, made it clear that the death of Mr. Allen was being investigated. We find no merit to the contention of appellant that he was in any way misled as to the nature of the potential charges against him. In his conversation with his cousin he had admitted knowing that Mr. Allen had died, and his contention that his formal statement was involuntary because of insufficient information as to the charges is entirely unpersuasive. Likewise we find no merit whatever to the suggestion made in appellant's brief that he lacked sufficient mental capacity to know or understand the statement made or the nature of the charges. In his brief counsel for appellant attacks the constitutionality of the death penalty in general and of the Tennessee statute authorizing its imposition, on eleven separate grounds. None of these has been briefed or argued, but each of them has previously been considered in detail in reported decisions of this Court. We therefore see no need to examine these assignments in detail but will briefly mention some of them. Appellant insists that the statute is deficient in not requiring notice of the aggravating circumstances to be relied upon by the State. This contention was rejected in Houston v. State, 593 S.W.2d 267 (Tenn. 1980), but, in any event, in the present case notice was given of the principal aggravating circumstance relied upon. Further, Rule 12.3(b) of the Tennessee Rules of Criminal Procedure has been amended to require such notice for trials occurring after August 22, 1984. The present trial occurred before that date. Since notice was actually given, however, and since it was not constitutionally required, we find this issue to be without merit. Also without merit is the contention that the statutes create two separate offenses so as to pose a double jeopardy problem. This issue was considered and rejected in the Houston case, and in State v. Austin, 618 S.W.2d 738, 742 (Tenn. 1981). Each of the other contentions advanced by appellant has been carefully examined in reported decisions of the Court, and we see no need to repeat those discussions here. Appellant has advanced a five-part challenge to the felony-murder rule in cases involving murder in the first degree. These contentions were considered in State v. Sheffield, 676 S.W.2d 542, 551 (Tenn. 1984), where identical arguments were considered and rejected. Many of the contentions advanced by appellant in connection with the constitutional issue are not even relevant to this case, such as the validity of some of the aggravating circumstances or the responsibility of an aider or abettor. Appellant has assigned as error the failure of the trial judge to permit individual examination of prospective jurors. There is no contention made in this case that any reversible error occurred during the lengthy jury examination. Further the trial judge indicated that he would grant individual examination if necessary, and some individual questioning was in fact permitted. This matter lay within the discretion of the trial judge, and we find no abuse of that discretion. See State v. Workman, 667 S.W.2d 44, 49 (Tenn. 1984). In two assignments of error counsel for appellant contends that reversible error occurred during closing argument at the guilt stage of the trial when one of the prosecuting attorneys undertook to remove 959 a book from counsel table and to refer to it. The book had reference to techniques in creating a reasonable doubt in the defense of criminal trials. The trial judge sustained a portion of the objections of defense counsel, and the remaining argument of the prosecutor was clearly directed toward rebuttal of the contention of counsel for appellant that reasonable doubt had been created in this case. Indeed the principal thrust of the closing argument of counsel for the defendant was insufficiency of evidence and reasonable doubt in a number of respects, and the prosecutor was clearly entitled to respond to these contentions. In our opinion, taken in context, nothing which occurred in connection with this incident could possibly have affected the results of the trial. In his final issue on appeal, counsel for appellant urges that the trial court committed reversible error in charging one of the statutory aggravating circumstances pertaining to an escape or an attempt to escape from lawful arrest or prosecution. The State had not insisted upon this circumstance, but at the conclusion of all of the evidence, the trial judge felt that this issue was raised by the evidence sufficiently to warrant an instruction. Whether or not the trial judge was correct in this regard, the jury did not find that the appellant had committed the homicide under circumstances falling within the parameter of that statute. Accordingly it did not impose the death penalty under that aggravating circumstance or find that appellant was guilty thereof. The issue is therefore probably moot. The trial judge objected significantly to the procedure outlined by this Court in previous decisions,[1] requiring the trial judge to charge the jury only on those aggravating and mitigating circumstances fairly raised by the evidence. He felt that a different procedure was preferable, but finally did undertake to emphasize those which the parties contended were applicable or which the court felt had been fairly raised. There was evidence contained both in appellant's signed statement and in the testimony that the victim of the homicide in the present case, Mr. Allen, had resisted appellant's attempt to rob him and had "tussled" with him. Indeed it was the primary insistence of appellant that the shooting was accidental and was the result of this struggle. It is basic statutory law in this state that a private person may arrest another for an offense committed in the presence of the arresting individual, or for a felony not committed in his presence. A private person may also arrest when a felony has been committed and he only has reasonable cause to believe that the arrested person committed it. See T.C.A. §§ 40-7-109(a)(1), (2), (3). A private person may even break into the dwelling house of an individual who has committed a felony after giving proper notice of his intention to make the arrest. T.C.A. § 40-7-112. While the evidence in this case was brief, there was proof from which a trier of fact might have found that Mr. Allen did attempt to confine or apprehend his assailant. The charge given, therefore, was not without foundation in the record, and reversible error was not committed in permitting the jury to consider it. Since the jurors did not base their sentence on this circumstance, however, we need not consider the preponderance or weight of the evidence on the point. The only aggravating circumstance found by the jurors, and the one on which the death penalty was based, was that the appellant committed the murder while engaging or attempting to engage in a robbery. T.C.A. § 39-2-203(i)(7). The evidence overwhelmingly establishes the guilt of appellant in this respect. In State *960 v. Prichett, 621 S.W.2d 127, 140-141 (Tenn. 1981), the Court held that the death penalty could properly be imposed under this aggravating circumstance even though "the felony of robbery may have been used by the jury to establish that the murder was murder in the first degree... ." We adhere to that holding, and are of the opinion that the "underlying felony" may be used as an aggravating circumstance at the sentencing phase of the trial. In this case there is hardly any suggestion of mitigating factors which could possibly outweigh the outrageous and totally antisocial behavior of the accused in committing this shocking homicide. The jurors were certainly not obligated to accept appellant's contention that the shooting was accidental. It was, under a clearly legitimate view of the evidence, a deliberate shooting and an attempt to remove the identity of a possible prosecuting witness, after a planned attempt at the robbery of an elderly, innocent person. It is indeed difficult, if not impossible, to explain away two fatal shots as being accidental and unintentional. This elderly victim was left by his robber on the street to die without any attempt to render aid or assistance. The accused was nearly 23 years of age. He had a criminal record, but this was not introduced before the jury. He saw fit not to take the stand at either the guilt or the sentencing phases of his trial. He was afforded a full and fair trial, and there is nothing to indicate any mitigating circumstances which could have outweighed the clearly aggravating circumstance which was proved and which was found by the jury. It is, of course, part of the duty of this Court under the applicable statutory provisions to review a death sentence and to determine whether it was imposed in any arbitrary fashion. The Court is also required to determine whether the evidence supports the jury's finding of an aggravating circumstance and its finding of the absence of any mitigating circumstances sufficiently substantial to outweigh the aggravating circumstances. The Court is also required to determine whether the sentence of death is excessive or disproportionate to the penalty imposed in similar cases. T.C.A. § 39-2-205(c). We have examined the record and the briefs and arguments of counsel with these provisions before us. We are of the opinion that the death penalty was justified in this case, and that its imposition was neither arbitrary nor disproportionate. In several other cases the death penalty has been approved where the homicide occurred during the perpetration of an armed robbery. See State v. Harries, 657 S.W.2d 414 (Tenn. 1983); State v. Johnson, 632 S.W.2d 542 (Tenn. 1982); State v. Coleman, 619 S.W. 112 (Tenn. 1981); Houston v. State, 593 S.W.2d 267 (Tenn. 1980). Numerous other cases could be cited, but we think that the foregoing sufficiently illustrate the proposition that a deliberate, wanton murder committed during the course of or in an attempt to commit an armed robbery is sufficient to warrant the death penalty where the jury finds no mitigating circumstances whatever. The judgment of conviction and the sentence are affirmed. Unless stayed or otherwise ordered by proper authority, the sentence will be carried out as provided by law on October 18, 1985. Costs are taxed to appellant. COOPER, C.J., and FONES and DROWOTA, JJ., concur. BROCK, J., files a dissent. BROCK, Justice, dissenting. I concur in the opinion of the Court in all respects except the imposition of the death penalty. With respect to the imposition of the death penalty, I adhere to the views expressed in my dissenting opinion in State v. Dicks, Tenn., 615 S.W.2d 126 (1981). NOTES [1] E.g., State v. Buck, 670 S.W.2d 600, 608 (Tenn. 1984).	{ "pile_set_name": "FreeLaw" }
It was the most ungrateful and unjust act ever perpetrated by a republic upon a class of citizens who had worked and sacrificed an...d suffered as did the women of this nation in the struggle of the Civil War only to be rewarded at its close by such unspeakable degradation as to be reduced to the plane of subjects to enfranchised slaves.LESSATTRIBUTION DETAIL » As a pastoral game, baseball attempts to close the gap between the players and the crowd. It creates the illusion, for instance, t...hat with a lot a hard work, a little luck, and possibly some extra talent, the average spectator might well be playing; not watching. For most of us can do a few of the things that ball players can do: catch a pop-up, field a ground ball, and maybe get a hit once in a while.... As a heroic game, football is not concerned with a shared community of near-equals. It seeks almost the opposite relationship between its spectators and players, one which stresses the distance between them. We are not allowed to identify directly with Jim Brown any more than we are with Zeus, because to do so would undercut his stature as something more than human.LESSATTRIBUTION DETAIL » I have never understood why they tried to start the revolution by taking over the universities. It should have been self-evident t...hat the net result of success would be to close the universities but leave the nation unaffected--at least, for quite a long time. Nor do I find it easy to believe that the rebels, as intelligent as most of them were, seriously expected that they could keep the universities alive as corporate bodies, once they had control of them, if they made the fundamental alterations in organization and role that they proposed to.LESSATTRIBUTION DETAIL » The Walrus and the CarpenterWere walking close at hand:...They wept like anything to seeSuch quantities of sand:"If this were only cleared away,"They said, "it would be grand!""If seven maids with seven mopsSwept it for half a year,Do you suppose," the Walrus said,"That they could get it clear?""I doubt it," said the Carpenter,And shed a bitter tear.LESSATTRIBUTION DETAIL »	{ "pile_set_name": "Pile-CC" }
Reproducibility of allergen, endotoxin and fungi measurements in the indoor environment. Measurements of biocontaminants in settled house dust once a year are commonly used to assess long-term exposure. To examine stability over time and seasonal variation, we measured concentrations of mite and cat allergens, endotoxin and mold spores in living room floor dust in 745 German homes collected twice a year in two different seasons. The study population consisted of adults and children living in five different areas in Germany. All dust samples were collected in a standardized manner from the living room floor and taken during the years 1995 to 1998. The median interval between the two dust samplings was approximately 7 months. Mite and cat allergens were measured in settled house dust by monoclonal antibodies, endotoxin by the limulus amebocyte lysate method, and total spore counts by cultural methods. Crude Pearson's correlation coefficients between log-transformed concentrations in the first and second dust samples ranged between 0.65 and 0.75 for allergens, 0.59 for endotoxin and only 0.06 for total spore counts. The strongest and most consistent seasonal effects were observed for fungi with highest levels in July-September. Cat allergen concentrations were found consistently to be increased in January-March. Mite allergens did not show a strong and consistent seasonal pattern. We conclude that repeated measurements of mite and cat allergens and endotoxin in settled house dust improve the estimate for annual mean concentrations. However, even a single observation of these biocontaminants may be a good proxy for a 1-year exposure since repeated measures were highly correlated. However, repeated measurements of fungi levels were only weakly correlated and thus repeated observations for assessment of annual means of total spore counts are needed.	{ "pile_set_name": "PubMed Abstracts" }
Here is a curated list of active, responsive and valid BitTorrent trackers. Add them to the list of trackers of your torrents to increase your chance of finding peers and improve download speed.(more…) There was a time that Apple macOS was the best platform to handle multimedia (audio, image, video). This might be still true in the GUI space. But Linux presents a much wider range of possibilities when you go to the command line, specially if you want to: Process hundreds or thousands of files at once Same as above, organized in many folders while keeping the folder structure Same as above but with much fine grained options, including lossless processing, pixel perfectness that most GUI tools won’t give you The Open Source community has produced state of the art command line tools as ffmpeg, exiftool and others, which I use every day to do non-trivial things, along with Shell advanced scripting. Sure, you can get these tools installed on Mac or Windows, and you can even use almost all these recipes on these platforms, but Linux is the native platform for these tools, and easier to get the environment ready. These are my personal notes and I encourage you to understand each step of the recipes and adapt to your workflows. It is organized in Audio, Video and Image+Photo sections. I use Fedora Linux and I mention Fedora package names to be installed. You can easily find same packages on your Ubuntu, Debian, Gentoo etc, and use these same recipes. Audio Show information (tags, bitrate etc) about a multimedia file ffprobe file.mp3 ffprobe file.m4v ffprobe file.mkv Lossless conversion of all FLAC files into more compatible, but still Open Source, ALAC Has been said the Fraunhofer AAC library can’t be legally linked to ffmpeg due to license terms violation. In addition, ffmpeg’s default AAC encoder has been improved and is almost as good as Fraunhofer’s, specially for constant bit rate compression. In this case, this is the command: Same as above but under a complex directory structure This is one of my favorites, extremely powerful. Very useful when you get a Hi-Fi, complete but useless WMA-Lossless collection and need to convert it losslesslly to something more portable, ALAC in this case. Change the FMT=flac to FMT=wav or FMT=wma (only when it is WMA-Lossless) to match your source files. Don’t forget to tag the generated files. Convert APE+CUE, FLAC+CUE, WAV+CUE album-on-a-file into a one file per track ALAC or MP3 If some of your friends has the horrible tendency to commit this crime and rip CDs as 1 file for entire CD, there is an automation to fix it. APE is the most difficult and this is what I’ll show. FLAC and WAV are shortcuts of this method. Make a lossless conversion of the APE file into something more manageable, as WAV: ffmpeg -i audio-cd.ape audio-cd.wav Now the magic: use the metadata on the CUE file to split the single file into separate tracks, renaming them accordingly. You’ll need the shnplit command, available in the shntool package on Fedora (to install: yum install shntool). Additionally, CUE files usually use ISO-8859-1 (Latin1) charset and a conversion to Unicode (UTF-8) is required: It is not UTF-8 encoded, it is some ISO-8859 variant, which I need to know to correctly convert it. My example uses a Brazilian Portuguese subtitle file, which I know is ISO-8859-15 (latin1) encoded because most latin scripts use this encoding. Now we are ready to add them all to the movie along with setting the movie name and embedding a cover image to ensure the movie looks nice on your media player list of content. Note that this process will write the movie file in place, will not create another file, so make a backup of your movie while you are learning: You’ll get a directory tree with decrypted VOB and BUP files. You can generate an ISO file from them or, much more practical, use HandBrake to convert the DVD titles into MP4/M4V (more compatible with wide range of devices) or MKV/WEBM files. Convert 240fps video into 30fps slow motion, the loss-less way Modern iPhones can record videos at 240 or 120fps so when you’ll watch them at 30fps they’ll look slow-motion. But regular players will play them at 240 or 120fps, hiding the slo-mo effect. We’ll need to handle audio and video in different ways. The video FPS fix from 240 to 30 is loss less, the audio stretching is lossy. # make sure you have the right packages installed dnf install mkvtoolnix sox gpac faac 1 Photo + 1 Song = 1 Movie The above method will create a very efficient 0.2 frames per second (-framerate 0.2) H.264 video from the photo while simply adding the audio losslessly. Such very-low-frames-per-second video may present sync problems with subtitles on some players. In this case simply remove the -framerate 0.2 parameter to get a regular 25fps video with the cost of a bigger file size. The -vf scale=960:-1 parameter tells FFMPEG to resize the image to 960px width and calculate the proportional height. Remove it in case you want a video with the same resolution of the photo. A 12 megapixels photo file (around 4032×3024) will get you a near 4K video. There is also a more efficient and completely lossless way to turn a photo into a video with audio, using extended podcast techniques. But thats much more complicated and requires advanced use of GPAC’s MP4Box and NHML. In case you are curious, see the Podcast::chapterize() and Podcast::imagify() methods in my music-podcaster script. The trick is to create an NHML (XML) file referencing the image(s) and add it as a track to the M4A audio file. -Directory, -FileName and -RegionName specify the things you want to see in the output. You can remove -RegionName for a cleaner output. The -r is to search recursively. This is pretty powerful. Make photos timezone-aware Your camera will tag your photos only with local time on CreateDate or DateTimeOriginal tags. There is another set of tags called GPSDateStamp and GPSTimeStamp that must contain the UTC time the photos were taken, but your camera won’t help you here. Hopefully you can derive these values if you know the timezone the photos were taken. Here are two examples, one for photos taken in timezone -02:00 (Brazil daylight savings time) and on timezone +09:00 (Japan): This shows that the local time when the photo was taken was 2013:10:12 23:45:36. To use exiftool to set timezone to -02:00 actually means to find the correct UTC time, which can be seen on GPSDateTime as 2013:10:13 01:45:36Z. The difference between these two tags gives us the timezone. So we can read photo time as 2013:10:12 23:45:36-02:00. The source code currently brings to life (as an example), integrated with some Bluemix services and Docker infrastructure, a PHP application (the WordPress popular blogging platform), but it could be any Python, Java, Ruby etc app. Before we start: understand Bluemix 3 pillars I feel it is important to position what Bluemix really is and which of its parts we are going to use. Bluemix is composed of 3 different things: Bluemix is a hosting environment to run any type of web app or web service. This is the only function provided by the CloudFoundry Open Source project, which is an advanced PaaS that lets you provision and de-provision runtimes (Java, Python, Node etc), libraries and services to be used by your app. These operations can be triggered through the Bluemix.net portal or by the cf command from your laptop. IBM has extended this part of Bluemix with functions not currently available on CloudFoundry, notably the capability of executing regular VMs and Docker containers. Bluemix provides pre-installed libraries, APIs and middleware. IBM is constantly adding functions to the Bluemix marketplace, such as cognitive computing APIs in the Watson family, data processing middleware such as Spark and dashDB, or even IoT and Blockchain-related tools. These are high value components that can add a bit of magic to your app. Many of those are Open Source. UI to build, manage and execute the app delivery pipeline, which does everything needed to transform your pure source code into a final running application. The Track & Plan module, based on Rational Team Concert, to let your team mates and clients exchange activities and control project execution. This tutorial will dive into #1 and some parts of #3, while using some services from #2. The architecture of our app When fully provisioned, the entire architecture will look like this. Several Bluemix services (MySQL, Object store) packaged into a CloudFoundry App (bridge app) that serves some Docker containers that in turns do the real work. Credentials to access those services will be automatically provided to the containers as environment variables (VCAP_SERVICES). Structure of Source Code The example source code repo contains boilerplate code that is intentionally generic and clean so you can easily fork, add and modify it to fit your needs. Here is what it contains: bridge-app folder and manifest.yml file The CloudFoundry manifest.yml that defines app name, dependencies and other characteristics to deploy the app contents under bridge-app. containers Each directory contains a Dockerfile and other files to create Docker containers. In this tutorial we’ll use only the phpinfo and wordpress directories, but there are some other useful examples you can use. .bluemix folder When this code repository is imported into Bluemix via the “Deploy to Bluemix” button, metadata in here will be used to set up your development environment under DevOps Services. admin folder Random shell scripts, specially used for deployments. Watch the deployment The easiest way to deploy the app is through DevOps Services: Click to deploy Provide a unique name to your copy of the app, also select the target Bluemix space The idea is to encapsulate all these steps in code so deployments can be done entirely unattended. Its what I call brainless 1-click deployment. There are 2 ways to do that: A regular shell script that extensively uses the cf command. This is the admin/deploy script in our code. An in-code delivery pipeline that can be executed by Bluemix DevOps Services. This is the .bluemix/pipeline.yml file. From here, we will detail each of these steps both as commands (on the script) and as stages of the pipeline. Instantiation of external services needed by the app… I used the cf marketplace command to find the service names and plans available. ClearDB provides MySQL as a service. And just as an example, I’ll provision an additional Object Storage service. Note the similarities between both methods. Creation of an empty CloudFoundry app to hold together these services The manifest.yml file has all the details about our CF app. Name, size, CF build pack to use, dependencies (as the ones instantiated in previous stage). So a plain cf push will use it and do the job. Since this app is just a bridge between our containers and the services, we’ll use minimum resources and the minimum noop-buildpack. After this stage you’ll be able to see the app running on your Bluemix console. Creation of Docker images The heavy lifting here is done by the Dockerfiles. We’ll use base CentOS images with official packages only in an attempt to use best practices. See phpinfo and wordpress Dockerfiles to understand how I improved a basic OS to become what I need. The CCS_BIND_APP on the script and BIND_TO on the pipeline are key here. Their mission is to make the bridge-app’s VCAP_SERVICES available to this container as environment variables. In CloudFoundry, VCAP_SERVICES is an environment variable containing a JSON document with all credentials needed to actually access the app’s provisioned APIs, middleware and services, such as host names, users and passwords. See an example below. A container group with 2 highly available, monitored and balanced identical wordpress containers See the results At this point, WordPress (the app that we deployed) is up and running inside a Docker container, and already using the ClearDB MySQL database provided by Bluemix. Access the URL of your wordpress container group and you will see this: Bluemix dashboard also shows the components running: But the most interesting evidence you can see accessing the phpinfo container URL or IP. Scroll to the environment variables section to see all services credentials available as environment variables from VCAP_SERVICES: So I’m using sed, the text-editor-as-a-command, to edit WordPress configuration file (/etc/wordpress/wp-config.php) and change some patterns there into appropriate getenv() calls to grab credentials provided by VCAP_SERVICES. Dockerfile best practices The containers folder in the source code presents one folder per image, each is an example of different Dockerfiles. We use only the wordpress and phpinfo ones here. But I’d like to highlight some best practices. A Dockerfile is a script that defines how a container image should be built. A container image is very similar to a VM image, the difference is more related to the file formats that they are stored. VMs uses QCOW, VMDK etc while Docker uses layered filesystem images. From the application installation perspective, all the rest is almost the same. But only only Docker and its Dockerfile provides a super easy way to describe how to prepare an image focusing mostly only on your application. The only way to automate this process on the old Virtual Machine universe is through techniques such as Red Hat’s kickstart. This automated OS installation aspect of Dockerfiles might seem obscure or unimportant but is actually the core of what makes viable a modern DevOps culture. Being a build script, it starts from a base parent image, defined by the FROM command. We used a plain official CentOS image as a starting point. You must select very carefully your parent images, in the same way you select the Linux distribution for your company. You should consider who maintains the base image, it should be well maintained. Avoid creating images manually, as running a base container, issuing commands manually and then committing it. All logic to prepare the image should be scripted in your Dockerfile. In case complex file editing is required, capture edits in patches and use the patch command in your Dockerfile, as I did on wordpress Dockerfile. To create a patch: diff -Naur configfile.txt.org configfile.txt > configfile.patch Then see the wordpress Dockerfile to understand how to apply it. Always that possible, use official distribution packages instead of downloading libraries (.zip or .tar.gz) from the Internet. In the wordpress Dockerfile I enabled the official EPEL repository so I can install WordPress with YUM. Same happens on the Django and NGINX Dockerfiles. Also note how I don’t have to worry about installing PHP and MySQL client libraries – they get installed automatically when YUM installs wordpress package, because PHP and MySQL are dependencies. To chose to go with Docker in some parts of your application means to give up some native integrations and facilities naturally and automatically provided by Bluemix. With Docker you’ll have to control and manage some more things for yourself. So go with Docker, instead of a buildpack, if: If you need portability, you need to move your runtimes in and out Bluemix/CloudFoundry. If a buildpack you need is less well maintained then the equivalent Linux distribution package. Or you need a reliable and supported source of pre-packaged software in a way just a major Linux distribution can provide. The best balance is to use Bluemix services/APIs/middleware and native buildpacks/runtimes whenever possible, and go with Docker on specific situations. Leveraging the integration that Docker on Bluemix provides. I’ve searched for a long time and finally found a US regular bank that will let me open a free checking account. It is BBVA Compass bank. All these services are free: ATM withdraw and deposit (BBVA’s and AllPoint ATMs), full featured Internet banking, full featured mobile banking, Visa debit card, Apple Pay and more. The non-free services are listed here and exact rates depend on the US state where the account was opened. To open a checking account, you must personally visit a physical branch in US and spend 40 minutes on an interview. You will leave the branch with an open account and routing numbers containing a $26 balance plus valid user and password that can be used on BBVA’s app and Internet banking. Free Visa debit card will arrive to some US address in a week or two, so no ATM until then. They have 2 free checking account types. You should chose the one that includes free or charge AllPoint ATM usage which are very popular throughout US, and can be found in almost every 7 Eleven store. Use the AllPoint app to find one near you. (more…) WordPress is packaged for Fedora and can be installed as a regular RPM (with DNF/YUM). The benefits of this method are that you don’t need to mess around with configuration files, filesystem permissions and since everything is pre-packaged to work together, additional configurations are minimal. At the end of this 3 minutes tutorial, you’ll get a running WordPress under an SSL-enabled Apache using MariaDB as its backend. On December 3 Apple has open sourced the Swift programming language on Swift.org. The language was first released (not Open Source yet) about the same time as iOS 8 and was created by Apple to make Mac and iOS app development an easier task. Swift is welcome as one more Open Source language and project but is too early to make a lot of noise about it. Here are my arguments: (more…) I don’t know about you senior bloggers but I’m starting to hate the way the WordPress community has evolved and what it became. From a warm and advanced blogging software and ecosystem it is now an aberration for poor site makers. Themes are now mostly commercial, focused on institutional/marketing sites and not blogs anymore. WordPress is simply a very poor tool for this purpose. You can see this when several themes are getting much more complex than WordPress per se. (more…) Before iOS 8, the Polar H7 heart sensor with bluetooth needed special apps to pair. Now it pairs natively on the Settings app and starts sending heart rate to the new Health app on iOS 8, which will keep recording the data and building a graph like this: At the Fedora 20 release party another guy stepped up and presented+demonstrated OpenShift, which was the most interesting new feature from Red Hat for me. First of all I had to switch my mindset about cloud from IaaS (infrastructure as a service, where the granularity are virtual machines) to PaaS. I heard the PaaS buzzword before but never took the time to understand what it really means and its implications. Well, I had to do that at that meeting so I can follow the presentation, of course hammering the presenter with questions all the time.(more…) Few weeks ago I attended the Fedora 20 release party at São Paulo Red Hat offices. It was nice to hang together with other Fedora enthusiasts, get a refresh about newest Fedora features and also share my experiences as (I considere myself) a power user. For some reason nobody published a simple guide like this. Maybe nobody tryied this way. I just tryied and it works with OS X Mountain Lion on a Mid 2012 MacBook Air. If you have a Mac computer or laptop and want to install OS X, and all that you have is the operating system installation ISO image, you just need an external USB storage (disk or pen drive) of 5GB minimum size. Those regular 120GB or 1TB external disks will work too. Just remember that all data on this external storage will be erased, even if the Mac OS X installation ISO is just 4.7GB. So make a backup of your files and after installtion you can re-format the external disk and recover the files on it. To make the OS X installation ISO image file usable and bootable from the external storage, use the Mac OS terminal app or, on Linux, use the command line. This is the magic command: dd if="OS X Install DVD.iso" of=/dev/disk1 bs=10m You might want to change the red part of this command to the disk name that you get when inserted the external storage. Remember to not use things like disk1s1 or, on Linux, sdc1. The highlighted blue part on these examples are the partition name, and you don’t want that. You want to use the whole storage, otherwise it will not boot the computer. After the command finishes execution, boot the Mac computer with the alt/option key pressed. Several devices will appear on screen for you to choose wich one to boot. Select the one with the USB logo and called “EFI Boot“. Mac OS X installation app will boot and you can start the process. Remember that the default behavior here is to upgrade the installed system. If you want a clean install, select the Disk Utility app on the menu and make sure you erase and create a new partition on the Mac internal storage. As a side technical note, this is all possible because ISO images — primarily designed for optical disks — can also be written to regular other storages as pen drives. And Apple has also put the right bits on these ISO images to allow it to boot from non-optical disks too.	{ "pile_set_name": "Pile-CC" }
Lollapalooza Argentina Tickets Brave festival hunters of the internet, do we have something for you! Yes, Festival period looms over the horizon and we’ve got Lollapalooza Argentina tickets for your pleasure! With a sensational line-up and an even more sensational atmosphere, Lollapalooza Argentina has always been a staple for any intrepid festival goer! So buy your Lollapalooza Argentina tickets, and get ready for one of the best experiences of your life!	{ "pile_set_name": "Pile-CC" }
Similar to my article about taking random on the blockchain too seriously, I think we may have over engineered the decentralization of Cryptogs at #ETHDenver too. It takes a lot of transactions to play Cryptogs fully decentralized. The first three transactions are just to get the game started and we think a tiny bit of optional centralization might make things run smoother. That’s why we’ve added a short-lived backend cache to allow for off-chain game coordination. But don’t worry, you can go full cypherpunk at any time: Privacy is very important to us, but seriously, it’s just blockchain pogs. All we store is game metadata and it expires quickly: We’ve also consolidated the tedious commit/reveal ceremony so the entire game is played with one or two transactions per player. We think it’s a lot smoother now and we would love your feedback in discord or slack! We stand on the shoulders of crypto giants. I sure hope my next project will do them justice. For now, head on over to Cryptogs.io and create a game! ❤️ Like, Share, Leave your comment If you like this post, don’t forget to like, share with your friends and colleagues and leave your comment below about the post. And Follow me…….	{ "pile_set_name": "OpenWebText2" }
SteamOS brewmaster update 2.25 released add some more missing packages to the brewmaster repository usbmount - fix typo in configuration that caused automounting to fail steamos-base-files - Fix for setting the timezone linux - kernel updated to latest LTS 3.18.17, merged additional alchemist kernel changes fglrx - updated AMD driver to 15.5 steamos-compositor - Add HD mode selection step when starting the Steam session steamos-beta-repo boost1.55 cdebconf db5.3 gnutls28 libestr libjpeg-turbo liblogging liblognorm libpsl bind9 - CVE-2015-4620 [cve.mitre.org] iceweasel - CVE-2015-2743 [cve.mitre.org] CVE-2015-4000 [cve.mitre.org] CVE-2015-2734 [cve.mitre.org] CVE-2015-2735 [cve.mitre.org] CVE-2015-2736 [cve.mitre.org] CVE-2015-2737 [cve.mitre.org] CVE-2015-2738 [cve.mitre.org] CVE-2015-2739 [cve.mitre.org] CVE-2015-2740 [cve.mitre.org] CVE-2015-2728 [cve.mitre.org] CVE-2015-2731 [cve.mitre.org] CVE-2015-2724 [cve.mitre.org] [update - the installers were rebuilt after the initial release and I have updated the MD5 hashes below to correspond to the new versions]This update applies to brewmaster_beta as well and includes all the beta changes in 2.20, a fix for automounting USB storage devices, and a lot of additional packages added to the repository.==== SteamOS build 25 2015-07-14 ======== SteamOS build 20 2015-07-13 ====Added assorted missing packages for debootstrap and enabling the beta repositoryInstaller MD5 hashes79c26e91521037ebe5b43ed48a1e5b81 SteamOSDVD.iso65da432968b730f4280370198ccd695f SteamOSInstaller.zip	{ "pile_set_name": "OpenWebText2" }
Q: Java hashset vs Arrays.sort I am trying to solve the below 'codility' exercise: A zero-indexed array A consisting of N different integers is given. The array contains integers in the range [1..(N + 1)], which means that exactly one element is missing. Your goal is to find that missing element. Write a function: class Solution { public int solution(int[] A); } that, given a zero-indexed array A, returns the value of the missing element. For example, given array A such that: A[0] = 2 A[1] = 3 A[2] = 1 A[3] = 5 the function should return 4, as it is the missing element. Assume that: N is an integer within the range [0..100,000]; the elements of A are all distinct; each element of array A is an integer within the range [1..(N + 1)]. Complexity: expected worst-case time complexity is O(N); expected worst-case space complexity is O(1), beyond input storage (not counting the storage required for input arguments). Elements of input arrays can be modified. I came up with two solutions: 1) Gives 100%/100% class Solution { public int solution(int[] A) { int previous = 0; if (A.length != 0) { Arrays.sort(A); for (int i : A) { if (++previous != i) { return previous; } } } return ++previous; } } 2) Gives an error WRONG ANSWER, got 65536 expected 100001 class SolutionHS { public int solution(int[] A) { int previous = 0; HashSet<Integer> hs = new HashSet<>(); if (A.length != 0) { for (int a : A) { hs.add(a); } for (Integer i : hs) { if (++previous != i) { return previous; } } } return ++previous; } } My question is: Shouldn't both approaches (using hashset and Arrays.sort) work the same way? If not can you tell me what the difference is? A: HashSet is not sorted, so when you iterate over the elements of the Set, you don't get them in an ascending order, as your code expects. If you used a TreeSet instead of HashSet, your code would work. The HashSet solution will give the correct answer if you change the second loop to : for (int i = 0; i <= A.length; i++) { if (!hs.contains(i)) { return i; } } This loop explicitly checks whether each integer in the relevant range appears in the HashSet and returns the first (and only one) which doesn't. Anyway, both your implementations don't meet the O(n) running time and O(1) space requirements. In order you meet the required running time and space, you should calculate the sum of the elements of the array and subtract that sum from (A.length+1)*A.length/2.	{ "pile_set_name": "StackExchange" }
Blood borne macrophages are essential for the triggering of muscle regeneration following muscle transplant. The transplantation of satellite cells may constitute a strategy for rebuilding muscle fibres in inherited myopathies. However, its development requires a great understanding of the role of environmental signals in the regenerative process. It is therefore essential to identify the key events triggering and controlling this process in vivo. We investigated whether macrophages play a key role in the course of the regenerative process using skeletal muscle transplants from transgenic pHuDes-nls-LacZ mice. Before grafting, transplants were conditioned with macrophage inflammatory protein 1-beta (MIP 1-beta; stimulating the macrophages infiltration or vascular endothelial growth factor (VEGF) stimulating angiogenesis). Treatment of transplants with MIP 1-beta and VEGF both accelerated and augmented monocyte-macrophage infiltration and satellite cell differentiation and/or proliferation, as compared to controls. In addition, VEGF treatment enhanced the number of newly formed myotubes. When a complete depletion of host monocyte-macrophages was experimentally induced, no regeneration occurred in transplants. Our data suggest that the presence of blood borne macrophages is required for triggering the earliest events of skeletal muscle regeneration. The understanding of macrophage behaviour after muscle injury should allow us to develop future strategies of satellite cell transplantation as a treatment for muscular dystrophies.	{ "pile_set_name": "PubMed Abstracts" }
INTRODUCTION {#s1} ============ Pediatric glioblastoma (GBM) is a relatively rare primary brain tumor in children \[[@R1]\]. Maximum surgical resection is considered the key and prognosis-determining factor in the treatment, followed by radiotherapy \[[@R1], [@R2]\]. Unfortunately, pediatric GBM is poorly studied at the molecular and genomic levels. Radiotherapy plays a critical role in eradicating the post-surgical residual microtumor \[[@R3]\]. Yet the molecular and genomic changes post-radiation in pediatric GBM have not been well examined. We have recently identified many radiation-responsive genes in adult radioresistant GBM cells that explain the radioresistance and increased malignant features of recurrent GBM \[[@R4]\]. However, adult and pediatric GBMs are distinct from each other at both molecular and genetic levels \[[@R2]\]. We are presenting a full RNA sequencing profile of both the radiation-naïve pediatric GBM (SJ-GBM2) cell line and stable radioresistant pediatric GBM (SJ-GBM2-10gy) cell line that we recently developed \[[@R5], [@R6]\]. Our data demonstrated that radiation perturbed the expression of many genes related to many different known pathways in cancer biology. The irradiated cells exhibited an enhanced growth rate, overexpressed protease cathepsin B, and both subunits of the rate-limiting enzyme of DNA synthesis ribonucleotide reductase (RR). In this study, we shed light on the irradiation responsive mRNA changes that transform the tumor cells toward a more aggressive and resistant form, for which treatment choices are limited. This study opens the door to further examining the possibility of targeting these modified pathways as a therapeutic strategy to block GBM tumor recurrence and progression. RESULTS {#s2} ======= Radioresistant irradiated pediatric GBM cells exhibited higher growth rate than control cells {#s2_1} --------------------------------------------------------------------------------------------- The in-vitro growth rate of the SJ-GBM2 and SJ-GBM2-10gy cells was evaluated using an MTT growth assay over a period of 10 days. SJ-GBM2-10gy cells showed a superior divergent growth starting from day 3, having the difference in growth maximized on day 7 when the control cells significantly slowed down their proliferation rate (Figure [1](#F1){ref-type="fig"}). The control cells SJ-GBM2 reached about 7.4 growth fold in 10 days, while the irradiated cells reached a 10.5 fold from their baseline. This represents an estimated 30% increase in growth (Figure [1A](#F1){ref-type="fig"}). ![Irradiation of the pediatric GBM cells enhanced proliferation and expression of malignant-promoting proteins:\ (A) Growth curves of SJGBM2 and SJGBM2-10gy cells. (B) Western blot for RR M1 (94 kDa) and M2 (45 kDa) subunits and pro-cathepsin B (Pro-CatB) (43 kDa) in SJGBM2 and SJGBM2-10gy cells. (C) Direct immunofluorescence probing for RRM2 and cathepsin B (Pro-CatB) in both cells after a 24 h incubation in fresh medium. ^\^P \< 0.05.](oncotarget-09-34122-g001){#F1} Irradiated radioresistant pediatric GBM overexpresses ribonucleotide reductase {#s2_2} ------------------------------------------------------------------------------ To probe for a mechanism promoting the superior growth rate in irradiated cells, the expression of both ribonucleotide reductase (RR) subunits was measured. The RR enzyme, specifically the RRM2 subunit, has been reported to be essential for proliferation and invasion of GBM cells \[[@R7]\]. Immunoblotting of control and irradiated cells revealed an increase in the expression of RRM1 subunit by 2-fold, and an increase in the RRM2 subunit by 3.5-fold in irradiated cells relative to control cells (Figure [1B](#F1){ref-type="fig"}). This increase in cellular expression of RRM2 was confirmed by immunofluorescence probing of intact cells, demonstrating the distribution of RRM2 in the cytoplasm of the irradiated cells and was greater than the control cells (Figure [1B, 1C](#F1){ref-type="fig"}). Irradiated radioresistant pediatric GBM overexpresses pro-cathepsin B {#s2_3} --------------------------------------------------------------------- We were interested in evaluating whether protease may play of role in promoting invasion and progression of irradiated radioresistant GBM. Cathepsin B, a cysteine protease, has been shown to play a role in tumor growth and invasion \[[@R8], [@R9]\]. We probed for the differential expression level of pro-cathepsin B in control and irradiated cells. Western blot of cell lysates and immunofluorescence of intact cells revealed 3-fold overexpression of pro-cathepsin B in irradiated cells over control cells (Figure [1B, 1C](#F1){ref-type="fig"}). In addition to being localized to the cytoplasm, pro-cathepsin B was present in the processes of the irradiated cells, a feature that may be important in the invasiveness of GBM into the surrounding tissue (Figure [1C](#F1){ref-type="fig"}). Irradiation of pediatric GBM cells induces differential expression of 1192 radiation-responsive genes {#s2_4} ----------------------------------------------------------------------------------------------------- Total mRNAs from SJGBM2 and SJGBM2-10gy cells were harvested and subjected to further analysis. To screen for global mRNA changes following irradiation, we profiled transcriptomes of the control SJ-GBM2 cell line and its derivative radioresistant irradiated SJ-GBM2-10gy cells by RNA sequencing (Table [1](#T1){ref-type="table"} and [Supplementary Table 1](#SD2){ref-type="supplementary-material"}). The criteria for differentially expressed genes were 2-fold or greater than statistically significant values (P* \< 0.05). We identified 1192 radiation responsive genes. Among these 1192 radiation responsive genes, 584 were upregulated and 608 were downregulated ([Supplementary Tables 2](#SD3){ref-type="supplementary-material"} and [3](#SD4){ref-type="supplementary-material"}). ###### Enriched gene ontology categories of differentially expressed genes following irradiation based on sets of statistically significant (more than 2-fold) upregulated and downregulated genes (P \< 0.05) Differentially expressed Category P-value -------------------------------------------------------- --------------------------------------- ----------- Upregulated GO:0048863: Stem cell differentiation 6.60E-03 GO:0010628: Positive regulation of gene expression 7.70E-03 GO:0002040: Sprouting angiogenesis 3.20E-02 GO:0008284: Positive regulation of cells proliferation 2.40E-02 GO:0070848: Response to growth factor 7.40E-02 GO:0001558: Regulation of cell growth 7.60E-02 GO:0055114: Oxidation reduction process 3.00E-02 GO:0071356: Cellular response to tumor necrosis factor 3.60E-02 GO:0006954: Inflammatory response 4.10E-02 GO:0016055: Wnt signaling pathway 8.40E-02 GO:0043066: Negative regulation of apoptotic process 9.40E-02 GO:0004222: Metalloendopeptidase activity 2.40E-02 Downregulated GO:0007155: Cell adhesion 4.90E-03 GO:0043065: Positive regulation of apoptosis 1.30E-04 GO:008285: Negative regulation of cell proliferation 4.10E-02 GO:0002020: Protease binding 1.20E-03 Experiments were performed in triplicate. Upregulation of genes promoting tumor growth and aggressiveness following irradiation {#s2_5} ------------------------------------------------------------------------------------- Gene ontology analysis of the mRNA data was utilized to categorize genes into functional groups. It revealed that upregulated genes were enriched in positive regulation of stem cells differentiation, angiogenesis, cell proliferation, cell growth, inflammatory response, positive regulation of the Wnt signaling pathway, response to hypoxia, metalloendopeptidase activity, cellular response to tumor necrosis factor and negative regulation of apoptotic process (Table [1](#T1){ref-type="table"} and [Supplementary Table 2](#SD3){ref-type="supplementary-material"}, and [Supplementary Table 4](#SD5){ref-type="supplementary-material"}). The upregulated genes were enriched in positive regulation of gene expression and tumor cell proliferation such as KIT, connective tissue growth factor CTGF and ID1, ID2, and TLE1-FOXG1 transcriptional factors that have been reported to enhance growth and proliferation of GBM cells \[[@R10]--[@R13]\]. G protein-coupled receptor kinase 5 (GRK5) plays an important role in tumor cells' proliferation \[[@R14]\]. Fibroblast growth factor 4 (FGF4) also has been correlated with a greater malignancy profile in high-grade gliomas \[[@R15]\].The radioresistant cells had upregulated expression of many anti-apoptotic genes, including BCL2, CD74, and WT1, which regulates GBM cells proliferation and apoptosis \[[@R16]\]. A significant upregulation (10-fold) of the AIM2 gene, a tumor-associated antigen, was found. This gene upregulation was observed in GBM patients and in malignant cell lines as well \[[@R17]\]. Proteolytic enzymes such as ADAM28, MMP12 and MMP17, which can enhance extracellular invasion and expansion of tumor volume, were also upregulated in the irradiated SJGBM2-10gy cells ([Supplementary Table 4](#SD5){ref-type="supplementary-material"}). Downregulated genes were enriched in the apoptotic process, tumor suppression, protease binding and cell adhesion {#s2_6} ----------------------------------------------------------------------------------------------------------------- The gene ontology analysis was conducted to analyze differentially expressed genes. Compared with control cells, downregulated genes in the irradiated SJ-GBM2-10gy cells were enriched in growth inhibitor, transcription DNA-templated, cell adhesion, apoptotic process, and protease binding (Tables [1](#T1){ref-type="table"} and [2](#T2){ref-type="table"}, [Supplementary Table 3](#SD4){ref-type="supplementary-material"}). Tumor irradiation has been shown to cause silencing of many tumor suppressor genes, which in turn enhances tumor aggressive growth and invasion \[[@R18]\]. Many of the well-known tumor suppressor genes were found downregulated in the irradiated SJGBM2-10gy including DAB2IP, ING2, interleukin 1 beta, and MEG3 (Table [2](#T2){ref-type="table"}). Downregulation of DAB2IP induces radioresistance by accelerating DNA double strand repair after radiation and evasion of apoptotic process in prostate carcinoma \[[@R19]\]. Inhibitor of Growth Family member 2 (ING2) is a tumor suppressor that is involved in activation of p53/Tp53-dependent apoptosis \[[@R20]\]. Interleukin 1 beta is known to suppress GBM cells through promoting hypoxia-induced apoptosis by downregulation of HIF1 \[[@R21]\]. Maternally expressed gene 3 (MEG3) plays a role in activation of p53-dependent apoptosis and is found downregulated in the glioma cells compared with normal brain cells \[[@R22]\]. Interestingly, the irradiated cells showed significant repression of the main cellular metalloprotease inhibitor proteins called TIPM4 and alpha2 macroglobulin (A2M) \[[@R23]--[@R26]\]. Downregulation of protease inhibitors causes unopposed digestion of the extracellular matrix around the tumor by metalloproteases, which were also upregulated in irradiated cells, and therefore, facilitating tumor invasion of the extracellular space. ###### Downregulated genes of selected enriched gene ontology categories following irradiation of SJ-GBM2 cells are shown based on sets of statistically significant changes (P \< 0.05) Gene ontology group P-value Fold changes Gene symbol Gene description ------------------------------------------- ----------- --------------------------------------------------------------- ------------- -------------------------------------- Cell adhesion 4.90E-03 0.3390 CD33 CD33 molecule 0.4851 EDIL3 EGF like repeats and discoidin domains 3 0.3426 EPHA4 EPH receptor A4 0.4796 F11R F11 receptor 0.0456 L1CAM L1 cell adhesion molecule 0.3634 SPOCK1 SPARC/osteonectin, cwcv and kazal like domains proteoglycan 1 0.1247 TNFAIP6 TNF alpha induced protein 6 0.3202 ALCAM activated leukocyte cell adhesion molecule 0.4053 ADGRB1 adhesion G protein-coupled receptor B1 0.4680 BCAM basal cell adhesion molecule (Lutheran blood group) 0.1871 CDH3 cadherin 3 0.3202 CDH8 cadherin 8 0.4662 COL5A1 collagen type V alpha 1 chain 0.2467 COL8A1 collagen type VIII alpha 1 chain 0.0839 CNTN2 contactin 2 0.1860 CNTN4 contactin 4 0.4905 CNTNAP3 contactin associated protein-like 3 0.4111 EMP2 epithelial membrane protein 2 0.2666 FAP fibroblast activation protein alpha 0.3239 LGALS3BP galectin 3 binding protein 0.3272 ITGA11 integrin subunit alpha 11 0.3245 ITGA9 integrin subunit alpha 9 0.2359 LAMA3 laminin subunit alpha 3 0.2795 PTPRK protein tyrosine phosphatase, receptor type K 0.1867 ROBO2 roundabout guidance receptor 2 0.2710 TNC tenascin C Positive regulation of apoptotic process 1.30E-04 0.4109 AKAP13 A-kinase anchoring protein 13 0.3966 DAB2IP DAB2 interacting protein 0.3180 FGD4 FYVE, RhoGEF and PH domain containing 4 0.3340 KLF11 Kruppel like factor 11 0.2253 ARHGEF16 Rho guanine nucleotide exchange factor 16 0.1708 ARHGEF4 Rho guanine nucleotide exchange factor 4 0.3533 TNFRSF8 TNF receptor superfamily member 8 0.4738 ALDH1A2 aldehyde dehydrogenase 1 family member A2 0.1373 EEF1A2 eukaryotic translation elongation factor 1 alpha 2 0.4137 GAL galanin and GMAP prepropeptide 0.3390 ING2 inhibitor of growth family member 2 0.2705 IFIT2 interferon induced protein with tetratricopeptide repeats 2 0.4339 IRF5 interferon regulatory factor 5 0.4589 JMY junction mediating and regulatory protein, p53 cofactor 0.0767 NGFR nerve growth factor receptor 0.0816 PNMA2 paraneoplastic Ma antigen 2 0.3719 PAWR pro-apoptotic WT1 regulator 0.4911 STK3 serine/threonine kinase 3 Negative regulation of cell proliferation 4.10E-02 0.2946 CEBPA CCAAT/enhancer binding protein alpha 0.3390 CD33 CD33 molecule 0.3966 DAB2IP DAB2 interacting protein 0.4179 DLC1 DLC1 Rho GTPase activating protein 0.3340 KLF11 Kruppel like factor 11 0.2957 RERG RAS like estrogen regulated growth inhibitor 0.3533 TNFRSF8 TNF receptor superfamily member 8 0.4053 ADGRB1 adhesion G protein-coupled receptor B1 0.4738 ALDH1A2 aldehyde dehydrogenase 1 family member A2 0.4351 CHD5 chromodomain helicase DNA binding protein 5 0.1004 F2R coagulation factor II thrombin receptor 0.3390 ING2 inhibitor of growth family member 2 0.4605 IRF1 interferon regulatory factor 1 0.4571 IL1B interleukin 1 beta 0.3036 LDOC1 leucine zipper down-regulated in cancer 1 0.4785 LIF leukemia inhibitory factor 0.0953 MEG3 maternally expressed 3 (non-protein coding) 0.2795 PTPRK protein tyrosine phosphatase, receptor type K 0.4911 STK3 serine/threonine kinase 3 0.4718 SLIT3 slit guidance ligand 3 Protease binding 1.20E-03 0.0331 CD70 CD70 molecule 0.1539 TIMP4 TIMP metallopeptidase inhibitor 4 0.2020 A2M alpha-2-macroglobulin 0.2780 CSTA cystatin A 0.1772 CST6 cystatin E/M 0.2666 FAP fibroblast activation protein alpha 0.4143 IL1R1 interleukin 1 receptor type 1 0.1026 RYR1 ryanodine receptor 1 0.2443 SERPINA1 serpin family A member 1 0.3182 SERPINA5 serpin family A member 5 0.4862 SERPINE1 serpin family E member 1 Experiments were performed in triplicate. DISCUSSION {#s3} ========== Tumor radiation plays a critical role in pediatric brain tumors after gross total resection \[[@R1]--[@R3]\]. Unlike brain tumors in adults, the benefit of adjuvant chemotherapy is limited. As a result, it is typical that solely radiotherapy is utilized to eradicate any remnant tumor cells after surgery \[[@R1]--[@R3]\]. Ironically, irradiation of tumors is known to transform tumor cells into a more aggressive, radioresistant form, for which the treatment options are limited \[[@R27]\]. However, post-radiation transcriptome changes of the pediatric GBM have not been closely studied. The pediatric GBM cell line SJ-GBM2 is a common line that has been used for in vitro studies and is considered a radiation-naive cell line as it has not previously been irradiated \[[@R28], [@R29]\]. We previously described a stable radioresistant pediatric GBM model of irradiated SJ-GBM2 cells \[[@R5], [@R30]\]. In the current study, we further characterized these radioresistant cells and examined mRNA changes induced by irradiation. The results showed that the irradiated cells were more aggressive and possessed a higher proliferation rate when compared with their progenitors. SJ-GBM2 cells showed 7.4-fold growth on day 10 of incubation, while the irradiated SJ-GBM2-10gy cells grew up to 10.5-fold during the same period, suggesting that irradiation promotes a higher cell proliferation rate in radioresitant cells (Figure [1A](#F1){ref-type="fig"}). This rapid growth was paralleled by the increase in the expression of RR subunits, the main enzymes involved in DNA synthesis during cell division (Figure [1B, 1C](#F1){ref-type="fig"}). RR activity is critical for tumor cell growth \[[@R31]\]. The RRM2 subunit specifically has been linked to DNA repair capacity after radiation \[[@R32]\]. Our data suggested that RR overexpression in the irradiated cells may contribute to their ability to grow after radiation. In order to understand the changes in gene expression induced by irradiation, we performed a complete RNA sequencing of SJ-GBM2 and SJ-GBM2-10gy cells. Of the 32998 genes sequenced, a relatively small number (3.6%) of genes following irradiation were differentially expressed by meeting the criteria of a more than two-fold change ([Supplementary Table 1](#SD2){ref-type="supplementary-material"}). The upregulated genes such as KIT, ID1, ID2, GRK5, CTGF, LEF1, NTRK3 and PGF are considered oncogenes that promote tumor proliferation, invasion and gene expression, in GBM or other types of cancers \[[@R11], [@R12], [@R14], [@R33]--[@R36]\]. KIT is an oncogene that enhances GBM proliferation and growth and it was found to be upregulated in patient-derived GBM samples \[[@R10]\]. BMP1 is involved in many signaling pathways in GBM and correlate with poor prognosis in glioma patient \[[@R37]\]. Among the upregulated genes there was a significant increase in the expression of glutathione peroxidase 3 (GPX3), which is known to be an oxidative stress-induced antioxidant \[[@R38]\]. This increase of GPX3 may protect cells against reactive oxygen species produced after radiation. Gene ontology showed that many anti-apoptotic and anti-inflammatory genes were upregulated in the irradiated cells (Table [1](#T1){ref-type="table"} and [Supplementary Table 4](#SD5){ref-type="supplementary-material"}). The downregulated genes were enriched in adhesion molecules (Table [2](#T2){ref-type="table"}). High-grade gliomas alter their expression of extracellular matrix adhesion proteins for tumor progression and invasion into the normal surrounding brain tissue \[[@R39]\]. Irradiation of cells depressed the expression of many adhesion molecules such as CHD3, CHD8, FAP, BCAM, L1CAM, TNC, ITGA11, and ITGA9. Eighteen pro-apoptotic genes, along with 21 tumor suppressor genes, were downregulated following irradiation (Table [2](#T2){ref-type="table"}). This explains the acquired radioresistant feature of irradiated cells and the increased malignant nature that was observed in irradiated cells (Figure [1A](#F1){ref-type="fig"}). Specifically, the DAB2IP gene was found to play a tumor suppressor role in medulloblastoma and a lower expression of DAB2IP caused resistance to radiation in prostate carcinoma \[[@R19], [@R40]\]. P53 is believed to be the regulator of many radiation responsive genes that alter tumor cells sensitivity to radiation \[[@R41]\]. Any loss or mutation in the P53 function leads to radioresistance \[[@R41]\]. Our results revealed that the downregulation of genes involved in radiation responsive activation of P53-apoptotic pathway such as ING2, IL2B and MEG3, enabled cells to acquire radioresistance. In addition, irradiation also altered metalloprotease activity. Although irradiated cells have lower expression of protease inhibitors TIPM4 and A2M, the expression of metalloproteases such as MMP12, MMP17 and cathepsin B was augmented. The net effect is the enhancement in metalloprotease activity, allowing the invasion and expansion of GBM after radiation. Alpha-2 macroglobulin (A2M), a large plasma glycoprotein natural inhibitor of cathepsin B and many other growth factors especially epidermal growth factors, exhibits the capability of abrogating the malignant potential of astrocytoma cells such as cell proliferation, invasion, and migration, and, as such, it can be exploited for therapeutic purposes \[[@R25], [@R26], [@R42]--[@R46]\]. Alpha-2 macroglublin has been proposed as a molecule conferring cancer resistance to the long-lived (30-year lifespan) naked mole rat, whose A2M transcript level is 140-fold higher than that of the control, and no tumor has ever been observed in these rats \[[@R47]--[@R49]\]. In this study, we report the alterations of gene expressions in response to radiation, which might play a critical role in the acquisition of radioresistance by irradiated pediatric GBM cells. The results indicated that irradiated cells were not only radioresistant, but they also transformed into a more aggressive, malignant GBM. This parallels the clinical observation that recurrent GBM is more aggressive and malignant after irradiation. This malignant transformation emphasizes the importance of developing a treatment regimen consisting of a multiple-agent cocktail that acts on multiple implicated pathways to effectively target irradiated pediatric GBM. An alternative to radiation or perhaps a new therapy- targeting differentially expressed genes, such as metalloproteases, growth factors, and oncogenes- that aims to minimize oncogenic changes following radiation is necessary to improve recurrent pediatric GBM survival. As a main cellular inhibitor of all tumor-associated metalloproteinases, and a sequester of many growth factors, alpha 2-macroglobulin might be exploited as a novel therapy to modulate pediatric GBM growth and invasion \[[@R42]--[@R46]\]. MATERIALS AND METHODS {#s4} ===================== Reagents and cells {#s4_1} ------------------ The pediatric glioblastoma cell line (SJ-GBM2) was obtained from the Children's Oncology Group (COG), (Dallas, TX, USA). Cell lines were cultured in Eagle's minimum essential medium containing 10% (v/v) fetal bovine serum, and supplemented with 1% sodium pyruvate and 0.1% gentamicin. Culture medium materials were obtained from Life Technologies, Inc. (Grand Island, NY, USA). Generation of the stable pedicatric radioresistant GBM model {#s4_2} ------------------------------------------------------------ We previously generated and described a stable radioresistant GBM model \[[@R5]\]. Briefly, to generate the SJ-GBM2-10gy, SJ-GBM2 cell lines were grown to confluence and then irradiated with a Pantak HF320 X-ray machine (Agfa NDT Ltd., Reading, UK) operating at 300 kV at a dosage of 2.09 Gy/min to a total radiation dose of 10 Gy. Over the course of weeks, most cells died and less than ∼1% of cells survived the irradiation. These radioresistant SJGBM2-10gy cells were allowed to grow to confluence and were perpetuated for experiments. MTT viability and Western blot assays {#s4_3} ------------------------------------- SJ-GBM2 and SJ-GBM2-10gy cell growths were measured by MTT assay. Cells were plated in an initial density of 0.05 × 10⁶ cell/ml in 96-well micro-well plates and incubated for 1 to 10 days. A daily readout of the cellular viability was recorded for growth rate measurement. Cell lysates from both irradiated and control cell lines were analyzed for the expression of ribonucleotide reductase subunits and cathepsin B by Western blot. Antibodies used were mouse anti RRM1 (Santa Cruz Biotechnology, sc-377415), mouse anti-RRM2 (Santa Cruz Biotechnology, sc-376973), mouse anti pro-cathepsin B (Life Technologies, Inc., 414800) and mouse anti b-actin (Santa Cruz Biotechnology, sc-47778). Secondary antibody used was HRP goat anti mouse (Li-Cor, 926-80010). Immunofluorescence {#s4_4} ------------------ SJ-GBM2 and SJ-GBM2-10gy cells were grown on chamber slides for 24 h. Cells were fixed with 3.7% paraformaldehyde in PBS, washed with ice-cold phosphate-buffered saline (PBS), permeabilized with 0.2% Triton 100 and incubated in 1% bovine serum albumin (BSA) in PBS blocking buffer. Next, cells then were incubated in 37° C with anti-pro-cathepsin B and anti-RRM2 for 1 h. Cells then were washed with 0.01% Tween PBS, and incubated in the dark with correspondent Texas horse anti mouse (Vector, TI2000) secondary antibodies for 1 h. Cells then were washed and counterstained with DAPI (Invitrogen, D1306) for 5 min. Confocal images were captured with a Carl Zeiss LSM510 microscope (Jena, Germany) equipped with a plan-apochromat 20×/0.8 NA or 40×/1.2NA lens available at the Imaging Core Facility at the Children's Research Institute, Medical College of Wisconsin (Milwaukee, WI, USA). Red fluorophore (A546) was excited with a diode laser (561 nm) and DAPI was excited with a 405 laser. Laser power to the sample was controlled with an acousto-optic tunable filter (AOTF) and the appropriate dichroics and filters for each fluorophore were used during image acquisition. The images were corrected for pixel saturation using with photomultiplier detector gain and amplifier offset controls as per the manufacturer's recommendations. Images were taken four to eight times and collected using Aim 4.2 software. RNA library preparation and sequencing {#s4_5} -------------------------------------- RNA sequencing was done as previously described \[[@R4]\]. In brief, RNA-sequencing libraries were prepared using the TruSeq Stranded mRNA Library Prep Kit (Illumina, Inc., San Diego, CA, USA) according to the manufacturer's protocol. PolyA mRNA from an input of 500 hg high quality total RNA (RINe \> 8) was purified and fragmented. First strand complementary deoxyribonucleic acid (cDNA) syntheses were performed using random hexameres and ProtoScript II Reverse Transcriptase (New England BioLabs Inc., Ipswich, MA, USA). The 3′ ends of the cDNA were adenylated and then indexing adaptors were ligated. Polymerase chain reactions were used to selectively enrich those DNA fragments that have adapter molecules on both ends and to amplify the amount of DNA in the library. The libraries were quantified using the Promega QuantiFluor dsDNA System on a Quantus Fluorometer (Promega, Madison, WI, USA). The size and purity of the libraries were analyzed using the High Sensitivity D1000 Screen Tape on an Agilent 2200 TapeStation instrument. The libraries were normalized, pooled, and subjected to cluster, and pair read sequencing was performed for 150 cycles on a HiSeq4000 instrument (Illumina, Inc., San Diego, CA, USA), according to the manufacturer's instructions. Gene ontology analysis {#s4_6} ---------------------- The gene ontology enrichment analysis was performed using DAVID Bioinformatics Resources 6.7, NIAIS/NIH (<http://david.abcc.ncifcrf.gov/>). SUPPLEMENTARY MATERIALS TABLES {#s5} ============================== We would like to thank Lydia Washechek of the Center for Imaging Research for editing the manuscript. CONFLICTS OF INTEREST None declared. FUNDING Musella Foundation Grant, Department of Neurosurgery Larson Endowment Grant. GBM : Giloblastoma PBS : phosphate-buffered SJ-GBM2 : radiation-naïve pediatric GBM RR : ribonucleotide reductase SJ-GBM2-10gy : stable radioresistant pediatric GBM	{ "pile_set_name": "PubMed Central" }
MIT Fellow Says Facebook ‘Lifted’ His Ideas for Libra Cryptocurrency - espeed https://www.coindesk.com/mit-fellow-accuses-facebook-of-lifting-his-ideas-for-libra-cryptocurrency ====== paulsutter Oh come on, neither a basket of commodities nor a basket of currencies are original ideas. During the security token craze of 2017/2018 many similar ideas were proposed and we don’t see those folks whining about Libra. One example was a local currency based on a basket of goods such as real estate so that employers could pay a salary that adjusted as rents and other costs changed locally. Hundreds of these ideas were discussed freely in telegram groups. The article is just outrage porn. ~~~ blhack Hey that’s actually a great idea. ------ cameldrv Please. Even I had this idea in 2012 and I got it from being a user of Chaum’s digicash in the nineties and understanding parts of how the IMF works, etc. I even helped (not successfully) launch it in 2013. These ideas have been around for a good while by many people, it’s just that crypto is mainstream enough and facebook has enough clout now to take it seriously. If facebook ripped off anyone it was John Maynard Keynes. That’s not to say that it is even that good of an idea or that facebook will be successful with it. ------ vitno I know people who were working on, what is now called, Libra at FB more than a year ago though. The paper was published a year ago. This just looks like a case of multiple people having the same idea. ~~~ yodaml It may just be another case of the "adjacent possible" principle at work. ~~~ TeMPOraL "Adjacent possible" is the case of one of the weirdest possible definition for a very simple concept. I see people quoting this: "The adjacent possible is a kind of shadow future, hovering on the edges of the present state of things, a map of all the ways in which the present can reinvent itself." (Whatever the hell that means.) Even though the concept is much simpler: "adjacent possible" is the set of things within reach. Or: all the things on the border between what we have, and what we could have. ------ ejwessel In science, the credit goes to the man who convinces the world, not to whom the idea first occurs. \- Francis Darwin. ------ BubRoss This is just like when Google stole my idea to run fiber optic internet to people's houses. I totally had that idea a long time ago when I was trying to download a gif with a 28.8 modem. I'm not sure which of the neighborhood kids told Google about my idea but they sure screwed me over. ~~~ jboles Yeah, I once had an idea for auto-scrolling based off tracking eye gaze through the webcam. I never told Microsoft or Samsung about it, but they totally stole my idea!!1eleventyone ~~~ dmihal Even worse: Google stole my idea for self driving cars. I was like " it would be cool if cars drove themselves" and sure enough, Google copies me. Do you think I have grounds for a lawsuit? ------ rdl The idea of a market-basket currency goes back to at least 1976 and Hayek. [https://en.wikipedia.org/wiki/The_Denationalization_of_Money](https://en.wikipedia.org/wiki/The_Denationalization_of_Money) ~~~ m-i-l The idea of a supranational currency goes back to at least 1940 and Keynes - see [https://en.wikipedia.org/wiki/Bancor](https://en.wikipedia.org/wiki/Bancor) . ------ anbop MIT is supposed to create ideas that are “lifted” by others. Produce your patent or shut up. ------ compsciphd cry me a river. It happens Docker did the same thing to me. Compare these two papers (published in 2010 and 2011 in conferences that docker and everyone else in the space are regular participants at, for reference Docker was announced in March 2013) [https://www.usenix.org/legacy/event/atc10/tech/full_papers/P...](https://www.usenix.org/legacy/event/atc10/tech/full_papers/Potter.pdf) [https://www.usenix.org/legacy/events/lisa11/tech/full_papers...](https://www.usenix.org/legacy/events/lisa11/tech/full_papers/Potter.pdf) It was then patented (patent filed in 2011, issued in November 2013) [https://patents.google.com/patent/US8589947B2/en](https://patents.google.com/patent/US8589947B2/en) This was also my "job talk" to IBM Research and it got me a post doc, but didn't get much traction in support of continuing to pursue / refine the ideas within IBM Research (which I find sort of ironic in retrospect with their recent strategic moves) ------ Animats It's certainly not a novel idea. Arguably, it's "E-Gold 2.0".[1] [1] [https://en.wikipedia.org/wiki/E-gold](https://en.wikipedia.org/wiki/E-gold) ------ codegladiator > this paper was published as part of this free-for-all part of the Free > Science part of the Royal Society effort But but ... can facebook not "lift for free" ? ------ quotemstr Nobody owns ideas. ~~~ csallen If only more people understood this. Not only does nobody own an idea, but we really don't want to live in a world where the opposite is true. ~~~ allana Right to Read is a good piece on this topic: [https://www.gnu.org/philosophy/right-to- read.html](https://www.gnu.org/philosophy/right-to-read.html) ------ 0xC0FFEE The paper was published 18 July 2018. The public inital commit of libra was on 18 June 2019 and had 1,063 changed files. That could be a coincidence or not. Fact is, only one has realized the idea. ------ xwdv No sympathy for this guy at all. Think just because you’re an “MIT fellow” your claims to an idea carry more weight than people from other institutions or organizations? Get out of here with this entitlement, tons of people come up with exactly the same ideas all the time. ~~~ gibba999 Plus, 9 times out of 10, it's the MIT types who lift ideas from others and promote them with MIT's increasingly well-polished hype machine. Within MIT, Media Lab is central to this problem. ------ malicioususer11 mark zuckerberg stole something? call the Police! :3 ------ doctorpangloss Facebook's faithful copying is the large tech corp _standard operating procedure_. Google, Amazon, Microsoft and Apple will start product lines based on accurate rumors about what the others are doing, and then cancel them as soon as their competitors do. This form of "copy thy neighbor" just happened with something like three major R&D products/features, one of which was cancelled and another leaked in the tech press. Sandy Pentland cares a lot about these things and it's too bad Facebook just ripped this stuff off. But he will have the last laugh: People already don't want to work at Facebook. It didn't matter so much that all those supposedly smart people aren't really capable of meaningful innovation. There will be a lot fewer of those smart people now. ~~~ skybrian Which products/features do you mean? ~~~ petre Google+? Personal assistants? Self driving vehicles? Cargo drones?	{ "pile_set_name": "HackerNews" }
758 F.2d 649 U.S.v.Masters 81-6657 United States Court of Appeals,Fourth Circuit. 3/7/85 1 D.S.C. AFFIRMED	{ "pile_set_name": "FreeLaw" }
--- abstract: 'Transmission spectroscopy of exoplanets is a tool to characterize rocky planets and explore their habitability. Using the Earth itself as a proxy, we model the atmospheric cross section as a function of wavelength, and show the effect of each atmospheric species, Rayleigh scattering and refraction from 115 to 1000 nm. Clouds do not significantly affect this picture because refraction prevents the lowest 12.75 km of the atmosphere, in a transiting geometry for an Earth-Sun analog, to be sampled by a distant observer. We calculate the effective planetary radius for the primary eclipse spectrum of an Earth-like exoplanet around a Sun-like star. Below 200 nm, ultraviolet (UV) O$_2$ absorption increases the effective planetary radius by about 180 km, versus 27 km at 760.3 nm, and 14 km in the near-infrared (NIR) due predominantly to refraction. This translates into a 2.6% change in effective planetary radius over the UV-NIR wavelength range, showing that the ultraviolet is an interesting wavelength range for future space missions.' author: - 'Y. Bétrémieux and L. Kaltenegger' title: \| Transmission spectrum of Earth as a transiting exoplanet\ from the ultraviolet to the near-infrared --- Introduction ============ Many planets smaller than Earth have now been detected with the Kepler mission, and with the realization that small planets are much more numerous than giant ones (Batalha et al. 2013), future space missions, such as the James Webb Space Telescope (JWST), are being planned to characterize the atmosphere of potential Earth analogs by transiting spectroscopy, explore their habitability, and search for signs of life. The simultaneous detection of large abundances of either O$_{2}$ or O$_{3}$ in conjunction with a reducing species such as CH$_{4}$, or N$_2$O, are biosignatures on Earth (see e.g. Des Marais et al. 2002; Kaltenegger et al. 2010a and reference therein). Although not a clear indicative for the presence of life, H$_2$O is essential for life. Simulations of the Earth’s spectrum as a transiting exoplanet (Ehrenreich et al. 2006; Kaltenegger & Traub 2009; Pallé et al. 2009; Vidal-Madjar et al. 2010; Rauer et al. 2011; García Muñoz et al. 2012; Hedelt et al. 2013) have focused primarily on the visible (VIS) to the infrared (IR), the wavelength range of JWST (600-5000 nm). No models of spectroscopic signatures of a transiting Earth have yet been computed from the mid- (MUV) to the far-ultraviolet (FUV). Which molecular signatures dominate this spectral range? In this paper, we present a model of a transiting Earth’s transmission spectrum from 115 to 1000 nm (UV-NIR) during primary eclipse. While no UV missions are currently in preparation, this model can serve as a basis for future UV mission concept studies. Model description {#model} ================= To simulate the spectroscopic signatures of an Earth-analog transiting its star, we modified the Smithsonian Astrophysical Observatory 1998 (SAO98) radiative transfer code (see Traub & Stier 1976; Johnson et al. 1995; Traub & Jucks 2002; Kaltenegger & Traub 2009 and references therein for details), which computes the atmospheric transmission of stellar radiation at high spectral resolution from a molecular line list database. Updates include a new database of continuous absorber’s cross sections, as well as N$_2$, O$_2$, Ar, and CO$_2$ Rayleigh scattering cross sections from the ultraviolet (UV) to the near-infrared (NIR). A new module interpolates these cross sections and derives resulting optical depths according to the mole fraction of the continuous absorbers and the Rayleigh scatterers in each atmospheric layer. We also compute the deflection of rays by atmospheric refraction to exclude atmospheric regions for which no rays from the star can reach the observer due to the observing geometry. Our database of continuous absorbers is based on the MPI-Mainz-UV-VIS Spectral Atlas of Gaseous Molecules[^1]. For each molecular species of interest (O$_2$, O$_3$, CO$_2$, CO, CH$_4$, H$_2$O, NO$_2$, N$_2$O, and SO$_2$), we created model cross sections composed of several measured cross sections from different spectral regions, at different temperatures when measurements are available, with priority given to higher spectral resolution measurements (see Table \[tbl\_crsc\]). We compute absorption optical depths for different altitudes in the atmosphere using the cross section model with the closest temperature to that of the atmospheric layer considered. Note that we do not consider line absorption from atomic or ionic species which could produce very narrow but possibly detectable features at high spectral resolution (see also Snellen et al. 2013). The Rayleigh cross sections, $\sigma_R$, of N$_2$, O$_2$, Ar, and CO$_2$, which make-up 99.999% of the Earth’s atmosphere, are computed with $$\label{rayl} {\sigma_{R}} = \frac{32\pi^{3}}{3} \left( \frac{{\nu_{0}}}{n_{0}} \right)^{2} w^{4} F_K ,$$ where $\nu_0$ is the refractivity at standard pressure and temperature (or standard refractivity) of the molecular species, $w$ is the wavenumber, $F_K$ is the King correction factor, and $n_{0}$ is Loschmidt’s constant. Various parametrized functions are used to describe the spectral dependence of $\nu_0$ and $F_K$. Table \[tbl\_rayl\] gives references for the functional form of both parameters, as well as their spectral region. The transmission of each atmospheric layer is computed with Beer’s law from all optical depths. We use disc-averaged quantities for our model atmosphere. We use a present-day Earth vertical composition (Kaltenegger et al. (2010b) for SO$_2$; Lodders & Fegley, Jr. (1998) for Ar; and Cox (2000) for all other molecules) up to 130 km altitude, unless specified otherwise. Above 130 km, we assume constant mole fraction with height for all the molecules except for SO$_2$ which we fix at zero, and for N$_2$, O$_2$, and Ar which are described below. Below 100 km, we use the US 1976 atmosphere (COESA 1976) as the temperature-pressure profile. Above 100 km, the atmospheric density is sensitive to and increases with solar activity (Hedin 1987). We use the tabulated results of the MSIS-86 model, for solar maximum (Table A1.2) and solar minimum conditions (Table A1.1) published in Rees (1989), to derive the atmospheric density, pressure, and mole fractions for N$_2$, O$_2$, and Ar above 100 km. We run our simulations in two different spectral regimes. In the VIS-NIR, from 10000 to 25000 cm$^{-1}$ (400-1000 nm), we use a 0.05 cm$^{-1}$ grid, while in the UV from 25000 to 90000 cm$^{-1}$ (111-400 nm), we use a 0.5 cm$^{-1}$ grid. For displaying the results, the VIS-NIR and the UV simulations are binned on a 4 cm$^{-1}$ and a 20 cm$^{-1}$ grid, respectively. The choice in spectral resolution impacts predominantly the detectability of spectral features. The column abundance of each species along a given ray is computed taking into account refraction, tracing specified rays from the observer back to their source. Each ray intersects the top of the model atmosphere with an impact parameter $b$, the projected radial distance of the ray to the center of the planetary disc as viewed by the observer. As rays travel through the planetary atmosphere, they are bent by refraction along paths define by an invariant $L = (1 + \nu(r)) r \sin\theta(r)$ where both the zenith angle, $\theta(r)$, of the ray, and the refractivity, $\nu(r)$, are functions of the radial position of the ray with respect to the center of the planet. The refractivity is given by $$\label{refrac} \nu(r) = \left( \frac{n(r)}{n_{0}} \right) \sum_{j} f_{j}(r) {\nu_{0}}_{j} = \left( \frac{n(r)}{n_{0}} \right) \nu_{0}(r) ,$$ where ${\nu_{0}}_{j}$ is the standard refractivity of the j$^{th}$ molecular species while $\nu_{0}(r)$ is that of the atmosphere, $n(r)$ is the local number density, and $f_{j}(r)$ is the mole fraction of the j$^{th}$ species. Here, we only consider the main contributor to the refractivity (N$_2$, O$_2$, Ar, and CO$_2$) which are well-mixed in the Earth’s atmosphere, and fix the standard refractivity at all altitudes at its surface value. If we assume a zero refractivity at the top of the atmosphere, the minimum radial position from the planet’s center, $r_{min}$, that can be reached by a ray is related to its impact parameter by $$\label{refpath} L = (1 + \nu(r_{min})) r_{min} = R_{top} \sin\theta_{0} = b ,$$ where $R_{top}$ is the radial position of the top of the atmosphere and $\theta_{0}$ is the zenith angle of the ray at the top of the atmosphere. Note that $b$ is always larger than $r_{min}$, therefore the planet appears slightly larger to a distant observer. For each ray, we specify $r_{min}$, compute $\nu(r_{min})$, and obtain the corresponding impact parameter. Then, each ray is traced through the atmosphere every 0.1 km altitude increment, and column abundances, average mole fractions, as well as cumulative deflection along the ray are computed for each atmospheric layer (Johnson et al. 1995; Kaltenegger & Traub 2009). We characterize the transmission spectrum of the exoplanet using effective atmospheric thickness, $\Delta z_{eff}$, the increase in planetary radius due to atmospheric absorption during primary eclipse. To compute $\Delta z_{eff}$ for an exoplanet, we first specify $r_{min}$ for $N$ rays spaced in constant altitude increments over the atmospheric region of interest. We then compute the transmission, $T$, and impact parameter, $b$, of each ray through the atmosphere, and finally use, $$\begin{aligned} R_{eff}^{2} = R_{top}^{2} - \sum_{i = 1}^{N} \left( \frac{T_{i+1} + T_{i}}{2} \right) (b_{i+1}^{2} - b_{i}^{2}) \label{reff} \\ R_{top} = R_{p} + \Delta z_{atm} \\ \Delta z_{eff} = R_{eff} - R_{p} , \end{aligned}$$ where $R_{eff}$ is the effective radius of the planet, $R_{top}$ is the radial position of the top of the atmosphere, $R_{p}$ is the planetary radius (6371 km), $\Delta z_{atm}$ is the thickness of the atmosphere, and $i$ denotes the ray considered. Note that $(N+1)$ refer to a ray that grazes the top of the atmosphere. The rays define $N$ projected annuli whose transmission is the average of the values at the borders of the annulus. The top of the atmosphere is defined where the transmission is 1, and no bending occurs ($b_{N+1} = R_{top}$). We choose R$_{top}$ where atmospheric absorption and refraction are negligible, and use 100 km in the VIS-NIR, and 200 km in the UV for $\Delta z_{atm}$. To first order, the total deflection of a ray through an atmosphere is proportional to the refractivity of the deepest atmospheric layer reached by a ray (Goldsmith 1963). The planetary atmosphere density increases exponentially with depth, therefore some of the deeper atmospheric regions can bend all rays away from the observer (see e.g. Sidis & Sari 2010, García Muñoz et al. 2012), and will not be sampled by the observations. At which altitudes this occurs depends on the angular extent of the star with respect to the planet. For an Earth-Sun analog, rays that reach a distant observer are deflected on average no more than 0.269$\degr$. We calculate that the lowest altitude reached by these grazing rays range from about 14.62 km at 115 nm, 13.86 km at 198 nm (shortest wavelength for which all used molecular standard refractivities are measured), to 12.95 km at 400 nm, and 12.75 km at 1000 nm. As this altitude is relatively constant in the VIS-NIR, we incorporate this effect in our model by excluding atmospheric layers below 12.75 km. To determine the effective planetary radius, we choose standard refractivities representative of the lowest opacities within each spectral region: 2.88$\times10^{-4}$ for the VIS-NIR, and 3.00$\times10^{-4}$ for the UV. We use 80 rays from 12.75 to 100 km in the VIS-NIR, and 80 rays from 12.75 to 200 km altitude in the UV. In the UV, the lowest atmospheric layers have a negligible transmission, thus the exact exclusion value of the lowest atmospheric layer, calculated to be between 14.62 and 12.75 km, do not impact the modeled UV spectrum. Results and discussion {#discussion} ====================== The increase in planetary radius due to the additional atmospheric absorption of a transiting Earth-analog is shown in Fig. \[spectrum\] from 115 to 1000 nm. The individual contribution of Rayleigh scattering by N$_2$, O$_2$, Ar, and CO$_2$ is also shown, with and without the effect of refraction by these same species, respectively. The individual contribution of each species, shown both in the lower panel of Fig. \[spectrum\] and in Fig. \[absorbers\], are computed by sampling all atmospheric layers down to the surface, assuming the species considered is the only one with a non-zero opacity. In the absence of absorption, the effective atmospheric thickness is about 1.8 km, rather than zero, because the bending of the rays due to refraction makes the planet appear larger to a distant observer. The spectral region shortward of 200 nm is shaped by O$_2$ absorption and depends on solar activity. Amongst the strongest O$_2$ features are two narrow peaks around 120.5, and 124.4 nm, which, increase the planetary radius by 179-185 and 191-195 km, respectively. The strongest O$_2$ feature, the broad Schumann-Runge continuum, increases the planetary radius by more than 150 km from 134.4 to 165.5 nm, and peaks around 177-183 km. The Schumann-Runge bands, from 180 to 200 nm, create maximum variations of 30 km in the effective planetary radius. O$_2$ features can also be seen in the VIS-NIR, but these are much smaller than in the UV. Two narrows peaks around 687.0 and 760.3 nm increase the planetary radius to about 27 km, at the spectral resolution of the simulation. Ozone absorbs in two different broad spectral regions in the UV-NIR increasing the planetary radius by 66 km around 255 nm (Hartley band), and 31 km around 602 nm (Chappuis band). Narrow ozone absorption, from 310 to 360 nm (Huggins band), produce variations in the effective planetary radius no larger than 2.5 km. Weak ozone bands are also present throughout the VIS-NIR: all features not specifically identified on the small VIS-NIR panel in Fig. \[spectrum\] are O$_3$ features, and show changes in the effective planetary radius on the order of 1 km. NO$_2$ and H$_2$O are the only other molecular absorbers that create observable features in the spectrum (Fig. \[spectrum\], small VIS-NIR panel). NO$_2$ shows a very weak band system in the visible shortward of 510 nm, which produces less than 1 km variations in the effective planetary radius. H$_2$O features are observable only around 940 nm, where they increase the effective planetary radius to about 14.5 km. Rayleigh scattering (Fig. \[spectrum\]) increases the planetary radius by about 68 km at 115 nm, 27 km at 400 nm, and 5.5 km at 1000 nm, and dominates the spectrum from about 360 to 510 nm where few molecules in the Earth’s atmosphere absorb, and refraction is not yet the dominant effect. In this spectral region, NO$_2$ is the dominant molecular absorber but its absorption is much weaker than Rayleigh scattering. The lowest 12.75 km of the atmosphere is not accessible to a distant observer because no rays below that altitude can reach the observer in a transiting geometry for an Earth-Sun analog. Clouds located below that altitude do not influence the spectrum and can therefore be ignored in this geometry. Figure \[spectrum\] also shows that refraction influences the observable spectrum for wavelengths larger than 400 nm. The combined effects of refraction and Rayleigh scattering increases the planetary radius by about 27 km at 400 nm, 16 km at 700 nm, and 14 km at 1000 nm. In the UV, the lowest 12.75 km of the atmosphere have negligible transmission, so this atmospheric region can not be seen by a distant observer irrespective of refraction. Both Rayleigh scattering and refraction can mask some of the signatures from molecular species. For instance, the individual contribution of the H$_2$O band in the 900-1000 nm region can increase the planetary radius by about 10 km. However, H$_2$O is concentrated in the lowest 10-15 km of the Earth’s atmosphere, the troposphere, hence its amount above 12.75 km increases the planetary radius above the refraction threshold only by about 1 km around 940 nm. The continuum around the visible O$_2$ features is due to the combined effects of Rayleigh scattering, ozone absorption, and refraction. It increases the effective planetary radius by about 21 and 17 km around 687.0 and 760.3 nm, respectively. The visible O$_2$ features add 6 and 10 km to the continuum values, at the spectral resolution of the simulation. [Figure \[data\] compares our effective model from Fig. \[spectrum\] with atmospheric thickness with the one deduced by Vidal-Madjar et al. (2010) from Lunar eclipse data obtained in the penumbra. The contrast of the two O$_2$ features are comparable with those in the data. However, there is a slight offset (about 3.5 km) and a tilt in the main O$_3$ absorption profile. Note that, Vidal-Madjar et al. (2010) estimate that several sources of systematic errors and statistical uncertainties prevent them from obtaining absolute values better than $\pm$2.5 km. Also, we do not include limb darkening in our calculations. However, for a transiting Earth, the atmosphere eclipses an annular region on the Sun, whereas during Lunar eclipse observations, it eclipses a band across the Sun (see Fig. 4 in Vidal-Madjar et al. 2010), leading to different limb darkening effects.]{} Many molecules, such as CO$_2$, H$_2$O, CH$_4$, and CO, absorb ultraviolet radiation shortward of 200 nm (see Fig. \[absorbers\]). However, for Earth, the O$_2$ absorption dominates in this region and effectively masks their signatures. For planets without molecular oxygen, the far UV would still show strong absorption features that increase the planet’s effective radius by a higher percentage than in the VIS to NIR wavelength range. Conclusions =========== The UV-NIR spectrum (Fig. \[spectrum\]) of a transiting Earth-like exoplanet can be divided into 5 broad spectral regions characterized by the species or process that predominantly increase the planet’s radius: one O$_2$ region (115-200 nm), two O$_3$ regions (200-360 nm and 510-700 nm), one Rayleigh scattering region (360-510 nm), and one refraction region (700-1000 nm). From 115 to 200 nm, O$_2$ absorption increases the effective planetary radius by up to 177-183 km, except for a narrow feature at 124.4 nm where it goes up to 191-195 km, depending on solar conditions. Ozone increases the effective planetary radius up to 66 km in the 200-360 nm region, and up to 31 km in the 510-700 nm region. From 360 to 510 nm, Rayleigh scattering predominantly increases the effective planetary radius up to 31 km. Above 700 nm, refraction and Rayleigh scattering increase the effective planetary radius to a minimum of 14 km, masking H$_2$O bands which only produce a further increase of at most 1 km. Narrow O$_2$ absorption bands around 687.0 and 760.3 nm, both increase the effective planetary radius by 27 km, that is 6 and 10 km above the continuum, respectively. NO$_2$ only produces variations on the order of 1 km or less above the continuum between 400 and 510 nm. One can use the NIR as a baseline against which the other regions in the UV-NIR can be compared to determine that an atmosphere exists. From the peak of the O$_2$ Schumann-Runge continuum in the FUV, to the NIR continuum, the effective planetary radius changes by about 166 km, which translates into a 2.6% change. The increase in effective radius of the Earth in the UV due to O$_2$ absorption shows that this wavelength range is very interesting for future space missions. 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M. 2000, , 145, 289 Yoshino, K., Cheung, A. S.-C., Esmond, J. R., Parkinson, W. H., Freeman, D. E., Guberman, S. L., Jenouvrier, A., Coquart, B., & Mérienne, M. F. 1988, , 36, 1469 Yoshino, K., Esmond, J. R., Cheung, A. S.-C., Freeman, D. E., & Parkinson, W. H. 1992, , 40, 185 Zelikoff, M., Watanabe, K., & Inn, E. C. Y. 1953, , 21, 1643 [cccc]{} O$_{2}$ & 303 & 115.0 - 179.2 & Lu et al. (2010)\ & 300 & 179.2 - 203.0 & Yoshino et al. (1992)\ & 298 & 203.0 - 240.5 & Yoshino et al. (1988)\ & 298 & 240.5 - 294.0 & Fally et al. (2000)\ O$_{3}$ & 298 & 110.4 - 150.0 & Mason et al. (1996)\ & 298 & 150.0 - 194.0 & Ackerman (1971)\ & 218 & 194.0 - 230.0 & Brion et al. (1993)\ & 293, 273, 243, 223 & 230.0 - 1070.0 & Bogumil et al. (2003)\ NO$_{2}$ & 298 & 15.5 - 192.0 & Au & Brion (1997)\ & 298 & 192.0 - 200.0 & Nakayama et al. (1959)\ & 298 & 200.0 - 219.0 & Schneider et al. (1987)\ & 293 & 219.0 - 500.01 & Jenouvrier et al. (1996) + Mérienne et al. (1995)\ & 293, 273, 243, 223 & 500.01 - 930.1 & Bogumil et al. (2003)\ CO & 298 & 6.2 - 177.0 & Chan et al. (1993)\ CO$_{2}$ & 300 & 0.125 - 201.6 & Huestis & Berkowitz (2010)\ H$_{2}$O & 298 & 114.8 - 193.9 & Mota et al. (2005)\ CH$_{4}$ & 295 & 120.0 - 142.5 & Chen & Wu (2004)\ & 295 & 142.5 - 152.0 & Lee et al. (2001)\ N$_{2}$O & 298 & 108.2 - 172.5 & Zelikoff et al. (1953)\ & 302, 263, 243, 225, 194 & 172.5 - 240.0 & Selwyn et al. (1977)\ SO$_{2}$ & 293 & 106.1 - 171.95 & Manatt & Lane (1993)\ & 295 & 171.95 - 262.53 & Wu et al. (2000)\ & 358, 338, 318, 298 & 262.53 - 416.66 & Vandaele et al. (2009)\ [ccc]{} N$_{2}$ & 149 - 189 & Griesmann & Burnett (1999)\ & 189 - 2060 & Bates (1984)\ O$_{2}$ & 198 - 546 & Bates (1984)\ Ar & 140 - 2100 & Bideau-Mehu et al. (1981)\ CO$_{2}$ & 180 - 1700 & Bideau-Mehu et al. (1973)\ N$_{2}$ & $\geq$ 200 & Bates (1984)\ O$_{2}$ & $\geq$ 200 & Bates (1984)\ Ar & all & Bates (1984)\ CO$_{2}$ & 180 - 1700 & Sneep & Ubachs (2005)\ [^1]: Hannelore Keller-Rudek, Geert K. Moortgat, MPI-Mainz-UV-VIS Spectral Atlas of Gaseous Molecules, www.atmosphere.mpg.de/spectral-atlas-mainz	{ "pile_set_name": "ArXiv" }
Order entered April 12, 2016 In The Court of Appeals Fifth District of Texas at Dallas No. 05-15-00963-CR CORNELIUS TURNER, Appellant V. THE STATE OF TEXAS, Appellee On Appeal from the 194th Judicial District Court Dallas County, Texas Trial Court Cause No. F15-52355-M ORDER The Court GRANTS appellant’s April 11, 2016 motion to extend time to file his brief. We ORDER appellant’s brief filed as of the date of this order. /s/ LANA MYERS JUSTICE	{ "pile_set_name": "FreeLaw" }
1. Introduction =============== Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy derived from precursors of plasmacytoid dendritic cells. This disease entity was recognized in the 2008 World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues, where it was separately included in the group of acute myeloid leukemia (AML) and related precursor neoplasm.^\[[@R1]\]^ This disease almost always presents with cutaneous involvement as the 1st manifestation, with subsequent or concurrent spread to bone marrow and peripheral blood.^\[[@R2]--[@R4]\]^ Although it is extremely rare, a minority but significant proportion of patients present without skin lesions. Furthermore, BPDCN present at other sites has not been yet reported. To date, nasal cavity lesion as the 1st manifestation in BPDCN has not been reported yet. Here we report 2 cases of BPDCN preseting as masses of nasal cavity and nasopharynx with leukemic manifestation without skin lesion in adolescent patients. In addition, we briefly reviewed previous cases of BPDCN without skin manifestation. 2. Case reports =============== 2.1. Case 1 ----------- The 1st patient was a 16-year-old girl who presented with recurrent epistaxis. She had no significant medical history or family history of cancer or known genetic disorders. On sinonasal computed tomography (CT), a 2.9-cm sized, polypoid mass was noted in the nasal cavity. Cutaneous examination was unremarkable. Biopsy of this mass was performed. Histologically, the nasal mucosa diffusely expanded. It was infiltrated by atypical lymphoid infiltrates. Infiltrative tumor cells were diffuse, monomorphic medium-sized cells with fine chromatin, irregular nuclei, and scanty cytoplasm, showing blastic morphology. Mucosal glands often became widely spaced and lost. An angiocentric and angiodestructive growth pattern were not identified. Mucosal ulceration and necrosis were not identified either (Fig. [1](#F1){ref-type="fig"}A, B). Immunohistochemically, atypical lymphoid cells were positive for CD2, CD4, CD56, and CD123 with focal weak staining for TCL-1, but negative for CD20, CD3, TdT, MPO, and EBV-encoded small RNA (Fig. [1](#F1){ref-type="fig"}C--F). No clonal TCRG or IgH gene rearrangement was detected. Peripheral blood work-up revealed pancytopenia while bone marrow biopsy revealed involvement of neoplastic cells, similar to histology and immunohistochemical findings of nasal cavity mass. ![Histologic and immunohistochemical findings of blastic plasmacytoid dendritic cell neoplasm (BPDCN) of the 1st case. (A) At low magnification, microscopic examination reveals that the nasal mucosa is diffusely expanded and infiltrated by atypical lymphoid infiltrates. (B) Infiltrative tumor cells are diffuse, monomorphic medium-sized cells with fine chromatin, irregular nuclei, and scanty cytoplasm, reminiscent of blasts. Immunohistochemically, these tumor cells show immunoreactivity for CD4 (C), CD56 (D), CD123 (E), and focal TCL1 (F).](medi-98-e14344-g001){#F1} The patient was treated with induction chemotherapy with Berlin-Frankfurt-Münster regimen used for acute lymphoblastic leukemia. She achieved complete remission. After the 1st remission, she received allogenic peripheral blood stem-cell transplant (PBSCT). No relapse was observed at 14 months after transplantation. Interestingly, she had no skin lesions at initial diagnosis or during the course of their illness. 2.2. Case 2 ----------- The 2nd patient was a previous healthy 17-year-old female who presented with nasal obstruction and voice change for a month. CT scans revealed a large enhancing nasopharyngeal mass involving adenoid and several small indeterminate lymph nodes at the neck. Biopsy of the nasopharyngeal mass was performed. Microscopically, the nasopharyngeal mucosa was entirely replaced by diffuse atypical lymphoid cells with blastoid morphology (Fig. [2](#F2){ref-type="fig"}A, B). Immunohistochemically, these atypical lymphoid cells were positive for CD4, weak CD56, CD123, TCL1, and TdT, but negative for CD20, CD3, CD8, and CD1a (Fig. [2](#F2){ref-type="fig"}C--F). Peripheral blood count results were as follows: WBC, 4890/μL; Hb, 11 g/dL; and platelet, 127/μL. Blast was measured 13% of WBCs. Bone marrow biopsy showed infiltration of blastic tumor cells and demonstrated increase of CD4+, CD56+, TdT+, CD10−, and CD34− blasts up to 95% of total nucleated cells. Abdominal scan revealed mild hepatosplenomegaly while PET scan suggested hypermetabolism at nasopharynx, systemic lymph nodes, breast, liver, spleen, and bone marrow. Based on these findings, the diagnosis was most consistent with BPDCN for the 2 cases. ![Histologic and immunohistochemical findings of blastic plasmacytoid dendritic cell neoplasm (BPDCN) of the 2nd case. (A) At low magnification, the nasopharyngeal mucosa is entirely replaced by diffuse atypical lymphoid cells microscopically. (B) Diffuse monomorphous infiltrate of medium-sized blast cells showing irregular nuclei with scanty cytoplasm. Immunohistochemically, these atypical lymphoid cells are positive for CD4 (C), weak CD56 (D), CD123 (E), and TCL1 (F).](medi-98-e14344-g002){#F2} The patient was treated with AraC/Idarubicin (AId) induction chemotherapy. However, persistent blasts (32.5% of total nucleated cells) were observed in bone marrow biopsy. She is now taking Cladribin/Ara-C/G-CSF (CLAG) reinduction chemotherapy. After the remission, she received allogenic PBSCT. No relapse was observed at 11 months after transplantation. Interestingly, she also had no skin lesions at initial diagnosis or during the course of their illness. 3. Discussion ============= In this study, we report 2 cases of BPDCN in adolescent patients who had unusual extracutaneous manifestation without skin lesion. Clinicopathologically, the differential diagnosis of our cases included extranodal NK/T-cell lymphoma, acute leukemia of ambiguous lineage, and NK lymphoblastic leukemia/lymphoma. Nasal cavity lesion as the 1st clinical manifestation and CD56-positive tumor cells raised the possibility of extranodal NK/T-cell lymphoma. However, absence of angioinvasion, no expression of cytoplasmic CD3, and cytotoxic granule proteins such as granzyme B and no association with EBV ruled out the diagnosis of extranodal NK/T-cell lymphoma. According to the 2017 WHO criteria, tumors that express some immunophenotypic features of BPDCN but not all immunohistochemical markers may be better classified as "acute leukemia of ambiguous lineage."^\[[@R5]\]^ At present, NK lymphoblastic leukemia/lymphoma is considered a provisional entity. It should be diagnosed after ruling out BPDCN. Blastic cells expressing CD56 and CD2 raised the possibility of NK lymphoblastic leukemia/lymphoma. However, CD4 positivity made it doubtful for such diagnosis. In such cases, immunohistochemical analysis including the most characteristic and reliable marker is essential for the diagnosis of BPDCN. BPDCN was initially characterized by the expression of CD4, CD56, and the lack of B cells, T cells, myeloid or monocytic cells, and NK cell markers. More specific plasmacytoid dendritic cell markers (CD123, CD303, and TCL1) have been recently used to diagnose BPDCN.^\[[@R6],[@R7]\]^ Since they are concomitantly expressed in only 46% of patients, it has been proposed that diagnosis of BPDCN can be made when 4 of these 5 markers (CD4, CD56, CD123, CD303, and TCL1) are expressed.^\[[@R8]\]^ Although tumor cells of the 1st case showed focal positive for TCL1, both of 2 cases showed all 5 markers except CD303 which was not performed in our institution. Therefore, our 2 cases were histologically diagnosed with BPDCN. The BPDCN without cutaneous lesion is exceedingly rare to diagnose. Patients without cutaneous involvement have been described in the literature. Table [1](#T1){ref-type="table"} presents a summary of 39 published cases of BPDN without skin involvement. Bone marrow involvement was observed in the majority of patients at diagnosis. Through hematopathology consultation service at the National Institutes of Health, Jegalian et al^\[[@R6]\]^ have evaluated 55 BPDCN cases. Among them, 9 (16%) patients lacked cutaneous disease at presentation. A retrospective multicenter study of 43 patients (the GIMEMA study) presenting with leukemic manifestation was reported in 2012.^\[[@R14]\]^ Among 43 patients, 8 (19%) cases had no cutaneous manifestations.^\[[@R14]\]^ In these patients lacking skin involvement, other extracutaneous and extramedullary sites in lymph node, spleen, and liver are most commonly observed. Rauh et al^\[[@R13]\]^ have demonstrated that patients with BPDN without skin involvement and leukemic presentation show adverse prognosis than those with skin involvement. Interestingly, no case of BPDCN presenting with nasal cavity mass has been reported. It is of note that we identified nasal cavity as the unusual site of BPDCN. ###### Summary of 39 published cases of BPDCN without skin involvement in the literatures. ![](medi-98-e14344-g003) Lack of traditional lineage-specific markers for B cells, T cells, myeloid, or monocytic cells with the absence of cutaneous manifestation has diagnostic challenge. The diagnosis of BPDCN is usually suspected in patients with skin lesion. Despite the absence of skin lesions and tumor involvement of unusual site, the diagnosis of BPDCN should not be ruled out since a minority of cases present with leukemia without skin involvement. Accurate recognition of BPDCN is important because of its different clinical course and outcome as well as treatment strategy compared to other differential diagnoses. In this regard, our 2 cases are significant as they have unusual presentation with leukemia in the absence of characteristic cutaneous manifestations. 4. Conclusion ============= In conclusion, our 2 cases demonstrate an atypical presentation without skin manifestation, characteristic of BPDCN. Although BPDCN without skin lesion is extremely rare, it should be considered in the differential diagnosis of blastic leukemia with an undifferentiated and ambiguous immunophenotype. Author contributions ==================== Conceptualization: Seung Eun Lee, Yoon Kyung Jeon, Wook Youn Kim. Supervision: Yoon Kyung Jeon, Wook Youn Kim. Visualization: Dohee Kwon, Ha Young Park. Writing -- original draft: Seung Eun Lee. Writing -- review & editing: Seung Eun Lee, Yoon Kyung Jeon, Wook Youn Kim. Abbreviations: AML = acute myeloid leukemia, BPDCN = blastic plasmacytoid dendritic cell neoplasm, CT = computed tomography, WHO = World Health Organization. Written informed consent was obtained from the patient for publication of this case report and its accompanying images. The authors have no funding and conflicts of interest to disclose.	{ "pile_set_name": "PubMed Central" }
Q: Using ScheduledExecutorService, How to Start a Thread without waiting for other thread to complete at fixed interval? I want to run a task at every particular interval of time regardless of completion of previous thread. And I've used ScheduledExecutorService with the schedule time at every one second. But the problem is, in my Runnable, If I make thread to sleep for 5 seconds, My ScheduledExecuterService also getting executed in every 5 seconds while it supposed to run each thread at 1 second. It seems like it ScheduledExecuterService is waiting for previous thread to completion. But I want, The task to be triggered at every 1 second no matter what if job inside the task waits for longer time. Here's is my code. public class MyTask implements Runnable { public void run() { System.out.println("hi there at: "+ new java.util.Date()); try { Thread.sleep(5000); } catch (InterruptedException e) { // TODO Auto-generated catch block e.printStackTrace(); } } } And here's my ScheduledExecutorService Code. public class JavaScheduledExecutorServiceExample { public static void main(String[] args) { ScheduledExecutorService execService = Executors.newScheduledThreadPool(5); execService.scheduleAtFixedRate(new MyTask(), 0, 1000, TimeUnit.MILLISECONDS); } } Correct me If I'm doing something wrong. And If I'm wrong, is there any alternative to achieve the same? Providing Any best practices could be more helpful :) A: "If any execution of this task takes longer than its period, then subsequent executions may start late, but will not concurrently execute." The behavior you are seeing is consistent with the javadocs I believe this will perform the way you specified: public class JavaScheduledExecutorServiceExample { private static ScheduledExecutorService execService = null; private static int timesAsleep = 0; public static class MyTask implements Runnable { public void run() { System.out.println("hi there at: "+ new java.util.Date()); // schedule again execService.schedule(new MyTask(), 1000, TimeUnit.MILLISECONDS); try { int i = timesAsleep; timesAsleep++; System.out.println("asleep " + i + "----------------------"); Thread.sleep(5000); System.out.println("awoke " + i + "----------------------"); } catch (InterruptedException e) { // TODO Auto-generated catch block e.printStackTrace(); } } } public static void main(String[] args) { execService = Executors.newScheduledThreadPool(5); execService.schedule(new MyTask(), 1000, TimeUnit.MILLISECONDS); } } Notice the use schedule() instead of scheduleAtFixedRate() on the ScheduledExecutorService instance. It also schedules the next task as soon as it starts the new task.	{ "pile_set_name": "StackExchange" }
Erik Schelzig: Who does he think he is? You know it's time for state lawmakers to go home when they start fainting during their sessions. House Speaker Kent Williams, who is diabetic, collapsed this morning as he presided from the podium. Lawmakers crowded around the fallen Williams, and he hopped up a few minutes later and drank a little orange juice. On his way to the Legislative Plaza cafeteria, he smiled and said he was OK. Just a case of low blood sugar, he said. He returned to the House podium this afternoon. "Like a dummy, I didn't eat breakfast this morning," Williams said. "I've been diabetic for 20 years and that's only the second time that's happened, that my blood sugar got that low. But I'm fine." In other news, state troopers dragged the AP's Erik Schelzig out of the chamber as he was using his cell phone to take pictures of the collapsed Williams. Taking pictures isn't against House rules, but the troopers apparently got a little carried away in the excitement. A few legislators were in Schelzig's face about it, too. One of them called him "a piece of shit." Another one threatened to "whup his ass." "They stormed in with the troopers and everything and dragged him out," Rep. Gerald McCormick, R-Chattanooga, told us. "The speaker was passed out on the floor and I guess some people thought it was disrespectful" to take pictures of it. Something tells Pith these lawmakers might live to regret starting this little fight with the press. Update: The press corps is in a tizzy over all this and threatening reprisals. "These are the tactics of Afghan opium warlords when they don't like shit," one writer says. Pith isn't sure we can control this volatile situation.	{ "pile_set_name": "OpenWebText2" }
Hundreds of leads in case of missing Maine girl Authorities in Waterville on Monday offered a $30,000 reward for information that would lead investigators to Ayla Reynolds. Story highlights 20-month-old Ayla Reynolds was last reported seen more than a week ago Her father said he doesn't know what happened to her Ayla was at his home when she was last seen December 16 Police said Wednesday they have received 370 leads in the disappearance of a 20-month-old Maine girl, whose father reiterated he doesn't know what happened to her. "It is important the public hear it from me personally that I have no idea what happened to Ayla (Reynolds) and that I am not hiding," Justin Dipietro said in a statement. Authorities in Waterville on Monday offered a $30,000 reward for information that would lead investigators to find the girl. Police Chief Joseph Massey said the last reported sighting of the toddler was on December 16, when her father said he put her to bed. Police are confident that someone took Ayla from the house, the chief said. Ayla is described as having blond hair, being about 2 feet, 9 inches tall, and weighing 30 pounds. She was last seen wearing green pajamas with white polka dots and the words "Daddy's Princess" across the front. When she disappeared, the girl had her arm in a soft cast. The toddler's mother, Trista Reynolds, told HLN's Nancy Grace last week that Dipietro waited almost 24 hours to take Ayla to the emergency room after the girl broke her arm several weeks ago. Reynolds also said her daughter often would return with bruises after visits with Dipietro. Dipietro, 24, said he would never do anything to hurt Ayla, who was in his sole custody when she disappeared. "The questions of Ayla's arm or bruises or anything else being said are simply ludicrous," Dipietro said in his statement. "I would never want anyone to spend even a minute in my shoes. No one should ever have to experience this." Police searched Dipietro's home with his permission. Reynolds, 23, on December 15, the day before Ayla went missing, filed a complaint seeking sole custody. She told HLN she didn't tell Dipietro she was going to court because he was "vindictive" and "verbally abusive." "Now, me and him had had the discussion within that week that he told me himself that he was going to file the custody papers against me," Reynolds said. "So I decided to go and file against him." The mother told Grace that she had raised Ayla for 18 months and Dipietro became involved only after "I needed to go and get a little bit of help for myself." She told HLN she underwent rehab. Police do not have anyone connected to the case in custody. Dipietro, who released his first statement last week, Wednesday thanked those who are aiding the effort to find his daughter. "I have to believe that Ayla is with somebody and I just want that person to find the courage to do the right thing and find a way to return her safely," the father said. "The truth is the truth and when the case is solved it will be out there. Until then, please try to remain positive and hopeful as I remain confident that Ayla will return safely."	{ "pile_set_name": "Pile-CC" }
Q: Соединить две окружности. В чём ошибка? Пытаюсь повторить полигон, тот что изображен зеленой линией на рисунке ниже. Пользовался этими советами: Совет первый Совет второй Оба дают результат с некоторым смещением вдоль окружностей. Помогите, пожалуйста, в чем моя ошибка. Jsfiddle проект Писал на JS, но подойдёт любое другое решение. Даже без кода, в чистой теории, в чем неверен мой подход. // A: Поскольку нужны только внешние касательные (могут быть ещё внутренние), то подход может быть не слишком сложным: Пусть центр большей окружности CR, меньшей cr. Вектор разности d, его длина и нормализованный вектор: d = cr - CR dlen = length(d) ud = d / dlen Общие касательные к окружностям разного радиуса пересекаются где-то в точке OP. Касательная вместе с радиусами к точкам касания образует два подобных прямоугольных треугольника (поскольку радиус перпендикулярен касательной). Из подобия следует Coeff = R / (R - r) OP = CR + d * Coeff Синус и косинус угла A этого треугольника ca = R / (dlen * Coeff) sa = Sqrt(1-caca) Точки касания большой окружности могут быть получена поворотом вектора udR на A и -A P.x = CR.x + ca * R * ud.x + sa * R * ud.y P.y = CR.y - sa * R * ud.x + ca * R * ud.y Q.x = CR.x + ca * R * ud.x - sa * R * ud.y Q.y = CR.y + sa * R * ud.x + ca * R * ud.y Аналогично для малой окружности с использованием её центра и радиуса. Тест: fiddle: (подправил последовательность точек и знаки углов) let c1 = this.state.circles[0]; let c2 = this.state.circles[1]; let l = getVectorLen(c1,c2); let v = {x: c2.x-c1.x, y: c2.y-c1.y}; let uv = {x: v.x / l, y: v.y / l}; let ca = (c2.r - c1.r) / l; let sa = Math.sqrt(1 - caca); let ps = [ c1.x - ca c1.r * uv.x - sa * c1.r * uv.y, c1.y + sa * c1.r * uv.x - ca * c1.r * uv.y, c1.x - ca * c1.r * uv.x + sa * c1.r * uv.y, c1.y - sa * c1.r * uv.x - ca * c1.r * uv.y, c2.x - ca * c2.r * uv.x + sa * c2.r * uv.y, c2.y - sa * c2.r * uv.x - ca * c2.r * uv.y, c2.x - ca * c2.r * uv.x - sa * c2.r * uv.y, c2.y + sa * c2.r * uv.x - ca * c2.r * uv.y ];	{ "pile_set_name": "StackExchange" }
Q: Email hacking/masking prevention Can someone please explain to me how its possible that someone hacks a server and uses its email to send emails from a address thats not listed on the server and how to prevent it. When I look at the mail queue there are emails there from and to yahoo.com accounts, how does this happen and how can I prevent this. Running centos 6, interworx and qmail if that helps. A: This is the nature of how email works, unfortunately. There is nothing preventing you or I from sending an email from any address we choose, this is by design. What we can tell though is the IP address the email originated from in the mail headers, and this will give us an idea of where the original message came from. In the old internet, most mail servers were run as open relays. This means that to send an email from yahoo.com to google.com, you could use any open relay you found on the internet. If the IP got banned, its okay because it isn't your IP, and you could just change relays. Now, with most modern mail servers, this isn't really an option. SMTP servers will only relay a message if you are authenticated, preventing random internet users from abusing your services. The server would accept unauthenticated mail only for users on that particular mail server. Due to this change, spammers now need to completely compromise mail servers in order to abuse them. If an attacker compromises your server, there isn't much you can do to stop them from sending emails short of blocking outbound port 25 on the firewall. If you need to run a legitimate mail server, then this becomes a problem as you would be denying legit email from being sent. Also, I would check your IP against any blacklists. It may have ended up on some lists and you would then need to submit a delist request, including how you resolved the issue.	{ "pile_set_name": "StackExchange" }
1. Introduction =============== Mycobacterium tuberculosis is counted with justification among the most dangerous and successful microorganisms in today's world, especially in developing countries which have become the reservoir of resistant strains (the most burdened countries are in South Africa and East Asia) \[[@B1-molecules-19-00651]\]. These strains are causing the biggest number of problems connected to tuberculosis (TB) treatment \[[@B2-molecules-19-00651]\]. The main problem is resistance. It can be divided into three groups. The first one is called multidrug-resistant TB (MDR-TB) and these microbes are resistant to all first-line antituberculotic drugs (pyrazinamide - PZA, isoniazid - INH, rifampicin - RIF, ethambutol - ETH, streptomycin - STR). The second group is more treacherous. This type of resistance is called extensively or extremely drug-resistant TB (XDR-TB) with the resistance to the first-line anti-TB agents isoniazid and rifampicin together with the resistance to any fluoroquinolone used in the therapy and to at least one of three injectable second-line antituberculotic drugs (amikacin, kanamycin or capreomycin) \[[@B3-molecules-19-00651]\]. The last and the latest category was the most dreaded and was called totally drug-resistant TB (TDR-TB) and the first case was recorded in India \[[@B4-molecules-19-00651]\]. These mycobacterial strains were resistant to all current known therapy. Nowadays, this group has disappeared with the approval of bedaquiline for therapy of resistant forms of tuberculosis. Another problem is connected with the HIV pandemic. These two infectious diseases are influencing each other in a synergic way so this has resulted in efforts to develop new anti-tubercular agents. This work deals with a microwave-assisted synthesis of pyrazinamide analogues with potential antimycobacterial activity. It is caused by the fact that pyrazinamide is counted among the first-line anti-tuberculosis drugs used in current therapy. Its unique ability to kill the dormant forms of Mycobacterium tuberculosis is crucial in shortening the time needed for the treatment, so PZA has sterilizing activity especially in combination with rifampicin \[[@B5-molecules-19-00651]\]. PZA itself has multiple mechanisms of action. The first described was the activation of this prodrug via the enzyme pyrazinamidase (EC 3.5.1.19) to form pyrazinoic acid (POA). This metabolite causes a lowering of the inner compartment pH in mycobacterial cells. This leads to inhibition of membrane transport and then to cellular death \[[@B6-molecules-19-00651],[@B7-molecules-19-00651],[@B8-molecules-19-00651]\]. The gene encoding this enzyme is called pncA gene and its mutation is responsible for the origin of mycobacterial resistance to PZA \[[@B9-molecules-19-00651]\]. The second mechanism of action is connected with fatty acid synthase I (FAS I) (EC 2.3.1.85). It is suggested that the disruption of metabolism can be caused by inhibition of the cell membrane synthesis, which is essential for the survival of Mycobacteria, but this mechanism was mainly rejected for PZA itself by Boshoff because there is only low inhibition \[[@B10-molecules-19-00651]\]. On the other hand, the PZA analogues such as 5‑chloropyrazinamide, esters of pyrazinoic acid and esters of 5‑chloropyrazinoic acid were proven to act in this way \[[@B11-molecules-19-00651],[@B12-molecules-19-00651],[@B13-molecules-19-00651]\]. Recent research has suggested a novel mechanism of action of PZA - inhibition of trans-translation. This process is vital for survival and virulence of Mycobacteria and its inhibition leads to blockage of the proteosynthetic apparatus in ribosomes and to cellular death. These assumptions were proven by Zhang et al. \[[@B14-molecules-19-00651]\]. Although PZA is the first-line antituberculotic drug, it was found that this molecule has exhibited other interesting biological activities such as antifungal, antibacterial, antiviral and antineoplastic effects \[[@B15-molecules-19-00651],[@B16-molecules-19-00651],[@B17-molecules-19-00651],[@B18-molecules-19-00651],[@B19-molecules-19-00651],[@B20-molecules-19-00651]\]. There is another application of PZA derivatives that can be used in agriculture. The most successful pyrazine derivative diquat-dibromide (6,7-dihydrodipyrido\[1,2-a:2\',1\'-c\]pyrazinediium-dibromide), a non-selective, contact herbicide, which has been used to control many submerged and floating aquatic macrophytes, was found to interfere with the photosynthetic process by releasing strong oxidizers that rapidly disrupt and inactivate cells and cellular functions (at present banned in many EU countries) \[[@B21-molecules-19-00651]\]. Many structural variations of pyrazine compounds with herbicidal properties can be found in the patent literature \[[@B22-molecules-19-00651],[@B23-molecules-19-00651],[@B24-molecules-19-00651],[@B25-molecules-19-00651]\]. However, several pyrazine derivatives were also described as inhibitors of Hill reaction which inhibit photosynthetic electron transport (PET) in photosystem (PS) 2 \[[@B18-molecules-19-00651],[@B26-molecules-19-00651]\]. The site of action of these PET inhibitors in the photosynthetic apparatus was situated predominantly on the donor side of PS2, in the section between oxygen evolving complex and intermediate D^·^, i.e., tyrosine radical (Tyr~D~•) occurring on the 161^st^ position in D~2~ protein. Consequently, these compounds can be considered as PS2 herbicides which could have ultimately adverse effect on plant growth. In general, the PET-inhibiting effectiveness of pyrazine derivatives depends on compound lipophilicity and σ Hammett constants of individual substituents. Hosseini et al. studied the electronic and structural descriptors, which are the main factors for the cytotoxicity in the series of substituted N-phenylpyrazine-2-carboxamides \[[@B27-molecules-19-00651]\]. This study is focused on preparation of N-substituted structural and functional derivative of PZA (5-chloro-6-methylpyrazine-2,3-dicarbonitrile) that was treated with ring-substituted benzylamines using the advantages of a microwave reactor. It should be stressed that this type of syntheses has become popular due to its higher yields, shorter reaction times or solvent savings in comparison with conventional organic syntheses \[[@B28-molecules-19-00651]\]. One of the main advantages is the heating. It is uniform through the volume of the sample and the microwaves usually interact with molecules themselves not vessel sides. Another benefit is connected with the temperature reached by the solvent used. The final temperature is usually far higher than the standard boiling point of the solvent when using over- pressurized systems. It is reached and bypassed in seconds. Improved heating usually leads to higher yields and shorter reaction times. There is one limitation for choosing the conditions. It is the polarity of the solvent when the non-polar solvents cannot be used in the way the polar ones can be. If the polar solvent is used in the reaction, there is a direct coupling of microwaves with molecules. More polar solvents have greater ability to interact with microwave radiation. Using the solvents with low polarity (low absorbers) leads to longer times of heating and reaction. On the contrary, if the reagents themselves are polar it could lower the disadvantages of non-polar solvents. Finally there are new approaches to microwave accelerated methods using ionic liquids or solid phase reactions (adsorption on mineral oxides, phase transfer catalysis, neat reactions) \[[@B29-molecules-19-00651]\]. Microwave assisted condensation in polar solvent is used in this work to accelerate the aminodehalogenation reaction. The conditions for the synthesis were proven experimentally. Antimycobacterial activity of the all prepared compounds was determined and compounds were evaluated also in relation to inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. The structure-activity relationships between the chemical structure and in vitro biological activities of evaluated compounds are discussed. 2. Results and Discussion ========================= 2.1. Chemistry -------------- The starting compound 5-chloro-6-methylpyrazine-2,3-dicarbonitrile and the final compounds 1--15 were synthesized according to the general procedure shown in [Scheme 1](#molecules-19-00651-f006){ref-type="scheme"}. The aminodehalogenation reaction of this starting compound and ring-substituted benzylamines yielded a series of 15 secondary amines of which 14 were novel. 5-(Benzylamino)-6-methylpyrazine-2,3-dicarbonitrile (6) was previously synthesised by Takematsu et al. and the reported melting point was 118--119 °C \[[@B30-molecules-19-00651]\]. The compound we obtained melted at 128.7--130.7 °C. This difference can be caused by the mode of crystallization. All reactions were done using microwave reactor with focused field and yields were in the range between 17% and 62%. Lower yields were caused by the purification using preparative chromatography and recrystallization. It is also known that 3-nitro substitution, for which the yield was the lowest, is counted among the electron-withdrawing groups reducing the basicity of the amine nitrogen. Obtained analytical data were fully consistent with the proposed structures. [Table 1](#molecules-19-00651-t001){ref-type="table"} shows the substituents and other data of the synthesized compounds. ![Synthesis of starting compound \[[@B30-molecules-19-00651]\] and microwave assisted aminodehalogenation reaction resulting in a series of compounds 1--15.](molecules-19-00651-g006){#molecules-19-00651-f006} molecules-19-00651-t001_Table 1 ###### Experimentally determined values of lipophilicity log k, calculated values of log P, electronic Hammett's σ parameters and π parameters, 50% inhibition concentration IC~50~ \[μmol/L\] values related to PET inhibition in spinach chloroplasts in comparison with 3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU) standard and in vitro antimycobacterial activity against M. tuberculosis H37Rv (minimal inhibition concentration (MIC) \[μg/mL\]) of compounds 1--15 compared to pyrazinamide (PZA) and isoniazid (INH) standards. Compound R log P log k σ π IC~50~ \[μmol/L\] MIC M.tuberculosis H37Rv \[μg/mL\] ---------- ------------ --------- --------- ------- --------- ------------------- -------------------------------------- 1 2-CH~3~ 3.41 0.4668 −0.17 0.1674 114.0 \>100 2 3-CF~3~ 3.84 0.5369 0.43 0.2375 37.7 12.5 3 3,4-Cl 4.04 0.7538 0.60 0.4544 16.4 6.25 4 4-CH~3~ 3.41 0.5157 −0.17 0.2163 104.7 25 5 4-OCH~3~ 2.8 0.2820 −0.27 −0.0174 464.6 \>100 6 H 2.92 0.2994 0 0 \- 25 7 4-NH~2~ 2.12 −0.2014 −0.15 −0.5008 \- 25 8 3-Cl 3.48 0.5172 0.37 0.2178 57.4 12.5 9 2-Cl 3.48 0.4663 0.22 0.1669 79.0 6.25 10 2-F 3.08 0.3042 0.06 0.0048 195.6 12.5 11 4-CF~3~ 3.84 0.5626 0.51 0.2632 39.6 6.25 12 2-CF~3~ 3.84 0.4865 0.51 0.1871 71.6 12.5 13 2,4-OCH~3~ 2.67 0.3699 −0.55 0.0705 \- 25 14 3-NO~2~ 2.71 0.1808 0.71 −0.1186 487.4 12.5 15 4-Cl 3.48 0.5384 0.23 0.2390 86.5 12.5 PZA \- 12.5 INH \- 1.5625 DCMU 1.9 \- π = log k~(substituted)~ -- log k~(unsubstituted).~ 2.2. Calculated and Experimentally Set Lipophilicity ---------------------------------------------------- Lipophilicity is one of the most important factors that can affect the biological effect of the compound. It is connected with the membrane transport and other biological processes and it is also connected with solubility in the media. This physical-chemical property can be set experimentally. In this work we have used the Reversed Phase - High Performance Liquid Chromatography (RP-HPLC) methodology for measuring the capacity factors k with the calculation of log k that can be correlated to calculated values of lipophilicity log P (resp. Clog P). These calculations were carried out by using PC program CS ChemBioDraw Ultra 13.0. The results of these measurements are shown in the [Table 1](#molecules-19-00651-t001){ref-type="table"}. The lowest lipophilicity was shown by compound 7 (R = 4-NH~2~) and on the contrary, compound 3 (R = 3,4-Cl) was the most lipophilic compound of this series. Lipophilicity, based on log k values, increased for substituents in the benzyl part of the molecule as follows: 4-NH~2~ \< 3-NO~2~ \< 4-OCH~3~ \< H \< 2-F \< 2,4-OCH~3~ \< 2-Cl \< 2-CH~3~ \< 2-CF~3~ \< 4-CH~3~ \< 3-Cl \< 3-CF~3~ \< 4-Cl \< 4-CF~3~ \< 3,4-Cl The dependence of the measured log k parameters on the calculated log P values showed an approximate linearity, which is shown in [Figure 1](#molecules-19-00651-f001){ref-type="fig"}, and the corresponding correlation can be expressed by the following regression equation: ![Plot of experimentally measured log k parameter on calculated log P (CS ChemBioDraw Ultra version 13.0).](molecules-19-00651-g001){#molecules-19-00651-f001} 2.3. Biological Assays ---------------------- ### 2.3.1. Antimycobacterial In Vitro Screening All prepared compounds were tested against four strains of Mycobacterium. These were M. tuberculosis and three non-tuberculosis strains. The most active substances against M. tuberculosis were compounds 3, 9 and 11. Their activity expressed as minimal inhibition concentration (MIC) was 6.25 µg/mL and the activities of standards were 12.5 µg/mL for PZA and 1.5625 µg/mL for INH. Nearly the whole series showed activity against M. tuberculosis H37Rv, which was in the range from 25 to 6.25 µg/mL, but compounds 11 and 12 were also active against other strains and both of them were active against M. avium 152. These strains are usually resistant or unsusceptible to pyrazinamide. This is the reason why INH was chosen as second standard. Obtained results can be compared with other synthesised compounds and a comparison can be drawn between more mycobacterial strains not only M. tuberculosis. As shown in [Figure 2](#molecules-19-00651-f002){ref-type="fig"}, dependence of antimycobacterial activity on lipophilicity expressed by π constant (log k) as well as on the σ constant of the R substituent was observed. The most active compounds (MIC = 6.25 µg/mL) were 3 (R = 3,4-Cl), 9 (R = 2-Cl) and 11 (R = 4-CF~3~) and were mentioned above. All of these compounds are situated in the right upper quadrant of the Craig's plot. Further groups are represented by compounds 2 (R = 3-CF~3~), 8 (R = 3-Cl), 10 (R = 2-F), 12 (R = 2-CF~3~), 14 (R = 3-NO~2~) and 15 (R = 4-Cl) showing moderate activity with MIC = 12.5 µg/mL and compounds 4 (R = 4-CH~3~), 6 (R = H), 7 (R = 4-NH~2~) and 13 (R = 2,4-OCH~3~) with MIC = 25 µg/mL. Low antimycobacterial activity with MIC \>100 µg/mL was exhibited by compounds 1 (R = 2-CH~3~) and 5 (R = 4‑OCH~3~). It can be stated that the activity is more dependent on π constant than on σ constant. On the other hand this dependence is not unambiguous. However, it is clear that the lipophilicity is important for antimycobacterial activity and the most suitable ring substituents are electron-withdrawing groups such as halogen or trifluoromethyl moieties. ![Dependence of antimycobacterial activity of studied compounds on the π constant (log k) as well as on the σ constant of R substituent.](molecules-19-00651-g002){#molecules-19-00651-f002} ### 2.3.2. Antimycobacterial In Vitro Screening Against M. smegmatis This evaluation was performed against fast-growing Mycobacterium smegmatis using isoniazid and ciprofloxacin as standards. None of the compounds showed activity against this mycobacterial strain. This may be caused by the fact that this fast-growing mycobacterium is less susceptible to antibiotic treatment. ### 2.3.3. Antifungal and Antibacterial In Vitro Screening This evaluation was performed in order to obtain results for antifungal and antibacterial activity against eight fungal strains and eight bacterial strains. None of the prepared compounds showed antibacterial activity against the tested strains. On the contrary, compounds 7 (MIC = 500 µmol/L), 10 (MIC = 500 µmol/L) and 12 (MIC = 125 µmol/L) exhibited activity against Trichophyton mentagrophytes but in comparison to standards, this activity was negligible. It can be also caused by the bigger susceptibility of this fungal strain being evaluated. ### 2.3.4. Herbicidal Activity of Prepared Compounds The studied compounds inhibited photosynthetic electron transport in spinach chloroplasts ([Table 1](#molecules-19-00651-t001){ref-type="table"}). The PET inhibiting activity of studied compounds 1--15 expressed by IC~50~ value varied from 16.4 μmol/L (3) to 487.0 μmol/L (14). The inhibitory activity of the most active compounds 3 was 8.6 times lower than that of the standard DCMU (IC~50~ = 1.9 μmol/L), a well-known PS2 herbicide. Compounds 6 (R = H), 7 (R = 4-NH~2~) and 13 (R = 2,4-OCH~3~) were inactive and IC~50~ values related to PET inhibition could not be determined. It can be stated that the inhibitory activity increases linearly with increasing lipophilicity of the compounds based on the dependence of PET inhibiting activity of studied dicarbonitriles 1--15 on log P ([Figure 3](#molecules-19-00651-f003){ref-type="fig"}A) and log k ([Figure 3](#molecules-19-00651-f003){ref-type="fig"}B). ![Dependence of PET inhibiting activity on the log P (A) or log k (B) of compounds 1--15.](molecules-19-00651-g003){#molecules-19-00651-f003} Also if compound 14 (R = 3-NO~2~) was excluded, the dependence of PET inhibiting activity on the Hammett constant σ of R substituent showed again linear dependence ([Figure 4](#molecules-19-00651-f004){ref-type="fig"}). A linear increase of PET-inhibiting activity was observed in the range of σ from -0.15 (7; R = 4-NH~2~) to 0.6 (3; R = 3,4-Cl). ![Dependence of PET inhibiting activity of compounds 1--15 on the σ constant of the R substituent.](molecules-19-00651-g004){#molecules-19-00651-f004} The correlation between log (1/IC~50~) \[mol/L\] and log P or between log (1/IC~50~) \[mol/L\] and σ constant of R substituent could be expressed by the following equations: The use of both the above mentioned descriptors (log P and σ) in a multilinear correlation did not improve the results of statistical analysis: Similarly, better results of statistical analysis were obtained for the correlation between log (1/IC~50~) \[mol/L\] and log k than for multilinear correlation using two descriptors (log k and σ). pI 50 = 2.703 (±0.414) + 2.835 (±0.816) log k r = 0.934, s = 0.144, F = 61.8, n = 11 pI 50 = 2.997 × (± 0.331) + 2.034 × (± 0.738) log k \+ 0.481 (0.303) σ r = 0.976 s = 0.093 F = 80.2 n = 11 These results indicate that lipophilicity of the compound is determining for PET-inhibiting activity of the studied N-substituted 5-amino-6-methylpyrazine-2,3-dicarbonitriles. Lee et al. focused on the search for the minimum structural requirements for herbicidal evaluation of 5-(R^1^)-6-(R^2^)-N-(R^3^-phenyl)-pyrazine-2-carboxamide analogues as a new class of potent herbicides in a previous paper \[[@B31-molecules-19-00651]\]. Based on IC~50~ values of 19 pyrazine derivatives related to PET inhibition in spinach chloroplasts which were published by Dolezal et al. \[[@B15-molecules-19-00651]\], Lee derived and discussed quantitatively 3D-QSARs models between the substituents (R^1^--R^3^) changes of the analogues and their herbicidal activity using comparative molecular field analysis (CoMFA) and comparative molecular similarity indice analysis (CoMSIA) methods. It was predicted that the herbicidal activity increases when large steric substituents were introduced to one part of the ortho- and meta- positions on the N-phenyl ring as R^3^- substituent and small steric substituents on the other part. The same 19 pyrazine derivatives with herbicidal activity were also subjected to the two dimensional quantitative structure activity relationships studies using Vlife Molecular Design 3.0 module which contains various combinations of thermodynamic, electronic, topological and spatial descriptors \[[@B32-molecules-19-00651]\]. It was found that decreasing of number of hydrogen bond acceptor atoms and reduction the any atoms (single, double or triple bonded) separated from any oxygen atom by a seven bond distance in a molecule could be helpful for designing more potent herbicidal agents. Because the studied N-substituted 5-amino-6-methylpyrazine-2,3-dicarbonitriles were found to inhibit the Hill reaction, they can be considered as photosystem 2 (PS2) inhibitors, i.e., PS2 herbicides which ultimately adversely affect growth of weeds as well as agricultural plants. The PS2 inhibitors can act on the donor and/or the acceptor side of PS2. Using EPR spectroscopy it was found that N-phenylpyrazine-2-carboxamides interacted with the D^·^ intermediate which is situated at 161^st^ position in D~2~ protein occurring on the donor side of PS2. Due to interaction of these pyrazine derivatives with this part of PS2, the photosynthetic electron transport from the oxygen evolving complex to the reaction centre of PS2 was impaired and consequently, the electron transport between PS2 and PS1 was inhibited \[[@B33-molecules-19-00651]\]. Use of an artificial electron-donor, 1,5-diphenylcarbazide (DPC), acting in the Z^·^/D^·^ intermediate is suitable to estimate whether the studied PET inhibitor acts only on the donor or also on the acceptor side of PS2. Complete restoration of PET after DPC addition to chloroplasts activity of which was inhibited by an inhibitor, indicates that PET between the core of PS2 (P680) and the secondary quinone acceptor Q~B~ was not affected by this inhibitor. Consequently, its site of inhibitory action is situated on the donor side of PS2. However, upon addition of DPC to the studied dicarbonitriles only partial restoration of PET was observed (up to 85% of the control) and therefore it could be assumed that the studied compounds block PET not only by interaction with proteins occurring in the section between the oxygen evolving complex (OEC) and the Z^·^/D^·^ intermediate but to PET inhibition contributes also their interaction with some constituents of photosynthetic apparatus on the acceptor side of PS2. Similar results were obtained previously with 5-tert-butyl-N-(3-hydroxy-4-chlorophenyl)pyrazine-2-carboxamide and 5-tert-butyl-6-chloro-N-(3-fluorophenyl)pyrazine-2-carboxamide \[[@B33-molecules-19-00651]\]. Compounds 1--15 affected the chlorophyll a (Chla) fluorescence in spinach chloroplasts. As shown in [Figure 5](#molecules-19-00651-f005){ref-type="fig"}, the intensity of the Chla emission band at 686 nm belonging to the pigment--protein complexes in photosystem 2 decreased in the presence of compound 3 \[[@B34-molecules-19-00651]\]. This finding indicates a perturbation of the Chla--protein complexes in the thylakoid membrane caused by the tested compound. Similar Chla fluorescence decrease in spinach chloroplasts was observed previously with several PET inhibitors, i.e., N-benzylpyrazine-2-carboxamides \[[@B35-molecules-19-00651]\], ring-substituted 3-hydroxynaphthalene-2-carboxanilides \[[@B36-molecules-19-00651]\] and 1-hydroxynaphthalene-2-carboxanilides \[[@B37-molecules-19-00651]\], 2-hydroxynaphthalene-1-carboxanilides \[[@B38-molecules-19-00651]\] and ring-substituted 4-arylamino-7-chloroquinolinium chlorides \[[@B39-molecules-19-00651]\]. ![Fluorescence emission spectra of Chla of untreated spinach chloroplasts and chloroplasts treated with 0, 0.13, 0.25 and 0.51 mmol/L of compound 3 (R = 3,4-Cl) (the curves from top to bottom); excitation wave length λ = 436 nm; chlorophyll concentration 10 mg/L.](molecules-19-00651-g005){#molecules-19-00651-f005} 3. Experimental =============== 3.1. General ------------ All the chemicals used for preparation of starting compound and final products were purchased from Sigma-Aldrich (Sigma-Aldrich, St. Louis, MO, USA) and were reagent or higher grade of purity. Starting compound was prepared according to proven methodology of conventional organic synthesis. The final aminodehalogenation reactions were performed in CEM Discover microwave reactor with focused field (CEM Corporation, Matthews, NC, USA) connected to the Explorer 24 autosampler (CEM Corporation) and this equipment was running under CEM's Synergy™ software for monitoring the progress of reactions. The reaction progress was checked by Thin Layer Chromatography (TLC) (Alugram^®^ Sil G/UV254, Machery-Nagel, Postfach, Germany) using 254 nm wavelength UV detection. All the obtained products were purified by crystallization or by preparative flash chromatography (CombiFlash^®^ Rf, Teledyne Isco Inc., Lincoln, NE, USA), using gradient elution with hexane (LacheNer, Neratovice, Czech Republic) and ethyl acetate (Penta, Prague, Czech Republic) as mobile phases. Silica gel (0.040--0.063 nm, Merck, Darmstadt, Germany) was used as the stationary phase. NMR spectra were recorded on Varian Mercury--VxBB 300 (299.95 MHz for ^1^H and 75.43 MHz for ^13^C) or Varian VNMR S500 (499.87 MHz for ^1^H and 125.71 MHz for ^13^C) spectrometers (Varian Corporation, Palo Alto, CA, USA). Chemical shifts were reported in ppm (δ) and were applied indirectly to tetramethylsilane as a signal of solvent (2.49 for ^1^H and 39.7 for ^13^C in DMSO-d~6~). Infrared spectra were recorded with spectrometer FT-IR Nicolet 6700 (Thermo Scientific, Waltham, MA, USA) using attenuated total reflectance (ATR) methodology. Melting points were assessed by SMP3 Stuart Scientific (Bibby Scientific Ltd., Staffordshire, UK) and were uncorrected. Elemental analyses were measured with EA 1110 CHNS Analyzer (Fisons Instruments S. p. A., Carlo Erba, Milano, Italy). Calculation of electronic Hammett's σ parameters was carried out on the software ACD/Percepta ver. 2012 (Advanced Chemistry Development, Inc., Toronto, ON, Canada). 3.2. Starting Compound and Final Products Synthesis --------------------------------------------------- The starting compound 5-chloro-6-methylpyrazine-2,3-dicarbonitrile was synthesized in a two-step reaction according to the reported methodology \[[@B30-molecules-19-00651]\]. The first step was a condensation reaction between diaminomaleonitrile (0.025 mol) and pyruvic acid (0.025 mol), which were dissolved in methanol (60 mL), and hydrochloric acid (10 mL, 15%) was added dropwise. It takes two hours to react at room temperature. After the evaporation of two thirds of the solvent, hot water (80 mL) was added and then the rest of methanol was evaporated in vacuo. The whole mixture was cooled to 5 °C to initiate the crystallization. The product was collected by suction, dried overnight and subsequently chlorinated with phosphoryl chloride. Product (0.015 mol) was again dissolved in POCl~3~ (0.060 mol) and cooled to 0 °C. Pyridine (0.020 mol) was added dropwise and after the termination of the exothermic reaction, the mixture was heated to 90 °C for 2 h. Excess POCl~3~ was evaporated in vacuo and the rest of product was extracted into toluene three or four times, the toluene was evaporated and then the crude product was recrystallized from chloroform. The starting compound (1.12 mmol) was finally treated with 15 variously ring-substituted benzylamines (2.24 mmol) and all these aminodehalogenation reactions took place in the microwave reactor. The conditions used for microwave syntheses were as follows---150 °C, 30 min, 120 W, methanol as a solvent, pyridine as a base and were set experimentally. The reaction was monitored by TLC using hexane/ethyl acetate 2:1 mixture as mobile phase. The final compounds were purified using flash column chromatography with gradient elution using a hexane/ethyl acetate system and if necessary recrystallization from a mixture of ethanol and water. 3.3. Analytical Data of the Prepared Compounds ---------------------------------------------- 5-Methyl-6-\[(2-methylbenzyl)amino\]pyrazine-2,3-dicarbonitrile (1). Light orange crystalline solid. Yield 47.9%; M.p. 152.1--152.9 °C; IR (ATR-Ge, cm^−1^): 3381~m~ (-NH-), 2226~m~ (-CN), 1570~vs~, 1521~s~, 1403~vs~, 1349~m~ (arom.); ^1^H-NMR (500 MHz) δ 8.61 (1H, bs, NH), 7.25--7.10 (4H, m, H3\', H4\', H5\', H6\'), 4.56 (2H, s, NCH~2~), 2.47 (3H, s, CH~3~), 2.33 (3H, s, CH~3~); ^13^C-NMR (125 MHz) δ 152.9, 147.5, 136.0, 135.6, 130.2, 130.1, 127.5, 127.2, 125.9, 117.4, 115.7, 114.8, 42.5, 21.3, 19.0; Elemental analysis: calc. for C~15~H~13~N~5~ (MW 263.12): 68.42% C, 4.98% H, 26.60% N; found 68.22% C, 5.17% H, 26.44% N. 5-Methyl-6-{\[3-(trifluoromethyl)benzyl\]amino}pyrazine-2,3-dicarbonitrile (2). Yellow-orange crystalline solid. Yield 51.6%; M.p. 158.5--159.7 °C (decomp.); IR (ATR-Ge, cm^−1^): 3377~m~ (-NH-), 2227~m~ (-CN), 1570~vs~, 1521~s~, 1402~vs~, 1353~m~, 1324~vs~ (arom.), 1128~vs~ (-C-F); ^1^H-NMR (300 MHz) δ 8.75 (1H, bs, NH), 7.77--7.60 (1H, m, H2\'), 7.68--7.50 (3H, m, H4\', H5\', H6\'), 4.69 (2H, d, J = 4.6 Hz, NCH~2~), 2.46 (3H, s, CH~3~); ^13^C-NMR (75 MHz) δ 152.9, 147.7, 139.6, 131.8, 130.0, 129.6, 129.2 (q, J = 31.5 Hz), 124.5 (q, J = 4.0 Hz), 124.4 (q, J = 272.3 Hz), 124.0 (q, J = 4.0 Hz), 117.7, 115.6, 114.8, 44.0, 21.2; Elemental analysis: calc. for C~15~H~10~F~3~N~5~ (MW 317.27): 56.78% C, 3.18% H, 22.07% N; found 56.59% C, 3.30% H, 21.93% N. 5-\[(3,4-Dichlorobenzyl)amino\]-6-methylpyrazine-2,3-dicarbonitrile (3). Light yellow crystalline solid. Yield 60.9%; M.p. 154.4--156.2 °C; IR (ATR-Ge, cm^−1^): 3329~m~ (-NH-), 2227~m~ (-CN), 1568~vs~, 1516~s~, 1466~m~, 1402~vs~ (arom.); ^1^H-NMR (300 MHz) δ 8.69 (1H, bs, NH), 7.61 (1H, d, J = 1.9 Hz, H2\'), 7.57 (1H, d, J = 8.2 Hz, H5\'), 7.33 (1H, dd, J = 8.2 Hz, J = 1.9 Hz, H6\'), 4.59 (2H, s, NCH~2~), 2.46 (3H, s, CH~3~); ^13^C-NMR (75 MHz) δ 152.8, 147.8, 139.4, 131.1, 130.6, 130.0, 129.8, 129.6, 127.9, 117.8, 115.6, 114.8, 43.3, 21.2; Elemental analysis: calc. for C~14~H~9~Cl~2~N~5~ (MW 318.16): 52.85% C, 2.85% H, 22.01% N; found 52.71% C, 3.05% H, 21.88% N. 5-Methyl-6-\[(4-methylbenzyl)amino\]pyrazine-2,3-dicarbonitrile (4). Light yellow crystalline solid. Yield 60.5%; M.p. 140.8--142.3 °C; IR (ATR-Ge, cm^−1^): 3370~s~ (-NH-), 2223~m~ (-CN), 1576~vs~, 1519~s~, 1438~m~, 1400~vs~, 1351~s~ (arom.); ^1^H-NMR (300 MHz) δ 8.68 (1H, bs, NH), 7.24--7.18 (2H, m, AA\', BB\', H2\', H6\'), 7.14--7.09 (2H, m, AA\', BB\', H3\', H5\'), 4.55 (2H, bs, NCH~2~), 2.44 (3H, s, CH~3~), 2.26 (3H, s, CH~3~); ^13^C-NMR (75 MHz) δ 152.8, 147.5, 136.4, 135.0, 130.1, 128.1, 127.5, 117.3, 115.7, 114.9, 44.1, 21.2, 20.8; Elemental analysis: calc. for C~15~H~13~N~5~ (MW 263.30): 68.42% C, 4.98% H, 26.60% N; found 68.30% C, 5.17% H, 26.43% N. 5-\[(4-Methoxybenzyl)amino\]-6-methylpyrazine-2,3-dicarbonitrile (5). Ochre crystalline solid. Yield 61.3%; M.p. 153.0--154.2 °C (decomp.); IR (ATR-Ge, cm^−1^): 3345~m~ (-NH-), 2948~w~ (-OCH~3~), 2223~m~ (-CN), 1585~s~, 1570~vs~, 1511~vs~, 1462~m~, 1403~vs~ (arom.); ^1^H-NMR (300 MHz) δ 8.66 (1H, bs, NH), 7.29--7.23 (2H, m, AA\', BB\', H2\', H6\'), 6.90--6.84 (2H, m, AA\', BB\', H3\', H5\'), 4.52 (2H, bs, NCH~2~), 3.71 (3H, s, OCH~3~), 2.43 (3H, s, CH~3~); ^13^C-NMR (75 MHz) δ 158.6, 152.8, 147.4, 130.1, 129.9, 129.0, 117.3, 115.7, 114.9, 113.9, 55.2, 43.8, 21.2; Elemental analysis: calc. for C~15~H~13~N~5~O (MW 279.30): 64.51% C, 4.69% H, 25.07% N; found 64.35% C, 4.81% H, 24.84% N. 5-(Benzylamino)-6-methylpyrazine-2,3-dicarbonitrile (6) \[[@B30-molecules-19-00651]\]. Yellow-orange crystalline solid. Yield 53.3%; M.p. 128.7--130.7 °C (described in the literature 118--119 °C); IR (ATR-Ge, cm^−1^): 3404~m~ (‑NH-), 2228~m~ (-CN), 1564~vs~, 1508~vs~, 1454~m~, 1400~vs~, 1357s (arom.); ^1^H-NMR (300 MHz) δ 8.72 (1H, bs, NH), 7.37--7.20 (5H, m, H2\', H3\', H4\', H5\', H6\'), 4.61 (2H, d, J = 3.3 Hz, NCH~2~), 2.45 (3H, s, CH~3~); ^13^C-NMR (75 MHz) δ 152.9, 147.5, 138.1, 130.1, 128.5, 127.5, 127.2, 117.4, 115.7, 114.9, 44.3, 21.2; Elemental analysis: calc. for C~14~H~11~N~5~ (MW 249.27): 67.46% C, 4.45% H, 28.10% N; found 67.21% C, 4.63% H, 27.95% N. 5-\[(4-Aminobenzyl)amino\]-6-methylpyrazine-2,3-dicarbonitrile (7). Brown crystalline solid. Yield 37.2%; M.p. 154.9--156.5 °C; IR (ATR-Ge, cm^−1^): 3413~m~ (-NH~2~), 3376~m~ (-NH-), 2234~m~ (-CN), 1572~vs~, 1519~vs~, 1440~m~, 1402~vs~, 1352~s~ (arom.); ^1^H-NMR (300 MHz) δ 8.54 (1H, bs, NH), 7.04--6.94 (2H, m, AA\', BB\', H2\', H6\'), 6.54--6.45 (2H, m, AA\', BB\', H3\', H5\'), 4.97 (2H, bs, NH~2~), 4.41 (2H, d, J = 3.8 Hz, NCH~2~), 2.41 (3H, s, CH~3~); ^13^C-NMR (75 MHz) δ 152.7, 148.0, 147.3, 130.2, 128.7, 124.7, 117.0, 115.8, 114.9, 113.9, 44.2, 21.2; Elemental analysis: calc. for C~14~H~12~N~6~ (MW 264.29): 63.62% C, 4.58% H, 31.80% N; found 63.48% C, 4.45% H, 31.65% N. 5-\[(3-Chlorobenzyl)amino\]-6-methylpyrazine-2,3-dicarbonitrile (8). Yellow crystalline solid. Yield 60.2%; M.p. 151.0--151.8 °C; IR (ATR-Ge, cm^−1^): 3306~m~ (-NH-), 2248~m~ (-CN), 1567~vs~, 1513~vs~, 1468~m~, 1401~vs~, 1351~s~ (arom.); ^1^H-NMR (300 MHz) δ 8.70 (1H, t, J = 5.9 Hz, NH), 7.43--7.39 (1H, m, H2\'), 7.38--7.27 (3H, m, H4\', H5\', H6\'), 4.61 (2H, d, J = 5.9 Hz, NCH~2~), 2.46 (3H, s, CH~3~); ^13^C-NMR (75 MHz) δ 152.9, 147.7, 140.7, 133.2, 130.4, 130.0, 127.4, 127.2, 126.2, 117.7, 115.6, 114.9, 43.8, 21.2; Elemental analysis: calc. for C~14~H~10~ClN~5~ (MW 283.72): 59.27% C, 3.55% H, 24.68% N; found 59.08% C, 3.71% H, 24.57% N. 5-\[(2-Chlorobenzyl)amino\]-6-methylpyrazine-2,3-dicarbonitrile (9). Dark orange crystalline solid. Yield 24.7%; M.p. decomp.; IR (ATR-Ge, cm^−1^): 3381~m~ (-NH-), 2227~m~ (-CN), 1570~vs~, 1521~s~, 1474~m~, 1440~m~, 1401~s~, 1351~s~ (arom.); ^1^H-NMR (300 MHz) δ 8.68 (1H, bs, NH), 7.51--7.24 (4H, m, H3\', H4\', H5\', H6\'), 4.66 (2H, s, NCH~2~), 2.49 (3H, s, CH~3~); ^13^C-NMR (75 MHz) δ 153.0, 147.7, 134.9, 132.3, 130.0, 129.4, 129.1, 128.9, 127.4, 117.8, 115.6, 114.8, 42.4, 21.2; Elemental analysis: calc. for C~14~H~10~ClN~5~ (MW 283.72): 59.27% C, 3.55% H, 24.68% N; found 59.08% C, 3.68% H, 24.90% N. 5-\[(2-Fluorobenzyl)amino\]-6-methylpyrazine-2,3-dicarbonitrile (10). Dark yellow crystalline solid. Yield 60.8%; M.p. 134.8--136.3 °C; IR (ATR-Ge, cm^−1^): 3377~m~ (-NH-), 2231~m~ (-CN), 1573~vs~, 1523~s~, 1491~m~, 1402~s~, 1354~s~ (arom.); ^1^H-NMR (300 MHz) δ 8.68 (1H, t, J = 5.3 Hz, NH), 7.42--7.10 (4H, m, H3\', H4\', H5\', H6\'), 4.63 (2H, d, J = 5.3 Hz, NCH~2~), 2.46 (3H, s, CH~3~); ^13^C-NMR (75 MHz) δ 160.0 (d, J = 244.8 Hz), 152.9, 147.6, 129.8 (d, J = 20.4 Hz), 129.8, 129.4 (d, J = 8.3 Hz), 124.6 (d, J = 17.8 Hz), 124.5 (d, J = 6.6 Hz), 117.7, 115.5 (d, J = 9.2 Hz), 115.2, 114.8, 38.3, 21.2; Elemental analysis: calc. for C~14~H~10~FN~5~ (MW 267.26): 62.92% C, 3.77% H, 26.20% N; found 62.71% C, 3.59% H, 26.38% N. 5-Methyl-6-{\[4-(trifluoromethyl)benzyl\]amino}pyrazine-2,3-dicarbonitrile (11). Light yellow crystalline solid. Yield 38.3%; M.p. 148.4--149.6 °C; IR (ATR-Ge, cm^−1^): 3397~m~ (-NH-), 2232~m~ (-CN), 1570~vs~, 1520~s~, 1422~m~, 1399~s~, 1324~vs~ (arom.), 1114~vs~ (-C-F); ^1^H-NMR (300 MHz) δ 8.54 (1H, t, J = 5.3 Hz, NH), 7.71--7.64 (2H, m, AA\', BB\', H2\', H6\'), 7.38--7.52 (2H, m, AA\', BB\', H3\', H5\'), 4.69 (2H, d, J = 5.3 Hz, NCH~2~), 2.51 (3H, s, CH~3~); ^13^C-NMR (75 MHz) δ 152.9, 147.7, 143.1, 130.0, 128.2, 127.9 (q, J = 31.5 Hz), 125.4 (q, J = 3.7 Hz), 124.5 (q, J = 272.0 Hz), 117.8, 115.6, 114.8, 44.0, 21.2; Elemental analysis: calc. for C~15~H~10~F~3~N~5~ (MW 317.27): 56.78% C, 3.18% H, 22.07% N; found 56.59% C, 2.99% H, 21.91% N. 5-Methyl-6-{\[2-(trifluoromethyl)benzyl\]amino}pyrazine-2,3-dicarbonitrile (12). Yellow-orange crystalline solid. Yield 49.1%; M.p. 157.8--159.4 °C (decomp.); IR (ATR-Ge, cm^−1^): 3408~m~ (-NH-), 2230~m~ (-CN), 1569~vs~, 1522~s~, 1430~m~, 1409~s~, 1398~s~, 1368~s~, 1314~vs~ (arom.), 1114~vs~ (-C-F); ^1^H-NMR (300 MHz) δ 8.76 (1H, bs, NH), 7.77--7.71 (1H, m, H3\'), 7.64--7.43 (3H, m, H4\', H5\', H6\'), 4.77 (2H, bs, NCH~2~), 2.51 (3H, s, CH~3~); ^13^C-NMR (75 MHz) δ 153.0, 147.7, 136.3, 132.9, 130.0, 128.3, 127.8, 126.4 (q, J = 30.3 Hz), 126.1 (q, J = 6.0 Hz), 124.7 (q, J = 274.0 Hz), 118.0, 115.5, 114.7, 41.1, 21.2; Elemental analysis: calc. for C~15~H~10~F~3~N~5~ (MW 317.27): 56.78% C, 3.18% H, 22.07% N; found 56.62% C, 3.08% H, 22.00% N. 5-\[(2,4-Dimethoxybenzyl)amino\]-6-methylpyrazine-2,3-dicarbonitrile (13). Ochre crystalline solid. Yield 62.3%; M.p. 151.6--152.9 °C; IR (ATR-Ge, cm^−1^): 3336~m~ (-NH-), 2924~w~ (-OCH~3~), 2224~m~ (-CN), 1609~s~, 1574~vs~, 1509~vs~, 1467~m~, 1440~s~, 1405~vs~ (arom.); ^1^H-NMR (300 MHz) δ 8.45 (1H, t, J = 5.7 Hz, NH), 7.07 (1H, d, J = 8.2 Hz, H6\'), 6.55 (1H, d, J = 2.5 Hz, H3\'), 6.43 (1H, dd, J = 8.2 Hz, J = 2.5 Hz, H5\'), 4.47 (2H, d, J = 5.7 Hz, NCH~2~), 3.80 (3H, s, OCH~3~), 3.72 (3H, s, OCH~3~), 2.44 (3H, s, CH~3~); ^13^C-NMR (75 MHz) δ 160.1, 158.1, 153.0, 147.4, 130.2, 128.8, 117.3, 117.2, 115.8, 114.9, 104.6, 98.5, 55.7, 55.4, 39.5, 21.3; Elemental analysis: calc. for C~16~H~15~N~5~O~2~ (MW 309.32): 62.13% C, 4.89% H, 22.64% N; found 62.36% C, 5.01% H, 22.52% N. 5-Methyl-6-\[(3-nitrobenzyl)amino\]pyrazine-2,3-dicarbonitrile (14). Orange-red crystalline solid. Yield 17.2%; M.p. decomp.; IR (ATR-Ge, cm^−1^): 3394~m~ (-NH-), 2231~m~ (-CN), 1571~vs~, 1547~m~, 1524~vs~, 1478~m~, 1430~m~, 1396~s~, 1366~s~, 1348~vs~ (arom.); ^1^H-NMR (300 MHz) δ 8.79 (1H, t, J = 5.8 Hz, NH), 8.23 (1H, s, H2\'), 8.11 (1H, d, J = 7.8 Hz, H4\'), 7.81 (1H, d, J = 7.8 Hz, H6\'), 7.62 (1H, t, J = 7.8 Hz, H5\'), 4.73 (2H, d, J = 5.8 Hz, NCH~2~), 2.47 (3H, s, CH~3~); ^13^C-NMR (75 MHz) δ 152.9, 148.0, 147.8, 140.6, 134.4, 130.0, 130.0, 122.5, 122.3, 117.9, 115.6, 114.8, 43.8, 21.2; Elemental analysis: calc. for C~14~H~10~N~6~O~2~ (MW 294.27): 57.14% C, 3.43% H, 28.56% N; found 56.93% C, 3.64% H, 28.56% N. 5-\[(4-Chlorobenzyl)amino\]-6-methylpyrazine-2,3-dicarbonitrile (15). Brown crystalline solid. Yield 30.8%; M.p. 152.8--154.8 °C (decomp.); IR (ATR-Ge, cm^−1^): 3378~m~ (-NH-), 2230~m~ (-CN), 1570~vs~, 1521~s~, 1487~m~, 1441~m~, 1403~s~, 1347~s~ (arom.), 804~s~ (-C-Cl); ^1^H-NMR (500 MHz) δ 8.42 (1H, bs, NH), 7.39--7.33 (4H, m, H2\', H3\', H5\', H6\'), 4.59 (2H, s, NCH~2~), 2.45 (3H, s, CH~3~); ^13^C-NMR (125 MHz) δ 152.8, 147.6, 137.2, 131.8, 130.0, 129.4, 128.5, 117.6, 115.6, 114.8, 43.7, 21.2; Elemental analysis: calc. for C~14~H~10~ClN~5~ (MW 283.72): 59.27% C, 3.55% H, 24.68% N; found 59.16% C, 3.65% H, 24.62% N. 3.4. Lipophilicity HPLC Determination and Calculations ------------------------------------------------------ Experimental lipophilicity parameter log k was ascertained using an Agilent Technologies 1200 SL HPLC system with a SL G1315C Diode-Array Detector, ZORBAX XDB-C18 5 μm, 4 × 4 mm, Part No. 7995118-504 chromatographic pre-column and ZORBAX Eclipse XDB-C18 5 μm, 4.6 × 250 mm, Part No. 7995118-585 column (Agilent Technologies Inc., Colorado Springs, CO, USA). The separation process was controlled by Agilent ChemStation, version B.04.02 extended by spectral module (Agilent Technologies Inc.). A solution of MeOH (HPLC grade, 70%) and H~2~O (HPLC-Milli-Q Grade, 30%) was used as mobile phase. The total flow of the column was 1.0 mL/min, injection 20 μL, column temperature 30 °C. Detection wavelength λ= 210 nm and monitor wavelength λ= 270 nm were chosen for this measurement. The KI methanol solution was used for the dead time (TD) determination. Retention times (TR) of synthesized compounds were measured in minutes. The capacity factors k were calculated using Microsoft Excel according to formula k = (TR − TD)/TD, where TR is the retention time of the solute and TD denotes the dead time obtained via an unretained analyte. Log k, calculated from the capacity factor k, is used as the lipophilicity index converted to log P scale. Values of log P and Clog P were calculated with the PC programme CS ChemBioDraw Ultra 13.0 (CambridgeSoft, Cambridge, MA, USA). 3.5. Biological Assays ---------------------- ### 3.5.1. Antimycobacterial In Vitro Screening Mycobacterial screening was performed against four mycobacterial stems (M. tuberculosis H37Rv CNCTC My 331/88, M. kansasii CNCTC My 235/80, M. avium ssp. avium CNCTC My 80/72, M. avium CNCTC My 152/73 (Czech National Collection of Type Cultures, National Institute of Public Health, Prague, Czech Republic)) using isoniazid and pyrazinamide (Sigma-Aldrich) as standards. Culturing medium was Sula's semisynthetic medium (Trios, Prague, Czech Republic) with pH 6.0. Tested compounds were dissolved in dimethylsulfoxide (DMSO) and diluted with medium to final concentrations 100, 50, 25, 12.5, 6.25, 3.125 and 1.5625 μg/mL. The method used for this assay was microdilution broth panel method. The final concentration of DMSO did not exceed 1% (v/v) and did not affect the growth of Mycobacteria. The cultures were grown in Sula's medium at 37 °C in humid dark atmosphere. The antimycobacterial activity was determined using Alamar Blue colouring after 14 days, resp. 6 days against M. kansasii, of incubation as MIC (µg/mL). This evaluation was done in cooperation with Department of Clinical Microbiology, University Hospital in Hradec Kralove, Hradec Kralove, Czech Republic. ### 3.5.2. Antimycobacterial In Vitro Screening Against M. smegmatis This assay was focused on the activity against fast growing Mycobacterium smegmatis MC2155 (CIT Collection, Cork Institute of Technology, Cork, Ireland). The method used there was also microdilution broth panel method and as the medium was used Middlebrook 7H9 Broth with 10% of OADC supplement (Sigma-Aldrich). Tested compounds were dissolved in DMSO and medium and the final concentrations were set as 1000, 500, 250, 125, 62.5, 31.25, 15.625 and 7.8125 µg/mL. The final concentration of DMSO did not exceed 2% (v/v) and did not affect the growth of M. smegmatis. The standards used for determination of activity were isoniazid and ciprofloxacin. MIC was read after 48 h of incubation at 37 °C, addition of Alamar Blue stain was followed by 12 h of additional incubation with this reagent. This screening was performed under the patronage of the Department of Biological Sciences, Cork Institute of Technology, Cork, Ireland. ### 3.5.3. Antifungal and Antibacterial In Vitro Screenings Antibacterial evaluation was made using the microdilution broth method in plates M27A-M1 (200+10) against eight bacterial stems from the Czech Collection of Microorganisms (Brno, Czech Republic) or clinical isolates from Department of Clinical Microbiology, University Hospital in Hradec Kralove (Hradec Kralove, Czech Republic) (Staphylococcus aureus CCM 4516/08, Staphylococcus aureus H 5996/08 methicillin resistant, Staphylococcus epidermidis H 6966/08, Enterococcus sp. J14365/08, Escherichia coli CCM 4517, Klebsiella pneumoniae D 11750/08, Klebsiella pneumoniae J 14368/05 ESBL positive, Pseudomonas aeruginosa CCM 1961). Mueller Hinton broth was used for the cultivation that was done in humid atmosphere at 35 °C. The readings were made after 24 and 48 h and MIC was set as 80% inhibition of control. The standards were neomycin, bacitracin, penicillin G, ciprofloxacin and phenoxymethylpenicillin and tested products were dissolved in DMSO (final concentration of DMSO did not exceed 1% (v/v)) \[[@B40-molecules-19-00651]\]. Antifungal evaluation was also accomplished with microdilution broth method. On the contrary, there was used RPMI 1640 broth with glutamine as medium and conditions were humid and dark atmosphere, pH 7.0 (buffered with 3-morpholinopropane-1-sulfonic acid) and 35 °C. Eight fungal strains were used (Candida albicans ATCC 44859, Candida tropicalis 156, Candida krusei E28, Candida glabrata 20/I, Trichosporon asahii 1188, Aspergillus fumigatus 231, Absidia corymbifera 272, Trichophyton mentagrophytes 445) together with 4 antimycotic standards amphotericin B, voriconazole, nystatin and fluconazole. The MIC was set as 80% inhibition of control and readings were made after 24 and 48 h (50% IC, 72 and 120 h for fibrous fungi) and tested compounds were also dissolved in DMSO (final concentration of DMSO in medium did not exceed 2.5% (v/v)) \[[@B41-molecules-19-00651]\]. ### 3.5.4. Study of the Inhibition of Oxygen Evolution Rate in Spinach Chloroplasts Chloroplasts were prepared from spinach (Spinacia oleracea L.) according to Masarovicova and Kralova \[[@B42-molecules-19-00651]\]. The inhibition of photosynthetic electron transport (PET) in spinach chloroplasts was determined spectrophotometrically (Genesys 6, Thermo Scientific, Madison, WI, USA) using an artificial electron acceptor 2,6-dichlorophenol-indophenol (DCPIP) according to Kralova et al. \[[@B43-molecules-19-00651]\] and the rate of photosynthetic electron transport (PET) was monitored as a photo-reduction of DCPIP. The measurements were carried out in a phosphate buffer (0.02 mol/L, pH 7.2) containing sucrose (0.4 mol/L), MgCl~2~ (0.005 mol/L) and NaCl (0.015 mol/L). The chlorophyll content was 30 mg/L in these experiments and the samples were irradiated (\~100 W/m^2^) from a 10 cm distance with halogen lamp (250 W) using a 4 cm water filter to prevent warming of the samples (suspension temperature 4 °C). The studied compounds were dissolved in DMSO due to their limited water solubility. The applied DMSO concentration (up to 4% (v/v)) did not affect the photochemical activity in spinach chloroplasts (PET). The inhibitory efficiency of the studied compounds was expressed as the IC~50~ values, i.e., molar concentration of the compounds causing 50% decrease in the oxygen evolution relative to the untreated control. The comparable IC~50~ value for a selective herbicide 3-(3,4-dichlorophenyl)-1,1-dimethylurea (Diurone^®^, DCMU) was about 1.9 μmol/L \[[@B44-molecules-19-00651]\]. ### 3.5.5. Study of Fluorescence of Chlorophyll a in Spinach Chloroplasts The fluorescence emission spectra of chlorophyll a (Chla) in spinach chloroplasts were recorded on fluorescence spectrophotometer F-2000 (Hitachi, Tokyo, Japan) using excitation wavelength λ~ex~ = 436 nm for monitoring fluorescence of Chla, excitation slit 20 nm and emission slit 10 nm. The samples were kept in the dark 2 min before measuring. The phosphate buffer used for dilution of the chloroplast suspension was the same as described above. Due to low aqueous solubility the compounds were added to a chloroplast suspension in DMSO solution. The DMSO concentration in all samples was the same as in the control (10% (v/v)). The chlorophyll concentration in chloroplast suspension was 10 mg/L. 4. Conclusions ============== A series of 15 pyrazinamide derivatives (14 of them novel) was synthesized by aminodehalogenation reactions focusing on microwave assisted synthesis. All the final compounds were characterized with IR, NMR and other analytical data and then subjected to in vitro evaluation in order to discover their potential antimycobacterial, antifungal, antibacterial and herbicidal activities. The lipophilicity was measured using RP-HPLC methodology and also calculated or predicted with the PC program CS ChemBioDraw Ultra 13.0. These values were compared and the dependence between log k and log P was linear. In antimycobacterial screening compounds 3 (R = 3,4-Cl), 9 (R = 2-Cl) and 11 (R = 4-CF~3~) showed good activity against wild strain M. tuberculosis H37Rv (MIC = 6.25 µg/mL) compared to the standards pyrazinamide (MIC = 12.5 µg/mL) and isoniazid (MIC = 1.56 µg/mL). Compounds 11 (R = 4-CF~3~) and 12 (R = 2-CF~3~) were active against the non-tuberculosis strains M. kansasii and M. avium as well. Although the majority of synthesized compounds were active, there is no clear dependence between lipophilicity and antimycobacterial activity, but it can be stated that the most potent substances were also from the group of most lipophilic compounds and the most favourable substitutions are the electron-withdrawing groups such as chlorine or trifluoromethyl. Activity against fast growing Mycobacteria was also determined but no active substances were identified. No interesting results were observed in antibacterial and antifungal screenings. Three compounds (7 (R = 4-NH~2~), 10 (R = 2-F), and 15 (R = 4-Cl)) showed insignificant activity against the fungus Trichophyton mentagrophytes, which was found to be worse compared to the standards. The rest of substances showed no in vitro antibacterial or antifungal activity. On the contrary, N-substituted 5-amino-6-methylpyrazine-2,3-dicarbonitriles were found to inhibit the Hill reaction in spinach chloroplasts which indicated that these compounds act as PS2 inhibitors.The IC~50~ values related to PET inhibition varied in the investigated set in the range from 16.4 μmol/L (3; R = 3,4-Cl) to 487.0 μmol/L (14; R = 3-NO~2~). The lipophilicity of the compounds was determinant for PET‑inhibiting activity. The site of inhibitory action of studied compounds in the photosynthetic apparatus is situated both on the donor and on the acceptor side of PS2. Perturbation of the Chla-protein complexes in the thylakoid membranes caused by the tested compounds was documented by a decrease of the Chla emission band intensity at 686 nm belonging to the pigment‑protein complexes in photosystem 2. Based on the obtained results it can be assumed that the antifungal and antibacterial activities of studied compounds are not directly dependent on lipophilicity. This conclusion cannot be applied for the herbicidal activity because there is a linear dependence between activity and lipophilicity. Dependence between antimycobacterial activity and the benzyl substituents was found. This reliance was expressed by the lipophilicity parameter log k resp. π constant and showed the importance of the ring-substituted benzyl moiety. The publication is co-financed by the European Social Fund and the state budget of the Czech Republic. Project No. CZ.1.07/2.3.00/20.0235, the title of the project: TEAB. This study was also supported by the Ministry of Health of Czech Republic (IGA NZ 13346), Grant Agency of Charles University B-CH/710312, the Slovak Grant Agency VEGA, Grant No. 1/0612/11, by the Project APVV-0061-11 and by Sanofi-Aventis Pharma Slovakia. The authors also wish to thank Ida Dufkova for performing and evaluating the antifungal and antibacterial assays and Barbora Servusova and Jan Zitko for English revisions. Sample Availability: Samples of the compounds are available from the authors. ###### Click here for additional data file. The authors declare no conflict of interest.	{ "pile_set_name": "PubMed Central" }
2. Označování pneumatik s ohledem na palivovou účinnost ( Ivo Belet zpravodaj. - Pane předsedo, v krátkosti bych rád poděkoval švédskému předsednictví za výbornou spolupráci. Domnívám se, že tato smlouva je zároveň ambiciózní i realistická. Přesvědčí nás přiklonit se k větší palivové účinnosti, menší hlučnosti a samozřejmě větší bezpečnosti. Mé poděkování směřuje i ke Komisi a stínovým zpravodajům, Matthiasi Grootemu a Jorgu Chatzimarkakisovi, za jejich skvělou práci.	{ "pile_set_name": "EuroParl" }
LAB PRESS RELEASE – FOR IMMEDIATE RELEASE A new cross-cultural study of social network site (SNS) users in Japan (Facebook and Mixi) and the US (Facebook), shows that Japanese SNS users are more concerned about Internet privacy than American SNS users, and suggests that Americans’ lower sense of concern is due to a higher level of general trust in strangers. That is, Americans are less likely to believe a stranger would take advantage of their private information, should it be leaked online. The researchers, from the Culture, Social Ecology, and Psychology Lab at Hokkaido University in Japan, argue that this concept of general trust has not been explored before in Internet privacy concern research. Yes, scholars have explored issues related to national privacy regulation and privacy policy visibility, and how they affect consumer trust on the Internet. But they argue that the trust talked about in previous research is trust based on knowledge about the Internet services consumers are giving their data to. “In reality however, no matter how much trust we put in our knowledge of data protection systems, we all know those systems can fail. How do we deal with that uncertainty?” – Lead author Robert Thomson In their study published this week in a leading academic journal Computers in Human Behavior (open access article link), the authors argue that this is where the concept of general trust comes into play. That is, the stronger a person’s belief is in the goodwill and benevolence of strangers in general, the less likely a person is to worry about what a stranger might do with leaked information. Taking the theory deeper, however, the study also suggests that cultural differences in Internet privacy concern are actually a natural byproduct of psychologies humans have acquired through adaptation to different social environments. Applying existing ideas from behavioral science and increasingly popular evolutionary psychology, the study shows that the concept of relational mobility is a core driver of the observed differences in general trust. “Relational mobility refers to the amount of opportunity and freedom people have in a society to form and sever interpersonal relationships,” explains co-author Dr. Masaki Yuki. “American society in general happens to be high in relational mobility. As social psychologist Toshio Yamagishi has argued, in a society like that, it is adaptive to develop the ability to trust strangers. If you don’t, you might be less willing to interact with strangers, missing out on potentially beneficial new relationships. Japanese society however, is low in relational mobility. There are less relationship opportunities outside of current social circles. Therefore, there’s less need to trust strangers.” The study analyzed survey responses from hundreds of users of SNSs, such as Facebook, in Japan and the US, and the data confirmed the theory. The researchers showed that SNS users who live in a high relational mobility social environment are more likely to trust strangers, and this general trust in turn reduces privacy concern. Thomson says the research has important implications for Internet platforms and services wishing to go global. “Data protection and informed consent should be the standard. But our findings drive home the fact that the importance of these steps may be more pertinent in some societies than others. If your market is Japan, for example, you will have to work hard to gain ? and keep ? consumer confidence that personal data will be used only in ways users have agreed to.” For more information, contact Robert Thomson at rob.thomson@lynx.let.hokudai.ac.jp or +81 (0) 80 4228 6132. ENDS Notes to Editors: PDF version of this press release can be downloaded here. The paper entitled, ‘A socio-ecological approach to national differences in online privacy concern: The role of relational mobility and trust’, is available online in the journal Computers in Human Behavior at http://www.sciencedirect.com/science/article/pii/S0747563215003763. The paper is open access until July 12th 2015, when accessed via this link: http://authors.elsevier.com/a/1R4VL2f~UVuA1p. Lead author Robert Thomson is a Japan Society for the Promotion of Science Doctoral Research Fellow, and is due to complete his doctorate at Hokkaido University in Japan (Sapporo City) this year. His research focuses on cross-cultural differences in behavior online. For more information, go to http://www.robthomo.com. The Culture, Social Ecology, and Psychology Lab is headed by Dr. Masaki Yuki, and explores how the nature of societies (the social ecologies) that surround us affect the way we think, feel, and behave. For more information, go to http://lynx.let.hokudai.ac.jp/~myuki/. The Center for Experimental Research in Social Science at Hokkaido University provides an infrastructure for research activities in order to understand “sociality of mind” as a basis of human and social science. For more information, go to http://lynx.let.hokudai.ac.jp/cerss/en/. ——– Facebook Open Graph og:image credit: Vie privée by g4ll4is	{ "pile_set_name": "OpenWebText2" }
Her law license was suspended earlier this year because of her own personal legal troubles. McTeer is facing felonies and misdemeanors in Canadian County, Logan County and Oklahoma County on a variety of crimes including charges for harboring a fugitive, public intoxication, DUI and possession of drug paraphernalia. McTeer is currently out on bond awaiting court appearances in her five pending criminal cases. She will make appearances in Logan County and Canadian County courts in Sept. on two different criminal cases involving public drunkenness and allegedly breaking her boyfriend out of prison. McTeer's next appearance in Oklahoma County Court is in Oct. We attempted to contact McTeer for this story; she did not answer the door at her Nichols Hills home. We contacted several defense attorneys listed as her representation on various legal documents, all of them denied currently representing her.	{ "pile_set_name": "Pile-CC" }
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Please Report if WinX DVD Ripper Platinum Discount Coupon/Deal/Giveaway has a problem such as expired, broken link, sold out, etc while the deal still exists. 9.6 Total Score Excellent!	{ "pile_set_name": "OpenWebText2" }
Daniel Johnson (journalist) Daniel Benedict Johnson (born 26 August 1957) is a British journalist who was the founding editor of Standpoint magazine. Biography Daniel Johnson is the son of the author Paul Johnson and brother of Cosmo Johnson, Sophie Johnson-Clark and entrepreneur Luke Johnson. After attending Langley Grammar School he graduated with a First in Modern History from Magdalen College, Oxford. Johnson was awarded a Shakespeare Scholarship to Berlin. Returning to English academia as a fellow of Queen Mary, University of London, he served as Director of Publications for the Centre for Policy Studies. Johnson made his name as a journalist covering the fall of the Berlin Wall as German correspondent for the Daily Telegraph. He has been a leader writer for both The Times and the Telegraph, as well as literary editor and associate editor for The Times. In 2008 he launched Standpoint magazine as founding editor. He stood down in December 2018. He was also a contributing editor to The New York Sun and a contributor to The Times Literary Supplement, The Literary Review, Prospect, Commentary, and The New Criterion, as well as The American Spectator and The Weekly Standard. In 2018, Johnson became the founding editor of a new political opinion website, The Article. He is Catholic, and is married with four children. He has asserted that Islam is not a peaceful religion. Bibliography 1989 German Neo-Liberals and the Social Market Economy 1991 Thomas Mann: Death in Venice and other stories 2007 White King and Red Queen: How the Cold War was Fought on the Chessboard References Category:1957 births Category:British male journalists Category:Living people Category:People educated at Langley Grammar School Category:Alumni of Magdalen College, Oxford Category:Opposition to Islam in the United Kingdom	{ "pile_set_name": "Wikipedia (en)" }
Q: Create an event for tab pages in C# I am developing an application in C# Windows Forms, and I would like to create an event handler/event handlers based on whether or not a particular tab page of a tab control is selected. So for example, if I have three tab pages: tabPage1, tabPage2, tabPage3, which belong to tabControl1, I need the code to either: Have three separate event handlers for each tab page Have one event handler and inside of the event handler there is code which can determine the tab page that is currently selected (e.g. a case statement of some sort) I have looked at several examples thus far, but none seem to do what I need. How can I create this event/ these events? A: May be something like this: Make use of TabControl.Selected private void tabControl1_Selected(Object sender, TabControlEventArgs e) { if(e.TabPage == tabPage1) DoSomethingInRelationOfTab1(); else if(e.TabPage == tabPage2) DoSomethingInRelationOfTab2(); .... .... }	{ "pile_set_name": "StackExchange" }
Q: double click on mvc 4 web grid I am preparing a mvc 4 application and I am pretty new to it. I would like to implement a functionality like by double clicking a row of mvc 4 webgrid I should call an action method in ajax. But unfortunately I could not find how to implement double click on mvc 4 web grid. Can you please help me on that? A: You could use the .dblclick() event in jQuery. For example: <script type="text/javascript"> $(function() { $('table td').dblclick(function() { $.ajax({ url: '@Url.Action("SomeAction", "SomeController")', type: 'POST', success: function(result) { // do something with the result from your AJAX call } }); }); }); </script> Obviously there are lots of improvements that could be done to this code. For example you could use HTML5 data-* attributes on your grid to specify the url to the controller action that needs to be invoked and then externalize this script in a separate javascript file. You might also need to adjust the jQuery selector to match your WebGrid element.	{ "pile_set_name": "StackExchange" }
Ralph Blasey Jr. Vice President of Agency that is in charge of security for Comey, Brennan, McCabe, Rice & Lynch — NO COINCIDENCES! Posted byu/Sea127 reddit.com This article puts it all together. Very comprehensive and to the point. No major issue with Mr Ralph Blasey Jr just “HAPPENS” to be VP over all Personal Private Security for Comey, Brennan, McCabe, Rice, Lynch, Podesta, etc? Yeap – she just has a normal everyday daddy and family we all have – and the public wasn’t suppose to know about… PAST POSITION(s) – Her father Ralph G. Blasey Jr.—a proven CIA operative who, from June-1962 to January-1974, was the Vice President of National Savings and Trust of Washington, D.C.—a CIA black budget bank best known for being 100 paces from the White House, and whom, in 1998, was taken over by SunTrust Bank—whose majority share owner is the CIA-linked investment fund BlackRock. (NOTE – Blackrock Secret contracted worth $100s Billions.) The main CIA operative involved in this war, and whom Ralph G. Blasey Jr. reported to, was Nicholas Deak (LINK)—a longtime OSS and CIA operative, both during and after World War II, who ran the CIA’smain BLACK BUDGET OPERATIONS under the direct command of the feared CIA Counterintelligence Chief James Jesus Angleton. To how the CIA prevented the total breakdown of the Western banking system in 1982, was by their illegally laundering hundreds-of-millions of dollars of Colombian drug cartel cash into it to keep it afloatin an operation overseen by the CIA’s “James Bond of Money” Nickolas Deak—but when the President Ronald Reagan administration found out what the CIA had done, and started investigating it, saw Deak, on 19 November 1985, being assassinated in his New York City office by a homeless woman named Lois Lang. (It was alleged that one Ralph G Blasey Jr was assigned this Deep State Wetworks, since he knew and worked with Mr Deak, and was his Senior). As CIA & FBI Directors come and go after 4+ decades, Mr Blasey stayed at the very top of CIA/FBI officials, and was transitioned into each new CIA/FBI Administration. If there is any Unelected, Stable, Reliable “Deep State” criminal agenda going on today, Mr Blasey Jr is a Major link Lifelong connection between each New Administration to carry out and plan any longterm “Criminal Coup” of our nation. Understand how someone 40+ years in the CIA from controlling Black Ops Secret Bank Budgets, to now Providing Personal Public Security to each of the “Deep State” criminals (Brennan, Comey, McCabe, Mueller, Rice, Lynch, etc) who have been fired, removed, and now facing criminal charges. The one link to them all are one Ralph G Blasey Jr – and the REAL TOP TIER DEEP STATE	{ "pile_set_name": "Pile-CC" }
Location & Hours of Operation The Records Division is on the first floor of the Durham County courthouse located at 510 South Dillard Street in Durham. The staff is available Monday through Friday from 8:30 a.m. until 5 p.m. Records Requests & Fees Contact: 919-560-0899 or 919-560-0898 Applicants can pay their fee in cash or credit at the Cashier's Office located on the first floor of the Durham County courthouse. Please note, the credit card service provider assesses a convenience fee for each permit or report. The fee schedule is listed below. All fees are non-refundable, including permit denials. Schedule of Service Fees Cash Credit Card Fingerprints $15.00 $18.45 Thumbprint - Cash Only $5.00 Concealed Carry Permit $90.00 $95.70 Renewal $75.00 $80.25 Duplicate $15.00 $18.45 Lamination $3.00 $6.09 Pistol Permit $5.00 $8.15 Report Copy $3.00 $6.09 Security Card for Building Access $10.00 $13.30 * Attorney's Requests Only Cash Credit Card Criminal History Check* $10.00 $13.30 Driver History Check* $10.00 $13.30 *Criminal background checks are available for court officials only. Members of the public in need of a criminal record check should visit the Clerk of Court's Office located on the first floor of the Durham County courthouse.	{ "pile_set_name": "Pile-CC" }
Immunology Driven by Large-Scale Single-Cell Sequencing. The immune system encompasses a large degree of phenotypic diversity and plasticity in its cell types, and more is to be uncovered. We argue that large, multiomic datasets of single-cell resolution, in conjunction with improved computational methods, will be essential to resolving immune cell identity. Existing datasets, combined with 'big data' methodologies, can serve as a platform to support future studies in immunology. Technical and analytical advances in multiomics and spatial integration can provide a reference for gene regulation and cellular interactions in spatially structured tissue contexts. We posit that these developments may allow guided functional studies of immune cell populations and lay the groundwork for informed cell engineering and precision medicine.	{ "pile_set_name": "PubMed Abstracts" }
Q: OpenMesh: remove_property : is not a member of Decimater::DecimaterT I'm trying to use the decimater algorithm in OpenMesh. I followed the basic setup presented in this link: http://openmesh.org/Documentation/OpenMesh-2.0-Documentation/decimater_docu.html but I get the following error which is comes from the modquadrict.hh(part of the library). error C2039: 'remove_property' : is not a member of 'OpenMesh::Decimater::DecimaterT<MeshT>' main.cpp #include "MyMesh.h" #include <conio.h> #include <iostream> int main() { MyMesh mesh; decimater deci (mesh); HModQuadric hModQuad; if(!OpenMesh::IO::read_mesh(mesh, "models/monkey.obj")); { std::cout<<"Cannot read mesh"; } deci.add(hModQuad); std::cout << deci.module( hM).name() << std::endl; getch(); return 0; } MyMesh.h #pragma once // OpenMesh #pragma warning(push) #pragma warning(disable: 4267) #include <OpenMesh/Core/IO/MeshIO.hh> #include <OpenMesh/Core/Mesh/TriMesh_ArrayKernelT.hh> #include <OpenMesh/Tools/Decimater/ModQuadricT.hh> #include <OpenMesh/Tools/Decimater/DecimaterT.hh> #pragma warning(pop) //Additional mesh parameters struct MeshTraits : public OpenMesh::DefaultTraits { VertexAttributes(OpenMesh::Attributes::Normal); FaceAttributes(OpenMesh::Attributes::Normal); }; typedef OpenMesh::TriMesh_ArrayKernelT<MeshTraits> MyMesh; // Decimater type typedef OpenMesh::Decimater::DecimaterT< MyMesh > decimater; // Decimation Module Handle type typedef OpenMesh::Decimater::ModQuadricT< decimater >::Handle HModQuadric; A: The problem was with this line. typedef OpenMesh::Decimater::ModQuadricT< decimater >::Handle HModQuadric; it should be like this: typedef OpenMesh::Decimater::ModQuadricT< MyMesh >::Handle HModQuadric; I was referring the documentation from version 2.0 while working on version 3.0 With recent versions, the templating depend on the mesh and not the decimater.	{ "pile_set_name": "StackExchange" }
Eloyi Eloyi may refer to Eloyi Christian Church, an Apostolic church in Botswana Eloyi language, a poorly attested Plateau language of Nigeria Eloyi people, an ethnic group in Nigeria	{ "pile_set_name": "Wikipedia (en)" }
School lunches and lunches brought from home: a comparative analysis. Considerable effort has been put forth to improve the nutritional quality of school meals by the National School Lunch Program (NSLP). However, a large percentage of children do not obtain their meals from school and instead bring lunch from home. Little research has focused on the content of these lunches. The purpose of the current study was to examine differences between school lunch and lunch brought from home. Children in the 2nd grade from seven schools in a large suburban school district were observed on three separate days. A total of 2107 observations were made, with 38.5% of these being lunches brought from home. Chi-squared analyses evaluated differences in the presence of specific food items between school lunch and lunch brought from home. Compared to children with a school lunch, children with a lunch brought from home were significantly less likely to have fruits (75.9% vs. 45.3%), vegetables (29.1% vs. 13.2%), and dairy (70.0% vs. 41.8%) (p < 0.001). Children with a lunch from home were more likely to have snacks high in sugar and/or fat (17.5% vs. 60.0%) and non 100% fruit juice/fruit drink (0.3% vs. 47.2%) (p < 0.001) than children with a school lunch. The NSLP has been widely criticized; however, conducting a comparison in this manner demonstrates advantages to children obtaining school lunches. Although it was beyond the scope of this study to examine diet quality (e.g., actual intake and nutrient/caloric density), these results provide compelling evidence that lunches brought from home should be an area of emphasis for research and intervention.	{ "pile_set_name": "PubMed Abstracts" }
Q: Best way to reorganize array of objects I need reorganize and array of linked objects by id to only one tree object. The depth level is unknown, so that I think that it should be done recursively. What is the most efficient way? I have the next array of objects: const arrObj = [ { "id": 1, "children": [ { "id": 2 }, { "id": 3 } ] }, { "id": 2, "children": [ { "id": 4 }, { "id": 5 } ] }, { "id": 3, "children": [ { "id": 6 } ] }, { "id": 4 } ] I want restructure for have a only one object like a tree: const treeObj = { "id": 1, "children": [ { "id": 2, "children": [ { "id": 4 }, { "id": 5 } ] }, { "id": 3, "children": [ { "id": 6 } ] } ] } Each object has other many properties. A: You can use a recursive mapping function over all the children. const arrObj = [ { "id": 1, "children": [ { "id": 2 }, { "id": 3 } ] }, { "id": 2, "children": [ { "id": 4 }, { "id": 5 } ] }, { "id": 3, "children": [ { "id": 6 } ] }, { "id": 4 } ]; const res = arrObj[0];//assuming the first element is the root res.children = res.children.map(function getChildren(obj){ const child = arrObj.find(x => x.id === obj.id); if(child?.children) child.children = child.children.map(getChildren); return child \|\| obj; }); console.log(res);	{ "pile_set_name": "StackExchange" }
11 Cal.App.2d 357 (1936) H. B. RASMUSSEN, Respondent, v. FRESNO TRACTION COMPANY (a Corporation) et al., Appellants. Civ. No. 1745. California Court of Appeals. Fourth Appellate District. January 21, 1936. W. H. Stammer, Everts, Ewing, Wild & Everts, A. W. Carlson and Richard H. Reeve for Appellants. David E. Peckinpah and Harold M. Child for Respondent. Barnard, P. J. This is a motion to dismiss the appeal or affirm the judgment. [1] We have frequently held that such a motion should not be granted where it appears, after examination of the opening brief and the papers filed in support of the motion, that the case cannot be decided without examining the entire record. (Brown v. Gow, 126 Cal.App. 113 [14 PaCal.2d 322]; Ross v. Mahoney, 134 Cal.App. 199 [25 PaCal.2d 268]; Barr v. Hall, 9 Cal.App.2d 426 [49 PaCal.2d 1124].) At least two of the points raised on this appeal could not be decided without a complete examination of the entire record. This is virtually conceded by the respondent, whose notice of motion states that the same would be based upon the entire record on this appeal and also upon the entire record in a prior appeal. Moreover, in his argument in support of this motion he goes outside of the opening brief and the moving papers and presents matters which require a study of the entire record. An examination of the opening brief and the moving papers indicates that the questions here raised call for careful consideration and will require a thorough examination of the evidence, in all of which the court is entitled to the assistance of the respondent. The motion is denied. Marks, J., and Jennings, J., concurred.	{ "pile_set_name": "FreeLaw" }
37 F.3d 477 UNITED STATES of America, Plaintiff-Appellee,v.Samuel William DONAGHE, Defendant-Appellant. No. 93-30058. United States Court of Appeals,Ninth Circuit. Argued and Submitted Dec. 15, 1993.Decided Sept. 30, 1994. Sheryl Gordon McCloud, Seattle, WA, for defendant-appellant. Sean Connelly, U.S. Dept. of Justice, Washington, DC, for plaintiff-appellee. Appeal from the United States District Court for the Western District of Washington. Before: BROWNING, NORRIS, and O'SCANNLAIN, Circuit Judges. O'SCANNLAIN, Circuit Judge: 1 We must decide whether the district court based its upward departure from the Sentencing Guidelines on proper factors and explained adequately the extent of its departure. 2 * On November 21, 1988, Samuel Donaghe was sentenced for making a false statement in a passport application in violation of 18 U.S.C. Sec. 1542. The district court did not apply the Sentencing Guidelines, because it was unclear at that time whether they were constitutional, and sentenced him to three years of probation. Because Donaghe had a history of sexually assaulting minors--he had been convicted of four such offenses previously--the court imposed the condition, among others, that Donaghe not associate with minors without the consent of the Probation Office. 3 On March 8, 1990, the district court revoked Donaghe's probation pursuant to 18 U.S.C. Sec. 3563 because he had violated conditions of probation. Specifically, Donaghe had possessed a firearm, failed to inform the Probation Office of his new employment, associated with a minor foreign exchange student for whom he was the host parent, and been convicted in state court of solicitation to commit assault and two counts of rape. The district court then sentenced Donaghe to five years imprisonment for the passport offense, again under pre-Guidelines law. 4 On appeal, this court vacated the sentence and held that the Guidelines applied. We remanded for resentencing, specifying that the district court consider United States v. White, 925 F.2d 284 (9th Cir.1991). United States v. Donaghe, No. 92-30183, 978 F.2d 716 (Table), 1992 WL 317200, 1992 U.S.App. LEXIS 29342 (9th Cir. Sept. 15, 1992). At resentencing on January 22, 1993, the district court adopted the Presentence Report ("PSR") that calculated Donaghe's criminal history category as 1, his total offense level as 4, and the resulting sentencing range as 0-6 months. The court also adopted the PSR's recommendation to depart upward and imposed a sentence of five years imprisonment and three years supervised release. II 5 When we remanded this case for resentencing under the Guidelines, we explicitly instructed the district court not to depart from the Guidelines based on Donaghe's conduct during probation. Instead, we stated that "[i]f the district court chooses to depart it must cite factors, available to it at the original sentencing, sufficient to support its decision. It may consider Donaghe's probation-violating conduct for its effect on the weighing of those departure factors." Donaghe, 1992 WL 317200, at * 1, LEXIS 29342, at * 3. 6 We relied on White to reach this conclusion. In that case, this court held that for resentencing under 18 U.S.C. Sec. 3565,1 the district court could not use probation conduct to "directly increase a sentence." White, 925 F.2d at 286. The court stated that the district court could depart from the Guidelines range, "provided that facts warranting departure were available at the initial sentencing." Id. at 287. However, the court also noted that "probation-violating conduct is not completely irrelevant to sentencing under Sec. 3565(b)2.... [T]he sentencing court can consider the conduct in determining whether to depart from the initial guideline range.... In other words, the court cannot make additional factual findings to justify a departure, but can reconsider its original decision not to depart in light of the defendant's subsequent actions." Id. 7 The Guidelines provide two means of departing upward from a sentence range: adjusting the criminal history category when the Guidelines do not adequately reflect the seriousness of the offender's past conduct or the likelihood that he or she will commit other crimes, under U.S.S.G. Sec. 4A1.3, p.s., and adjusting the offense level to take into consideration aggravating circumstances to a kind or a degree not considered by the Guidelines, according to U.S.S.G. Sec. 5K2.0, p.s. 8 In evaluating these adjustments, the reviewing court does "not search the record for permissible reasons for departure; instead, [it] analyze[s] the reasons actually given by the district court." United States v. Montenegro-Rojo, 908 F.2d 425, 428 (9th Cir.1990). Here, the district court, for the most part, relied on the PSR to articulate the reasons for departure. The PSR listed three factors that "were known to the Court at the time of the original sentence and would have justified an upward departure." First, Donaghe had been convicted between 1967 and 1973 of several sex-related crimes involving minors. Second, at the time of the original sentencing, he was being investigated for sexual misconduct with his nephew. Finally, a 1968 psychiatric evaluation diagnosed Donaghe as having a "sexual deviation, homosexuality with pedophilia." For the upward departure to be valid, all these factors must be proper bases for departure. Id. (If the district court "considered both proper and improper bases for departure, 'we have no way to determine whether any portion of the sentence was based upon consideration of the improper factors,' and must therefore vacate the sentence and remand for resentencing") (citation omitted). 9 * As a basis for its departure, the district court relied on its determination that Donaghe's criminal history category inadequately reflected his past criminal conduct. The Guidelines do not allow past sentences of imprisonment exceeding one year and one month and occurring more than fifteen years before the sentencing date to be considered in determining a criminal history category. U.S.S.G. Sec. 4A1.2(e)(1), (3). The Guidelines do not allow any other past sentences occurring more than ten years before the sentencing date to be considered in determining a criminal history category. U.S.S.G. Sec. 4A1.2(d)(2), (3). Donaghe's misconduct occurred fifteen years prior to the initial sentencing. 10 However, the commentary to section 4A1.2 creates an exception for sentences imposed outside these time periods where the court finds "evidence of similar, or serious dissimilar, criminal conduct." U.S.S.G. Sec. 4A1.2, comment. (n. 8). If the misconduct meets this description, "the court may consider this information in determining whether an upward departure is warranted." Id. 11 * Donaghe argues that his convictions for child molestation are not similar to the instant offense of falsifying a passport application. The government has the burden of demonstrating that such similarity exists. United States v. Starr, 971 F.2d 357, 362 (9th Cir.1992). The government argues that the crimes are similar because Donaghe was motivated to falsify the passport application in order to escape an investigation into new child molestation charges. Thus, the government maintains, the crimes were "inextricably linked." 12 The government's argument must fail. Although there may be a causal link between Donaghe's tendency toward sexually abusing children and the false application--because of his criminal behavior, he was in trouble and wanted to flee the country--this does not make the two crimes similar. The government's reasoning does not comport with this court's understanding of similarity, which requires a much closer likeness. For instance, in Starr, we held that possession of stolen property and embezzlement were similar to bank robbery, because all were "crimes of theft." 971 F.2d at 362. We did not require "[i]nquiry into the specific facts of the prior convictions." Id. And, in United States v. Cota-Guerrero, 907 F.2d 87 (9th Cir.1990), we concluded that past convictions for assault with a deadly weapon and assault and battery were similar to possession of a firearm by a felon because "they show a propensity toward violence and a willingness to use force." Id. at 89. As in Starr, we did not examine the particular facts surrounding each crime but instead concentrated on their general characteristics. 13 Child molestation and passport fraud have no characteristics in common. Unlike the crimes in Starr and Cota-Guerrero, they cannot be categorized together as crimes of fraud or of violence. They are linked only by the specific circumstances of this case, a factor not viewed as relevant. The crimes, thus, are not similar under the section 4A1.2 commentary. 2 14 The commentary to section 4A1.2 also creates an exception for serious dissimilar past crimes. Donaghe argues that this part of the commentary is not applicable to his case because it was introduced by amendment effective November 1, 1992 and his original sentencing occurred on November 21, 1988. We agree. 15 The amendment to the commentary of section 4A1.2 has been designated a clarifying change. U.S.S.G.App. C n. 472. Normally, when an amendment is deemed clarifying rather than substantive, it is applied retroactively. U.S.S.G. Sec. 1B1.11(b)(2). However, it will not be applied retroactively when, as here, it would violate the ex post facto clause. United States v. Smallwood, 35 F.3d 414, 417-18, n. 8 (9th Cir.1994). Thus, the 1992 amendment to the commentary to section 4A1.2 does not apply. 3 16 Section 4A1.3 also allows a court to depart because the criminal history category does not adequately reflect the likelihood that the offender will commit other crimes. The PSR improperly included Donaghe's 1968 diagnosis as a homosexual deviant as a factor for departure. Homosexuality is no longer categorized as a psychiatric disorder. Diagnostic and Statistical Manual of Mental Disorders (1987) (DSM-III-R). Further, the fact that someone is a homosexual is not indicative of his or her propensity to commit crimes. See Beam v. Paskett, 3 F.3d 1301, 1310 (9th Cir.1993) ("It goes without saying that society has abandoned its earlier belief that homosexuality presents a danger to the community."), cert. denied, --- U.S. ----, 114 S.Ct. 1631, 128 L.Ed.2d 354 (1994). 17 Although the PSR's notation that Donaghe was also diagnosed as an untreatable pedophile might be a reason for believing that he will commit other crimes, the court did not make factual findings supporting the existence of this factor, United States v. Lira-Barraza, 941 F.2d 745, 746 (9th Cir.1991) (en banc), other than to mention the outdated psychiatric report. Since it is not at all clear from the PSR that the twenty-five year old psychiatric evaluation is still valid or that a pedophile is likely to continue to molest children, the court's limited factual findings do not support the diagnosis as a basis for departure. 18 The district court also identified a January 1992 psychological evaluation, which concluded that Donaghe may continue his criminal behavior. Since this evaluation was not available as a factor at the initial sentencing, it cannot be a departure factor. B 19 The district court also based its departure on its determination that Donaghe's offense level was inadequate. Section 5K2.0 provides for adjusting an offense level if the offense involves "factors in addition to those identified that have not been given adequate consideration by the Commission," or "if the court determines that, in light of unusual circumstances, the guideline level attached to that factor is inadequate." U.S.S.G. Sec. 5K2.0, p.s. The pending criminal investigation of Donaghe for possible sexual misconduct with his nephew was a fact available at the initial sentencing and was a departure factor listed in the PSR. The government argues that the incident of passport fraud was atypical, because Donaghe's motive was to escape possible prosecution for sexual misconduct. The government contends that this justifies an upward departure in the offense level. 20 There is no mention in the Guidelines that the Sentencing Commission considered the reasons why a person might want to obtain a false passport. However, the version of section 5K2.0 in effect in November 1988 stated that "[h]arms identified as a possible basis for departure from the guidelines should be taken into account only when they are relevant to the offense of conviction." U.S.S.G.App. C n. 358. Intending to use the false passport for the purpose of escaping criminal prosecution is not an element of the crime of making a false statement in a passport application. See 18 U.S.C. Sec. 1542. Since Donaghe's reason for wanting a fake passport is not relevant to the offense of falsifying the application, that reason could not be a basis for increasing the offense level in 1988. See, e.g., United States v. Cervantes Lucatero, 889 F.2d 916, 917 & n. 1 (9th Cir.1989) (holding upward departure inappropriate where it was based on district court's determination that offender's reason for entering United States illegally was not to seek work and help his family but to "live off the land" and "violate its laws"). 21 The district court also identified as a factor supporting an increase in offense level the fact that "Judge Ingram in the original sentence imposed a special condition that he not be around minor children.... And the conduct for which Donaghe stands having committed on the revocation are all directly related to that conduct in the original sentence." The fact that Donaghe violated this probation condition was not available at the initial sentencing and so cannot be a departure factor. C 22 Because all of the factors considered by the district court were improper bases for departure, we must vacate the sentence and remand for resentencing. Montenegro-Rojo, 908 F.2d at 428. At resentencing, the district court must not base its departure on Donaghe's diagnosis as a homosexual, the similarity between passport fraud and sexual misconduct, Donaghe's prior molestation convictions or any of Donaghe's conduct during probation. III 23 Donaghe argues that the departure from a sentencing range of 0 to 6 months to a sentence of 60 months was unreasonable. A district court abuses its discretion in departing upward if it "gave no reason or justification for the extent of its departure." United States v. Beck, 992 F.2d 1008, 1009 (9th Cir.1993). The district court must make an "effort to tie the departure to the Guidelines," through a "reasoned explanation of the extent of the departure founded on the structure, standards and policies of the Act and Guidelines." United States v. Ramirez-Jiminez, 967 F.2d 1321, 1329 (9th Cir.1992) (quoting Lira-Barraza, 941 F.2d at 745). This is generally accomplished, in a case of inadequate criminal history, by "analog[izing] to higher criminal history categories." Beck, 992 F.2d at 1109. "Ordinarily, the court should determine whether a defendant's actual criminal history most closely resembles the next higher criminal history category before concluding that the defendant's record is so severe that comparison to a higher category is warranted." Starr, 971 F.2d at 363. 24 The district court here made no attempt to explain the extent of the departure when it adopted the recommendations of the PSR. The PSR calculated the new offense level of 24 (resulting in a sentencing range of 51 to 63 months) by adding to Donaghe's original level four offense a ten level increase for the two rape convictions, a five level increase for the solicitation to commit assault conviction, a three level increase for possession of a firearm, and a two level increase for his attempted solicitation of assault. These numbers appear to have been chosen at random; the report does not explain any rationale behind them. Neither does the report attempt to analogize Donaghe's supposedly unusual offense or inadequate criminal history to the next highest level or category. 25 Finally, the PSR conflates departures in offense level and in criminal history category. As explained above, some of the departure factors identified in the PSR are the type that might support an increased criminal history category, while others are the kind that might support a higher offense level. But the report increases only Donaghe's offense level and does not explain upon which of the factors it relies. It cannot rely on all the factors because some, like the prior convictions, could possibly support only a higher criminal history category. 26 We vacate the sentence and remand because the district court abused its discretion by not adequately explaining the extent of the departure. At resentencing, the district court must explain the extent of its departure by analogizing the increased criminal history category or offense level to the next relevant category or offense level.3 IV 27 Donaghe argues that the district court improperly ordered his sentence to run consecutively with his state law sentences for the probation-violating crimes. He points to the current language of section 5G1.3(b), providing for concurrent sentences. However, since we apply the Guidelines effective on the date of sentencing, United States v. Warren, 980 F.2d 1300, 1304 (9th Cir.1992), cert. denied, --- U.S. ----, 114 S.Ct. 397, 126 L.Ed.2d 344 (1993), we must apply the version of section 5G1.3(b) in force in November 1988. 28 The version of section 5G1.3 effective in November 1988 stated, "[i]f at the time of sentencing, the defendant is already serving one or more unexpired sentences, then the sentences for the instant offense(s) shall run consecutively to such unexpired sentences." U.S.S.C.App. C n. 289. Donaghe was serving a state sentence when the district court ordered consecutive sentences. Thus, applying the 1988 version to Donaghe's situation, the district court's imposition of consecutive sentences was appropriate.4 V 29 Donaghe argues that the district court cannot impose a period of supervised release on resentencing after probation revocation. His claim is not persuasive because the authorities he cites address resentencing after the revocation of supervised release. See 18 U.S.C. Sec. 3583; United States v. Behnezhad, 907 F.2d 896 (9th Cir.1990). 30 However, the controlling statute for resentencing after probation revocation is 18 U.S.C. Sec. 3565. The court in Behnezhad emphasized the difference between sections 3583 and 3565. After concluding that section 3583 did not allow a new term of supervised release, the court explained that section 3565 allowed for "greater flexibility to create terms of punishment for violations of probation." 907 F.2d at 899. "[W]hen a court revokes probation, it has the flexibility to structure a new sentence that may include probation, incarceration, fines and supervised release." Id. Therefore, the court did not err in imposing a three year term of supervised release. VI 31 Donaghe requests that the panel remand the case to a new judge. In United States v. Arnett, 628 F.2d 1162 (9th Cir.1979), the court stated that the relevant factors for making this decision are "(1) whether the original judge would reasonably be expected upon remand to have substantial difficulty in putting out of his or her mind previously-expressed views or findings determined to be erroneous or based on evidence that must be rejected, (2) whether reassignment is advisable to preserve the appearance of justice, and (3) whether reassignment would entail waste and duplication out of proportion to any gain in preserving the appearance of fairness." Id. at 1165 (quoting United States v. Robin, 553 F.2d 8, 10 (2d Cir.1977) (en banc)). 32 The Ninth Circuit has remanded under the first factor when the error was created by the judge. United States v. Larios, 640 F.2d 938, 943-44 (9th Cir.1981); United States v. Doe, 655 F.2d 920, 928-29 (9th Cir.1980). Here, Judge Tanner erred in identifying factors supporting departure that were not available at the initial sentencing. Also, he adopted the PSR's sentence recommendation, which relied on Donaghe's probation-violating conduct to justify an extreme upward departure, without explaining what "new light [the conduct] sheds on where to sentence within the original Guidelines range or whether or how much to depart." Donaghe, 1992 WL 317200, at * 1, 1992 U.S.App. LEXIS 29342, at * 3. 33 Although Judge Tanner created the error, there is no significant showing that he was biased against Donaghe. Reassignment to a new judge is not necessary to preserve the appearance of justice. VII 34 Because all of the departure factors identified by the district court were improper, we vacate the sentence and remand. Also, the district court's failure to explain the extent of the departure requires us to remand. However, the imposition of three years supervised release and consecutive sentences was proper. 35 AFFIRMED in part, REVERSED in part, VACATED and REMANDED. 1 This statute provides that on resentencing after probation revocation, the district court must impose "any other sentence that was available ... at the time of the initial sentencing." 18 U.S.C. Secs. 3565(a) and 3565(b) 2 Although the facts in White involved probation revocation under Sec. 3565(b), the court explained that Sec. 3565(a) used the same language, and so the case's analysis applied to both sections. Id. at 286 n. 1 3 Donaghe argues that on remand the Revocation Table of U.S.S.G. Sec. 7B1.4 should control resentencing. This table establishes sentencing ranges by taking account of criminal history categories and probation-violating conduct. However, in United States v. Dixon, 952 F.2d 260 (9th Cir.1991), the Ninth Circuit held that this section contradicted 18 U.S.C. Sec. 3565(a). Section 3565(a) requires the court to impose a sentence that was "available ... at the time of the initial sentencing," while the Revocation Table "require[s] courts to impose sentences that, in many cases, were not 'available' at the time of initial sentencing." Id. at 261. To the extent that the Guidelines conflicted with the statute, the court found them invalid. Id. at 260. Therefore, the district court should not be guided by the Revocation Table at resentencing 4 The government argues that U.S.S.G. Sec. 7B1.3(f), p.s. governs this question. However, in November 1988, that section did not exist	{ "pile_set_name": "FreeLaw" }
Tuamie - Masta Killa drops 9/17. Pre-order the limited cassette at www.grandgardenrecords.com ‘Masta Killa’ is Grand Garden’s first release and a look into the mind of producer Tuamie. Hailing from Richmond, VA Tuamie is one of the beat scene’s brightest young talents. A true “head” and lover of records Tuamie pride’s himself on making beats with unidentifiable samples. ‘Masta Killa’ is no generic beat tape mind you. The album is full of house, soul, and African rhythms generating a feeling of mid 90’s nostalgia while maintaining a contemporary sound. Tuamie has performed alongside Knxwldge, Ohbliv, P.U.D.G.E. and many more. Stay tuned for Tuamie's production on Vol. 4 of DJ House Shoes' "The Gift" series. This limited edition cassette release comes with a "plantable" download card that will grow flowers after planted in soil.	{ "pile_set_name": "Pile-CC" }
1. Introduction {#sec1} =============== The important recent achievement in Parkinson\'s disease (PD) research has been the identification of several causative and risk genes with their putative functions. Leucine-rich repeat kinase 2 (LRRK2) gene has been distinguishable from other known PD genes with a number of functional and epidemiologic features. LRRK2 is a highly conserved and widely expressed gene that encodes a unique multifunctional and multidomain protein, named dardarin \[[@B1]\]. Dardarin is a complex chain of 2 527 polypeptides containing two distinct enzymes, namely protein kinase and guanosine triphosphatase (GTPase), as well as multiple protein interaction domains \[[@B2]\]. These domains might interact with each other and other cell signaling proteins, thus playing a putatively key role in cellular function \[[@B3]--[@B5]\]. Intriguing is the fact that almost every LRRK2 domain is susceptible to PD-associated mutations resulting largely in idiopathic PD- (iPD-) like phenotype and pleomorphic neuronal pathology \[[@B2], [@B4]\]. Amongst the number of known LRRK2 mutations, p.Gly2019Ser mutation has emerged as an important determinant of familial autosomal dominant PD and iPD in North African Arabs, Ashkenazi Jews, and to a lesser degree in European and North American populations \[[@B6]\]. Interestingly, it appears that some LRRK2 mutations and disease-associated variants are specific to particular ethnic groups, most likely due to common founder effects \[[@B7]\]. This is evidently applicable to p.Gly2019Ser mutation, which is common in PD patients from the Western hemisphere and has not yet been reported in the big PD cohorts from East Asia. Similarly, several PD risk variants of LRRK2 including p.Gly2385Arg, p.Ala419Val, and p.Arg1628Pro have only been reported in East Asian populations and have been absent in the Western PD cohorts \[[@B8]\]. PD genetics has been largely unexplored in several world regions, including Central Asia. Here, we investigate 8 LRRK2 mutations and East Asian risk variants in an interesting population residing between Europe and Asia, in the first cohort of PD patients and healthy controls from Kazakhstan. 2. Study Methodology {#sec2} ==================== 2.1. Study Subjects {#sec2.1} ------------------- A total of 246 PD patients were consecutively recruited, with no regard to nationality, during 14 months from the National Center for Neurosurgery in Nur-Sultan city, movement disorders clinics in Almaty city, and a regional hospital in Shymkent city in Kazakhstan. The diagnoses of clinically established and clinically probable PD were made on the basis of the agreement between two movement disorder specialists according to the Movement Disorders Society (MDS) PD criteria \[[@B9]\]. Both iPD and familial PD cases with their available first-degree relatives were included in the study. Clinicodemographic characteristics of the cohort were uploaded to University College London (UCL) Research Data Capturing Database (Redcap) online secure database and its summary is given in [Table 1](#tab1){ref-type="table"}. There were 21 patients (8.5%, 21/246) with a family history of PD and/or tremor, and 31 (12.6%, 31/246) patients with the onset of PD before 40 years of age. The male to female ratio was 0.95 : 1. The mean age of PD onset was 55.06 ± 11.15 (range 14--77), and the mean age at the last examination was 61.7 ± 10.3 (range 28--83). Self-reported nationalities in 72.8% of the cohort were Kazakh, 20.7% were Russian, and the remaining nationalities were Uyghur (2.8%), Tatar (2%), Korean (1.3%), and Tajik (0.4%). Genomic DNAs of age- and gender-matched 200 unrelated control subjects were obtained from the research-ready database of neurologically healthy Kazakhs from the National Center for Biotechnology, Nur-Sultan (NCB). This study was approved by the Research Ethics Committee of NCB (4/29.08.2017) and the Institute of Neurology University College London (IoN UCL) (07/Q0512/26). Written informed consent for participation in the study was obtained from each subject. All personal information was hidden with unique study identifiers. 2.2. Genetic Analysis {#sec2.2} --------------------- Whole venous blood was collected from the subjects at the recruitment centers and sent to NCB for DNA extraction using the standardized laboratory protocols. DNAs were then shipped to IoN UCL for genetic analysis. At IoN, DNAs were checked for quality and concentrations using NanoDrop Spectrophotometer (Thermo Scientific, Waltham, MA, USA). Samples were uniformly diluted to 25 ng/μl, and 25 μl volume of DNA from each sample was transferred to 96-well plates. On the basis of the literature review, 8 LRRK2 single-nucleotide polymorphisms (SNPs) of interest were selected for the analysis. Five of them are commonly reported LRRK2 mutations: (c.6055G\>A) p.Gly2019Ser (rs34637584), (c.4322G\>A) p.Arg1441His (rs34995376), (c.5096A\>G) p.Tyr1699Cys (rs35801418), (c.6059T\>C) p.Ile2020Thr (rs35870237), and (c.4309A\>C) p.Asn1437His (rs74163686); and three of them are the East Asian-specific PD-associated variants: (c.7153G\>A) p.Gly2385Arg (rs34778348), (c.1256C\>T) p.Ala419Val (rs34594498), and (c.4883G\>C) p.Arg1628Pro (rs33949390) ([Figure 1](#fig1){ref-type="fig"}). The SNPs and surrounding 50 base-pairs were annotated in Ensembl genome browser (see S1 in the supplementary material for comprehensive analysis). The design of primers, adaptation of assays, and genetic analysis were performed in LGC Genomics, England. No positive and negative controls were available for the selected LRRK2 SNPs. LRRK2 genotyping was done using Kompetitive Allele-Specific Polymerase chain reaction (PCR) genotyping assay (KASP™, LGC Genomics. Herts, UK), a method that enables biallelic scoring of SNPs and insertion and deletions at specific loci through competitive allele-specific PCR. Genotyping followed the LGC Genomics protocol. SNP viewer Software (version 1.99, Hoddesdon, UK) was used to visualize the genotyping results (<https://www.biosearchtech.com/support/tools/genotyping-software/snpviewer>). Familial and young-onset PD cases with positive LRRK2 substitutions were sent for exome sequencing (WES) to Macrogen, South Korea. In addition, when LRRK2 mutations were identified in a proband, Sanger sequencing was performed for all available family members. Thus, we enrolled 13 additional living relatives for the p.Gly2385Arg and p.Ala419Val mutations from two families. 2.3. Statistical Analysis {#sec2.3} ------------------------- Statistical analysis was performed using IBM SPSPS version 21 (Chicago, USA). Genotype frequency distributions were tested for conformity to Hardy--Weinberg equilibrium (HWE). T-test and chi-squared tests were used at the level of significance 0.05. Odds ratios (OR) were calculated and presented with 95% confidence interval (CI) values. 3. Results {#sec3} ========== 3.1. KASP Coverage {#sec3.1} ------------------ 1.6--3.2% of samples were uncalled in KASP assay analysis and this was within the expected values \[[@B10]\]. The number of uncalled samples for each LRRK2 SNP is shown in Supplementary Materials ([](#supplementary-material-1){ref-type="supplementary-material"} and [](#supplementary-material-1){ref-type="supplementary-material"} for comprehensive analysis). 3.2. SPNs with Negative Findings {#sec3.2} -------------------------------- The following most pathogenic LRRK2 mutations p.Gly2019Ser, p.Arg1441His, p.Tyr1699Cys, p.Ile2020Thr, and p.Asn1437His were not found in our cohort of PD patients and controls. All of the 246 PD subjects and 200 controls were homozygous for wild-type alleles of these SNPs ([Table 2](#tab2){ref-type="table"}). The allelic frequencies for the aforementioned SNPs were in Hardy--Weinberg equilibrium (p=1). 3.3. SNPs with Positive Findings {#sec3.3} -------------------------------- ### 3.3.1. p.Gly2385Arg (c.7153G\>A) {#sec3.3.1} Monoallelic p.Gly2385Arg variant (rs34778348) was found in three PD cases (1.2%, n = 3/239) and two controls (1%, n = 2/199) ([Table 3](#tab3){ref-type="table"}). The first positive case was a young Kazakh male with an autosomal dominant family history of PD. He developed PD at the age of 38 years, and the onset symptoms were depression, anxiety, hyposmia, and left-hand tremor. He had an affected mother, who had developed PD at the age of 55 years and deceased at the age of 58 years. Interestingly, his mother had three female siblings with upper-limb tremor but no signs of bradykinesia ([Figure 2](#fig2){ref-type="fig"}). He had fast progression in the disease course and in two years from the disease onset developed difficulty in rising up from a chair, freezing episodes, urinary frequency, and gait abnormalities. His off-stage MDS UPDRS motor scale score was 79 with Hoehn--Yahr stage 3. There was a good response to levodopa. WES in the proband did not reveal any other known PD genes. p.Gly2385Arg variant was tested in six of his healthy relatives and in those with tremor (n = 4) by Sanger sequencing. The variant was present in one of the two unaffected siblings of the proband, unaffected 20-year-old daughter of the proband, and in only one out of the four relatives with tremor ([Figure 2](#fig2){ref-type="fig"}). The second PD case was a 71-year-old Kazakh female with sporadic PD onset at the age of 66 years. She had a mild and slowly progressive disease course. Her off-stage MDS UPDRS motor score was 16 and Hoehn--Yahr stage 1. Dopamine agonists effectively controlled her motor symptoms. The third PD case was a 65-year-old Kazakh female with sporadic PD with the onset at the age of 61 years. She had also a mild disease course and was not on levodopa. Her off-stage MDS UPDRS motor score was 14 and Hoehn--Yahr stage 2. p.Gly2385Arg positive healthy controls were 50-year-old and 54-year-old male and female subjects. The allelic and genotypic frequencies for p.Gly2385Arg were in Hardy--Weinberg equilibrium (p=0.9) and did not statistically differ between cases and controls (OR 1.25, 95% C.I.: 0.2071--7.5688, p=0.8) (Tables [2](#tab2){ref-type="table"} and [4](#tab4){ref-type="table"}). ### 3.3.2. p.Ala419Val (c.1256C\>T) {#sec3.3.2} LRRK2 p.Ala419Val variant (rs34594498) was positive in 9 PD cases (3.7%, n = 9/242) and 5 controls (2.5%, n = 5/199), giving the OR of 1.5 (95% C.I.: 0.4941--4.5463, p=0.4) ([Table 4](#tab4){ref-type="table"}). WES in the probands with young-onset and familial PD did not reveal any other known PD genes. One positive case had homozygous substitution in c.1256C\>T (T/T). This was a 52-year-old Kazakh patient with the onset of sporadic PD at the age of 48 years. The patient expressed akinetic-rigid PD with a good response to levodopa but early and severe motor complications. He reached HY stage 3 in four years from the onset of motor symptoms. Two unaffected children of the proband were heterozygous for LRRK2 c.1256C\>T substitution, whereas one unaffected sibling of the proband did not have LRRK2 c.1256C\>T substitution on Sanger sequencing segregation analysis ([Figure 3](#fig3){ref-type="fig"}) (see [](#supplementary-material-1){ref-type="supplementary-material"} in the supplementary material for comprehensive image analysis). Five out of the 9 LRRK2 p.Ala419Val carriers developed PD before the age of 50 years, the youngest manifestation being at the age of 26 years. The mean age at onset for the p.Ala419Val carriers was 48.3 ± 12.6 (range 26--69) and this did not significantly differ from the noncarriers (48.3 ± 12.6 v54.7 ± 12.3, p=0.19). The mean age at examination was 57.4 ± 12.9 (range 32--82), and mean disease duration was 9.1 ± 6.1 (range 2--20) ([Table 5](#tab5){ref-type="table"}). The mean HYS score for the positive cases was 2.5 ± 0.5. Interestingly, self-reported nationalities in three out of the nine positive cases were Russian, one case was half Kazakh and half Russian, and the remaining 5 cases were Kazakhs. Two of the Russian patients had an autosomal dominant history of PD with onset after the age of 50 years. All of the LRRK2 p.Ala419Val-positive cases had a good response to levodopa. The allele frequencies for LRRK2 p.Ala419Val in PD cases deviated from Hardy--Weinberg equilibrium (p=0.004) ([Table 2](#tab2){ref-type="table"}). ### 3.3.3. p.Arg1628Pro (c.4883G\>C) {#sec3.3.3} PD cases were negative for p.Arg1628Pro (rs33949390) variant, whereas two control subjects were found to be positive (1%, n = 2/199). The variant was in Hardy--Weinberg equilibrium (p=0.9) in controls. 4. Discussion {#sec4} ============= This study screened cohorts of PD patients and controls from Kazakhstan for five LRRK2 mutations and three Asian disease-associated variants. To date, over 80 LRRK2 disease-causing and disease-associated variants have been described in literature since the gene was discovered in 2004. However, only eight of them have been acknowledged as PD-causing mutations including p.Gly2019Ser, p.Arg1441His, p. Arg1441Cys, p.Arg1441Gly, p.Tyr1699Cys, p.Ile2020Thr, p. Asn1437His, and p. Ile2012Thr. All of these mutations affect the catalytic core of the LRRK2 enzyme \[[@B11]\]. Among these mutations, p.Gly2019Ser is the most common followed by the substitution of arginine (Arg) by glycine (Gly), cysteine (Cys), or histidine (His) in the position 1441 of LRRK2 gene \[[@B11]\]. p.Gly2019Ser mutation has a global prevalence of 1% in patients with iPD and around 4% in familial PD. It is noteworthy that p.Gly2019Ser has been predominantly reported in the North African population where it is responsible for 30--42% of familial and 30--34% of sporadic PD cases. Its prevalence shows high figures in Ashkenazi Jews (28% of familial PD and 10% in iPD) and among European as well as North American populations (6% and 3%, respectively) \[[@B12]\]. Conversely, p.Gly2019Ser mutation has not been reported in Asians (\<0.1%) \[[@B13], [@B14]\]. p.Gly2019Ser was reported in Russian PD cohorts (%), possibly in subjects of Ashkenazi Jewish origin \[[@B15]\]. The currently known most deleterious LRRK2 mutations associated with PD were not found in our cohort. The absence of these mutations in our cohort is similar to other Asian studies \[[@B6]\] This is probably due to the founder effects of these mutations, which seem to be specific to Western populations. 4.1. p.Gly2385Arg {#sec4.1} ----------------- LRRK2 p.Gly2385Arg substitution is located in the WD-40 domain, a toroidal beta-propeller structure responsible for protein-protein interactions \[[@B16]\]. There have been 5 independent case-control studies reporting this variant \[[@B6], [@B13], [@B16]--[@B18]\] and 14 studies screening their cohorts for p.Gly2385Arg \[[@B14], [@B19]\]. Originally, p.Gly2385Arg variant was identified in a small Taiwanese PD family, in a proband and his affected father \[[@B20]\]. Later, a number of studies in Chinese, Taiwanese, Korean, and Japanese populations have reported p.Gly2385Arg variant significantly more among PD patients than controls, with minor allele frequency (MAF) up to 0.4 in patients ([Table 6](#tab6){ref-type="table"}). Thus, p.Gly2385Arg variant was attributed to a risk factor for sporadic and familial PD. The population attributable risk for p.Gly2385Arg in Han-Chinese ethnicity was estimated to be around 4% \[[@B18]\], and the variant probably originated around 4800 years ago from one ancestor \[[@B16]\]. p.Gly2385Arg variant had a tendency for equal distribution across genders and age groups \[[@B6]\]. Regarding the clinical presentation, p.Gly2385Arg carriers expressed typical PD and homozygous cases were not clinically different from heterozygotes and non-carriers \[[@B13]\]. This variant seems not to influence the age of PD onset, as the mean ages of onset in p.Gly2385Arg carriers and non-carriers have not been consistently reported to significantly differ between these groups \[[@B6], [@B13], [@B17]\]. Reports on the association of p.Gly2385Arg carrier status with a family history of PD have also been inconsistent \[[@B16], [@B17]\]. In regards to non-Chinese populations, p.Gly2385Arg was found in 1.2% (2/166) of PD patients and 0.6% (2/306) of controls in Malay/Indian ethnicity from Singapore \[[@B8]\] The frequency of p.Gly2385Arg in cases and controls was not significantly different in this Singaporean study, and considerably lower than the frequency of 8--10% reported in Chinese PD subjects \[[@B6], [@B8]\]. A recent study on Malaysian PD subjects has found a significant association between p.Gly2385Arg and increased risk of PD \[[@B14]\] The variant was absent in 405 Iranian subjects \[[@B22]\] and positive in only one individual of Northern European origin among 14,002 screened Caucasian subjects \[[@B25]\]. Evidence from functional studies suggests that p.Gly2385Arg substitution leads to the replacement of hydrophobic glycine with the hydrophilic arginine and increases the net positive charge on the 40WD domain of LRRK2. Both LRRK2 proteins with wild-type and p.Gly2385Arg variant localized to the cytoplasm forming aggregates, but the intensity of apoptosis is higher in p.Gly2385Arg variant under oxidative stress conditions \[[@B18]\]. The frequency of p.Gly2385Arg variant in our study (1.2% patients and 1% controls) was almost similar to non-Chinese Singaporean subjects. If MAF for Gly2385Arg in Chinese and Japanese PD populations was between 0.05 and 0.4 ([Table 6](#tab6){ref-type="table"}), MAF in our study was 0.007. This might suggest that p.Gly2385Arg could be found in non-Chinese Asians but in considerably less proportion. Due to a small amount of non-Chinese subjects screened for p.Gly2385Arg and its equal distribution between patients and healthy controls, currently, it is difficult to ascertain the role of this LRRK2 variant in the risk of PD among Central Asian populations. Contemporary data suggest that p.Gly2385Arg could be a risk factor for PD only in selected Asian races. On the other hand, among three patients positive to p.Gly2385Arg in our study, we had an interesting familial PD case, where proband and his deceased mother had PD, whereas maternal siblings and one maternal cousin of the proband had unilateral asymmetric UL tremor. Although all other known PD genes have been excluded by WES in the proband, p.Gly2385Arg did not completely segregate in the family, being positive in some unaffected family members and negative in some affected ([Figure 2](#fig2){ref-type="fig"}). To date, the variant has been shown to segregate with PD in only one small Taiwanese family with affected proband, affected father of the proband, and unaffected sibling. We showed the segregation of p.Gly2385Arg, although incomplete, in a larger family presenting not only with PD but tremor. The incomplete segregation in our family could be due to reduced penetrance or other unknown genetic factors. 4.2. p.Ala419Val {#sec4.2} ---------------- There have been nine reports describing p.Ala419Val variant \[[@B26]\]. The variant resides in the LRRK2 Armadillo domain and is predicted deleterious by online prediction tools with high conservation in the vertebrates \[[@B26]\]. Initially, the association between this variant and PD was described by Ross et al. \[[@B23]\] where p.Ala419Val was tested in 2,338 Asian subjects from Japan, Korea, and Taiwan (1,376 PD cases and 962) in a large-scale multicenter study. The study results revealed the OR of 2.27 (95% CI: 1.35--3.83, p=0.0011). Several studies before and after the reported association of p.Ala419Val with PD have found either no carriers of this variant in large cohorts of PD patients and controls or insignificant OR ([Table 7](#tab7){ref-type="table"}), thus considering the variant as putatively nonpathogenic population-specific SNP. The MAF for p.Ala419Val in PD patients has been 0.002--0.018 in Chinese, and 0.026--0.029 in Japanese and Korean populations in studies reporting positive association \[[@B23], [@B31]\]. Interestingly, the replication studies in the Chinese and Taiwanese ethnicities have yielded inconsistent results. While p.Ala419Val was negative or positive with insignificant OR in some studies, several studies and their meta-analysis reported a significant association between this variant and predominantly early-onset PD ([Table 7](#tab7){ref-type="table"}, \[[@B26]\]). This has been explained by possible natural sampling variation and population heterogeneity \[[@B30]\] on the one hand. On the other hand, Li et al. \[[@B26]\] argued that the discrepancy is likely to result from different mean ages at onset (AAO) of PD patients in these studies. Thus, while the mean AAO in p.Ala419Val-positive reports on Chinese ethnicity was \<55 years \[[@B23], [@B26], [@B29]\], negative reports on the same population had AAO above 60 years \[[@B28], [@B30], [@B31], [@B33]\]. Provided the fact that p.Ala419Val might have a strong association with early-onset Chinese PD, the likelihood of yielding positive findings could be higher in young-onset PD cohorts. The MAF for p.Ala419Val in PD patients in our study was 0.02, which is higher than in Chinese and Taiwanese populations and closer to Japanese and Korean ([Table 7](#tab7){ref-type="table"}). Taking into account the young mean AAO in our Kazakhstani PD cohort (55.06 ± 11.15) and reference to Li et al. \[[@B26]\], one might explain the high MAF for p.Ala419Val. Moreover, the AAO in p.Ala419Val-positive PD patients was remarkably young (48.3 ± 12.6) in our study. However, the high frequency (MAF 0.012) of p.Ala419Val in healthy Kazakhstani controls, who also had a mean age of below 55 years, and insignificant OR do not allow us to ascertain the pathogenicity of p.Ala419Val in Kazakhstani PD. We have found a previously unreported homozygous carrier of p.Ala419Val variant with PD onset before 50 years and relatively aggressive disease course. If this LRRK2 variant is nonpathogenic and not rare in our population, the likelihood of p.Ala419Val homozygous carriers would increase and this might result in the HWE deviation. p.Ala419Val variant seems to be present not only in Kazakhs but also in self-reported Russian patients with late-onset or familial PD. Considering the reported specificity of p.Ala419Val to Asian populations, we could speculate that these self-reported Russian subjects in our study could have a mixed ethnic background, particularly with Tatars, an Asian population with some Russian phenotypic features. Alternatively, the variant could also be present in the Russian population. 4.3. p.Arg1628Pro {#sec4.3} ----------------- Regarding p.Arg1628Pro, data from a meta-analysis, including 19 studies with a total of 9,927 PD patients and 8,602 controls, suggest that the variant is significantly associated with the risk of PD in East Asian populations \[[@B34]\]. We failed to find this variant in our PD patients but it was present in controls. This might suggest that p.Arg1628Pro could be a common benign polymorphism in Kazakhstani population. We have to acknowledge the limitations in our study due to the relatively small sample size, the nonhomogeneous ethnic composition of the PD cohort, as only 72.8% of the PD cohort were Kazakhs. In addition, controls were not perfectly matched to cases by age, gender, and ethnicity. 5. Conclusions {#sec5} ============== The negative findings on common LRRK2 PD causing mutations, and the presence of LRRK2 Asian-specific variants in our PD patients, although at insignificant level compared with controls, suggest that further large-cohort genetic studies are required in Central Asia to ascertain the pathogenicity of LRRK2 Asian-specific variants in the Central Asian PD population. Cases were collected as part of the SYNaPS Study Group collaboration funded by The Wellcome Trust and Strategic Award (Synaptopathies) Funding (WT093205MA and WT104033AIA). This research was conducted as part of the Queen Square Genomics group at University College London, supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. This research was funded by the Medical Research Council (MRC) (MR/S01165X/1, MR/S005021/1, and G0601943). Data Availability ================= VCF files from exome sequencing used to support the findings of this study are available from the corresponding author upon request. Conflicts of Interest ===================== The authors have no conflicts of interest. Supplementary Materials {#supplementary-material-1} ======================= ###### S1: the 8 LRRK2 SNPs and surrounding 50 base-pairs annotated in Ensembl genome browser S2: calculations of allelic and genotypic frequencies, odds ratios, and Hardy--Weinberg equilibrium S3: chromatogram for Ala419Val homozygous variant with family segregation S4: the results of KASP analysis. ###### Click here for additional data file. ![LRRK2 protein: functional domain and the localization of 8 variants. ANK-ankyrin repeat; ARM-armadillo; LRR-leucine-rich repeat; ROC-Ras of complex proteins: GTPase; COR-C-terminal of ROC; WD40-WD-40 domain. Pathogenic mutations are highlighted in blue, and East Asian disease-associated variants are highlighted in red.](PD2020-2763838.001){#fig1} ![Familial case with p.Gly2385Arg variant. III:2 Proband 40 years old, PD onset at 38 years. II:1 Affected mother of the proband. PD onset at 55 years. Died at 58 years. Levodopa responsive PD. II:3 affected maternal aunt. 10 years\' history of unilateral right-hand tremor at rest and action. II:5 Affected maternal aunt, 54 years old. 10 years\' history of positional unilateral tremor. III:9 son of II:5. Right-hand positional tremor. II:9 Affected maternal aunt, 4-5 years\' history of right-hand positional tremor.](PD2020-2763838.002){#fig2} ![Homozygous p.Ala419Val proband and his family tree.](PD2020-2763838.003){#fig3} ###### Clinical and demographic characteristics of the cohort. ---------------------------------------------------------------------------------------------------------------------------------------------- Cases Controls ------------------------------------------------- --------------------------------------------------- ---------------------------------------- Number 246 200 Ethnic groups, abs number (%) Kazakhs 179 (72.8%) Russians 51 (20.7%) Uygurs 7 (2.8%) Tatars 5 (2%) Koreans 3 (1.3%) Tajiks 1 (0.4%) Sex distribution Males---120, females---126\ Males---62, females---138\ M : F ratio−0.95 : 1 M : F ratio 0.4 : 1 Age at examination (mean) 61.7 ± 10.3 (range 28--83)\ Mean age---54.93 ± 4.8 (47--66)\ For males---60.3 ± 10.6 (range 28--82), p=0.03\ For males---55.27 ± 4.8 (47--66)\ For females---63.1 ± 9.9 (range---32--83) For females---54.78 ± 4.7 (47--65) Age of onset (mean) 55.06 ± 11.15 (range 14--77)\ For males---53.3 ± 11.9 (range 14--76), p=0.01\ For females---56.8 ± 9.9 (range 26--77) Disease duration (mean) 13.2 ± 9.3 (range 1--24) HY stage off (mean) 2.4 ± 0.6 (range 1--5)\ For males---2.3 ± 0.7 p=0.6\ For females---2.4 ± 0.6 Family history of PD and tremor, abs number (%) 21 (8.5%) Young-onset cases, abs number (%) 31 (12.6%) before the age of 40\ 65 (26.4%) before the age of 50 ---------------------------------------------------------------------------------------------------------------------------------------------- M : F--male to female. ###### Allele frequency and distribution of the 8 tested LRRK2 variants. SNP Hardy--Weinberg equilibrium p-value Number of samples Allele n ^a^ Frequency Genotype n ^b^ Frequency --------------------------- --------------------------------------- ------------------- -------- --------- ----------- ---------- --------- ----------- p.Gly2019Ser (c.6055G\>A) 1 198 controls GG 198 1.00 G 396 1.00 GA 0 0.00 A 0 0.00 AA 0 0.00 1 241 PD 482 1.00 GG 241 1.00 G 0 0.00 GA 0 0.00 A AA 0 0.00 p.Arg1441His (c.4322G\>A) 1 199 controls GG 199 1.00 G 398 1.00 GA 0 0.00 A 0 0.00 AA 0 0.00 1 240 PD 480 1.00 GG 240 1.00 G 0 0.00 GA 0 0.00 A AA 0 0.00 p.Tyr1699Cys (c.5096A\>G) 1 196 controls GG 196 1.00 G 392 1.00 GA 0 0.00 A 0 0.00 AA 0 0.00 1 239 PD 478 1.00 GG 239 1.00 G 0 0.00 GA 0 0.00 A AA 0 0.00 p.Ile2020Thr (c.6059T\>C) 1 198 controls TT 198 1.00 T 396 1.00 TC 0 0.00 C 0 0.00 CC 0 0.00 1 242 PD 484 1.00 TT 242 1.00 T 0 0.00 TC 0 0.00 C CC 0 0.00 p.Asn1437His (c.4309A\>C) 1 199 controls AA 198 1.00 A 398 1.00 AC 0 0.00 C 0 0.00 CC 0 0.00 1 240 PD 480 1.00 AA 240 1.00 A 0 0.00 AC 0 0.00 C CC 0 0.00 p.Gly2385Arg (c.7153G\>A) 0.94 199 controls GG 197 0.99 G 396 0.995 GA 2 0.01 A 2 0.005 AA 0 0.00 0.92 239 PD GG 236 0.99 G 475 0.993 GA 3 0.01 A 3 0.007 AA 0 0.00 p.Ala419Val (c.1256C\>T) 0.85 199 controls CC 194 0.98 C 393 0.988 CT 5 0.02 T 5 0.012 TT 0 0.00 0.004 242 PD 0.98 CC 233 0.97 C 474 0.02 CT 8 0.04 T 10 TT 1 0.00 p.Arg1628Pro (c.4883G\>C) 0.94 199 controls GG 197 0.99 G 396 0.995 GT 2 0.01 C 2 0.005 TT 0 0.00 1 236 PD GG 236 1.00 G 472 1.00 GT 0 0.00 C 0 0.00 TT 0 0.00 n1---number of alleles, n2---number of genotypes, PD--Parkinson\'s disease, HWE--Hardy--Weinberg equilibrium, and NA--not applicable. ###### p.Gly2385Arg-positive PD patients and their characteristics. Number (246--7 uncalled = 239) Mean age at examination Mean age of onset Mean disease duration Family history Mean HY stage off ------------- -------------------------------- ------------------------- ------------------- ----------------------- ---------------- ------------------- Carriers 3 58.6 ± 13.4 55 ± 12.1 4 ± 0.8 1 2 ± 0.8 Noncarriers 236 61.7 ± 10.3 55 ± 11.1 6.8 ± 4.7 20 2.3 ± 1.5 p value 0.77 0.99 0.01 0.56 ###### The allelic frequency and odds ratios for the positive LRRK2 Asian disease-associated variants. SNP Nucleotide change Amino acid change MAF Or (95% CI) p value ------------ ------------------- ------------------- ----------- ------------- ------------------------ ----- rs34778348 c.7153G\>A p.Gly2385Arg^a^ 0.007 (A) 0.005 (A) 1.25 (0.2071--7.5688) 0.8 rs34594498 c.1256C\>T p.Ala419Val^b^ 0.02 (T) 0.012 (T) 1.5 (0.4941 -- 4.5463) 0.4 rs33949390 c.4883G\>C p.Arg1628Pro^c^ 0.0 (C) 0.005 (C) NA NA MAF--minor allele frequency, NA--not applicable, OR--odds ratio, and PD--Parkinson\'s disease. ###### p.Ala419Val-positive PD patients and their characteristics. Number 246-4uncalled = 242 Mean age at examination Mean age of onset Mean disease duration Family history Mean HY stage off ------------- ---------------------------- ------------------------- ------------------- ----------------------- ---------------- ------------------- Carriers 9 57.4 ± 12.9 48.3 ± 12.6 9.1 ± 6.1 2 2.5 ± 0.5 Noncarriers 233 61.6 ± 10.4 54.7 ± 12.3 6.8 ± 7 19 2.2 ± 0.7 P value 0.38 0.19 0.3 0.02 HY--Hoehn--Yahr. ###### Studies investigating LRRK2 p.Gly2385Arg variant in Asian populations. -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Cases Controls Ethnicity OR MAF for PD patients ---------------------------------- ------------------------------------- ----------------- --------------------------------------- -------------------------------------------------------------------------------- ------------------------------------------------------------ Funayama et al., 2007 \[[@B13]\] 448/52 (11.6%) (2 homozygous cases) 457/22 (4.8%) Japanese OR for the frequency of A allele 2.63, 95% CI: 1.56--4.35, p = 1.24 × 10^−4^ 0.06 Di Fonzo at al., 2006 \[[@B6]\] 608/61 (10%) 373/18 (4.8%) Han Chinese from Taiwan OR = 2.24, 95% CI: 1.29--3.88, p = 0.004 0.05 Fung et al., 2006 \[[@B17]\] 305/27 (9%) 176/1 (0.5%) Han Chinese from Taiwan 16.99, 95% CI: 2.29 to 126.21, p=0.0002 0.4 No positive cases with FH An et al., 2008 \[[@B21]\] 600/71 (1 homozygous) (11.9%) 334/11 (3.3%) Han Chinese OR 3.9, 95% CI = 2.1--7.5, p \< 0.01 0.06 Tan et al., 2007 \[[@B18]\] 494/37 (7.27%) (1 homozygous) 495/18 (3.64%) Ethnic Chinese OR 2.1, 95% CI: 1.1--3.9, p=0.014 PAR of 4% for the Gly2385Arg heterozygous genotype. Tan et al., 2007 \[[@B8]\] 166/2 (Malays) 306/2 (Malays) Malay 98/173, Indian ethnicity 66/133 OR 2.83, 95% CI 0.40, 20.2, p\_0.3 0.003 for Malays Farrer et al., 2007 \[[@B16]\] 410/34 335/13 (3.9%) Ethnic Chinese OR 2.24 95% CI 1.16--4.32, p \< 0.014 MAF 0.08\ 23.1% (n = 6/26) of patients with familial parkinsonism. Ross et al., 2011 \[[@B23]\] 1,376 962 Japan, Korea, Taiwan OR: 1.73, 95% CI: 1.20--2.49, p=0.0026 MAF 3.3% Japan\ Control: 75 PD: 173 Korea\ Control: 587 \\|PD: 844 Taiwan\ Control: 300 PD: 369 Mata et al., 2005 \[[@B20]\] 100 probands with PD FH/2 cases Taiwan 1 family with 2 members Zabetian et al., 2009 \[[@B24]\] 601/69 (11.5%) 1628/101 (6.2%) Japanese OR, 1.83; 95% CI: 1.31--2.54; p = 3.3 × 10^−4^ Gapalai et al., 2015 \[[@B14]\] 695 507 Malaysian OR 2.22 (p=0.019) MAF = 0.026 -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- OR--odds ratio, MAF--minor allele frequency, PAR--population attributable risk, and FH--family history. ###### Studies investigating LRRK2 p.Ala419Val variant in Asian populations. --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Cases Controls Ethnicity OR MAF for patients/controls ----------------------------------- ---------------- -------------- -------------------------------------------------------- ------------------------------------------ --------------------------- Di Fonzo et al., 2006 \[[@B6]\] 582/10 341/3 Han Chinese from Taiwan 1.95 (0.53--7.15), p \> 0.05 0.008/0.004 Nuytemans et al., 2009 \[[@B27]\] 620/1 540/0 Belgian p \> 0.05 Jasinska-Myga, 2010 \[[@B12]\] 165/0 364/0 Arab-Berber ethnicity n/a Tan et al., 2010 \[[@B28]\] 250/0 250/0 Han Chinese n/a Ross et al., 2011 \[[@B23]\] 1,376 962 Japan, Korea, Taiwan OR: 2.27, 95% CI: 1.35--3.83, p=0.0011 Japan PD: 173 Control: 75 Japan: OR 1.26 (0.38 to 4.22) Korea PD: 844 Control: 587 Korea: OR 2.21 (1.2 to 4.06) Taiwan PD: 369 Control: 300 Taiwan: OR 7.51 (0.95 to 59.6) Li et al., 2012 \[[@B29]\] 729/22 585/4 Han Chinese OR, 4.14; 95% CI: 1.53--12.74 0.015 Wu et al., 2012 \[[@B30]\] 1517/13 1487/13 Han Chinese from China and Singapore Taiwanese 0.98 (0.45 to 2.18) 0.004 Gopalai et al., 2013 \[[@B31]\] 404/1 424/3 Chinese (223/236), Malay (122/110), and Indian (59/78) 0.35, 95% CI: 0.01 to 3.79; p=0.624 0.002 cases\ 0.004 Controls Heckman et al., 2013 \[[@B32]\] 369/10 300/1 Taiwan, South Korea, Japan OR 8.33 (1.06--65.43) Taiwanese 0.013\ Japanese -- 0.026\ South Korea 0.029 Wu-Chou et al., 2013 \[[@B33]\] 626/0 473/0 Han Chinese from Taiwan n/a Li et al., 2015 \[[@B26]\] 500/18 574/9 Chinese OR 2.57, 95% CI: 1.13--5.86, p=0.025 0.018 --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- OR--odds ratio and MAF--minor allele frequency. [^1]: Academic Editor: Carlo Ferrarese	{ "pile_set_name": "PubMed Central" }
seventy-four fifths of a meter? 1480 How many micrometers are there in 7515.531 centimeters? 75155310 What is 0.5313645 nanograms in kilograms? 0.0000000000005313645 Convert 457.5582mg to grams. 0.4575582 What is 4.996193 milligrams in kilograms? 0.000004996193 Convert 29557.8 millilitres to litres. 29.5578 What is 3/5 of a millennium in decades? 60 What is 3/25 of a milligram in micrograms? 120 What is 44/5 of a millennium in centuries? 88 Convert 13.89986t to grams. 13899860 How many micrometers are there in three sixteenths of a centimeter? 1875 Convert 877.0183l to millilitres. 877018.3 Convert 2.125653 litres to millilitres. 2125.653 What is 2.6 millilitres in litres? 0.0026 How many seconds are there in 262948.3 minutes? 15776898 What is 4/3 of a decade in months? 160 What is seven halves of a centimeter in millimeters? 35 Convert 9133.882t to grams. 9133882000 What is three eighths of a litre in millilitres? 375 What is three fifths of a gram in milligrams? 600 How many millilitres are there in 22.9918 litres? 22991.8 What is 53/5 of a gram in milligrams? 10600 Convert 0.7787359 nanometers to meters. 0.0000000007787359 What is 192.0421 decades in years? 1920.421 What is 5244.29mm in centimeters? 524.429 How many centimeters are there in 5192.562nm? 0.0005192562 What is two fifteenths of a hour in seconds? 480 What is 8835259.5 seconds in hours? 2454.23875 What is 179054.5 weeks in microseconds? 108292161600000000 What is 21/4 of a gram in milligrams? 5250 How many micrometers are there in 845.693 centimeters? 8456930 How many kilometers are there in 985430.9m? 985.4309 How many kilograms are there in 34/5 of a tonne? 6800 How many minutes are there in 5/4 of a week? 12600 What is 81.50365 decades in years? 815.0365 Convert 9449.609 micrograms to nanograms. 9449609 How many kilograms are there in 342.93t? 342930 How many grams are there in twenty-one fifths of a kilogram? 4200 How many millilitres are there in one fifth of a litre? 200 Convert 87402.03ml to litres. 87.40203 How many nanoseconds are there in 9.732215 days? 840863376000000 What is 3.760793 minutes in seconds? 225.64758 What is 6962.992m in kilometers? 6.962992 Convert 11.116575 hours to days. 0.463190625 How many years are there in 27/2 of a century? 1350 What is 3/10 of a milligram in micrograms? 300 Convert 2486.23 litres to millilitres. 2486230 Convert 0.4776988 nanograms to tonnes. 0.0000000000000004776988 What is 1/10 of a minute in seconds? 6 How many centimeters are there in 1.289613 micrometers? 0.0001289613 How many micrometers are there in seven halves of a centimeter? 35000 What is 978.649 litres in millilitres? 978649 What is 7/2 of a litre in millilitres? 3500 How many millilitres are there in 5/4 of a litre? 1250 How many millennia are there in 22.4439 decades? 0.224439 Convert 181902.2 milliseconds to microseconds. 181902200 How many centimeters are there in 32.59094km? 3259094 What is twenty-five halves of a hour in seconds? 45000 What is 21733.503ns in minutes? 0.00000036222505 How many grams are there in 31/5 of a kilogram? 6200 How many milliseconds are there in 3/40 of a second? 75 What is 26/5 of a litre in millilitres? 5200 What is 2257.215s in minutes? 37.62025 What is 29/5 of a litre in millilitres? 5800 What is 88530.72 tonnes in milligrams? 88530720000000 What is twelve sevenths of a week in hours? 288 Convert 0.9240893 minutes to nanoseconds. 55445358000 What is 8986.228 decades in millennia? 89.86228 What is 3/25 of a gram in milligrams? 120 Convert 0.6482019 kilograms to grams. 648.2019 What is one sixteenth of a week in seconds? 37800 How many micrometers are there in one tenth of a meter? 100000 What is sixty-four fifths of a microsecond in nanoseconds? 12800 Convert 27.09706 nanometers to meters. 0.00000002709706 Convert 0.1791055m to kilometers. 0.0001791055 What is 7/2 of a centimeter in millimeters? 35 What is 7.028893kg in tonnes? 0.007028893 How many years are there in fifty-four fifths of a millennium? 10800 How many meters are there in 750994.5km? 750994500 Convert 624744.5ml to litres. 624.7445 How many kilograms are there in 523447.1g? 523.4471 What is 26/5 of a century in months? 6240 What is 818.0905mm in kilometers? 0.0008180905 What is one tenth of a centimeter in millimeters? 1 How many micrograms are there in 18/5 of a milligram? 3600 What is thirteen quarters of a meter in millimeters? 3250 How many years are there in twenty-one halves of a decade? 105 How many millilitres are there in 27/5 of a litre? 5400 How many kilograms are there in 3/10 of a tonne? 300 How many litres are there in 40.218 millilitres? 0.040218 Convert 0.523379 milligrams to grams. 0.000523379 What is 1/4 of a litre in millilitres? 250 How many kilograms are there in 49/4 of a tonne? 12250 What is 0.7695305 kilometers in micrometers? 769530500 What is 0.1757359mm in micrometers? 175.7359 How many microseconds are there in 29.59061 hours? 106526196000 What is one eighteenth of a week in minutes? 560 How many months are there in three tenths of a millennium? 3600 How many seconds are there in three fifths of a minute? 36 Convert 0.73689m to nanometers. 736890000 What is 1.640366 kilograms in nanograms? 1640366000000 How many millilitres are there in sixty-four fifths of a litre? 12800 What is 0.1754202ml in litres? 0.0001754202 How many months are there in 55/3 of a decade? 2200 What is 1/30 of a decade in months? 4 What is 52/5 of a meter in centimeters? 1040 Convert 52.935372ns to hours. 0.00000000001470427 How many litres are there in 3.47695ml? 0.00347695 Convert 5701.51km to millimeters. 5701510000 What is 6768.672 weeks in minutes? 68228213.76 Convert 73.79231g to tonnes. 0.00007379231 What is 86036.77ug in grams? 0.08603677 How many grams are there in 0.4097521 kilograms? 409.7521 How many months are there in eighteen fifths of a century? 4320 What is seventeen halves of a week in minutes? 85680 How many millilitres are there in 7/2 of a litre? 3500 How many grams are there in 64.39407ng? 0.00000006439407 How many hours are there in 353859.57 nanoseconds? 0.000000098294325 How many grams are there in 0.4683002 micrograms? 0.0000004683002 How many millilitres are there in 52.5512l? 52551.2 Convert 0.5265485kg to nanograms. 526548500000 How many years are there in eleven quarters of a millennium? 2750 Convert 787099.5kg to tonnes. 787.0995 What is 51724.71 milliseconds in days? 0.000598665625 How many centimeters are there in 55/4 of a meter? 1375 Convert 83.07357us to minutes. 0.0000013845595 How many years are there in one tenth of a decade? 1 What is fifty-seven fifths of a millennium in decades? 1140 What is 425317.8 meters in nanometers? 425317800000000 Convert 2442.50964us to days. 0.0000000282697875 How many centuries are there in 255636.5 decades? 25563.65 Convert 31089.81m to kilometers. 31.08981 What is 3/5 of a century in months? 720 How many milligrams are there in 2/125 of a gram? 16 What is 886.229 milligrams in kilograms? 0.000886229 What is 70.74623 kilometers in meters? 70746.23 How many millilitres are there in 2548.415 litres? 2548415 What is 76.1778us in hours? 0.0000000211605 How many grams are there in 731843.2mg? 731.8432 How many seconds are there in 1/15 of a day? 5760 How many centimeters are there in 5/4 of a meter? 125 What is 13/8 of a kilometer in meters? 1625 What is seven halves of a decade in years? 35 What is 3/25 of a gram in milligrams? 120 Convert 0.1309855ug to milligrams. 0.0001309855 Convert 0.5334475 millennia to months. 6401.37 How many months are there in 7692.3 years? 92307.6 What is 0.8969137ml in litres? 0.0008969137 What is eleven tenths of a millimeter in micrometers? 1100 Convert 66.8747l to millilitres. 66874.7 How many grams are there in 90.08933 kilograms? 90089.33 Convert 7.019236m to micrometers. 7019236 Convert 707484.6g to tonnes. 0.7074846 What is 37/2 of a tonne in kilograms? 18500 How many millilitres are there in seven eighths of a litre? 875 Convert 753.091 millennia to years. 753091 How many nanograms are there in 27/2 of a microgram? 13500 How many millilitres are there in 37/5 of a litre? 7400 How many centimeters are there in one tenth of a meter? 10 Convert 4817.415s to minutes. 80	{ "pile_set_name": "DM Mathematics" }
Temporal patterns of evoked cerebral blood flow during reading. This study describes the dynamics of flow activation by reading and investigates the potential use of repeated flow velocity measurements for the lateralization of speech. Using simultaneous transcranial Doppler recordings from both middle cerebral arteries and averaging techniques in 25 healthy volunteers, we describe the changes in blood flow velocity caused by repetitive reading tasks of variable duration in comparison with a resting state. Reading aloud evoked a characteristic temporal flow pattern in both hemispheres, consisting of three relative maxima in flow velocity during and after activation. Flow velocities lower than baseline were common during longer lasting activation. The amplitudes of two of the observed peaks decreased depending on the duration of the task. Reading silently produced a markedly different temporal pattern of activation than reading aloud. There were individually reproducible significant side to side differences. Right-handed persons (n = 15) almost without exception showed a significantly higher increase in flow velocity on the left hemisphere (e.g., reading silently 8.7% versus 5.3%; P < 0.0001). Three out of ten left-handed individuals, however, exhibited no significant side to side difference or exhibited lateralization to the right during one or more of the tasks. These findings suggest that reading induces task-specific temporal patterns of regional neuronal activity, which show habituation with longer duration of activation. Additionally, the observed side to side differences could be useful to predict language dominance.	{ "pile_set_name": "PubMed Abstracts" }
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iple of 2 and c(-8). 16 What is the lowest common multiple of 22 and (60/9)/((-2)/(-6))? 220 Let r = -25/51 + -299/153. Suppose 4f - 76 = o, 2f - 2o = -3f + 92. What is the common denominator of r and 7 + -4 - (-28)/f? 45 Let v(y) = -3y2 + 2y*2 + 3y + 4 + 0y. Let u be v(4). Suppose 2r = -2, -3n + un + 25 = -r. What is the least common multiple of n and 2? 8 Let u = -15 - -11. Find the common denominator of (71/u)/(5/(-2)) and 101/12. 60 Find the common denominator of 5/(-20)2 - (-303)/54 and 4/11. 99 Let g = -8 + 22. Calculate the common denominator of -87/4 and ((-6)/20)/(1/g). 20 Suppose 0 = 2d + 5g + 26, d + 4g + 7 = 4d. Let k be (0 - (1 + d)) + 1. Let b = k + -1. Calculate the least common multiple of b and 10. 10 Let y(h) = -h2 + 11h - 15. Let n be -3 - (-4 - -2) - -10. Suppose a + 3a + 13 = 3j, 5a = j - 8. Calculate the lowest common multiple of j and y(n). 3 Let w = -12/59 + -837/236. Find the common denominator of 23/8 and w. 8 Suppose 0m - 5m = -285. What is the smallest common multiple of m and 3? 57 Suppose 5q + 0q - 40 = 0. Suppose 0f = -4f - 24. Calculate the common denominator of -13/5 and (86/f)/(q/12). 10 Suppose 0k = 3k - 9. Find the common denominator of 39/5 and k - (2 + 16/(-6)). 15 Suppose -10 = 4m + 5n + 74, -3m - 4n = 63. Find the common denominator of m/(-5)1/3 and -89/8. 40 Let z(d) = d*2 - d. Let a be z(2). Suppose -ah + 8 = -0h. What is the least common multiple of h and 3? 12 Suppose 6 = 5a - 49. Suppose 3s + 38 - a = 0. What is the smallest common multiple of (24/s)/((-2)/6) and 2? 8 Let h be (1/(-5))/((-14)/(-791155)). Let w be 0 - (-111295 + -2). Let d = w + h. Find the common denominator of d and -3/16. 112 Find the common denominator of 23/8 and 89/(-1 + (6 - 3)). 8 Find the common denominator of 513/24 + 1 and (-5)/354/(-16). 8 Calculate the common denominator of (236/10)/((-36)/(-30)) and -83/21. 21 Let c(u) = 5u2 - 3u - 6. What is the smallest common multiple of 12 and c(-2)? 60 Suppose -2 = 3f - 2f. Let l be ((0 - f)/(-2))/(-431). Let a = l + -22415/1293. Calculate the common denominator of a and 23/7. 21 Let v = -18795/2 + 10000. Suppose 4c = -3f - 1803 - 107, -4f - 2c - 2550 = 0. Let l = f + v. Find the common denominator of -53/14 and l. 14 Let t = 1279/12 + -338/3. Find the common denominator of -1/4 and t. 12 Suppose -2f = 3f - 25. What is the common denominator of -19/2 and f/15 - 831/36? 4 Let o = 34 - -8. Calculate the least common multiple of o and 21. 42 Let a = 56/101 + 3223/2020. What is the common denominator of -115/28 and a? 140 Calculate the common denominator of -2 + ((-1428)/64)/(-7) and (7/(-3))/((-24)/68). 144 Suppose -128 = a - 32. What is the common denominator of 1438/120 - 4/10 and -3 + 4/(a/76)? 12 Suppose 0a = 3a - 30. Let c be 9 + (-5 + 0 - -3). Suppose 0 - c = -y. What is the least common multiple of a and y? 70 Find the common denominator of 59/9 and 74/(-27)(-2)/(-4). 27 Let a = -43/3 + 38. Find the common denominator of a and -11/30. 30 Let p(q) be the second derivative of -q5/20 - 5q*4/6 - 11q3/6 - q2 + 4q. Let f = -1 + 3. What is the lowest common multiple of f and p(-9)? 16 Let u = -5 + 21. What is the least common multiple of (0 - 14/3)/(10/(-30)) and u? 112 Let z = -247463/18 + 13744. Calculate the common denominator of z and -125/18. 18 Let s = 839/154 + -100/11. Let i be 85195/(-24) - 2/(-3). Let r = -3558 - i. Find the common denominator of r and s. 56 Let b be (-8)/4 - 2/(-1). Suppose -5x - 1 + 11 = b. What is the common denominator of x + 373/(-6) and 101/6? 6 What is the common denominator of -42 and (-2 - 16/(-7))/(8/(-236))? 7 Let k = -22 - -37. Let x = 22 - k. Calculate the smallest common multiple of 2 and x. 14 Suppose 6d - 3d = -25380. Let j = d + 118501/14. Find the common denominator of j and -5/4. 28 Suppose -f + 2 = -0. Let o(l) = -7l - 48. Calculate the smallest common multiple of f and o(-7). 2 Let b be 4 + (-2 - 3/(-1)). Suppose -3w + 10 + b = 0. Calculate the lowest common multiple of w and 5. 5 Let a(z) be the second derivative of z3/6 + 3z*2 - 3z. What is the least common multiple of 8 and a(5)? 88 Let f be (862/(-274))/((-1224)/(-2248)). Let w be -1 + -2 + 41920/13974. Let v = f - w. Find the common denominator of 16/11 and v. 99 Let v(j) = -50j + 12. Let h be v(11). Calculate the common denominator of 17/18 and 7/(-28) + h/(-24). 18 Find the common denominator of 11/(-66) + (-290)/6 and 63/34. 34 Let k = 44495/18 + -2477. Let z = -1085135/99784 - 2/12473. Find the common denominator of z and k. 72 Let t = -3/1466 - -45479/16126. Calculate the common denominator of -1/4 and t. 44 Suppose 0 = 2t - 3t + 3. Let j = 4 - 1. Suppose 4c + 35 = 2u + tu, 14 = 2u + jc. Calculate the lowest common multiple of u and 5. 35 Suppose 3b + 13 = b + 5o, 4b - o = 1. What is the smallest common multiple of b(-4 + 2) - -22 and 14? 140 Let l be ((-4)/7)/((-18)/63). Suppose 2d = 6d - 16, li = 2d - 4. What is the lowest common multiple of i and 44? 44 Suppose -4 = q + 4h - 5, 5 = 5q + 4h. Let z(x) = -10x*3 - 1. Calculate the smallest common multiple of z(-1) and q. 9 Suppose -4 = -2u, 2u + 64 = 5p - u. What is the least common multiple of 80 and p? 560 Let v = -53347527/91 - -586248. Let l = v - 80/13. Calculate the common denominator of l and -47/5. 35 Let a = 1899/1352 - 5/169. What is the common denominator of 5210/1120 + 4/14 and a? 16 Let x = 6367/510 - -4/255. Find the common denominator of x and 13/6. 6 Find the common denominator of 1162/288 - (-12)/(-54) and 85/8. 16 Suppose 0 = 2q - 3w - 7, -5 + 19 = 2q + 4w. What is the lowest common multiple of 5/312/2 and q? 10 Let g = -59 - -68. What is the lowest common multiple of g and 9? 9 Let g(h) = h - 3. Let z be g(7). Suppose -5u + zu + 20 = 0. Calculate the smallest common multiple of 10 and u. 20 Suppose -f - 3b = b - 24, f - 4b + 8 = 0. What is the lowest common multiple of f and 6? 24 Let k = 61 + -56. Calculate the lowest common multiple of 4 and k. 20 Suppose -4b - 23 + 7 = 0. Calculate the common denominator of (-2)/6 - (-74)/b and ((-2)/(-8) + 1)790/25. 6 Calculate the smallest common multiple of 11 and (-1146)/(-57) - (-2)/(-19). 220 Let t = 3/4028 + -191339/12084. Let y be (-12 - -9) + (-1 - -1356). Let w = 5507/4 - y. What is the common denominator of w and t? 12 Suppose -4p + 8 = -0p. Find the common denominator of (-224)/121/p and 65/4. 12 Let s be (-5388)/(-7) - (-2)/7. What is the common denominator of 69/(-4) - (-1)/1 and (-3)/(-15)s/24? 12 Suppose 4h + 5i + 20 = -h, -4i = 3h + 15. Let d = h - -2. Calculate the lowest common multiple of d and (-1)/((-2)/(-1))-12. 6 Let f(g) = g*2 - 2. Calculate the smallest common multiple of 14 and f(4). 14 Suppose -4y - 94 - 38 = 0. Let q = -19 - y. Calculate the lowest common multiple of (-5 + 3)-1 - -4 and q. 42 Let w be -1(3 - (2 + 1)). Let d(s) = s*2 + 1. Let q be d(-1). Suppose -t + 1 = -2v + 9, -3v - qt + 5 = w. Calculate the lowest common multiple of 7 and v. 21 Let c(a) = a + 10. Let z be c(-7). Suppose 0 = 3w + 3m - 15, 0 = w - 6w - zm + 15. Suppose ws + 36 = 3s. What is the lowest common multiple of s and 1? 12 Let i(q) = 4q. Let h(o) = 7o. Let a(c) = 3h(c) - 5i(c). Let d = 11 + -7. Calculate the smallest common multiple of a(2) and d. 4 Suppose m + x = 1, 3m + 3x + x = 0. Let p = 33 + -18. Suppose 2h - md - p = 3h, -2d = 2h. What is the least common multiple of h and 7? 35 Let h = 19 - 17. Let u(r) = -7r3 + 1. What is the least common multiple of u(-1) and h? 8 Let l = -3329/186 - 91/31. What is the common denominator of -25/12 and l? 12 Let v = -1055924/11 + 95920. Let m = -10915837/22 + 496291. Let x = v + m. Calculate the common denominator of x and 1/22. 22 Suppose 36 = x + 3. Calculate the lowest common multiple of x and 24. 264 Let v(i) = -i3 + 2i2 - 1. Let k be v(1). Suppose -l = 3l - 44. Calculate the lowest common multiple of (-9)/4(-4 - k) and l. 99 Let b = 11078/5 - 2227. What is the common denominator of b and 63/8? 40 Suppose 30y = 19y + 99. Calculate the smallest common multiple of y and 6. 18 Let z(j) = 2j - 2. Suppose -26 = -7*n + 23. Calculate the least common multiple of z	{ "pile_set_name": "DM Mathematics" }
A horned lizard sits motionless in the desert sun, eyeing a young coyote skulking nearby. Five inches long, with a crown of horns like a dinosaur, the lizard's mottled skin helps it blend into the background. Nevertheless, the coyote spots it. The predator pounces and holds the lizard down. Then it gingerly nibbles – and immediately regrets it. A stream of nasty-tasting blood squirts from the lizard's eyes, straight into the coyote's mouth. The coyote steps back, shaking its head from side to side in disgust. It retreats, wiping its muzzle, while the uninjured lizard skitters away to safety. To the disappointment of kids who want to see them squirt blood, horned lizards rarely squirt at humans. If you catch one, it will sit demurely in your palm. It won't bite. It might hiss, or puff itself up at little. But only canids and felids like bobcats, are treated to a stream of foul-tasting blood. The blood squirt is far from their only trick. Horned lizards have evolved a unique arsenal of defences, which they use selectively to drive off the many predators that attack them. They might look like miniature Smaugs, but they need all the help they can get not to end up as dinner. There are 17 known species of horned lizard, all in the genus Phrynosoma. Most of them seem to be capable of squirting blood. Actually, anything that can find one would eat it They differ in colour, size and the number and arrangement of horns and spines along their backs. Most are about the size of a pack of playing cards. They have wide, flat bodies, like spiky satellite dishes, and short stumpy legs. "They are short-legged and stubby-bodied," says Larry Powell of the University of Calgary in Alberta, Canada. "When they run, they give it their best, but they're just not built for speed." Instead of being sleek like an iguana, horned lizards are built for defence. They have to be, since so many things try to eat them. Horned lizards mostly live in dry places: from Guatemala and Mexico, through the deserts of Arizona and California, to the dry prairies of southern Canada. They are prey for hawks, shrikes, roadrunners, snakes, coyotes, foxes, wolves, bobcats and even carnivorous grasshopper mice. "Actually," Powell says, "anything that can find one would eat it." So they do their best not to be found. Camouflage is their first line of defence. They match their colours to their background, blending in against brown scrubby brush or the mottled greys of mud. Some species mimic inedible objects. The round-tailed horned lizard is almost indistinguishable from the rocks it hides in, when it hunches up its back and tucks in its legs. I'm trying to get an idea of what's going on in the lizard's brain Many predators detect prey through movement, so horned lizards have mastered the art of stillness. The arrangement of the horns along their sides even breaks up the shadows they cast on the ground, like a cloak of invisibility. "They all stick to this basic program of being short, tubby, spiky, and hard to find," says Powell. On a good day, Powell is lucky to find three. "I sometimes wonder if the only individuals we get data on are the ones with bad nerves, the ones who run, since if they stay put you probably won't see them." When a predator approaches, the lizards are reluctant to move. They only do so after evaluating the danger. They carefully consider what is attacking, and what the appropriate defence might be. Wade Sherbrooke of the American Museum of Natural History, based in Tucson, Arizona, has spent almost four decades trying to understand how horned lizards think. In 2014, P. sherbrookei was named after him. "I'm trying to get an idea of what's going on in the lizard's brain, how it's categorizing the world out there that it has to deal with," says Sherbrooke. It all seems to come down to the predator's attack style. Canids such as dogs use teeth and claws to tear their prey into bite-size pieces. Snakes swallow their meals whole. Meanwhile, a grasshopper mouse will prefer to nibble, zombie-style, through the skull to get to the brains. It's sort of like a person wearing a fat suit Sherbrooke set Texas horned lizards in cages, and pitted them against whip snakes and rattlesnakes to see if the lizards could tell the difference. No problem, it turns out. "They're better at identifying snakes than most people in Tucson," says Sherbrooke. Whip snakes are lightning fast, and actively hunt their prey. The portly horned lizard cannot outrun one, so it opts for camouflage and keeping still. However, rattlesnakes don't chase. They wait for prey to come to them before biting, injecting venom and swallowing. So when a horned lizard encounters a rattlesnake, it runs for its life, safe in the knowledge that the snake will probably not follow. Neither defence works every time, but on average, standing still for a whip snake and running from a rattlesnake are a horned lizard's best bets. If the lizard does get caught, all is not lost. Snakes, and some birds such as roadrunners, need to swallow their prey whole. That means they have to get their mouth around the entire body. A horned lizard will not make it easy. A Texas horned lizard or Alberta's short-horned lizard will tip up on its front legs, fan out its ribs to form a dorsal shield, or puff up its torso to make itself as big as possible. "It's sort of like a person wearing a fat suit," says Powell. The technique works. A whip snake trying to get its mouth around a Texas horned lizard may well give up, because it just can't fit the whole thing in. Instead of puffing up, regal horned lizards roll over. When threatened by a whip snake, the lizard flips onto its back. This exposes a pure white belly, white legs, and the white outline of its spines along its edge – which rather resemble teeth. The lizard also splays its short legs out stiffly at its sides, like a wrestler struggling not to be turned over. Some scientists suggest they are playing dead, but Sherbrooke disagrees. "What good does playing dead do when you have a predator trying to eat you?" he asks. He thinks they are advertising their size and spininess. "If you're small, you get eaten by a lot of things," he says, so appearing bigger and spikier might be useful if your adversary is trying to swallow you whole. Finally, there is horned lizards' best-known defence: blood squirting. They reserve this for two groups of predators: cats and canids, the group that includes dogs, coyotes and wolves. The process is quite simple. A pouch below the lizard's eyes, the ocular sinus, swells as it fills with blood. With a sudden surge of pressure, blood forcefully squirts out in a stream that can travel up to 6ft (2m). They shake their heads, they salivate profusely, and try to clear the material out of their mouths To show that horned lizards can discern dogs from other large predators, Sherbrooke recruited a golden retriever called Dusty. She was trained to bark, paw and gently nibble at a horned lizard. Within a minute of Dusty barking, each lizard squirted her. "She was the perfect dog," says Sherbrooke. In contrast, the lizards were less concerned when Sherbrooke tried to mimic Dusty's behaviour. "I got down on all fours and I barked, used my front 'paws' to paw her, but I didn't bite," he says. The lizards were not fooled, and mostly ignored his dog impersonation. "I was somewhat relieved that I wasn't that easily mistaken for a dog," he says. Canids are not averse to blood, but they dislike horned lizard blood, even though it is not poisonous. "They have an almost violent reaction," Sherbrooke says. "They shake their heads, they salivate profusely, and try to clear the material out of their mouths." It takes about 15 minutes to recover. The blood contains a chemical that binds to receptors in the canid's mouth: receptors that humans apparently lack. "I've tasted the blood many, many times," says Sherbrooke. He never detected anything more than a mild acrid aftertaste. The blood is most effective when delivered directly into the mouth, rather than the eyes or nose. This might explain why horned lizards often wait until the last second, when they are already in their attacker's jaws, before squirting. If you eat ants, it's like living on M&Ms The lizards probably get the unpleasant chemical in their blood from their food. They mostly eat ants, and many eat highly venomous harvester ants. This does have a downside, though: they even need a defence against their own food. A horned lizard will lap up its food with the tip of its sticky tongue. It does not chew the ants. Instead, before swallowing, it wraps the ants in strands of thick mucus secreted by special cells at the back of its throat. This protects the lizard from the ants' stings, allowing them to exploit a resource that most animals can't. The lizards' ant-based diet might be what drove them to evolve so many defences. "If you eat ants, it's like living on M&Ms," says Powell. "Individually they don't contribute a lot." To make up for it, a horned lizard has to eat a lot of ants, and to do that it needs a big stomach. The desert horned lizard has a stomach that makes up 13% of its mass: akin to a 150-pound person with an almost 20-pound stomach. They can give birth to up to 48 live offspring at a time To accommodate such a large stomach, ant-eaters need to be stocky. "If you're going to be stocky you can't run fast," says Powell. "If you can't run fast, you're going to rely on camouflage or horns, and you end up with all these defensive behaviours." Of course, sometimes camouflage, armour and squirting blood aren't enough, and a horned lizard gets eaten anyway. But even then they sometimes manage one last act of defiance: it's not unheard-of for a horned lizard to become lodged in the throat or stomach of a bird or snake, killing its attacker. Besides, horned lizards have one last defence against death: they have lots of babies. Their wide abdomens accommodate larger broods than most lizards, so they can give birth to up to 48 live offspring at a time, or lay up to 45 eggs. So while an individual horned lizard might succumb to a particularly determined coyote or carnivorous mouse, it has a good chance of passing on its genes before it does.	{ "pile_set_name": "OpenWebText2" }
Gunshot wounds to the head and neck. The types of injury which occur as a result of the civil disturbances in the north of Ireland are described. Four cases of gunshot wounds to the head and neck are described, each of particular clinical interest. The recent literature on the subject is reviewed and the consensus of opinion appears to be that the safest policy is to explore all cases of penetrating wounds of the neck	{ "pile_set_name": "PubMed Abstracts" }
Live cell imaging and biophotonic methods reveal two types of mutant huntingtin inclusions. Huntington's disease (HD) is an autosomal dominant, neurodegenerative disorder that can be characterized by the presence of protein inclusions containing mutant huntingtin within a subset of neurons in the brain. Since their discovery, the relevance of inclusions to disease pathology has been controversial. We show using super-resolution fluorescence imaging and Förster resonance energy transfer (FRET) in live cells, that mutant huntingtin fragments can form two morphologically and conformationally distinct inclusion types. Using fluorescence recovery after photobleaching (FRAP), we demonstrate that the two huntingtin inclusion types have unique dynamic properties. The ability to form one or the other type of inclusion can be influenced by the phosphorylation state of serine residues at amino acid positions 13 and 16 within the huntingtin protein. We can define two types of inclusions: fibrillar, which are tightly packed, do not exchange protein with the soluble phase, and result from phospho-modification at serines 13 and 16 of the N17 domain, and globular, which are loosely packed, can readily exchange with the soluble phase, and are not phosphorylated in N17. We hypothesize that the protective effect of N17 phosphorylation or phospho-mimicry seen in animal models, at the level of protein inclusions with elevated huntingtin levels, is to induce a conformation of the huntingtin amino-terminus that causes fragments to form tightly packed inclusions that do not exit the insoluble phase, and hence exert less toxicity. The identification of these sub-types of huntingtin inclusions could allow for drug discovery to promote protective inclusions of mutant huntingtin protein in HD.	{ "pile_set_name": "PubMed Abstracts" }
Indian Motocycle Manufacturing Company Indian is an American brand of motorcycles originally produced from 1901 to 1953 in Springfield, Massachusetts, United States. Hendee Manufacturing Company initially produced the motorcycles, but the name was changed to The Indian Motocycle Manufacturing Company [sic] in 1928. The Indian factory team took the first three places in the 1911 Isle of Man Tourist Trophy. During the 1910s, Indian became the largest manufacturer of motorcycles in the world. Indian's most popular models were the Scout, made from 1920 to 1946, and the Chief, made from 1922 to 1953. The Indian Motocycle Manufacturing Company went bankrupt in 1953. Various organizations tried to perpetuate the Indian Brand name in subsequent years, with limited success. In 2011, Polaris Industries purchased Indian Motorcycles and moved operations from North Carolina and merged them into their existing facilities in Minnesota and Iowa. Since August 2013, Polaris have marketed three modern Indian motorcycles that reflect Indian's traditional styling. Latest News for: Indian publicity The announcement came as the company kicked off its new publicity campaign to redefine the Bajaj brand's identity as "The World's Favourite Indian" to mark its dramatic transition from a domestic scooter maker to a global motorcycle powerhouse ... company's new publicity campaign.... In its annual report, entitled “PublicGood or Private Wealth,” Oxfam found that the bottom 50% of Indians, in terms of income, only saw a 3% rise in their wealth ... A report by the PublicHealthFoundation of India in June 2018 found that the rising cost of medicines ...... After 10 am, it is time for public meetings across the town ... But Kavita Jain interrupts Kharkara stating that Middha has to address other public meetings too. Speaking to The IndianExpress, Middha says that his meetings with public and supporter go on till late in the night but there is no exact time for him to go to the bed in the poll season.... ... which are aimed at building capacities and capabilities of Afghan nationals and institutions for governance and delivery of public services, developing socio-economic infrastructure, securing and promoting livelihood options," IndianEmbassy in Afghanistan noted in a statement.... An Indian cricket board official, who has been interacting with the two players, says a line from Pandya has stayed in his mind ... "How can you expect them to be with the Indian team now? They will fly back home," Edulji had told this newspaper ... They were teenagers then and would publicly chat with fellow cricketers about their sexual 'conquests'.... In a recent interview with IndianpublicationDNA, Ranveer opened about his super-successful Bollywood career and the ‘journey of becoming a hero, not an actor’ ... In a recent interview with Indianpublication DNA, Ranveer opened about his super-successful Bollywood career and the ‘journey of becoming a hero, not an actor’ ... .... Dehradun... The 10 protesters arrested on Monday have been booked under sections 147 (rioting), 341 (wrongful restraint), 332 (voluntarily causing hurt to deter public servant from his duty) and 353 (assault or criminal force to deter public servant from discharge of his duty) of the IndianPenal Code (IPC). .... Senior inspector Prasad Pandhare of Dadar GRP said that Rautu has been arrested under sections 420 (cheating), 465 and 468 (forgery), 471 (fraudulently using a genuine document, 170 (impersonating a public servant), and 171 (Wearing garb or carrying token used by public servant with fraudulent intent), of the IndianPenal Code... .... He also claimed that the opposition parties do not have the leadership to challenge him ... The forthcoming election is going to be held on the question of whether the Indianpublic desires a strong government or a weak one. In the past, the public had suffered during the governments led by past Prime Ministers like Indrakumar Gujral and Chandrashekhar....	{ "pile_set_name": "Pile-CC" }
Le Mans, 18 June 2013 - Aston Martin Racing and Gulf have unveiled the winner of their livery design competition. The design, inspired by the change in atmosphere as day gives way to night during the 24 Hours of Le Mans, was created by Jonathan Wesley from Kettering in the UK and will adorn the #97 Vantage GTE throughout race week. Darren Turner (GB), Stefan Mücke (D) and Peter Dumbreck (GB), drivers of the #97 Vantage GTE, selected Jonathan’s design from the hundreds of entries received. He will now attend the race weekend as a VIP guest of Gulf to see his winning design compete in the 90th 24 Hours of Le Mans. "I have been excited ever since I got the news that my design had been chosen,” comments Jonathan. “I loved the chance of being able to design a Gulf Aston Martin, but it's already such a classic livery that I was wondering what I could do. “I was just sketching a few thoughts out and I liked the idea of the car being a different colour on both sides. I thought about the Gulf corporate colours – dark blue, light blue, orange and white – and I came up with the idea of ‘daylight to dusk’, which to me is the most exciting part of the race. “So it moves from the white with the broad orange stripe dividing things to the dark blue of the night. The orange and blue lines represent the streaks that you often see in photos of the cars at night and the whole design sort of summed up the essence of Le Mans to me." Gulf, which has partnered Aston Martin Racing for five years and has signed a further three-year deal, ran the livery competition to allow fans to participate in the team’s most ambitious Le Mans campaign, marking the centenary year of Aston Martin. Sam Cork, Global Brand Manager at Gulf explained: “Gulf has been responsible for some extremely iconic motorsport liveries and we wanted to give fans the opportunity to play their part. To design the livery for a Gulf Aston Martin, racing at Le Mans in the brand’s centenary year, is really something quite special. “This livery will enter Gulf and Aston Martin Racing’s history books and Jonathan should be extremely proud to be the winner, as we had hundreds of entries from all over the world. The design is excellent. It is everything we hoped for. We can’t wait to see it take to the track for the most exciting endurance race of the year.” The #97 car is one of five Aston Martin Racing Vantage GTEs competing in the 24-hour race, but the only one to carry the competition-winning design. Aston Martin	{ "pile_set_name": "OpenWebText2" }
5" (sch. 40) BAILEIGH® CNC Roll Bender - $RFQ Benders - Pipe Tube & Bar CNC Manufacturer: Baileigh Model: R-CNC150 Condition: New CALL FOR AVAILABILITY AND BEST PRICING! FEATURES:The largest in its class the R-CNC150 roll bender is capable of bending up to 5” Schedule 40 Pipe. This pyramid style bending machine will enable the operator to create material calibrations for easy programming of multi-radius parts. With four position interchangeable bottom rolls the R-CNC150 provides increased control and flexibility when bending complex extrusions for the Window and Door Industry. This feature helps to decrease the ovality when bending round tube in the furthest position while also allowing for a decrease in Minimum radius when using the machine in its closest setting. Multiple speeds on both X and Y axis provide the user with the ability to create elaborate shapes with smooth transitions between segments and with the standard photocell lens each part will begin and end at the same place each time. Designed to work in either the horizontal or vertical position this machine offers the ultimate in control. To learn more please contact our sales force directly and we will send over a formal quotation. 40 programs 24 different parts (segments) per program 75 profile calibrations 2 Speeds (rotation of the rolls) 4 Speeds (Top roll movement) Top roll movement can be progressive or direct Progressive – Top roll go to position with profile moving. Direct – Top roll go to position with profile stopped MADE IN PORTUGAL	{ "pile_set_name": "Pile-CC" }
Highly selective hydrolytic kinetic resolution of terminal epoxides catalyzed by chiral (salen)Co(III) complexes. Practical synthesis of enantioenriched terminal epoxides and 1,2-diols. The hydrolytic kinetic resolution (HKR) of terminal epoxides catalyzed by chiral (salen)Co(III) complex 1 x OAc affords both recovered unreacted epoxide and 1,2-diol product in highly enantioenriched form. As such, the HKR provides general access to useful, highly enantioenriched chiral building blocks that are otherwise difficult to access, from inexpensive racemic materials. The reaction has several appealing features from a practical standpoint, including the use of H(2)O as a reactant and low loadings (0.2-2.0 mol %) of a recyclable, commercially available catalyst. In addition, the HKR displays extraordinary scope, as a wide assortment of sterically and electronically varied epoxides can be resolved to > or = 99% ee. The corresponding 1,2-diols were produced in good-to-high enantiomeric excess using 0.45 equiv of H(2)O. Useful and general protocols are provided for the isolation of highly enantioenriched epoxides and diols, as well as for catalyst recovery and recycling. Selectivity factors (k(rel)) were determined for the HKR reactions by measuring the product ee at ca. 20% conversion. In nearly all cases, k(rel) values for the HKR exceed 50, and in several cases are well in excess of 200.	{ "pile_set_name": "PubMed Abstracts" }
Formula 3 Red Bull Ring: summer weekend of MP Motorsport The softest compound that Formula 3 got this weekend was the soft tyres with the red colour. Liam Lawson was 16th fastest when he completed his first push lap, Richard Verschoor 21st and Simo Laaksonen was 20th fastest. After their cooldown lap to let the tyres recover and to avoid traffic they went again back up to speed for improving their lap time. Simo Laaksonen did much better this time he was 7th fastest, Verschoor 13th and Lawson 15th. The quickest lap time during the first run was for Armstrong with a time of 1:19.866. The second run on a new set of tyres got disturbed by a red flag caused by Logan Sargeant after he got launched off a kerb straight into the wall. The clock got stopped with 4 minutes and 13 seconds left. This meant that there was only time for an out lap and one last push lap. Richard Verschoor qualified 14th in that lap, Liam Lawson 17th and Simo Laaksonen 19th. The top 25 cars qualified all in one second! Two ART drivers got disqualified at the end, and this made all MP Motorsport drivers move up two places on the start grid. Race one Ricard Verschoor started 12th, Liam Lawson 15th and Simo Laaksonen 17th after they gained two positions because of the disqualifying of ART. The start of the race went well and without any incidents. Richard improved one position, Liam went three places forward, and Laaksonen was the only one with a loss of three places. Liam Lawson overtook Richard during the third lap for the 11th position, but he fell back to the 14th position two laps later. Laaksonen was recovering from the first lap and gained back three positions. Some minor changes happened during the rest of the race. Verschoor managed to overtake Niko Kari for position ten but had to give it back for some laps before he took it back again. Richard eventually finished the race 10th, Liam Lawson 14th and 18th for Simo Laaksonen. Race two An excellent start for Richard Verschoor while he moved up four places during the first lap. Liam Lawson moved up to position 12 while Simo Laaksonen had to give up one position. Liam moved up another two places during lap three what made him 10th. The progress of Verschoor turned around at lap 8. He got overtaken by two drivers and one lap later by Vips as well. The virtual safety car went on in lap 11 and got switched off in lap 12 at that time Verschoor was 9th, Liam Lawson 10th and Simo Laaksonen 20th. Lawson tried to overtake Verschoor on the outside of the second last corner during lap 14, but that didn’t work out. He dropped down to position 12. Lawson then got pushed off the track in the exit of turn three by Niko Kari. This resulted in a broken front wing for Liam Lawson what he had to repair in the pit. Richard Verschoor ended the race 9th but he got a penalty what made him 12th in the end. Simo Laaksonen finished 18th and Liam Lawson 25th.	{ "pile_set_name": "Pile-CC" }
Manifest refraction versus autorefraction for patients with subfoveal choroidal neovascularization. To compare the results from manifest refraction using trial lenses and a standard visual acuity protocol to results from autorefraction for obtaining refractive error and best corrected visual acuity in patients enrolled in a randomized clinical trial. During a 4-month period, 29 patients with subfoveal choroidal neovascularization (CNV), who were enrolled in the Submacular Surgery Trials (SSTs) Pilot Study at the Wilmer Ophthalmological Institute, gave verbal consent to participate in this study. Best corrected visual acuity was obtained using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity charts and standardized room lighting after performance of manifest refraction, according to the SST protocol, and autorefraction. Refractive error (spherical equivalent) and visual acuity scores were obtained in both eyes of all patients. On average, manifest refraction gave a spherical equivalent that was 1.04 D more plus than autorefraction (95% limits of agreement = 0.74, 1.34). On average, the visual acuity score was 1.5 letters better after manifest refraction than after autorefraction (95% limits of agreement = 0, 3.0). The comparison of the two methods of refraction was subdivided according to visual acuity level and eye disease (age-related macular degeneration or ocular histoplasmosis syndrome). Despite large differences in spherical equivalent between manifest refraction and autorefraction, the visual acuity scores were close (mean difference, 1.5 letters). Other studies comparing subjective refraction and autorefraction have shown similar results. Autorefraction in patients with subfoveal CNV may be a satisfactory alternative to manifest refraction in clinical trials and field studies in which best corrected visual acuity is of interest.	{ "pile_set_name": "PubMed Abstracts" }
Case: 11-41328 Document: 00512042106 Page: 1 Date Filed: 11/02/2012 IN THE UNITED STATES COURT OF APPEALS FOR THE FIFTH CIRCUIT United States Court of Appeals Fifth Circuit FILED November 2, 2012 No. 11-41328 Summary Calendar Lyle W. Cayce Clerk UNITED STATES OF AMERICA Plaintiff-Appellee v. ARTEMIO LOMAS Defendant-Appellant Appeal from the United States District Court for the Southern District of Texas USDC No. 5:11-CR-770-2 Before JONES, DENNIS, and HAYNES, Circuit Judges. PER CURIAM:* A jury convicted Artemio Lomas of one count of conspiracy to possess with intent to distribute 1,000 kilograms or more of marijuana in violation of 21 U.S.C. §§ 846 and 841(a)(1), (b)(1)(A) and two counts of possession with intent to distribute 100 kilograms or more of marijuana in violation of § 841(a)(1), (b)(1)(B). The district court sentenced Lomas to three concurrent terms of 151 months in prison. Lomas argues for the first time on appeal that the district * Pursuant to 5TH CIR. R. 47.5, the court has determined that this opinion should not be published and is not precedent except under the limited circumstances set forth in 5TH CIR. R. 47.5.4. Case: 11-41328 Document: 00512042106 Page: 2 Date Filed: 11/02/2012 No. 11-41328 court erred in calculating the drug quantity attributable to him under the Sentencing Guidelines by using the gross weight rather than the net weight. Because Lomas did not object in the district court to the drug quantity attributed to him, our review is for plain error. United States v. Conn, 657 F.3d 280, 284 (5th Cir. 2011); United States v. Sparks, 2 F.3d 574, 589 (5th Cir. 1993). Simply put, Lomas has not demonstrated that the court used the gross weight rather than the net weight. Neither the trial testimony nor the presentence report (PSR) referenced either gross weight or net weight. Furthermore, the district court was entitled to rely on the jury’s finding that Lomas conspired to possess with intent to distribute 1000 kilograms or more of marijuana and Lomas’s admission that the facts in the PSR were correct. See United States v. Arnold, 416 F.3d 349, 362 (5th Cir. 2005); United States v. Ramirez, 557 F.3d 200, 204 (5th Cir. 2009). In light of the trial testimony, the jury’s finding, and Lomas’s admission, Lomas has not show that the district court committed any error, and certainly not clear or obvious error, when it relied on the drug quantity indicated in the PSR. See United States v. Rodriguez, 602 F.3d 346, 363 (5th Cir. 2010). AFFIRMED. 2	{ "pile_set_name": "FreeLaw" }
Pages 06 February, 2011 Scenes from the Indian Film Industry Ever since I started blogging, aside from a couple of reviews from the Indian Film Industry, most of my reviews have been about films made in the US. I think it is about time I did a little bit in promoting the wonderful cinema that is being produced in my own country, India. Just a quick note to inform the worldwide public that most of the people in the Indian Film Industry and a whole lot of citizens of India do not like the title "Bollywood" that has become so popular internationally. It's pretty much considered degrading and disrespectful to a vastly talented and original film industry. So it would be nice if everyone recognized the Indian Film Industry as just that and not a re-hash of Hollywood. So here is a list of just a few of my favorite Indian films. I would like to warn you that you might be shocked to learn that a number of these do not contain any lavish music or dance sequences :-) Udaan (2010) - Udaan (Flight) is one of the few indian films reviewed on my blog. It is a brilliant coming-of-age film that traces the journey of a teenager returning to his authoritarian father after many years in a boarding school. The performances from all the actors are simply brilliant and the story is as real as it can be. One of the few recent releases that have gone under my all time favorites. Jaane Bhi Do Yaaron (1983) - JDBY (Let It Go Friends) is a comic satire on the corruption that handicaps India and one which is unfortunately as true today as it was when the film was released in 1983. The movie is about two photographers who want nothing more than to run a successful photo shop, but due to unfortunate events get entangled in a murder that takes them from beautiful newspaper journalists, to shady business tycoons, to the middle of a rather modern theatrical performance of Ramaya (which is till date one of the most comic scenes in the history of Indian Cinema). It was also responsible for kickstarting the career of some of India's most prominent actors. If you find the movie interesting make sure you give Manjula Negi's article "It Just Happened" a read. Link to the article - http://www.openthemagazine.com/article/art-culture/it-just-happened Khosla Ka Ghosla (2006) - Khosla Ka Ghosla (Khosla's Nest) is once again a look at real life. The movie follows a middle class family's ordeals as they try to recover a plot of land illegally taken over by a local property dealer. Done in a light heartedly subtle comical fashion, the movie doubles as a con caper film as well. Note: "Khosla" is a common Indian surname. Lagaan (2001) - Probably one of the most well known and popular Indian films, Lagaan (Tax) is a fictionalized period drama that is based in India during the British Raj. It has some great characters, dance, music, and in a nutshell its about a village's quest to get rid of the yearly tax they have to pay to the British by playing a cricket match against them. Please, even if you are not familiar with cricket, do not let is hold you from watching the movie. Ek Ruka Hua Faisla (1986) - Loosely translated it means "A held up judgement", but what it really is, is a remake of "12 Angry Men". I have watched this film many a times over the years and just happened to watch 12 Angry Men recently. Maybe it is my fondness for the Indian version, or maybe I found that the supporting characters in the original lacked the depth found in the remake, I do prefer the Indian version a whole lot more. So, have a go at it, even if it is to compare the two. Dil Chahta Hai (2001) - "The Heart Wants" or Dil Chahta Hai is another coming-of-age film following three friends as they learn about relationships, friendship, love, work and pretty much everything else that life is all about. Once again a great cast and interesting story with strong performances make this a must watch film. The film also had a very urban feel and look to it, and having lived in a metropolitan city all my life, it was something me and my friends could easily relate to. Rang De Basanti (Pain It Yellow) (2008) - So, another coming-of-age film of sorts (Yes! I see a pattern here as well), the movie looks at the youth of India through its main characters. What the film brilliantly does is portrays their thought process, their beliefs, and their aspirations by giving them all dual identities. In the present time they are all college going individuals, but in a process of making a documentary they each relive an important character from India's freedom struggle. The movie moves seamlessly between the two eras and culminates as the lost young souls realize the importance of their identity and eventually take drastic measures to rid our nation of corruption. Inspirational and heartening are two words that really describe the movie. Bluffmaster (2005) - I am sure a whole lot of my fellow countrymen and women will cringe at the fact that I recommended this movie as a must watch. The reason why I do recommend it is because it has good song and dance sequences (you didn't think you could get out of it... did you?), it makes use of multiple starts who go about doing their jobs commendably, and lastly it is about a conman, so you know you will have a pretty good twist at the end. Now, I am not going to name the english movie it is loosely based on, but it does take some inspiration from it. Nevertheless, this rather modern film is perfect for some light fun viewing. Satya (1998) - The South East Asian film industry is in a league of its own. They have specially been known for making some phenomenal gangster based films. So, being part of Asia, India was not going to be left behind. Satya (Truth) is the journey of a young man from the time he comes to Mumbai to his untimely death. It is also a hard hitting look at the Mumbai underworld and the lives of the various people who are drawn into a lifestyle of guns, women, and shady deals. Watch it for its raw feel and for the various characters, each of whom makes the movie his/her own. Iqbal (2005) - Iqbal is a story about, well Iqbal. An 18-year-old deaf and dumb village boy who has only one aspiration and that is to play in India's National Cricket Team. The story is less about cricket, but more about facing adversities in life and aiming towards your goal. Iqbal, in this journey of his, on one hand faces criticism from his coach and father, but on the other hand has his sister and a washed up ex-cricketer who support and guide him towards success. The movie is simply a reminder that you should never let go of your dream and hard work always pays off. So there you have it. 10 films from India that are a must watch. They are all available on DVD and all come with english subtitles. So, if ever in the mood for some foreign (or local if you are from India and have not seen any of the above) film watching, do give these movies a try. You will not be disappointed.	{ "pile_set_name": "Pile-CC" }
--- gpu/command_buffer/tests/gl_copy_texture_CHROMIUM_unittest.cc.orig 2019-04-08 08:32:57 UTC +++ gpu/command_buffer/tests/gl_copy_texture_CHROMIUM_unittest.cc @@ -562,7 +562,7 @@ class GLCopyTextureCHROMIUMES3Test : public GLCopyText bool ShouldSkipNorm16() const { DCHECK(!ShouldSkipTest()); -#if (defined(OS_MACOSX) \|\| defined(OS_WIN) \|\| defined(OS_LINUX)) && \ +#if (defined(OS_MACOSX) \|\| defined(OS_WIN) \|\| defined(OS_LINUX) \|\| defined(OS_BSD)) && \ (defined(ARCH_CPU_X86) \|\| defined(ARCH_CPU_X86_64)) // Make sure it's tested; it is safe to assume that the flag is always true // on desktop.	{ "pile_set_name": "Github" }
Przechówko Przechówko is a village in the administrative district of Gmina Świecie, within Świecie County, Kuyavian-Pomeranian Voivodeship, in north-central Poland. It lies approximately south-west of Świecie, north-east of Bydgoszcz, and north of Toruń. References Category:Villages in Świecie County	{ "pile_set_name": "Wikipedia (en)" }
After creating a Google account a google+ profile is automatically created. So if you own a Gmail account then you definitely have a google+ profile too. But after some time you realize that Google plus is not your cup of tea and you prefer Facebook or twitter much over google plus. A good news is Google allow us to delete our google+ account or profile without deleting or affecting other Google services like Gmail and YouTube. So if you have made your mind to no longer use Google+ and delete your profile then here’s a step by step guide to delete your google plus account. Permanently Delete Your Google Plus Account Note after deleting your Google+ account some of the data within your Google+ account will be lost. This data includes your Google+ posts, comments and circles. Although some data will be not be deleted. This data includes: Your Google+ Photos, Contacts and pages will be not deleted. Your YouTube channel will be will not be deleted. Your Google drive will not be deleted. And most importantly your Gmail account will not be deleted and you can still access it. Almost anything related to your Google account like adwords, analytics or adsense will not be deleted. So now I hope everything is clear, just follow the below steps to permanently delete your Google plus account. So first of all login to your Google plus account. Now click on your profile picture on the top right corner and further select My Account. This will open your Google account settings. Under Account Preferences click on Delete your account or services. Now you will have two options i.e Delete products and Delete Google Account and data. You have to select Delete products. If you want to delete your entire Google account then you can select Delete Google Account and data. But still it’s highly not recommended. It will ask you to re-enter your password. Once you have entered your password you will be redirected to a page where you will have options to delete Google+, YouTube and Gmail. Simply click the trash button at the right side of Google+. This will permanently delete your Google plus account. If you want you can also delete your Gmail or YouTube account by clicking the trash button. So that was a quick guide to disable or delete your Google plus profile from your google account. If you have any doubt’s then do let us know in comments.	{ "pile_set_name": "OpenWebText2" }
GM finally am able to get kind of caught up with all my blog sites. Have helped my older sister with her estate sale. And this week isn’t going to be any better. I signed up for a Debate Watch Party that should be fun. Watching upwithchris it about the Suprememe Court. Hope everyone on TOD has a great day. Morning all. Down with an awful cold, head stuffed, tears streaming, throat scratchy. Husband still in the grip of a nasty coughing cold. Still, the sun is up and the trees are turning beautiful colors, so all’s right with the world. It’s a Good Morning here in the land of “Pleasant Living”. I hope everyone is doing well even with the fall allergy season. Just do something to help the POTUS today. Find one more person to register to vote. In NYT, there’s an article, “Psst: We Feel Bad About Our Arms” and it shows 3 pictures of FLOTUS. “May I suggest that some of her colleagues, a growing cohort of copycat arm-flashers, might want to check the mirror before again preening sans sleeves? It’s time to face the truth: we don’t all look like the First Lady.” It compares FLOTUS fashion trend to others First Lady trends, as Mamie Eisenhower’s bangs, etc. Basically, we just have one beautiful FLOTUS, inside & out. I meant to thank someone yesterday for posting that video of Michelle’s introductory speech for The 2008 Pres run – she’s just as special as he is. The Up With Chris segment about the Supreme Court once again highlights why Pres. Obama and Democrats need to win. A rightwing court that will/choose to hear cases on affirmative action, voting rights act, marriage equality etc is a dangerous one. Good morning every one. I remember that Black Female attorney from being at Rainbow Push on Saturday mornings. Nearly a year or so she exposed voter suppression and the map of shame in addition to how to fight back. Then she said voter suppression was either coming to our state or a state near us. I posted their link here a while back. I see the map’s been updated. It is now an ” Animated Map of Shame” which allow you to click on it and see how quickly many states rushed to pass government-issued photo ID laws without considering the consequences. Hi good Peeps, Today’s a marvelous day. Enjoy it, but I must say that we have our work cut out or us. The corporate media has it’s marching orders to defibrillate Romney’s dying campaign by any means necessary. Why? Cuz media need their pound of flesh re: Romney’s & superpac ad revenue. GOP never intended for that inconvenient thing called Democracy to get in the way of their venal agenda. There’s very little difference between what al Qaeda has done and the tactics of the GOP. I’m not being hyperbolic here. These people WANT power. All of it. They’ll do anything, anything, to get it. So folks whatever we can each do to convert our healthy poll numbers into ACTUAL votes cast should our ONE and ONLY focus now. Polls don’t WIN elects; VOTES do. T Please help however you can. Thanks We need a GOP that is willing to compromise to move the country forward. We don’t need a party which will obstruct every dang thing the current administration proposes. Hopefully, now that the Repubs have figured out that they failed at making President Obama a one-term President, they’ll actually do something constructive like pass the Jobs Act. Wow, McCain was pretty honest in that particular statement. He went as far as saying that americans are a little bit hopeful now ! Isn’t he undermining the Romney/Ryan message ? Maybe he wants Romney to lose, so either Huntsman or Jeb Bush could have a chance in 2016 ?? (I remember reading that John McCain pushed Huntsman to run this year….) Whoever picked Candy Crowley to moderate the debates needs to be punched over and over and over again. And if that person was a man, he needs to be punched hard in the nuts. HARD. I haven’t watched CNN for a long time and thank goodness. Axelrod and Governor O’Malley were the reasons I watched this morning and Maryland, you are fucking lucky to have Governor O’Malley. Crowley kept interrupting Axelrod over and over again but he got his points through. He sure did. O’Malley also did well and has the patience of a saint considering he was sitting next to GOP woman hater Roy Blunt who kept lying and lying and having his lies aided by Candy Crowley. Crowley practically crawled into McCain’s lap and almost gave him a lap dance….that’s how much she was GOP shilling. She’s a moron. A bloody moron. An amoeba is smarter than her. Whoever picked her to moderate the debate is a fucking fool and should be punched over and over and over again. As a current resident of MD, I feel proud to say that yes, we have a great gov, although admittedly I didn’t help to build that since I was not yet an MD resident when O’Malley got elected. Candy Crowley deserves to be mocked, harassed and humiliated if she ever pushes that bullshyte during the debate on Wednesday. I for one will be scrutinizing her very very closely. And something tells me that I and all of us here at TOD won’t be the only ones. Candy Crowley HAS BEEN PUT ON NOTICE. When Chris Christie first ran for Freeholder and was sued for defamation, it wasn’t his fault and he did nothing wrong. When Chris Christie went from “not a candidate for US Attorney” to being appointed US Attorney after he was directly responsible for raising hundreds of thousands (and his brother donates hundreds of thousands) for Bush, the donations had nothing to do with it. And when many top NJ lawyers pointed out that Christie didn’t have any experience in criminal law and his appointment was directly connected to the above hundreds of thousands in donations for Bush, that was just a coincidence. Well up and at ’em O’s!!!!! It’s wonderful to join my TODdies on this great getting up day! I’m tuning in to the Sunday shows today, cause it’s much easier to swallow when our team is ahead. Imagine Chrispie flopping around like a beached whale trying to defend Mittwit? That can’t be fun for him. Also, with exception of a few, the moderators smell blood and they go on a feeding frenzy like the sharks they are. It doesn’t matter whose blood at this point. Not to mention, they want to be seen as shaping the winner. Expect them to be less hostile. My political take today is Wednesday can’t get here soon enough. Wednesday is my Zumba nite, but I’m going to jiggle my wiggle for a PBO debate victory. I’m going to try and at least stay in the room. During the previous debates, I would hang in the doorway and either run away or come back into the room depending on the question and whose turn it was to answer it. cookemom – lol going in and out of the room. I only do that for POTUS debates and when my baseball team is in the playoffs. I am afraid I am going to leave the TV off and just follow a live blogging of it – too stressful otherwise. I’m a chicken I know!! I’m basically a chicken so yesterday’s post of Michelle Obama introducing her husband at a campaign in ’08 talking about getting over fear spoke to me. I am still nervous about the debate especially about Romney’s intent to smear our PBO saying he lies. I don’t fear PBO’s debating or explaining skills will not be up to speed. What I fear is the way the media will paint the debate results and their complicency in helping Romney by not holding him to the fire using commercial breaks to aid him and the same tactics they used in the infamous ’08 Primary Debate with George Stephanopolis and Charlie Gibbs. It’s been a really busy week for me (fiscal year-end). I was able to join the canvass to NOVA yesterday. All I can say is that people are really engaged and from what I can see at least in Northern Virginia things are looking really good. The campaign has a big fundraising deadline tonight. Please donate what you can and if you can’t can you please retweet my link. Thanks and have a great productive O’Day!!! Ashes 2 ashes, dust 2 dust, I hate 2 have 2 ask again but I must, I must. Can you donate $5 b4 the deadline 2nite? https://t.co/gzOTDChe I like this tweet, because I am tired of people acting like, and speaking like the President is winning by default……just everyone else is being so bad. He is winning because he is so GOOD and doing things RIGHT, and he is getting his message across. People try to take credit from him all the time, and I get angry about that. He has been a good president, he has done good things, and he is a good campaigner, the best I’ve seen. No one in my memory can compare to him, certainly not Saint Ronnie. He was basically lazy, and read a script. This man understands what is going on, and is the most involved president I’ve known of. Yes, I just had to set someone at Old Orange straight on this issue. Apart from his solid record of accomplishments during the last 3.5 years, President Obama is simply unparalleled in the campaigning department. I also agree that President Obama has not just been lucky. He is an excellent candidate and campaigner and he has a good campaign group. They have strategized for months and because they have a plan can jump on sudden opportunities that fit their narrative. Luck? LUCK IS OPPORTUNITY MEETING HARD WORK AND PREPARATION. Got a plaque that says that after many people told my daughter she was lucky for getting so many academic scholarships at the end of her senior year in high school. She was demoralized that people did not recognize the hard work she had put in to get straight As all through high school, for being the president of the National Honor Society, on high school and community sports teams, on the ski team, involved with her church youth group and for starting and participating in a high school tutoring group. The plaque spoke to me about her work. The words also depict President Obama’s hard work. Successful white folks are successful because of hard work. Successful black folks are successful because of luck. I first saw this attitude in sports — the black guy is naturally gifted, the white guy lacks the gift but makes up for it with hard work. Why? Because black people are lazy so if they do well it HAS to be luck. This drives me even CRAZIER than I already am. During the Republican presidential primary debates, a telling pattern emerged. Mitt Romney, who first ran for public office back in 1994, called Rick Perry a “career politician.” Mitt Romney, who owned stock in and profited from Fannie Mae and Freddie Mac, criticized Newt Gingrich for working for Freddie Mac. Mitt Romney, who lobbied for funding for the Salt Lake City Olympics and has many of DC’s top Republican lobbyists intimately connected to his campaign, attacked Rick Santorum as a lobbyist. It seemed that each attack that Mitt Romney leveled at his opponents was done before they had an opportunity to say it about him. If precedent holds, then the best way to interpret Romney’s charge that Obama will “say things that aren’t true” is that he is attempting to inoculate himself against the abundance of falsehoods he plans on espousing at the debates. Mitt Romney’s propensity for flip-flopping long ago passed into self-parody, perfectly epitomized by his own campaign’s reference to an etch-a-sketch. But it is important to remember that his ability to say one thing one day and say the opposite the next with a straight face is rooted in his casual relationship with the truth. . . As a quick refresher, here is but a small sampling of Mitt’s lies in the past, and those he is most likely to repeat. Paul Ryan To Fox News: ‘I Don’t Have The Time’ To Explain How We Will Pay For Our Tax Plan By Adam Peck ————————————– Ryan has been the Republican vice presidential nominee for nearly three months, and has still not found the time to explain how a Romney administration would fund its tax plan of 20 percent deductions across the board. Perhaps that is because if he did, voters would balk at the cuts that would need to occur in programs like Medicare for the plan to remain revenue neutral. Ryan’s refusal to talk specifics only lends further credibility to the various studies and reports that have found time to do the math. And as ThinkProgress has reported, those studies from non-partisan organizations show that the Romney/Ryan tax plan would actually result in a huge tax cut for the wealthiest Americans. And the only way to keep it revenue neutral is to balance their plan on the backs of middle class families, who would see a tax increase of more than $2,000. So, NBC nightly news will be focusing on Afghanistan, and Calling it -at the Brink. All week long, as the media I so surprised that their are Green on Blue attacks? So surprised? The Taliban captures these Afghan police forces, and tells them either kill Americans, or your Family dies. And Ruchard Engle is well aware of this, he just has an agenda. That is all! Don’t forget today is the last day of the quarter for the various campaigns. In addition to PBO, we need to give to those downstream races in order to send PBO a Congress he can work with. I’ve decided to help out Claire McCaskill of Missouri, Sherrod Brown of Ohio, Joe Donnelly Indiana, Elizabeth Warren of Mass, and Joe Tester of Montana. These are close races, but there are many others. Find a few and show them some love today. After the Romney campaign spends all week tampering down expectations of Mittwit’s debate performance, Chrispie raises the bar higher than ever. I do believe there’s sabotage afoot, that man is no friend of his Repub leader. David Gregory is now begging David Plouffe to talk to Pres. Obama about coming on to Meet The Press. The look Plouffe gave him was priceless. Plouffe then said “well, there’s 37 days until the election. Anything’s possible.” David Gregory is such a goof…..I will never watch his show even if the President goes on there which he won’t. David Gregory’s ratings are in the toilet and like his best friend Mitt Robme, nothing can improve his favorables…….people don’t like them. Thanks UT. Done. And do not forget our Senate races. Just did one for one of my Senator’s friends. We need to keep the Senate solid for POB and get the help to Nancy. I also just did one for our Ms. Smashing Nancy!HZ David Gregory is an asshole. He lied on MTP that Pres. Obama fundraised in Las Vegas the day after the attacks in Libya that killed four Americans. This NEVER happened. Twitter is on fire calling him and Meet The Press out. Journalist Jon Ralston is pissed off too and calling David Gregory out for perpetuating that GOP lie. $2.00 $3.00 grateful for whatever. I am almost to one of my three goal. 1. Do all I can with my group in my city to phone bank, organize to go door to door. 2. Set up and meet my goal for my FR Page 3. Be first on TOD at least once. 4. GET POB/BIDEN re-elected .4More 4 -44. Thank (((((((( Love my TOD Family)))))))) Give some goodness claps. My gut is great today. Miracles are happening. Thank you all for your beautiful thoughts. You lift my heart and spirit up so much.HZ	{ "pile_set_name": "Pile-CC" }
Last-wish ID cards? A Michigan lawmaker says a person's end-of-life wishes should be accessible during an emergency. You may have what's called a "living will" that determines what kind of care -- if any -- you want if you have, say, a heart attack. But if you don't have that document with you, emergency responders are going to try to bring you back to life. "Their first default is to resuscitate, and in your case, that's wrong. It's not what you wanted to do, but they didn't know that because they didn't have the document," says State Sen. Roger Kahn, R-Saginaw. "When they (living wills) are not followed, you are assaulted by the medical system and then charged a bill for it." Kahn says state-issued ID cards that link to living wills would let emergency responders know whether you want to be resuscitated. "You have to have legislation which says that the ambulance personnel shall search for that document, which, in my opinion, should be available by pressing a button or two." Kahn says such a program would spare the pain and expense of unwanted treatment. Kahn -- who is a physician -- says many people resuscitated after suffering a heart attack outside of a hospital don't survive or have a very poor quality of life afterward. "Statistics show that if you have an out-of-hospital cardiac arrest, half of the people die in the field before anybody gets there," Kahn says. "Of the remaining half, another half die during CPR, which includes putting tubes in your body and breaking your ribs. "So now there are one-quarter that are still alive. Half of them will die in the emergency room, and of the one-eighth who are now alive -- 12 percent -- half of them will die during the hospitalization. And now of the six percent alive, half of those have permanent brain damage." Kahn says the financial impact of using extraordinary lifesaving measures can take a big toll on families and on the state. "We have priorities that need to be honored for the individual, and society as a whole," Kahn says. "There's always a competition for the dollars to do that and for the laws that embrace our people's rights."	{ "pile_set_name": "Pile-CC" }
Effects of age on the glucoregulatory response following acute glucoprivation induced by 2-deoxyglucose (2DG) in the adrenal medulla of Sprague Dawley rats. Impairment in glucose homeostasis is one of the factors that may alter the feeding drive, hunger and satiety signals, which essential to maintain a sufficient level of energy for daily activities especially among the elderly. Adrenal medulla is one of the important organs that involves in glucose homeostasis through secretion of catecholamines. The catecholamines biosynthesis pathway utilizes various enzymes and protein kinases. The aims of this study are to investigate the effects of age on the biosynthetic pathway of catecholamines in adrenal medulla by determining the level of blood glucose and blood catecholamines, the gene and protein expression of biosynthetic catecholamine enzymes (TH, DBH and PNMT) as well as protein kinase substrates that involved in the phosphorylation of TH in 2DG-induced rats. Adrenal medulla from male Sprague Dawley rats at the age of 3-months (n=12) and 24-months (n=12) were further divided into two groups: 1) treatment group with 2DG to create glucoprivation condition and 2) the vehicle group which received normal saline as control. The results showed that the level of glucose, adrenaline and noradrenaline were increased in response to acute glucoprivation conditions in both young and old rats. No age-related differences were found in the basal gene expression of the enzymes that involved in the catecholamines biosynthesis pathway. Interestingly the expressions of TH and DBH protein as well as the level of TH phosphorylation at Ser40, PKA, PKC and ERK1/2 substrates were higher in basal condition of the aged rats. However, contradicted findings were obtained in glucoprivic condition, which the protein expressions of DBH, pERK1/2 and substrates for pPKC were increased in young rats. Only substrate for pCDK was highly expressed in the old rats in the glucoprivic condition, while pPKC and pERK1/2 were decreased significantly. The results demonstrate that adrenal medulla of young and old rats are responsive to glucose deficit and capable to restore the blood glucose level by increasing the levels of blood catecholamines. The present findings also suggest that, at least in rats, aging alters the protein expression of the biosynthetic catecholamine enzymes as well as protein kinase substrates that may attenuate the response to glucoprivation.	{ "pile_set_name": "PubMed Abstracts" }
Posts Tagged ‘low ropes course’ “Many would say that a challenge course is simply an elaborate playground that affords a participant fun along with a sense of adventure. In some ways this is true, but such a statement is much too limited in what it conveys.” For the beginning adventure education professional, Challenge Course Programming (AE 251) covers important content. After all, challenge courses are ubiquitous in our profession, and trends suggest this will continue. Simply put, they allow us to “bring the adventure to our backyard.” Their popularity has resulted, in part, from their accessibility and controllability – qualities inherent to many “artificial” adventure learning environments – both of which can yield powerful learning experiences that can be facilitated to apply to home, work or school. This course introduces the class to the operation of a variety of low and high challenge course initiatives for adventure programming in problem solving, trust, team building, self-confidence, and communication skills. Includes belay and high ropes rescue techniques. A.E. Jobs Backdoorjobs.com Are you looking for opportunities to work, travel, play, learn, help, create, experience and grow in the U.S. or abroad? Come explore, dream, discover and do with Backdoorjobs.com: Short-Term Job Adventures! Seasonal Jobs Cool Works® is about you finding a seasonal job or career in some of the greatest places on Earth. Get a summer job in Yellowstone, Yosemite, or another national park. Find a summer job as a camp counselor. Ski resorts, ranches, theme parks, tour companie Wilderdom Wilderdom explores human-nature relations and seeks sustainable solutions to modern-living. This link is to their job listings Minnesota State Masters in Experiential Education The M.S. in Experiential Education at Minnesota State Mankato began in 1971 as a joint venture between the University and Minnesota Outward Bound School (now Voyageur Outward Bound School). Today, it’s the oldest program of its kind in the United States. Links of Interest American Alpine Journal Published since 1929, The American Alpine Journal is the premiere annual record of significant mountaineering and long rock climbing ascents worldwide. American Alpine Club members receive the 500-page American Alpine Journal (retail $35) free with member Magazine for Backcountry skiers Off-Piste Magazine is the backcountry skier’s magazine. We offer a soulful perspective on backcountry skiing and related ski culture. Rooted in touring for turns and the lifestyle of dedicated skiers, our content focuses on the spirit, culture, and equipm St. Paul Lodge The St. Paul Ski Lodge is a unique backcountry lodge in the southwestern Rocky Mountains, between Silverton and Ouray, Colorado. No matter if you prefer telemarking, cross-country, snowboarding, alpine skiing, or snowshoeing, you will find pleasing terrai	{ "pile_set_name": "Pile-CC" }
"DIN We have endured bitter hardship and countless battles.." "but at long last, our home planet has been restored." "We would not be standing on" "Cybertronian soil were it not for the valiant efforts of both those assembled here.." "and our absent comrades" "Ratchet, who remains on Earth to safeguard our human friends, and Cliffjumper, who made the ultimate sacrifice." "But on this day, at the dawn of a new era, we gather to bestow a special honor one earned by Bumblebee." "Through his bravery and devotion to the cause of peace, long before, he rid this universe of the scourge of the Decepticon warmonger." "Megatron." "Megatron!" "Megatron!" "Unicron?" "I do not understand." "Why am I not one with the Allspark?" "Do I yet live?" "You do not, yet you cannot join the Allspark because my lifeblood once flowed through your veins." " Dark energon." " It binds you to my" " Anti-spark." " Optimus Prime used the Matrix of Leadership to imprison you within the Earth's core." "So how is it that you speak to me now?" "The foolish Prime rendered only my material form dormant." "But my energy form was roused from slumber when I sensed the awakening of an ancient rival across the cosmos." "Primus. so, it would seem that Optimus succeeded in restoring" "Cybertron after my demise." "I now wish to finish what I began eons ago, and for that, my" "Anti-spark requires a vessel." " So..." "I will live again?" " Only to serve me." "Your husk will simply be an instrument of my will." "In the company of your fellow Autobots, in the presence of our creator, Primus, the living core of our planet, and by the authority vested in me by the Matrix of Leadership," "Bumblebee..." "arise a warrior." " Nice work." " Warrior, big time!" " You go, B." "Let's get this party started!" "Welcome to the club, B." "Warrior today, and who knows?" "Prime tomorrow?" "Slow down, Smokey." "I'm not sure I'd wish a Prime's" " responsibility on anyone." " I am sorry to interrupt your celebration." " Here it comes." " Primes never party." "but I must take my leave of you." " Sir, may I ask why?" "Though Cybertron is once again able to support life, our planet is currently incapable of generating new lives" "Not until I retrieve the wellspring from which all life on Cybertron is born and ultimately returns..." " The Allspark." " You mean it isn't here?" "Nor has it been, Smokescreen..." "not for thousands of years." "As the war for Cybertron reached a tipping point and the Decepticon army appeared to be unstoppable, I opted to safeguard the Allspark from" "Megatron by covertly sending it to a distant sector of the galaxy." "The Matrix of Leadership will enable me to guide us to its present location." "What are we waiting for?" "Let's take the warship" " and bring it back." " These remain dangerous times, Bumblebee." "We cannot leave Cybertron unsecured not with Starscream and Shockwave unaccounted for." "Not to mention our stray Predacon." "Ultra Magnus, you will supervise patrols to find and capture the fugitive Decepticons." " I would be honored." " Bulkhead, you will lead the reconstruction effort." "Begin by building a landing field to welcome returning refugees." "Wheeljack, I will require your extensive experience" " navigating deep space." " When do we leave?" "Megatron:" "Super-luminous space drive." "Impressive." "One of many upgrades that I've made to your limited corporeal form and wholly necessary to reach Cybertron." "So... we are to rule together, as one? You will rule nothing!" "I travel to Cybertron for one reason only" " to destroy Primus personally." " But... to destroy Primus..." " is to destroy Cybertron!" " Thus will begin the new age the age of chaos! Whoa, whoa, whoa!" "How are you gonna attach the cladding when the framing structure's incomplete, huh? Labor issues?" " Any news of our fugitives?" " Just signs of recent scavenging in former Decepticon installations." "The 'Con warship can't detect their life signals?" "Shockwave must have found a way to shield or disable them." "I'll feel better when that gruesome twosome are locked up with the others." "Okay, you got my attention." "What do you want?" "We're prisoners of war." "We have rights!" "When are we going to have access to an oil bath?" "Well, when are you gonna tell me where I can find your pals?" "I told you before, Shockwave had dozens of secret labs hidden across Cybertron top-secret." "A shame." "Your finish is looking pretty drab." "I don't know where they are, I swear!" "But I have an idea where you might try looking." "Well, someone may want to think about renaming the sea of rust." "I'm just sayin'." "Though I was hoping more of us would be rushing back here to see it you know, now that it's all bright and shiny." "Cybertron will populate in time, kid." "You have to remember refugees could be returning from light-years away." "Movement." "Two contacts at .84" "Approach with caution." "My name is Ultra Magnus." "Are you Autobot or Decepticon? Neither." "Predacons! Phase beats flame every time!" "Scrap!" "Bumblebee, I need an emergency ground bridge, stat! Hang tight, chief." "I'm getting you out of here." "Where's the patient?" "He is suffering from a multitude of internal injuries, most quite severe." "So, anyone care to explain what two more Predacons are" " doing on Cybertron?" " I thought Optimus said new life wasn't possible without the Allspark." "I'm no authority, but something tells me cloning old bones doesn't constitute new life." "Shockwave's been playing in his lab since the war." " Why stop now?" " Doesn't matter where those beasts came from." "We got to take 'em down." "If Shockwave's back in business, there could be more of" " them a lot more." " We need to call Optimus." "Really, Bulk?" "And interrupt his quest to save the future of our race on Cybertron?" "Why send the Allspark to Theta-Scorpio, one of the most hazardous star systems in the galaxy?" "Precisely to deter Megatron from searching this region for it." "With all the gamma bursts and planetoid collisions out here, how can you be sure it survived?" "The Allspark itself is comprised of pure energy." "In order to contain it and launch it off-world, Alpha Trion forged a vessel capable of extracting it from the ether." "it is this indestructible reliquary we seek." "Well, I'll try not to scratch the paint on this tub," " but no promises." " We cannot risk being stranded if our ship is damaged." "It is best that you remain here," " Wheeljack." " You're the boss." "Watch your step." " Who made him leader?" " He did snuff Megatron." "I'm not leading." " I'm scouting." " Fair enough." "But you do realize we're nowhere near where we found those" " Predacons, right?" " We're not looking for those" "Predacons." "I followed this energon trail, which means he was wounded..." "And I know we aren't the ones who wounded him." "Whoa." "You mean we've been tracking... ...Predaking?" "Hold fire!" "Recognize this, Predaking?" "You served aboard Megatron's warship." "Surely you're familiar with this little treasure from his vault the Immobilizer." "It causes instant stasis-lock, though the victim remains fully conscious a living death." "But we didn't come here to fight, your highness." "Then why have you violated my refuge, Autobot?" "We need answers." "Do you know of any other" "Predacons currently on Cybertron?" "Indeed legions of them." "Behold my subjects a countless multitude, rendered extinct ages ago by the great cataclysm, unearthed by the shifting of plates during our" " planet's restoration." " Yeah, well, me and" "Ultra Magnus just about got scrapped by two living" "Predacons." "Know anything about them," " your highness?" " Two?" "Where?" "We came to ask your help in finding them." " For revenge?" " No." "Optimus Prime would deem it a tragedy to stain Cybertron's fresh soil with any newly spilled energon." "So help us prove what Megatron was never willing to that more than one race can peacefully coexist on our planet." "You assume that because I turned against Megatron, I can forgive the Autobots their role in the destruction of my brethren on Earth?" "Leave me be and dare not trespass here again." "I have returned, partner." "I trust you haven't strained yourself tinkering in your lab while I was toiling in the field like a common drone?" "I mean, I seem to supply old bones faster than you grow new clones." "Starscream, given our lack of infrastructure and frequent need to relocate in order to avoid detection, it is not logical to expect greater productivity at this point in time." "At least your new clones lack the arrogance of your last effort the one who named himself "Predaking" Be careful, you clumsy brutes!" "Where have you been?" "Gutting Autobots." "What?" "!" "You were ordered to avoid all contact with the enemy!" " I don't hear you laughing now, Darksteel." " We weren't followed." "Fools!" "Now that they know of your existence, we have lost the element of surprise!" "The Autobots are weak." "They fled like cowards." "We have no need to fear them." "Perhaps, Skylynx, but we must not underestimate them, either." "their treacherous scout was able to fell the mighty Megatron" " rest his Spark." " As such, it is paramount that we harvest the CNA necessary to clone more of you" " many more of you." " So that we may build an army of beasts great enough to eradicate the Autobots and conquer Cybertron in Lord Megatron's memory and name." "Arcee:" "What makes you think we'll find Shockwave's cloning lab here?" "Yeah, wasn't Darkmount Megatron's military H.Q.?" "If the intel I received from Knockout is accurate... we'll find a map of Shockwave's entire lab network in the Citadel's databank." "Not good." "Optimus, plasma storm incoming!" "Get out of there!" "That Allspark container may be" " indestructible, but you aren't!" " I am too close to turn back. "Lord Smokescreen" emperor of destruction." "How can you sit there?" "That's some bad mojo." "What do you know?" "Knockout actually shot" " straight for once." " What'd you have to do" " buff his finish?" " Close." "Let's download the data and get out of here." "Hey." "Something's heading our way." "Predaking?" " Movin' too fast." " Starscream?" "Minions of the Prime, prepare to be obliterated!" " Megatron?" " You skewered bucket-head with a giant saber and managed to miss his Spark?" " How are you still alive?" " And where'd you score the upgrade?" "Megatron cannot answer you at this moment, though I can inform you with utmost authority that he owes his new lease on life to me Unicron!" "And I will not be so easy to deliver into oblivion." " Bothersome pest." " That pest is the very one who robbed me of my Spark." "And now I possess the power" " to return the favor!" " You possess nothing!" "It is I who possess all that you were and ever will be." " We need to retreat." " The only way out is down." "We can't call for a ground bridge until we put some space between Unicron and us!" "Behold my infinite might!" "Let's roll." "Come on, chief." "We're out of time." "Whoa!" "Stop!" " A smelting pit?" " Cybertron's been dormant for thousands of years, but that's still burning?" "Ratchet, we need a ground bridge." "Optimus, if we don't get out of here right now..." "Optimus!" "That's why he's Prime." "Cutting it a little close, don't you think?" "Wheeljack, set a course for Cybertron." "Hang on to your hubcaps." "That's the future of life on Cybertron, huh?" "I kind of figured it'd be bigger." "Hold tight! No!" "Servant of Prime, you will now join your brethren!" "You got that right! I... am..." "weak!" "But our merciless attack drove the Autobots into submission!" "They fled for their very Sparks!" "A victory over unworthy opponents, especially one that did not result in their demise, is far from an achievement." "Clearly, our improved state is not enough to accomplish the deed for which I have come." "For that, I shall require a much greater instrument of destruction." "How is this happening?" "I mean, we put out a call inviting refugees back to Cybertron, and Unicron's" " the first in line?" " Not to mention those Predacons." "What have we come home to?" "What are we supposed to call him, huh "Megacron"?" ""Unitron"?" " Really?" "That's your biggest issue right now?" "Right, right." "All right, good." "So, what's the game plan?" "While Unicron may now inhabit a mortal form, he is still a god and thus cannot be defeated by customary means." "Optimus?" "Wheeljack!" "This is Bumblebee." "We have an urgent situation." "Bumblebee, this is Optimus Prime." "Proceed." "Optimus!" "Can you hear me?" "Come in, please." " Wheeljack, do you read?" " That hit we took did some damage." "Receiver's operational, but we can't transmit." " Nothing." " You have your voice back." "Now is not the time to go radio-silent." "Optimus, in the event that you can hear us, Unicron has found his way back to Cybertron." "Repeat the Chaos-bringer is here, on our soil, in possession of Megatron's body." "Wheeljack, ensure that the light-speed drive is" " still fully operational." " So, what now I mean, besides hoping that Optimus got the message?" "We figure out why Unicron's here." " And what he wants." " The big "U" could have taken" "Earth behind our backs." "Why come back to Cybertron?" "There would be only one reason, Wheeljack." "To destroy the Spark of his archenemy Primus." "But that's the core of our planet!" "It isn't fair." "How many more times do we have to save a world have to fight for the survival of our home?" "Regrettably, the struggle between creation and destruction is an eternal one." "And the battle lines which separate the two... run through the very Spark of Cybertron." "Good and evil." "Order and chaos." "One victorious, one vanquished, each forming the core of their own separate worlds" "Cybertron..." "and Earth." "And now.." "The darkness has followed us." "all the way home." "Hmm." "Tracks." "The Autobot spoke the truth." "Other Predacons do exist.." "though it seems they took flight here." "Locating my new brethren will be a futile endeavor, unless I allow them to locate me." "Vitals are improving." "You will be back on your struts In good time." "Exactly how long is good time?" "Because with Optimus missing in action, we could really use Ultra Magnus' counsel." "Bumblebee, we have each been witness to those among us who have risen above their station time and again rappers, scouts, even field medics." "The Chaos-bringer is at our doorstep, and now, more than ever before, we cannot afford" " to wait for salvation." " We'll launch an attack on" "Darkmount, provided Unicron's still there." "Or first attempt to locate him, in the event he is not." "The beacon it worked!" " Predaking?" "Alive?" " You know this primitive life-form?" "Yes a warrior once under my command, though I thought he had perished in battle." "How fortunate that I was wrong, for Predaking is a loyal and powerful combatant who could very well be the greater instrument of destruction which you seek." " Megatron?" " Warrior!" "I call upon you to serve your master." "In the name of the mighty legions of Predacons who preceded me, I shall never again yield to your charge." "But I will heed your previous advice and face my true enemy... as a beast!" "You dare to deceive me and" " have both of us destroyed?" " Perhaps not destroyed just damaged enough that our shared form will no longer be of use to you and force you to abandon what remains, for regaining my freewill, even over a mangled and deficient frame, is preferable to enduring a waking life as your slave!" "For your insolence, I will only make you endure greater suffering! Now..." "let us learn more of these mighty legions of which you spoke by peering directly into your mind." "Ahh." "I know now what I require to tear this world asunder... and where I might find them." "Shockwave." "How was your journey?" "Long." "Explain why you have summoned me to the middle of nowhere." "Because I have located our army." "The clones sniffed out quite the mother lode, wouldn't you say?" "I recommend that we utilize the warship's operating system to search for Megatron's life signal." "Doc, that remodel who kicked our tailpipes he might have looked and sounded like old bucket-head, but it wasn't him." "That much I know." "But even if a fraction of" "Megatron's Spark still flickers within his body, the ship's scanners may pick it up." "So, you find me amusing?" "Ow." "That hurt!" "That bone could be your comrade someday!" "Now stop fooling around and return to the task at hand!" "I do find it curious..." "that I am not the only one currently seeking the remains of mighty legions." " It cannot be!" " It defies logic." "Lord Megatron!" "But but how?" "Y-You, uh oh, what does it matter?" "Our master is back and looking far more imposing than ever!" "My liege, rest assured, we have been working tirelessly in your absence to build an army powerful enough to conquer Cybertron." "I do not wish to conquer this world." "I wish to eradicate it." "Ye... uh a-apologies, lord Megatron." " I-I can't say that I'm following." " Silence!" "Your master is under my control." "I am the Destroyer of worlds, the Bringer of chaos, and" " the Lord of the undead." " Unicron." "I say we show the Lord of the undead what it's like to be unliving!" "Rip him to shreds!" " Megatron's life signal." " So, somewhere inside that new" " body armor, he's still alive?" " He's perished and returned before a phenomenon no doubt aided by the blood of Unicron, which has coursed through his veins." "The coordinates indicate he's left Darkmount." "Triangulating his exact position." "We were there earlier today." " Predaking's refuge?" " Unicron's retracing our steps?" "Whoa, wait." "What in Alpha Trion's beard is that?" "My legion... arise, and purge this world with your dragon fire!" "Terrorcons created from Predacons?" " It defies all science." " We're doomed! Given that we are dealing with Unicron himself, the energy mass can be only one thing dark energon." " But for what purpose?" " We all saw it." "The valley was filled with ancient Predacon bones." "Unicron's raising an undead army." "One currently traveling across the hydrax plateau towards... the well of Allsparks, the most direct route to Cybertron's core... and Primus." "The past shall consume the future, the dead shall consume the living, and chaos shall reign supreme!" "Unicron clearly seeks to access our planet's core from the same point of entry that we used to restore it." "No doubt, with every intention of undoing our efforts." "So, what do we do?" "We put ourselves between Unicron's army and the well." "Our strongest assets are this warship and whatever relics" " might be stored in its vault." " Last time I looked, just the" "Polarity Gauntlet and the Immobilizer." "Hopefully the genuine article this time." "I'll round up the secret weapons." "Bulkhead, think you can pilot this ship?" "'Con engineering." "User-friendly, right?" "Ratchet, you've given your all to save this world once already." "Where are you taking us?" "We have a right to know!" "Greetings, fellow Decepticons." "Starscream." "Thank the stars!" "We can finally escape" " this dreaded ship." " No, doctor." "We must, in fact, take this ship... by whatever means necessary." "Primary fusion cannons, null-rays, ion blasters everything we need to stand a fighting chance against" " Unicron's army." " B, in case I never get another chance to say this, you've really proved your mettle." "I'd like to think my actions always spoke louder than my words, Arcee." "But it didn't hurt to watch and learn from the best." "It would be nice if Optimus showed up about now." "I was referring to a powerful little two-wheeler I know." "Autobots!" "Surrender this warship! Ah-Ah-Ah." "Funny how the Immobilizer can freeze bots in their tracks..." " before it's activated." " And, in case you're wondering, Smokescreen is in no position to come to your rescue right now." "Scrap." " Skylynx, look!" "One of us!" " Indeed, Darksteel most likely our predecessor." "The burial ground desecrated, strip-mined of all that remained of our ancestors." "You should have been here to see 'em rise and shine!" " They live?" " If you call being undead "living"" "Dark magic perpetrated by the demon who lives in Megatron's skin." "Just be glad you're alive so the demon can't" " pull your strings." " Do you not comprehend the scope of this tragedy?" "We three are proof that our mighty race might once again have flourished." "Their remains must be reclaimed, if for no other reason" " than to be properly laid back to rest." " And who made you boss?" "I am not your boss." "I am your King!" "Nah, Scream won't use it." "He needs us if he's gonna stand" " any chance of surviving Unicron." " You misunderstand." "I do not intend to use this warship for battle but for quickly getting as far as possible from this doomed planet." "Earth would be nice, now that" "Unicron no longer seems to be calling it home." "Shut up, you!" "Now move away from the controls," " Bulkhead, or get stiff!" " There's just one thing you've overlooked, Scream." "That device you're holding" " not the Immobilizer." " What?" "!" "What do you mean?" "Aah-ya-yah!" "I will silence you forever." "Huh?" "Now will you believe I'm joining the winning team?" " Knockout, we needed that!" " Wait." "It... really was the Immobilizer?" "Ha! All hail.." "Predaking." "An impressive display for my creations." "But would it not be more logical to employ your might elsewhere this time? Fine!" "I hope Unicron destroys you first!" "Why'd you do it, Knockout?" "Why'd you turn against Starscream?" "Even if I had helped him seize this ship, he would have probably just fired me out of the first airlock." "Oh and he's rude." " Are we there yet?" " Right on schedule." "And so is Unicron." " Resistance?" " From my own warship." "Demon hordes, take flight..." "and eviscerate them!" "Maybe Starscream had the right idea." "Zombiecon!" "Zombiecon!" "Is it Optimus?" "Predaking." " More flying pests!" " Whom to root for?" "The lines have certainly blurred." "Predacon allies." "You called it, B." "And to think Optimus almost passed down the Matrix to me." " Whoa." "What?" "!" " Yeah, I said it." "But "right place, right time" doesn't mean "right bot"" "I know that now." "Brace for impact!" "Whew!" "Nothing a little carnauba wax won't fix up." "Ugh." "Huh? My legion, the time is upon us." "Destroy Primus with your dragon fire!" " We're the last line of defense." " I would recommend leaving that to those more suited for the task." "Skylynx!" "Darksteel!" "Allow nothing to enter the well." "Really?" "This is how it ends?" "We're not losing our planet not without taking Unicron with it." "What?" "A familiar resonance pure energy, not unlike Primus... one I have not encountered since ancient days." "The Allspark!" " Optimus." " I never thought I'd be so happy to see that big rig!" "We must keep the Allspark from Unicron's reach." "I thought the container was indestructible." "Indeed." "But if this vessel once trapped the Allspark," "I fear that it can also be emptied of it." "So, the Prime returns!" "Ugh!" "Ugh!" "Jacky!" "Thank you, Prime for delivering the Allspark so that" " I may erase it from existence." " Not while I stand before you, Unicron." "Megatron, you and I once united to save a world from Unicron." " We must do so again." " Megatron may hear you, but he cannot help you.." "for he is enduring eternal suffering." "Your efforts to protect Cybertron's most sacred relic are futile!" "My legion is within reach of Primus your planet's very core." "And we both know that the Allspark cannot thrive in a poisoned well." "Downside to wearing metal near a Polarity Gauntlet..." "You're subject to the laws of magnetism." "Optimus, go!" "Save the Allspark!" "I've been worse." "So, how are we gonna get that thing to safety?" "By the only means available to us under these most dire of circumstances." "The very survival of our species upon this or any world depends upon it." "I shall devour your Allspark whole!" "What?" "!" "A trick?" "! As a being comprised of pure energy," "Unicron's Antispark was vulnerable to this reliquary of the Primes." " But if he's in there, where's" " Praise the Allspark!" " Master!" "You're alive!" " Indeed." "Your new battle armor will take things to the next level," "My liege." "Together we will reunite all" "Decepticons and once again grind Cybertron under" " your mighty heel!" " No!" "What?" "Why?" "Because I now know the true meaning of oppression... and have thus lost my taste for inflicting it." "Uh, you've clearly been traumatized, master." "A good power-down and a stroll around the smelting pit will put you back in touch with your inner warlord." "Enough!" "The Decepticons are no more, and that is final." "Yes." "Well, we all have plenty to think about, don't we?" "This is not quite how I envisioned my rise to the throne, but since lord Megatron all but surrendered it to me," "I will gladly revive the Decepticons in my name." "Though perhaps a throne is more befitting of an actual King." "I am not here to seize thrones, Starscream.." "but to settle scores." "In order to both protect the Allspark and secure Unicron's defeat, it was necessary for me to empty the vessel's contents." " Into where?" " The Matrix of Leadership." "As such, my own Spark can no longer be separated from" " the multitude of others within me." " Are you telling us... that you are now.." "one with the Allspark?" "That's what you say when someone kicks the." "To not return the Allspark to the well would be to prevent future generations of new life from existing on Cybertron." "My quest must be completed." "Optimus, I didn't return to save a life only to lose the one I care most about." "Ratchet's restored planets." "he'll find a way to save you!" "We can turn to Vector Sigma, just like we did before." "Because the Matrix must now be relinquished with the Allspark, it cannot be restored or passed down to another." "But while this may very well mark the end of the age of Primes, leadership can be earned with or without the Matrix, and, in my view.." "you have each acted as a Prime." "Well, I... never really had the best role models." "As even Megatron has demonstrated on this day, every sentient being possesses the capacity for change." "I ask only this of you, fellow Autobots keep fighting the noblest of fights." "You can count on us to keep the peace." "Above all, do not lament my absence.." "for in my Spark, I know that this is not the end.." "but merely a new beginning.." "simply put, another transformation."	{ "pile_set_name": "OpenSubtitles" }
Twitter has updated its app for both Android and iOS devices today. The iOS users have been updated with some new features. Now on Twitter, you can discover, install and launch the app from within the tweets you are making. Surely the feature is not supporting all apps at the start but twitter stated that they will make fast progress and include most of the iOS apps in their latest updates. The developers at twitter have explained the app on how to install and their deep linking process. There are some new features regarding Twitter Cards that have been mention on the blog as well. The description suggests that it will bring quite a revolution to the way world use Twitter, ” Twitter cards make it possible for you to attach media experiences to Tweets that link to your content. Simply add a few lines of HTML to your webpages, and users who Tweet links to your content will have a “card” added to the Tweet that’s visible to all of their followers. Meanwhile, you can download a twitter video downloader right now. Furthermore the developers posted some interesting notes regarding the new introductory procedure of twitter card, One of the most important features in the new Cards is the ability to allow users to download your app (if the user doesn’t already have it installed), or deep-link into your own app (if the app is already installed on the user’s mobile device). The ability to enable app installs and deep-linking is globally available across all Twitter Card types – you’ll just need to add a new set of markup tags as detailed below. What’s New in Version 5.5 Twitter for iPhone now helps you discover, install and launch your favorite apps from Tweets. This update also includes the following improvements: • Faster launch times and general performance upgrades • “Retweeted by” in Tweet detail is now tappable • Fix for reply-to-self in conversations • Fix for a bug that prevented undoing retweets in some cases Source: Twitter Blog	{ "pile_set_name": "OpenWebText2" }
Close window on Button click in ASP DOT NET. To close a browser window there is only one Way i.e to add JavaScript. Below are the two methods of making a browser window (page) close.Method 1 : On page load add the script to the button onclick attribute . It will occur a bit faster.Method 2 : If User wants to validate some Process before Window close, Its better to use Method 2 ,Because using the first Method no server side code will get executed..Here On Button Click Use the Script to close the window.So Before closing the window we can Validate the Process in the Applications 'Method 2 : on Button Click Use the Script Protected Sub btnClose_Click(ByVal sender As Object, ByVal e As System.EventArgs) Handles btnClose.Click If Page.IsValid Then Response.Write("") End If End SubEnd Class	{ "pile_set_name": "Pile-CC" }
… … … Discover Yoga Discover Yourself Ardha Pawanmuktasana (One Leg Wind Release Pose) Method Step 1:Lie down on your back; adjust your lower back by sliding your hips and tailbone down towards your heels so that lower back is firmly resting on the floor without any gap or arch. Step 2: Inhale and raise your right leg up to 60 degree (use your core muscles to raise your right leg up); keep your right leg stretched and while maintaining the stretch, bend your right knee and place your right thigh on the right side of your chest; hug your right leg with both the hands; try to hold your elbows with the opposite hands; keep your left leg straight and stretched, left hamstrings pressed against the floor with your left heel sliding out and left toes flexing in. Step 3: You may also choose to keep your left leg straight on the floor while keeping a bolster below your left knee; hold for half a minute or as per your comfort with normal breathing; release and repeat the same sequence with your left leg. Note In case of discomfort at back, bend your left knee, place your left foot on the floor and then raise your right leg up. Benefits Massages your lower back and gives relief to lower back pain. Improves digestion; helps dealing with gastric problems. The pressure on the abdomen releases any trapped gases in the large intestine. In women, the asana massages the pelvic muscles and reproductive organs and is beneficial for menstrual disorders as well. It also reduces fat in the abdominal area, thighs and buttocks Contraindications Pregnant woman should not practice Ardha Pawanmuktasana People suffering with piles or hernia should perform this asana only in supervision and consultation with a yoga expert. You should avoid this asana if you have undergone a recent abdominal surgery as there is a lot of pressure on the abdomen.	{ "pile_set_name": "Pile-CC" }
BP sums up its response to Deepwater disaster BP CEO Bob Dudley reflected on the company’s response to the Deepwater Horizon oil rig explosion in a keynote speech at CERAWeek in Houston, Texas, on 21 April. He confirmed that the company had spent USD44 billion in response to the 2010 disaster in the Gulf of Mexico that killed 11 crewman and caused the largest-ever oil spill in US waters. This included USD14 billion recompensing victims, a further USD 14 billion on clean-up activity, and USD 1 billion on restoration projects. He said the company’s safety culture had since been completely changed, with “sharper oversight and additional levels of protection”. Training, he said, is now focused on best practice, and advanced technology, when approved, is used at all BP’s oil wells. Looking forward to 2035, Dudley said he believes the oil, natural gas, and coal industries will be equally split, each sharing 27% of the global energy market. The rest would be filled by unconventional resources, such as oil shale fracking and biomass energy. However, he said the current low oil price can be expected to continue in to the medium term, which will mean a period of massive restructuring and economic suffering for mature regions such as the North Sea, North Dakota, and parts of Texas. As the third anniversary of the entry into force of the Maritime Labour Convention 2006 (MLC) approaches, Seafarers’ Rights International (SRI) is embarking on a comprehensive study on the effectiveness of the Convention. The study has been commissioned by the International Transport Workers’ Federation. It will be an in-depth and... Read more →	{ "pile_set_name": "Pile-CC" }
A while back I created a post about limits in Microsoft Teams. Today I’m looking at limits within Microsoft Flow. Number of Flows created by a user When you are happily creating many flows and you think that there is no limit to what you can do with Microsoft Flow then you might run into this one! There is a limit of 250 flows that a single user can create. After this you simply get the following error and you can’t save any more flows. If you hit the 250 limit you can raise a support ticket and then the limit will be raised. Do Until limited to 60 runs by default When running Do Until loops Flow will only run 60 times through the actions inside a Do until. Luckily it is possible to change this limit within the flow editor. The above limits I didn’t find on any of the Microsoft Limitation pages. If you are interested in other limitation here is the official Limits and configuration in Microsoft Flow post. Some of the interesting limits from the above article I’ve included below. Run duration and retention These are the limits for a single flow run. Name Limit Notes Run duration 30 days Includes workflows with pending steps like approvals. After 30 days, any pending steps time-out. Timed-out approvals are removed from the approvals center. If someone attemps to approve a timed-out request, they’ll receive an error message. Storage retention 30 days This is from the run start time. Min recurrence interval 1 minute Max recurrence interval 500 days Looping and debatching limits These are limits for a single flow run. Name Limit Notes ForEach items 5,000 You can use the filter action to filter larger arrays as needed. Until iterations 5,000 SplitOn items 5,000 ForEach Parallelism 1 Definition limits These are limits for a single flow. Name Limit Notes Actions per workflow 250 You can add nested workflows to extend this as needed. Allowed action nesting depth 5 You can add nested workflows to extend this as needed. Max characters per expression 8,192 action / trigger name limit 80 description length limit 256 What should we do with these Microsoft Flow Limitations? When looking at the Definition limits. I’m slightly worried about the Actions per workflow and the Allowed action nesting depth most of the other limits you can easily work around. but these two limits mean that when your flow has grown to much you will be stuck and are forced to split your flow across multiple flows. This is where it becomes important to design your flows the right way straight from the beginning. Even when your flow is still quite small. Share this: Tweet WhatsApp Email Like this: Like Loading...	{ "pile_set_name": "OpenWebText2" }
Silurus Silurus is a genus of catfishes native to Europe and Asia. Species There are currently 18 recognized species in this genus: Silurus aristotelis Garman, 1890 (Aristotle's catfish) Silurus asotus Linnaeus, 1758 (Amur catfish) Silurus biwaensis Tomoda, 1961 (Lake Biwa giant catfish) Silurus burmanensis Thant, 1967 Silurus caobangensis V. H. Nguyễn, T. H. N. Vũ & T. D. P. Nguyễn, 2015 (Yellow catfish) Silurus dakrongensis V. H. Nguyễn, T. H. N. Vũ & T. D. P. Nguyễn, 2015 (Dakrong catfish) Silurus duanensis X. Y. Hu, J. H. Lan & C. G. Zhang, 2004 Silurus glanis Linnaeus, 1758 (Wels catfish) Silurus grahami Regan, 1907 Silurus langsonensis V. H. Nguyễn, T. H. N. Vũ & T. D. P. Nguyễn, 2015 (Flower catfish) Silurus lanzhouensis H. L. Chen, 1977 (Lanzhou catfish) Silurus lithophilus Tomoda, 1961 (Rock catfish) Silurus mento Regan, 1904 (Kunming catfish) Silurus meridionalis H. L. Chen, 1977 (Yangtze catfish) Silurus microdorsalis Mori, 1936 (Slender catfish) Silurus soldatovi Nikolskii & Soin, 1948 (Soldatov's catfish) Silurus triostegus Heckel, 1843 (Mesopotamian catfish) References Category:Siluridae Category:Catfish genera Category:Taxa named by Carl Linnaeus Category:Freshwater fish genera Category:Taxonomy articles created by Polbot	{ "pile_set_name": "Wikipedia (en)" }
He was a beautiful man inside and out, and I knew that he loved me. But when it came to our sex life, there were no fireworks. It turns out, low libido was to blame. And he wouldn’t talk about it. Not really. Years later I admitted to myself that the fact that his desire rarely burned brightly left our intimate exchanges limited in every way. While he seemed unconcerned, I wanted more — more frequency, more variety, more heat. In Love? Overlooking the Obvious? When you’re emotionally invested, when you get along well, when so many elements of a loving partnership exist — you tell yourself that sex is a small thing and you can adjust your expectations. But overlooking major sexual disconnects is a bad idea. That may include something as obvious as low libido, a mismatch in what you each enjoy, or a lack of sexual attraction on the part of your partner for you, or you for him or her. As for my relationship? I was in love. I was strong. I was lucky to have found him. (These were all the clichés I told myself.) I decided I could manage with a “minimalist” sex life. I had before — surviving extended periods with no affection, much less sex — and he was affectionate. Romantic, too. He just wasn’t into sex. Low Libido in Your Partner. Now What? His low-light libido? I suppose I sensed it early on, though we courted carefully and slowly, which I had adored. I was still bruised after divorce, and didn’t want to hurry anything. He had his own reasons for exercising care, and we were emotionally attached long before we became intimate. But the lack of sex? It was a challenge. I lived with it for as long as I could – until it began to erode my self-esteem, my sense of femininity, my need to be desired, and ultimately our connection. To lie in bed next to the person you love, to reach out and be rebuked or simply to be ignored for a month, for two, for longer… It’s painful. Kill the Sex, Kill the Relationship? Some might say that if the sex disappears, the relationship is already dead. I wouldn’t go that far, though surely it’s a sign of serious problems. I had hoped he would discuss the subject with time, as I encouraged him to tell me what he liked (a narrow menu) and what he didn’t (plenty). I dressed to please him, to no avail. I recognized signs of depression, which I understood, due to stress at work. There was always appreciation for my efforts, followed by a kiss and sleep for him – and lying awake for yours truly. Eventually the absence of a satisfying sex life became too heavy a burden for me to bear. I said my goodbyes, regretfully, and also with a measure of relief. Sexless Marriage? Had we been married, I suspect I would’ve compared the “now” to the “then” – trying to ascertain the differences in our sex life over time, and changes that led us to a less than happy outcome. Naturally, that assumes a sex life that was active and satisfying before or at the beginning of marriage. Just how many unions become “sexless” by definition – due to routine, to busy schedules, or to the inevitable fatigue and disagreements that come along with children? Regardless of our marital status, I blamed myself. At the time I felt our bedroom problems were due to some inadequacy on my part – I wasn’t sexy enough, I wasn’t thin enough, I wasn’t exciting enough. I now see the reality was “it’s not me, it’s you” though I can also view our mismatched libidos as “it’s not me, it’s us.” Reasons for Low Libido The reasons for low libido are many, as I discovered when researching – not only to figure out this man in my life, but to explain my own periods of delinquent desire. That research provided me with reassurance concerning my own periodic disinterest. According to one source, Health 24, among the causes are: hormonal changes, stress, depression, illness, body image issues, certain antidepressants, as well as drugs and alcohol. In my case, looking back on periods when my interest was nil, this statement says it all: When stressful events take over, they suck the sexual energy right out of you. Bingo. And don’t tell me I’m alone on that score. Doesn’t that culprit sound familiar to some of you? Single Parent? Libido on the Lamb Job worries, kid worries, money worries – and no time to yourself. This is the story of single motherhood that I experienced for a decade. The story is similar for many single mothers I’ve known and for that matter, worn out married mothers during their “blur years.” Libido takes a tumble until pressures ease. And of course stress (for some of us) takes a toll on eating, and disordered eating may lead to body image issues or exacerbate those we already have, and, well… you get the picture. We feel less “worthy” of sex, and tuck away our sexuality as a consequence. But what about a sustained “normal” state in which sex is unimportant? We may think that all men are randy and ready 24/7, but what if it’s not the case? Aren’t men and women entitled to not want sex? The man I loved may have suffered low testosterone, he may have been asexual, he may have been homosexual and denying it to himself, having been raised in a somewhat repressive environment. The bottom line was – sex wasn’t a big deal to him, but after years of feeling the chill of physical isolation, it was to me. Help! I Need Somebody If once upon a time you were hungry for sex, your appetite wanes, and you want it back – then what? The Health24 reference is informative: If a lack of sexual interest is bringing you down, there are steps you can take to boost your sex drive. A healthy diet, the right amount of exercise and a daily dose of fresh air can help whet your sexual appetite. Allowing yourself to explore a new erotic desire or fantasy can spark new-found interest in sex. I’ve found that prescription to be useful. When I’m paying more attention to nutrition and exercise, I’m hungrier for all aspects of life – including good sex. Ditto – make that double ditto – on injecting a dose of shared fantasy. Libido Enhancers? Libido Realities But we shouldn’t oversimplify. Let’s remember the effects of medications, pain, fatigue, natural changes to the body over time, and of course, stress. Don’t we need to deal with those causes – at least to some extent? Don’t we need to remember that we’re all wired differently when it comes to what attracts us and what doesn’t, and how our bodies respond? I will say that I’m delighted to read more around the Internet that addresses erotic play and playfulness in general when it comes to our sex lives. When did we all become so serious? Why must we count, grade, and dissect? Can’t we explore, exchange, and have fun? Who, What, Where, When… in the Bedroom In an entertaining and informative article filled with delicious references, William Quincy Belle takes up his provocative plume in defense of our sex lives in all their variations. In “Sex: What Are the Neighbours Doing,” he expounds on sexuality from a variety of angles including breadth of activities, frequency of same, the nature of our changing partnerships, and assumptions about aging. My favorite line in his article? If it feels good, do it. Naturally – and I imagine he would agree – that presumes “safely” and with consenting adults. Switching Sex to the “On” Position As for low libido – or simply living without sex – while some may find it unthinkable, many of us have been there, myself included. We learn to live with it, and even make peace with it. We think we’re “over it” — convinced that age or hormones are to blame — only to find that when relationship conditions change (or a new object of desire appears on the scene), happily, we aren’t over it at all. The factors that dim desire are many, and likewise, sexual interest may rev back up as the emotional, physical, or circumstantial landscape eases obstacles, and presents new opportunities for pleasure and connection. Occasionally I think about my old beau and what we shared. It was wonderful and I don’t regret any of it. I also don’t regret moving on. I didn’t want to say goodbye to my sexual self. I wanted fireworks, and though it took some time, I was delighted when I was able to welcome them back. You May Also Enjoy	{ "pile_set_name": "OpenWebText2" }
Electroretinographic responses that may reflect activity of parvo- and magnocellular post-receptoral visual pathways. The electroretinogram (ERG) is a complex retinal response to visual stimuli that contains receptoral and post-receptoral components. Here, data are presented using stimuli that isolate the responses of L (long wavelength sensitive)- or M (middle wavelength sensitive)-cones or that stimulate the two simultaneously. The data show that at a temporal frequency of 12 Hz, ERG responses are L- to M-cone opponent with little inter-individual variability. Furthermore, the ratio of L- to M-cone-driven response strengths in the ERGs is about unity. These are also properties of the L- and M-cone opponent chromatic channel mediated by parvocellular activity. Similar to the parvocellular-mediated temporal sensitivity, the ERG response is robust to moderate changes in state of cone adaptation. Thus, the 12-Hz ERG shares distinct characteristics with the post-receptoral red-green sensitive parvocellular pathway. At higher temporal frequencies, the responses are not cone opponent, the inter-individual variability is larger, the mean L/M ratio is larger than unity, and the responses change more strongly when the state of cone adaptation is altered. These properties are reminiscent of the magnocellular non-opponent channel. The data suggest that under well-controlled conditions, the ERG can be used to study post-receptoral processes of the visual system.	{ "pile_set_name": "PubMed Abstracts" }
Pamela Tate Pamela Tate is a justice of the Court of Appeal of the Supreme Court of Victoria in Australia. She was appointed to the position in 2010, having previously served as the Solicitor-General of Victoria. Background Tate was born in Dunedin, New Zealand, and studied philosophy at the University of Otago, where she graduated with first-class honours. She studied law at Monash University, graduating in 1987, again with first-class honours. She received a Commonwealth scholarship to undertake three years of postgraduate study at the University of Oxford. Career Before being called to the Bar in 1991, Tate worked as an associate to High Court Justice Sir Daryl Dawson. She then became one of Australia's most successful barristers in public law, appearing in a number of high-profile cases. She developed particular expertise in constitutional, administrative and commercial law. Tate was the Solicitor-General of Victoria, the state's second-highest law officer, between 2003 and 2010. She was the first woman to be appointed as Solicitor-General and the first to have been chosen after public advertisement of the position, as opposed to private selection. She was appointed to the Court of Appeal of the Supreme Court of Victoria on 14 September 2010. References Category:Australian barristers Category:Living people Category:Monash Law School alumni Category:New Zealand emigrants to Australia Category:People from Dunedin Category:Lawyers from Melbourne Category:University of Otago alumni Category:Year of birth missing (living people) Category:Solicitors-General of Victoria Category:Australian Senior Counsel Category:Judges of the Supreme Court of Victoria Category:Australian women judges	{ "pile_set_name": "Wikipedia (en)" }
Q: how to read cookies in jquery? I am creating a cookie with a key and value of an object using carhartl’s jQuery cookie plugin,In one of my method I call create cookie and right after that I call get cookie;but the read method doesn't work: makeCookie methode: function makeCookie(name,value){ $.cookie(name,value); } readCookie method: function readCookie(name){ $.parseJSON($.cookie(name)); } and calling these 2 methods: makeCookie('chatPopups',popUps); var all=readCookie('chatPopups'); alert(all); popUps is a global javascript object; The error I get is : SyntaxError: JSON.parse: unexpected character at line 1 column 2 of the JSON data can anybody help me? A: Solved the problem,changed makeCookie method to this: function makeCookie(name,value){ $.cookie(name,$.param(value),{ path: '/' }); } and readCookie method to this: function readCookie(name){ var readCookie=$.cookie(name); readCookie = readCookie.split('&'); if(readCookie.length != 0){ for (i=0; i<readCookie.length; i++) { readCookie[i] = readCookie[i].split('='); popUps[readCookie[i][0]] = readCookie[i][1]; } } }	{ "pile_set_name": "StackExchange" }
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this impossible thing suddenly became possible political sensation beto o'rourke and never in a million years wanted to pursue politics the tragedy that changed everything the night before he died i do remember my dad saying you know you you should think about running for office the regret that lets so many people down on trump as disgusting as the things are that he says there's a lot to learn better on black lives matter when george floyd is publicly murdered no one had to be told to take to the streets and demand justice and his lifelong running mate tell me a little bit about your wife her gift and her curse is telling the truth she also will kick my ass when i need it you can't live in this world today and not be curious in fact if ever there was a time to hear from more than the usual suspects it's now this is the carlos watson show maybe we'll surprise you maybe you'll be mad at us sometimes or inspired not only do i hope people will see more with the show but i hope they'll do more and be more people the good stuff starts now better welcome to the show thank you for joining me thank you for having me on i'm i'm excited to talk with you yeah i i love uh your background it's so beautiful i uh i'm living in california these days and i'm a son of miami florida and so anytime i see something beautiful i'm attracted to it the better o'rourke phenomenon was the biggest political story of 2018 as he tried to unseat long-time republican senator ted cruz beto's nice guy style made him a political celebrity with beyonce lebron james and jim carrey all publicly supporting him but when the votes were counted beto came up short cbs news projects that senator ted cruz has won re-election in the state of texas still wanting to fight for the values and ideals he believes in beto launched another campaign he ran for president of the united states but just eight months later came this democratic presidential candidate and former texas representative beta o'rourke announced he is suspending his campaign today with his powered by the people grassroots organization beto was putting all of his energy into turning texas blue for the presidential election something that hasn't been done in four decades i'm counting on you i'm counting on you [Applause] [Music] beto tell me a little bit about why you think you became such a political sensation if if you can take a step back like why did you take off why did it happen how do you see it as the person who actually had the true front row seat i think a lot of it has to do with the senate campaign that we ran first of all it was so unlikely you know that a guy named beto o'rourke a congressman from the furthest westernmost of the 254 counties of texas who had a name id in texas of like one or two percent would be able to successfully challenge an incumbent republican senator who's one of the most well-known figures in the state of texas a state which last elected a democrat to the senate in 1988 mission impossible um laughable um quixotic at at best and the way that we ran no posters no consultants no focus group test of the message no talking points our guiding principle was everyone gets to be involved and have been now to each one of the 254 counties of texas it doesn't matter how red or rural your community we're not going to write you off we're going to show up and this impossible thing suddenly became possible did you know that the uh kaepernick moment was gonna hap was gonna be a moment like when when did that okay we're at a town hall meeting ostensibly about public education and the first few questions i get are about the topic at hand and then this young man stands up i kind of wanted to know how you personally felt about like you had the nfl players kneeling during the national anthems i wanted to know if you found that disrespectful to our country to our veterans and anybody related to that i i was my batteries were were low my tank was was about empty and in some ways that was a good thing because it just allowed me to speak directly from the heart unfiltered my short answer is no i don't think it's disrespectful here's my longer answer but i'm gonna try to try to make sure that i get this right after i gave my answer where i look there are people who sacrificed in uniform there are people who sacrifice like you know john lewis who got beat within an inch of his life in 1965 uh crossing the edmund pettus bridge or four years before that there are a lot of people who sacrificed and struggled to bring us to this point and and perhaps the best way to honor that service is to take a knee or to stand up for the things that you really believe in and that you think will ensure that everyone's civil rights the dignity and respect owed to all of our fellow americans is is guaranteed and is insured and carlos i remember immediately afterwards the two folks who are traveling with me in in the campaign look at me and they're like kind of looking at me like like you know the campaign was starting to do well betso and we were starting to gain some traction and you and you had to answer that question and you had to answer it like that but thankfully uh a woman in houston texas who caught the live stream of that exchange clipped it and shared it and all of a sudden a lot of the country was was talking about it and i got to tell you i felt so grateful that i got to play whatever tiny minuscule role in advancing that that conversation better looking back now i mean you came painstakingly close to winning what would you do differently in order to have won i always come back to you know could i have tried harder could we have spent more hours of the day uh campaigning across texas you know if bethel hadn't said that the president should be impeached i always saying the president should be impeached in 2017 and you know in in a somewhat reliably conservative state maybe that didn't fly so high while not being happy with the result i've accepted it and have been able to to move on but but also i'll tell you this i've moved on with a lot of the people who made that campaign possible those those 20 000 volunteers so many of them have signed up to help lead the effort that we're running across texas right now it's called powered by people and it's basically volunteers engaging again all across the state of texas to try to elect a democratic majority to the state legislature and to try to help joe biden and kamala harris become the first democratic nominees to win the state of texas since 1976 [Music] you grew up in el paso yeah you've been there the whole distance yeah born and raised my dad's grandfather's father came here with the railroad you know past was a big railroad hub and so that brought him here and your works have have stayed ever since my dad was was on the edge of hippie dumb and then perhaps the the best legacy from that connection with um maybe the hippie world is just a love of outdoors so i love taking my kids backpacking in fact we just got back from a 10-day road trip through new mexico and colorado camping under the stars for a lot of that and that's something i got from my dad are you more like him you more like your mom are you a bled i'm a blend like my mom uh who who ran the family business i started a small business here in el paso in the 1990s a technology business and then a publishing business covering city hall and arts and culture in sila juarez and in el paso texas but like my dad i was very interested and involved in politics from a relatively young age and if i had met you in high school did you think you were the kind of guy who not only would have gotten involved in politics but you would have run for president like like was it that deep in you no yeah no you i don't know that you would recognize me um i was painfully shy and and introverted and unsure of myself in the world and what my role and function and purpose for for being alive was i loved music and and in particular punk rock and um and the punk rock community that for a very awkward weird strange kid was very welcoming and affirming and i i thought that's where i was going to be headed in my life i i thought i was going to either be playing music or or helping to put the music out for for others who were doing that and and was very happy to do that and never in a million years wanted to pursue politics but when i when i moved back to el paso from new york where i had gone to college i got involved and i was able to shed that shyness and that uh maybe almost fear of engaging with and talking to people that i didn't know and discovered that i loved it loved knocking on doors when i was a first time candidate in 2005 for for city council love talking to people loved meeting them loved bringing people together loved being brought together with others and i've really never looked back now your dad was a republican or did i make that up he was a a democrat for most of his life he was the co-chairman of the texas campaign for jesse jackson when jesse was running for president and i have a very fond memory of jesse jackson being in our living room in el paso texas where he held a press conference jesse jackson not only was the most electrifying speaker i had heard in my life at that point he may very well still be the most electrifying speaker i had ever heard we must never surrender america will get better and better keep hope alive keep hope alive but my dad um somewhat inexplicably and if you were here i'd i'd love to ask him uh after that campaign after supporting jesse after being a lifelong democrat uh changed parties but he was still the same person at at the end of the day but had just changed parties and he never got to see you run for office beto did he know did he know though that that's that's where you were headed did were you ever able to share that with him not totally um it's really interesting um the the night before he died and remember he was hit by a car when he was on his bicycle get some miles in on july 3rd of 2001. the night before july 2nd somehow fate god chance brought us together we were having a dinner of leftovers in the backyard of my parents house my mom was out my sisters were out just my dad and me sitting down with a bottle of wine maybe two bottles of wine over the course of of dinner and we we just and we kind of been estranged for um a while you know we just didn't see eye to eye on a lot of things we didn't get along couldn't quite find the language to communicate and i do remember my dad saying you know you you should think about running for office at some point um you know these things that you're excited about that have you fired up um there's a way that you can make a difference and you know it's not easy um but it may be something that that you you ought to think about pursuing so um i'm really grateful that we had that last conversation together um and and though he didn't see me run for office maybe somehow he knew that that was a possibility for me better tell me a little bit about your wife and am i overreading and saying that that that there's something there between the two of you that has also contributed to the man you've become or or had you kind of gotten a lot of the way here which which actually allowed the relationship uh to uh to take off yeah i gotta tell you amy uh to whom i've been married now almost 15 years absolutely changed my life and changed me for the better i think she forced me to think really seriously about who i am and who i want to be and what i'm willing to do to make that happen she's given me this unconditional love and support which is the most powerful force in in the world she also though will kick my ass when when i need it if i start bitchin and moanin about you know this or that is unfair or why didn't things work out the the way that we planned um she will remind me there are a lot of people who have it a lot harder than you do there are a lot of people who are counting on you right now so you better figure this out and get up and get after it beta do you think amy will ever run for office will we ever see her her name on the ballot it's so interesting um i watched michelle obama's extraordinary speech at the beginning of the democratic national convention it is up to us to add our voices and our votes to the course of history one of the things that michelle said was her admission that she hates politics she just doesn't like this stuff i think amy sees things very similarly she can't gladhand she can't fake it she can't say that was a great speech if if that was a terrible speech um her gift and her curse is telling the truth i think that for for those reasons she does not see herself in a a public role or maybe better put she doesn't see herself in the leading role in in public life but i'd like to see her do that or at least think about it [Music] tell me about your run for president like like when you look back on it what are the three or four things that stand out most for you first and foremost just how extraordinarily fortunate i am to have had the chance to do that i am so grateful for the opportunity to run to serve you as the next president of the united states of america thank you i think also carlos about how exhausted i was after that senate race where i had spent two years literally on the road day in day out traveling as 254 counties of texas without ever a thought or dream of running for another office certainly not the presidency of the united states of america and then to suddenly and unexpectedly at the conclusion that race be presented with that opportunity and have a number of people that i care very much about and admire and trust and respect encouraging me to run and beginning that campaign without having any of the the planning the infrastructure the preparation the rest and i think to be honest the the depth of understanding necessary to mount a campaign that is not the 254 counties of texas but the tens and thousands of counties across the the united states i really know that i let so many people down who gave us so much and and we owed them uh a much better campaign that could have gone a much longer distance they could have been far more grounded and and far more effective in the fight that we waged but i can't go back and and i can only go forward and i can only give this effort to make sure that texas meets the moment you know i i think i heard you say somewhere that texas is bidens to lose do you really believe that like as someone who is as as experienced and shrewd when it comes to politics and and numbers counting i do we are doing the necessary field work right now to make sure that texas is ready for example powered by people our organization has made just under 20 million voter contact attempts human beings connecting with human beings just like we did in the 2018 u.s senate race so the conditions are there we can do this we've got to give ourselves permission to believe again and then we have to bring it to pass this is for democrats to lose right now including joe biden ladies and gentlemen el proximo presidente de los estados i know that you're a student broadly in general and even people you deeply disagree with i'm sure you learn from what if anything have you learned from president trump uh over the last several years in whatever dimension you want to offer it there's a lot to learn i mean the tv ads the mailers the stuff you see on on facebook it is packaged and produced it has been made safe for consumption it is pole tested and focused group approved donald trump so successfully and powerfully broke through all of that he seemed to not only be speaking his mind he seemed to be speaking his id certainly his ego as disgusting as the things are that he says mexicans are rapists and and criminals the countries of africa are shitholes he wants more immigrants like those from sweden the whitest place on on planet earth you know immigrants are an invasion and infestation they're animals who who the talks like that the most powerful man in the world is talking like that and it completely blows past uh all of the filters and all of the the pre-approved messages from the parties and the people in power and it connects directly with people for better and as we have seen for worse we have just learned a short while ago that there has been a shooting in el paso and so i just ask for for everyone's strength for el paso right now the shooting in el paso that took place on august 3rd of last year this guy heard donald trump and went out to go fight literally that invasion that he had heard about and use a military weapon to take people out like you take them out on on a battlefield slaughtered 23 people shopping for school supplies on the weekend before the first day of school in el paso i think i've learned just how powerful that that rhetoric is beto do you think that if uh trump loses that he should be prosecuted or at least reviewed his actions in office should be reviewed for potential prosecution part of our our genius is the rule of law and the idea that that no one is above the law and certainly no one is below the law if we are to allow someone because of the position of power that they held escape the law would be to set a very dangerous precedent for this country if you've broken the law there has to be a consequence i appreciate that you that you're bringing that that energy to the fight i'm reminded of uh of bogey at the end of casablanca i don't know if you've ever seen that movie of course it's a yeah it's a great it's a great movie and he says to louie at the end welcome to the fight [Music] beto as we wrap up i want to hit a bunch of topics really quickly do you mind if i do that with you and hit you i'd love to hear what comes to mind who are two or three of the candidates you think people should pay attention to if you look at candace valenzuela um she is running for united states congress trying to unseat a long-serving republican incumbent she would be the first afro-latina member of of congress sima lajavardian a daughter of immigrants from iran to this country who has built a successful law practice and is a first-time candidate also for the united states congress who is running against trump's most powerful enabler in in the house right now dan crenshaw how do you think about the question of white male privilege the more i think about it the more i understand that it is definitional educational economic uh opportunities um housing criminal justice there is not an aspect of american life that is not in some ways defined by the power that white america has accrued ever since there was a white america last question are you a sports fan are you a uh do you have a team you have someone you root for my kids are are big celtics fans and so that's one thing that i want to work on during quarantine is my my sports iq so that i'm connecting with my kids better well good luck then to your boys in the celtics i love kimball walker so tell them they have good taste thank you so much for uh for joining me i wish you the best for i wish all of us the best uh for a good fall thank you so much thanks thanks for having me on i was honored to join you and and i i really enjoyed the conversation so um would be glad to come back anytime uh any time it works for you i'm grateful thank you so much thank you i really enjoyed having better o'rourke on today you know he and i got to speak for the first time a week ago and i told him i was trying to do something different with the show and that i only wanted people to come on who were really going to open up who weren't going to repeat the same things and he was true to his word i loved what he shared about his dad you know talking about jesse jackson gave me real color and real clarity on who beto is and who he was in that moment when he was answering the question about colin kaepernick really told me a lot love what he had to say about his wife what a lucky person to have someone like that in his life and then talk about beto making news you know the idea of trump being prosecuted after he leaves office that could create a big fight it also could create real energy anyhow i hope you enjoyed the show i'll see you soon hey tune into the carlos watson show it's like no other you're going to enjoy it every weekday on youtube	{ "pile_set_name": "YoutubeSubtitles" }
978 A.2d 6 (2009) 2009 VT 48 STATE of Vermont v. Timothy MUMLEY. No. 08-114. Supreme Court of Vermont. May 8, 2009. 7 Thomas Donovan, Jr., Chittenden County State's Attorney, and Pamela Hall Johnson, Deputy State's Attorney, Burlington, for Plaintiff-Appellee. Edward M. Kenney, South Burlington, for Defendant-Appellant. 8 Present: REIBER, C.J., DOOLEY, JOHNSON, SKOGLUND and BURGESS, JJ. ¶ 1. SKOGLUND, J. Defendant Timothy Mumley appeals from a jury conviction for attempted kidnapping in violation of 13 V.S.A. §§ 9, 2405(a)(1)(D). Defendant argues that the Chittenden District Court committed reversible error when it denied his motion to suppress statements he made to police while in custody. We agree, and reverse. ¶ 2. Defendant's conviction arises from an incident that occurred on October 20, 2006. On that date, defendant allegedly tried to pull a woman into his pickup truck while she was pushing her child in a stroller on a Winooski sidewalk. Defendant was arrested and taken to the Winooski Police Department, where he was questioned by a detective in an interrogation room. The entire interrogation was video-recorded. ¶ 3. Prior to questioning defendant, the detective warned defendant of his privilege against self-incrimination and his right to counsel as required by Miranda v. Arizona, 384 U.S. 436, 86 S.Ct. 1602, 16 L.Ed.2d 694 (1966), and 13 V.S.A. § 5234. He read defendant his warnings one-by-one, from a Miranda-waiver form. The form listed each of the Miranda rights followed by the question "Do you understand?" and a blank space for a reply. After reciting each warning to defendant, the detective asked defendant whether he understood. Defendant replied "yes" to each of these questions. The detective recorded defendant's replies on the form. ¶ 4. Underneath the Miranda-rights portion of the form was the title "Waiver," and the following paragraph: I have been advised of my rights and I understand them. No threats or promises have been made to me. Knowing my rights, I agree to waive them and talk with you now. I understand that I am waiving my right to be represented by an attorney, to talk with an attorney before questioning and to have an attorney present during questioning. Under this paragraph was a space for the date and time and a space for a signature or "time of taping." ¶ 5. The detective did not read the entire waiver paragraph to defendant. Rather, the detective read only the following: "I have been advised of my rights and I understand them. No threats or promises have been made to me. Knowing my rights, I agree to waive ...." The detective did not provide defendant with the opportunity to read the balance of the form nor did he have defendant sign the form. The following exchange then occurred: Detective: Do you want to talk to me? Defendant: What about? Detective: Ah, what, ah ... you can talk to me, you can tell me to pound sand. You know, those are your rights, okay? Now, it doesn't affect them one way or the other. What I'm concerned about is that, I want to make sure, you know, what happened tonight, you be given an opportunity to, you know, explain your actions which will happen in a court of law. But this is also an opportunity for you, if you want it, you can write down a sworn statement and apologize for what happened tonight. That's something. It's your choice you know. Defendant: Which is what? Detective: Do you understand what is going on here at all? Defendant: No, no, I don't. Detective: Well, as I stated over at your apartment, you're under arrest for attempted kidnapping. Defendant: Okay. 9 ¶ 6. The detective made no more attempts to secure a waiver of defendant's rights to silence and to an attorney. Eventually, defendant answered some of the detective's questions. ¶ 7. Defendant sought to suppress the statements he made during the interrogation. In his motion to suppress, defendant argued that he did not waive his rights, or, in the alternative, that the waiver was invalid under Miranda. Defendant also argued that the detective violated his rights by failing to secure a recorded waiver as required by 13 V.S.A. § 5237. Section 5237 provides that a person who has been informed of his or her right to counsel as required by § 5234 may waive those rights: in writing, or by other record, ... if the court, at the time of or after waiver, finds of record that he has acted with full awareness of his rights and of the consequences of a waiver and if the waiver is otherwise according to law. The court shall consider such factors as the person's age, education, and familiarity with the English language, and the complexity of the crime involved. 13 V.S.A. § 5237. The State responded, arguing that, considering the totality of the circumstances, defendant knowingly and intelligently waived his Miranda rights, and that defendant's waiver was valid under § 5237 because it was video-recorded. ¶ 8. The district court denied defendant's motion. It concluded that "assuming the court finds that defendant possessed the requisite experience, education, background, and intelligence to understand the nature of his Miranda rights and the consequences of waiving them," defendant made a valid implicit waiver of his Miranda rights. The court then concluded that because this waiver was recorded on video it was valid under § 5237. ¶ 9. At trial, the complainant testified that defendant tried to pull her into his black pickup truck while she was pushing her child in a stroller on a sidewalk, returning home from the post office. She further testified about the encounter as follows. As the complainant walked north on Weaver Street, defendant started following her in his truck, making rude, sexually suggestive remarks, and asking her if she wanted a ride. She was walking northward on the west side of Weaver Street, and defendant was travelling northward in the wrong lane of traffic, weaving around parked cars, so that he was in the lane of traffic adjacent to her. During this portion of the encounter the complainant threatened to call the police. At some point, defendant proceeded ahead of her to the intersection of Weaver and Union Streets and turned left onto Union Street. She proceeded to the same intersection, crossed Union Street, and turned left, walking on the north side of Union Street. While the complainant was walking on Union Street, defendant, who was ahead of her, turned around in a driveway, drove back toward her, then crossed into the wrong lane of traffic again, stopped the truck, and attempted to grab her and pull her into his pickup. Defendant drove off when the driver of a green Ford in the oncoming lane of Union Street honked the horn twice. ¶ 10. One eyewitness testified for the State. The witness testified that while traveling north on Weaver Street in her green Ford Taurus, she noticed that traffic had stopped because of a dark pickup truck that had stopped in the middle of the road two cars in front of her. She testified that the man in the pickup truck was speaking with someone on the sidewalk. According to the witness, after she honked her horn twice, the truck "took off," and the witness then observed the complainant, "visibly upset ... motoring towards the 10 end of [Weaver] [S]treet." In contrast to the complainant's testimony, the witness testified that the truck did not turn left on Union Street, but rather either continued straight or turned right, and that the witness did not turn left on Union Street. The witness testified that after observing the encounter she continued straight on Weaver Street. ¶ 11. The arresting officer and a detective also testified for the State. The officer testified that defendant's truck and license plate number matched the description given by the complainant. The detective testified that the complainant correctly identified defendant in a photo lineup. The detective also testified that, during the interrogation at the police station, defendant admitted: (1) that he had seen the complainant; (2) that he had driven by her several times; (3) that the complainant spoke to him; (4) that the complainant told defendant that she was calling the police; and (5) that, when asked why the complainant would threaten to call the police, defendant replied that he did not know. ¶ 12. At trial, the defense argued that the complainant's story was improbable and that neither defendant nor the eyewitness made a left on Union Street toward the site of the alleged attempted kidnapping. ¶ 13. On appeal, defendant argues that he did not make a valid waiver of his Miranda rights because: (a) silence in response to a request to waive does not constitute waiver; and (b) the court failed to properly apply the totality-of-the-circumstances approach articulated in State v. Malinowski, 148 Vt. 517, 518-20, 536 A.2d 921, 922-23 (1987). Defendant also argues that the waiver was invalid under § 5237 because: (a) that section requires waivers to be affirmative, express, and recorded; and (b) the trial court failed to consider the factors set forth in the statute. Finally, defendant makes several arguments regarding the court's refusal to viewor to allow the jury to viewthe vehicle defendant was driving at the scene of the alleged crime. We agree with defendant that the court erred in not evaluating the factors set forth in Malinowski and § 5237, and do not reach the balance of his arguments. ¶ 14. Under the United States Supreme Court's landmark decision in Miranda, "a heavy burden rests on the government to demonstrate that the defendant knowingly and intelligently waived his privilege against self-incrimination and his right to retained or appointed counsel." 384 U.S. at 475, 86 S.Ct. 1602; see also State v. Stanislaw, 153 Vt. 517, 529, 573 A.2d 286, 293 (1990) ("The State bears a heavy burden in showing a waiver of Miranda rights."). Courts may find that a defendant knowingly and intelligently waived his Miranda rights only "upon an inquiry into the totality of the circumstances surrounding the interrogation." Fare v. Michael C., 442 U.S. 707, 724-25, 99 S.Ct. 2560, 61 L.Ed.2d 197 (1979) (citing Miranda, 384 U.S. at 475-77, 86 S.Ct. 1602). "The totality approach permits indeed, it mandatesinquiry into all the circumstances surrounding the interrogation." Id. at 725, 99 S.Ct. 2560. We noted in Malinowski that in Fare v. Michael C. the United States Supreme Court specifically mandated a totality-of-the-circumstances approach to evaluating Miranda waivers. 148 Vt. at 522, 536 A.2d at 924. In order for a court to find that a defendant has made a knowing and intelligent waiver, we require it to make findings regarding the "defendant's experience, education, background, intelligence or capacity to understand the warnings and the meaning of a waiver." Id.; see also State v. Tribble, 2005 VT 132, ¶ 27, 179 Vt. 235, 892 A.2d 232 ("In reviewing whether a 11 defendant made a valid waiver, we consider the totality of the circumstances."). ¶ 15. In addition to our case law, our statutory law requires courts to consider the circumstances under which a defendant waives the privilege against self-incrimination and the right to counsel as guaranteed by Miranda and § 5234 before concluding that the waiver was valid. Under § 5237, a defendant's waiver is valid if the court finds that "he has acted with full awareness of his rights and of the consequences of a waiver and if the waiver is otherwise according to law." In making such findings, "[t]he court shall consider such factors as the person's age, education, and familiarity with the English language, and the complexity of the crime involved." Id. (emphasis added). Although the statute's discretionary "such factors as" language affords trial courts flexibility in choosing which factors to consider, the mandatory "shall" creates a requirement impervious to judicial discretion. See Town of Victory v. State, 174 Vt. 539, 544, 814 A.2d 369, 376 (2002) (mem.) ("Use of the word `shall' in a statute generally means that the action is mandatory...."). In short, under § 5237, a court must consider factors indicating whether a defendant acted with full awareness of his rights, and the consequences of waiving those rights, before finding that the defendant knowingly and intelligently waived them. ¶ 16. Here, the trial court's decision and order denying defendant's motion to suppress contains no consideration of factors indicating a knowing and intelligent waiver of Miranda rights as required by Fare and Malinowski, and no consideration of factors indicating his awareness of his § 5234 rights and the consequences of waiving them as required by § 5237. Instead, as far as we can tell from its order, the court reached its conclusion that defendant made a valid waiver of his rights by "assuming ... that defendant possessed the requisite experience, education, background, and intelligence to understand the nature of his ... rights and the consequences of waiving them." The trial court erred under Malinowski and § 5237 by failing to make the required inquiry. ¶ 17. The State argues that defendant failed to preserve the issue we address above, and, alternatively, that any erroneous admission did not prejudice defendant's case. Neither argument has merit. ¶ 18. The State contends that defendant did not preserve the argument that his waiver was invalid because his motion to suppress the statements at issue argued only that there was no waiver at all. This Court has long held that issues not presented at trial may not be raised on appeal. See, e.g., Lanphere v. Beede, 141 Vt. 126, 129, 446 A.2d 340, 341 (1982) ("Contentions not raised or fairly presented to the trial court are not preserved for appeal."); Bebee v. Steel, 2 Vt. 314, 316 (1829) (same). However, where a litigant's argument is clear enough for the trial court to evaluate it and for an opponent to respond to it, the claim is adequately preserved for appeal. EBWS, LLC v. Britly Corp., 2007 VT 37, ¶ 12, 181 Vt. 513, 928 A.2d 497. ¶ 19. We read defendant's motion to suppress as arguing primarily that he did not waive his Miranda and § 5234 rights, and arguing alternatively that any implied waiver was not knowing and intelligent, and therefore was invalid. In support of his motion, defendant explicitly cited Stanislaw for the proposition that the State must prove a "knowing and intelligent" waiver, and argued that "[t]he detective's conduct in this matter could not more closely match Miranda's scenario of an invalid waiver." Although we would not 12 place a trial court in error regarding an issue it did not have the opportunity to address, the trial court here had that opportunity. Moreover, the trial court referenced the factors it was required to consider, but erred by making an assumption instead of making the required factual findings. Defendant placed the issue of validity squarely before the trial court and thus preserved it. ¶ 20. The State's argument that any erroneous admission of statements was harmless and nonprejudicial also fails. Under the Vermont Rules of Criminal Procedure, "[a]ny error ... which does not affect substantial rights shall be disregarded." V.R.Cr.P. 52(a). "For the error to be harmless, the reviewing court must find beyond a reasonable doubt that the jury would have returned a guilty verdict regardless of the error." State v. Oscarson, 2004 VT 4, ¶ 30, 176 Vt. 176, 845 A.2d 337. When conducting a harmless-error analysis to determine whether the jury would have convicted without the offending evidence, we consider the extent to which the offending evidence was inculpatory, whether it was cumulative or duplicative of other evidence, and how prominent it was at trial. See State v. Keith, 160 Vt. 257, 265-66, 628 A.2d 1247, 1252-53 (1993) (considering whether erroneously admitted evidence was inculpatory or exculpatory), overruled on other grounds by State v. Brillon, 2008 VT 35 ¶ 42, 183 Vt. 475, 955 A.2d 1108;[1]State v. Lynds, 158 Vt. 37, 42, 605 A.2d 501, 503 (1991) (considering prominence of erroneously admitted evidence at trial and presence or absence of corroborating and contradictory evidence). Analyzing these factors helps us understand how heavily the jury was likely to have relied on the evidence. ¶ 21. Here, the trial court erroneously admitted five statements that defendant made to police while in custody: (1) that defendant had seen the complainant; (2) that he had driven by her several times; (3) that the complainant spoke to him; (4) that the complainant told him that she was calling the police; and (5) that, when the detective asked him why the complainant would threaten to call the police, defendant replied that he did not know. ¶ 22. The extent to which the statements were inculpatory or duplicative varied. Defendant's statement that he had seen the complainant placed him at the scene of the alleged attempted kidnapping. Similarly, defendant's statements that the complainant spoke to him, that she threatened to call the police, and that he did not know why she would do so, constituted an admission that there had been an interaction between them. However, all of these statements were corroborated by eyewitness testimony, the complainant's testimony, or both. ¶ 23. Most prejudicial was defendant's statement that he drove by the complainant several times. This statement substantially undermined the defense's theory of the case. The defense argued that defendant may have had an interaction with the complainant, but that he never turned left on Union Street toward the site of the alleged attempted kidnapping or turned his truck around. The eyewitness's testimony that neither she nor defendant turned left on Union Street tended to support the defense's theory and discredit the complainant's version of events. Defendant's statement that he drove past the complainant several times had the potential *13 to cast significant doubt on the defense's theory and to bolster the complainant's story. Additionally, because the eyewitness in the green Ford testified that defendant went straight or right at the intersection of Weaver and Union, defendant's statement that he drove past the complainant several times is corroborated by the complainant's testimony alone. ¶ 24. All of defendant's statements to police were fairly prominent at trial. In addition to offering them into evidence, the State referred to defendant's statements in its opening and closing statements. In its opening, the State explained that the evidence would show: [Defendant] admitted that he had seen thisa woman, this person pushing a stroller. He also made statements that there was a conversation. And he also told the police that at some point the woman mentioned to him, that she mentioned something about calling the police and the police asked [defendant], "Why would she say that?" And [defendant]'s response was, "I don't know." Defendant's statements were introduced at trial through the detective who interrogated him, and were central to the detective's testimony. The prosecuting attorney referred to them four additional times while questioning the detective. In its closing, the State summarized the erroneously admitted statements and suggested what inferences the jury could draw from them: Does he admit to [the detective] that he was in Winooski? You bet. Does he admit to [the detective] that he saw a young woman? You bet. Does he admit to [the detective] that he saw that stroller? Yup. Does he admit that he actually had a conversation with this woman? Yup. Does he admit that he heard her say, "I'm going to call the police." Yes.[2] ¶ 25. In short, defendant's erroneously admitted statements to police were harmful enough to his case and prominent enough at trial to have prejudiced defendant's case. In the aggregate, they create a reasonable doubt as to whether the jury would have rendered a guilty verdict without them, and thus require us to reverse defendant's conviction and remand for proceedings consistent with this opinion. ¶ 26. In conclusion, the trial court erred by admitting defendant's custodial statements without conducting the required totality-of-the-circumstances inquiry into the validity of defendant's waiver. Because we cannot conclude beyond a reasonable doubt that the error was harmless, we reverse. Reversed and remanded. NOTES [1] The United States Supreme Court recently overruled Brillon on grounds unrelated to today's decision. Vermont v. Brillon, ___ U.S. ___, ___, 129 S.Ct. 1283, 1287, 173 L.Ed.2d 231 (2009). [2] The record indicates that the State's closing argument continued as follows: But then an interesting thing happened. By this time he knows he's in trouble and he decides to shift the blame away from him to her and he tells the police officer this story about driving up Weaver Street or driving in Winooski and he sees a woman acting weird and she's saying something, he doesn't have a clue what she's saying, she's yelling at him, and so instead of just passing by and just going home, by the way, it's raining at this point, instead of going home, he turns around and comes back to get another look at her. The statements referred to in this part of the State's closing argument were not entered into evidence and were not objected to by defendant. We therefore do not evaluate their potential effect on the jury verdict.	{ "pile_set_name": "FreeLaw" }
Determination and application of the permitted daily exposure (PDE) for topical ocular drugs in multipurpose manufacturing facilities. Limits for the carry-over of product residues should be based on toxicological evaluation such as described in the "Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities". The toxicological evaluation should be performed also for locally administered drugs to ensure patient safety. Currently, there is no guidance on setting PDE for ocular drug substances in particular. The purpose of this investigation was to identify and describe a method for calculating a PDE value for topical ocular drugs (PDEocular). As an alternative method, extrapolation of a PDE for systemically administered drugs to a PDEocular is presented. These methods may be applied in cross-contamination risk assessments for manufacturing of topical ocular drugs. Similarly, the methods apply to systemically administered drugs, if their production precedes manufacturing of a topical ocular drug. We have examined pharmacokinetic (PK) properties of topical ocular drugs and compared them to the PK parameters of systemically administered drugs. Furthermore, we examined possible adverse effects of the carry-over in topical ocular drugs at therapeutic doses.	{ "pile_set_name": "PubMed Abstracts" }
Ricardo (footballer, born 1980) Ricardo Jorge Ferreira Pinto da Silva (born 19 August 1980), known simply as Ricardo, is a Cape Verdean professional footballer who plays for Portuguese club C.D. Feirense as a central defender or right back. Club career Ricardo was born in Azurém, Guimarães, Portugal, and he started playing football with amateurs Centro de Cultura e Desporto Desportivo de Ronfe and G.D. Serzedelo. In the following three years he played in the third division, representing F.C. Famalicão (one season) and S.C. Freamunde (two). In the summer of 2004, Ricardo moved straight to the Primeira Liga, signing with S.C. Beira-Mar. He featured in 29 games in his first season (24 starts), but suffered relegation; he continued to appear regularly for the Aveiro team during his spell, overall playing two seasons apiece in each of Portugal's major levels. Ricardo returned to the top flight for 2008–09, joining F.C. Paços de Ferreira. In the following campaign's opener he scored with his head to earn his side a point against FC Porto in a 1–1 home draw, and was an everpresent defensive figure in his two-year stint. In June 2010, Ricardo signed with Vitória de Guimarães also in the top tier – he had been brought up as a youth at the Minho club. In January 2012, after a brief spell in China, he returned to Portugal and Paços on a three-and-a-half-year contract. International career Although born in Portugal, Ricardo opted to represent Cape Verde through ancestry. He received his first call-up in May 2008, first appearing on 27 May in a friendly with Luxembourg. In June 2010, Ricardo started in the 0–0 draw that the minnows (ranked 117th) managed against Portugal, as the Europeans were preparing for that year's FIFA World Cup. References External links Category:1980 births Category:Living people Category:People from Guimarães Category:Portuguese people of Cape Verdean descent Category:Cape Verdean footballers Category:Portuguese footballers Category:Association football defenders Category:Primeira Liga players Category:LigaPro players Category:Portuguese Second Division players Category:G.D. Serzedelo players Category:F.C. Famalicão players Category:S.C. Freamunde players Category:S.C. Beira-Mar players Category:F.C. Paços de Ferreira players Category:Vitória S.C. players Category:C.D. Feirense players Category:Chinese Super League players Category:Shandong Luneng Taishan F.C. players Category:Cape Verde international footballers Category:Cape Verdean expatriate footballers Category:Portuguese expatriate footballers Category:Expatriate footballers in China	{ "pile_set_name": "Wikipedia (en)" }
Q: Synchronized statement, unclear java doc example Currently I am trying to understand synchronized in Java getting to this java doc example under synchronized statements the example with the class MsLunch and the two instance variables c1 and c2. It states: Suppose, for example, class MsLunch has two instance fields, c1 and c2, that are never used together. All updates of these fields must be synchronized, but there's no reason to prevent an update of c1 from being interleaved with an update of c2 — and doing so reduces concurrency by creating unnecessary blocking. To me this sounds like c1 and c2 are not allowed to be used together. That is the reason why both statements which are incrementing c1 and c2 have to be synchronized. But why do they say in the next sentence that there is no reson to prevent an update of c1 from being interleaved with an update of c2. This sentences makes absolutely no sense to me. First they say they are not used together and now it is ok to increment c1 while at the same time c2 is being incremented. Can someone please elaborate this paragraph to me. Bear in mind that I am no native English speaker and there could be in fact a language problem in understanding this issue. A: c1 and c2 are two completely independant counters. A thread should be able to increament c1 while another thread increments c2. If you simply synchronized the inc1() and inc2() method, you would prevent thread 1 to increment c1 while thread 2 is incrementing c2 (and vice-versa). This would have a negative impact on performance. So you use two separate locks to synchronize each incrementation. If the value of c2 for example depended on the value of c1, then you would have to use a single lock to avoid race conditions.	{ "pile_set_name": "StackExchange" }
The epigenome directs the genome to execute gene expression programs required for normal life. It comprises two different components: the chromatin structure, and a pattern of DNA methylation1. A gene can be found in different epigenetic states resulting from differences in histone modification and DNA methylation. Epigenetic modifications play an important role during normal development by regulating gene expression through stable activation or silencing of differentiation-associated genes. Unlike genetic changes, epigenetic changes do not alter the primary DNA sequence and are therefore reversible. Collas et al2 describe strategies for reprogramming somatic cells to pluripotency. More specifically, Collas describes how an extract of undifferentiated embryonic stem cells (ESC) can elicit pluripotency and differentiation plasticity in an otherwise more developmentally restricted cell type. This procedure involves reversible permeabilization of a somatic cell, transient incubation of the permeabilized somatic cells with intracellular extracts of ESCs, and resealing of the somatic cells. The reprogrammed ESC-like pluripotent cells may then be differentiated into a particular cell type, and then be used for treating a patient in need of that particular cell type. Hendrix et al3 show methods for altering the behavior of metastatic melanoma by employing embryonic stem cell-preconditioned 3 dimensional matrices. WO/2008/014426 discloses methods of isolating compounds from the microenvironment of ESCs and using these compounds to treat and/or prevent the growth and/or dissemination of aggressive tumor cells in a patient. More specifically, the invention relates to the administration to the patient of inhibitors of Nodal activity, including, but not limited to, those that are exclusively produced by human ESCs. Such compounds may be isolated from a substrate or a matrix, such as MATRIGEL, that was conditioned by human ESCs. WO/2008/014426 also provides methods for contacting tumor cells with a matrix, such as MATRIGEL, that comprises human ESCs or a matrix that has been preconditioned by human ESCs. Ingber D. E.4 raises the possibility of developing a tissue engineering approach to cancer therapy in which biologically-inspired materials that mimic the embryonic microenvironment are used to induce cancers to revert into normal tissues. It is further suggested that since physical factors may contribute to cancer formation, then biomaterials and scaffolds used for medical devices and tissue engineering applications could provide yet another modality for cancer therapy. WO09/098698 discloses scaffolds prepared from cell extracts for use in conditions necessitating tissue/organ regeneration, repair or replacement. Although many drugs are in use for cancer treatment, there is a desire for additional and more effective compositions and methods for cancer treatment and prevention. The present invention addresses this need.	{ "pile_set_name": "USPTO Backgrounds" }
#ifndef ABSTRACT_H #define ABSTRACT_H #ifdef PROFILE #define printf(a, b) Serial.println(b) #endif #if defined ARDUINO_SAM_DUE \|\| defined ADAFRUIT_GRAND_CENTRAL_M4 #define HostOS 0x01 #endif #ifdef CORE_TEENSY #define HostOS 0x04 #endif #ifdef ESP32 #define HostOS 0x05 #endif #ifdef _STM32_DEF_ #define HostOS 0x06 #endif /* Memory abstraction functions / /===============================================================================/ bool _RamLoad(char filename, uint16 address) { File f; bool result = false; if (f = SD.open(filename, FILE_READ)) { while (f.available()) _RamWrite(address++, f.read()); f.close(); result = true; } return(result); } /* Filesystem (disk) abstraction fuctions / /===============================================================================/ File rootdir, userdir; #define FOLDERCHAR '/' typedef struct { uint8 dr; uint8 fn[8]; uint8 tp[3]; uint8 ex, s1, s2, rc; uint8 al[16]; uint8 cr, r0, r1, r2; } CPM_FCB; typedef struct { uint8 dr; uint8 fn[8]; uint8 tp[3]; uint8 ex, s1, s2, rc; uint8 al[16]; } CPM_DIRENTRY; #if defined board_teensy41 static DirFat_t fileDirEntry; #else static dir_t fileDirEntry; #endif File _sys_fopen_w(uint8 filename) { return(SD.open((char)filename, O_CREAT \| O_WRITE)); } int _sys_fputc(uint8 ch, File& f) { return(f.write(ch)); } void _sys_fflush(File& f) { f.flush(); } void _sys_fclose(File& f) { f.close(); } int _sys_select(uint8 disk) { uint8 result = FALSE; File f; digitalWrite(LED, HIGH ^ LEDinv); if (f = SD.open((char)disk, O_READ)) { if (f.isDirectory()) result = TRUE; f.close(); } digitalWrite(LED, LOW ^ LEDinv); return(result); } long _sys_filesize(uint8 filename) { long l = -1; File f; digitalWrite(LED, HIGH ^ LEDinv); if (f = SD.open((char)filename, O_RDONLY)) { l = f.size(); f.close(); } digitalWrite(LED, LOW ^ LEDinv); return(l); } int _sys_openfile(uint8 filename) { File f; int result = 0; digitalWrite(LED, HIGH ^ LEDinv); f = SD.open((char)filename, O_READ); if (f) { f.dirEntry(&fileDirEntry); f.close(); result = 1; } digitalWrite(LED, LOW ^ LEDinv); return(result); } int _sys_makefile(uint8 filename) { File f; int result = 0; digitalWrite(LED, HIGH ^ LEDinv); f = SD.open((char)filename, O_CREAT \| O_WRITE); if (f) { f.close(); result = 1; } digitalWrite(LED, LOW ^ LEDinv); return(result); } int _sys_deletefile(uint8 filename) { digitalWrite(LED, HIGH ^ LEDinv); return(SD.remove((char)filename)); digitalWrite(LED, LOW ^ LEDinv); } int _sys_renamefile(uint8 filename, uint8* newname) { File f; int result = 0; digitalWrite(LED, HIGH ^ LEDinv); f = SD.open((char)filename, O_WRITE \| O_APPEND); if (f) { if (f.rename((char)newname)) { f.close(); result = 1; } } digitalWrite(LED, LOW ^ LEDinv); return(result); } #ifdef DEBUGLOG void _sys_logbuffer(uint8* buffer) { #ifdef CONSOLELOG puts((char)buffer); #else File f; uint8 s = 0; while ((buffer + s)) // Computes buffer size ++s; if (f = SD.open(LogName, O_CREAT \| O_APPEND \| O_WRITE)) { f.write(buffer, s); f.flush(); f.close(); } #endif } #endif bool _sys_extendfile(char* fn, unsigned long fpos) { uint8 result = true; File f; unsigned long i; digitalWrite(LED, HIGH ^ LEDinv); if (f = SD.open(fn, O_WRITE \| O_APPEND)) { if (fpos > f.size()) { for (i = 0; i < f.size() - fpos; ++i) { if (f.write((uint8)0) != 1) { result = false; break; } } } f.close(); } else { result = false; } digitalWrite(LED, LOW ^ LEDinv); return(result); } uint8 _sys_readseq(uint8* filename, long fpos) { uint8 result = 0xff; File f; uint8 bytesread; uint8 dmabuf[BlkSZ]; uint8 i; digitalWrite(LED, HIGH ^ LEDinv); f = SD.open((char)filename, O_READ); if (f) { if (f.seek(fpos)) { for (i = 0; i < BlkSZ; ++i) dmabuf[i] = 0x1a; bytesread = f.read(&dmabuf[0], BlkSZ); if (bytesread) { for (i = 0; i < BlkSZ; ++i) _RamWrite(dmaAddr + i, dmabuf[i]); } result = bytesread ? 0x00 : 0x01; } else { result = 0x01; } f.close(); } else { result = 0x10; } digitalWrite(LED, LOW ^ LEDinv); return(result); } uint8 _sys_writeseq(uint8 filename, long fpos) { uint8 result = 0xff; File f; digitalWrite(LED, HIGH ^ LEDinv); if (_sys_extendfile((char)filename, fpos)) f = SD.open((char)filename, O_RDWR); if (f) { if (f.seek(fpos)) { if (f.write(_RamSysAddr(dmaAddr), BlkSZ)) result = 0x00; } else { result = 0x01; } f.close(); } else { result = 0x10; } digitalWrite(LED, LOW ^ LEDinv); return(result); } uint8 _sys_readrand(uint8* filename, long fpos) { uint8 result = 0xff; File f; uint8 bytesread; uint8 dmabuf[BlkSZ]; uint8 i; long extSize; digitalWrite(LED, HIGH ^ LEDinv); f = SD.open((char)filename, O_READ); if (f) { if (f.seek(fpos)) { for (i = 0; i < BlkSZ; ++i) dmabuf[i] = 0x1a; bytesread = f.read(&dmabuf[0], BlkSZ); if (bytesread) { for (i = 0; i < BlkSZ; ++i) _RamWrite(dmaAddr + i, dmabuf[i]); } result = bytesread ? 0x00 : 0x01; } else { if (fpos >= 65536L BlkSZ) { result = 0x06; // seek past 8MB (largest file size in CP/M) } else { extSize = f.size(); // round file size up to next full logical extent extSize = ExtSZ * ((extSize / ExtSZ) + ((extSize % ExtSZ) ? 1 : 0)); if (fpos < extSize) result = 0x01; // reading unwritten data else result = 0x04; // seek to unwritten extent } } f.close(); } else { result = 0x10; } digitalWrite(LED, LOW ^ LEDinv); return(result); } uint8 _sys_writerand(uint8* filename, long fpos) { uint8 result = 0xff; File f; digitalWrite(LED, HIGH ^ LEDinv); if (_sys_extendfile((char)filename, fpos)) { f = SD.open((char)filename, O_RDWR); } if (f) { if (f.seek(fpos)) { if (f.write(_RamSysAddr(dmaAddr), BlkSZ)) result = 0x00; } else { result = 0x06; } f.close(); } else { result = 0x10; } digitalWrite(LED, LOW ^ LEDinv); return(result); } static uint8 findNextDirName[13]; static uint16 fileRecords = 0; static uint16 fileExtents = 0; static uint16 fileExtentsUsed = 0; static uint16 firstFreeAllocBlock; uint8 _findnext(uint8 isdir) { File f; uint8 result = 0xff; bool isfile; uint32 bytes; digitalWrite(LED, HIGH ^ LEDinv); if (allExtents && fileRecords) { _mockupDirEntry(); result = 0; } else { while (f = userdir.openNextFile()) { f.getName((char)&findNextDirName[0], 13); isfile = !f.isDirectory(); bytes = f.size(); f.dirEntry(&fileDirEntry); f.close(); if (!isfile) continue; _HostnameToFCBname(findNextDirName, fcbname); if (match(fcbname, pattern)) { if (isdir) { // account for host files that aren't multiples of the block size // by rounding their bytes up to the next multiple of blocks if (bytes & (BlkSZ - 1)) { bytes = (bytes & ~(BlkSZ - 1)) + BlkSZ; } fileRecords = bytes / BlkSZ; fileExtents = fileRecords / BlkEX + ((fileRecords & (BlkEX - 1)) ? 1 : 0); fileExtentsUsed = 0; firstFreeAllocBlock = firstBlockAfterDir; _mockupDirEntry(); } else { fileRecords = 0; fileExtents = 0; fileExtentsUsed = 0; firstFreeAllocBlock = firstBlockAfterDir; } _RamWrite(tmpFCB, filename[0] - '@'); _HostnameToFCB(tmpFCB, findNextDirName); result = 0x00; break; } } } digitalWrite(LED, LOW ^ LEDinv); return(result); } uint8 _findfirst(uint8 isdir) { uint8 path[4] = { '?', FOLDERCHAR, '?', 0 }; path[0] = filename[0]; path[2] = filename[2]; if (userdir) userdir.close(); userdir = SD.open((char)path); // Set directory search to start from the first position _HostnameToFCBname(filename, pattern); fileRecords = 0; fileExtents = 0; fileExtentsUsed = 0; return(_findnext(isdir)); } uint8 _findnextallusers(uint8 isdir) { uint8 result = 0xFF; char dirname[13]; bool done = false; while (!done) { while (!userdir) { userdir = rootdir.openNextFile(); if (!userdir) { done = true; break; } userdir.getName(dirname, sizeof dirname); if (userdir.isDirectory() && strlen(dirname) == 1 && isxdigit(dirname[0])) { currFindUser = dirname[0] <= '9' ? dirname[0] - '0' : toupper(dirname[0]) - 'A' + 10; break; } userdir.close(); } if (userdir) { result = _findnext(isdir); if (result) { userdir.close(); } else { done = true; } } else { result = 0xFF; done = true; } } return result; } uint8 _findfirstallusers(uint8 isdir) { uint8 path[2] = { '?', 0 }; path[0] = filename[0]; if (rootdir) rootdir.close(); if (userdir) userdir.close(); rootdir = SD.open((char)path); // Set directory search to start from the first position strcpy((char)pattern, "???????????"); if (!rootdir) return 0xFF; fileRecords = 0; fileExtents = 0; fileExtentsUsed = 0; return(_findnextallusers(isdir)); } uint8 _Truncate(char* filename, uint8 rc) { File f; int result = 0; digitalWrite(LED, HIGH ^ LEDinv); f = SD.open((char)filename, O_WRITE \| O_APPEND); if (f) { if (f.truncate(rc BlkSZ)) { f.close(); result = 1; } } digitalWrite(LED, LOW ^ LEDinv); return(result); } void _MakeUserDir() { uint8 dFolder = cDrive + 'A'; uint8 uFolder = toupper(tohex(userCode)); uint8 path[4] = { dFolder, FOLDERCHAR, uFolder, 0 }; digitalWrite(LED, HIGH ^ LEDinv); SD.mkdir((char)path); digitalWrite(LED, LOW ^ LEDinv); } uint8 _sys_makedisk(uint8 drive) { uint8 result = 0; if (drive < 1 \|\| drive>16) { result = 0xff; } else { uint8 dFolder = drive + '@'; uint8 disk[2] = { dFolder, 0 }; digitalWrite(LED, HIGH ^ LEDinv); if (!SD.mkdir((char)disk)) { result = 0xfe; } else { uint8 path[4] = { dFolder, FOLDERCHAR, '0', 0 }; SD.mkdir((char)path); } digitalWrite(LED, LOW ^ LEDinv); } return(result); } / Console abstraction functions / /===============================================================================*/ int _kbhit(void) { return(Serial.available()); } uint8 _getch(void) { while (!Serial.available()); return(Serial.read()); } uint8 _getche(void) { uint8 ch = _getch(); Serial.write(ch); return(ch); } void _putch(uint8 ch) { Serial.write(ch); } void _clrscr(void) { Serial.println("\e[H\e[J"); } #endif	{ "pile_set_name": "Github" }
Vue.component('dropdown', { template: '#tmpl-dropdown', props: { id: { type: String, }, visible: { type: Boolean, default: false, }, items: { type: Array, default: [], }, classes: { type: Array, default: () => [], }, }, methods: { clicked: function(item) { if (item.click && !item.disabled) { item.click(); } if (!item.preventClose) { closeDropdown(); } }, }, }); let openedDropdown; let clickHndl = function(event) { if (!openedDropdown) { return; } var element = event.target; while (element) { if (element === openedDropdown) { return; } element = element.parentElement; } // Click outside the dropdown, close it closeDropdown(); }; function closeDropdown() { if (!openedDropdown) { return; } document.removeEventListener('click', clickHndl); if (openedDropdown.className.indexOf('hidden') < 0) { openedDropdown.className = (openedDropdown.className + ' hidden').trim(); } openedDropdown = undefined; } function openDropdown(element) { element = parseElement(element); if (!element) { console.error('Invalid dropdown element'); return; } event.stopPropagation(); closeDropdown(); if (getComputedStyle(element.parentElement).position === 'relative') { // Position the dropdown relatively to the parent element.style.left = (window.event.clientX - element.parentElement.offsetLeft + element.parentElement.scrollLeft) + 'px'; element.style.top = (window.event.clientY - element.parentElement.offsetTop + element.parentElement.scrollTop) + 'px'; } else { // Position the dropdown absolutely on the window element.style.left = (window.event.clientX + window.scrollX) + 'px'; element.style.top = (window.event.clientY + window.scrollY) + 'px'; } document.addEventListener('click', clickHndl); element.className = element.className.split(' ').filter(c => c !== 'hidden').join(' '); openedDropdown = element; const maxLeft = Math.min(window.innerWidth, element.parentElement.clientWidth) + element.parentElement.scrollLeft; const maxTop = Math.min(window.innerHeight, element.parentElement.clientHeight) + element.parentElement.scrollTop; if (element.parentElement.offsetLeft + element.offsetLeft + parseFloat(getComputedStyle(element).width) >= maxLeft) { if (parseFloat(element.style.left) - parseFloat(getComputedStyle(element).width) >= 0) { element.style.left = (parseFloat(element.style.left) - parseFloat(getComputedStyle(element).width)) + 'px'; } } if (element.parentElement.offsetTop + element.offsetTop + parseFloat(getComputedStyle(element).height) >= maxTop) { if (parseFloat(element.style.top) - parseFloat(getComputedStyle(element).height) >= 0) { element.style.top = (parseFloat(element.style.top) - parseFloat(getComputedStyle(element).height)) + 'px'; } } if (parseFloat(element.style.left) < 0) { element.style.left = 0; } if (parseFloat(element.style.top) < 0) { element.style.top = 0; } }	{ "pile_set_name": "Github" }
Q: Looking for up-to-date F# PowerPack Is there someone who working on F# Power Pack ? Seriously - last update is Dec10 for old F# Core. So I've got own rebuild for some parts (Linq2sql) for .net4 and new core and I think there is someone else who got the same and someone who is working on it - where can I find it ? Or F# PP is dead ? Also I can see only lesser compiler fixes. I like this work but it's not official tree. OK, just kidding, the question is still being about F# Power Pack. A: According to a comment in this blog post, updating the F# PowerPack isn't a high priority just yet.	{ "pile_set_name": "StackExchange" }
Share This Amazon’s Champions of Fire Is Back Next Month for More Mobile eSports Fun Mobile eSports Gaming Isn’t Going Anywhere Amazon is bringing back Champions of Fire this year, an eSports tournament focused on competitive but casual mobile games. Last year’s event was a big success for Amazon (as was Mobile Masters last month) so it isn’t too surprising to see it pop up again in 2017. This time, however, they’re going bigger. On December 2nd and 3rd at the Time Inc. Studios in New York City, 12 of the world’s most popular gaming celebrities like Swiftor, NampaiKid, and MystIc7 will compete against each other in top casual mobile games like Disney Crossy Road, Pac-Man 256, Beach Buggy Racing and the upcoming Sonic Forces: Speed Battle. The prize pool is a cool $50,000 and the entire event will be broadcast live on Amazon’s Appstore’s Twitch channel. It will also air at a later time nationwide on the CBS Sports Network. Below is the list of participating games with more to come: Beach Buggy Racing Beat Fever Cooking Craze Disney Crossy Road Minion Rush Flappy Bird Family Pac-Man 256 Real Racing 3 Sonic Forces: Speed Battle (Coming Soon) And here are the celebrity gamers competing: Swiftor NampaiKid MystIc7 Northernlion Hafu Naomi Kyle Avajaijai xChocoBars Champions of Fire is unique in that it encourages anyone, no matter their gaming experience, to take part in competitive gaming events. Amazon’s philosophy is that eSports can involve any type of game, regardless of platform. Because mobile games have a shorter learning curve, tournaments surrounding them are fun to watch and viewers can understand what’s going on even if they aren’t gamers. While hardcore gamers may scoff at mobile games being part of the eSports culture, it appears to be gaining a lot of traction in the last couple years. You can read about last month’s Mobile Masters competition here which featured tournaments on three mobile games: World of Tanks Blitz, Power Rangers: Legacy Wars, and Vainglory. If you’d like to learn more about Champions of Fire, you can check out the event pages here and here.	{ "pile_set_name": "Pile-CC" }
Slate's Blacklist of Black Conservatives Sonny Bunch February 23, 2010 1:09 PM Slate's The Root -- the portion of the website where they cordon off their African-American content -- has compiled a list of "Black folks we'd like to remove from black history." Some of the choices are funny (Dennis Rodman) some are head-scratching (the doctor who prescribed Michael Jackson his meds?) while others are downright offensive. The continuous pathology in the liberal black community to denigrate black conservatives as "not really black" continues apace here: Clarence Thomas, Michael Steele, and Alan Keyes are listed alongside Idi Amin, Papa and Baby Doc Duvalier, and Robert Mugabe. Oh, and Marion Barry. I imagine that is the excuse that the authors of the list will throw out there if questioned about including a trio of black Republicans alongside cannibals and mass murderers: "Hey, we included a black Democrat too! He was even our very first choice!" Of course, there's a huge difference between admitting to being embarrassed of Democrat who was caught in a FBI sting doing crack, muttered "Bitch set me up" as the feds burst through the door, and served time in prison as a result -- to say nothing of his myriad tax problems and, most recently, blatant corruption in D.C.'s contracting process -- and being embarrassed about the GOP entries on the list. What is so embarrassing about Clarence Thomas -- the second black man on the Supreme Court? He would be a source of pride for the African American community, except for the fact that he's a conservative. He's a minority within a minority. One would think that mocking a minority simply for his status as such is something that writers at The Root would want to avoid.	{ "pile_set_name": "Pile-CC" }
Q: Unity Sprite Editor: Can You Preview A Background Image While Setting Pivot? I've Googled around a lot, and I checked the Unity Asset store but I cannot seem to find what I think is a common problem (or perhaps I'm doing it wrong). The issue is when I use the Sprite Editor I cannot see a reference image which is useful for setting the sprite pivot. When I open the Sprite Editor on a given image file, I cannot seem to add a background reference image: I want to be able to see a background image (of a specific character for example) that I can position and then use that to set the pivot. Do you know of any way to do this? Asset Store references are acceptable. I found one for Animation pivot setting but not for static images. Any and all suggestions welcome (if you have a workflow suggestion that mitigates this issue, feel free to suggest :) ) A: I found a free option that works well enough: http://gnupart.tistory.com/entry/Unity3D-Custom-Sprite-Pivot-Editor-in-SceneView	{ "pile_set_name": "StackExchange" }
Davydkin, Belgorod Oblast Davydkin () is a rural locality (a khutor) in Volokonovsky District, Belgorod Oblast, Russia. The population was 108 as of 2010. There are 2 streets. References Category:Rural localities in Belgorod Oblast	{ "pile_set_name": "Wikipedia (en)" }

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