Miracle-dz/UniFAR-FTUs huggingface dataset:
D120 and K152 within the PH Domain of T Cell Adapter SKAP55 Regulate Plasma Membrane Targeting of SKAP55 and LFA-1 Affinity Modulation in Human T Lymphocytes

ABSTRACT The β2-integrin lymphocyte function-associated antigen 1 (LFA-1) is needed for the T cell receptor (TCR)-induced activation of LFA-1 to promote T cell adhesion and interaction with antigen-presenting cells (APCs). LFA-1-mediated cell-cell interactions are critical for proper T cell differentiation and proliferation. The Src kinase-associated phosphoprotein of 55 kDa (SKAP55) is a key regulator of TCR-mediated LFA-1 signaling (inside-out/outside-in signaling). To gain an understanding of how SKAP55 controls TCR-mediated LFA-1 activation, we assessed the functional role of its pleckstrin homology (PH) domain. We identified two critical amino acid residues within the PH domain of SKAP55, aspartic acid 120 (D120) and lysine 152 (K152). D120 facilitates the retention of SKAP55 in the cytoplasm of nonstimulated T cells, while K152 promotes SKAP55 membrane recruitment via actin binding upon TCR triggering. Importantly, the K152-dependent interaction of the PH domain with actin promotes the binding of talin to LFA-1, thus facilitating LFA-1 activation. These data suggest that K152 and D120 within the PH domain of SKAP55 regulate plasma membrane targeting and TCR-mediated activation of LFA-1.
Is there a Laffer curve between aggregate output and public sector employment ?

This paper develops a model of the relationship between public sector employment, total output and aggregate real demand in market prices, where public employment has a positive productivity effect on private output. Public employment crowds out private employment and output because its increase induces higher wages and taxes. The valuation of government output is also taken into account. While public employment affects total output and aggregate real demand in an a priori ambiguous way, numerical simulations suggest that the relationship may be nonlinear; positive, when public sector is “small” and negative when it is “large”. Using the annual data from 22 OECD countries over the period 1960–1996 and estimating and testing for threshold models and more commonly used specifications with multiplicative interaction terms give support to this nonlinearity hypothesis between public employment and private sector output.
Probing the Role of the Dopamine D1 Receptor in Psychostimulant Addiction

Pharmacological studies have shown that blockade of the dopamine D1 receptor attenuates locomotor behaviors and prevents sensitization to psychostimulants. However, due to possible cross‐reactivities of the D1 receptor antagonists, the exact role of the D1 receptor in response to psychostimulants is still not definitive. To address this issue, we used D1 receptor mutant mice and tested locomotor responses of the mutant mice and wild‐type control mice after cocaine and amphetamine treatments. We found that the D1 receptor mutant mice exhibit significantly reduced locomotor responses to repeated cocaine administration compared to wild‐type mice. Moreover, D1 receptor mutant mice were less sensitive than the wild‐type mice to acute amphetamine administration over a dose range, although they exhibited apparently similar behavioral responses to those of the wild‐type mice after repeated amphetamine administration at the 5 mg/kg dose. These studies suggest that the D1 receptor plays an essential role in mediating cocaine‐induced locomotor responses in mice. In addition, the D1 receptor also participates in behavioral responses induced by amphetamine administration. Further molecular studies are in progress to address the intracellular signaling mechanisms in response to D1 receptor activation by psychostimulants.
Language Models are Unsupervised Multitask Learners

Natural language processing tasks, such as question answering, machine translation, reading comprehension, and summarization, are typically approached with supervised learning on taskspecific datasets. We demonstrate that language models begin to learn these tasks without any explicit supervision when trained on a new dataset of millions of webpages called WebText. When conditioned on a document plus questions, the answers generated by the language model reach 55 F1 on the CoQA dataset matching or exceeding the performance of 3 out of 4 baseline systems without using the 127,000+ training examples. The capacity of the language model is essential to the success of zero-shot task transfer and increasing it improves performance in a log-linear fashion across tasks. Our largest model, GPT-2, is a 1.5B parameter Transformer that achieves state of the art results on 7 out of 8 tested language modeling datasets in a zero-shot setting but still underfits WebText. Samples from the model reflect these improvements and contain coherent paragraphs of text. These findings suggest a promising path towards building language processing systems which learn to perform tasks from their naturally occurring demonstrations.
Effect of flood hydrograph duration , magnitude , and shape on bed-load 1 transport dynamics 2 3

1 Phillips et al. Effect of flood hydrograph duration, magnitude, and shape on bed-load 1 transport dynamics 2 3 Authors C. B. Phillips, K. M. Hill, C. Paola, M. B. Singer, and D. J. Jerolmack 4 5 Civil and Environmental Engineering, Northwestern University, Evanston, IL. 6 Civil, Environmental, and Geo-Engineering, University of Minnesota, Minneapolis, MN. 7 Earth Sciences, University of Minnesota, Minneapolis, MN. 8 St. Anthony Falls Laboratory, University of Minnesota, Minneapolis, MN. 9 Earth and Ocean Sciences, Cardiff University, Cardiff, UK. 10 Earth and Environmental Sciences, University of Pennsylvania, Philadelphia, PA. 11 12 Corresponding author: Colin B. Phillips (colinbphillips@gmail.com) 13 14 Key Points 15
Traditional budgeting during financial crisis El presupuesto tradicional en la crisis económica

This study examines the evolution of budgeting practices in the extremely difficult Spanish economic environment. In order to analyse if companies are still maintaining their budgeting process and if, right now, they are facing more difficulties in forecasting accurate indicators, two similar web surveys were addressed over two periods of time, firstly in 2008 at the beginning of the financial crisis, and secondly in 2013 after five years of a downward trend. In addition, in-depth interviews were conducted to investigate how companies brought more flexibility to their budgeting process in order to cope with environmental uncertainty. The survey indicates that 97% of respondents are still using a traditional budgeting process being this result similar to the one found in 2008. However, 2013 showed that the reliance on forecasted information is being increasingly questioned. Furthermore the study revealed that the respondents are bringing more flexibility to their processes, being able to modify the objectives once the budget is approved and to obtain new resources outside the budgeting process. This paper contributes to revealing information about difficulties in setting reliable objectives in a turbulent environment and provides data about the evolution of budgeting practices over five years during an austere economic crisis.
Central effects of glucocorticoid receptor antagonist RU-38486 on lipopolysaccharide and stress-induced fever.

Intracerebroventricular administration of the glucocorticoid type II receptor antagonist RU-38486 leads to an increased fever after injection of lipopolysaccharide (LPS) in awake unrestrained rats, indicating that endogenous glucocorticoids act centrally to lower temperature after the intraperitoneal injection of LPS. The current study examined where in the brain glucocorticoids exert these effects on fever and if these effects involve plasma interleukin-6 and corticosterone. RU-38486 injected intracerebroventricularly (10 ng/animal) led to a significantly greater rise in biotelemetered body temperature (BT) 120-240 min post-LPS (50 mg/kg ip) compared with controls (0.89 +/- 0.14 vs. 0.44 +/- 0.22 degree C, P = 0.0482), confirming our earlier study, and also led to a significantly greater rise in BT after exposure to an open field when the RU-38486 was infused intracerebroventricularly (10 ng/ml, 1 microliter/h) for 20 h before the exposure (1.48 +/- 0.18 vs. 1.06 +/- 0.11 degree C, P = 0.023). When rats were injected with RU-38486 into the anterior hypothalamus (1 ng/animal), there was an increased rise in BT after injection of LPS (1.74 +/- 0.27 vs. 0.82 +/- 0.22 degree C, P = 0.0075) but not after exposure to an open field (1 ng intrahypothalamically, 1 h preexposure). There were no differences in plasma interleukin (IL)-6-like activity or plasma corticosterone after intracerebroventricular injection of RU-38486 and intraperitoneal injection of LPS. We conclude that endogenous glucocorticoids are working centrally to modulate fever after LPS and exposure to open field, and that LPS-induced fever is modulated by glucocorticoids in the anterior hypothalamus. (ABSTRACT TRUNCATED AT 250 WORDS)
Protein synthesis of the pro-inflammatory S 100 A 8 / A 9 complex in plasmacytoid dendritic cells and cell surface S 100 A 8 / A 9 on leukocyte subpopulations in systemic lupus

Introduction: Systemic lupus erythematosus (SLE) is an autoimmune disease with chronic or episodic inflammation in many different organ systems, activation of leukocytes and production of pro-inflammatory cytokines. The heterodimer of the cytosolic calcium-binding proteins S100A8 and S100A9 (S100A8/A9) is secreted by activated polymorphonuclear neutrophils (PMNs) and monocytes and serves as a serum marker for several inflammatory diseases. Furthermore, S100A8 and S100A9 have many pro-inflammatory properties such as binding to Toll-like receptor 4 (TLR4). In this study we investigated if aberrant cell surface S100A8/A9 could be seen in SLE and if plasmacytoid dendritic cells (pDCs) could synthesize S100A8/A9. Methods: Flow cytometry, confocal microscopy and real-time PCR of flow cytometry-sorted cells were used to measure cell surface S100A8/A9, intracellular S100A8/A9 and mRNA levels of S100A8 and S100A9, respectively. Results: Cell surface S100A8/A9 was detected on all leukocyte subpopulations investigated except for T cells. By confocal microscopy, real-time PCR and stimulation assays, we could demonstrate that pDCs, monocytes and PMNs could synthesize S100A8/A9. Furthermore, pDC cell surface S100A8/A9 was higher in patients with active disease as compared to patients with inactive disease. Upon immune complex stimulation, pDCs up-regulated the cell surface S100A8/A9. SLE patients had also increased serum levels of S100A8/A9. Conclusions: Patients with SLE had increased cell surface S100A8/A9, which could be important in amplification and persistence of inflammation. Importantly, pDCs were able to synthesize S100A8/A9 proteins and up-regulate the cell surface expression upon immune complex-stimulation. Thus, S100A8/A9 may be a potent target for treatment of inflammatory diseases such as SLE.
Automated computerized intensive care unit severity of illness measure in the Department of Veterans Affairs: Preliminary results

ObjectiveTo evaluate the feasibility of an automated intensive care unit (ICU) risk adjustment tool (acronym: SISVistA) developed by selecting a subset of predictor variables from the Acute Physiology and Chronic Health Evaluation (APACHE) III available in the existing computerized database of the Department of Veterans Affairs (VA) healthcare system and modifying the APACHE diagnostic and comorbidity approach. DesignRetrospective cohort study. SettingSix ICUs in three Ohio Veterans Affairs hospitals. Patient SelectionThe first ICU admission of all patients from February 1996 through July 1997. Outcome MeasureMortality at hospital discharge. MethodsThe predictor variables, including age, comorbidity, diagnosis, admission source (direct or transfer), and laboratory results (from the ± 24-hr period surrounding admission), were extracted from computerized VA databases, and APACHE III weights were applied using customized software. The weights of all laboratory variables were added and treated as a single variable in the model. A logistic regression model was fitted to predict the outcome and the model was validated using a bootstrapping technique (1,000 repetitions). Main ResultsThe analysis included all 4,651 eligible cases (442 deaths). The cohort was predominantly male (97.5%) and elderly (63.6 ± 12.0 yrs). In multivariate analysis, significant predictors of hospital mortality included age (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.04–1.09), comorbidity (OR, 1.11; 95% CI, 1.08–1.15), total laboratory score (OR, 1.07; 95% CI, 1.06–1.08), direct ICU admission (OR, 0.39; 95% CI, 0.31–0.49), and several broad ICU diagnostic categories. The SISVistA model had excellent discrimination and calibration (C statistic = 0.86, goodness-of-fit statistics;p > .20). The area under the receiver operating characteristic curve of the validated model was 0.86. ConclusionsUsing common data elements often found in hospital computer systems, SISVistA predicts hospital mortality among patients in Ohio VA ICUs. This preliminary study supports the development of an automated ICU risk prediction system on a more diverse population.
Small‐Molecule Induction of Neural Crest‐like Cells Derived from Human Neural Progenitors

Neural crest (NC) cells are stem cells that are specified within the embryonic neuroectodermal epithelium and migrate to stereotyped peripheral sites for differentiation into many cell types. Several neurocristopathies involve a deficit of NC‐derived cells, raising the possibility of stem cell therapy. In Hirschsprung's disease the distal bowel lacks an enteric nervous system caused by a failure of colonization by NC‐derived cells. We have developed a robust method of producing migrating NC‐like cells from human embryonic stem cell–derived neural progenitors using a coculture system of mouse embryonic fibroblasts. Significantly, subsequent exposure to Y27632, a small‐molecule inhibitor of the Rho effectors ROCKI/II, dramatically increased the efficiency of differentiation into NC‐like cells, identified by marker expression in vitro. NC‐like cells derived by this method were able to migrate along NC pathways in avian embryos in ovo and within explants of murine bowel, and to differentiate into cells with neuronal and glial markers. This is the first study to report the use of a small molecule to induce cells with NC characteristics from embryonic stem cells that can migrate and generate neurons and support cells in complex tissue. Furthermore, this study demonstrates that small‐molecule regulators of ROCKI/II signaling may be valuable tools for stem cell research aimed at treatment of neurocristopathies. STEM CELLS 2009;27:2896–2905
Conditional Knock-out Reveals a Requirement for O-Linked N-Acetylglucosaminase (O-GlcNAcase) in Metabolic Homeostasis*

Background: The physiological functions of the O-GlcNAcase in development and metabolism are unclear. Results: Conditional disruption of the O-GlcNAcase in mice leads to metabolic deregulation and semi-penetrant perinatal lethality. Conclusion: Murine O-GlcNAcase maintains metabolic homeostasis and is particularly important during pregnancy and the postpartum period of development. Significance: The findings reported here suggest a general role for OGA in the overall maintenance of metabolic homeostasis. O-GlcNAc cycling is maintained by the reciprocal activities of the O-GlcNAc transferase and the O-GlcNAcase (OGA) enzymes. O-GlcNAc transferase is responsible for O-GlcNAc addition to serine and threonine (Ser/Thr) residues and OGA for its removal. Although the Oga gene (MGEA5) is a documented human diabetes susceptibility locus, its role in maintaining insulin-glucose homeostasis is unclear. Here, we report a conditional disruption of the Oga gene in the mouse. The resulting homozygous Oga null (KO) animals lack OGA enzymatic activity and exhibit elevated levels of the O-GlcNAc modification. The Oga KO animals showed nearly complete perinatal lethality associated with low circulating glucose and low liver glycogen stores. Defective insulin-responsive GSK3β phosphorylation was observed in both heterozygous (HET) and KO Oga animals. Although Oga HET animals were viable, they exhibited alterations in both transcription and metabolism. Transcriptome analysis using mouse embryonic fibroblasts revealed deregulation in the transcripts of both HET and KO animals specifically in genes associated with metabolism and growth. Additionally, metabolic profiling showed increased fat accumulation in HET and KO animals compared with WT, which was increased by a high fat diet. Reduced insulin sensitivity, glucose tolerance, and hyperleptinemia were also observed in HET and KO female mice. Notably, the respiratory exchange ratio of the HET animals was higher than that observed in WT animals, indicating the preferential utilization of glucose as an energy source. These results suggest that the loss of mouse OGA leads to defects in metabolic homeostasis culminating in obesity and insulin resistance.
How Well Do Psychosocial Interventions Work in Bipolar Disorder?

Objective: Although medication is the mainstay of treatment for bipolar disorder, several adjunctive psychosocial interventions have been manualized over the last decade. This paper's objective is to empirically evaluate the different treatment approaches. Method: We conducted a systematic review of the recent literature pertaining to psychosocial interventions in bipolar, using MEDLINE and PsycINFO. Bibliographies of papers were scrutinized for further relevant references. Articles published from 1999 up to and including 2006 were reviewed. Randomized controlled trials were emphasized. Conclusions: Although psychological models of bipolar disorder fail to inform the psychotherapy treatment to the same extent as in unipolar depression, manualized adjunctive, short-term psychotherapies have been shown to offer fairly consistent benefits to bipolar disorder patients. Cognitive-behavioural therapy, family-focused therapy, and psychoeducation offer the most robust efficacy in regard to relapse prevention, while interpersonal therapy and cognitive-behavioural therapy may offer more benefit in treating residual depressive symptoms.
Interleukin‐6 undergoes transition from growth inhibitor associated with neuroendocrine differentiation to stimulator accompanied by androgen receptor activation during LNCaP prostate cancer cell progression

Interleukin‐6 (IL‐6) has been implicated in the modulation of growth and differentiation in many cancers, and is associated with poor prognosis in renal cell carcinoma, ovarian cancer, lymphoma, melanoma, and prostate cancer. The effects of IL‐6 on the growth of LNCaP human prostate cancer cells are puzzling with some groups showing growth stimulation, while others showing growth inhibition. In this study, we investigated the discrepancy of the effects of IL‐6 on prostate cancer cells.
Sources Of Seedling And Adult Plant Resistance In Advanced Wheat Lines To Puccinia

Forty advanced wheat lines, obtained from SPII, along with susceptible check were studied to assess their seedling and adult plant resistance to yellow rust. The seedling reaction was evaluated in greenhouse by using race 6E150A+,Yr27. Adult plant resistance were also evaluated by measuring of final rust severity (FRS), and coefficient of infection (CI) under natural infection conditions with twice artificial inoculation during 201
University of Groningen GENOTYPE POLYMORPHISMS OF NAT 2 AND CYP 2 E 1 GENES ASSOCIATED WITH DRUG INDUCED LIVER INJURY ( DILI ) IN INDONESIAN TUBERCULOSIS PATIENTS

Email: diahperwitasari2003@ yahoo.com ABSTRACT Currently, Indonesia is in the fifth rank of highest TB prevalence over the world. One of the TB problem is low patients’ adherence due to the oral antituberculosis induced hepatotoxicity. Polymorphisms of NAT2 and CYP2E1 genes had important role in the isoniazid (INH)-induced hepatotoxicity. The aim of this study was to evaluate the polymorphisms profile of NAT2 and CYP2E1 genes associated with hepatotoxicity induced by INH. We used cohort design in Public Health Centers and Lung Clinics of Yogyakarta and Lampung. The inclusion criteria were adult subjects (> 18 yo), newly diagnosed TB and treated by oral antituberculosis, normal function of renal and live and willingness to participate in this study. Subjects were excluded when having positive reaction of HbsAg test, history of HIV and abnormality of renal and liver function. The SNPs of NAT2 and CYP2E1 were designed using IPlex method of DNA sequenom. Among 57 TB patients, we found 14 patients with higher INH serum concentration and experienced increase of ALT-AST. Subjects with SNPs of rs 2070676, rs 1329149, rs 3813867, rs 6413432, rs 8192772, rs 2031920, rs 2515641, rs 8192775, rs 915908 of CYP2E1 experienced increase of ALT and AST. Subjects with SNPs of rs 1799930, rs1799931, rs1801279, rs1801280, rs1799929 , rs1208, rs1041983 of NAT2 are associated with the increase of ALT and AST. The polymorphisms of CYP2E1 and NAT2 may have a role in the mechanisms of INH induced DILI.
Title Deleted in liver cancer 1 ( DLC 1 ) negatively regulatesRho / ROCK / MLC pathway in hepatocellular carcinoma

Aims: Deleted in liver cancer 1 (DLC1), a member of RhoGTPase activating protein (GAP) family, is known to have suppressive activities in tumorigenicity and cancer metastasis. However, the underlying molecular mechanisms of how DLC1 suppresses cell motility have not been fully elucidated. Rho-kinase (ROCK) is an immediate down-stream effector of RhoA in mediating cellular cytoskeletal events and cell motility. In the present study, we aimed to investigate the effects of DLC1 on Rho/ROCK signaling pathway in hepatocellular carcinoma (HCC). Methodology/Principal Findings: We demonstrated that DLC1 negatively regulated ROCK-dependent actomyosin contractility. From immumofluorescence study, we found that ectopic expression of DLC1 abrogated Rho/ROCK-mediated cytoskeletal reorganization including formation of stress fibers and focal adhesions. It also downregulated cortical phosphorylation of myosin light chain 2 (MLC2). These inhibitory events by DLC1 were RhoGAP-dependent, as RhoGAPdeficient mutant of DLC1 (DLC1 K714E) abolished these inhibitory events. In addition, from western study, DLC1 inhibited ROCK-related myosin light chain phosphatase targeting unit 1 (MYPT1) phosphorylation at Threonine 853. By examining cell morphology under microscope, we found that ectopic expression of dominant-active ROCK released cells from DLC1induced cytoskeletal collapse and cell shrinkage. Conclusion: Our data suggest that DLC1 negatively regulates Rho/ROCK/MLC2. This implicates a ROCK-mediated pathway of DLC1 in suppressing metastasis of HCC cells and enriches our understanding in the molecular mechanisms involved in the progression of hepatocellular carcinoma. Citation: Wong CC-L, Wong C-M, Ko FC-F, Chan L-K, Ching Y-P, et al. (2008) Deleted in Liver Cancer 1 (DLC1) Negatively Regulates Rho/ROCK/MLC Pathway in Hepatocellular Carcinoma. PLoS ONE 3(7): e2779. doi:10.1371/journal.pone. 0002779 Editor: Neil Hotchin, University of Birmingham, United Kingdom Received April 20, 2008; Accepted June 30, 2008; Published July 23, 2008 Copyright: 2008 Wong et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The study was funded by Hong Kong Research Grants Council (HKU 7436/04M), RGC Collaborative Reseaarch Fund (HKU 1/06C), Michael and Betty Kadoorie Cancer Genetics Research Program 2004. I.O. L. Ng is Loke Yew Professor in Pathology. Competing Interests: The authors have declared that no competing interests exist. * E-mail: iolng@hkucc.hku. hk