Miracle-dz/UniFAR-FTUs huggingface dataset:
Evidence for Irreversible Inhibition of Glycogen Synthase Kinase-3β by Tideglusib*

Background: Tideglusib is a GSK-3 inhibitor currently undergoing clinical trials for Alzheimer disease and progressive supranuclear palsy. Results: Removal of unbound compound does not recover the enzyme activity, and the dissociation rate constant is close to zero. The protein shows a low turnover rate in neurons. Conclusion: Tideglusib is an irreversible inhibitor of GSK-3β. Significance: The irreversibility and the long enzyme half-life may possess interesting pharmacodynamic implications. Tideglusib is a GSK-3 inhibitor currently in phase II clinical trials for the treatment of Alzheimer disease and progressive supranuclear palsy. Sustained oral administration of the compound to a variety of animal models decreases Tau hyperphosphorylation, lowers brain amyloid plaque load, improves learning and memory, and prevents neuronal loss. We report here that tideglusib inhibits GSK-3β irreversibly, as demonstrated by the lack of recovery in enzyme function after the unbound drug has been removed from the reaction medium and the fact that its dissociation rate constant is non-significantly different from zero. Such irreversibility may explain the non-competitive inhibition pattern with respect to ATP shown by tideglusib and perhaps other structurally related compounds. The replacement of Cys-199 by an Ala residue in the enzyme seems to increase the dissociation rate, although the drug retains its inhibitory activity with decreased potency and long residence time. In addition, tideglusib failed to inhibit a series of kinases that contain a Cys homologous to Cys-199 in their active site, suggesting that its inhibition of GSK-3β obeys to a specific mechanism and is not a consequence of nonspecific reactivity. Results obtained with [35S]tideglusib do not support unequivocally the existence of a covalent bond between the drug and GSK-3β. The irreversibility of the inhibition and the very low protein turnover rate observed for the enzyme are particularly relevant from a pharmacological perspective and could have significant implications on its therapeutic potential.
Understanding Leadership: Paradigms and Cases

PART ONE: UNDERSTANDING LEADERSHIP The Leadership Scene Leadership Paradigms Characteristics of Leadership Paradigms Micro-Level Leadership Theories Emotion in Leadership Macro-Level Leadership Integrating Theories and Paradigms PART TWO: CASES BMW Sheer Driving Pleasure W L Gore & Associates Natural Leadership Novartis People Chemistry Royal Australian Navy Commanding New Leadership SAP Leader of the Internet Pack Bonduelle Leadership, French Style Ekato R[um]hr - und Mischtechnik GmbH Mixing People and Innovation Schering-Plough Mentoring Presidents Swatch Leading through Emotion Rodenstock Working with Vision
Restriction of HIV-1 Replication in Primary Macrophages by IL-12 and IL-18 through the Upregulation of SAMHD1

Monocyte-derived macrophages (MDM) can polarize into different subsets depending on the environment and the activation signal to which they are submitted. Differentiation into macrophages allows HIV-1 strains to infect cells of the monocytic lineage. In this study, we show that culture of monocytes with a combination of IL-12 and IL-18 led to macrophage differentiation that was resistant to HIV-1 infection. In contrast, M-CSF–derived MDM were readily infected by HIV-1. When monocytes were differentiated in the presence of M-CSF and then further treated with IL-12/IL-18, cells became resistant to infection. The restriction on HIV-1 replication was not dependent on virus entry or coreceptor expression, as vesicular stomatitis virus-pseudotyped HIV-1 replication was also blocked by IL-12/IL-18. The HIV-1 restriction factor sterile α motif and HD domain–containing protein-1 (SAMHD1) was significantly overexpressed in IL-12/IL-18 MDM compared with M-CSF MDM, and degradation of SAMHD1 by RNA interference or viral-like particles carrying the lentiviral protein Vpx restored HIV-1 infectivity of IL-12/IL-18 MDM. SAMHD1 overexpression induced by IL-12/IL-18 was not dependent on IFN-γ. Thus, we conclude that IL-12 and IL-18 may contribute to the response against HIV-1 infection through the induction of restriction factors such as SAMHD1.
The UK Productivity Puzzle

Labour productivity growth in the United Kingdom has been particularly weak since the start of the crisis. The recent strength in hiring and modest pickup in productivity growth suggest that spare capacity within firms is unlikely to explain much of the current weakness. Factors related to the nature of the financial crisis are likely to be having a persistent impact on the level of productivity — but there remains considerable uncertainty around any interpretation of the puzzle.
A History of Nerve Functions: From Animal Spirits to Molecular Mechanisms

1. Introduction: Greek science and the recognition of nerves' function 2. Galen's physiology of the nervous system 3. Nerve, brain, and soul in the Middle Ages 4. Renaissance and the New Physiology 5. New physical and chemical models of nerve in the Enlightenment 6. New systematizations of nerve function in the Enlightenment 7. Electricity as the Agent of Nerve Action 8. Nerve fiber form and transformation 9. Wallerian degeneration: early and late phases 10. Nerve regeneration 11. Characterization of axoplasmic transport 12. Molecular models of transport 13. Actions of neurotoxins and neuropathic changes related to transport 14. Purposeful reflexes and instinctive behavior 15. Neural events related to learning and memory 16. Epilogue Bibliography.
The association of comorbid depression with mortality in patients with type 2 diabetes.

OBJECTIVE We assessed whether patients with comorbid minor and major depression and type 2 diabetes had a higher mortality rate over a 3-year period compared with patients with diabetes alone. RESEARCH DESIGN AND METHODS In a large health maintenance organization (HMO), 4,154 patients with type 2 diabetes were surveyed and followed for up to 3 years. Patients initially filled out a written questionnaire, and HMO-automated diagnostic, laboratory, and pharmacy data and Washington State mortality data were collected to assess diabetes complications and deaths. Cox proportional hazards regression models were used to calculate adjusted hazard ratios of death for each group compared with the reference group. RESULTS There were 275 (8.3%) deaths in 3,303 patients without depression compared with 48 (13.6%) deaths in 354 patients with minor depression and 59 (11.9%) deaths among 497 patients with major depression. A proportional hazards model with adjustment for age, sex, race/ethnicity, and educational attainment found that compared with the nondepressed group, minor depression was associated with a 1.67-fold increase in mortality (P = 0.003), and major depression was associated with a 2.30-fold increase (P < 0.0001). In a second model that controlled for multiple potential mediators, both minor and major depression remained significant predictors of mortality. CONCLUSIONS Among patients with diabetes, both minor and major depression are strongly associated with increased mortality. Further research will be necessary to disentangle causal relationships among depression, behavioral risk factors (adherence to medical regimens), diabetes complications, and mortality.
BDNF moderates early environmental risk factors for anxiety in mouse

Anxiety is known to be influenced by both adverse childhood experiences and genetic susceptibility factors. A polymorphism in the brain‐derived neurotrophic factor (BDNF) gene modulates the association between adverse early experiences and risk for anxiety and depression in adulthood. An animal model of this gene‐by‐environment risk factor is lacking. Using two different early environmental manipulations, we found that a heterozygous null mutation in the mouse BDNF gene moderated the long‐term effect of maternal care on innate anxiety behavior. Although changes in maternal care were associated with mild changes in anxiety in wild‐type mice, this effect was magnified in heterozygous null BDNF mice with high‐ and low‐maternal care associated with low and high levels, respectively, of avoidance behavior as measured in the open field and elevated plus maze tests. These data argue for an increased sensitivity to early environmental influences of mice with reduced BDNF function and support the important role of this neurotrophic factor in the developmental plasticity of brain circuits controlling anxiety.
Zac1 Regulates Cell Cycle Arrest in Neuronal Progenitors via Tcf4

ABSTRACT Imprinted genes play a critical role in brain development and mental health, although the underlying molecular and cellular mechanisms remain incompletely understood. The family of basic helix-loop-helix (bHLH) proteins directs the proliferation, differentiation, and specification of distinct neuronal progenitor populations. Here, we identified the bHLH factor gene Tcf4 as a direct target gene of Zac1/Plagl1, a maternally imprinted transcriptional regulator, during early neurogenesis. Zac1 and Tcf4 expression levels concomitantly increased during neuronal progenitor differentiation; moreover, Zac1 interacts with two cis-regulatory elements in the Tcf4 gene locus, and these elements together confer synergistic activation of the Tcf4 gene. Tcf4 upregulation enhances the expression of the cyclin-dependent kinase inhibitor gene p57Kip2, a paternally imprinted Tcf4 target gene, and increases the number of cells in G1 phase. Overall, we show that Zac1 controls cell cycle arrest function in neuronal progenitors through induction of p57Kip2 via Tcf4 and provide evidence for cooperation between imprinted genes and a bHLH factor in early neurodevelopment.
Comparison of two online flocculation monitoring techniques for predicting turbidity removal by granular media filtration

Particulate matter removal in drinking water treatment via direct granular filtration requires specific flocculation conditions (a process typically termed ‘high energy flocculation’). Predicting filtered water turbidity based on flocculated water characteristics remains difficult. This study has sought to establish a relationship between filtered water turbidity and the flocculated water characteristics. Flocculation of low‐turbidity raw water was evaluated online using a Photometric Dispersion Analyser (PDA) and a Dynamic Particle Analyser in a modified jar test followed by a bench‐scale anthracite filter. Coagulants used were alum, PASS100 and ferric sulphate, in addition to a polydiallyldimethylammonium chloride (polyDADMAC) cationic polymer. They were dosed in warm and cold waters, and flocculated with intensities (G) from 0 to 100 s−1. Of the two instruments selected to analyse flocculation performance, the Dynamic Particle Analyser was shown to be the most sensitive, detecting small changes in floc growth kinetics and even floc growth under low flocculation conditions which remained undetected by the PDA. Floc size was shown to be insufficient in predicting particulate matter removal by direct granular filtration as measured by turbidity, although a threshold dv value (50 µm) could be identified for the test conditions evaluated in this project, above which turbidity was systematically lower than 0.2 NTU.
Exploring Bias in the Protein Data Bank Using Contrast Classifiers

In this study we analyzed the bias existing in the Protein Data Bank (PDB) using the novel contrast classifier approach. We trained an ensemble of neural network classifiers, called a contrast classifier, to learn the distributional differences between non-redundant sequence subsets of PDB and SWISS-PROT. Assuming that SWISS-PROT is a representative of the sequence diversity in nature while the PDB is a biased sample, output of the contrast classifier can be used to measure whether the properties of a given sequence or its region are underrepresented in PDB. We applied the contrast classifier to SWISS-PROT sequences to analyze the bias in PDB towards different functional protein properties. The results showed that transmembrane, signal, disordered, and low complexity regions are significantly underrepresented in PDB, while disulfide bonds, metal binding sites, and sites involved in enzyme activity are overrepresented. Additionally, hydroxylation and phosphorylation posttranslational modification sites were found to be underrepresented while acetylation sites were significantly overrepresented. These results suggest the potential usefulness of contrast classifiers in the selection of target proteins for structural characterization experiments.
The emergency severity index triage algorithm version 2 is reliable and valid.

OBJECTIVES Initial studies have shown improved reliability and validity of a new triage tool, the Emergency Severity Index (ESI), over conventional three-level scales at two university medical centers. After pilot implementation and validation, the ESI was revised to include pediatric and updated vital signs criteria. The goal of this study was to assess ESI version (v.) 2 reliability and validity at seven emergency departments (EDs) in three states. METHODS In part 1, interrater reliability was assessed using weighted kappa analysis of written training cases and postimplementation by a random sampling of actual patient triages. In part 2, validity was analyzed using a prospective cohort with stratified random sampling at each site. The ESI was compared with outcomes including resource consumption, inpatient admission, ED length of stay, and 60-day all-cause mortality. RESULTS Weighted kappa analysis of interrater reliability ranged from 0.70 to 0.80 for the written scenarios (n = 3289) and 0.69 to 0.87 for patient triages (n = 386). Outcomes for the validity cohort (n = 1042) included hospitalization rates by ESI triage level: level 1, 83%; 2, 67%; 3, 42%; 4, 8%; level 5, 4%. Sixty-day all-cause mortality by triage level was as follows: level 1, 25%; 2, 4%; 3, 2%; 4, 1%; and 5, 0%. CONCLUSIONS ESI v. 2 triage produced reliable, valid stratification of patients across seven sites. ESI triage should be evaluated as an ED casemix identification system for uniform data collection in the United States and compared with other major ED triage methods.
Expanded dependent health insurance coverage and the labor supply of young adults: Outcomes from state policies and the Aordable Care Act

One of the least controversial policies from the Affordable Care Act (ACA) is the expansion of dependent health insurance coverage for young adults. However, little is known about the potential labor market outcomes that may arise from the policy. In this paper I use changes in state policies and the ACA to examine the effect of dependent health insurance coverage on the labor market, higher education, and marital decisions of young adults. Prior to the ACA, there was no uniform policy on dependent coverage in the United States. In the early 2000s, states began implementing policies to expand dependent coverage of young adults. Using variation in the timing of policy implementation across states and eligibility criteria within states, I find that these policies decreased the labor supply of eligible young adults. In addition, I find that these young adults were more likely to be full-time students as result of the dependent coverage laws. I extend the analysis to the Affordable Care Act which expands the ability of individuals to obtain health insurance through their parent’s plan until the age of 26. I find that the ACA caused an increase in the health insurance rate and a decrease in the labor supply of young adults. This decrease in labor supply is accompanied with an increase in young adults becoming full-time students. In addition, I find that the ACA decreased the likelihood that females were married. To my knowledge, this paper provides the first set of evidence regarding health insurance as a determinant in employment, higher education, and marital decisions of young adults. Feedback received at The University of Arizona is greatly appreciated. Price Fishback, Theresa Gutberlet, Gautam Gowrisankaran, Kei Hirano, Taylor Jaworski, Ashley Langer, Ron Oaxaca, Jessamyn Schaller, Todd Sorensen, and Tiemen Woutersen provided helpful feedback.
Bread Wheat (Triticum aestivum L.) Grain Protein Concentration Is Related to Early Post-Flowering Nitrate Uptake under Putative Control of Plant Satiety Level

The strong negative correlation between grain protein concentration (GPC) and grain yield (GY) in bread wheat complicates the simultaneous improvement of these traits. However, earlier studies have concluded that the deviation from this relationship (grain protein deviation or GPD) has strong genetic basis. Genotypes with positive GPD have an increased ability to uptake nitrogen (N) during the post-flowering period independently of the amount of N taken up before flowering, suggesting that genetic variability for N satiety could enable the breakage of the negative relationship. This study is based on two genotypes markedly contrasted for GPD grown under semi-hydroponic conditions differentiated for nitrate availability both before and after flowering. This allows exploration of the genetic determinants of post-flowering N uptake (PANU) by combining whole plant sampling and targeted gene expression approaches. The results highlights the correlation (r² = 0.81) with GPC of PANU occurring early during grain development (flowering–flowering + 250 degree-days) independently of GY. Early PANU was in turn correlated (r² = 0.80) to the stem-biomass increment after flowering through its effect on N sink activity. Differences in early PANU between genotypes, despite comparable N statuses at flowering, suggest that genetic differences in N satiety could be involved in the establishment of the GPC. Through its strong negative correlation with genes implied in N assimilation, root nitrate concentration appears to be a good marker for evaluating instantaneous plant N demand, and may provide valuable information on the genotypic N satiety level. This trait may help breeders to identify genotypes having high GPC independently of their GY.
Non-suicidal self-injury in eating disorders : advancements in etiology and treatment

Part I: Background and General Aspects. - Non-Suicidal Self-Injury and Eating Disorders: Dimensions of Self-Harm. - Epidemiology and Sociocultural Aspects of Non -Suicidal Self-Injury and Eating Disorders. - Developmental Influences in NSSI and Eating Disorders. - Etiological Models. - Psychological Meanings and Functions. - The Patients' Perspective. Part II: Assessment & Treatment: Functional Assessment and Treatment Planning. - Cognitive Behavior Therapy. - Dialectical Behavior Therapy. - Family Therapy. - Mentalization Based Therapy. - Interpersonal Psychotherapy. - Pharmacotherapy. - Part III: Specific Topics: Co-Occurring Health/ Risk-taking Behaviors. - Experiences of the Body. - Peer influences. - Internet/Social Media influence. - Prevention & Postvention. - Primary Care & Inpatient. - Males - A unique approach.
Use of a Novel Grammatical Inference Approach in Classification of Amyloidogenic Hexapeptides

The present paper is a novel contribution to the field of bioinformatics by using grammatical inference in the analysis of data. We developed an algorithm for generating star-free regular expressions which turned out to be good recommendation tools, as they are characterized by a relatively high correlation coefficient between the observed and predicted binary classifications. The experiments have been performed for three datasets of amyloidogenic hexapeptides, and our results are compared with those obtained using the graph approaches, the current state-of-the-art methods in heuristic automata induction, and the support vector machine. The results showed the superior performance of the new grammatical inference algorithm on fixed-length amyloid datasets.
An Introduction To Post-Colonial Theory

1. Introduction: Points of Departure. 2. Lines of Resistance Metropolitan Therorizing Said and Orientalism. 3. Bhabha and Ambivalence. 4. Spivak and the Subaltern. 5. Intersections and Implications. 6. Conclusion. 7. Notes. Index.
A Cross-Cultural Study of Pragmatically Requestive Speech Act Realization Patterns

Since there have been few pragmatic studies, especially at the local level, that have dealt with the adolescents, and since the language and culture are inseperable, this study examines pragamtically requestive speech acts realizations patterns between English native and non-native adolescents in Dubai, UAE and Ismailia, Egypt. It looks at how the speech acts’ requesting strategies differ across different cultures in terms of the social distance, size of imposition and power. It also looks at the types of politeness strategies, which could increase or decrease the degree of the imposion on the hearer(s), employed by the two groups in terms of the aforementioned sociolinguistic variables. The subjects of this study were divided into two groups. the first group consists of 30 English native adolescents from UK, US and Canada while the second group consists of 30 English non-native adolescents from Pakistan, United Arab Emirates, Egypt, Iran, Malaysia, India, Germany and Philippines. The study have utilized the Discourse Completion Tests (DCTs) distributed to the voluntary students. It revealed significant differences between the two groups in employing the request’s strategies. Additionally, it revealed significant differences between them in employing the politeness strategies. This study provides implications to the students, teachers, educational syllabus designers, decision makers, authors for preventing pragmatic failure/ error to happen and for facilitating effective communications across cultures, too.
Prevalence and predictors of HIV sero-discordance among cohabiting couples tested in northern Tanzania

Introduction In sub-Saharan Africa where HIV/AIDS epidemic is predominantly generalized, majority of HIV infections occur among heterosexual couples. The majority of people do not know their sero-status. Thus, utilisation of Couples’ HIV Counselling and Testing (CHCT) services remain to be critical in preventing new infections. The objective was to establish prevalence and predictors of HIV sero-discordance among cohabiting couples presenting for CHCT services in northern Tanzania. Methods A cross-sectional study inteveviewed 1,333 couples aged 18-49 years tested from 2005 to 2007 in Kilimanjaro and Arusha regions. A CHCT checklist was used to collect data from couples. Data were analyzed using STATA 10. Results Generally, 220(16%) out of 1,333 couples were HIV sero-discordant. In sero-discordance unions, women were likely to be HIV positive than men (71% versus 29% respectively p<0.001). HIV sero-discordant relationship was associated with age (35-45 years) for both men and women (Adjusted Odds Ratio (AOR): 2.3, 95% Confidence Interval (CI): 1.7-3.2) and (AOR: 2.6, 95% CI 1.9-3.7) respectively. Women with older men partners were less likely to be in HIV sero-discordance relationships (AOR: 0.5 95% CI 0.3-09). Arusha couples were likely to be HIV sero-discordant than those of Kilimanjaro (AOR: 2.3 95% CI 1.7-3.2). Couples living far away from CHCT centres were less likely to be sero-discordant than those live nearby (AOR: 0.4 95% CI 0.2-0.9). Conclusion HIV sero-discordance prevalence is high among our participants. Thus, we recommend CHCT utilization should widely be promoted as entry point in treatment as prevention strategy in order to protect uninfected partners in HIV sero-discordance relationships.
Bloch point structure in a magnetic nanosphere

The micromagnetic singularity, the so-called Bloch point, can form a metastable state in the nanosphere. We classify possible types of Bloch points and derive analytically the shape of magnetization distribution inside different Bloch point. We show that external gradient field can stabilize the Bloch point: the shape of the Bloch point becomes radial-dependent one and compute the magnetization structure of the nanosphere, which is in a good agrement with performed spin-lattice simulations.