Miracle-dz/UniFAR-FTUs huggingface dataset:
Mechanistic insights on the reduction of glutathione disulfide by protein disulfide isomerase

Significance Protein disulfide isomerase (PDI) is a ubiquitous enzyme involved in disulfide bond formation during protein folding. It has been related to neurological diseases (Parkinson or Alzheimer’s) because of unfolded protein response phenomena. It also participates in the regulation of the glutathione redox buffer [glutathione/glutathione disulfide (GSH/GSSG)] in the endoplasmic reticulum, also important in protein folding. PDI catalyzes the nucleophilic attack of thiolates to disulfide bonds (thiol-disulfide exchange), enhancing the formation of correct disulfide links that drive protein folding and ensure protein function. This reaction is ubiquitous to disulfide-oxidoreductases across several organisms, and it shows a distinctive chemistry. We present the enzymatic mechanism of PDI in the GSH/GSSG buffer and discuss the chemistry of thiol-disulfide exchange. We explore the enzymatic mechanism of the reduction of glutathione disulfide (GSSG) by the reduced a domain of human protein disulfide isomerase (hPDI) with atomistic resolution. We use classical molecular dynamics and hybrid quantum mechanics/molecular mechanics calculations at the mPW1N/6–311+G(2d,2p):FF99SB//mPW1N/6–31G(d):FF99SB level. The reaction proceeds in two stages: (i) a thiol-disulfide exchange through nucleophilic attack of the Cys53-thiolate to the GSSG-disulfide followed by the deprotonation of Cys56-thiol by Glu47-carboxylate and (ii) a second thiol-disulfide exchange between the Cys56-thiolate and the mixed disulfide intermediate formed in the first step. The Gibbs activation energy for the first stage was 18.7 kcal·mol−1, and for the second stage, it was 7.2 kcal·mol−1, in excellent agreement with the experimental barrier (17.6 kcal·mol−1). Our results also suggest that the catalysis by protein disulfide isomerase (PDI) and thiol-disulfide exchange is mostly enthalpy-driven (entropy changes below 2 kcal·mol−1 at all stages of the reaction). Hydrogen bonds formed between the backbone of His55 and Cys56 and the Cys56-thiol result in an increase in the Gibbs energy barrier of the first thiol-disulfide exchange. The solvent plays a key role in stabilizing the leaving glutathione thiolate formed. This role is not exclusively electrostatic, because an explicit inclusion of several water molecules at the density-functional theory level is a requisite to form the mixed disulfide intermediate. In the intramolecular oxidation of PDI, a transition state is only observed if hydrogen bond donors are nearby the mixed disulfide intermediate, which emphasizes that the thermochemistry of thiol-disulfide exchange in PDI is influenced by the presence of hydrogen bond donors.
The African Union’s data protection Convention 2014: a possible cause for celebration of human rights in Africa?

ABSTRACT It is now widely recognised that the unregulated processing of personal information has had a significant impact on key human rights like privacy, dignity, integrity, personality and autonomy. However, while other regions of the world have taken concerted action to protect the personal rights of individuals by adopting data protection instruments, Africa has generally lagged behind. This is so in spite of the steady growth in access to and usage of ICT and the internet which has facilitated the exploitation of individuals’ personal information with the attendant risk of infringement of their rights. An important step to change this situation was taken when African leaders in June 2014, agreed to a landmark Convention on data protection. This Convention has provoked mixed reactions from stakeholders and privacy advocates. While some are sceptical as to the effectiveness of this Convention, others have welcomed it as a cause for celebration of human rights on the continent. This paper assesses the potential impact this Convention will have on the protection of individual's personal data.
Neural Correlates of Probabilistic Category Learning in Patients with Schizophrenia

Functional neuroimaging studies of probabilistic category learning in healthy adults report activation of cortical-striatal circuitry. Based on previous findings of normal learning rate concurrent with an overall performance deficit in patients with schizophrenia, we hypothesized that relative to healthy adults, patients with schizophrenia would display preserved caudate nucleus and abnormal prefrontal cortex activation during probabilistic category learning. Forty patients with schizophrenia receiving antipsychotic medication and 25 healthy participants were assessed on interleaved blocks of probabilistic category learning and control tasks while undergoing blood oxygenation level-dependent functional magnetic resonance imaging. In addition to the whole sample of patients with schizophrenia and healthy adults, a subset of patients and healthy adults matched for good learning was also compared. In the whole sample analysis, patients with schizophrenia displayed impaired performance in conjunction with normal learning rate relative to healthy adults. The matched comparison of patients and healthy adults classified as good learners revealed greater caudate and dorsolateral prefrontal cortex activity in the healthy adults and greater activation in a more rostral region of the dorsolateral prefrontal, cingulate, parahippocampal and parietal cortex in patients. These results demonstrate that successful probabilistic category learning can occur in the absence of normal frontal-striatal function. Based on analyses of the patients and healthy adults matched on learning and performance, a minority of patients with schizophrenia achieve successful probabilistic category learning and performance levels through differential activation of a circumscribed neural network which suggests a compensatory mechanism in patients showing successful learning.
Targeted overexpression of tumor necrosis factor-&agr; increases cyclin-dependent kinase 5 activity and TRPV1-dependent Ca2+ influx in trigeminal neurons

Abstract We reported earlier that TNF-&agr;, a proinflammatory cytokine implicated in many inflammatory disorders causing orofacial pain, increases the activity of Cdk5, a key kinase involved in brain development and function and recently found to be involved in pain signaling. To investigate a potential mechanism underlying inflammatory pain in trigeminal ganglia (TGs), we engineered a transgenic mouse model (TNFglo) that can conditionally overexpresses TNF-&agr; upon genomic recombination by Cre recombinase. TNFglo mice were bred with Nav1.8-Cre mouse line that expresses the Cre recombinase in sensory neurons to obtain TNF-&agr;:Nav1.8-Cre (TNF-&agr; cTg) mice. Although TNF-&agr; cTg mice appeared normal without any gross phenotype, they displayed a significant increase in TNF-&agr; levels after activation of NF&kgr;B signaling in the TG. IL-6 and MCP-1 levels were also increased along with intense immunostaining for Iba1 and GFAP in TG, indicating the presence of infiltrating macrophages and the activation of satellite glial cells. TNF-&agr; cTg mice displayed increased trigeminal Cdk5 activity, and this increase was associated with elevated levels of phospho-T407-TRPV1 and capsaicin-evocated Ca2+ influx in cultured trigeminal neurons. Remarkably, this effect was prevented by roscovitine, an inhibitor of Cdk5, which suggests that TNF-&agr; overexpression induced sensitization of the TRPV1 channel. Furthermore, TNF-&agr; cTg mice displayed more aversive behavior to noxious thermal stimulation (45°C) of the face in an operant pain assessment device as compared with control mice. In summary, TNF-&agr; overexpression in the sensory neurons of TNF-&agr; cTg mice results in inflammatory sensitization and increased Cdk5 activity; therefore, this mouse model would be valuable for investigating the mechanism of TNF-&agr; involved in orofacial pain.
Bridging the Gap

This article recovers the popular imaginaries surrounding an obsolete video game platform, the Neo Geo Advanced Entertainment System (AES), through a thematic discourse analysis of British and North American gaming magazines from the 1990s. Released in Japan in 1990, the Neo Geo AES was marketed as a home video game system capable of bridging the gap between the public space of the gaming arcade and the domestic environment of the home. “Imaginaries” in this context refer to the dreams and fantasies that accompanied the Neo Geo AES’s negotiation of arcade and home spaces as well as the discourses, images, ideas, and beliefs that helped mold its identity as a cultural object. Gaming magazines, I argue, help articulate how the system’s failure was tied to its unsuccessful navigation of cultural tensions during a period when gaming culture underwent a rapid relocation from the arcade to the home.
Frequency Domain Decision Feedback Equalization for Uplink SC-FDMA

Single carrier frequency division multiple access (SC-FDMA) is one well-known scheme, which has recently become a preferred choice for uplink channels. Due to the usage of single carrier, the performance of SC-FDMA systems degrades in deep frequency selective fading channels. In this paper, we propose a structure of equalizer based on frequency domain decision feedback which could be used for multi-user SC-FDMA systems. Specific parameters of the equalizer are analyzed as well. This algorithm is applicable to various carrier allocations in multi-user systems such as localized allocation, distributed allocation, and frequency-hopping (FH) allocation. To reduce the complexity, it is not necessary to derive the inversion of matrix, which is required in the traditional decision feedback equalizer for single carrier frequency domain equalization (SC-FDE-DFE). It is shown by the simulation results that perfect performance could be achieved under all kinds of situations for multi-user systems. This structure can be used in the broadcasting uplink channels with SC-FDMA scheme.
What Are the Dominant Projects in the GitHub Python Ecosystem?

GitHub, a popular social-software-development platform, has fostered a variety of software ecosystems where projects depend on one another and co-evolve together. The projects located in the central hub of the ecosystem are supposed to be important and could affect a number of other projects. However, few researches have investigated the dominant projects in a software ecosystem. In this study, we aim to identify the most influential projects in the GitHub Python ecosystem. We first construct the GitHub Python ecosystem with 19797 projects by identifying their inter-dependencies. Then, we calculate the four kinds of centrality metrics to measure the centrality and influence of each project in the ecosystem. Finally, we evaluate the project's popularity using GitHub social methods and compare the consistency of the two measurements. Our results indicate that 1) the most influential projects are mostly custom libraries; 2) only a small number of projects have large values of the centrality metrics; 3) the dominant projects are not always popular among the GitHub users. Our results help the researchers and practitioners gain a better understanding of the GitHub Python ecosystem.
A runtime approach for estimating resource usage

In the era of information explosion, a program is necessary to be scalable. Therefore, scalability analysis becomes very important in software verification and validation. However, current approaches to empirical scalability analysis remain limitations related to the number of supported models and performance. In this paper, we propose a runtime approach for estimating the program resource usage with two aims: evaluating the program scalability and revealing potential errors. In this approach, the resource usage of a program is first observed when it is executed on inputs with different scales, the observed results are then fitted on a model of the usage according to the program's input. Comparing to other approaches, ours supports diverse models to illustrate the resource usage, i.e., linear-log, power-law, polynomial, etc. We currently focus on the computation cost and stack frames usage as two representatives of resource usage, but the approach can be extended to other kinds of resource. The experimental result shows that our approach achieves more precise estimation and better performance than other state-of-the-art approaches.
Fostering coping by adolescents with newly diagnosed cancer.

OBJECTIVES To review a research program about adolescents' coping with life-threatening illness and nurses' role in fostering the adolescents' coping efforts. DATA SOURCES Research studies, review articles, and book chapters. CONCLUSIONS Adolescents who have cancer are at risk of negative health outcomes. Promoting positive coping during the developmental period of adolescence helps adolescents to assume greater responsibility for their health actions. IMPLICATIONS FOR NURSING PRACTICE Certain behaviors initiated by health care providers on hopefulness in adolescents assists the ill adolescents in articulating their hopes and realising or redefining those hopes.
Economic evaluation of factorial randomised controlled trials: challenges, methods and recommendations

Increasing numbers of economic evaluations are conducted alongside randomised controlled trials. Such studies include factorial trials, which randomise patients to different levels of two or more factors and can therefore evaluate the effect of multiple treatments alone and in combination. Factorial trials can provide increased statistical power or assess interactions between treatments, but raise additional challenges for trial‐based economic evaluations: interactions may occur more commonly for costs and quality‐adjusted life‐years (QALYs) than for clinical endpoints; economic endpoints raise challenges for transformation and regression analysis; and both factors must be considered simultaneously to assess which treatment combination represents best value for money. This article aims to examine issues associated with factorial trials that include assessment of costs and/or cost‐effectiveness, describe the methods that can be used to analyse such studies and make recommendations for health economists, statisticians and trialists. A hypothetical worked example is used to illustrate the challenges and demonstrate ways in which economic evaluations of factorial trials may be conducted, and how these methods affect the results and conclusions. Ignoring interactions introduces bias that could result in adopting a treatment that does not make best use of healthcare resources, while considering all interactions avoids bias but reduces statistical power. We also introduce the concept of the opportunity cost of ignoring interactions as a measure of the bias introduced by not taking account of all interactions. We conclude by offering recommendations for planning, analysing and reporting economic evaluations based on factorial trials, taking increased analysis costs into account. © 2017 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd.
Glutathione Peroxidase-1 Deficiency Augments Proinflammatory Cytokine-induced Redox Signaling and Human Endothelial Cell Activation*

Background: Recent studies suggest that deficiency of the antioxidant enzyme glutathione peroxidase-1 (GPx-1) may contribute to cardiovascular disease risk. Results: In human endothelial cells, GPx-1 deficiency and its accompanying oxidant stress increased adhesion molecule expression by augmenting NFκB and JNK activation. Conclusion: GPx-1 deficiency promotes a proinflammatory state by redox mechanisms. Significance: This study provides insights into the mechanisms by which GPx-1 regulates endothelial activation and atherogenesis. Glutathione peroxidase-1 (GPx-1) is a crucial antioxidant enzyme, the deficiency of which promotes atherogenesis. Accordingly, we examined the mechanisms by which GPx-1 deficiency enhances endothelial cell activation and inflammation. In human microvascular endothelial cells, we found that GPx-1 deficiency augments intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression by redox-dependent mechanisms that involve NFκB. Suppression of GPx-1 enhanced TNF-α-induced ROS production and ICAM-1 expression, whereas overexpression of GPx-1 attenuated these TNF-α-mediated responses. GPx-1 deficiency prolonged TNF-α-induced IκBα degradation and activation of ERK1/2 and JNK. JNK or NFκB inhibition attenuated TNF-α induction of ICAM-1 and VCAM-1 expression in GPx-1-deficient and control cells, whereas ERK1/2 inhibition attenuated only VCAM-1 expression. To analyze further signaling pathways involved in GPx-1-mediated protection from TNF-α-induced ROS, we performed microarray analysis of human microvascular endothelial cells treated with TNF-α in the presence and absence of GPx-1. Among the genes whose expression changed significantly, dual specificity phosphatase 4 (DUSP4), encoding an antagonist of MAPK signaling, was down-regulated by GPx-1 suppression. Targeted DUSP4 knockdown enhanced TNF-α-mediated ERK1/2 pathway activation and resulted in increased adhesion molecule expression, indicating that GPx-1 deficiency may augment TNF-α-mediated events, in part, by regulating DUSP4.
Molecular Reconstruction of mGluR5a-Mediated Endocannabinoid Signaling Cascade in Single Rat Sympathetic Neurons

Endocannabinoids (eCB) such as 2-arachidonylglycerol (2-AG) are lipid metabolites that are synthesized in a postsynaptic neurons and act upon CB1 cannabinoid receptors (CB1R) in presynaptic nerve terminals. This retrograde transmission underlies several forms of short and long term synaptic plasticity within the CNS. Here, we constructed a model system based on isolated rat sympathetic neurons, in which an eCB signaling cascade could be studied in a reduced, spatially compact, and genetically malleable system. We constructed a complete eCB production/mobilization pathway by sequential addition of molecular components. Heterologous expression of four components was required for eCB production and detection: metabotropic glutamate receptor 5a (mGluR5a), Homer 2b, diacylglycerol lipase α, and CB1R. In these neurons, application of l-glutamate produced voltage-dependent modulation of N-type Ca2+ channels mediated by activation of CB1R. Using both molecular dissection and pharmacological agents, we provide evidence that activation of mGluR5a results in rapid enzymatic production of 2-AG followed by activation of CB1R. These experiments define the critical elements required to recapitulate retrograde eCB production and signaling in a single peripheral neuron. Moreover, production/mobilization of eCB can be detected on a physiologically relevant time scale using electrophysiological techniques. The system provides a platform for testing candidate molecules underlying facilitation of eCB transport across the plasma membrane.
A clinical approach to the threat of emerging influenza viruses in the Asia‐Pacific region

Seasonal influenza epidemics and periodic pandemics are important causes of morbidity and mortality. Patients with chronic co‐morbid illness, those at the extremes of age and pregnant women are at higher risks of complications requiring hospitalization, whereas young adults and obese individuals were also at increased risk during the A(H1N1) pandemic in 2009. Avian influenza A(H5N1) and A(H7N9) viruses have continued to circulate widely in some poultry populations and infect humans sporadically since 1997 and 2013, respectively. The recent upsurge in human cases of A(H7N9) infections in Mainland China is of great concern. Sporadic human cases of avian A(H5N6), A(H10N8) and A(H6N1) have also emerged in recent years while there are also widespread poultry outbreaks due to A(H5N8) in many countries. Observational studies have shown that treatment with a neuraminidase inhibitor (NAI) for adults hospitalized with severe influenza is associated with lower mortality and better clinical outcomes, especially when administered early in the course of illness. Whether higher than standard doses of NAI would provide greater antiviral effects in such patients will require further investigation. High‐dose systemic corticosteroids were associated with worse outcomes in patients with severe influenza. There is an urgent need for developing more effective antiviral therapies for treatment of influenza infections.
Special Education Voucher Programs, Reflective Judgment, and Future Legislative Recommendations

As of 2015, 17 special education voucher programs (SVPs) existed in 13 states and proposals continue to emerge. Eligible parents utilize these vouchers to enroll their children in private schools and thereby relinquish special education services and protections provided under the Individuals with Disabilities Education Act (IDEA). Using a reflective judgment lens, this article presents a balanced review of the competing perspectives that shape the debates over SVPs. In addition, this article recommends how future SVP legislation could better serve the needs of students with disabilities, their families, and both public and private schools.
Rapid Evolution of Primate Type 2 Immune Response Factors Linked to Asthma Susceptibility

Host immunity pathways evolve rapidly in response to antagonism by pathogens. Microbial infections can also trigger excessive inflammation that contributes to diverse autoimmune disorders including asthma, lupus, diabetes, and arthritis. Definitive links between immune system evolution and human autoimmune disease remain unclear. Here we provide evidence that several components of the type 2 immune response pathway have been subject to recurrent positive selection in the primate lineage. Notably, rapid evolution of the central immune regulator IL13 corresponds to a polymorphism linked to asthma susceptibility in humans. We also find evidence of accelerated amino acid substitutions as well as repeated gene gain and loss events among eosinophil granule proteins, which act as toxic antimicrobial effectors that promote asthma pathology by damaging airway tissues. These results support the hypothesis that evolutionary conflicts with pathogens promote tradeoffs for increasingly robust immune responses during animal evolution. Our findings are also consistent with the view that natural selection has contributed to the spread of autoimmune disease alleles in humans.
Generalizability of Evidence-Based PTSD Psychotherapies to Suicidal Individuals: A Review of the Veterans Administration and Department of Defense Clinical Practice Guidelines

Posttraumatic stress disorder (PTSD) is strongly associated with suicide. The 2010 Department of Veterans Affairs/Department of Defense Clinical Practice Guidelines for PTSD (VA/DoD CPG) endorse cognitive therapy and its variants as empirically supported PTSD treatments. However, we lack an understanding about whether these treatments are generalizable to patients with suicidal ideation and/or behaviors. Randomized controlled trials (RCTs) cited in the VA/DoD CPGs were systematically reviewed for methodology, suicide-related content, and adverse event reporting. Thirty-eight RCTs were reviewed. Twenty-three reported suicide-related exclusion criteria, 15 made no mention of suicide-related inclusion/exclusion criteria. Thirty-six RCTs included depression assessments containing suicide-related items, but no suicide-relevant data were reported. Two RCTs outlined suicide risk monitoring procedures. Suicidal PTSD participants are underrepresented in PTSD RCTs and suicide risk assessment procedures were inconsistently reported. Standardized reporting of RCT methods pertaining to suicide risk to determine generalizability and safety of empirically supported PTSD treatments to this clinical population is needed.