Miracle-dz/UniFAR-FTUs huggingface dataset:
A double-blind, placebo-controlled trial to assess the efficacy of quetiapine fumarate XR in very heavy-drinking alcohol-dependent patients.

BACKGROUND Despite advances in developing medications to treat alcohol dependence, few such medications have been approved by the Food and Drug Administration. Identified molecular targets are encouraging and can lead to the development and testing of new compounds. Atypical antipsychotic medications have been explored with varying results. Prior research suggests that the antipsychotic quetiapine may be beneficial in an alcohol-dependent population of very heavy drinkers. METHODS In this double-blind, placebo-controlled trial, 224 alcohol-dependent patients who reported very heavy drinking were recruited across 5 clinical sites. Patients received either quetiapine or placebo and Medical Management behavioral intervention. Patients were stratified on gender, clinical site, and reduction in drinking prior to randomization. RESULTS No differences between the quetiapine and placebo groups were detected in the primary outcome, percentage heavy-drinking days, or other drinking outcomes. Quetiapine significantly reduced depressive symptoms and improved sleep but had no effect on other nondrinking outcomes. Results from a subgroup analysis suggest that patients who reduced their drinking prior to randomization had significantly better drinking outcomes during the maintenance phase (p < 0.0001). No significant interactions, however, were observed between reducer status and treatment group. Finally, quetiapine was generally well tolerated. Statistically significant adverse events that were more common with quetiapine versus placebo include dizziness (14 vs. 4%), dry mouth (32 vs. 9%), dyspepsia (13 vs. 2%), increased appetite (11 vs. 1%), sedation (15 vs. 3%), and somnolence (34 vs. 9%). CONCLUSIONS This multisite clinical trial showed no efficacy for quetiapine compared with placebo at reducing alcohol consumption in heavy-drinking alcohol-dependent patients.
Five Dimensions of Research Ethics: A Stakeholder Framework for Creating a Climate of Research Integrity

The authors explore five dimensions of research ethics: (1) normative ethics, which includes meta-ethical questions; (2) compliance with regulations, statutes, and institutional policies; (3) the rigor and reproducibility of science; (4) social value; and (5) workplace relationships. Each of the five dimensions is important not only because it addresses an aspect of good research done in a good manner but also because it addresses the concerns of key stakeholders in the research enterprise. The five-dimension framework can guide institutions as they answer three questions central to any research ethics program: (1) Who should champion research ethics? (2) What should interventions look like? and (3) Who should participate in the interventions? The framework is valuable because the answers to these three questions are radically different depending on the dimension under consideration. An expanded vision of research ethics does not entail that institutions should require additional online training or approvals from institutional review boards. However, without acknowledging all five dimensions, programs risk missing an important aspect of research ethics or ignoring the interests of important stakeholders.
C57BL/6 Mice Genetically Deficient in IL-12/IL-23 and IFN-γ Are Susceptible to Experimental Autoimmune Myasthenia Gravis, Suggesting a Pathogenic Role of Non-Th1 Cells1

Immunization with Torpedo acetylcholine receptor (TAChR) induces experimental autoimmune myasthenia gravis (EAMG) in C57BL/6 (B6) mice. EAMG development needs IL-12, which drives differentiation of Th1 cells. The role of IFN-γ, an important Th1 effector, is not clear and that of IL-17, a proinflammatory cytokine produced by Th17 cells, is unknown. In this study, we examined the effect of simultaneous absence of IL-12 and IFN-γ on EAMG susceptibility, using null mutant B6 mice for the genes of both the IL-12/IL-23 p40 subunit and IFN-γ (dKO mice). Wild-type (WT) B6 mice served as control for EAMG induction. All mice were immunized with TAChR in Freund’s adjuvant. dKO mice developed weaker anti-TAChR CD4+T cells and Ab responses than WT mice. Yet, they developed EAMG symptoms, anti-mouse acetylcholine receptor (AChR) Ab, and CD4+ T cell responses against mouse AChR sequences similar to those of WT mice. dKO and WT mice had similarly reduced AChR content in their muscles, and IgG and complement at the neuromuscular junction. Naive dKO mice had significantly fewer NK, NKT, and CD4+CD25+Foxp3+ T regulatory (Treg) cells than naive WT mice. Treg cells from TAChR-immunized dKO mice had significantly less suppressive activity in vitro than Treg cells from TAChR-immunized WT mice. In contrast, TAChR-specific CD4+ T cells from TAChR-immunized dKO and WT mice secreted comparable amounts of IL-17 after stimulation in vitro with TAChR. The susceptibility of dKO mice to EAMG may be due to reduced Treg function, in the presence of a normal function of pathogenic Th17 cells.
Forty Years of Clathrin‐coated Vesicles

The purification of coated vesicles and the discovery of clathrin by Barbara Pearse in 1975 was a landmark in cell biology. Over the past 40 years, work from many labs has uncovered the molecular details of clathrin and its associated proteins, including how they assemble into a coated vesicle and how they select cargo. Unexpected connections have been found with signalling, development, neuronal transmission, infection, immunity and genetic disorders. But there are still a number of unanswered questions, including how clathrin‐mediated trafficking is regulated and how the machinery evolved.
Endemic Melioidosis in Residents of Desert Region after Atypically Intense Rainfall in Central Australia, 2011

After heavy rains and flooding during early 2011 in the normally arid interior of Australia, melioidosis was diagnosed in 6 persons over a 4-month period. Although the precise global distribution of the causal bacterium Burkholderia pseudomallei remains to be determined, this organism can clearly survive in harsh and even desert environments outside the wet tropics.
Cardiovascular physiology in premotor Parkinson's disease: A neuroepidemiologic study

Changes in cardiovascular physiology in Parkinson's disease (PD) are common and may occur prior to diagnostic parkinsonian motor signs. We investigated associations of electrocardiographic (ECG) abnormalities, orthostasis, heart rate variability, and carotid stenosis with the risk of PD diagnosis in the Cardiovascular Health Study, a community‐based cohort of older adults. ECG abnormality, orthostasis (symptomatic or asymptomatic), heart rate variability (24‐hour Holter monitoring), and any carotid stenosis (≥1%) by ultrasound were modeled as primary predictors of incident PD diagnosis using multivariable logistic regression. Incident PD cases were identified by at least 1 of the following: self‐report, antiparkinsonian medication use, and ICD‐9. If unadjusted models were significant, they were adjusted or stratified by age, sex, and smoking status, and those in which predictors were still significant (P ≤ .05) were also adjusted for race, diabetes, total cholesterol, low‐density lipoprotein, blood pressure, body mass index, physical activity, education level, stroke, and C‐reactive protein. Of 5888 participants, 154 incident PD cases were identified over 14 years of follow‐up. After adjusting models with all covariates, those with any ECG abnormality (odds ratio [OR], 1.45; 95% CI, 1.02–2.07; P = .04) or any carotid stenosis (OR, 2.40; 95% CI, 1.40–4.09; P = .001) at baseline had a higher risk of incident PD diagnosis. Orthostasis and heart rate variability were not significant predictors. This exploratory study suggests that carotid stenosis and ECG abnormalities occur prior to motor signs in PD, thus serving as potential premotor features or risk factors for PD diagnosis. Replication is needed in a population with more thorough ascertainment of PD onset. © 2012 Movement Disorder Society
Does trauma exposure predict prescription drug problems beyond the contribution of post-traumatic stress disorder and depression? An analysis of the Mind Your Heart cohort study

ABSTRACT It is not clear from prior studies whether trauma exposure predicts substance use problems independent of psychiatric comorbidities. Most prior studies were cross-sectional in nature, and none focused on prescription drug problems. To address this gap in the literature, the current article is a secondary analysis of veterans from the Mind Your Heart prospective cohort study. The primary research question is whether trauma exposure predicts prescription drug problems even after controlling for major psychiatric symptoms, such as post-traumatic stress disorder and depression. Multinomial logistic regression was used to assess whether the 10-item lifetime Brief Trauma Questionnaire (e.g., serious car accidents, war traumas, life-threatening illness, natural disasters, physical, or sexual abuse) predicts prescription drug problems as determined by a self-report categorical question (three answer choices) over a 4-year follow-up time period (n = 661 [100%] at year 1; 83.4% at year 2; 85.9% at year 3; and 78.2% at year 4). Trauma exposure was positively associated with prescription drug problems in unadjusted and age-, sex-, and race-adjusted analyses at follow-up. After accounting for post-traumatic stress disorder (PTSD Checklist-17 Civilian Version) and depression (Patient Health Questionnaire-9) symptoms, trauma exposure was no longer associated with prescription drug problems at all time points (relative risk ratios range 0.91–1.47). These results were robust to different missing data strategies. Trauma exposure was not associated with prescription drug problems over a 4-year follow-up in a prospective cohort study of veterans. Future directions include detailed measures of prescription drug problems and recruitment from community sites.
Working outside of your wheelhouse: Effects of incentives and framing on transactive memory systems and performance

People collaborate to address tasks that can often be decomposed into smaller components. These components beg different forms of expertise and may differ in value to the group. We show that transactive memory structure is affected by the interaction between task component value, incentive framing (i.e., whether task incentives take the form of gains or losses), and the distribution of expertise with respect to task components. We find that when groups include a member with expertise in a highly valuable task component, that member is exceptionally motivated and puts forth high levels of effort. Only groups with such an expert successfully realized the potential performance benefit associated with high-value domains. Groups recalled more items under loss framing than under gains framing, but only when the potential losses were low and constant across components. We integrate our findings into the extant literatures on transactive memory and gains/loss framing.
Fluoxetine administered to juvenile monkeys: effects on the serotonin transporter and behavior.

OBJECTIVE This study examined the long-term effects of fluoxetine administered to juvenile rhesus monkeys who, as young adults, were imaged with positron emission tomography for two serotonergic markers: serotonin transporter (SERT) and serotonin 1A (5-HT1A) receptor. An equal number of monkeys separated from their mothers at birth-an animal model of human childhood stress-were also studied. METHOD At birth, 32 male rhesus monkeys were randomly assigned to either maternal separation or normal rearing conditions. At age 2, half (N=8) of each group was randomly assigned to fluoxetine (3 mg/kg) or placebo for 1 year. To eliminate the confounding effects of residual drug in the brain, monkeys were scanned at least 1.5 years after drug discontinuation. Social interactions were assessed both during and after drug administration. RESULTS Fluoxetine persistently upregulated SERT, but not 5-HT1A receptors, in both the neocortex and the hippocampus. Whole-brain voxel-wise analysis revealed that fluoxetine had a significant effect in the lateral temporal and cingulate cortices. In contrast, neither maternal separation by itself nor the rearing-by-drug interaction was significant for either marker. Fluoxetine had no significant effect on the behavioral measures. CONCLUSIONS Fluoxetine administered to juvenile monkeys upregulates SERT into young adulthood. Implications regarding the efficacy or potential adverse effects of SSRIs in patients cannot be directly drawn from this study. Its purpose was to investigate effects of SSRIs on brain development in nonhuman primates using an experimental approach that randomly assigned long-term SSRI treatment or placebo.
Leptomeningeal Collaterals Strongly Correlate with Reduced Cerebrovascular Reactivity Measured by Acetazolamide-challenged Single-photon Emission Computed Tomography Using a Stereotactic Extraction Estimation Analysis in Patients with Unilateral Internal Carotid Artery Stenosis

Objective To assess the correlation between the angiographic appearance of cerebral collateral pathways or the degree of internal carotid artery stenosis (ICAS) and reduced cerebrovascular reactivity (CVR) estimated by single-photon emission computed tomography (SPECT) image analysis in patients with unilateral ICAS. Methods A retrospective analysis was performed in 42 patients with unilateral ICAS who underwent cerebral angiography and acetazolamide-challenged SPECT of the brain. Cerebral blood flow quantitation was performed using the quantitative SPECT/dual-table autoradiography method. The CVR in the middle cerebral artery (MCA) territory was evaluated using the stereotactic extraction estimation based on the Japanese extracranial-intracranial bypass trial (SEE-JET) program and classified as reduced (<18.4%) or non-reduced (≥18.4%). Angiographic collateralization was classified as circle of Willis (type 1), extracranial-intracranial (type 2), and leptomeningeal (type 3). The degree of ICAS was defined as severe (≥70% stenosis) or non-severe (<70%). Results Eight patients showed reduced CVR, including 6 (46%) of 13 with type 3 collaterals and 2 (7%) of 29 without type 3 collaterals (p=0.006). In contrast, type 1 and type 2 collaterals and severe ICAS were not significantly associated with reduced CVR. Conclusion In patients with unilateral ICAS, leptomeningeal collaterals are strongly correlated with reduced CVR in the MCA territory, which presumably increases the risk of cerebral hyperperfusion after carotid artery stenting (CAS). Therefore, these findings may be clinically applicable to the perioperative management of CAS.
Dipyrone (metamizole) markedly interferes with platelet inhibition by aspirin in patients with acute and chronic pain: A case-control study

BACKGROUND Nonopioid analgesic drugs may interfere with platelet inhibition by aspirin. Recent in vitro and clinical studies in patients with cardiovascular disease have suggested that this pharmacodynamic interaction may also occur with dipyrone, a nonopioid analgesic popular in Europe, Asia and South America. OBJECTIVE Dipyrone is used extensively in acute and chronic pain. This study was undertaken to provide clinical data, so far missing, on its interactions in this group of patients. DESIGN A case-control study. SETTING Primary care in one European university hospital centre. PATIENTS In total, 27 patients with stable cardiovascular, cerebrovascular or peripheral arterial disease and acute or chronic pain were identified and given dipyrone for at least 5 days in combination with low-dose aspirin. In total, 10 comparable patients on low-dose aspirin alone served as controls. MAIN OUTCOME MEASURES Platelet-rich plasma was prepared to determine arachidonic acid-induced aggregation (aggregometry) and thromboxane formation (immunoassay). Platelet sensitivity to aspirin was examined in vitro. The presence of dipyrone (metabolites) in plasma was confirmed by HPLC. Additional in vitro measurements examined the aspirin/dipyrone interaction in healthy donors. RESULTS Inhibition of aggregation was observed in only six of 27 patients receiving aspirin with dipyrone, with absence of complete inhibition by antiplatelet therapy showing in 78% of patients. In contrast, aggregation was completely inhibited in nine of 10 control patients (P < 0.001). Platelet thromboxane synthesis was higher in patients receiving dipyrone + aspirin compared with controls (387 ± 89 vs. 7 ± 1 ng ml−1, P < 0.001). Aspirin added in vitro failed to inhibit aggregation and thromboxane synthesis in platelet-rich plasma from dipyrone-treated patients. In vitro measurements with blood from healthy individuals confirmed that dipyrone dramatically reduces inhibition of platelet thromboxane synthesis by aspirin. CONCLUSIONS Dipyrone given for 5 days or longer blunts platelet inhibition by low-dose aspirin in the majority of recipients. TRIAL REGISTRATION German Clinical Trials Register: DRKS ID DRKS00000204. Universal Trial Number (UTN): U1111-1113-3946.
Evaluation of Research Ethics Committees: Criteria for the Ethical Quality of the Review Process

ABSTRACT Repeatedly, adequacy, performance and quality of Ethics Committees that oversee medical research trials are being discussed. Although they play a crucial role in reviewing medical research and protecting human subjects, it is far from clear to what degree they fulfill the task they have been assigned to. This eventuates in the call for an evaluation of their activity and, in some places, led to the establishment of accreditation schemes. At the same time, IRBs have become subject of detailed legislation in the process of the ongoing global juridification of medical research. Unsurprisingly, there is a tendency to understand the evaluation of RECs as a question of controlling their legal compliance. This paper discusses the need for a quality evaluation of IRBs from an ethical point of view and, by systematically reviewing the major ethical guidelines for IRBs, proposes a system of criteria that should orientate any evaluation of IRBs.
Combined Side-Channel and Fault Analysis Attack on Protected Grain Family of Stream Ciphers

In this paper, we first demonstrate a new Differential Power Analysis (DPA) attack technique against the Grain family of stream ciphers (Grain v1 and Grain-128) by resynchronizing the cipher multiple times with the same value of the secret key and randomly generated different initialization vectors (IVs). Subsequently, we develop a combined side channel and fault analysis attack strategy targeting various fault attack countermeasures for the Grain cipher family. We considered clock glitch induced faults occurring in practice for a hardware implementation of the cipher to devise our novel attack technique. Our proposed combined attack strategy works well even if the useful ciphertexts are not available to the adversary. Further, the power trace classifications of a Grain cipher implementation on SASEBO G-II standard side channel evaluation board is shown in order to validate our proposed attack against the cipher. The captured power traces were analyzed using Least Squares Support Vector Machine (LS-SVM) learning algorithm based multiclass classifiers to classify the power traces into the respective Hamming distance (HD) classes. To extract power samples with high information about HD classes, Signal-tonoise ratio (SNR) metric was chosen for feature selection. The experimental results of power trace classifications of test set showed a high success rate of 98% when the five largest SNR sample instants over a clock cycle were chosen as features. Our proposed attack strategy can also be extended to other stream cipher designs based on Fibonacci configured shift registers.
Moving-Target Defense Against Botnet Reconnaissance and an Adversarial Coupon-Collection Model

We consider a cloud based multiserver system consisting of a set of replica application servers behind a set of proxy (indirection) servers which interact directly with clients over the Internet. We study a proactive moving-target defense to thwart a DDoS attacker's reconnaissance phase and consequently reduce the attack's impact. The defense is effectively a moving-target (motag) technique in which the proxies dynamically change. The system is evaluated using an AWS prototype of HTTP redirection and by numerical evaluations of an “adversarial” coupon-collector mathematical model, the latter allowing larger-scale extrapolations.
Characterization of zfs1 as an mRNA-binding and -destabilizing Protein in Schizosaccharomyces pombe*

Tristetraprolin is a vertebrate CCCH tandem zinc finger protein that can bind to and destabilize certain mRNAs containing AU-rich element binding sites. zfs1 is the single gene in the fission yeast, Schizosaccharomyces pombe, that encodes a protein containing the critical features of the tristetraprolin zinc finger domain. zfs1 has been linked to pheromone signal transduction control and to the coordination of mitosis, but no biological function has been ascribed to the zfs1 protein. Through a functional genomics approach we compared transcript levels in wild-type and zfs1-deficient S. pombe strains; those elevated in the zfs1-deficient strain were examined for the presence of potential tristetraprolin-like binding sites. One such potential target transcript was encoded by arz1, a gene encoding a protein of unknown function that contains armadillo repeats. arz1 mRNA decay was inhibited in the zfs1-deficient strain when it was expressed under the control of a thiamine-repressible promoter. Mutations within one AU-rich element present in the arz1 3′-untranslated region protected this transcript from zfs1-promoted decay, whereas mutating another potential binding site had no effect. Binding assays confirmed a direct interaction between zfs1 and arz1 mRNA-based probes; this interaction was eliminated when key residues were mutated in either zfs1 zinc finger. zfs1 and its targets in S. pombe represent a useful model system for studies of zinc finger protein/AU-rich element interactions that result in mRNA decay.
Teaching English to young learners in Osijek

The question of an optimal age for foreign language learning has been in the focus of interest of both linguists and educationalists for a long time. The fact that young children when exposed to a language in a natural environment acquire it with almost no effort to a high degree of fluency influenced the spread of the view that an early start of foreign language learning in a classroom setting could also be advantageous. With the development of psychology and psycholinguistics many empirical studies were undertaken in all parts of the world, based on the hypothesis that young children are better language learners than older children and adults. In spite of systematic research the question of optimal age for foreign language learning has not yet been answered. However, in many countries the introduction of a foreign language in the early school years has been seriously considered. Early foreign language learning projects are still in progress. Very often they are obstructed by difficulties. Some of these projets and the problems related to them are discussed in this paper