Miracle-dz/UniFAR-FTUs huggingface dataset:
Us Versus Them

Intergroup competition makes social identity salient, which in turn affects how people respond to competitors’ hardships. The failures of an in-group member are painful, whereas those of a rival out-group member may give pleasure—a feeling that may motivate harming rivals. The present study examined whether valuation-related neural responses to rival groups’ failures correlate with likelihood of harming individuals associated with those rivals. Avid fans of the Red Sox and Yankees teams viewed baseball plays while undergoing functional magnetic resonance imaging. Subjectively negative outcomes (failure of the favored team or success of the rival team) activated anterior cingulate cortex and insula, whereas positive outcomes (success of the favored team or failure of the rival team, even against a third team) activated ventral striatum. The ventral striatum effect, associated with subjective pleasure, also correlated with self-reported likelihood of aggressing against a fan of the rival team (controlling for general aggression). Outcomes of social group competition can directly affect primary reward-processing neural systems, which has implications for intergroup harm.
Antigen-specific B-cell unresponsiveness induced by chronic Mycobacterium avium subsp. paratuberculosis infection of cattle.

Mycobacterium avium subsp. paratuberculosis infection of cattle results in a chronic granulomatous enteritis. Clinical disease (i.e., cachexia, diarrhea, and high fecal bacterial counts) is preceded by a lengthy subclinical stage of disease. The immunologic mechanisms associated with the progression of infected cattle from subclinical to clinical disease are unclear. In this study, a cell proliferation assay was used in combination with flow cytometry to compare peripheral blood lymphocyte responses of cattle with subclinical paratuberculosis to responses of cattle with clinical paratuberculosis. B cells from cattle with subclinical disease proliferated vigorously upon stimulation with M. avium subsp. paratuberculosis antigen, with up to 12.4% of the total B cells responding. However, B cells from cattle with clinical disease did not proliferate upon antigen stimulation despite good proliferation in response to concanavalin A stimulation. In addition, these animals had high percentages of peripheral blood B cells. B cells from noninfected animals did not proliferate upon M. avium subsp. paratuberculosis antigen stimulation. Thus, it appears that B-cell proliferation is a sensitive indicator of subclinical Johne's disease. Furthermore, the immunologic mechanisms responsible for the antigen-specific unresponsiveness of peripheral blood B cells may be significant in the eventual progression from subclinical to clinical Johne's disease in cattle.
Hexokinase 2‐dependent hyperglycolysis driving microglial activation contributes to ischemic brain injury

Hyperglycolysis, observed within the penumbra zone during brain ischemia, was shown to be detrimental for tissue survival because of lactate accumulation and reactive oxygen species overproduction in clinical and experimental settings. Recently, mounting evidence suggests that glycolytic reprogramming and induced metabolic enzymes can fuel the activation of peripheral immune cells. However, the possible roles and details regarding hyperglycolysis in neuroinflammation during ischemia are relatively poorly understood. Here, we investigated whether overactivated glycolysis could activate microglia and identified the crucial regulators of neuroinflammatory responses in vitro and in vivo. Using BV 2 and primary microglial cultures, we found hyperglycolysis and induction of the key glycolytic enzyme hexokinase 2 (HK2) were essential for microglia‐mediated neuroinflammation under hypoxia. Mechanistically, HK2 up‐regulation led to accumulated acetyl‐coenzyme A, which accounted for the subsequent histone acetylation and transcriptional activation of interleukin (IL)‐1β. The inhibition and selective knockdown of HK2 in vivo significantly protected against ischemic brain injury by suppressing microglial activation and IL‐1β production in male Sprague–Dawley rats subjected to transient middle cerebral artery occlusion (MCAo) surgery. We provide novel insights for HK2 specifically serving as a neuroinflammatory determinant, thus explaining the neurotoxic effect of hyperglycolysis and indicating the possibility of selectively targeting HK2 as a therapeutic strategy in acute ischemic stroke.
Utility of B-13 Progenitor-Derived Hepatocytes in Hepatotoxicity and Genotoxicity Studies

AR42J-B-13 (B-13) cells form hepatocyte-like (B-13/H) cells in response to glucocorticoid treatment. To establish its utility in toxicity and genotoxicity screening, cytochrome P450 (CYP) induction, susceptibility to toxins, and transporter gene expression were examined. Conversion to B-13/H cells resulted in expression of male-specific CYP2C11 and sensitivity to methapyrilene. B-13/H cells constitutively expressed CYP1A, induced expression in response to an aryl hydrocarbon receptor agonist, and activated benzo[α]pyrene to a DNA-damaging species. Functional CYP1A2 was not expressed due to deletions in the Cyp1a2 gene. A B-13 cell line stably expressing the human CYP1A2 was therefore engineered (B-13−TR/h1A2) and the derived B-13/H cells expressed metabolically functional CYP1A2. Treatment with the cooked food mutagen 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine resulted in a dose-dependent increase in DNA damage. B-13/H cells expressed constitutive androstane receptor (CAR) and induced CYP2B1 mRNA levels in response to classical CAR activators. However, translation to functional CYP2B1 protein was low and increased minimally by CAR activator treatment. B-13/H cells expressed high levels of pregnane X-receptor (PXR) and induced CYP3A1 in response to classical PXR activators. CYP3A genes were inducible, functional, and activated aflatoxin B1 to a DNA-damaging species. All 23 major hepatic transporters were induced when B-13 cells were converted to B-13/H cells, although in many cases, levels remained below those present in adult rat liver. However, bile salt export pump, Abcb1b, multidrug resistance-associated protein, and breast cancer resistance protein transporters were functional in B-13/H cells. These data demonstrate that the B-13 cell generates hepatocyte-like cells with functional drug metabolism and transporter activities, which can alone—or in a humanized form—be used to screen for hepatotoxic and genotoxic endpoints in vitro.
The Human Gonadotropin Releasing Hormone Type I Receptor Is a Functional Intracellular GPCR Expressed on the Nuclear Membrane

The mammalian type I gonadotropin releasing hormone receptor (GnRH-R) is a structurally unique G protein-coupled receptor (GPCR) that lacks cytoplasmic tail sequences and displays inefficient plasma membrane expression (PME). Compared to its murine counterparts, the primate type I receptor is inefficiently folded and retained in the endoplasmic reticulum (ER) leading to a further reduction in PME. The decrease in PME and concomitant increase in intracellular localization of the mammalian GnRH-RI led us to characterize the spatial distribution of the human and mouse GnRH receptors in two human cell lines, HEK 293 and HTR-8/SVneo. In both human cell lines we found the receptors were expressed in the cytoplasm and were associated with the ER and nuclear membrane. A molecular analysis of the receptor protein sequence led us to identify a putative monopartite nuclear localization sequence (NLS) in the first intracellular loop of GnRH-RI. Surprisingly, however, neither the deletion of the NLS nor the addition of the Xenopus GnRH-R cytoplasmic tail sequences to the human receptor altered its spatial distribution. Finally, we demonstrate that GnRH treatment of nuclei isolated from HEK 293 cells expressing exogenous GnRH-RI triggers a significant increase in the acetylation and phosphorylation of histone H3, thereby revealing that the nuclear-localized receptor is functional. Based on our findings, we conclude that the mammalian GnRH-RI is an intracellular GPCR that is expressed on the nuclear membrane. This major and novel discovery causes us to reassess the signaling potential of this physiologically and clinically important receptor.
Population Genetic History of Aristeus antennatus (Crustacea: Decapoda) in the Western and Central Mediterranean Sea

Aristeus antennatus is an ecologically and economically important deep-water species in the Mediterranean Sea. In this study we investigated the genetic variability of A. antennatus sampled from 10 sampling stations in the Western and Central Mediterranean. By comparing our new samples with available data from the Western area, we aim to identify potential genetic stocks of A. antennatus and to reconstruct its historical demography in the Mediterranean. We analyzed two regions of mitochondrial DNA in 319 individuals, namely COI and 16S. We found two main results: i) the genetic diversity values consistent with previous data within the Mediterranean and the absence of barriers to gene flow within the Mediterranean Sea; ii) a constant long-term effective population size in almost all demes but a strong signature of population expansion in the pooled sample about 50,000 years B.P./ago. We propose two explanation for our results. The first is based on the ecology of A. antennatus. We suggest the existence of a complex meta-population structured into two layers: a deeper-dwelling stock, not affected by fishing, which preserves the pattern of historical demography; and genetically homogeneous demes inhabiting the fishing grounds. The larval dispersal, adult migration and continuous movements of individuals from "virgin" deeper grounds not affected by fishing to upper fishing areas support an effective 'rescue effect' contributing to the recovery of the exploited stocks and explain their genetic homogeneity throughout the Mediterranean Sea. The second is based on the reproduction model of this shrimp: the high variance in offspring production calls for a careful interpretation of the data observed under classical population genetics and Kingman's coalescent. In both cases, management policies for A. antennatus will therefore require careful evaluation of the meta-population dynamics of all stocks in the Mediterranean. In the future, it will be particularly relevant to sample the deepest ones directly.
Vascular Protective Effects of Angiotensin Converting Enzyme Inhibitors and their Relation to Clinical Events

Summary: Endothelial cells are a rich source of a variety of vasoactive substances, which either cause vasodilation or vasoconstriction. Important endothelium‐derived vasodilators are prostacyclin, bradykinin, nitric oxide and endothelium‐derived hyperpolarizing factor. In particular, nitric oxide inhibits cellular growth and migration. In concert with prostacyclin, nitric oxide exerts potent anti‐atherogenic and thromboresistant properties by preventing platelet aggregation and cell adhesion. Endotheliumderived contracting factors include the 21 amino acid peptide endothelin (ET), vasoconstrictor prostanoids such as thromboxane A2 and prostaglandin H2, as well as free radicals and components of the renin angiotensin system. In hypertension, elevated blood pressure transmits into cardiovascular disease by causing endothelial dysfunction. Hence, modern therapeutic strategies in human hypertension focus on preserving or restoring endothelial integrity. Angiotensin converting enzyme (ACE) inhibitors are a primary candidate for that concept as they inhibit the circulating and local renin angiotensin system. Angiotensin converting enzyme is an endothelial enzyme which converts angiotensin‐I (A‐I) into angiotensin‐II (A‐II). This effect of the ACE inhibitor prevents direct effects of angiotensin‐II such as vasoconstriction and proliferation in the vessel wall but also prevents activation of the ET system and of plasminogen activator inhibitor. Furthermore, inhibition of ACE prolongs the half‐life of bradykinin and stabilizes bradykinin receptors linked to the formation of nitric oxide and prostacyclin. In isolated arteries ACE inhibitors prevent the contractions induced by angiotensin II and enhance relaxation induced by bradykinin. Chronic treatment of experimental hypertension with ACE inhibitors normalizes endothelium‐dependent relaxation to acetylcholine and other agonists. In addition, the dilator effects of exogenous nitric oxide donors are enhanced, at least in certain models of hypertension. In humans with essential hypertension ACE inhibitors augment endothelium‐dependent relaxation to bradykinin, while those to acetylcholine remain unaffected, at least in the time frame of the published studies, i.e. 3‐6 months. In patients with coronary artery disease, however, paradoxical vasoconstriction to acetylcholine is markedly reduced after 6 months of ACE inhibition. After myocardial infarction ACE inhibitors reduce the development of overt heart failure, the occurrence of reinfarction and cardiovascular death in hypertensive patients. These effects have also been demonstrated in a subgroup analysis of the SOLVD (Studies of Left Ventricular Dysfunction) trial. Thus, in summary, ACE inhibitors are an important class of drugs providing cardiovascular protection in patients with increased cardiovascular risk.
Stimulus Competition by Inhibitory Interference

When two stimuli are present in the receptive field of a V4 neuron, the firing rate response is between the weakest and strongest response elicited by each of the stimuli when presented alone (Reynolds, Chelazzi, & Desimone, 1999). When attention is directed toward the stimulus eliciting the strongest response (the preferred stimulus), the response to the pair is increased, whereas the response decreases when attention is directed to the other stimulus (the poor stimulus). When attention is directed to either of the two stimuli presented alone, the firing rate remains the same or increases slightly, but the coherence between the neuron's spike train and the local field potential can increase (Fries, Reynolds, Rorie, & Desimone, 2001). These experimental results were reproduced in a model of a V4 neuron under the assumption that attention modulates the activity of local interneuron networks. The V4 model neuron received stimulus-specific excitation from V2 and synchronous inhibitory inputs from two local interneuron networks in V4. Each interneuron network was driven by stimulus-specific excitatory inputs from V2 and was modulated by the activity of the frontal eye fields. Stimulus competition was present because of a delay in arrival time of synchronous volleys from each interneuron network. For small delays, the firing rate was close to the rate elicited by the preferred stimulus alone, whereas for larger delays, it approached the firing rate of the poor stimulus. When either stimulus was presented alone, the neuron's response was not altered by the change in delay, but could change due to modulation of the degree of synchrony of the corresponding interneuron network. The model suggests that top-down attention biases the competition between V2 columns for control of V4 neurons primarily by changing the relative timing of inhibition, whereas changes in the degree of synchrony of interneuron networks modulate the response to a single stimulus. The new mechanism proposed here for attentional modulation of firing rate, gain modulation by inhibitory interference, is likely to have more general applicability to cortical information processing.
Inferring causative variants in microRNA target sites

MicroRNAs (miRNAs) regulate genes post transcription by pairing with messenger RNA (mRNA). Variants such as single nucleotide polymorphisms (SNPs) in miRNA regulatory regions might result in altered protein levels and disease. Genome-wide association studies (GWAS) aim at identifying genomic regions that contain variants associated with disease, but lack tools for finding causative variants. We present a computational tool that can help identifying SNPs associated with diseases, by focusing on SNPs affecting miRNA-regulation of genes. The tool predicts the effects of SNPs in miRNA target sites and uses linkage disequilibrium to map these miRNA-related variants to SNPs of interest in GWAS. We compared our predicted SNP effects in miRNA target sites with measured SNP effects from allelic imbalance sequencing. Our predictions fit measured effects better than effects based on differences in free energy or differences of TargetScan context scores. We also used our tool to analyse data from published breast cancer and Parkinson's disease GWAS and significant trait-associated SNPs from the NHGRI GWAS Catalog. A database of predicted SNP effects is available at http://www.bigr. medisin.ntnu. no/mirsnpscore/. The database is based on haplotype data from the CEU HapMap population and miRNAs from miRBase 16.0.
Dietary modification of inflammation with lipids

The n-3 polyunsaturated fatty acids (PUFA) eicosapentaenoic acid (EPA) and docosahexaenoicacid (DHA) are found in high proportions in oily fish and fish oils. The n-3 PUFA are structurally and functionally distinct from the n-6 PUFA. Typically, human inflammatory cells contain high proportions of the n-6 PUFA arachidonic acid and low proportions of n-3 PUFA. The significance of this difference is that arachidonic acid is the precursor of 2-series prostaglandins and 4-series leukotrienes, which are highly-active mediators of inflammation. Feeding fish oil results in partial replacement of arachidonic acid in inflammatory cell membranes by EPA. This change leads to decreased production of arachidonic acid-derived mediators. This response alone is a potentially beneficial anti-inflammatory effect of n-3 PUFA. However, n-3 PUFA have a number of other effects which might occur downstream of altered eicosanoid production or might be independent of this activity. For example, animal and human studies have shown that dietary fish oil results in suppressed production of pro-inflammatory cytokines and can decrease adhesion molecule expression. These effects occur at the level of altered gene expression. This action might come about through antagonism of the effects of arachidonic acid-derived mediators or through more direct actions on the intracellular signalling pathways which lead to activation of transcription factors such as nuclear factor kappa B (NFêB). Recent studies have shown that n-3 PUFA can down regulate the activity of the nuclear transcription factor NFêB. Fish oil feeding has been shown to ameliorate the symptoms in some animal models of chronic inflammatory disease and to protect against the effects of endotoxin and similar inflammatory challenges. Clinical studies have reported that oral fish oil supplementation has beneficial effects in rheumatoid arthritis and among some patients with asthma, supporting the idea that the n-3 PUFA in fish oil are antiinflammatory. There are indications that inclusion of n-3 PUFA in enteral and parenteral formulas might be beneficial to patients in intensive care or post-surgery.
Protective Effect of IL-18 on Kainate- and IL-1β-Induced Cerebellar Ataxia in Mice1

The pathogenesis of sporadic cerebellar ataxia remains unknown. In this study, we demonstrate that proinflammatory cytokines, IL-18 and IL-1β, reciprocally regulate kainate-induced cerebellar ataxia in mice. We show that systemic administration of kainate activated IL-1β and IL-18 predominantly in the cerebellum of mice, which was accompanied with ataxia. Mice deficient in caspase-1, IL-1R type I, or MyD88 were resistant to kainate-induced ataxia, while IL-18- or IL-18R α-deficient mice displayed significant delay of recovery from ataxia. A direct intracerebellar injection of IL-1β-induced ataxia and intracerebellar coinjection of IL-18 counteracted the effect of IL-1β. Our data firstly show that IL-18 and IL-1β display differential direct regulation in kainate-induced ataxia in mice. Our results might contribute toward the development of a new therapeutic strategy for cerebellar ataxia in humans.
A Latent Variable Model of Synchronous Parsing for Syntactic and Semantic Dependencies

We propose a solution to the challenge of the CoNLL 2008 shared task that uses a generative history-based latent variable model to predict the most likely derivation of a synchronous dependency parser for both syntactic and semantic dependencies. The submitted model yields 79.1% macro-average F1 performance, for the joint task, 86.9% syntactic dependencies LAS and 71.0% semantic dependencies F1. A larger model trained after the deadline achieves 80.5% macro-average F1, 87.6% syntactic dependencies LAS, and 73.1% semantic dependencies F1.
Influence of Aerobic Training and Detraining on Serum BDNF, Insulin Resistance, and Metabolic Risk Factors in Middle-Aged Men Diagnosed With Metabolic Syndrome

Objective:To study the influence of aerobic exercise training on brain-derived neurotrophic factor (BDNF), insulin resistance, and lipid profile in middle-aged men diagnosed with metabolic syndrome (MetS). Design:This is an experimental repeated measure study. Setting:Subjects participated in aerobic training programs (18 sessions of 25-40 minutes per session) in Guilan University gymnasium and court. Participants:A total of 21 middle-aged men (50-65 years old) diagnosed with MetS participated. Interventions:We randomly divided 21 middle-aged men with MetS into exercise and control groups. The exercise group followed an aerobic training program (18 sessions, 3/wk) at 50% to 60% of peak (25-40 minutes per session) and 6 weeks of detraining. Blood samples were collected at baseline, end of the training, and detraining. Main Outcome Measures:High BDNF level in patients with MetS and its reduction after chronic aerobic exercise. Results:Aerobic training significantly decreased all the metabolic risk factors, including overall MetS z score, insulin resistance, and lipid profile (P < 0.05). After the detraining period, plasma triglyceride, high-density lipoprotein, and also overall MetS z score remained unchanged (P < 0.05); however, serum BDNF, which was decreased by aerobic training (P = 0.013), restored to the baseline at the end of the detraining (P = 0.018). Conclusions:Improved metabolic risk factors along with decreased serum BDNF in response to aerobic training and the opposite direction during the detraining emphasize the importance of physical activity in the treatment of MetS and prevention of related diseases.