Miracle-dz/UniFAR-FTUs huggingface dataset:
Partial lipodystrophy and insulin resistant diabetes in a patient with a homozygous nonsense mutation in CIDEC

Lipodystrophic syndromes are characterized by adipose tissue deficiency. Although rare, they are of considerable interest as they, like obesity, typically lead to ectopic lipid accumulation, dyslipidaemia and insulin resistant diabetes. In this paper we describe a female patient with partial lipodystrophy (affecting limb, femorogluteal and subcutaneous abdominal fat), white adipocytes with multiloculated lipid droplets and insulin‐resistant diabetes, who was found to be homozygous for a premature truncation mutation in the lipid droplet protein cell death‐inducing Dffa‐like effector C (CIDEC) (E186X). The truncation disrupts the highly conserved CIDE‐C domain and the mutant protein is mistargeted and fails to increase the lipid droplet size in transfected cells. In mice, Cidec deficiency also reduces fat mass and induces the formation of white adipocytes with multilocular lipid droplets, but in contrast to our patient, Cidec null mice are protected against diet‐induced obesity and insulin resistance. In addition to describing a novel autosomal recessive form of familial partial lipodystrophy, these observations also suggest that CIDEC is required for unilocular lipid droplet formation and optimal energy storage in human fat.
Vitamin D Receptor Polymorphism and Breast Cancer Risk

AbstractThe objective was to perform a meta-analysis to summarize the available evidence from prospective nested case-control studies on the association of vitamin D receptor (VDR) polymorphism and the risk of breast cancer.We searched PubMed, ISI web of science, EMBASE, and reference lists for included articles. Study specific odds ratios (ORs) and 95% confidence intervals (CIs) were pooled by using fixed-effect or random-effects models.Eight studies were included in the meta-analysis. There were no association between Fok1 gene allele contrast f versus F (OR: 0.859; 95%CI: 0.685–1.079), ff versus FF (OR: 0.893; 95%CI: 0.763–1.045), recessive models ff versus FF+Ff (OR: 0.932; 95%CI: 0.796–1.092), and dominant models ff+Ff versus FF (OR: 0.899; 95%CI: 0.780–1.037). The estimated VDR polymorphism showed no significant association between Bsm1, Taq1, Apa1 polymorphism, and breast cancer risk. In the Caucasian ethnic subgroup, no association was found between allele contrast, recessive models, and dominant models on Fok1, Bsm1 polymorphism, and breast cancer risk.VDR polymorphism (Fok1, Bsm1, Taq1, and Apa1) were not associated with the risk of breast cancer in the general population as well as Caucasian population.
Typological and developmental considerations on specific language impairment in monolingual and bilingual children: A Processability Theory account

ABSTRACT This article suggests a method to deal with cross-linguistic differences in children with Specific Language Impairment. The differences in vulnerable structures reflect typological properties of the surrounding language (e.g., Leonard 2014a, 2014b). This article adds a developmental perspective to the discussion by interpreting the vulnerable structures through the framework of Processability Theory (PT; Pienemann 1998, 2015) and placing them along a developmental continuum. Studies focusing on production of grammatical structures in children with SLI from 19 different language backgrounds are examined. The results of the analyses suggest that the major grammatical problems in children with SLI belong to the later stages of the PT hierarchy. PT gives an alternative interpretation to earlier accounts by offering a developmental perspective and a metric that allows us to measure both languages in bilingual children.
Mechanisms of Nrf2 Protection in Astrocytes as Identified by Quantitative Proteomics and siRNA Screening

The Nrf2 (NF-E2 related factor 2)-ARE (antioxidant response element) pathway controls a powerful array of endogenous cellular antioxidant systems and is an important pathway in the detoxification of reactive oxygen species (ROS) in the brain. Using a combination of quantitative proteomics and siRNA screening, we have identified novel protective mechanisms of the Nrf2-ARE pathway against oxidative stress in astrocytes. Studies from our lab and others have shown Nrf2 overexpression protects astrocytes from oxidative stress. However, the exact mechanisms by which Nrf2 elicits these effects are unknown. In this study, we show that induction of Nrf2 reduces levels of reactive oxygen species (ROS) produced by various oxidative stressors and results in robust cytoprotection. To identify the enzymes responsible for these effects, we used stable isotope labeling by amino acids in cell culture (SILAC) and quantitative shotgun proteomics to identify 72 Nrf2-regulated proteins in astrocytes. We hypothesized a subset of these proteins might play a critical role in Nrf2 protection. In order to identify these critical proteins, we used bioinformatics to narrow our target list of proteins and then systematically screened each candidate with siRNA to assess the role of each in Nrf2 protection. We screened each target against H2O2, tert-butyl hydroperoxide, and 4-hydroxynonenal and subsequently identified three enzymes–catalase, prostaglandin reductase-1, and peroxiredoxin-6–that are critical for Nrf2-mediated protection in astrocytes.
HUBBLE SPACE TELESCOPE WFC3 GRISM SPECTROSCOPY AND IMAGING OF A GROWING COMPACT GALAXY AT z = 1.9

We present HST/WFC3 grism near-IR spectroscopy of the brightest galaxy at z > 1.5 in the GOODS-South WFC3 ERS grism pointing. The spectrum is of remarkable quality and shows the redshifted Balmer lines Hβ, Hγ, and Hδ in absorption at z = 1.902 ± 0.002. The absorption lines can be produced by a post-starburst stellar population with a luminosity-weighted age of ≈0.5 Gyr. The mass-to-light ratio inferred from the spectrum implies a stellar mass of (4 ± 1) × 1011 M☉. We determine the morphology of the galaxy from a deep WFC3 H160 image. Similar to other massive galaxies at z ∼ 2 the galaxy is compact, with an effective radius of 2.1 ± 0.3 kpc. Although most of the light is in a compact core, the galaxy has two red, smooth spiral arms that appear to be tidally induced. The spatially resolved spectroscopy demonstrates that the center of the galaxy is quiescent whereas the surrounding disk is forming stars, as it shows Hβ in emission. The galaxy interacts with a companion at a projected distance of 18 kpc, which also shows prominent tidal features. The companion is a factor of ∼10 fainter than the primary galaxy and may have a lower metallicity. It is tempting to interpret these observations as evidence for the growth of compact, quiescent high-redshift galaxies through minor mergers, which has been proposed by several recent observational and theoretical studies. Interestingly both objects host luminous active galactic nuclei, which implies that these mergers can be accompanied by significant black hole growth.
Differential effects of caspase inhibitors on endotoxin-induced myocardial dysfunction and heart apoptosis.

Endotoxin is one of the major factors causing myocardial depression and death during sepsis in humans. Recently, it was reported that endotoxin may induce cardiomyocyte apoptosis. Also, multiple caspase activation has been implicated in endotoxin-induced apoptosis in several organ systems. In this study, we investigated whether endotoxin would increase myocardial caspase activities and evaluated the effects of in vivo administration (3 mg/kg) of the broad-spectrum caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone(z-VAD.fmk), the caspase-3-like inhibitor benzyloxycarbonyl-Asp-Glu-Val-Asp-chloromethylketone (z-DEVD.cmk), and the caspase-1-like inhibitor acetyl-Tyr-Val-Ala-Asp-chloromethylketone (Ac-YVAD. fmk), on endotoxin-induced myocardial dysfunction and apoptosis. Endotoxin administration (10 mg/kg iv) induced myocardial contractile dysfunction that was associated with caspase activity increases and nuclear apoptosis. Broad-spectrum z-VAD.fmk and z-DEVD.cmk improved endotoxin-induced myocardial dysfunction and reduced caspase activation and nuclear apoptosis when given immediately and 2 h after endotoxin. In contrast, no effects of Ac-YVAD.fmk were observed on myocardial function and caspase-induced apoptosis. Administration of caspase inhibitors 4 h after endotoxin treatment was not able to protect the rat heart from myocardial dysfunction and nuclear apoptosis. These observations provide evidence that in our model, caspase activation plays a role in endotoxin-induced myocardial apoptosis. Caspase inhibition strategy may represent a therapeutic approach to endotoxin-induced myocardial dysfunction.
Issues and Strategies in Treating Refractory Obsessive-Compulsive Disorder

The World Health Organization has determined that obsessive-compulsive disorder (OCD) is the 10th leading medical cause of disability across the globe. Unfortunately, a substantial proportion of patients with OCD fail to respond to medication trials. In the pivotal double-blind, placebo-controlled trials that established the efficacy of clomipramine and the selective serotonin reuptake inhibitors (SSRIs), 40% to 60% of patients were nonresponders to a given drug. Moreover, patients who do not respond to their first medication trial may be less likely than treatment-naive patients to respond to subsequent trials. For example, only 33% of patients participating in double-blind trials who had failed trials of one or more serotonin reuptake inhibitors (SRIs) benefited from a subsequent trial of sertra-line, compared with 53% of those who were treatment naive (Rasmussen, Baer, Eisen, and Shera, unpublished data, 15th Annual Meeting, American Psychiatric Association, May 17-22, 1997). At the Fourth International Obsessive-Compulsive Disorder Conference, held in February 2000 in St. Thomas, US Virgin Islands, an afternoon panel was devoted to considering issues and strategies related to treatment-refractory OCD. The panel presentations were divided into three groups: time to response and outcome after long-term followup; pharmacologic strategies for nonresponders; and new data concerning nonpharmacologic interventions.
Duplicate Detection in Biological Data using Association Rule Mining

Recent advancement in biotechnology has produced a massive amount of raw biological data which are accumulating at an exponential rate. Errors, redundancy and discrepancies are prevalent in the raw data, and there is a serious need for systematic approaches towards biological data cleaning. This work examines the extent of redundancy in biological data and proposes a method for detecting duplicates in biological data. Duplicate relations in a real-world biological dataset are modeled into forms of association rules so that these duplicate relations or rules can be induced from data with known duplicates using association rule mining. Our approach of using association rule induction to find duplicate relations is new. Evaluation of our method on a real-world dataset shows that our duplicate association rules can accurately identify up to 96.8% of the duplicates in the dataset at the accuracy of 0.3% false positives and 0.0038% false negatives.
Lifetime fitness consequences of early‐life ecological hardship in a wild mammal population

Abstract Early‐life ecological conditions have major effects on survival and reproduction. Numerous studies in wild systems show fitness benefits of good quality early‐life ecological conditions (“silver‐spoon” effects). Recently, however, some studies have reported that poor‐quality early‐life ecological conditions are associated with later‐life fitness advantages and that the effect of early‐life conditions can be sex‐specific. Furthermore, few studies have investigated the effect of the variability of early‐life ecological conditions on later‐life fitness. Here, we test how the mean and variability of early‐life ecological conditions affect the longevity and reproduction of males and females using 14 years of data on wild banded mongooses (Mungos mungo). Males that experienced highly variable ecological conditions during development lived longer and had greater lifetime fitness, while those that experienced poor early‐life conditions lived longer but at a cost of reduced fertility. In females, there were no such effects. Our study suggests that exposure to more variable environments in early life can result in lifetime fitness benefits, whereas differences in the mean early‐life conditions experienced mediate a life‐history trade‐off between survival and reproduction. It also demonstrates how early‐life ecological conditions can produce different selection pressures on males and females.
The effect of information and communication technologies, workplace re-organization and trade on the demand for employees' skills: A comparative analysis of Greek and Swiss enterprises

This paper aims at investigating empirically at the firm level the effect of the use of modern information and communication technologies (ICT), and also of two other factors, the adoption of new forms of workplace organization (which is regarded as a ‘complement’ of ICT), and trade (export) activities (a major characteristic of modern economy), on the demand for employees’ (vocational) education and skills. The study is based on firm-level data collected through a common questionnaire from firms’ samples of similar composition (concerning firm sizes and industries) in Greece and Switzerland; from these data econometric models of similar specification have been constructed for both countries. The results of multivariate analysis show that the intensive use of ICT correlates positively with the employment shares of high-educated personnel and negatively with the ones of the low-educated personnel. These findings are consistent with the hypothesis of ‘skill-biased technical change’. Further, the intensive use of “employee voice”-oriented organizational practices correlates positively with the employment shares of high-educated employees in both countries, and also negatively with the employment share of low-educated ones only for the Swiss firms. The results for the “work design” organizational practices are more ambiguous. Thus, there is only partial confirmation of the hypothesis of skilled-biased organizational change. Finally, we found some evidence in favour of the trade effect (export activities) only for the Swiss firms. Our results show both similarities and differences in the above aspects between Greece and Switzerland, and indicate that national context characteristics affect the relationship of the demand for employees’ (vocational) education and skills with ICT use, adoption of new forms of workplace organization and trade.
Protein composition of the hepatitis A virus quasi-envelope

Significance The nonlytic cellular egress of picornaviruses in extracellular vesicles is likely to be important in disease pathogenesis, but the mechanism(s) underlying this process and the origins of the membranes surrounding virions exiting the cell are poorly understood. We describe a quantitative proteomics analysis of quasi-enveloped hepatitis A virus (eHAV) virions that shows capsids are selected as cargo for vesicular export via a highly specific process, and that infectious eHAV virions possess a host protein complement similar to that of exosomes with CD9 and DPP4 displayed on their surface. eHAV-associated proteins are highly enriched for endolysosomal components and lack markers of autophagy, suggesting an exosome-like mechanism of endosomal sorting complex required for transport-mediated eHAV biogenesis involving endosomal budding that is distinct from the autophagosome-mediated release proposed previously for enteroviruses. The Picornaviridae are a diverse family of RNA viruses including many pathogens of medical and veterinary importance. Classically considered “nonenveloped,” recent studies show that some picornaviruses, notably hepatitis A virus (HAV; genus Hepatovirus) and some members of the Enterovirus genus, are released from cells nonlytically in membranous vesicles. To better understand the biogenesis of quasi-enveloped HAV (eHAV) virions, we conducted a quantitative proteomics analysis of eHAV purified from cell-culture supernatant fluids by isopycnic ultracentrifugation. Amino acid-coded mass tagging (AACT) with stable isotopes followed by tandem mass spectrometry sequencing and AACT quantitation of peptides provided unambiguous identification of proteins associated with eHAV versus unrelated extracellular vesicles with similar buoyant density. Multiple peptides were identified from HAV capsid proteins (53.7% coverage), but none from nonstructural proteins, indicating capsids are packaged as cargo into eHAV vesicles via a highly specific sorting process. Other eHAV-associated proteins (n = 105) were significantly enriched for components of the endolysosomal system (>60%, P < 0.001) and included many common exosome-associated proteins such as the tetraspanin CD9 and dipeptidyl peptidase 4 (DPP4) along with multiple endosomal sorting complex required for transport III (ESCRT-III)-associated proteins. Immunoprecipitation confirmed that DPP4 is displayed on the surface of eHAV produced in cell culture or present in sera from humans with acute hepatitis A. No LC3-related peptides were identified by mass spectrometry. RNAi depletion studies confirmed that ESCRT-III proteins, particularly CHMP2A, function in eHAV biogenesis. In addition to identifying surface markers of eHAV vesicles, the results support an exosome-like mechanism of eHAV egress involving endosomal budding of HAV capsids into multivesicular bodies.
Plasma Vasoprotective Eicosanoid Concentrations in Healthy Greyhounds and Non‐Greyhound Dogs

Background Hypertension and albuminuria often coexist in Greyhounds, suggesting generalized vascular dysfunction that could contribute to the development of a variety of diseases in this breed. Eicosanoid metabolites of arachidonic acid (AA) mediate endothelial function, vascular reactivity, and proteinuria in humans and in rodent models. Hypothesis The eicosanoid profile of Greyhounds is shifted toward metabolites that promote vascular dysfunction, hypertension, and proteinuria. Animals Healthy Greyhounds (n = 20) and non‐Greyhound (n = 20) dogs that were consecutively enrolled in a blood donor program. Methods Prospective study. Plasma eicosanoid metabolites were assayed by liquid chromatography/electrospray ionization mass spectrometry (LC/ESI/MS) and compared to systolic blood pressure (SP) measurements and urine albumin concentration. Results Isomers of hydroxyeicosatetraenoic acid (HETE) were higher in Greyhounds than non‐Greyhounds (median, range in pmol/mL: 5(S)HETE 19.82, 8.55–32.95 versus 13.54, 4.33–26.27, P = . 033; 8(S)HETE 9.39, 3.28–19.84 versus 5.80, 2.25–17.66, P = . 002; 9(S)HETE 9.46, 2.43–13.79 versus 5.82, 1.50–17.16, P = . 026; 12(S)HETE 10.17, 3.81–40.06 versus 7.24, 2.9–16.16, P = . 022). Dihydroxyeicosatrienoic acid (DHET) isomers also were higher in Greyhounds compared to non‐Greyhounds (mean ± SD in pmol/mL: 8,9DHET 5.78 ± 2.13 versus 4.03 ± 1.36, P = .004; 11,12DHET 11.98 ± 2.86 versus 8.90 ± 3.48, P = .004; 14,15DHET 7.23 ± 2.19 versus 5.76 ± 1.87, P = .028). Albuminuria correlated with total DHET (rs = 0.46, P = .003). SP was positively correlated with 11,12EET (rs = 0.42, P = .006) and 20(S)HETE (rs = 0.38, P = .017). SP and 8,9EET were inversely correlated (rs = −0.49, P = .001). Conclusions and Clinical Importance Plasma eicosanoid profile in Greyhounds was consistent with activation of metabolic pathways known to promote vascular dysfunction and might contribute to higher blood pressures and albuminuria. Inhibition of these eicosanoid pathways should be evaluated as therapeutic targets in Greyhounds.
Platelet Aggregometry Testing: Molecular Mechanisms, Techniques and Clinical Implications

Platelets play a fundamental role in normal hemostasis, while their inherited or acquired dysfunctions are involved in a variety of bleeding disorders or thrombotic events. Several laboratory methodologies or point-of-care testing methods are currently available for clinical and experimental settings. These methods describe different aspects of platelet function based on platelet aggregation, platelet adhesion, the viscoelastic properties during clot formation, the evaluation of thromboxane metabolism or certain flow cytometry techniques. Platelet aggregometry is applied in different clinical settings as monitoring response to antiplatelet therapies, the assessment of perioperative bleeding risk, the diagnosis of inherited bleeding disorders or in transfusion medicine. The rationale for platelet function-driven antiplatelet therapy was based on the result of several studies on patients undergoing percutaneous coronary intervention (PCI), where an association between high platelet reactivity despite P2Y12 inhibition and ischemic events as stent thrombosis or cardiovascular death was found. However, recent large scale randomized, controlled trials have consistently failed to demonstrate a benefit of personalised antiplatelet therapy based on platelet function testing.
Metabolism Is Central to Tolerogenic Dendritic Cell Function

Immunological tolerance is a fundamental tenant of immune homeostasis and overall health. Self-tolerance is a critical component of the immune system that allows for the recognition of self, resulting in hyporeactivity instead of immunogenicity. Dendritic cells are central to the establishment of dominant immune tolerance through the secretion of immunosuppressive cytokines and regulatory polarization of T cells. Cellular metabolism holds the key to determining DC immunogenic or tolerogenic cell fate. Recent studies have demonstrated that dendritic cell maturation leads to a shift toward a glycolytic metabolic state and preferred use of glucose as a carbon source. In contrast, tolerogenic dendritic cells favor oxidative phosphorylation and fatty acid oxidation. This dichotomous metabolic reprogramming of dendritic cells drives differential cellular function and plays a role in pathologies, such as autoimmune disease. Pharmacological alterations in metabolism have promising therapeutic potential.
Functional roles of an ERG current isolated in cerebellar Purkinje neurons.

Transcripts encoding ERG potassium channels are expressed by most neurons of the CNS. By patch-clamp whole cell recording from Purkinje neurons in slices of young (5-9 days old) mouse cerebellum we have been able to isolate a tail current [IK(ERG)] with the same characteristics as previously described for ERG channels. In zero external Ca2+ and high K+ (40 mM) the V1/2 of activation was -50.7 mV, the V1/2 of inactivation was -70.6 mV, and the deactivation rate was double exponential and voltage dependent. IK(ERG) was 93.0% blocked by WAY-123,398 (1 microM) and 78.2% by haloperidol (2 microM). The role of IK(ERG) on evoked firing was studied in adult mice, where WAY-123,398 application decreased the first spike latency, increased the firing frequency, and suppressed the frequency adaptation. However, the shape of individual action potentials was not affected. Stimulation of presynaptic climbing fibers evoked the Purkinje neuron "complex spike," composed of an initial spike and several spikelets. IK(ERG) block caused an increase of the number of spikelets of the "complex spike. " These data show, for the first time, an IK(ERG) in a neuron of the CNS, the cerebellar Purkinje neuron, and indicate that such a current is involved in the control of membrane excitability, firing frequency adaptation, and in determining the effects of the climbing fiber synapse.