Miracle-dz/UniFAR-FTUs huggingface dataset:
Secreted protein acidic and rich in cysteine (SPARC) induces lipotoxicity in neuroblastoma by regulating transport of albumin complexed with fatty acids

SPARC is a matrix protein that mediates interactions between cells and the microenvironment. In cancer, SPARC may either promote or inhibit tumor growth depending upon the tumor type. In neuroblastoma, SPARC is expressed in the stromal Schwannian cells and functions as a tumor suppressor. Here, we developed a novel in vivo model of stroma-rich neuroblastoma using non-tumorigenic SHEP cells with modulated levels of SPARC, mixed with tumorigenic KCNR cells. Tumors with stroma-derived SPARC displayed suppressed growth, inhibited angiogenesis and increased lipid accumulation. Based on the described chaperone function of SPARC, we hypothesized that SPARC binds albumin complexed with fatty acids and transports them to tumors. We show that SPARC binds albumin with Kd=18.9±2.3 uM, and enhances endothelial cell internalization and transendothelial transport of albumin in vitro. We also demonstrate that lipids induce toxicity in neuroblastoma cells and show that lipotoxicity is increased when cells are cultured in hypoxic conditions. Studies investigating the therapeutic potential of SPARC are warranted.
Classification of GPCRs Using Family Specific Motifs

The classification of G-Protein Coupled Receptor (GPCR) sequences is an important problem that arises from the need to close the gap between the large number of orphan receptors and the relatively small number of annotated receptors. Equally important is the characterization of GPCR Class A subfamilies and gaining insight into the ligand interaction since GPCR Class A encompasses a very large number of drug-targeted receptors. In this work, we propose a method for Class A subfamily classification using sequence-derived motifs which characterizes the subfamilies by discovering receptor-ligand interaction sites. The motifs that best characterize a subfamily are selected by the Distinguishing Power Evaluation (DPE) technique we propose. The experiments performed on GPCR sequence databases show that our method outperforms state-of-the-art classification techniques for GPCR Class A subfamily prediction. An important contribution of our work is to discover key receptor-ligand interaction sites which is very important for drug design.
Intraindividual Variability in Inhibitory Function in Adults with ADHD – An Ex-Gaussian Approach

Objective Attention deficit disorder (ADHD) is commonly associated with inhibitory dysfunction contributing to typical behavioral symptoms like impulsivity or hyperactivity. However, some studies analyzing intraindividual variability (IIV) of reaction times in children with ADHD (cADHD) question a predominance of inhibitory deficits. IIV is a measure of the stability of information processing and provides evidence that longer reaction times (RT) in inhibitory tasks in cADHD are due to only a few prolonged responses which may indicate deficits in sustained attention rather than inhibitory dysfunction. We wanted to find out, whether a slowing in inhibitory functioning in adults with ADHD (aADHD) is due to isolated slow responses. Methods Computing classical RT measures (mean RT, SD), ex-Gaussian parameters of IIV (which allow a better separation of reaction time (mu), variability (sigma) and abnormally slow responses (tau) than classical measures) as well as errors of omission and commission, we examined response inhibition in a well-established GoNogo task in a sample of aADHD subjects without medication and healthy controls matched for age, gender and education. Results We did not find higher numbers of commission errors in aADHD, while the number of omissions was significantly increased compared with controls. In contrast to increased mean RT, the distributional parameter mu did not document a significant slowing in aADHD. However, subjects with aADHD were characterized by increased IIV throughout the entire RT distribution as indicated by the parameters sigma and tau as well as the SD of reaction time. Moreover, we found a significant correlation between tau and the number of omission errors. Conclusions Our findings question a primacy of inhibitory deficits in aADHD and provide evidence for attentional dysfunction. The present findings may have theoretical implications for etiological models of ADHD as well as more practical implications for neuropsychological testing in aADHD.
Potential benefits of statins on morbidity and mortality in chronic obstructive pulmonary disease: a review of the evidence

Studies show reduced forced expiratory volume in 1 s (FEV1) in patients with chronic obstructive pulmonary disease (COPD) is an important independent predictor of cardiovascular death and is characterised by both pulmonary and systemic inflammation. Evidence shows statins have important anti-inflammatory effects in both the lungs and arteries. Although randomised control trials are yet to be reported, non-randomised studies have consistently shown benefit in COPD patients taking statins compared with those not. These include reductions in both cardiovascular and respiratory morbidity/mortality. Other potential benefits include a reduced decline in FEV1 and reduced risk of lung cancer. It is argued that confounding by a “healthy user effect” is unlikely to explain the observed benefit. Given the undisputed benefit of statins in high risk populations and the growing body of data suggesting statins may benefit patients with COPD, the question arises “Should statins be considered more often in patients with COPD? ”.
Quantum compositeness of gravity: black holes, AdS and inflation

Gravitational backgrounds, such as black holes, AdS, de Sitter and inflationary universes, should be viewed as composite of N soft constituent gravitons. It then follows that such systems are close to quantum criticality of graviton Bose-gas to Bose-liquid transition. Generic properties of the ordinary metric description, including geodesic motion or particle-creation in the background metric, emerge as the large-N limit of quantum scattering of constituent longitudinal gravitons. We show that this picture correctly accounts for physics of large and small black holes in AdS, as well as reproduces well-known inflationary predictions for cosmological parameters. However, it anticipates new effects not captured by the standard semi-classical treatment. In particular, we predict observable corrections that are sensitive to the inflationary history way beyond last 60 e-foldings. We derive an absolute upper bound on the number of e-foldings, beyond which neither de Sitter nor inflationary Universe can be approximated by a semi-classical metric. However, they could in principle persist in a new type of quantum eternity state. We discuss implications of this phenomenon for the cosmological constant problem.
Muscle Carnosine Is Associated with Cardiometabolic Risk Factors in Humans

Background Carnosine is a naturally present dipeptide abundant in skeletal muscle and an over-the counter food additive. Animal data suggest a role of carnosine supplementation in the prevention and treatment of obesity, insulin resistance, type 2 diabetes and cardiovascular disease but only limited human data exists. Methods and Results Samples of vastus lateralis muscle were obtained by needle biopsy. We measured muscle carnosine levels (high-performance liquid chromatography), % body fat (bioimpedance), abdominal subcutaneous and visceral adiposity (magnetic resonance imaging), insulin sensitivity (euglycaemic hyperinsulinemic clamp), resting energy expenditure (REE, indirect calorimetry), free-living ambulatory physical activity (accelerometers) and lipid profile in 36 sedentary non-vegetarian middle aged men (45±7 years) with varying degrees of adiposity and glucose tolerance. Muscle carnosine content was positively related to % body fat (r = 0.35, p = 0.04) and subcutaneous (r = 0.38, p = 0.02) but not visceral fat (r = 0.17, p = 0.33). Muscle carnosine content was inversely associated with insulin sensitivity (r = -0.44, p = 0.008), REE (r = -0.58, p<0.001) and HDL-cholesterol levels (r = -0.34, p = 0.048). Insulin sensitivity and physical activity were the best predictors of muscle carnosine content after adjustment for adiposity. Conclusion Our data shows that higher carnosine content in human skeletal muscle is positively associated with insulin resistance and fasting metabolic preference for glucose. Moreover, it is negatively associated with HDL-cholesterol and basal energy expenditure. Intervention studies targeting insulin resistance, metabolic and cardiovascular disease risk factors are necessary to evaluate its putative role in the prevention and management of type 2 diabetes and cardiovascular disease.
Robust Semantics for Argumentation Frameworks

We suggest a so-called `robust' semantics for a model of argumentation which represents arguments and their interactions, called `argumentation frameworks'. We study a variety of additional definitions of acceptability of arguments; we explore the properties of these definitions; we describe their interrelationships: e.g. robust models can be characterized using the minimal (well-founded) models of a meta-framework. The various definitions of acceptability of argument sets can all deal with contradiction within an argumentation framework.
Face affect recognition deficits in personality-disordered offenders: association with psychopathy

Background. There is a limited literature examining face affect recognition in offenders. In line with the Integrated Emotion Systems (IES) model, existing studies suggest a psychopathy-related deficit in sad/fear recognition. However, many of these studies have small samples, and few include a healthy control group in order to examine the contribution of criminality. Method. We compared the performance of male criminals with dissocial (antisocial) personality disorder (PD group) and healthy male IQ-matched controls, on a morphed face affect-processing task and examined the relationship between psychopathy (assessed using the Psychopathy Checklist: Screening Version, PCL: SV), score and performance on this task in the PD sample. Results. The PD group had a specific deficit in the recognition of sad facial affect that was present even at 100% expression intensity. This deficit could not be attributed to impulsive responding as the PD group generally had longer mean reaction times than healthy controls. Within the PD group, those with high scores on the PCL: SV were less accurate than low scorers at classifying sad facial affect. There was also a significant negative correlation between total psychopathy score and sad affect recognition accuracy. There were no specific relationships between affect recognition and the subcomponents of psychopathy. Conclusions. The findings suggest that criminality/antisocial personality may be associated with a deficit in the recognition of aversive cues in others, and that this deficit is more severe in psychopathic offenders. The findings lend further support to the IES model.
Chiral Plasma Pharmacokinetics and Urinary Excretion of Bupropion and Metabolites in Healthy Volunteers

Bupropion, widely used as an antidepressant and smoking cessation aid, undergoes complex metabolism to yield numerous metabolites with unique disposition, effect, and drug–drug interactions (DDIs) in humans. The stereoselective plasma and urinary pharmacokinetics of bupropion and its metabolites were evaluated to understand their potential contributions to bupropion effects. Healthy human volunteers (n = 15) were administered a single oral dose of racemic bupropion (100 mg), which was followed by collection of plasma and urine samples and determination of bupropion and metabolite concentrations using novel liquid chromatography–tandem mass spectrometry assays. Time-dependent, elimination rate–limited, stereoselective pharmacokinetics were observed for all bupropion metabolites. Area under the plasma concentration-time curve from zero to infinity ratios were on average approximately 65, 6, 6, and 4 and Cmax ratios were approximately 35, 6, 3, and 0.5 for (2R,3R)-/(2S,3S)-hydroxybupropion, R-/S-bupropion, (1S,2R)-/(1R,2S)-erythrohydrobupropion, and (1R,2R)-/(1S,2S)-threohydrobupropion, respectively. The R-/S-bupropion and (1R,2R)-/(1S,2S)-threohydrobupropion ratios are likely indicative of higher presystemic metabolism of S- versus R-bupropion by carbonyl reductases. Interestingly, the apparent renal clearance of (2S,3S)-hydroxybupropion was almost 10-fold higher than that of (2R,3R)-hydroxybupropion. The prediction of steady-state pharmacokinetics demonstrated differential stereospecific accumulation [partial area under the plasma concentration-time curve after the final simulated bupropion dose (300–312 hours) from 185 to 37,447 nM⋅h] and elimination [terminal half-life of approximately 7–46 hours] of bupropion metabolites, which may explain observed stereoselective differences in bupropion effect and DDI risk with CYP2D6 at steady state. Further elucidation of bupropion and metabolite disposition suggests that bupropion is not a reliable in vivo marker of CYP2B6 activity. In summary, to our knowledge, this is the first comprehensive report to provide novel insight into mechanisms underlying bupropion disposition by detailing the stereoselective pharmacokinetics of individual bupropion metabolites, which will enhance clinical understanding of bupropion’s effects and DDIs with CYP2D6.
Up-Regulation of Intestinal Epithelial Cell Derived IL-7 Expression by Keratinocyte Growth Factor through STAT1/IRF-1, IRF-2 Pathway

Background Epithelial cells(EC)-derived interleukin-7 (IL-7) plays a crucial role in control of development and homeostasis of neighboring intraepithelial lymphocytes (IEL), and keratinocyte growth factor (KGF) exerts protective effects on intestinal epithelial cells and up-regulates EC-derived IL-7 expression through KGFR pathway. This study was to further investigate the molecular mechanism involved in the regulation of IL-7 expression by KGF in the intestine. Methods Intestinal epithelial cells (LoVo cells) and adult C57BL/6J mice were treated with KGF. Epithelial cell proliferation was studied by flow cytometry for BrdU-incorporation and by immunohistochemistry for PCNA staining. Western blot was used to detect the changes of expression of P-Tyr-STAT1, STAT1, and IL-7 by inhibiting STAT1. Alterations of nuclear extracts and total proteins of IRF-1, IRF-2 and IL-7 following IRF-1 and IRF-2 RNA interference with KGF treatment were also measured with western blot. Moreover, IL-7 mRNA expressions were also detected by Real-time PCR and IL-7 protein level in culture supernatants was measured by enzyme linked immunosorbent assay(ELISA). Results KGF administration significantly increased LoVo cell proliferation and also increased intestinal wet weight, villus height, crypt depth and crypt cell proliferation in mice. KGF treatment led to increased levels of P-Tyr-STAT1, RAPA and AG490 both blocked P-Tyr-STAT1 and IL-7 expression in LoVo cells. IRF-1 and IRF-2 expression in vivo and in vitro were also up-regulated by KGF, and IL-7 expression was decreased after IRF-1 and IRF-2 expression was silenced by interfering RNA, respectively. Conclusion KGF could up-regulate IL-7 expression through the STAT1/IRF-1, IRF-2 signaling pathway, which is a new insight in potential effects of KGF on the intestinal mucosal immune system.
Spherical V-Fe-MCM-48: The Synthesis, Characterization and Hydrothermal Stability

Spherical MCM-48 mesoporous sieve co-doped with vanadium and iron was successfully synthesized via one-step hydrothermal method. The material was characterized by X-ray diffraction (XRD), nitrogen adsorption-desorption isotherms, inductively coupled plasma (ICP), scanning electron microscopy (SEM), transmission electron microscopy (TEM), diffuse reflectance UV-vis spectra, and X-ray photoelectron spectra (XPS) techniques. Results indicated that the V-Fe-MCM-48 showed an ordered 3D cubic mesostructure with spherical morphology, narrow pore size distribution and high specific surface area. Most of vanadium and iron atoms existing as tetrahedral V4+ and Fe3+ species were co-doped into the silicate framework. The particle sizes of V-Fe-MCM-48 were smaller and the specific area was much higher than those of of V-MCM-48. Additionally, the synthesized V-Fe-MCM-48 exhibited improved hydrothermal stability compared with the pure MCM-48.
Financial Innovation, Macroeconomic Stability and Systemic Crises

We present a general equilibrium model of intermediation designed to capture some of the key features of the modern financial system. The model incorporates financial constraints and state-contingent contracts, and captures the spillovers associated with asset fire sales during periods of stress. If a sufficiently severe shock occurs during a credit expansion, these spillovers can potentially generate a systemic financial crisis that may be self-fulfilling. Our model suggests that financial innovation and greater macroeconomic stability may have made financial crises in developed countries less likely than in the past, but potentially more severe.
Evidence for inducible nitric-oxide synthase expression and activity in vascular smooth muscle of streptozotocin-diabetic rats.

Experiments were performed to investigate whether nitric-oxide synthase (NOS) activity can be detected in vascular smooth muscle (VSM) from 12- to 14-week streptozotocin (STZ)-diabetic rats. Concentration-response curves to norepinephrine (NE) of superior mesenteric arteries from diabetic and age- and gender-matched control rats were obtained in the presence of dexamethasone (0.1 microM) to prevent in vitro induction of iNOS. Incubation of endothelium-intact arteries from diabetic rats with the nonselective NOS inhibitor, N(5)-(1-iminoethyl)L-ornithine (L-NIO) (300 microM), increased the NE sensitivity (expressed as the pD2 or -log EC50) from 6.58 +/- 0.05 to 8.39 +/- 0.12 (mean +/- S.E.M., n = 8). L-NIO produced a significantly smaller increase in the NE pD2 value in endothelium-intact arteries from control rats (from 6.51 +/- 0.03 to 7.08 +/- 0.03, p < 0.05). On endothelium removal, L-NIO still increased the NE pD2 value in diabetic arteries, from 7.48 +/- 0.03 to 8.38 +/- 0.15 (p < 0.05), but had no effect in control arteries. The selective iNOS inhibitor S-ethylisothiourea (EIT), but not the selective nNOS inhibitor 7-nitroindazole (7-NINA), produced an increase in the NE pD2 value in endothelium-denuded mesenteric arteries from diabetic but not control rats. Immunohistochemical staining indicated the presence of iNOS (but not eNOS or nNOS) in the medial and adventitial layers of mesenteric arteries from diabetic but not control rats. Quantitative measurement of cytosolic NOS activity indicated no significant calcium-dependent (nNOS) activity in control or diabetic arteries, or calcium-independent (iNOS) activity in control arteries. However, significant calcium-independent (iNOS) activity was detected in diabetic arteries. These data suggest that iNOS is functionally expressed in VSM of arteries from 12- to 14-week STZ-diabetic rats. The possible causes and consequences of the iNOS induction are discussed.
Clinical and Angiographic Outcomes From Indirect Revascularization Surgery for Moyamoya Disease in Adults and Children: A Review of 63 Procedures

BACKGROUND:Several forms of indirect cerebral revascularization have been proposed to promote neovascularity to the ischemic brain. OBJECTIVE:To present clinical and angiographic outcomes of indirect revascularization by encephaloduroarteriosynangiosis and burr holes for the treatment of Moyamoya disease in adults and children. METHODS:Data from 63 hemispheres treated in 42 patients (average age, 30 years; 33 adults; 30 female patients; median follow-up, 14 months) were reviewed. In hemispheres with preoperative and postoperative (6- to 12-month) angiograms available, superficial temporal artery (STA) and middle meningeal artery (MMA) diameters were measured. Preoperative and postoperative corrected arterial sizes were compared. RESULTS:Seven patients (17%) had transient ischemic attacks that resolved within 1 month of surgery. No patients suffered moyamoya-related hemorrhage after treatment. Two patients developed additional symptoms many years after surgery. In 18 hemispheres with preoperative and postoperative angiograms, there was an average postoperative increase in STA and MMA diameters of 51% (P = .003) and 49% (P = .002), respectively. Both children and adults displayed revascularization. Two patients did not demonstrate increased vessel size. STA blush and new branches and MMA blush and new branches were identified in 12, 14, 14, and 16 hemispheres, respectively. Angiographic blush was identified in 59% of frontal and 19% of parietal burr holes (P = .03). Surgical complications included 2 subdural hemorrhages requiring evacuation and 2 new ischemic deficits (1 transient). CONCLUSION:Indirect revascularization by encephaloduroarteriosynangiosis and burr holes for moyamoya results in long-term resolution of ischemic and hemorrhagic manifestations in 95% of adults and children. The MMA appears to contribute significantly to the revascularization on follow-up angiograms with increased size and neovascularity comparable to that of the STA. Angiographically, parietal burr holes do not contribute as significantly as frontal burr holes.
Genetic score of power‐speed and endurance track and field athletes

Athletic excelling capability in a specific sport results from the combined influence of hundreds of genetic polymorphisms. The aim of the current study was to characterize athletes' polygenetic scores. We developed two polygenetic scores: (a) Power Genetic Distance Score based on two polymorphisms (PGDS2; ACEI/D, ACTN3C/T) or five polymorphisms (PGDS5; ACTN3C/T, ACEI/D, IL6‐174G/C, NOS3T/C, AGTMET235THR); and (b) Endurance Genetic Distance Score based on two polymorphisms (EGDS2; ACEI/D, ACTN3C/T) or five polymorphisms (EGDS5; PPARGC1AGly482Ser, PPARAintron7G/C, PPARDT294C, NRF2A/C, HIFC/T). Eighty‐two power‐speed athletes, 87 endurance athletes, and 119 nonathletic controls participated in the study. Genomic DNA was extracted from peripheral blood. Power‐speed athletes' mean PGDS2 (46.1) and PGDS5 (29.4) were significantly higher compared with their mean EGDS2 (36.4) and EGDS5 (23.1; P < 0.05, P < 0.01, respectively); and compared with controls' mean PGDS2 (36.6) and PGDS5 (24.2; P < 0.05, P < 0.05, respectively). Endurance athletes' mean EGDS2 (60.3) and EGDS5 (35.3) were significantly higher compared with their mean PGDS2 (26.9) and PGDS5 (21.8; P < 0.001, P < 0.001, respectively); and compared with controls' mean EGDS2 (51.2) and EGDS5 (26.1; P < 0.05, P < 0.001, respectively). We conclude that polygenetic scores can differentiate power‐speed from endurance athletes. Whether these scores may be used to identify elite power‐speed or endurance athletes' needs to be addressed in future studies.