Miracle-dz/UniFAR-FTUs huggingface dataset:
High Selectivity of the γ-Aminobutyric Acid Transporter 2 (GAT-2, SLC6A13) Revealed by Structure-based Approach*

Background: GAT-2 is physiologically and pharmacologically important for regulating peripheral GABAergic mechanisms. Results: We identify GAT-2 ligands, including drugs, metabolites, and fragments, using comparative modeling, virtual screening, and experiments. Conclusion: GAT-2 is a high selectivity/low affinity transporter that is resistant to inhibition by typical GABAergic inhibitors. Significance: Our results explain pharmacological and physiological effects of GAT-2 ligands and identify specificity determinants in the SLC6 family. The solute carrier 6 (SLC6) is a family of ion-dependent transporters that mediate uptake into the cell of osmolytes such as neurotransmitters and amino acids. Four SLC6 members transport GABA, a key neurotransmitter that triggers inhibitory signaling pathways via various receptors (e.g., GABAA). The GABA transporters (GATs) regulate the concentration of GABA available for signaling and are thus targeted by a variety of anticonvulsant and relaxant drugs. Here, we characterize GAT-2, a transporter that plays a role in peripheral GABAergic mechanisms, by constructing comparative structural models based on crystallographic structures of the leucine transporter LeuT. Models of GAT-2 in two different conformations were constructed and experimentally validated, using site-directed mutagenesis. Computational screening of 594,166 compounds including drugs, metabolites, and fragment-like molecules from the ZINC database revealed distinct ligands for the two GAT-2 models. 31 small molecules, including high scoring compounds and molecules chemically related to known and predicted GAT-2 ligands, were experimentally tested in inhibition assays. Twelve ligands were found, six of which were chemically novel (e.g., homotaurine). Our results suggest that GAT-2 is a high selectivity/low affinity transporter that is resistant to inhibition by typical GABAergic inhibitors. Finally, we compared the binding site of GAT-2 with those of other SLC6 members, including the norepinephrine transporter and other GATs, to identify ligand specificity determinants for this family. Our combined approach may be useful for characterizing interactions between small molecules and other membrane proteins, as well as for describing substrate specificities in other protein families.
Maximal oxygen consumption and pulmonary circulation in patients with chronic bronchitis

Abstract. In order to study the relations between maximal oxygen consumption during exercise (V̇O2max) and the pulmonary circulation when pulmonary artery pressure (PPA) and pulmonary vascular resistance (PVR) are normal or close to normal, we evaluated twenty‐three patients with chronic bronchitis, in stable clinical condition. All these patients performed a progressive exercise test on a bicycle ergometer until exhaustion (V̇O2max); they were also subjected to right heart catheterization at rest and during light exercise at constant load. In these patients with moderate functional impairment, we observed on average a significant, although weak, correlation (r=‐0·52, P<0·01) between pulmonary vascular resistance at rest and V̇O2max. When V̇O2max exceeded 2 l min‐1, PVR was below 210 dyn s cm‐5. From the heart rate during maximal exercise we computed the oxygen pulse (O2Pmax). In eight patients O2Pmax was reduced (≤ 11 ml) with maximal heart rate close to its predicted value; in seven of these subjects PVR was abnormal and P̄PA at rest was at least 20 mmHg.
Maspin is Useful in the Distinction of Pancreatic Adenocarcinoma From Chronic Pancreatitis: A Tissue Microarray Based Study

Maspin, a member of the serpin family of serine protease inhibitors, has been shown to limit invasion and metastases in breast and prostate carcinomas. Maspin gene expression is up-regulated in pancreatic cancer, but not in normal pancreatic tissue. Maspin expression has been documented using immunohistochemical studies in pancreatic adenocarcinoma and high-grade intraductal dysplasia. We studied pancreatic ductal adenocarcinomas and chronic pancreatitis utilizing tissue microarray technology to determine the utility of maspin in differentiating these lesions. Immunohistochemistry was performed on tissue microarrays made from 72 cases of pancreatic ductal adenocarcinoma and 24 cases of chronic pancreatitis. Carcinomas were graded as well, moderately, or poorly differentiated using the WHO criteria. The primary antibody used was monoclonal antimaspin antibody (clone G167-70, 1:800, PharMingen, San Diego, CA). Nuclear and/or cytoplasmic staining for maspin was qualitatively scored from 1+ to 3+ based on intensity. Cases were considered positive if one or more cores demonstrated staining. Cases of chronic pancreatitis showed focal, weak (1+ to 2+) staining within occasional benign ductal epithelial cells in 29% of cases (7/24). Diffuse and intense (3+) staining was present in ducts with squamous metaplasia (3 cases). The majority of ducts showed no staining. Ductal adenocarcinomas showed diffuse staining in 91% (66/72) of cases with generally more intense staining than cases of chronic pancreatitis. Maspin may be helpful in differentiating ductal adenocarcinoma from chronic pancreatitis, once squamous metaplasia is ruled out.
Combination of antagonistic yeasts with two food additives for control of brown rot caused by Monilinia fructicola on sweet cherry fruit

Aims: To evaluate beneficial effect of two food additives, ammonium molybdate (NH4‐Mo) and sodium bicarbonate (NaBi), on antagonistic yeasts for control of brown rot caused by Monilinia fructicola in sweet cherry fruit under various storage conditions. The mechanisms of action by which food additives enhance the efficacy of antagonistic yeasts were also evaluated.
Antiinflammatory activity of extracts and fractions from the leaves of Gochnatia polymorpha .

The aqueous and ethanol extracts from the leaves of Gochnatia polymorpha and further fractions obtained from the latter extract using solvents with increasing polarity, including its aqueous residue and the amino acid, 4‐hydroxy‐N‐methyl‐proline were investigated by carrageenin‐induced pedal oedema formation. It was shown that the aqueous and ethanol extracts and the ethyl acetate fraction demonstrated significant antiinflammatory activity. The chemical investigation of the latter fraction revealed the presence of caffeic acid, chlorogenic acid, 3‐0‐methylquercetin, hyperosid and rutin. The amino acid 4‐hydroxy‐N‐methyl‐proline, a nonprotein amino acid that has not been reported before in the Asteraceae was isolated as a major compound and identified by spectroscopic methods. Copyright © 2000 John Wiley & Sons, Ltd.
Review: Neuropathological features of unexplained sudden unexpected death in infancy: current evidence and controversies

Sudden infant death syndrome (SIDS) is a leading cause of postneonatal infant death in the developed world. The cause of SIDS is unknown but several hypotheses have been proposed, including the ‘triple risk hypothesis’, which predicts that foetal development of infants who subsequently succumb to SIDS is abnormal, leaving them unable to respond appropriately to stressors. Consistent with this hypothesis, a large number of studies have reported changes in the brain in SIDS. However, on nearly every subject, the reported findings vary widely between studies. Inconsistencies in the definitions of SIDS used and in control group selection are likely to underlie much of this variability. Therefore, in our analysis, we have included only those studies that met simple criteria for both the definition of SIDS and the control group. Of the 153 studies retrieved by our review of the literature, 42 (27%) met these criteria. Foremost among the findings reported by these studies are abnormalities of the brain stem, in particular brain stem gliosis and defects of neurotransmission in the medulla. However, these studies have not identified what could be considered in diagnostic terms a causative structural or biochemical abnormality for use in routine clinical practice. An assessment of changes in the architecture and composition of brain regions and changes in neurotransmission in multiple systems in a single, large cohort of well‐ and consistently characterized infants dying suddenly of a range of causes is needed before the inter‐relation of these different features can be appreciated.
Protein and albumin-to-creatinine ratios in random urines accurately predict 24 h protein and albumin loss in patients with kidney disease

Background Random urine protein-to-creatinine (PCR) and albumin-to-creatinine (ACR) ratios have been proposed as alternatives to 24 h urine measurements to simplify sample collection and overcome errors. The aim of this study was to examine the ability of PCR and ACR to predict urinary 24 h protein and albumin loss, respectively, in patients with kidney disease, and determine the most appropriate time of collection. Methods Eighty-three patients were recruited from a renal outpatient clinic. In a 24 h period, each collected an early-morning urine (EMU), second and third voids, and the remaining urine passed that day. PCR and ACR were determined in random urines and compared with the 24 h loss of protein and albumin, respectively. Results For all patients, median (range) 24 h urine protein and albumin losses were 220 (30–15600) and 60 (<8–10,557) mg, respectively. Ratios derived from each of three random urines correlated well with 24 h protein or albumin loss (Spearman's r s > 0.87, P < 0.0001). Receiver operator characteristic (ROC) curve analysis showed PCR accurately predicted both an abnormal 24 h urine protein ≥150 mg/24 h (areas under curves [AUC] 0.90–0.92) and significant proteinuria above 300 mg/24 h (AUC between 0.97 and 1.00). ACR accurately predicted both an abnormal 24 h urine albumin ≥30 mg/24 h (AUC 0.98 to 0.99) and frank albuminuria at ≥300 mg/24 h or ≥700 mg/24 h (AUC between 0.99 and 1.00). EMU and random urines performed equally well in predicting proteinuria and albuminuria from PCR and ACR, respectively. Conclusions By careful choice of cut-offs, both PCR and ACR can be used in patients with kidney disease to rule in or rule out abnormal 24 h losses of protein and albumin. EMU and, importantly, random samples can be used as surrogates for 24 h urine collections.
The role of CYP3A5 genotypes in dose requirements of tacrolimus and everolimus after heart transplantation

Kniepeiss D, Renner W, Trummer O, Wagner D, Wasler A, Khoschsorur GAli, Truschnig‐Wilders M, Tscheliessnigg K‐H. The role of CYP3A5 genotypes in dose requirements of tacrolimus and everolimus after heart transplantation. Clin Transplant 2011: 25: 146–150. © 2009 John Wiley & Sons A/S.
Ultrastructural Localization and Molecular Associations of HCV Capsid Protein in Jurkat T Cells

Hepatitis C virus core protein is a highly basic viral protein that multimerizes with itself to form the viral capsid. When expressed in CD4+ T lymphocytes, it can induce modifications in several essential cellular and biological networks. To shed light on the mechanisms underlying the alterations caused by the viral protein, we have analyzed HCV-core subcellular localization and its associations with host proteins in Jurkat T cells. In order to investigate the intracellular localization of Hepatitis C virus core protein, we have used a lentiviral system to transduce Jurkat T cells and subsequently localize the protein using immunoelectron microscopy techniques. We found that in Jurkat T cells, Hepatitis C virus core protein mostly localizes in the nucleus and specifically in the nucleolus. In addition, we performed pull-down assays combined with Mass Spectrometry Analysis, to identify proteins that associate with Hepatitis C virus core in Jurkat T cells. We found proteins such as NOLC1, PP1γ, ILF3, and C1QBP implicated in localization and/or traffic to the nucleolus. HCV-core associated proteins are implicated in RNA processing and RNA virus infection as well as in functions previously shown to be altered in Hepatitis C virus core expressing CD4+ T cells, such as cell cycle delay, decreased proliferation, and induction of a regulatory phenotype. Thus, in the current work, we show the ultrastructural localization of Hepatitis C virus core and the first profile of HCV core associated proteins in T cells, and we discuss the functions and interconnections of these proteins in molecular networks where relevant biological modifications have been described upon the expression of Hepatitis C virus core protein. Thereby, the current work constitutes a necessary step toward understanding the mechanisms underlying HCV core mediated alterations that had been described in relevant biological processes in CD4+ T cells.
Modulation of the scotopic electroretinogram and oscillatory potentials with systemic hyperoxia and hypercapnia in humans

Purpose. Systemic hyperoxia reduces blood flow to the retina while systemic hypercapnia has the opposite effect. However, the effect this modification in blood flow has on neuroretinal function in humans has not been documented yet. The purpose of this study was to evaluate the effect of pure oxygen and carbogen breathing on scotopic electroretinograms (ERGs) and oscillatory potentials (OPs) in humans. Methods. Thirty-five healthy adults volunteered for this study. The ERGs and OPs were recorded: 1) during room air breathing, 2) after a period of pure oxygen (O 2) or carbogen breathing, 3) in room air just after the flow of gas was interrupted, and 4) 10 minutes after the end of the gas administration. Results. The amplitude and latency of the a- and b-waves were not altered during systemic hyperoxia. The amplitude of OP3 increased during hyperoxia while the amplitude of the other OPs was not altered. The latency of all OPs remained stable throughout the O 2 session. Ten minutes after the end of pure O 2 breathing, the a- and b-wave latencies were delayed. No change was found in the amplitude of the a-wave during the carbogen session that increased the end-tidal carbon dioxide by 7.1%, whereas the b-wave was reduced ten minutes after the end of carbogen breathing. The amplitude of OP5 was reduced during carbogen breathing, as well as 10 minutes later. The amplitude of all other OPs, as well as the latencies of all ERG and OP components remained stable throughout the carbogen session. Conclusions. Breathing pure O 2 or carbogen did not compromise retinal function in any major way, likely due to adequate retinal and choroidal regulatory mechanisms. Further investigations are required to better delineate the impact and temporal characteristics of such physiological challenges on retinal function.
Colorectal cancer screening in human immunodeficiency virus population: Are they at average risk?

AIM To evaluate if human immunodeficiency virus (HIV) population is getting adequate screening for colon cancer in the highly active anti-retroviral treatment (HAART) era with improved longevity, and the prevalence of polyps and adenomas in this population, when compared with the general population. METHODS We conducted retrospective chart review of average-risk HIV population for colon cancer attending our infectious disease clinic. Individuals who underwent diagnostic colonoscopy were excluded. We extracted various demographic, HIV disease-specific and colonoscopy data including histo-pathological reports in the last 10 years. Total population was divided into a study group, who underwent screening colonoscopy and a control group who did not. We analyzed data using standard statistical methods and software. RESULTS We found that 25% of average-risk HIV-infected population was screened for colon cancer using colonoscopy. There was no difference in gender and ethnic distribution between the groups. We found wider distribution of age (50-84 years with mean 56 years) in the control group when compared to (50-73 years with mean 58 years) the study group. However, there were 89% of subjects with well-controlled HIV disease measured by HIV RNA copies of < 75 in the study group when compared with 70% in the control group (P < 0.0001). We noticed polyp detection rate of 55% and adenoma detection rate of 32% in HIV population. CONCLUSION It is unclear whether HIV or HAART medications play a role in increased prevalence of adenomas. We suggest that when estimating the risk for colonic neoplasms, HIV population should be considered as a high-risk group and screened accordingly.
Induction of Plasminogen Activator Inhibitor-1 by Urokinase in Lung Epithelial Cells*

The plasminogen/plasmin system, urokinase-type plasminogen activator (uPA), its receptor (uPAR), and its inhibitor (PAI-1), influence extracellular proteolysis and cell migration in lung injury or neoplasia. In this study, we sought to determine whether tcuPA (two chain uPA) alters expression of its major inhibitor PAI-1 in lung epithelial cells. The expression of PAI-1 was evaluated at the protein and mRNA level by Western blot, immunoprecipitation, and Northern blot analyses. We found that tcuPA treatment enhanced PAI-1 protein and mRNA expression in Beas2B lung epithelial cells in a time- and concentration-dependent manner. The tcuPA-mediated induction of PAI-1 involves post-transcriptional control involving stabilization of PAI-1 mRNA. Inactivation of the catalytic activity of tcuPA had little effect on PAI-1 induction and the activity of the isolated amino-terminal fragment was comparable with full-length single- or two-chain uPA. In contrast, deletion of either the uPA receptor binding growth factor domain or kringle domain (^kringle) from full-length single chain uPA markedly attenuated the induction of PAI-1. Induction of PAI-1 by exposure of lung epithelial cells to uPA is a newly recognized pathway by which PAI-1 could regulate local fibrinolysis and urokinase-dependent cellular responses in the setting of lung inflammation or neoplasia.
Four Types of Attitudes in ICT Acceptance and Use? A Critical Assessment on the Basis of Empirical and Scientometric Data

User attitudes are a major predictor of the endogenous variables in ICT adoption models. However it is known in the community that the predictive validity of user attitudes on behavioral intention to adopt ICT suffers from inconsistencies. Being a basic predictor of behavioral intention in models like TRA or TPB, user attitudes turned out not to be predictive of behavior in other studies [1]. Some authors have addressed this problem and introduced solution approaches based on splitting the construct into four different sub constructs. This paper evaluates these approaches on the basis of social psychological literature, PLS results of a survey, and scientometric data of fourteen IS top journals. The findings indicate that the problem of insignificance is not caused by a conceptual misspecification, but rather by a combination of conceptual and situational factors affecting the relationship between attitude and behavioral intention.
Daily rhythm of glucose‐induced insulin secretion by isolated islets from intact and pinealectomized rat

Abstract: It is well known that pinealectomy induces in rats a diminished glucose tolerance, insulin resistance, a reduction in GLUT4 content in adipose and muscular tissues, a decrease in hepatic and muscular glycogenesis, impairment of glucagon action and an increase in blood pyruvate concentration. In addition, it has been shown that melatonin suppresses insulin secretion in several experimental conditions. The objective of the present study was to investigate the daily rhythm of glucose‐induced insulin secretion and glucose oxidation by isolated pancreatic islets and to investigate the effect of chronic absence of melatonin (30 days of pinealectomy) on this rhythmic process. The data obtained confirmed the presence of a strong 24‐hr rhythm of insulin secretion by isolated pancreatic islets. In addition, it was demonstrated that the glucose‐metabolizing ability of the B‐cell follows a daily rhythm phase locked to insulin secretion rhythm. Most interesting, however, was the demonstration that the daily rhythmic processes of insulin secretion and B‐cell –[U‐14C]‐glucose oxidation by isolated pancreatic islets is completely modified by the chronic absence of the pineal gland. Thus, pinealectomy induced in all groups an increase in 24‐hr mean glucose‐stimulated insulin secretion and [U‐14C]‐glucose oxidation, in addition to some alterations in the rhythmic amplitude and a remarkable phase‐advancing of the daily curves for 8.3 mm glucose (a condition similar to that observed in fed animals and where the B‐cells are supposedly more active). These observations strongly suggest that the presence of the pineal gland may be necessary for the proper synchronization of these metabolic rhythms with other circadian rhythms like activity–rest and feeding.
Osteoarticular involvement among 202 brucellosis cases identified in Central Anatolia region of Turkey.

OBJECTIVE The musculoskeletal system is one of the most commonly affected systems in brucellosis. The objective of this study was to determine the frequency, types, and clinical features of osteoarticular involvement among cases with brucellosis in the Central Anatolia region of Turkey and to establish the differences between patients with and without osteoarticular involvement. METHODS Included in this study were 202 patients with Brucellosis presented between June 2003 and June 2009. The diagnosis of osteoarticular system complications was established by physical examination and radiological findings obtained by diagnostic imaging tools. Magnetic resonance images of thoracic, lumbar or sacral vertebrae were acquired from patients with back pain, low back pain and sacro-iliac joint pain. RESULTS Osteoarticular involvement was noted in 94 patients (46.5%). The most common sources of infection are employment in farming and/or consumption of un-pasteurized milk or dairy products, especially fresh cheese in 53 (75.7%) cases. The mean age is 46.7±18 years. Sacroiliitis is the most frequent osteoarticular involvement (60.6%), 82.4% of which is bilateral. Sacroiliitis was followed by spondylodiscitis in 36 (38.3%), peripheral arthritis in 15 (16%), bursitis in 1(1.1%) case. Patients with osteoarticular involvement received medical treatment for at least three months. CONCLUSION The ratio and anatomical region of osteoarticular involvement in brucellosis show variability among countries. In this study, it is demonstrated that sacroiliitis is the most common form of osteoarticular involvement in the Central Anatolia region of Turkey. In endemic countries such as Turkey, this disease should be included in the differential diagnosis for patients with symptoms of sacroiliitis, spondylodiscitis or those with articular pain.