Miracle-dz/UniFAR-FTUs huggingface dataset:
Structural Basis for Degenerate Recognition of Natural HIV Peptide Variants by Cytotoxic Lymphocytes*

It is well established that even small changes in amino acid side chains of antigenic peptide bound to major histocompatibility complex (MHC) protein may completely abrogate recognition of the peptide-MHC (pMHC) complex by the T cell receptor (TCR). Often, however, several nonconservative substitutions in the peptide antigen are accommodated and do not impair its recognition by TCR. For example, a preponderance of natural sequence variants of the human immunodeficiency virus p17 Gag-derived peptide SLYNTVATL (SL9) are recognized by cytotoxic T lymphocytes, which implies that interactions with SL9 variants are degenerate both with respect to the class I MHC molecule and with respect to TCR. Here we study the molecular basis for this degenerate recognition of SL9 variants. We show that several SL9 variants bind comparably well to soluble HLA-A2 and to a particular soluble TCR and that these variants are active in the cognate cytotoxicity assay. Natural SL9 variation is restricted by its context in the HIV p17 matrix protein. High resolution crystal structures of seven selected SL9 variants bound to HLA-A2 all have remarkably similar peptide conformations and side-chain dispositions outside sites of substitution. This preservation of the peptide conformation despite epitope variations suggests a mechanism for the observed degeneracy in pMHC recognition by TCR and may contribute to the persistence of SL9-mediated immune responses in chronically infected individuals.
A Overview of Ocular Leprosy After 2 Decades of Multidrug Therapy

On the basis of clinical descriptions, leprosy seems to be one of the oldest diseases recorded in history. The causative infectious agent was first recognized in 1873, but rigorous scientific methodology has only been applied in the past few decades to help us to understand some characteristics of the disease and many remain mysterious. Apart from the skin, nasal mucosa, and certain peripheral nerves, the anterior segment of the eye is the most common site of disease caused by Mycobacterium leprae. Manifestations of leprosy in the eye are related to the epidemiology and pathophysiology of the systemic disease. Infection by M. leprae results in a complex humoral and cellular immune response. Antibody detection tests have shown that M. leprae infects most people exposed to it, but most do not develop recognizable clinical disease since they mount an adequate immune response that limits bacterial multiplication. Only a small number of those infected develop the clinical disease of leprosy. The determinants of an individual’s immune response to M. leprae, including the possible role of infective dose and route of infection, are still poorly understood. Clinical leprosy is a spectrum of disease. At one end, there are paucibacillary (PB; sometimes known as tuberculoid) type patients. They have relatively intact cellular immune function and, consequently, low bacillary loads. At the other end of the spectrum, there are multibacillary (MB; sometimes known as lepromatous) patients, with markedly impaired cellular immunity and very high bacillary loads. Many patients, known as borderline, lie between the 2 extremes; these patients have variable degrees of cellular immunity toward M. leprae. The immune
Fate of Mycobacterium tuberculosis within Murine Dendritic Cells

ABSTRACT The interaction of microbes with dendritic cells (DCs) is likely to have an enormous impact on the initiation of the immune response against a pathogen. In this study, we compared the interaction ofMycobacterium tuberculosis with murine bone marrow-derived DCs and macrophages (Mφ) in vitro. M. tuberculosis grew equally well within nonactivated DCs and Mφ. Activation of DCs and Mφ with gamma interferon and lipopolysaccharide inhibited the growth of the intracellular bacteria in a nitric oxide synthase-dependent fashion. However, while this activation enabled Mφ to kill the intracellular bacteria, the M. tuberculosis bacilli within activated DCs were not killed. Thus, DCs could restrict the growth of the intracellular mycobacteria but were less efficient than Mφ at eliminating the infection. These results may have implications for priming immune responses to M. tuberculosis. In addition, they suggest that DCs may serve as a reservoir for M. tuberculosis in tissues, including the lymph nodes and lungs.
Extraction of event-related signals from multichannel bioelectrical measurements

Independent component analysis (ICA) is a powerful tool for separating signals from their mixtures. In this field, many algorithms were proposed, but they poorly use a priori information in order to find the desired signal. Here, we propose a fixed point algorithm which uses a priori information to find the signal of interest out of a number of sensors. We particularly applied the algorithm to cancel cardiac artifacts from a magnetoencephalogram.
Detection of oxytetracycline and chlortetracycline residues in agricultural fields in Turkey.

Tetracycline residues in the soil were investigated in this study due to their wide use in veterinary medicine and fertilization of agricultural fields with manure containing antibiotics. Soil samples were characterized by using various physicochemical parameters. Solid phase extraction and high performance liquid chromatography were used to detect oxytetracycline and chlortetracycline residues in the soils. The mean recovery rates of oxytetracycline and chlortetracycline were 51.07±27.66% and 62.12±17.05%, respectively. The concentrations of tetracyclines detected in soil samples were ranged from 0.019 mg kg to 0.144 mg kg.
Phase I and pharmacokinetic study of imatinib mesylate in patients with advanced malignancies and varying degrees of liver dysfunction: a study by the National Cancer Institute Organ Dysfunction Working Group.

PURPOSE To develop dosing guidelines and to evaluate the pharmacokinetics of imatinib in patients with liver dysfunction (LD). PATIENTS AND METHODS Patients (N = 89) with varying solid tumors and liver function were stratified into four groups according to serum total bilirubin and AST and were treated with escalating doses of imatinib. Plasma and urine were assayed for concentrations of imatinib and its active metabolite, CGP74588. RESULTS In the mild LD group, dose-limiting toxicity, specifically nausea/vomiting and fatigue, occurred in two patients at the 600 mg/d dose level. In the moderate and severe LD groups, the maximal dose evaluated was 300 mg/d. Grade 3 to 4 toxicities consisted primarily of liver function test elevations (24%), nausea/vomiting (10%), fatigue (6%), and edema (5%). After the first imatinib dose, the mean (+/- SD) dose-normalized areas under the plasma concentration-time curve from time 0 to infinity (AUC(0-infinity)) were 162 +/- 155, 171 +/- 72, 182 +/- 157, and 185 +/- 172 (mug/mL x h)/mg for normal, mild, moderate, and severe LD groups, respectively. Renal excretion of imatinib was less than 10% of the total dose in all groups. CONCLUSION Imatinib exposure (as measured by the dose-normalized AUC) did not differ between patients with normal liver function and those with LD. The maximal recommended dose of imatinib for patients with mild LD is 500 mg/d. Dosing guidelines for patients with moderate and severe LD remain undetermined.
Cooling and ice growth across the Eocene-Oligocene transition

The Eocene-Oligocene (E-O) climate transition (ca. 34 Ma) marks a period of Antarctic ice growth and a major step from early Cenozoic greenhouse conditions toward today's glaciated climate state. The transition is represented by an increase in deep-sea benthic foraminiferal oxygen isotope (18O) values occurring in two main steps that reflect the temperature and 18O of seawater. Existing benthic Mg/Ca paleotemperature records do not display a cooling across the transition, possibly reflecting a saturation state effect on benthic foraminiferal Mg/Ca ratios at deep-water sites. Here we present data from exceptionally well preserved foraminifera deposited well above the calcite compensation depth that provide the first proxy evidence for an 2.5 °C ocean cooling associated with the ice growth. This permits interpretation of E-O 18O records without invoking Northern Hemisphere continental-scale ice.
Quantitative analysis of (-)-N-(11)C-propyl-norapomorphine in vivo binding in nonhuman primates.

UNLABELLED (-)-N-(11)C-propyl-norapomorphine ((11)C-NPA) is a new dopamine agonist PET radiotracer that holds potential for imaging the high-affinity states of dopamine D(2)-like receptors in the living brain. The goal of this study was to develop and evaluate analytic strategies to derive in vivo (11)C-NPA binding parameters. METHODS Two baboons were scanned 4 times after (11)C-NPA injections. The metabolite-corrected arterial input functions were measured. Regional brain time-activity curves were analyzed with kinetic and graphical analyses, using the arterial time-activity curve as the input function. Data were also analyzed with the simplified reference-tissue model (SRTM) and graphical analysis with reference-region input. RESULTS (11)C-NPA exhibited moderately fast metabolism, with 31% +/- 5% of arterial plasma concentration corresponding to the parent compound at 40 min after injection. Plasma clearance was 29 +/- 1 L/h, and plasma free fraction (f(1)) was 5% +/- 1%. For kinetic analysis, a 1-tissue compartment model (1TCM) provided a good fit to the data and more robust derivations of the tissue distribution volumes (V(T), in mL/g) than a 2-tissue compartment model (2TCM). Using 1TCM, V(T)s in the cerebellum and striatum were 3.4 +/- 0.4 and 7.5 +/- 2 mL/g, respectively, which led to estimates of striatal binding potential (BP) of 4.0 +/- 1.1 mL/g and striatal equilibrium specific-to-nonspecific partition coefficient (V(3)") of 1.2 +/- 0.2. V(T) values derived with graphical analysis were well correlated with but slightly lower than V(T) values derived with kinetic analysis. V(3)" values derived with SRTM were well correlated with but slightly higher than V(3)" values derived with kinetic analysis. Using any method, a significant difference was detected in BP and V(3)" values between the 2 animals. It was determined that 30 min of scanning data were sufficient to derive V(3)" values using kinetic, graphical (arterial input and reference-region input), and SRTM analyses. CONCLUSION This study indicates that (11)C-NPA is a suitable PET tracer to quantify the agonist high-affinity sites of D(2)-like receptors.
Aspects histo-épidémiologiques des cancers génitaux de la femme dans la région du Littoral, Cameroun

Décrire les caractéristiques épidémiologiques et histopathologiques des tumeurs malignes génitales de la femme dans la région du littoral du Cameroun. Il s'agissait d'une étude rétrospective descriptive et analytique portant sur les cancers des organes génitaux de la femme, histologiquement prouvés pendant une période de 10 ans (2004-2013), répertoriés dans les registres des trois laboratoires d'anatomopathologie de la région (Hôpital Laquintinie de Douala, Hôpital Général de Douala, laboratoire Anapathos) et des services d'oncologie de ces hôpitaux. Les variables étudiées étaient: la fréquence, l’âge, le sexe, la localisation de la tumeur et le type histopathologique. Au total, 802 cas de cancers génitaux de la femme ont été recensés, soit une fréquence annuelle de 80,2 cas en moyenne. Le col utérin avec 580 cas (72,32%) a été la localisation la plus fréquente; suivi de l'endomètre (corps utérin) avec 93 cas (11,60%), puis des ovaires 91 cas (11,35%). L’âge moyen des patientes était de 50, 30±12,67 ans, avec les extrêmes allant de 14 à 85 ans. Selon le type histologique, les tumeurs épithéliales ont été les plus fréquemment rencontrées, soit 758 patientes (94,51%), les lymphomes venaient en seconde position avec 29 cas (3, 62%), les autres variétés histologiques (sarcomes, tumeurs germinales, tumeurs du mésenchyme et du cordon) représentant moins chacune de 1%. Les tumeurs malignes des organes génitaux féminins sont fréquentes dans la région du littoral du Cameroun, elles sont dominées essentiellement par le cancer du col utérin. Les tumeurs épithéliales sont le type histologique le plus fréquent.
Anti-tuberculosis drug susceptibility testing of Mycobacterium bovis BCG Tokyo strain.

SETTING The Mycobacterium bovis bacille Calmette-Guérin (BCG) vaccine is the only vaccine against tuberculosis (TB), owing to its valuable protective effects and low virulence. However, it can occasionally cause systemic infection in immunocompromised hosts. Isoniazid (INH), rifampicin (RMP), streptomycin (SM) and ethambutol (EMB) are known to be effective anti-tuberculosis drugs and are used for the treatment of BCG infections. Unfortunately, there are few studies of the susceptibility of BCG vaccine strains to these drugs. OBJECTIVE To measure the minimum inhibitory concentrations (MICs) of BCG Tokyo vaccine products for anti-tuberculosis drugs and assess vaccine safety in terms of drug susceptibility. DESIGN We measured the MIC for one seed and five product lots of BCG Tokyo strain for INH, RMP, SM and EMB using Middlebrook 7H11 agar plates. RESULTS The MIC results for INH were 0.06 and 0.125 mg/ml for the product and seed lots, respectively. The MIC results for RMP, SM and EMB were 0.25-0.5, 0.25 and 2-4 microg/ml, respectively. CONCLUSION Our results indicate that the BCG Tokyo strain was susceptible to the major anti-tuberculosis drugs and treatable even in cases of severe adverse events, including systemic infection.
Large-scale exploration and analysis of drug combinations

MOTIVATION Drug combinations are a promising strategy for combating complex diseases by improving the efficacy and reducing corresponding side effects. Currently, a widely studied problem in pharmacology is to predict effective drug combinations, either through empirically screening in clinic or pure experimental trials. However, the large-scale prediction of drug combination by a systems method is rarely considered. RESULTS We report a systems pharmacology framework to predict drug combinations (PreDCs) on a computational model, termed probability ensemble approach (PEA), for analysis of both the efficacy and adverse effects of drug combinations. First, a Bayesian network integrating with a similarity algorithm is developed to model the combinations from drug molecular and pharmacological phenotypes, and the predictions are then assessed with both clinical efficacy and adverse effects. It is illustrated that PEA can predict the combination efficacy of drugs spanning different therapeutic classes with high specificity and sensitivity (AUC = 0.90), which was further validated by independent data or new experimental assays. PEA also evaluates the adverse effects (AUC = 0.95) quantitatively and detects the therapeutic indications for drug combinations. Finally, the PreDC database includes 1571 known and 3269 predicted optimal combinations as well as their potential side effects and therapeutic indications. AVAILABILITY AND IMPLEMENTATION The PreDC database is available at http://sm.nwsuaf. edu.cn/lsp/predc.php.
Analysis of peptide residues interacting with MHC molecule or T cell receptor. Can a peptide bind in more than one way to the same MHC molecule?

It has generally been assumed implicitly that one can define amino acid residues of a T cell antigenic determinant peptide that interact with the MHC molecule, i.e., residues that form the "agretope. " However, if the same peptide can be seen in different conformations or orientations in the same MHC molecule by different T cells, then we would predict that some residues would appear to interact with the TCR of one T cell clone but with the MHC molecule as the peptide is seen by another T cell clone. To test this hypothesis, we synthesized 36 analogue peptides of an immunogenic fragment (P133-146) of sperm whale myoglobin with three different substitutions for each of 12 amino-acid residues and analyzed the role of each residue for I-Ed-binding and for activation of two Th clones, 14.1 and 14.5, specific for the peptide. The two T cell clones showed slightly different fine specificity from each other in that the truncated peptide P136-144 could stimulate 14.5 but not 14.1. The binding activity of nonstimulatory analogues to the I-Ed molecule was measured by functional inhibition analyses using truncated wild-type peptides as stimulators and nonstimulatory analogues as inhibitors. Paradoxical results were obtained that could not be explained by the peptide binding in a single way to the same I-Ed molecule. Some residues appeared to reciprocally reverse their roles for binding to I-Ed vs binding to the TCR when assessed using T-cell clone 14.5 compared to clone 14.1. These results fit the prediction of the above hypothesis and indicate the possibility that the same peptide, P133-146, can bind in more than one way to the same Ia molecule. The T cell clones, 14.1 and 14.5, appear to recognize different P133-146-I-Ed complexes in which the peptide is bound differently. Moreover, a given residue may not have a unique function of always interacting with the MHC molecule or TCR, but may change from one role to the other as it is presented to different T cells.
Insulin Can Rapidly Increase Cell Surface Insulin Binding Capacity in Rat Adipocytes: A Novel Mechanism Related to Insulin Sensitivity

To elucidate the acute effect of insulin on its receptor, rat adipocytes were preincubated with insulin, washed with KCN to inhibit receptor cycling, and 125I-labeled insulin binding was measured. Preincubating cells from young insulin-sensitive rats with insulin increased cell surface binding up to approximately fourfold without changing apparent receptor affinity. This effect was rapid (t1/2 <5 min) and had a similar dose-response relationship as the effect on glucose transport. It was also energy dependent because preincubation with KCN completely abolished the effect of subsequent insulin exposure. The increased binding capacity was not recovered after cell solubilization or in partially purified receptors or isolated plasma membranes. Cells pretreated with insulin were less sensitive to the ability of trypsin to remove cell surface receptors, suggesting a conformational change of the receptors. This was also supported by the finding that the polyclonal binding in insulin-treated antibody B10 inhibited 125I-insulin binding in insulin-treated but not in control cells. Vanadate mimicked the effect of insulin to increase insulin binding, whereas concanavalin A, vasopressin, phorbol esters, or the adenosine analogue phenyl isopropyl adenosine was without effect. Insulin-resistant adipocytes from obese rats displayed no increase in cell surface binding after insulin treatment, despite normal tyrosine kinase activity in response to insulin. Thus, both insulin and vanadate elicit a rapid effect to markedly increase the number of cell surface insulin binding sites in intact rat adipocytes. This appears to occur independently of protein kinase C and the inhibitory GTP binding protein (Gi). Furthermore, the effect of insulin could not be demonstrated in insulin-resistant cells, suggesting that this mechanism may be of importance for the regulation of insulin sensitivity.
An Ultralow Loss Superjunction Reverse Blocking Insulated-Gate Bipolar Transistor With Shorted-Collector Trench

A novel superjunction (SJ) reverse-blocking (RB) insulated gate bipolar transistor (IGBT) is proposed and investigated for the first time. The device features a shorted collector trench (SCT) at the bottom, an SJ structure in the drift region, and an N1-layer as well as N2-layer at the bottom and top side of N-pillar, respectively. First, the SCT combined with the N2 enables the SJ RB-IGBT to sustain a high reverse breakdown voltage (BVR). The SCT assists in depleting the N1 in the reverse blocking state, enabling a high BVR under the condition of a high N1 doping that is required to maintain a high forward breakdown voltage (BVF). The N2 acts as a field-stop layer in the reverse blocking state. Second, unlike the conventional SJ IGBT, the SJ RB-IGBT maintains bipolar conducting mode in the ON-state even with high N/P pillar doping of 6 × 1015cm-3, due to carrier store effect induced by N2. Thus, a low ON-state voltage (VON) is obtained. Third, the SJ junction extracts the plasma into separate pillars during turn OFF, enabling a fast turn-OFF speed that is comparable with unipolar devices. The SJ RB-IGBT realizes bidirectional blocking capability >1200V and turn-OFF loss 80% lower than that of the state-of-the-art RB-IGBT.
Evaluation of Prognosis in Patients with Perforation Peritonitis Using Mannheim Peritonitis Index

Peritonitis is defined as inflammation of the serous membrane that lines the abdominal cavity and the organs contained therein. Most cases of peritonitis are caused by an invasion of the peritoneal cavity by bacteria, so that when the term peritonitis is used without specification bacterial peritonitis is implied. Peritonitis is one of the most common infections, and an important problem that a surgeon has to face.
Extra‐acral cutaneous sclerosing perineurioma with CD34 fingerprint pattern

Sclerosing perineuroma is a variant of extraneural perineurioma that, as a rule, occurs in acral sites. However, it has also been occasionally reported in non‐acral regions. Recently, CD34 expression in a pattern reminiscent of the human fingerprint has been observed in a subset of perineuriomas, but this immunohistochemical finding has not been documented in non‐acral sclerosing perineuriomas. We report a case of sclerosing perineurioma presenting CD34 expression in a fingerprint‐like pattern on the skin of the neck (a previously unreported site for this neoplasm) of a 56‐year‐old man. In addition, alpha smooth‐muscle actin showed a similar pattern of expression, suggesting that the cell population implicated in the remarkable immunolabeling is most probably fibroblastic/myofibroblastic. Other immunohistochemical findings included epithelial membrane antigen and claudin1—positive lesional cells, and the absence of S100, glucose transporter protein 1, MUC4 and desmin.
Periictal heart rate variability analysis suggests long‐term postictal autonomic disturbance in epilepsy

Background: One of the possible pathomechanisms of sudden death in epilepsy (SUDEP) is a postictal dysregulation of autonomic nervous system. We performed a heart rate variability (HRV) analysis of the periictal state to analyze whether a cardiac autonomic disturbance exists after an epileptic seizure.
The Fog of Feedback: Ambiguity and Firm Responses to Multiple Aspiration Levels

This study examines how firms respond to feedback from comparisons of a single performance indicator to multiple aspiration levels. Empirically, we compare firm performance to both historical and social aspiration levels, and examine the impact of the correlation of these two indicators on new products introductions. We argue that three types of feedback  ambiguous (weak correlations), contradictory (negative correlation), and consistent feedback (positive correlation)have different implications for firm responses. Our findings demonstrate that both contradictory and consistent feedback increase a firm’s propensity to respond to feedback. However, ambiguous feedback lowers a firm’s propensity to respond due to motivation and coordination problems that arise when performance signals are ambiguous. Our study builds and augments theories of ambiguity and performance feedback in organizations.