Miracle-dz/UniFAR-FTUs huggingface dataset:
One NY-ESO-1-Derived Epitope That Promiscuously Binds to Multiple HLA-DR and HLA-DP4 Molecules and Stimulates Autologous CD4+ T Cells from Patients with NY-ESO-1-Expressing Melanoma1

NY-ESO-1 is expressed by a broad range of human tumors and is often recognized by Abs in the sera of cancer patients with NY-ESO-1-expressing tumors. The NY-ESO-1 gene also encodes several MHC class I- and class II-restricted tumor epitopes recognized by T lymphocytes. In this study we report one novel pan-MHC class II-restricted peptide sequence, NY-ESO-1 87–111, that is capable of binding to multiple HLA-DR and HLA-DP4 molecules, including HLA-DRB1*0101, 0401, 0701, and 1101 and HLA-DPB1*0401 and 0402 molecules. We also demonstrate that peptide NY-ESO-1 87–111 stimulates Th1-type and Th-2/Th0-type CD4+ T cells and clones when presented in the context of these HLA-DR and HLA-DP4 molecules. Both bulk CD4+ T cells and CD4+ T cell clones were capable of recognizing not only peptide-pulsed APCs, but also autologous dendritic cells, either loaded with the NY-ESO-1 protein or transfected with NY-ESO-1 cDNAs. Using IFN-γ and IL-5 ELISPOT assays and PBL from patients with NY-ESO-1-expressing tumors, we observed the existence of Th1-type circulating CD4+ T cells recognizing peptide NY-ESO-1 87–111 in the context of HLA-DP4 molecules. Taken together, these data represent the first report of an HLA-DR- and HLA-DP-restricted epitope from a tumor Ag. They also support the relevance of cancer vaccine trials with peptides NY-ESO-1 87–111 in the large number of cancer patients with NY-ESO-1-expressing tumors.
The impact of calcium assay change on a local adjusted calcium equation

Background Deriving and validating local adjusted calcium equations is important for ensuring appropriate calcium status classification. We investigated the impact on our local adjusted calcium equation of a change in calcium method by the manufacturer from cresolphthalein complexone to NM-BAPTA. Methods Calcium and albumin results from general practice requests were extracted from the Laboratory Information Management system for a three-month period. Results for which there was evidence of disturbance in calcium homeostasis were excluded leaving 13,482 sets of results for analysis. The adjusted calcium equation was derived following least squares regression analysis of total calcium on albumin and normalized to the mean calcium concentration of the data-set. The revised equation (NM-BAPTA calcium method) was compared with the previous equation (cresolphthalein complexone calcium method). Results The switch in calcium assay resulted in a small change in the adjusted calcium equation but was not considered to be clinically significant. The calcium reference interval differed from that proposed by Pathology Harmony in the UK. Conclusions Local adjusted calcium equations should be re-assessed following changes in the calcium method. A locally derived reference interval may differ from the consensus harmonized reference interval.
Day-to-day experience in resolution of pain after surgery

Abstract We know little about the individual pain experience of patients recovering from surgery in the first weeks after hospital discharge. Here, we examine individual differences in the day-to-day experience after 2 major surgeries: lower limb total major joint arthroplasty (TJA) and cesarean delivery (CD). Fifty-five TJA patients and 157 CD patients were recruited to complete questionnaires and record their daily pain experiences after surgery. After hospital discharge, patients recorded their pain intensity once daily for 60 days (CD) or twice daily for 2 weeks, once daily for 2 weeks, weekly for 8 weeks, and monthly for 3 months (TJA). Pain scores were modeled using growth curve and Bayesian change-point models. Individual differences in the model fits were examined for evidence of day-to-day differences in pain. A log time model was the simplest model that fit the data, but examination of the residuals revealed high autocorrelation representing misspecification. A change-point model fit the data better and revealed that the form of recovery fundamentally changed between days 10 and 21 after surgery. These data add meaningfully to our understanding of recovery from pain after surgery by extending the period of frequent observations a few days after surgery to a 2-month period. These high time resolution data suggest that there is a typical experience of pain resolution after surgery, but that meaningful subpopulations of experience may exist. They also indicate that a transition occurs within 1 month after surgery from 1 pattern of change in pain over time to another.
Phylogenetic distribution of streptococcal superantigen SSA allelic variants provides evidence for horizontal transfer of ssa within Streptococcus pyogenes

Phylogenetic analyses recently found the gene encoding the streptococcal superantigen SSA of Streptococcus pyogenes to occur in several well-differentiated clones comprising 10 (12.5%) of 80 clonal lineages examined. To determine if distinct clonal lineages carried the same ssa coding sequence or harbored a group of allelic variants, ssa was sequenced from 23 S. pyogenes strains representing the 10 clones identified by multilocus enzyme electrophoresis. Three alleles of ssa were found in natural populations of S. pyogenes. ssa-1 and ssa-3 differed by a single synonymous substitution in codon 94; both encoded SSA-1. Each of these alleles was present in phylogenetically diverse clones that had not shared a recent common ancestor. ssa-2 was present in a single clonal lineage. It was identical to ssa-3 at codon 94 but had a nonsynonymous substitution at codon 28 that changed the second amino acid of the mature protein from serine to arginine. This substitution altered the predicted isoelectric point and affected the apparent molecular mass during sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Despite sequence variation both upstream of and within the ssa locus, all ssa-positive lineages expressed either SSA-1 or SSA-2. The observed patterns of ssa allele-clone distribution provide evidence for individual incidences of horizontal transfer and recombination of ssa among distinct group A streptococcal lineages. Although the extensive homology of SSA to the staphylococcal superantigen SEB raises the possibility of intergeneric gene transfer, a search for ssa in 68 genetically diverse clones of Staphylococcus aureus did not identify the gene. Moreover, the absence of ssa among 119 representative strains of Lancefield group B, C, or G streptococci suggests that ssa is confined to S. pyogenes.
Determination of Wear Metals in Lubrication Oils: A Comparison Study of ICP-OES and FAAS

Certain wear metals (Fe, Cr, Ni, Cu and Zn) of various lubrication oils were determined by means of ICP-OES and FAAS. The kerosene dilution method, which is used widely together with ICP-OES, was applied with both methods here. Calibration standards were made from a commercial organo-metallic standard. Our aim was to clarify the possibility of using the quick kerosene dilution method together with FAAS for a rapid check for certain indicator metals. Metal determinations with FAAS were accurate enough for quantitative work in machine condition diagnostics and waste oil characterization, when compared with those with ICP-OES.
Transforming Normality into Pathology: The DSM and the Outcomes of Stressful Social Arrangements∗

The sociology of stress shows how nondisordered people often become distressed in contexts such as chronic subordination; the losses of status, resources, and attachments; or the inability to achieve valued goals. Evolutionary psychology indicates that distress arising in these contexts stems from psychological mechanisms that are responding appropriately to stressful circumstances. A diagnosis of mental disorder, in contrast, indicates that these mechanisms are not functioning as they are designed to function. The American Psychiatric Association's Diagnostic and Statistical Manual, however, has come to treat both the natural results of the stress process and individual pathology as mental disorders. A number of social groups benefit from and promote the conflation of normal emotions with dysfunctions. The result has been to overestimate the number of people who are considered to be disordered, to focus social policy on the supposedly unmet need for treatment, and to enlarge the social space of pathology in the general culture.
Ascorbic Acid in Plants: Biosynthesis and Function

Ascorbic acid (vitamin C) is an abundant component of plants. It reaches a concentration of over 20 mM in chloroplasts and occurs in all cell compartments, including the cell wall. It has proposed functions in photosynthesis as an enzyme cofactor (including synthesis of ethylene, gibberellins and anthocyanins) and in control of cell growth. A biosynthetic pathway via GDP-mannose, GDP-L-galactose, L-galactose, and L-galactono-1,4-lactone has been proposed only recently and is supported by molecular genetic evidence from the ascorbate deficient vtc1 mutant of Arabidopsis thaliana. Other pathways via uronic acids could provide minor sources of ascorbate. Ascorbate, at least in some species, is a precursor of tartrate and oxalate. It has a major role in photosynthesis, acting in the Mehler peroxidase reaction with ascorbate peroxidase to regulate the redox state of photosynthetic electron carriers and as a cofactor for violaxanthin de-epoxidase, an enzyme involved in xanthophyll cyclemediated photoprotection. The hypersensitivity of some of the vtc mutants to ozone and UV-B radiation, the rapid response of ascorbate peroxidase expression to (photo)oxidative stress, and the properties of transgenic plants with altered ascorbate peroxidase activity all support an important antioxidative role for ascorbate. In relation to cell growth, ascorbate is a cofactor for prolyl hydroxylase that posttranslationally hydroxylates pro line residues in cell wall hydroxyproline-rich glycoproteins required for cell division and expansion. Additionally, high ascorbate oxidase activity in the cell wall is correlated with areas of rapid cell expansion. It remains to be determined if this is a causal relationship and, if so, what is the mechanism. Identification of the biosynthetic pathway now opens the way to manipulating ascorbate biosynthesis in plants, and, along with the vtc mutants, this should contribute to a deeper understanding of the proposed functions of this multifacetted molecule.
Elastic properties of cells in the context of confluent cell monolayers: impact of tension and surface area regulation

Epithelial cells usually form a dense continuous cobblestone-like sheet that is frequently exposed to a variety of mechanical challenges encompassing osmotic stress and external forces. The response to external forces was investigated and the question of how individual polar epithelial cells organized in confluent monolayers respond to pharmaceutical stimuli targeting the key players of cellular mechanics was answered. In particular, we ask how epithelial cells respond to changes in cortical and membrane tension by surface area regulation if challenged by diverse chemical and mechanical cues. Here, a tension-based model is used that allows capturing the relevant modes of cell deformation. Together with independent measurements of membrane tension, cortical tension and excess surface area of confluent MDCK II cells it is possible to draw a mechanistic picture of how confluent cells respond to mechanical stimuli in general. Changes in tension are provoked by external stimuli directed towards the contractile actomyosin cortex (cytochalasin D, blebbistatin), and changes in the excess surface area are produced by cholesterol extraction (methyl-β-cyclodextrin) or inhibition of dynamin (dynasore). A combination of AFM-indentation experiments with membrane–tether pulling at the same position allowed us to simultaneously monitor changes in membrane tension, cortical tension and excess surface area. Generally, we observed that removing or producing excess surface area of the plasma membrane readily adjusts membrane tension that is pivotal for the mechanical response of confluent cells. We found that isolated apical membranes from confluent MDCK II monolayers display similar mechanical properties as the apical side of living MDCK II cells in a confluent monolayer confirming that membrane mechanics in conjunction with cytoskeletal adhesion dominates the elastic response of confluent epithelial cells at large strain.
YOHIMBINE REVERSAL OF KETAMINE-XYLAZINE IMMOBILIZATION OF RACCOONS (PROCYON LOTOR)

Six adult raccoons (Procyon lotor) were sedated with a combination of ketamine hydrochloride (KH) at 10 mg/kg body weight and xylazine hydrochloride (XH) at 2 mg/kg body weight intramuscularly (i.m.). Twenty min after the KH-XH combination was given, yohimbine hydrochloride (YH) at either 0.1 mg/kg (Trial 1) or 0.2 mg/kg (Trial 2) body weight or a saline control (Trial 3) was administered intravenously (i.v.). The time to arousal, time to sternal recumbency and time to walking were recorded. These times were significantly shortened after YH administration [e.g., mean time to walking (MTW) at 0.2 mg/kg YH = 23.7 min] as compared to the saline controls (MTW = 108.8 min). Heart and respiratory rates both increased after YH administration, while body temperature remained constant. A fourth trial was performed using a higher ratio of KH to XH (45:1 rather than 5:1) to mimic sedation as performed in the field. The mean time to arousal (MTA) and MTW in this trial (1.3 and 23.7 min, respectively) were significantly shorter than controls and similar to YH trials performed after immobilization with 5:1 KH-XH. Yohimbine hydrochloride may be useful in field studies that require sedation of raccoons using KH-XH combinations.
[Safety of intravenous thrombolysis in cerebral microbleeds patients with prior antiplatelet therapy].

OBJECTIVE To evaluate the safety of intravenous thrombolysis (IVT) in cerebral microbleeds (CMBs) patients with prior antiplatelet therapy. METHODS Four hundred and forty nine patients with acute ischemic stroke aged (66.8 ± 12.9) years, including 298 males and 151 females, underwent susceptibility-weighted imaging (SWI) examination and MRI-guided IVT therapy between June 2009 and June 2015. The presence of CMBs, previous antiplatelet therapy, HT subtypes according to ECASS II criteria and functional outcome based on modified Rankin scale (mRS) at 3 months were analyzed in logistic regression model. RESULTS Total 934 CMBs were detected in 172 (38.3%) patients, among whom 63 (14.0%) previously received antiplatelet therapy. All patients received intravenous recombinant tissue-plasminogen activator (rt-PA) for thrombolysis with the onset-to needle time of (229.0 ± 103.7) min. The pretreatment National Institutes of Health Stroke Scale (NIHSS) score was 10 (IQR 5-15). Logistic regression analysis indicated that prior antiplatelet use increased neither risk of parenchymal hematoma (PH) (OR=0.809,95% CI:0.201-3.262, P=0.766) nor adverse functional outcome (OR=1.517, 95% CI:0.504-4.568, P=0.459) in patients with CMBs; while in patients with multiple CMBs (≥ 3) prior antiplatelet use increased risk of hemorrhagic transformation (OR=9.737, 95% CI: 1.364-69.494, P=0.023), but not adverse functional outcome (OR=1.697, 95% CI:0.275-10.487, P=0.569). CONCLUSION The study indicates that in patients with CMBs, thrombolytic therapy should not be excluded due to the prior use of antiplatelet; however, the larger prospective studies are needed in future for patients with multiple CMBs.
Serum zonulin is elevated in women with polycystic ovary syndrome and correlates with insulin resistance and severity of anovulation.

OBJECTIVE Evidence suggests that increased gut permeability may be associated with polycystic ovary syndrome (PCOS). Human zonulin is currently the only physiological mediator known to reversibly regulate gut permeability by disassembling intestinal tight junctions. So far, no data on serum zonulin levels in patients with PCOS are available. This study aimed to determine circulating serum zonulin levels in women with PCOS and discuss the relationship between zonulin, insulin resistance, and menstrual disorders in this group. DESIGN A case-control study. METHODS The study includes 78 women recently diagnosed with PCOS and 63 age-matched healthy controls recruited. Serum zonulin levels were determined by ELISA. Insulin resistance was assessed by homeostasis model assessment of insulin resistance (HOMA-IR) and Matsuda and DeFronzo's insulin sensitivity index (ISI). RESULTS PCOS women had higher serum zonulin levels (P=0.022). After adjustment for age and BMI, zonulin levels significantly correlated with HOMA-IR and ISI. Furthermore, PCOS women with more severe menstrual disorders had significantly higher zonulin levels and displayed an inverse correlation between zonulin and the number of menstrual cycles per year (r=-0.398, P<0.001). CONCLUSIONS Serum zonulin, a biomarker for gut permeability, is increased in PCOS women and correlates with insulin resistance and severity of menstrual disorders. It suggests that alterations in gut permeability may play a role in the pathophysiology of PCOS, and serum zonulin might be used as a biomarker for both risk stratification and therapeutic outcomes in PCOS women.
Caspase 1 deficiency reduces inflammation-induced brain transcription

The systemic inflammatory response syndrome (SIRS) is a life-threatening medical condition characterized by a severe and generalized inflammatory state that can lead to multiple organ failure and shock. The CNS regulates many features of SIRS such as fever, cardiovascular, and neuroendocrine responses. Central and systemic manifestations of SIRS can be induced by LPS or IL-1β administration. The crucial role of IL-1β in inflammation has been further highlighted by studies of mice lacking caspase 1 (casp1, also known as IL-1β convertase), a protease that cleaves pro-IL-1β into mature IL-1β. Indeed, casp1 knockout (casp1−/−) mice survive lethal doses of LPS. The key role of IL-1β in sickness behavior and its de novo expression in the CNS during inflammation led us to test the hypothesis that IL-1β plays a major role modulating the brain transcriptome during SIRS. We show a gene–environment effect caused by LPS administration in casp1−/− mice. During SIRS, the expression of several genes, such as chemokines, GTPases, the metalloprotease ADAMTS1, IL-1RA, the inducible nitric oxide synthase, and cyclooxygenase-2, was differentially increased in casp1−/− mice. Our findings may contribute to the understanding of the molecular changes that take place within the CNS during sepsis and SIRS and the development of new therapies for these serious conditions. Our results indicate that those genes may also play a role in several neuropsychiatric conditions in which inflammation has been implicated and indicate that casp1 might be a potential therapeutic target for such disorders.
Regulation of Calcium/Calmodulin-dependent Protein Kinase II Docking toN-Methyl-d-aspartate Receptors by Calcium/Calmodulin and α-Actinin*

Ca2+ influx through theN-methyl-d-aspartate (NMDA)-type glutamate receptor leads to activation and postsynaptic accumulation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) and ultimately to long term potentiation, which is thought to be the physiological correlate of learning and memory. The NMDA receptor also serves as a CaMKII docking site in dendritic spines with high affinity binding sites located on its NR1 and NR2B subunits. We demonstrate that high affinity binding of CaMKII to NR1 requires autophosphorylation of Thr286. This autophosphorylation reduces the off rate to a level (t 1 2 = ∼23 min) that is similar to that observed for dissociation of the T286D mutant CaMKII (t 1 2 = ∼30 min) from spines after its glutamate-induced accumulation (Shen, K., Teruel, M. N., Connor, J. H., Shenolikar, S., and Meyer, T. (2000) Nat. Neurosci. 3, 881–886). CaMKII as well as the previously identified NR1 binding partners calmodulin and α-actinin bind to the short C-terminal portion of the C0 region of NR1. Like Ca2+/calmodulin, autophosphorylated CaMKII competes with α-actinin-2 for binding to NR1. We conclude that the NR1 C0 region is a key site for recruiting CaMKII to the postsynaptic site, where it may act in concert with calmodulin to modulate the stimulatory role of α-actinin interaction with the NMDA receptor.
The validity of the Finnish Diabetes Risk Score for the prediction of the incidence of coronary heart disease and stroke, and total mortality

Background Cardiovascular disease shares several risk factors with type 2 diabetes. We tested whether the Finnish Diabetes Risk Score (FINDRISC), recently developed in a Finnish population to estimate the future risk of diabetes, would also identify individuals at high risk of coronary heart disease (CHD) and stroke, and total mortality in this same population. Design Independent risk factor surveys were conducted in 1987, 1992, and 1997 in Finland, comprising 8268 men and 9457 women aged 25-64 years and free of CHD and stroke at baseline. During the follow-up until the end of 2001, 699 incident acute CHD events, 324 acute stroke events, and 765 deaths occurred. Methods The data were analysed by using receiver operating characteristic (ROC) curves and the Cox-regression model. Results The areas under the ROC curves (AUC) were 71% for CHD, 73% for stroke, and 68% for total mortality in men and 78, 68, and 72% in women, respectively. The addition of systolic and diastolic blood pressures, total and high-density lipoprotein cholesterol, and smoking increased the AUC values modestly (the change of the absolute values from 2.6 to 6.5%), but the additional use of plasma glucose had only a slight effect on the AUC values for CHD and stroke. Conclusions The FINDRISC is a reasonably good predictor of CHD, stroke and total mortality.
Toll-like receptor 4 polymorphisms and atherogenesis.

BACKGROUND The ability to mount a prominent inflammatory response to bacterial pathogens confers an advantage in innate immune defense but may signal an increased risk of atherosclerosis. We determined whether recently discovered genetic variants of toll-like receptor 4 (TLR4) that confer differences in the inflammatory response elicited by bacterial lipopolysaccharide are related to the development of atherosclerosis. METHODS As part of the five-year follow-up in the Bruneck (Italy) Study, we screened 810 persons in the study cohort for the TLR4 polymorphisms Asp299Gly and Thr399Ile. The extent and progression of carotid atherosclerosis were assessed by high-resolution duplex ultrasonography. RESULTS As compared with subjects with wild-type TLR4, the 55 subjects with the Asp299Gly TLR4 allele had lower levels of certain proinflammatory cytokines, acute-phase reactants, and soluble adhesion molecules, such as interleukin-6 and fibrinogen. Although these subjects were found to be more susceptible to severe bacterial infections, they had a lower risk of carotid atherosclerosis (odds ratio, 0.54; 95 percent confidence interval, 0.32 to 0.98; P=0.05) and a smaller intima-media thickness in the common carotid artery (regression coefficient, -0.07; 95 percent confidence interval, -0.12 to -0.02; P=0.01). CONCLUSIONS The Asp299Gly TLR4 polymorphism, which attenuates receptor signaling and diminishes the inflammatory response to gram-negative pathogens, is associated with a decreased risk of atherosclerosis. This finding is consistent with the hypothesis that innate immunity may play a part in atherogenesis.