Miracle-dz/UniFAR-FTUs huggingface dataset:
Combination peptide immunotherapy suppresses antibody and helper T-cell responses to the major human platelet autoantigen glycoprotein IIb/IIIa in HLA-transgenic mice

Platelet destruction in immune thrombocytopenia is caused by autoreactive antibody and T-cell responses, most commonly directed against platelet glycoprotein IIb/IIIa. Loss of self-tolerance in the disease is also associated with deficient activity of regulatory T cells. Having previously mapped seven major epitopes on platelet glycoprotein IIIa that are recognized by helper T cells from patients with immune thrombocytopenia, the aim was to test whether peptide therapy with any of these sequences, alone or in combination, could inhibit responses to the antigen in humanized mice expressing HLA-DR15. None of the individual peptides, delivered by a putative tolerogenic regimen, consistently suppressed the antibody response to subsequent immunization with human platelet glycoprotein IIb/IIIa. However, the combination of glycoprotein IIIa peptides aa6-20 and aa711-725, which contain the predominant helper epitopes in patients and elicited the strongest trends to suppress when used individually, did abrogate this response. The peptide combination also blunted, but did not reverse, the ongoing antibody response when given after immunization. Suppression of antibody was associated with reduced splenocyte T-cell responsiveness to the antigen, and with the induction of a regulatory T-cell population that is more responsive to the peptides than to purified platelet glycoprotein IIb/IIIa. Overall, these data demonstrate that combinations of peptides containing helper epitopes, such as platelet glycoprotein IIIa aa6-20 and aa711-725, can promote in vivo suppression of responses to the major antigen implicated in immune thrombocytopenia. The approach offers a promising therapeutic option to boost T-cell regulation, which should be taken forward to clinical trials.
LncRNAs, MALAT1 and lnc-DC as potential biomarkers for multiple sclerosis diagnosis

Long non-coding RNAs (lncRNAs) play an important role in gene regulation and show greater tissue specificity and complexity of biological functions. There is on-going research in their contribution in autoimmune diseases like multiple sclerosis (MS). Our study aimed at the evaluation of serum levels of lncRNAs, MALAT1 and lnc-DC in MS patients and the investigation of the association between these lncRNAs and the disease activity. Serum from 45 MS patients and 45 healthy controls was separated. MALAT1 and lnc-DC expression levels were assayed by qRT-PCR. MALAT1 and lnc-DC were significantly increased in MS patients (P=0.004 and P=0.006, respectively) in comparison with controls. There was a significant increase in expression of MALAT1 in secondary progressive MS (SPMS) subgroup compared with controls (P<0.0001); however, significant elevation of lnc-DC was demonstrated in relapsing remitting MS (RRMS) subtype (P=0.003) compared with normal controls. A positive association between the expression levels of MALAT1 and lnc-DC (r = 0.513, P < 0.0001) in MS patients was detected. Moreover, positive correlation was observed between MALAT1and lnc-DC in RRMS (r = 0.569, P = 0.001). Serum levels of MALAT1 and lnc-DC may serve as potential novel molecular biomarkers for MS diagnosis and may provide a new direction for its treatment.
Nonylphenol, octylphenol, and bisphenol-A in the aquatic environment: A review on occurrence, fate, and treatment

This paper reviews the current knowledge on the occurrence, biodegradation, and photooxidation of nonylphenol (NP), octylphenol (OP), and bisphenol-A (BPA) in aquatic environment. Generally, the concentrations determined were 0.006–32.8, < 0.001–1.44, and 0.0005–4.0 μ g L−1 for NP, OP, and BPA respectively in river waters worldwide. Anthropogenic activities that can lead to run-off and storm water discharge may contribute to such concentrations in rivers. Pathways for biodegradation of NP and BPA appear to be similar. The influence of ferric ions, oxalate, hydrogen peroxide, and dissolved organic matter (DOM) on the photooxidation of NP and BPA in natural water is presented. Several techniques including nanofiltration, adsorption, sonochemical, photocatalytic, chlorination, ozonation, and ferrate(VI) oxidation for removals of NP, OP, and BPA are also reviewed.
Defining cooperative roles for colonic microbiota and Muc2 mucin in mediating innate host defense against Entamoeba histolytica

Amebiasis is caused by the protozoan parasite Entamoeba histolytica (Eh), a potentially fatal disease occurring mainly in developing countries. How Eh interacts with innate host factors in the gut is poorly understood. Eh resides and feed in/on the outer colonic mucus layer and thus share an ecological niche with indigenous microbiota. As gut microbiota regulates innate immune responses, in this study we characterized the cooperative roles that microbiota and the mucus layer play in Eh-induced pro-inflammatory responses in the colon. To study this, we used antibiotics treated and non-treated specific pathogen free Muc2-/- and Muc2+/+ littermates and germ-free mice inoculated with Eh in colonic loops as a short infection model. In antibiotic treated Muc2-/- and Muc2+/+ littermates, Eh elicited robust mucus and water secretions, enhanced pro-inflammatory cytokines and chemokine expression with elevated MPO activity and higher pathology scores as compared to the modest response observed in non-antibiotic treated littermates. Host responses were microbiota specific as mucus secretion and pro-inflammatory responses were attenuated following homologous fecal microbial transplants in antibiotic-treated Muc2+/+ quantified by secretion of 3H-glucosamine newly synthesized mucin, Muc2 mucin immunostaining and immunohistochemistry. Eh-elicited pro-inflammatory responses and suppressed goblet cell transcription factor Math1 as revealed by in vivo imaging of Eh-colonic loops in Math1GFP mice, and in vitro using Eh-stimulated LS174T human colonic goblet cells. Eh in colonic loops increased bacterial translocation of bioluminescent E. coli and indigenous bacteria quantified by FISH and quantitative PCR. In germ-free animals, Eh-induced mucus/water secretory responses, but acute pro-inflammatory responses and MPO activity were severely impaired, allowing the parasite to bind to and disrupt mucosal epithelial cells. These findings have identified key roles for intestinal microbiota and mucus in regulating innate host defenses against Eh, and implicate dysbiosis as a risk factor for amebiasis that leads to exacerbated immune responses to cause life-threatening disease.
Pregnancy and multiple sclerosis in the DMT era: A cohort study in Western Austria

Background: Multiple sclerosis (MS) predominantly affects women of child-bearing potential. Pregnancy in MS is still a controversial issue lacking standardized treatment recommendations. Objective: To examine the reciprocal effects of pregnancy, MS, and disease-modifying treatment (DMT). Methods: We analyzed 387 pregnancies in 239 women with relapsing remitting multiple sclerosis (RRMS) and ⩾1 pregnancy, establishment of diagnosis >1 year before conception, and ⩾2 years of follow-up after delivery. Relapse rates and Expanded Disability Status Scale (EDSS) scores were compared in the year before conception, during pregnancy, and 2 years postpartum. Binary logistic regression was used to investigate predictors of risk for relapses and disability progression during pregnancy and postpartum. Results: Risk of relapse and disability progression during pregnancy was predicted by pre-conception relapse activity, higher EDSS score at conception, use of highly effective disease-modifying treatment (H-DMT) pre-conception, and prolonged washout period. Postpartum relapse and disability progression was associated with relapse activity pre-conception and during pregnancy and use of H-DMT pre-conception. Early restart of DMT reduced the risk of postpartum relapse. Conclusion: A personalized approach in planning pregnancy in women with MS while on H-DMT needs to be adopted. It seems reasonable maintaining natalizumab closer to conception and restarting the drug early postpartum to reduce the considerable risk of disease reactivation during early pregnancy and after delivery.
Egocentrism in sub-clinical depression

ABSTRACT Depression is marked by rigid thinking and the inability to generate different and more positive views on the self. The current study conceptualises this a perspective-taking deficit, which is defined as a deficit in the ability to overcome one’s egocentrism. Previous research has demonstrated that individuals with depression are impaired in Theory of Mind reasoning and empathy – two social cognitions that involve cognitive and affective perspective-taking. Here, it was investigated whether these deficits generalise to visuo-spatial perspective-taking. To test this, a convenience sample (N = 268; n = 62 high depressive symptoms; n = 206 healthy control participants) completed a test-battery including measures of cognitive and visuo-spatial perspective-taking and closely matched cognitive and visuo-spatial control tasks. The results showed that individuals exhibiting high levels of depressive symptoms were specifically impaired on both perspective-taking tasks but performed equally well on the control tasks. Interventions to combat rigid thinking in depression are discussed.
Generalized breast density metrics

Mammograms represent data that can inform future risk of breast cancer. Data from two case-control study populations were analyzed. Population 1 included women (N = 180 age matched case-control pairs) with mammograms acquired with one indirect x-ray conversion mammography unit. Population 2 included women (N = 319 age matched case-control pairs) with mammograms acquired from 6 direct x-ray conversion units. The Fourier domain was decomposed into n concentric rings (radial spatial frequency bands). The power in each ring was summarized giving a set of measures. We investigated images in raw, for presentation (processed) and calibrated representations and made comparison with the percentage of breast density (BD) determined with the operator assisted Cumulus method. Breast cancer associations were evaluated with conditional logistic regression, adjusted for body mass index and ethnicity. Odds ratios (ORs), per standard deviation increase derived from the respective breast density distributions and 95% confidence intervals (CIs) were estimated. A measure from a lower radial frequency ring, corresponding 0.083–0.166 cycles mm−1 and BD had significant associations with risk in both populations. In Population 1, the Fourier measure produced significant associations in each representation: OR = 1.76 (1.33, 2.32) for raw; OR = 1.43 (1.09, 1.87) for processed; and OR = 1.68 (1.26, 2.25) for calibrated. BD also provided significant associations in Population 1: OR = 1.72 (1.27, 2.33). In Population 2, the Fourier measure produced significant associations for each representation as well: OR = 1.47 (1.19, 1.80) for raw; OR = 1.38 (1.15, 1.67) for processed; and OR = 1.42 (1.15, 1.75) for calibrated. BD provided significant associations in Population 2: OR = 1.43 (1.17, 1.76). Other coincident spectral regions were also predictive of case-control status. In sum, generalized breast density measures were significantly associated with breast cancer in both FFDM technologies.
Diagnosis of Pneumocystis jirovecii pneumonia with serum cell-free DNA in non-HIV-infected immunocompromised patients

Conventional respiratory tract specimens, such as bronchoalveolar lavage (BAL) fluid and induced sputum for diagnosing Pneumocystis jirovecii pneumonia (PCP) in immunocompromised patients are difficult to obtain. Besides, bronchoscopy is an invasive procedure that carries the risk of causing rapidly progressive respiratory insufficiency. By contrast, serum cell-free DNA (cfDNA) is easy to obtain and has been proven useful in diagnosing cancer, pregnancy associated complications, parasite infection and sepsis. In this study, we performed quantitative polymerase chain reaction (qPCR) to assess the diagnostic efficiency of using serum cfDNA, BAL fluid, and sputum DNA for PCP. Seventy-one patients (35 PCP patients and 36 non-PCP patients) were enrolled according to the clinical PCP diagnostic criteria. The sensitivity, specificity, positive predictive value, and negative predictive value of PCR using serum cfDNA were 68.6% (95% CI, 50.7–83.1), 97.2% (95% CI, 85.5–99.9), 96.0%, and 76.1%, respectively. PCR using BAL fluid and sputum had a high sensitivity (97.1% and 91.4%, respectively) but relatively low specificity (86.1% and 86.1%, respectively). The combination of the sputum PCR OR serum cfDNA PCR yielded a sensitivity of 97.1%. These results indicated that serum cfDNA might be a valuable method in PCP diagnosis.
EFFECT OF RECENT ANTIGEN PRIMING ON ADOPTIVE IMMUNE RESPONSES

When thoracic duct lymphocytes (TDL) or mesenteric lymph node (MLN) cells from mice primed 1 day before with either sheep erythrocytes (SRC) or horse erythrocytes (HRC) were transferred together with both SRC and HRC to irradiated mice, antibody responses measured 7 days later could not be detected to the priming antigen but were high to the other antigen. Furthermore, this unresponsiveness of TDL and MLN to the priming antigen could not be abrogated by delaying antigen challenge of the transferred cells for 1–2 wk. Previous work had shown that short-term priming with antigen also induced specific unresponsiveness in spleen cells on adoptive transfer. Unresponsiveness in these cells, however, was only of temporary duration, full recovery in the reactivity of the cells being observed when challenge with the priming antigen on transfer was delayed for 5 or more days. Since the present work showed that such recovery from initial unresponsiveness on transfer was unique to spleen cells and did not apply to TDL or MLN, it appeared that different mechanisms were responsible for the unresponsiveness in the three populations. It is proposed that the unresponsiveness detected in TDL and MLN cells in the present study resulted from a deficiency of antigen-reactive cells, these cells having been recruited to the spleen, i.e., a region of antigen concentration. This concept of antigen-induced selective recruitment of circulating lymphocytes was supported by evidence that 51Cr-labeled heterologous erythrocytes indeed localized largely in the spleen after intravenous injection but not in MLN.
Modulation of tactile perception by Virtual Reality distraction: The role of individual and VR-related factors

Background Virtual reality (VR) has shown to be an effective distraction method in health care. However, questions remain regarding individual and VR-related factors that may modulate the effect of VR. Purpose To explore the effect of VR distraction on tactile perception thresholds in healthy volunteers, in relation to personal characteristics and interactivity of VR applications. Methods A randomized three way cross-over study was conducted to investigate the effects of active and passive VR applications in 50 healthy participants. Main outcome measures were monofilament detection thresholds (MDT) and electrical detection thresholds (EDT). Personal characteristics (e.g. age, gender, susceptibility for immersion) and immersion in the VR conditions were analyzed for their effect on VR induced threshold differences. Results The use of VR caused a significant increase in both MDT and EDT compared to the control condition (MDT: F (2, 76) = 20.174, p < 0.001; EDT F (2, 76) = 6.907, p = 0.002). Furthermore, a significant difference in favour of active VR compared to passive VR was found in MDT (p = 0.012), but not in EDT. No significant gender effect was found. There was a significant positive correlation between age and active VR distraction (r = 0.333, p = 0.018). Immersion in the VR world was positively correlated with the effect of VR, whereas visualization and daydreaming were negatively correlated with VR effects. Conclusion VR increased tactile perception thresholds, with active VR having the largest effect. Results indicate that the efficacy of VR may increase with increasing age. Gender did not affect VR susceptibility.
Stigma management intervention to improve antiretroviral therapy adherence: Phase-I test of concept trial, Cape Town South Africa

ABSTRACT Combination antiretroviral therapy (cART) has transformed HIV infection from a universally fatal disease to a medically manageable chronic illness. We conducted a Phase-I test of concept intervention trial to examine feasibility and potential efficacy of behavioural self-regulation counselling designed to improve care retention and cART adherence. The intervention was culturally adapted from client-centered evidence–based interventions that are grounded in behavioural self-regulation theory and available in the US. The intervention adaptation included enhancements to directly address HIV stigma and alcohol-related sources of nonadherence. Fifty patients receiving cART in Cape Town, South Africa were randomised to receive either: (a) five weekly cellphone-delivered sessions of stigma and alcohol-enhanced behavioural self-regulation counselling or (b) a contact matched control condition. Participants were baseline assessed and followed for two weeks post-intervention, with 94% of participants retained throughout the study. Participants receiving the intervention significantly improved cART adherence from baseline-to-follow up and improvement was significantly greater than the control condition. Behaviours related to stigma and alcohol use that impede cART adherence were significantly reduced, and there was uptake of adherence improvement strategies. The current study supports the potential efficacy of relatively brief behavioural self-regulation counselling delivered by cellphone in a context of differentiated care in South Africa.
Psychiatric Characteristics of the Cardiac Outpatients with Chest Pain

Background and Objectives A cardiologist's evaluation of psychiatric symptoms in patients with chest pain is rare. This study aimed to determine the psychiatric characteristics of patients with and without coronary artery disease (CAD) and explore their relationship with the intensity of chest pain. Subjects and Methods Out of 139 consecutive patients referred to the cardiology outpatient department, 31 with atypical chest pain (heartburn, acid regurgitation, dyspnea, and palpitation) were excluded and 108 were enrolled for the present study. The enrolled patients underwent complete numerical rating scale of chest pain and the symptom checklist for minor psychiatric disorders at the time of first outpatient visit. The non-CAD group consisted of patients with a normal stress test, coronary computed tomography angiogram, or coronary angiogram, and the CAD group included those with an abnormal coronary angiogram. Results Nineteen patients (17.6%) were diagnosed with CAD. No differences in the psychiatric characteristics were observed between the groups. "Feeling tense", "self-reproach", and "trouble falling asleep" were more frequently observed in the non-CAD (p=0.007; p=0.046; p=0.044) group. In a multiple linear regression analysis with a stepwise selection, somatization without chest pain in the non-CAD group and hypochondriasis in the CAD group were linearly associated with the intensity of chest pain (β=0.108, R2=0.092, p=0.004; β= -0.525, R2=0.290, p=0.010). Conclusion No differences in psychiatric characteristics were observed between the groups. The intensity of chest pain was linearly associated with somatization without chest pain in the non-CAD group and inversely linearly associated with hypochondriasis in the CAD group.
Adaptor protein complex-1 (AP-1) is recruited by the HEATR5 protein Laa1 and its co-factor Laa2 in yeast

Cellular membrane trafficking mediated by the clathrin adaptor protein complex-1 (AP-1) is important for the proper composition and function of organelles of the endolysosomal system. Normal AP-1 function requires proteins of the HEAT repeat–containing 5 (HEATR5) family. Although HEATR5 proteins were first identified based on their ability to interact with AP-1, the functional significance of this interaction was unknown. We used bioinformatics-based phenotypic profiling and information from genome-wide fluorescence microscopy studies in the budding yeast Saccharomyces cerevisiae to identify a protein, Laa2, that mediates the interaction between AP-1 and the yeast HEATR5 protein Laa1. Further characterization of Laa2 revealed that it binds to both Laa1 and AP-1. Laa2 contains a motif similar to the characterized γ-ear–binding sites found in other AP-1–binding proteins. This motif in Laa2 is essential for the Laa1–AP-1 interaction. Moreover, mutation of this motif disrupted AP-1 localization and function and caused effects similar to mutations that remove the γ-ear of AP-1. These results indicate that Laa2 mediates the interaction between Laa1 and AP-1 and reveal that this interaction promotes the stable association of AP-1 with membranes in yeast.
A stochastic framework to model axon interactions within growing neuronal populations

The confined and crowded environment of developing brains imposes spatial constraints on neuronal cells that have evolved individual and collective strategies to optimize their growth. These include organizing neurons into populations extending their axons to common target territories. How individual axons interact with each other within such populations to optimize innervation is currently unclear and difficult to analyze experimentally in vivo. Here, we developed a stochastic model of 3D axon growth that takes into account spatial environmental constraints, physical interactions between neighboring axons, and branch formation. This general, predictive and robust model, when fed with parameters estimated on real neurons from the Drosophila brain, enabled the study of the mechanistic principles underlying the growth of axonal populations. First, it provided a novel explanation for the diversity of growth and branching patterns observed in vivo within populations of genetically identical neurons. Second, it uncovered that axon branching could be a strategy optimizing the overall growth of axons competing with others in contexts of high axonal density. The flexibility of this framework will make it possible to investigate the rules underlying axon growth and regeneration in the context of various neuronal populations.
Adenosine 2a Receptor Signal Blockade of Murine Autoimmune Arthritis via Inhibition of Pathogenic Germinal Center–Follicular Helper T Cells

CD4 germinal center (GC)–follicular helper T (Tfh) cells are important in the pathogenesis of autoimmune arthritis. Previous studies have shown that adenosine 2a receptor (A2aR; Adora2a) signaling can divert CD4 T cells away from the GC‐Tfh cell lineage during the primary response to foreign antigens. This study was undertaken to examine the effects of A2aR signaling on CD4 T cells during the recognition of self antigen in a murine model of autoimmune arthritis.