Miracle-dz/UniFAR-FTUs huggingface dataset:
Intradermal vaccination of HPV-16 E6 synthetic peptides conjugated to an optimized Toll-like receptor 2 ligand shows safety and potent T cell immunogenicity in patients with HPV-16 positive (pre-)malignant lesions

Background Amplivant is a molecularly optimized Toll-like receptor 2 ligand that can be covalently conjugated to tumor peptide antigens. In preclinical models, amplivant-adjuvanted synthetic long peptides (SLPs) strongly enhanced antigen presentation by dendritic cells, T cell priming and induction of effective antitumor responses. The current study is a first-in-human trial to investigate safety and immunogenicity of amplivant conjugated to human papillomavirus (HPV) 16-SLP. Methods A dose escalation phase I vaccination trial was performed in 25 patients treated for HPV16 positive (pre-)malignant lesions. Amplivant was conjugated to two SLPs derived from the two most immunodominant regions of the HPV16 E6 oncoprotein. The vaccine, containing a mix of these two conjugates in watery solution without any other formulation, was injected intradermally three times with a 3-week interval in four dose groups (1, 5, 20 or 50 µg per conjugated peptide). Safety data were collected during the study. Peptide-specific T cell immune responses were determined in blood samples taken before, during and after vaccination using complementary immunological assays. Results Toxicity after three amplivant-conjugated HPV16-SLP vaccinations was limited to grade 1 or 2, observed as predominantly mild skin inflammation at the vaccination site and sometimes mild flu-like symptoms. Adverse events varied from none in the lowest dose group to mild/moderate vaccine-related inflammation in all patients and flu-like symptoms in three out of seven patients in the highest dose group, after at least one injection. In the lowest dose group, vaccine-induced T cell responses were observed in the blood of three out of six vaccinated persons. In the highest dose group, all patients displayed a strong HPV16-specific T cell response after vaccination. These HPV16-specific T cell responses lasted until the end of the trial. Conclusions Amplivant-conjugated SLPs can safely be used as an intradermal therapeutic vaccine to induce robust HPV16-specific T cell immunity in patients previously treated for HPV16 positive (pre-) malignancies. Increased vaccine dose was associated with a higher number of mild adverse events and with stronger systemic T cell immunity. Trial registration numbers NCT02821494 and 2014-000658-12.
The metabolomics of human aging: Advances, challenges, and opportunities

As the global population becomes older, understanding the impact of aging on health and disease becomes paramount. Recent advancements in multiomic technology have allowed for the high-throughput molecular characterization of aging at the population level. Metabolomics studies that analyze the small molecules in the body can provide biological information across a diversity of aging processes. Here, we review the growing body of population-scale metabolomics research on aging in humans, identifying the major trends in the field, implicated biological pathways, and how these pathways relate to health and aging. We conclude by assessing the main challenges in the research to date, opportunities for advancing the field, and the outlook for precision health applications.
Ventricular-arterial coupling assessed by PWV/GLS ratio in hypertensive patients.

OBJECTIVE The physiological interaction between the left ventricle (LV) and the arterial system, defined as ventricular-arterial coupling (VAC), facilitates the optimal volume of cardiac work and cardiovascular performance. The aim of this study was to evaluate the benefit of PWV/GLS ratio associated with other vascular and cardiac performance parameters in hypertensive patients compared to age-matched healthy controls. PATIENTS AND METHODS We calculated the ratio of pulse wave velocity (PWV), as a marker of arterial stiffness, to global longitudinal strain (GLS), as a marker of left ventricular function in 135 patients divided in 3 groups, as follows: group 1 (HT + CAD) enrolled 54 hypertensive patients with coronary artery disease, group 2 (HT) enrolled 43 hypertensive patients and group 3 (CON) represented the control group consisting of 38 age-matched healthy subjects. RESULTS GLS values were significantly reduced in HT+CAD (-17.50±7.2) vs. HT (-17.95±5.3) vs. control (-20.13±4.6) (p-value <0.001). PWV values were higher in HT+CAD (9.90±3.1) and HT (9.70±2.5) vs. control (7.85±3.2) (p-value <0.001). VA coupling measured by the PWV/GLS ratio showed significantly lower values in HT+CAD and HT vs. control (p-value <0.001). The ROC curve identified a threshold of -0.054 of the PWV/GLS ratio to detect altered ventricular-arterial coupling AUROC = 0.836, 95% CI [0.762; 0.909]. CONCLUSIONS This study demonstrated that assessment of the PWV/GLS ratio represents a useful tool to detect altered ventricular-arterial coupling in hypertensive patients. The perspectives of future use could include monitoring of earlier development of multiple organ damage in hypertensive patients and the efficacy of the different hypertensive medications. Extensive prospective studies are needed to confirm this hypothesis.
The many layers of BOLD. The effect of hypercapnic and hyperoxic stimuli on macro- and micro-vascular compartments quantified by CVR, M, and CBV across cortical depth

Ultra-high field functional magnetic resonance imaging (fMRI) offers the spatial resolution to measure neuronal activity at the scale of cortical layers. However, cortical depth dependent vascularization differences, such as a higher prevalence of macro-vascular compartments near the pial surface, have a confounding effect on depth-resolved blood-oxygen-level dependent (BOLD) fMRI signals. In the current study, we use hypercapnic and hyperoxic breathing conditions to quantify the influence of all venous vascular and micro-vascular compartments on laminar BOLD fMRI, as measured with gradient-echo (GE) and spin-echo (SE) scan sequences, respectively. We find that all venous vascular and micro-vascular compartments are capable of comparable theoretical maximum signal intensities, as represented by the M-value parameter. However, the capacity for vessel dilation, as reflected by the cerebrovascular reactivity (CVR), is approximately two and a half times larger for all venous vascular compartments combined compared to the micro-vasculature at superficial layers. Finally, there is roughly a 35% difference in estimates of CBV changes between all venous vascular and micro-vascular compartments, although this relative difference was approximately uniform across cortical depth. Thus, our results suggest that fMRI BOLD signal differences across cortical depth are likely caused by differences in dilation properties between macro- and micro-vascular compartments.
Use of an Online Forum for Relatives of People With Psychosis and Bipolar Disorder: Mixed Methods Study

Background Relatives of people with psychosis or bipolar disorder experience high levels of distress but are typically not offered the support they need. Online peer forums may offer a solution, but knowledge about who uses them, how, and why is limited. This study reported on online forum use during the Relatives Education and Coping Toolkit (REACT) trial. Objective We aimed to report who used the forum and why; how sociodemographic factors are associated with participation; the relationship among frequency, type of use, and outcomes; and how the forum was used. Methods The relationships between key sociodemographic characteristics, levels of forum use, and distress were statistically analyzed. We used thematic and semantic analyses to understand the reasons for relatives joining the forum and the key topics initiated by them. We also used the University Centre for Computer Corpus Research on Language Semantic Analysis System to compare how relatives and REACT supporters (moderators) used the forum. Results A total of 348 participants with full forum use data from REACT were included in this study. The forum was accessed by 59.4% (207/348) of the relatives across the entire age range, with no significant associations between sociodemographic factors and forum participation, or between level or type of use and relatives’ distress levels. Relatives joined the forum primarily to find people in similar circumstances, express concerns, and talk about stressful events. Relatives were most concerned about recent events, negative emotions linked to caring, experiences of conflict or threat, and concerns about suicide. These posts underscored both the challenges the relatives were facing and the fact that they felt safe sharing them in this context. Conclusions Although only a proportion of REACT participants engaged actively with its forum, they were widely distributed across age and other sociodemographic groupings. Relatives used the forum for information, support, and guidance and to offer detailed information about their experiences. The topics raised highlighted the burden carried by relatives and the potential value of easy-access, moderated, peer-supported forums in helping relatives to manage the challenges they faced.
A Performance-Based Framework for Bridge Preservation Based on Damage-Integrated System-Level Behavior

The safety and condition of transportation infrastructure has been at the forefront of national debates in recent times due to catastrophic bridge failures, but the issue has been a longstanding challenge for transportation agencies for many years as resources continue to diminish. The performance of this infrastructure has a direct influence on the lives of most of citizens in developed regions by providing a critical lifeline between communities and the transportation of goods and services, and as a critical component of the transportation network, bridges have received a lot of attention regarding condition assessment and maintenance practices. Despite successful implementation of advanced evaluation techniques, what is still lacking is a fundamental understanding of the system behavior in the presence of deteriorating conditions that can be used for preservation decision-making. This paper aims to present a performance-based framework that can be used to characterize the behavior of in-service bridge superstructures. In order to measure the bridge system performance with deteriorating conditions, system-level behavior of a representative composite steel girder bridge, degraded with three common damage scenarios was investigated in this study. Results obtained from validated numerical analysis demonstrated significant impact of integrated damage mechanisms on the ultimate capacity, redundancy and system ductility of the simulated bridge superstructure. It is expected that the proposed framework for evaluating system behavior will provide a first step for establishing a critical linkage between design, maintenance, and rehabilitation of highway bridges, which are uncoupled in current infrastructure decision-making processes.
Is intestinal permeability increased in obesity? A review including the effects of dietary, pharmacological and surgical interventions on permeability and the microbiome

Obesity is among the diseases that have been associated with increased intestinal permeability or ‘leaky gut’, and this defect may facilitate dietary and microbial antigen influx leading to chronic inflammation, tissue damage and allergy. Such a defect is considered a factor predisposing to the inflammatory state associated with obesity, or to observations such as increased glucose in the wall of the intestine shown by combined positron emission tomography and magnetic resonance imaging in patients with type 2 diabetes treated with metformin, consistent with the report of a reduced rate of small intestinal glucose absorption in type 2 diabetes. Alterations in mucosal permeability may also impact the absorption of intraluminal molecules, which are dependent on diffusion for their concentrationdependent uptake. An example is the absorption of propionate by colonic mucosa that improves beta-cell function in humans. Altered barrier function has also been reported to be a factor impacting the effect of the microbiota in type 2 diabetes. The objective of this review is to appraise the evidence supporting the hypothesis that the intestinal barrier is deficient in human obesity. The review is based on a PubMed search using the terms overweight, obesity, weight loss, barrier, permeability, intestine, treatment, zonulin, endotoxin, lipopolysaccharide (LPS), LPSbinding globulin and combinations of these terms. The review includes observations of intestinal permeability in overweight or obesity at baseline, as well as after dietary, pharmacological and surgical interventions. The objective was not to appraise the evidence of altered microbiota in obesity that has been appraised elsewhere. Pivotal observations included the original observation (subsequently confirmed in other studies) of the altered composition in the microbiota of obese humans with a marked decrease in bacterial diversity, and similar characteristics to obese mice, with a higher proportion of Firmicutes and comparatively less Bacteroidetes. Studies conducted in lean and obese twins showed that obesity is associated with phylum-level changes in the microbiota, reduced bacterial diversity and altered representation of bacterial genes and metabolic pathway. Another analysis showed only small, but statistically significant, differences in phylum-level taxonomic composition between lean and obese individuals in several cohorts, with no association between body mass index (BMI) and taxonomic composition of stool microbiomes in the larger Human Microbiome Project and MetaHIT datasets. More recently, there have been recommendations on directions to advance the obesity-microbiome field, with particular emphasis on the development of microbiome-targeted therapies for obesity prevention and treatment. In the current review, effects of weight loss interventions on the intestinal permeability included effects on the microbiome, and the latter effects are also included.
Mental health of autistic adults during the COVID-19 pandemic: The impact of perceived stress, intolerance of uncertainty, and coping style

Autistic individuals are at particular risk of experiencing mental health problems during the COVID-19 pandemic, yet little is known about personal characteristics that may underlie this vulnerability. This longitudinal questionnaire study with 149 autistic and 147 non-autistic adults investigated the association between perceived stress and anxiety and depressive symptoms, measured 4 months later. In addition, the moderating impact of intolerance of uncertainty and coping styles on this association was examined. Confirming previous studies, autistic adults reported poorer mental health than non-autistic individuals. Results demonstrated similar moderation models across individuals with versus without autism. Perceived stress at timepoint 1 was associated with anxiety and depression at timepoint 2. Across both participant groups, individuals with maladaptive coping strategies and higher levels of intolerance of uncertainty at timepoint 1 showed more internalizing symptoms at timepoint 2. The findings demonstrate the burden of the pandemic on the mental health of autistic adults, especially on those with high levels of perceived stress, maladaptive coping strategies, or intolerance of uncertainty. Interventions to support autistic adults during and after the pandemic might involve providing psychoeducation about the impact of stress, coping, and intolerance of uncertainty on internalizing symptoms, and teaching more adaptive ways to cope with difficult circumstances. Lay abstract More and more research shows us that autistic individuals are at risk of experiencing mental health problems in response to the COVID-19 pandemic. However, little is known about why this is the case. At two timepoints during the pandemic, we asked 149 autistic and 147 non-autistic adults about feelings of anxiety, depression, and stress, and about characteristics that may explain why some (autistic) people have a larger chance of developing anxiety and depression during this pandemic. In our study, autistic adults experienced more anxiety and depression than non-autistic adults. Across autistic and non-autistic individuals, the people who experienced more stress at timepoint 1 experienced more anxiety and depression 4 months later. This was especially the case for those individuals who use maladaptive coping styles, such as denial or venting, and for those who have difficulties dealing with uncertain situations. Our findings show the burden of the COVID-19 pandemic on the mental health of autistic adults. Interventions to support autistic adults during and after the pandemic are needed, and they may want to focus on the negative impact of stress and teach autistic (and non-autistic) adults more adaptive ways to cope with stressful circumstances.
L-infinity algebras, Cartan homotopies and period maps

We prove that, for every compact Kaehler manifold, the period map of its Kuranishi family is induced by a natural L-infinity morphism. This implies, by standard facts about L-infinity algebras, that the period map is a "morphism of deformation theories" and then commutes with all deformation theoretic constructions (e.g. obstructions).
Distinct forms of regret linked to resilience versus susceptibility to stress are regulated by region-specific CREB function in mice

Regret describes recognizing alternative actions could have led to better outcomes. It remains unclear whether regret derives from generalized mistake appraisal or instead comprises dissociable, action-specific processes. Using a neuroeconomic task, we found that mice were sensitive to fundamentally distinct types of regret following exposure to chronic social defeat stress or manipulations of CREB, a transcription factor implicated in stress action. Bias to make compensatory decisions after rejecting high-value offers (regret type I) was unique to stress-susceptible mice. Bias following the converse operation, accepting low-value offers (regret type II), was enhanced in stress-resilient mice and absent in stress-susceptible mice. CREB function in either the prefrontal cortex or nucleus accumbens was required to suppress regret type I but bidirectionally regulated regret type II. We provide insight into how maladaptive stress response traits relate to distinct forms of counterfactual thinking, which could steer therapy for mood disorders, such as depression, toward circuit-specific computations through a careful description of decision narrative.
Late Pleistocene landscape changes and habitat specialization as promoters of population genomic divergence in Amazonian floodplain birds

Although vicariant processes are expected to leave similar genomic signatures among codistributed taxa, ecological traits such as habitat and stratum can influence genetic divergence within species. Here, we combined landscape history and habitat specialization to understand the historical and ecological factors responsible for current levels of genetic divergence in three species of birds specialized in seasonally flooded habitats in muddy rivers and which are widespread in the Amazon basin but have isolated populations in the Rio Branco. Populations of the white‐bellied spinetail (Mazaria propinqua), lesser wagtail‐tyrant (Stigmatura napensis) and bicolored conebill (Conirostrum bicolor) are currently isolated in the Rio Branco by the black‐waters of the lower Rio Negro, offering a unique opportunity to test the effect of river colour as a barrier to gene flow. We used ultraconserved elements (UCEs) to test alternative hypotheses of population history in a comparative phylogeographical approach by modelling genetic structure, demographic history and testing for shared divergence time among codistributed taxa. Our analyses revealed that (i) all three populations from the Rio Branco floodplains are genetically distinct from other populations along the Amazon River floodplains; (ii) these divergences are the result of at least two distinct events, consistent with species habitat specialization; and (iii) the most likely model of population evolution includes lower population connectivity during the Late Pleistocene transition (~250,000 years ago), with gene flow being completely disrupted after the Last Glacial Maximum (~21,000 years ago). Our findings highlight how landscape evolution modulates population connectivity in habitat specialist species and how organisms can have different responses to the same historical processes of environmental change, depending on their habitat affinity.
Impact of interleukin-32α on T helper cell-related cytokines, transcription factors, and proliferation in patients with type 2 diabetes mellitus

Abstract Objective The ability of interleukin (IL)-32α to induce T helper (Th) 1, Th17, and Treg cytokines (interferon gamma [IFN-γ], IL-17, and IL-10, respectively), and transcription factors ([signal transducer and activator of transcription (STAT) 1 and T-box (T-bet) for Th1, STAT3 and retinoid-related orphan receptor (ROR)-γt for Th17, and STAT5 and forkhead box P3 (Foxp3) for Treg]) were investigated in type 2 diabetes mellitus (T2DM). IL-32α effects on Th cell proliferation and related factors including IL-2 and NF-κB were also explored. Methods Serum levels of IL-32α in 31 patients and 31 healthy controls (HCs) were determined by ELISA assay. CD4+ T cells cultured with polyclonal activators in the presence and absence of recombinant IL-32α (rIL-32α). Gene expressions in cultured Th cells were assessed with real-time PCR. Cytokines in supernatants were measured with ELISA. Proliferation experiments were assessed by flow cytometry. Results The patients showed significant increase in IL-32α levels compared with HCs and its levels were positively correlated with fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c). rIL-32α enhanced IL-17 and IL-2 production, increased ROR-γt and NF-κB expression, and enhanced Th proliferation in both patients and HCs. In patients, IL-17, ROR-γt, NF-κB, and proliferation levels were higher than those in HCs, in cultures with and without rIL-32α (rIL-32α+ and rIL-32α-). IL-2 levels in rIL-32α+cultures of patients were significantly higher than the HCs, and it was positively correlated with proliferation rate and NF-κB expression. Conclusions Aberrant IL-32α levels are participated in T2DM pathogenesis. IL-32α potently induces Th17-related factors and amplifies the proliferative function of T cells. Highlights Enhanced serum levels of IL-32α in T2DM patients was correlated with FPG and HbA1c. IL-32α increases ROR-γt expression and IL-17 production, and induces Th17 cells. IL-32α enhances NF-κB expression and IL-2 production, and promotes Th proliferation. IL-32α is more effective for inducing Th17 cells and proliferation in the patients. IL-32α axis could be mentioned as a future therapeutic goal for the T2DM.