Miracle-dz/UniFAR-FTUs huggingface dataset:
Functional Heterogeneity and Therapeutic Targeting of Tissue-Resident Memory T Cells

Tissue-resident memory T (TRM) cells mediate potent local innate and adaptive immune responses and provide long-lasting protective immunity. TRM cells localize to many different tissues, including barrier tissues, and play a crucial role in protection against infectious and malignant disease. The formation and maintenance of TRM cells are influenced by numerous factors, including inflammation, antigen triggering, and tissue-specific cues. Emerging evidence suggests that these signals also contribute to heterogeneity within the TRM cell compartment. Here, we review the phenotypic and functional heterogeneity of CD8+ TRM cells at different tissue sites and the molecular determinants defining CD8+ TRM cell subsets. We further discuss the possibilities of targeting the unique cell surface molecules, cytokine and chemokine receptors, transcription factors, and metabolic features of TRM cells for therapeutic purposes. Their crucial role in immune protection and their location at the frontlines of the immune defense make TRM cells attractive therapeutic targets. A better understanding of the possibilities to selectively modulate TRM cell populations may thus improve vaccination and immunotherapeutic strategies employing these potent immune cells.
Systems approach to health service design, delivery and improvement: a systematic review and meta-analysis

Objectives To systematically review the evidence base for a systems approach to healthcare design, delivery or improvement. Design Systematic review with meta-analyses. Methods Included were studies in any patients, in any healthcare setting where a systems approach was compared with usual care which reported quantitative results for any outcomes for both groups. We searched Medline, Embase, HMIC, Health Business Elite, Web of Science, Scopus, PsycINFO and CINAHL from inception to 28 May 2019 for relevant studies. These were screened, and data extracted independently and in duplicate. Study outcomes were stratified by study design and whether they reported patient and/or service outcomes. Meta-analysis was conducted with Revman software V.5. 3 using ORs—heterogeneity was assessed using I2 statistics. Results Of 11 405 records 35 studies were included, of which 28 (80%) were before-and-after design only, five were both before-and-after and concurrent design, and two were randomised controlled trials (RCTs). There was heterogeneity of interventions and wide variation in reported outcome types. Almost all results showed health improvement where systems approaches were used. Study quality varied widely. Exploratory meta-analysis of these suggested favourable effects on both patient outcomes (n=14, OR=0.52 (95% CI 0.38 to 0.71) I2=91%), and service outcomes (n=18, OR=0.40 (95% CI 0.31 to 0.52) I2=97%). Conclusions This study suggests that a systems approaches to healthcare design and delivery results in a statistically significant improvement to both patient and service outcomes. However, better quality studies, particularly RCTs are needed. PROSPERO registration number CRD42017065920.
The factors associated with the presence of psychotic symptoms in the HELIAD Greek community study of older adults

Abstract Background The prevalence and associated factors related to psychotic symptoms in older adults are understudied. The objectives were to assess the prevalence, incidence and factors associated with psychotic symptoms in a representative Greek sample of community living older adults. Methods The sample includes n = 1,904 residents of the cities of Larissa and Maroussi in Greece participating in the Hellenic Longitudinal Investigation of Aging and Diet study with available data at baseline and n = 947 individuals at the 3-year follow-up. Past-month presence of delusions and hallucinations was assessed on the grounds of the 17 symptoms of the Columbia University Scale for Psychopathology in Alzheimer's Disease and 14 symptoms of the Neuropsychiatric Inventory Questionnaire. A comprehensive neuropsychological assessment for probable diagnosis of dementia and physical comorbidity was carried out by neurologists. Penalized logistic regression analyses were used to assess the socio-economic and clinical factors associated with psychotic symptoms. Results Past-month prevalence of psychotic symptoms was 1.9% and 1.0% when excluding cases of dementia. The prevalence of any delusion and hallucination was 0.8% and 0.3% when excluding dementia. The incidence of psychotic symptoms without dementia was 1.3%. Recent widows and farmers/breeders/craftsmen, versus public servants/teachers/executives, had both six times the odds of experiencing psychotic symptoms without dementia. Hearing impairment and the number of health conditions also increased the odds while increased age was protective. Conclusion Psychotic symptoms unrelated to dementia constitute a considerable mental health problem in old age. Paranoid delusions were the most prevalent. Socio-economic and health status factors are significant predictors of psychotic symptoms.
Current Evidence on the Role of the Gut Microbiome in ADHD Pathophysiology and Therapeutic Implications

Studies suggest that the bidirectional relationship existent between the gut microbiome (GM) and the central nervous system (CNS), or so-called the microbiome–gut–brain axis (MGBA), is involved in diverse neuropsychiatric diseases in children and adults. In pediatric age, most studies have focused on patients with autism. However, evidence of the role played by the MGBA in attention deficit/hyperactivity disorder (ADHD), the most common neurodevelopmental disorder in childhood, is still scanty and heterogeneous. This review aims to provide the current evidence on the functioning of the MGBA in pediatric patients with ADHD and the specific role of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) in this interaction, as well as the potential of the GM as a therapeutic target for ADHD. We will explore: (1) the diverse communication pathways between the GM and the CNS; (2) changes in the GM composition in children and adolescents with ADHD and association with ADHD pathophysiology; (3) influence of the GM on the ω-3 PUFA imbalance characteristically found in ADHD; (4) interaction between the GM and circadian rhythm regulation, as sleep disorders are frequently comorbid with ADHD; (5) finally, we will evaluate the most recent studies on the use of probiotics in pediatric patients with ADHD.
A short ORF-encoded transcriptional regulator

Significance The small size of short ORF-encoded peptides (SEPs) has made it difficult to identify their cellular binding partners using standard methods. Here, we show that the photo-crosslinking amino acid AbK can be incorporated into overexpressed, epitope-tagged SEP transgenes, allowing covalent bond formation between SEPs and their interactors in live cells. From an AP-MS–based screen of conserved mammalian SEPs, we identified short ORF-encoded histone binding protein (SEBHP), a micropeptide which acts as a transcriptional regulator, capable of modulating more than 15% of the active transcriptome. The methodology described herein will likely be of broad utility in annotating the essential physiological roles of SEPs. Recent technological advances have expanded the annotated protein coding content of mammalian genomes, as hundreds of previously unidentified, short open reading frame (ORF)-encoded peptides (SEPs) have now been found to be translated. Although several studies have identified important physiological roles for this emerging protein class, a general method to define their interactomes is lacking. Here, we demonstrate that genetic incorporation of the photo-crosslinking noncanonical amino acid AbK into SEP transgenes allows for the facile identification of SEP cellular interaction partners using affinity-based methods. From a survey of seven SEPs, we report the discovery of short ORF-encoded histone binding protein (SEHBP), a conserved microprotein that interacts with chromatin-associated proteins, localizes to discrete genomic loci, and induces a robust transcriptional program when overexpressed in human cells. This work affords a straightforward method to help define the physiological roles of SEPs and demonstrates its utility by identifying SEHBP as a short ORF-encoded transcription factor.
Effects of Exercise on the Skin Epithelial Barrier of Young Elite Athletes-Swimming Comparatively to Non-Water Sports Training Session

The benefits of swimming have been extensively assessed. However, swimming pools contain chlorine and other irritating chemicals that may induce contact dermatitis. To evaluate the effect of a swimming training session on transepidermal water loss (TWEL) in swimmers compared to football players, elite swimmers and football players were invited to participate (58 athletes) in the study, where TEWL was measured before, immediately after, and 30 min after a 2 h training session. The probe was held on the dorsum of the hand, volar forearm, and on the antecubital flexure for 1 min. The volar forearm, antecubital flexure, and hand dorsum showed a significant increase in TEWL in swimmers in both measurements after training compared to baseline (p < 0.001). In football players, an increase in TEWL was observed on the hands’ dorsum between baseline and after training measurements. The variations on TEWL levels before and immediately after the training session were higher among swimmers on the volar forearm (p = 0.002) and antecubital flexure (p = 0.019). Our findings support the effect of the training environment—swimming pool versus outdoor sports—on the skin barrier function, with an increase of transepidermal water loss immediately after exercise. Exposure to a swimming pool environment in a 2 h training session may lead to changes in skin barrier function.
Linear B-Cell Epitopes in Human Norovirus GII.4 Capsid Protein Elicit Blockade Antibodies

Human norovirus (HuNoV) is the leading cause of nonbacterial gastroenteritis worldwide with the GII.4 genotype accounting for over 80% of infections. The major capsid protein of GII.4 variants is evolving rapidly, resulting in new epidemic variants with altered antigenic potentials that must be considered for the development of an effective vaccine. In this study, we identify and characterize linear blockade B-cell epitopes in HuNoV GII.4. Five unique linear B-cell epitopes, namely P2A, P2B, P2C, P2D, and P2E, were predicted on the surface-exposed regions of the capsid protein. Evolving of the surface-exposed epitopes over time was found to correlate with the emergence of new GII.4 outbreak variants. Molecular dynamic simulation (MD) analysis and molecular docking revealed that amino acid substitutions in the putative epitopes P2B, P2C, and P2D could be associated with immune escape and the appearance of new GII.4 variants by affecting solvent accessibility and flexibility of the antigenic sites and histo-blood group antigens (HBAG) binding. Testing the synthetic peptides in wild-type mice, epitopes P2B (336–355), P2C (367–384), and P2D (390–400) were recognized as GII.4-specific linear blockade epitopes with the blocking rate of 68, 55 and 28%, respectively. Blocking rate was found to increase to 80% using the pooled serum of epitopes P2B and P2C. These data provide a strategy for expanding the broad blockade potential of vaccines for prevention of NoV infection.
Positive and Negative Affect Changes during Gender-Affirming Hormonal Treatment: Results from the European Network for the Investigation of Gender Incongruence (ENIGI)

Improving transgender people’s quality of life (QoL) is the most important goal of gender-affirming care. Prospective changes in affect can influence QoL. We aim to assess the impact of initiating gender-affirming hormonal treatment (HT) on affect. In the European Network for the Investigation of Gender Incongruence (ENIGI) study, we prospectively collected data of 873 participants (451 transwomen (TW) and 422 transmen (TM)). At baseline, psychological questionnaires including the Positive and Negative Affect Schedule (PANAS) were administered. The PANAS, levels of sex steroids and physical changes were registered at each follow-up visit during a 3-year follow-up period, starting at the initiation of hormonal therapy. Data were analyzed cross-sectionally and prospectively. Over the first three months, we observed a decline in positive affect (PA) in both TM and TW. Thereafter, PA reached a steady state in TW, whereas in TM there was also a second decline at 18 months. In both TM and TW there was no persisting difference comparing baseline to the 36-months results. Concerning negative affect (NA), we observed a decline during the first year in TM, which sustained during the second year and was not different anymore at 36 months compared to baseline. In TW though, we did not find any change of NA during the entire follow-up. Even if some of these results show significant differences, they should be considered with caution, since there was no control group and the absolute differences are small. No association between affect and the level of sex steroids was observed. Baseline QoL and psychological burden are related to affect independently from gender but are not necessarily good predictors of the evolution of one’s affect during the gender-affirming process. Further research is necessary to investigate these preliminary results.
SECONDARY METABOLITES DETERMINATIONS QUALITATIVELY FROM BARK OF BUTEA MONOSPERMA AND EUCALYPTUS GLOBULUS

Bark is the outermost layer of stems and roots of woody plants. A plant with bark includes trees, woody vines and shrubs. In the present investigation we were taking bark of Butea monosperma and Eucalyptus globulus. From these plants we determined secondary metabolites qualitatively using solvents like Water, n-hexane and Ethyl Acetate. Water, n- Hexane and Ethyl Acetate extract of bark of Eucalyptus globulus contains more number of phytochemicals as compared to Butea monosperma.
Long-range structural defects by pathogenic mutations in most severe glucose-6-phosphate dehydrogenase deficiency

Significance Mechanism of the loss of activity of the most severe patient-derived mutants of glucose-6-phosphate dehydrogenase (G6PD) deficiency has remained elusive despite the availability of the G6PD structures for decades. Structural and biophysical investigations have revealed a common mechanism and dynamics of how these mutations hinder the substrate-binding site, reducing enzymatic activity. These are triggered by a long-distance propagation of structural defects at the dimer interface and the binding site of the noncatalytic cofactor. These structural distortions are found among all of the class I mutants investigated, providing critical clues for drug design to address G6PD deficiency by correcting the structural defects. Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common blood disorder, presenting multiple symptoms, including hemolytic anemia. It affects 400 million people worldwide, with more than 160 single mutations reported in G6PD. The most severe mutations (about 70) are classified as class I, leading to more than 90% loss of activity of the wild-type G6PD. The crystal structure of G6PD reveals these mutations are located away from the active site, concentrating around the noncatalytic NADP+-binding site and the dimer interface. However, the molecular mechanisms of class I mutant dysfunction have remained elusive, hindering the development of efficient therapies. To resolve this, we performed integral structural characterization of five G6PD mutants, including four class I mutants, associated with the noncatalytic NADP+ and dimerization, using crystallography, small-angle X-ray scattering (SAXS), cryogenic electron microscopy (cryo-EM), and biophysical analyses. Comparisons with the structure and properties of the wild-type enzyme, together with molecular dynamics simulations, bring forward a universal mechanism for this severe G6PD deficiency due to the class I mutations. We highlight the role of the noncatalytic NADP+-binding site that is crucial for stabilization and ordering two β-strands in the dimer interface, which together communicate these distant structural aberrations to the active site through a network of additional interactions. This understanding elucidates potential paths for drug development targeting G6PD deficiency.
Overexpression of a Pak Choi Gene, BcAS2, Causes Leaf Curvature in Arabidopsis thaliana

The LBD (Lateral Organ Boundaries Domain) family are a new group of plant-specific genes, which encode a class of transcription factors containing conserved Lateral Organization Boundary (LOB) domains, and play an important role in regulating the adaxial–abaxial polarity of plant leaves. In Arabidopsis thaliana, ASYMMETRIC LEAVES 2 (AS2) has a typical LOB domain and is involved in determining the adaxial cell fate. In this study, we isolated the BcAS2 gene from the pak choi cultivar “NHCC001”, and analyzed its expression pattern. The results showed that the BcAS2 encoded a protein made up of 202 amino acid residues which were located in the nucleus and cytomembrane. The Yeast two-hybrid system (Y2H) assay indicated that BcAS2 interacts with BcAS1-1 and BcAS1-2 (the homologous genes of AS1 gene in pak choi). In the transgenic Arabidopsis thaliana that overexpressed BcAS2 gene, it presented an abnormal phenotype with a curly shape. Taken together, our findings not only validate the function of BcAS2 in leaf development in Arabidopsis thaliana, but also contribute in unravelling the molecular regulatory mechanism of BcAS2, which fulfills a special role by forming complexes with BcAS1-1/2 in the establishment of the adaxial–abaxial polarity of the lateral organs in pak choi.
Cross-Cultural Differences in Student Attitudes Toward Intimate Partner Violence: A Systematic Review

Intimate partner violence (IPV) is a major human rights and public health problem which occurs at exceptionally high rates among tertiary students. Attitudes toward IPV are increasingly being recognized as a key risk factor for IPV and targeted in IPV prevention programs on college and university campuses. Understanding the influence of culture on attitudes toward IPV is necessary to change attitudes supportive of IPV and ultimately reduce the occurrence of IPV in the student population. This review sought to systematically identify, appraise, and synthesize research studies examining cross-cultural differences in attitudes toward IPV among tertiary students. A comprehensive search of nine electronic databases was conducted from inception to 15 May 2019. Studies were required to have compared attitudes toward IPV (e.g., acceptance or justification of IPV) among two or more cultural groups (based on country, race, or ethnicity) of tertiary students. Eighteen articles met eligibility criteria for the review, representing over 6,800 students. The studies provide considerable evidence that student attitudes toward IPV differ across cultures. Students in the United States and ethnic majority students in the United States generally showed less accepting attitudes toward IPV than their counterparts in other countries and ethnic minority groups. The particular contexts in which IPV is justified may reflect cultural values and norms. The findings have important implications for prevention and intervention strategies aimed at improving attitudes toward IPV among tertiary students.
Ipomoeassin-F inhibits the in vitro biogenesis of the SARS-CoV-2 spike protein and its host cell membrane receptor

ABSTRACT In order to produce proteins essential for their propagation, many pathogenic human viruses, including SARS-CoV-2, the causative agent of COVID-19 respiratory disease, commandeer host biosynthetic machineries and mechanisms. Three major structural proteins, the spike, envelope and membrane proteins, are amongst several SARS-CoV-2 components synthesised at the endoplasmic reticulum (ER) of infected human cells prior to the assembly of new viral particles. Hence, the inhibition of membrane protein synthesis at the ER is an attractive strategy for reducing the pathogenicity of SARS-CoV-2 and other obligate viral pathogens. Using an in vitro system, we demonstrate that the small molecule inhibitor ipomoeassin F (Ipom-F) potently blocks the Sec61-mediated ER membrane translocation and/or insertion of three therapeutic protein targets for SARS-CoV-2 infection; the viral spike and ORF8 proteins together with angiotensin-converting enzyme 2, the host cell plasma membrane receptor. Our findings highlight the potential for using ER protein translocation inhibitors such as Ipom-F as host-targeting, broad-spectrum antiviral agents. This article has an associated First Person interview with the first author of the paper. Summary: Ipomoeassin-F blocks the Sec61-dependent translocation of SARS-CoV-2 proteins into and across the endoplasmic reticulum, highlighting the potential of Sec61 inhibitors as antiviral agents.
Enhanced biofilm and extracellular matrix production by chronic carriage versus acute isolates of Salmonella Typhi

Salmonella Typhi is the primary causative agent of typhoid fever; an acute systemic infection that leads to chronic carriage in 3–5% of individuals. Chronic carriers are asymptomatic, difficult to treat and serve as reservoirs for typhoid outbreaks. Understanding the factors that contribute to chronic carriage is key to development of novel therapies to effectively resolve typhoid fever. Herein, although we observed no distinct clustering of chronic carriage isolates via phylogenetic analysis, we demonstrated that chronic isolates were phenotypically distinct from acute infection isolates. Chronic carriage isolates formed significantly thicker biofilms with greater biomass that correlated with significantly higher relative levels of extracellular DNA (eDNA) and DNABII proteins than biofilms formed by acute infection isolates. Importantly, extracellular DNABII proteins include integration host factor (IHF) and histone-like protein (HU) that are critical to the structural integrity of bacterial biofilms. In this study, we demonstrated that the biofilm formed by a chronic carriage isolate in vitro, was susceptible to disruption by a specific antibody against DNABII proteins, a successful first step in the development of a therapeutic to resolve chronic carriage.
Hospital volume-outcome relationship in vulvar cancer treatment: a Japanese Gynecologic Oncology Group study

The concept of volume-outcome relationship was originally introduced by Luft et al. [1] more than four decades ago in 1979. In their initial report, the study team intended to introduce the idea of regionalizing surgical service to improve the surgical outcome, and the fundamental knowledge of volume-outcome relationship is nested in that the more experience is associated with the better performance [1,2]. Since then, a number of studies have examined the volume-outcome relationship in gynecologic malignancies including ovarian, cervical, and endometrial cancers in in the past decades [3-13].
Sn-doped hematite films as photoanodes for efficient photoelectrochemical water oxidation

Sn-doped hematite films were electrochemically deposited on a fluorine-doped tin oxide substrate for use as an anode for photoelectrochemical water oxidation. A high photocurrent of ∼2.8 mA cm−2 at 1.24 V vs. RHE and a conversion efficiency of 0.24% are achieved.