Miracle-dz/UniFAR-FTUs huggingface dataset:
Hippo Pathway and YAP Signaling Alterations in Squamous Cancer of the Head and Neck

Head and neck cancer affects the upper aerodigestive tract and is the sixth leading cancer worldwide by incidence and the seventh by cause of death. Despite significant advances in surgery and chemotherapy, molecularly targeted therapeutic options for this type of cancer are scarce and long term survival rates remain low. Recently, comprehensive genomic studies have highlighted the most commonly altered genes and signaling pathways in this cancer. The Hippo-YAP pathway has been identified as a key oncogenic pathway in multiple tumors. Expression of genes controlled by the Hippo downstream transcriptional coactivators YAP (Yes-associated protein 1) and TAZ (WWTR1, WW domain containing transcription regulator 1) is widely deregulated in human cancer including head and neck squamous cell carcinoma (HNSCC). Interestingly, YAP/TAZ signaling might not be as essential for the normal homeostasis of adult tissues as for oncogenic growth, altogether making the pathway an amenable therapeutic target in cancer. Recent advances in the role of Hippo-YAP pathway in HNSCC have provided evidence that genetic alterations frequent in this type of cancer such as PIK3CA (phosphatidylinositide 3-kinase catalytic subunit alpha) overexpression or FAT1 (FAT atypical cadherin 1) functional loss can result in YAP activation. We discuss current therapeutic options targeting this pathway which are currently in use for other tumor types.
Efficacy and Safety of Ghrelin Agonists in Patients with Diabetic Gastroparesis: A Systematic Review and Meta-Analysis

Background/Aims Ghrelin agonists are emerging prokinetic agents for treating gastroparesis. Although recent clinical trials have demonstrated their efficacy in patients with diabetic gastroparesis (DG), the impact of such agents on symptoms and gastric dysmotility remains unclear. We performed a systematic review and meta-analysis to evaluate the efficacy and safety of ghrelin agonists in patients with DG. Methods A search of common electronic databases (MEDLINE, Embase, and Cochrane Central Register of Controlled Trials) was preformed, using keyword combinations that referenced ghrelin and DG and retrieving all eligible randomized controlled trials (RCTs) of ghrelin agonists versus placebo in patients with DG. The primary outcome measure was the change in patient-reported overall gastroparesis symptom scores. Secondary outcomes included the change in gastric emptying time, specific symptoms related to gastroparesis, and adverse events. A random-effects model was applied to all study outcomes. Heterogeneity among studies was determined by the chi-square test and I2 statistics. Results We selected six RCTs of patients with DG (n=557) for meta-analysis. Ghrelin agonist administration (vs placebo) significantly improved overall gastroparesis symptoms (standardized mean difference, –0.34; 95% confidence interval, –0.56 to –0.13) and significantly improved symptoms related to gastroparesis, including nausea, vomiting, early satiety, and abdominal pain. Adverse events recorded for ghrelin agonists and placebo did not differ significantly. There was no significant heterogeneity among eligible studies. Conclusions Compared with placebo, ghrelin agonists are effective and well-tolerated for the treatment of DG.
Interleukin-22 Induces the Infiltration of Visceral Fat Tissue by a Discrete Subset of Duffy Antigen Receptor for Chemokine-Positive M2-Like Macrophages in Response to a High Fat Diet

Interleukin-22 (IL-22) is a cytokine with important functions in host defense and inflammatory responses and has recently been suggested to play a role in immune-inflammatory system in the context of obesity and its metabolic consequences. The specific cellular targets and mechanisms of IL-22-mediated obesity are largely unknown however. We here identified a previously unknown subset of monocyte-derived Duffy antigen receptors for chemokines (DARC)+ macrophages in epididymal fat adipose tissue and found that they are preferentially recruited into the crown-like structures of adipose tissue in the mouse upon high fat diet-induced obesity. Importantly, DARC+ macrophages highly express the IL-22 receptor (IL-22Ra1). Exposure to recombinant IL-22 shifts macrophages to an alternative M2 polarization pathway and augments DARC expression via a STAT5b signaling axis. STAT5b directly binds to the DARC promoter and a STAT5 inhibitor abrogates the IL-22-mediated induction of DARC. These M2-like DARC+ subpopulations of monocytes/macrophages were elevated in obese db/db mice compared to WT lean mice. Furthermore, subsets of CD14+ and/or CD16+ monocytes/macrophages within human peripheral blood mononuclear cell populations express DARC and the prevalence of these subsets is enhanced by IL-22 stimuli. This suggested that IL-22 is a critical cytokine that promotes the infiltration of adipose tissue macrophages, that regulate inflammatory processes. Taken together, our present findings provide important insights into the molecular mechanism by which IL-22 signal modulates DARC expression in M2-like macrophages.
Association of polymorphism in heat shock protein 70 genes with type 2 diabetes in Bangladeshi population

Type 2 diabetes mellitus (T2DM) is a chronic disorder of which stress is a major contributor. Under stressful condition, body synthesizes a family of molecular chaperone called Heat‐shock proteins (HSPs). Current study assessed the frequency and association of HSP70‐hom + 2,437 T/C polymorphism with T2DM risk among Bangladeshis.
Role of the Novel Hsp90 Co-Chaperones in Dynein Arms’ Preassembly

The outer and inner dynein arms (ODAs and IDAs) are composed of multiple subunits including dynein heavy chains possessing a motor domain. These complex structures are preassembled in the cytoplasm before being transported to the cilia. The molecular mechanism(s) controlling dynein arms’ preassembly is poorly understood. Recent evidence suggests that canonical R2TP complex, an Hsp-90 co-chaperone, in cooperation with dynein axonemal assembly factors (DNAAFs), plays a crucial role in the preassembly of ODAs and IDAs. Here, we have summarized recent data concerning the identification of novel chaperone complexes and their role in dynein arms’ preassembly and their association with primary cilia dyskinesia (PCD), a human genetic disorder.
Soothing the emotional brain: modulation of neural activity to personal emotional stimulation by social touch

Abstract Social touch may modulate emotions, but the neurobehavioral correlates are poorly understood. Here, we investigated neural responses to a picture of a deceased close person and if neural activity and connectivity are modulated by social touch from one’s romantic partner. Using functional magnetic resonance imaging, we found altered reactivity in several brain areas including the anterior cingulate cortex (ACC) and the anterior insula in response to the personal picture compared to a picture of an unfamiliar person. Hand holding with the romantic partner, compared to being alone, reduced reactivity in the ACC and cerebellum and provided subjective comfort. To separate physical touch from the emotional effect of partner presence, we evaluated hand holding with the partner relative to a stranger and found reduced reactivity in the anterior insula. Connectivity between the anterior insula and the ACC was reduced during partner touch, and the connectivity strength was negatively related to attachment security, with higher reported partner security associated with weaker connectivity. Overall, holding hands with one’s partner attenuates reactivity in emotional brain areas and reduces between-region connectivity.
N-Acyl Amino Acids: Metabolism, Molecular Targets, and Role in Biological Processes

The lipid signal is becoming increasingly crowded as increasingly fatty acid amide derivatives are being identified and considered relevant therapeutic targets. The identification of N-arachidonoyl-ethanolamine as endogenous ligand of cannabinoid type-1 and type-2 receptors as well as the development of different–omics technologies have the merit to have led to the discovery of a huge number of naturally occurring N-acyl-amines. Among those mediators, N-acyl amino acids, chemically related to the endocannabinoids and belonging to the complex lipid signaling system now known as endocannabinoidome, have been rapidly growing for their therapeutic potential. Here, we review the current knowledge of the mechanisms for the biosynthesis and inactivation of the N-acyl amino acids, as well as the various molecular targets for some of the N-acyl amino acids described so far.
Effectiveness of Calcium Phosphate Desensitising Agents in Dental Hypersensitivity Over 24 Weeks of Clinical Evaluation

Background: Calcium phosphate-based compounds are used to treat dental hypersensitivity (DH). Their long-term clinical behaviour needs further research. This study compared the 24-week effectiveness of Teethmate Desensitizer (TD), a pure tetracalcium phosphate (TTCP) and dicalcium phosphate dihydrate (DCPD) powder/water, to that of Dentin Desensitizer (DD), and Bite & White ExSense (BWE), both of calcium phosphate crystallites. Methods: A total of 105 subjects were selected. A random table was utilised to form three groups of 35 subjects. DH was evaluated using the evaporative sensitivity, tactile sensitivity tests, and the visual analogue scale (VAS) of pain. Response was recorded before the application of the materials (Pre-1), immediately after (Post-0), at 1 week (Post-1), 4 weeks (Post-2), 12 weeks (Post-3) and 24 weeks (Post-4). The non-parametric distribution was assessed with the Shapiro–Wilk statistical test. Intra-group differences for the six time points were evaluated with the Friedman statistical test and the Kruskal–Wallis test. Results: All the materials decreased DH after 24 weeks in comparison to Pre-1. However, the TTCP/DCPD cement showed the greatest statistical efficiency. Conclusions: The significant decrease of VAS scores produced by TD in the long term suggest the material as the most reliable in the clinical relief of DH.
Viral neutralization by antibody-imposed physical disruption

Significance During pathogenic invasion, neutralizing antibodies (nAbs) are involved in regulating immune clearance and evoking the host-protective response. We previously reported a highly potent nAb 8C11 against HEV, an RNA virus with an icosahedral capsid and associated with abundant acute hepatitis. Structural analysis demonstrates that the binding of 8C11 to HEV VLPs would result in tremendous spatial clashing with the capsid. Cryo-EM analysis showed that 8C11 binding leads to complete disorder of the outer rim of the VLP at earlier stages (∼15 min) and causes the dissociation of HEV VLPs into homodimer species within 2 h. Similar 8C11-mediated dissociation was observed for the native HEV virion. Our results categorize a viral neutralization mechanism and suggest a strategy to generate 8C11-like antibodies. In adaptive immunity, organisms produce neutralizing antibodies (nAbs) to eliminate invading pathogens. Here, we explored whether viral neutralization could be attained through the physical disruption of a virus upon nAb binding. We report the neutralization mechanism of a potent nAb 8C11 against the hepatitis E virus (HEV), a nonenveloped positive-sense single-stranded RNA virus associated with abundant acute hepatitis. The 8C11 binding flanks the protrusion spike of the HEV viruslike particles (VLPs) and leads to tremendous physical collision between the antibody and the capsid, dissociating the VLPs into homodimer species within 2 h. Cryo-electron microscopy reconstruction of the dissociation intermediates at an earlier (15-min) stage revealed smeared protrusion spikes and a loss of icosahedral symmetry with the capsid core remaining unchanged. This structural disruption leads to the presence of only a few native HEV virions in the ultracentrifugation pellet and exposes the viral genome. Conceptually, we propose a strategy to raise collision-inducing nAbs against single spike moieties that feature in the context of the entire pathogen at positions where the neighboring space cannot afford to accommodate an antibody. This rationale may facilitate unique vaccine development and antimicrobial antibody design.
Stressful Life Events and Racial Disparities in Cognition Among Middle-Aged and Older Adults.

BACKGROUND It is well-documented that African Americans have elevated risk for cognitive impairment and dementia in late life, but reasons for the racial disparities remain unknown. Stress processes have been linked to premature age-related morbidity, including Alzheimer's and related dementias (ADRD), and plausibly contribute to social disparities in cognitive aging. OBJECTIVE We examined the relationship between stressful life events and cognitive decline among African American and White participants enrolled in the Wisconsin Registry for Alzheimer's Prevention (WRAP). METHODS Linear mixed models including demographic, literacy, and health-related covariates were used to estimate (1) relationships between a life event index score and decline in cognitive test performance in two domains of executive function (Speed & Flexibility, Working Memory) and one domain of episodic memory (Verbal Learning & Memory) among 1,241 WRAP enrollees, stratified by race, and (2) contributions of stressful life events to racial differences in cognition within the full sample. RESULTS African Americans (N = 50) reported more stressful life events than Whites (N = 1,191). Higher stress scores associated with poorer Speed & Flexibility performance in both groups, though not with declines across time, and partially explained racial differentials in this domain. Among African Americans only, stressor exposure also associated with age-related decline in Verbal Learning & Memory. Stressor-cognition relationships were independent of literacy and health-related variables. CONCLUSIONS Greater lifetime stress predicted poorer later-life cognition, and, in a small sample of African Americans, faster declines in a key domain of episodic memory. These preliminary findings suggest that future work in large minority aging cohorts should explore stress as an important source of modifiable, socially-rooted risk for impairment and ADRD in African Americans, who are disproportionately exposed to adverse experiences across the life course.
A bioecological perspective on talent identification in junior-elite soccer: A Pan-European perspective

ABSTRACT Elite soccer clubs across Europe spend ever-increasing sums of money on transfers and salaries for world-class players. Consequently, clubs’ talent identification and development processes for junior players have become more professionalised. Based on a holistic ecological approach, this study presents an analysis of talent identification practices across some of the most productive soccer academies in Europe (N = 11). Data were collected via semi-structured interviews with 11 heads of academy recruitment from clubs in the “big five” European leagues. Clubs were purposively sampled based on their player productivity ranking. Interviews ranged from 52:26 minutes to 114:06 minutes in length (m = 87:53 ± 20.10 minutes). This study argues that holistic ecological approaches the environments were characterised through the interplay of factors that ranged from high-level internal to international level relationships. This resulted in the identification and recruitment of players from local and international environments. The purpose of recruitment was suggested to have a dual purpose: recruitment of players for the first team; recruitment of players for further development/monitoring and/or selling to another club.
Dietary Curcumin Supplementation Increases Antioxidant Capacity, Upregulates Nrf2 and Hmox1 Levels in the Liver of Piglet Model with Intrauterine Growth Retardation

Curcumin has improved effects on antioxidant capacity via multiple mechanisms. Intrauterine growth retardation (IUGR) has had adverse influences on human health. IUGR is always associated with elevated oxidative stress and deficiencies in antioxidant defense. Therefore, we chose IUGR piglets as a model to investigate the effects of IUGR on antioxidant capacity of newborn and weaned piglets and determine how these alterations were regulated after supplementation with curcumin in weaned IUGR piglets. In experiment 1, eight normal-birth-weight (NBW) and eight IUGR newborn piglets were selected to determine the effect of IUGR on the antioxidant capacity of neonatal piglets. In experiment 2, thirty-two weaned piglets from four experimental groups: NBW, NC (curcumin supplementation), IUGR, IC (curcumin supplementation) were selected. The results showed that both IUGR newborn and weaned piglets exhibited oxidative damage and lower antioxidant enzymes activities in the liver compared with the NBW piglets. Dietary curcumin supplementation increased body-weight gain, feed intake, activities of antioxidant enzymes, and the expressions of nuclear factor, erythroid 2-like 2 (Nrf2) and heme oxygenase-1 (Hmox1) proteins in the liver of weaned piglets with IUGR. In conclusion, IUGR decreased the antioxidant capacity of newborn and weaned piglets. Curcumin could efficiently improve the growth, increase hepatic antioxidant capacity, and upregulate Nrf2 and Hmox1 levels in the liver of IUGR weaned piglets.
Pediatric Infections by Human mastadenovirus C Types 2, 89, and a Recombinant Type Detected in Japan between 2011 and 2018

Between 2011 and 2018, 518 respiratory adenovirus infections were diagnosed in a pediatric clinic in Shizuoka, Japan. Detection and typing were performed by partial sequencing of both hexon- and fiber-coding regions which identified: adenovirus type 1 (Ad-1, n = 85), Ad-2 (n = 160), Ad-3 (n = 193), Ad-4 (n = 18), Ad-5 (n = 27), Ad-11 (n = 2), Ad-54 (n = 3), and Ad-56 (n = 1). Considering previous reports of the circulation of an endemic recombinant Ad-2, e.g., Ad-89, 100 samples typed as Ad-2 were randomly selected for further molecular typing by sequencing the penton base-coding region. Despite the high nucleotide sequence conservation in the penton base- coding region, 27 samples showed 98% identity to Ad-2. Furthermore, 14 samples showed 97.7% identity to Ad-2 and 99.8% identity to Ad-89, while the remaining 13 samples showed an average 98% pairwise identity to other Ad-C types and clustered with Ad-5. The samples typed as Ad-89 (n = 14) and as a recombinant Ad type (P5H2F2) (n = 13) represented 27% of cases originally diagnosed as Ad-2, and were detected sporadically. Therefore, two previously uncharacterized types in Japan, Ad-89 and a recombinant Ad-C, were shown to circulate in children. This study creates a precedent to evaluate the epidemiology and divergence among Ad-C types by comprehensively considering the type classification of adenoviruses.
Differences in Admission Blood Pressure Among Causes of Intracerebral Hemorrhage

Supplemental Digital Content is available in the text. Background and Purpose— It is unknown whether admission systolic blood pressure (SBP) differs among causes of intracerebral hemorrhage (ICH). We sought to elucidate an association between admission BP and ICH cause. Methods— We compared admission SBP across ICH causes among patients in the Cornell Acute Stroke Academic Registry, which includes all adults with ICH at our center from 2011 through 2017. Trained analysts prospectively collected demographics, comorbidities, and admission SBP, defined as the first recorded value in the emergency department or on transfer from another hospital. ICH cause was adjudicated by a panel of neurologists using the SMASH-U criteria. We used ANOVA to compare mean admission SBP among ICH causes. We used multiple linear regression to adjust for age, sex, race, Glasgow Coma Scale score, and hematoma size. In secondary analyses, we compared hourly SBP measurements during the first 72 hours after admission, using mixed-effects linear models adjusted for the covariates above plus antihypertensive agents. Results— Among 484 patients with ICH, admission SBP varied significantly across ICH causes, ranging from 138 (±24) mm Hg in those with structural vascular lesions to 167 (±35) mm Hg in those with hypertensive ICH (P<0.001). The mean admission SBP in hypertensive ICH was 17 (95% CI, 11–24) mm Hg higher than in ICH of all other causes combined. These differences remained significant after adjustment for age, sex, race, Glasgow Coma Scale score, and hematoma size (P<0.001), and this persisted throughout the first 72 hours of hospitalization (P<0.001). Conclusions— In a single-center ICH registry, SBP varied significantly among ICH causes, both on admission and during hospitalization. Our results suggest that BP in the acute post-ICH setting is at least partly associated with ICH cause rather than simply representing a physiological reaction to the ICH itself.
Acceptor Specificity of β-N-Acetylhexosaminidase from Talaromyces flavus: A Rational Explanation

Fungal β-N-acetylhexosaminidases, though hydrolytic enzymes in vivo, are useful tools in the preparation of oligosaccharides of biological interest. The β-N-acetylhexosaminidase from Talaromyces flavus is remarkable in terms of its synthetic potential, broad substrate specificity, and tolerance to substrate modifications. It can be heterologously produced in Pichia pastoris in a high yield. The mutation of the Tyr470 residue to histidine greatly enhances its transglycosylation capability. The aim of this work was to identify the structural requirements of this model β-N-acetylhexosaminidase for its transglycosylation acceptors and formulate a structure–activity relationship study. Enzymatic reactions were performed using an activated glycosyl donor, 4-nitrophenyl N-acetyl-β-d-glucosaminide or 4-nitrophenyl N-acetyl-β-d-galactosaminide, and a panel of glycosyl acceptors of varying structural features (N-acetylglucosamine, glucose, N-acetylgalactosamine, galactose, N-acetylmuramic acid, and glucuronic acid). The transglycosylation products were isolated and structurally characterized. The C-2 N-acetamido group in the acceptor molecule was found to be essential for recognition by the enzyme. The presence of the C-2 hydroxyl moiety strongly hindered the normal course of transglycosylation, yielding unique non-reducing disaccharides in a low yield. Moreover, whereas the gluco-configuration at C-4 steered the glycosylation into the β(1-4) position, the galacto-acceptor afforded a β(1-6) glycosidic linkage. The Y470H mutant enzyme was tested with acceptors based on β-glycosides of uronic acid and N-acetylmuramic acid. With the latter acceptor, we were able to isolate and characterize one glycosylation product in a low yield. To our knowledge, this is the first example of enzymatic glycosylation of an N-acetylmuramic acid derivative. In order to explain these findings and predict enzyme behavior, a modeling study was accomplished that correlated with the acquired experimental data.