Miracle-dz/UniFAR-FTUs huggingface dataset:
VCP/p97 controls signals of the ERK1/2 pathway transmitted via the Shoc2 scaffolding complex: novel insights into IBMPFD pathology

Valosin-containing protein (VCP), also named p97, is an essential hexameric AAA+ ATPase with diverse functions in the ubiquitin system. Here we demonstrate that VCP is critical in controlling signals transmitted via the essential Shoc2-ERK1/2 signaling axis. The ATPase activity of VCP modulates the stoichiometry of HUWE1 in the Shoc2 complex as well as HUWE1-mediated allosteric ubiquitination of the Shoc2 scaffold and the RAF-1 kinase. Abrogated ATPase activity leads to augmented ubiquitination of Shoc2/RAF-1 and altered phosphorylation of RAF-1. We found that in fibroblasts from patients with inclusion body myopathy with Paget’s disease of bone and frontotemporal dementia (IBMPFD) that harbor germline mutations in VCP, the levels of Shoc2 ubiquitination and ERK1/2 phosphorylation are imbalanced. This study provides a mechanistic basis for the critical role of VCP in the regulation of the ERK1/2 pathway and reveals a previously unrecognized function of the ERK1/2 pathway in the pathogenesis of IBMPFD.
Full squat produces greater neuromuscular and functional adaptations and lower pain than partial squats after prolonged resistance training

Abstract The choice of the optimal squatting depth for resistance training (RT) has been a matter of debate for decades and is still controversial. In this study, fifty-three resistance-trained men were randomly assigned to one of four training groups: full squat (F-SQ), parallel squat (P-SQ), half squat (H-SQ), and Control (training cessation). Experimental groups completed a 10-week velocity-based RT programme using the same relative load (linear periodization from 60% to 80% 1RM), only differing in the depth of the squat trained. The individual range of motion and spinal curvatures for each squat variation were determined in the familiarization and subsequently replicated in every lift during the training and testing sessions. Neuromuscular adaptations were evaluated by one-repetition maximum strength (1RM) and mean propulsive velocity (MPV) at each squatting depth. Functional performance was assessed by countermovement jump, 20-m sprint and Wingate tests. Physical functional disability included pain and stiffness records. F-SQ was the only group that increased 1RM and MPV in the three squat variations (ES = 0.77–2.36), and achieved the highest functional performance (ES = 0.35–0.85). P-SQ group obtained the second best results (ES = 0.15–0.56). H-SQ produced no increments in neuromuscular and functional performance (ES = −0.11–0.28) and was the only group reporting significant increases in pain, stiffness and physical functional disability (ES = 1.21–0.87). Controls declined on all tests (ES = 0.02–1.32). We recommend using F-SQ or P-SQ exercises to improve strength and functional performance in well-trained athletes. In turn, the use of H-SQ is inadvisable due to the limited performance improvements and the increments in pain and discomfort after continued training.
Quercetin protects rats from catheter‐related Staphylococcus aureus infections by inhibiting coagulase activity

Coagulase (Coa) activity is essential for the virulence of Staphylococcus aureus (S aureus), one of the most important pathogenic bacteria leading to catheter‐related bloodstream infections (CRBSI). We have demonstrated that the mutation of coagulase improved outcomes in disease models of S aureus CRBSI, suggesting that targeting Coa may represent a novel antiinfective strategy for CRBSI. Here, we found that quercetin, a natural compound that does not affect S aureus viability, could inhibit Coa activity. Chemical biological analysis revealed that the direct engagement of quercetin with the active site (residues Tyr187, Leu221 and His228) of Coa inhibited its activity. Furthermore, treatment with quercetin reduced the retention of bacteria on catheter surfaces, decreased the bacterial load in the kidneys and alleviated kidney abscesses in vivo. These data suggest that antiinfective therapy targeting Coa with quercetin may represent a novel strategy and provide a new leading compound with which to combat bacterial infections.
Effect of Disease-Associated Germline Mutations on Structure Function Relationship of DNA Methyltransferases

Despite a large body of evidence supporting the role of aberrant DNA methylation in etiology of several human diseases, the fundamental mechanisms that regulate the activity of mammalian DNA methyltransferases (DNMTs) are not fully understood. Recent advances in whole genome association studies have helped identify mutations and genetic alterations of DNMTs in various diseases that have a potential to affect the biological function and activity of these enzymes. Several of these mutations are germline-transmitted and associated with a number of hereditary disorders, which are potentially caused by aberrant DNA methylation patterns in the regulatory compartments of the genome. These hereditary disorders usually cause neurological dysfunction, growth defects, and inherited cancers. Biochemical and biological characterization of DNMT variants can reveal the molecular mechanism of these enzymes and give insights on their specific functions. In this review, we introduce roles and regulation of DNA methylation and DNMTs. We discuss DNMT mutations that are associated with rare diseases, the characterized effects of these mutations on enzyme activity and provide insights on their potential effects based on the known crystal structure of these proteins.
Response to Late-Window Endovascular Revascularization Is Associated With Collateral Status in Basilar Artery Occlusion.

Background and Purpose- The benefit of endovascular therapy in extended time windows has been demonstrated in patients with anterior circulation large vessel occlusion ischemic stroke and favorable imaging profile. We evaluated whether collaterals and thrombus burden influence the associations between revascularization, time-to-treatment, and outcome in endovascular therapy-treated patients with basilar artery occlusion. Methods- We retrospectively analyzed clinical and imaging data of consecutive endovascular therapy-treated patients with basilar artery occlusion included in the multicenter Basilar Artery Treatment and Management Collaboration. The BATMAN (Basilar Artery on Computed Tomography Angiography score, which evaluates thrombus burden and collaterals) and the PC-CS (Posterior Circulation Collateral score, which evaluates collaterals) were assessed on computed tomography angiography, blinded to clinical outcome. Good outcome was defined as modified Rankin Scale score of ≤3 within 3 months; revascularization (successful reperfusion) as modified Thrombolysis in Cerebral Infarction 2b-3 (or TIMI [Thrombolysis In Myocardial Infarction] 2-3 in the BASICS [Basilar Artery International Cooperation Study] registry). Results- We included 172 patients with basilar artery occlusion treated with endovascular therapy (124 with mechanical thrombectomy): mean (SD) age 65 (13) years, median National Institutes of Health Stroke Scale 22 (interquartile range 12-30), 64 (37%) treated >6 hours. Revascularization (achieved in 79% of patients) was associated with good outcome ( P=0.003). The use of new generation thrombectomy devices was associated with good outcome ( P=0.03). In patients who achieved revascularization, 29/46 (63%) of patients with a favorable BATMAN score and 26/51 (51%) with favorable PC-CS had good outcomes. In logistic regression analysis (adjusted for age, National Institutes of Health Stroke Scale, and time-to-treatment ≤6/>6 hours), revascularization was associated with good outcome in patients with favorable BATMAN score (odds ratio, 15.8; 95% CI, 1.4-175; P=0.02) or PC-CS (odds ratio, 9.4; 95% CI, 1.4-64; P=0.02). In patients who achieved revascularization, early (time-to-treatment ≤6 hours) but not late treatment was associated with improved outcome in patients with unfavorable BATMAN score (18/52 [35%]; odds ratio, 15; 95% CI, 1.9-124; P=0.01) or PC-CS (16/44 [36%]; odds ratio, 5.5; 95% CI, 1.4-21; P=0.01). Conclusions- Revascularization is associated with good outcome in patients with basilar artery occlusion with good collaterals and less extensive occlusion, even >6 hours after onset.
Antibiotic Prescribing and Respiratory Viral Testing for Acute Upper Respiratory Infections Among Adult Patients at an Ambulatory Cancer Center

Abstract Background Outpatient antibiotic prescribing for acute upper respiratory infections (URIs) is a high-priority target for antimicrobial stewardship that has not been described for cancer patients. Methods We conducted a retrospective cohort study of adult patients at an ambulatory cancer center with URI diagnoses from 1 October 2015 to 30 September 2016. We obtained antimicrobial prescribing, respiratory viral testing, and other clinical data at first encounter for the URI through day 14. We used generalized estimating equations to test associations of baseline factors with antibiotic prescribing. Results Of 341 charts reviewed, 251 (74%) patients were eligible for analysis. Nearly one-third (32%) of patients were prescribed antibiotics for URIs. Respiratory viruses were detected among 85 (75%) of 113 patients tested. Antibiotic prescribing (P = .001) and viral testing (P < .001) varied by clinical service. Sputum production or chest congestion was associated with higher risk of antibiotic prescribing (relative risk [RR], 2.3; 95% confidence interval [CI], 1.4–3.8; P < .001). Viral testing on day 0 was associated with lower risk of antibiotic prescribing (RR, 0.4; 95% CI 0.2–0.8; P = .01), though collinearity between viral testing and clinical service limited our ability to separate these effects on prescribing. Conclusions Nearly one-third of hematology–oncology outpatients were prescribed antibiotics for URIs, despite viral etiologies identified among 75% of those tested. Antibiotic prescribing was significantly lower among patients who received an initial respiratory viral test. The role of viral testing in antibiotic prescribing for URIs in outpatient oncology settings merits further study.
Comparative chemical analysis of body odor in great apes

Olfaction is important across the animal kingdom for transferring information on, for example, species, sex, group membership, or reproductive parameters. Its relevance has been established in primates including humans, yet research on great apes still is fragmentary. Observational evidence indicates that great apes use their sense of smell in various contexts, but the information content of their body odor has not been analyzed. Our aim was therefore to compare the chemical composition of body odor in great ape species, namely Sumatran orangutans (Pongo abelii (Lesson, 1827), one adult male, five adult females, four nonadults), Western lowland gorillas (Gorilla gorilla gorilla (Savage, 1847), one adult male, two adult females, one nonadult), common chimpanzees (Pan troglodytes (Blumenbach, 1775), four adult males, nine adult females, four nonadults), and bonobos (Pan paniscus (Schwarz, 1929), two adult males, four adult females, two nonadults). We collected 195 samples (five per individual) of 39 captive individuals using cotton swabs and analyzed them using gas chromatography mass spectrometry. We compared the sample richness and intensity, similarity of chemical composition, and relative abundance of compounds. Results show that species, age, and potentially sex have an impact on the variance between odor profiles. Richness and intensity varied significantly between species (gorillas having the highest, bonobos the lowest richness and intensity), and with age (both increasing with age). Richness and intensity did not vary between sexes. Odor samples of the same species were more similar to each other than samples of different species. Among all compounds identified some were associated with age (N = 7), sex (N = 6), and species‐related (N = 37) variance. Our study contributes to the basic understanding of olfactory communication in hominids by showing that the chemical composition of body odor varies across species and individuals, containing potentially important information for social communication.
Psychosocial Health Interventions by Social Robots: Systematic Review of Randomized Controlled Trials

Background Social robots that can communicate and interact with people offer exciting opportunities for improved health care access and outcomes. However, evidence from randomized controlled trials (RCTs) on health or well-being outcomes has not yet been clearly synthesized across all health domains where social robots have been tested. Objective This study aimed to undertake a systematic review examining current evidence from RCTs on the effects of psychosocial interventions by social robots on health or well-being. Methods Medline, PsycInfo, ScienceDirect, Scopus, and Engineering Village searches across all years in the English language were conducted and supplemented by forward and backward searches. The included papers reported RCTs that assessed changes in health or well-being from interactions with a social robot across at least 2 measurement occasions. Results Out of 408 extracted records, 27 trials met the inclusion criteria: 6 in child health or well-being, 9 in children with autism spectrum disorder, and 12 with older adults. No trials on adolescents, young adults, or other problem areas were identified, and no studies had interventions where robots spontaneously modified verbal responses based on speech by participants. Most trials were small (total N=5 to 415; median=34), only 6 (22%) reported any follow-up outcomes (2 to 12 weeks; median=3.5) and a single-blind assessment was reported in 8 (31%). More recent trials tended to have greater methodological quality. All papers reported some positive outcomes from robotic interventions, although most trials had some measures that showed no difference or favored alternate treatments. Conclusions Controlled research on social robots is at an early stage, as is the current range of their applications to health care. Research on social robot interventions in clinical and health settings needs to transition from exploratory investigations to include large-scale controlled trials with sophisticated methodology, to increase confidence in their efficacy.
Adsorption of Trichoderma reesei cellulase on cellulose: Experimental data and their analysis by different equations

The adsorption of cellulase from Trichoderma reesei MCG 77 on Avicel was measured at varying cellulase (2–8 g/L) and Avicel (10–200 g/L) concentrations at pH 4.8 and 50°C. Different mathematical equations were derived for the evaluation of the experimental data. The fraction of cellulase protein that can maximally be adsorbed is 0.96, and 1 g Avicel can bind maximally 0.092 g cellulase protein. The Michaelis constant for the adsorption equilibrium [cellulase] + [Avicel] ⇌ [cellulase Avicel] complex is between 2.0 and 2.3 · 10−5 mol/L. This value is based on the assumption that cellulase has an average molecular weight of 48.000. The apparent molecular weight of Avicel, i.e., that amount in grams that can bind 1 mol cellulase, is 520,000. Under maximum binding the enzyme covers on Avicel a surface of 42 m2/g, and the occupied volume is 0.186 cm3/g Avicel.
Histone H3 Lysine 9 Methyltransferase G9a Is a Transcriptional Coactivator for Nuclear Receptors*

Methylation of Lys-9 of histone H3 has been associated with repression of transcription. G9a is a histone H3 Lys-9 methyltransferase localized in euchromatin and acts as a corepressor for specific transcription factors. Here we demonstrate that G9a also functions as a coactivator for nuclear receptors, cooperating synergistically with nuclear receptor coactivators glucocorticoid receptor interacting protein 1, coactivator-associated arginine methyltransferase 1 (CARM1), and p300 in transient transfection assays. This synergy depends strongly on the arginine-specific protein methyltransferase activity of CARM1 but does not absolutely require the enzymatic activity of G9a and is specific to CARM1 and G9a among various protein methyltransferases. Reduction of endogenous G9a diminished hormonal activation of an endogenous target gene by the androgen receptor, and G9a associated with regulatory regions of this same gene. G9a fused to Gal4 DNA binding domain can repress transcription in a lysine methyltransferase-dependent manner; however, the histone modifications associated with transcriptional activation can inhibit the methyltransferase activity of G9a. These findings suggest a link between histone arginine and lysine methylation and a mechanism for controlling whether G9a functions as a corepressor or coactivator.
Crisis in the Family and Positive Youth Development: The Role of Family Functioning

The family is a very important institution that provides relationships and contexts in which adolescents are included and where the trajectory of positive development can be activated. A family crisis can affect family functioning and endanger adolescent development. Therefore, we aimed to explore the association of crisis in the family with positive youth development (PYD), and further, whether adolescent-perceived family functioning mediates or moderates this relation. The sample consisted of Slovak adolescents (N = 341, 44% boys, mean age = 13.16) who completed questionnaires that included questions on family crisis and joint family activities, the Alabama parenting questionnaire and the Very Short PYD questionnaire in the baseline measurement of the Care4Youth cohort study. We found a positive association of perceived positive parenting (B = 0.51; p < 0.001) and family activities (B = 0.50; p < 0.001) with PYD, whereas crisis in the family (B = −0.42; p = 0.01) and perceived poor supervision (B = −0.30; p < 0.001) were negatively associated with PYD. Using serial mediation model, we found following pathway which connected crisis in the family with PYD: crisis in the family → perceived poor parental supervision → joint family activities → PYD. This implies that family interventions and counselling to support parenting skills, especially parental supervision and family activities, to those with the signs of an ongoing family crisis may help to counteract the negative effect of the family crisis on PYD.
Muscle radiodensity loss during cancer therapy is predictive for poor survival in advanced endometrial cancer

Treatment‐related toxicities and decreased levels of patient performance during cancer therapy might contribute to body composition changes and thereby impact outcomes. However, the effect of longitudinal body composition changes on outcomes in patients with advanced endometrial cancer is unknown. This study investigated the association between body composition changes during staging surgery and adjuvant chemoradiotherapy and outcomes in patients with stage III endometrial cancer.
Development of a Nomogram to Predict the Risk of 30-Day Re-Exacerbation for Patients Hospitalized for Acute Exacerbation of Chronic Obstructive Pulmonary Disease

Abstract Acute exacerbation (AE) is the main cause of increased disability and mortality for patients with Chronic Obstructive Pulmonary Disease (COPD). Short-term re-exacerbation after discharge is common for in-hospital patients with AECOPD. Thus, we aimed to design a scoring system to effectively predict the 30-day re-exacerbation using simple and easily accessible variables. We retrospectively enrolled 686 cases hospitalized for AECOPD in two Chinese hospitals from 2005 to 2017. A variety of parameters were collected like demographics, clinical manifestations and treatments in stable and AE period. The optimal subset of covariates in the multivariate logistic analysis was identified by the smallest Akaike Information Criterion (AIC) and was further used to develop a practical and reliable nomogram to predict the 30-day re-exacerbation. The efficacy of the nomogram was internally validated by concordance index (C-index) and a calibration plot. The incidence of 30-day re-exacerbation was 15.8%. Based on the smallest AIC, eight easily-accessible parameters were included in the nomogram, including sex, COPD assessment test (CAT) scores, AE with respiratory failure in the previous year, new purulent sputum, new cardiovascular events, combined antibiotic therapy, theophylline therapy for AE and ICU admission. Our nomogram revealed good discriminative ability with the C-index of 0.702. The calibration curve showed good agreement between nomogram-predicted probability and actual observation. Incorporating eight common variables, a nomogram for 30-day re-exacerbation after discharge with high predictive performance was constructed for patients with AECOPD, which was helpful in predicting individualized risk of re-exacerbation and offering individualized post-discharge support.
Enhanced default mode connectivity predicts metacognitive accuracy in traumatic brain injury.

OBJECTIVE To examine the role that intrinsic functional networks, specifically the default mode network, have on metacognitive accuracy for individuals with moderate to severe traumatic brain injury (TBI). METHOD A sample of 44 individuals (TBI, n = 21; healthy controls [HCs], n = 23) were included in the study. All participants underwent an MRI scan and completed neuropsychological testing. Metacognitive accuracy was defined as participants' ability to correctly judge their item-by-item performance on an abstract reasoning task. Metacognitive values were calculated using the signal detection theory approach of area under the receiver operating characteristic curve. Large-scale subnetworks were created using Power's 264 Functional Atlas. The graph theory metric of network strength was calculated for six subsystem networks to measure functional connectivity. RESULTS There were significant interactions between head injury status (TBI or HC) and internetwork connectivity between the anterior default mode network (DMN) and salience network on metacognitive accuracy (R2 = 0.13, p = .047) and between the posterior DMN and salience network on metacognitive accuracy (R2 = 0.15, p = .038). There was an interpretable interaction between head injury status and internetwork connectivity between the attention network and salience network on metacognitive accuracy (R2 = 0.13, p = .067). In all interactions, higher connectivity predicted better metacognitive accuracy in the TBI group, but this relationship was reversed for the HC group. CONCLUSION Enhanced connectivity to both anterior and posterior regions within the DMN facilitates metacognitive accuracy postinjury. These findings are integrated into a larger literature examining network plasticity in TBI. (PsycINFO Database Record (c) 2019 APA, all rights reserved).