syedzayyan/paper_mill_benchmark huggingface dataset:
Proteasome-dependent truncation of the negative heterochromatin regulator Epe1 mediates antifungal resistance.

Epe1 histone demethylase restricts h3k9-methylation-dependent heterochromatin, preventing it from spreading over, and silencing, gene-containing regions in fission yeast.External stress induces an adaptive response allowing heterochromatin island formation that confers resistance on surviving wild-type lineages.Here we investigate the mechanism by which epe1 is regulated in response to stress.Exposure to caffeine or antifungals results in epe1 ubiquitylation and proteasome-dependent removal of the n-terminal 150 residues from epe1, generating truncated epe1 (t epe1) which accumulates in the cytoplasm.Constitutive t epe1 expression increases h3k9 methylation over several chromosomal regions, reducing expression of underlying genes and enhancing resistance.Reciprocally, constitutive non-cleavable epe1 expression decreases resistance.T epe1-mediated resistance requires a functional jmj c demethylase domain.Moreover, caffeine-induced epe1-to-t epe1 cleavage is dependent on an intact cell integrity map kinase stress signaling pathway, mutations in which alter resistance.Thus, environmental changes elicit a mechanism that curtails the function of this key epigenetic modifier, allowing heterochromatin to reprogram gene expression, thereby bestowing resistance to some cells within a population.H3k9me-heterochromatin components are conserved in human and crop-plant fungal pathogens for which a limited number of antifungals exist.Our findings reveal how transient heterochromatin-dependent antifungal resistant epimutations develop and thus inform on how they might be countered.

Journal: Nature structural & molecular biology (2022)
Publication types: Journal Article;Research Support, Non-U.S. Gov't
The Variation in the Diastolic Period with Interventricular Septal Displacement and Its Relation to the Right Ventricular Function in Pulmonary Hypertension: A Preliminary Cardiac Magnetic Resonance Study.

Pulmonary hypertension (ph) is known to alter the biventricular shape and temporal phases of the cardiac cycle.The presence of interventricular septal (ivs) displacement has been associated with the severity of ph.There has been limited cardiac magnetic resonance (cmr) data regarding the temporal parameters of the cardiac cycle in ph.This study aimed to quantify the temporal changes in the cardiac cycle derived from cmr in ph patients with and without ivs displacement and sought to understand the mechanism of cardiac dysfunction in the cardiac cycle.Methods: patients with ph who had cmr and right heart catheterization (rhc) examinations were included retrospectively.Patients were divided into an ivs non-displacement (ivsnd) group and an ivs displacement (ivsd) group according to ivs morphology, as observed on short-axis cine cmr images.Additionally, age-matched healthy volunteers were included as the health control (hc).Temporal parameters, ivs displacement, ventricular volume and functional parameters were obtained by cmr, and pulmonary hemodynamics were obtained by rhc.The risk stratification of the ph patients was also graded according to the guidelines.Results: a total of 70 subjects were included, consisting of 33 ivsd patients, 15 ivsnd patients, and 22 hc patients.In the ivsnd group, only the right ventricle ejection fraction (rvef) was decreased in the ventricular function, and no temporal change in the cardiac cycle was found.A prolonged isovolumetric relaxation time (irt) and shortened filling time (ft) in both ventricles, along with biventricular dysfunction, were detected in the ivsd group (p < 0.001).The irt of the right ventricle (irtrv) and ft of the right ventricle (ftrv) in the ph patients were associated with pulmonary vascular resistance, right cardiac index, and ivs curvature, and the irtrv was also associated with the rvef in a multivariate regression analysis.A total of 90% of the ph patients in the ivsd group were stratified into intermediate- and high-risk categories, and they showed a prolonged irtrv and a shortened ftrv.The irtrv was also the predictor of the major cardiovascular events.Conclusions: the temporal changes in the cardiac cycle were related to ivs displacement and mainly impacted the diastolic period of the two ventricles in the ph patients.The irt and ft changes may provide useful pathophysiological information on the progression of ph.

Journal: Diagnostics (Basel, Switzerland) (2022)
Publication types: Journal Article
Gastrointestinal Symptomatology as a Predictor of Esophagogastroduodenoscopy Findings in the Bariatric Population: a Retrospective Cohort Study with Review of the Literature.

Esophagogastroduodenoscopy (egd) is a useful test to diagnose significant pathologies before bariatric surgery.Controversy remains about its role in the preoperative workup of asymptomatic patients.This study aims to describe findings and changes in the management related to egd.A secondary objective was to review the existing literature on the subject to analyze the role of patients' gastrointestinal symptomatology as an indication to undergo a preoperative egd.Material and methods a retrospective chart review of patients operated at the centre hospitalier universitaire de sherbrooke (chus) since the opening of the clinique médico-chirurgicale du traitement de l'obésité (cmcto) was conducted, alongside a review of the literature.Pathologic findings on egd were classified into 4 groups (groups 0 to 3).Results of this study were combined with literature to calculate weighted averages of global sensitivity, specificity, positive/negative predictive values, and likelihood ratios of gastrointestinal symptomatology as a predictor of pathologic endoscopy findings.Results a total of 737 patients were included in the study.Of those, 236 (35,7%) were considered symptomatic.Significant pathologic findings on egd (group 2 and 3) were present for 270 patients (36.6%).Changes in medical management occurred in 22.8% of cases and in surgical management in 3.5% of cases.When combining past studies with the present one, the presence of symptoms had a sensitivity of 57.4% and a specificity of 82.4% for findings on egd.Conclusion considering that this exam is relatively safe, that it allows uncovering a great number of pathologies altering management, and that symptoms are not a good screening test to decide of its indication, the authors recommend that all bariatric surgery patients undergo an egd in their preoperative workup.

Journal: Obesity surgery (2022)
Publication types: Journal Article;Review
Oxidative stress in the aging substantia nigra and the etiology of Parkinson's disease.

Parkinson's disease prevalence is rapidly increasing in an aging global population.With this increase comes exponentially rising social and economic costs, emphasizing the immediate need for effective disease-modifying treatments.Motor dysfunction results from the loss of dopaminergic neurons in the substantia nigra pars compacta and depletion of dopamine in the nigrostriatal pathway.While a specific biochemical mechanism remains elusive, oxidative stress plays an undeniable role in a complex and progressive neurodegenerative cascade.This review will explore the molecular factors that contribute to the high steady-state of oxidative stress in the healthy substantia nigra during aging, and how this chemical environment renders neurons susceptible to oxidative damage in parkinson's disease.Contributing factors to oxidative stress during aging and as a pathogenic mechanism for parkinson's disease will be discussed within the context of how and why therapeutic approaches targeting cellular redox activity in this disorder have, to date, yielded little therapeutic benefit.We present a contemporary perspective on the central biochemical contribution of redox imbalance to parkinson's disease etiology and argue that improving our ability to accurately measure oxidative stress, dopaminergic neurotransmission and cell death pathways in vivo is crucial for both the development of new therapies and the identification of novel disease biomarkers.

Journal: Aging cell (2019)
Publication types: Journal Article;Review
Social pain by non-social agents: Exclusion hurts and provokes punishment even if the excluding source is a computer.

Prior research has shown that being excluded by computer-agents in experimental exclusion paradigms threatens individuals' basic needs to a similar extent as being excluded by humans.It is less clear, however, why this similarity between computer and human exclusion occurs, and whether it applies only to reactions immediately after the exclusion event (reflexive stage), or also to reactions that occur further downstream (e.g., reflective stage).Four studies (n = 1048) with three different exclusion paradigms provide several key insights: first, the similarity between computer and human exclusion is robust and pervasive, as bayesian analyses provide consistent support that the source of exclusion (human vs.Computer) does not affect reflexive need satisfaction.Second, this similarity also extends to reflective reactions and punishing behavior.Finally, the present studies extend our knowledge about the processes underlying this similarity by uncovering the role of anthropomorphism.Implications and directions for future research are discussed.

Journal: Acta psychologica (2022)
Publication types: Journal Article
The use of transcranial direct current stimulation (tDCS) to reduce impulsivity and aggression in adults with mild intellectual developmental disabilities: the tDCS-RIADD randomised controlled trial protocol.

Challenging behaviours, in particular aggressive behaviours, are prevalent among people with intellectual developmental disabilities.Predictors of challenging behaviours are numerous, including past history of aggression, poor coping skills and impulsivity.Factors like motor or rapid-response impulsivity (rri) have neurobiological underpinnings that may be amenable to change via neuromodulation using non-invasive brain stimulation techniques like transcranial direct current stimulation (t dcs).Methods this study aims to determine the efficacy of anodal t dcs in reducing rri and incidents of aggression in people with intellectual developmental disabilities (idd) in residential or hospital settings.Using a single blind, randomised, sham-controlled trial design, adults with idd, with a history of impulsivity leading to aggression, will be randomised to receive either repetitive anodal or sham t dcs applied to the left dorsolateral prefrontal cortex.Outcome measures assessing impulsivity and aggression will be collected for up to 1 month following the last t dcs session.Discussion the results of this study may pave the way for developing targeted interventions for impulsivity and aggressive behaviours in people with idd.

Journal: Trials (2022)
Publication types: Clinical Trial Protocol;Journal Article
Downregulated long intergenic non-coding RNA 00,174 represses malignant biological behaviors of lung cancer cells by regulating microRNA-584-3p/ribosomal protein S24 axis.

The detailed regulatory mechanism of linc00174 in lung cancer (lc) development remains largely unknown.This research was designed to probe into the impacts of linc00174 in lc cells through modulating the micro rna (mi r)-584-3p/ribosomal protein s24 (rps24) axis.Linc00174, mi r-584-3p, and rps24 expression levels in lc cells and tissues were examined.The constructs altering linc00174, mi r-584-3p, or rps24 expression were transfected into lc cells to examine the malignant phenotypes of lc cells.The relations among linc00174, mi r-584-3p, and rps24 were validated.Linc00174 and rps24 were high-expressed while mi r-584-3p was low-expressed in lc.Downregulated linc00174 or rps24 or upregulated mi r-584-3p inhibited the malignant biological behaviors of lc cells.The silenced mi r-584-3p could reverse the repressive effects of reduced linc00174 on the development of lc cells; while rps24 overexpression inverted the repressive effects of mi r-584-3p elevation on lc cells.Mechanically, linc00174 bound to mi r-584-3p that targeted rps24.Repressed linc00174 can relieve the malignant phenotypes of lc cells via modulating the mi r-584-3p/rps24 axis.

Journal: Functional & integrative genomics (2022)
Publication types: Journal Article
Versatile LC-MS-Based Workflow with Robust 0.1 ppm Sensitivity for Identifying Residual HCPs in Biotherapeutic Products.

Residual host cell proteins (hcps) in the drug product can affect product quality, stability, and/or safety.In particular, highly active hydrolytic enzymes at sub-ppm levels can negatively impact the shelf life of drug products but are challenging to identify by liquid chromatography-mass spectrometry/mass spectrometry (lc-ms/ms) due to their high dynamic range between hcps and biotherapeutic proteins.We employed new strategies to address the challenge: (1) native digest at a high protein concentration; (2) sodium deoxycholate added during the reduction step to minimize the inadvertent omission of hcps observed with native digestion; and (3) solid phase extraction with 50% me cn elution prior to lc-ms/ms analysis to ensure effective m ab removal.A 50 cm long nanoflow charged surface hybrid column was also packed to allow for higher sample load for increased sensitivity.Our workflow has increased the sensitivity for hcp identification by 10- to 100-fold over previous reports and showed the robustness as low as 0.1 ppm for identifying hcps (34.5 to 66.2 k da mw).The method capability was further confirmed by consistently identifying >85% of 48 ups-1 proteins (0.10 to 1.34 ppm, 6.3 to 82.9 k da mw) in a monoclonal antibody (m ab) and the largest number (746) of mouse proteins from nist m ab reported to date by a single analysis.Our work has filled a significant gap in hcp analysis for detecting and demonstrating hcp clearance, in particular, extremely low-level hydrolases in drug process development.

Journal: Analytical chemistry (2022)
Publication types: Journal Article
Status of glycemic excursions and hypoglycemia in patients with type 1 diabetes 2 months after first initiation of intermittently scanned continuous glucose monitoring: a pilot study.

To investigate glycemic excursions and changes in time in hypoglycemia (hy t) in japanese type 1 diabetes (t1d) patients 2 months after the first initiation of intermittently scanned continuous glucose monitoring (is cgm).Methods we enrolled 15 adult t1d patients on insulin therapy to evaluate changes in the parameters for glycemic excursions 2 months after initiating is cgm by using the wilcoxon signed-rank test.Binomial logistic regression analyses were also used to identify predictors of hypoglycemia.Results a total of 14 patients were available for analysis.Median hb a1c decreased significantly from 7.6% (interquartile range, 6.9-8.3%) to 7.2% (6.7-7.8%) (p= 0.047).Mean glucose, standard deviation of glucose, time in range, and time above range were not significantly different from baseline, while time below range (from 2.2 [1.0-6.9] to 5.0 [2.0-10.8]%;p= 0.016), hy t (from 26.8 [14.5-75.5] to 56.8 [21.7-110.9] min/day;p= 0.030), and time in severe hypoglycemia (sh t, from 4.3 [0.0-8.9] to 11.0 [0.0-24.3] min/day;p= 0.022) increased significantly.Additionally, sh t increased significantly only during daytime.The factor associated with hy t was found to be the reduction in total insulin dose after 2 months.Conclusions in t1d patients with a median hb a1c of 7.6%, hb a1c was significantly decreased 2 months after initiating is cgm, while hy t increased, particularly during daytime.Study results suggest that a reduction in the total insulin dose of about 0.10 u/kg may be required in some cases.These findings need to be taken into account when initiating is cgm.Supplementary information the online version contains supplementary material available at .

Journal: Diabetology international (2022)
Publication types: Journal Article
Severe acute infection and chronic pulmonary disease are risk factors for developing post-COVID-19 conditions.

Post-covid-19 conditions, also known as "long covid", has significantly impacted the lives of many individuals, but the risk factors for this condition are poorly understood.In this study, we performed a retrospective ehr analysis of 89,843 individuals at a multi-state health system in the united states with pcr-confirmed covid-19, including 1,086 patients diagnosed with long covid and 1,086 matched controls not diagnosed with long covid.For these two cohorts, we evaluated a wide range of clinical covariates, including laboratory tests, medication orders, phenotypes recorded in the clinical notes, and outcomes.We found that chronic pulmonary disease (cpd) was significantly more common as a pre-existing condition for the long covid cohort than the control cohort (odds ratio: 1.9, 95% ci: [1.5, 2.6]).Additionally, long-covid patients were more likely to have a history of migraine (odds ratio: 2.2, 95% ci: [1.6, 3.1]) and fibromyalgia (odds ratio: 2.3, 95% ci: [1.3, 3.8]).During the acute infection phase, the following lab measurements were abnormal in the long covid cohort: high triglycerides (meanlong covid: 278.5 mg/d l vs.Meancontrol: 141.4 mg/d l), low hdl cholesterol levels (meanlong covid: 38.4 mg/d l vs.Meancontrol: 52.5 mg/d l), and high neutrophil-lymphocyte ratio (meanlong covid: 10.7 vs.Meancontrol: 7.2).The hospitalization rate during the acute infection phase was also higher in the long covid cohort compared to the control cohort (ratelong covid: 5% vs.Ratecontrol: 1%).Overall, this study suggests that the severity of acute infection and a history of cpd, migraine, cfs, or fibromyalgia may be risk factors for long covid symptoms.Our findings motivate clinical studies to evaluate whether suppressing acute disease severity proactively, especially in patients at high risk, can reduce incidence of long covid.

Journal: medRxiv : the preprint server for health sciences (2022)
Publication types: Preprint;Journal Article
One-stage versus two-stage approach for concomitant gallbladder and common bile duct stones: which one is more proper in patients over 80 years old?

At present, the optimal treatment for common bile duct (cbd) stones combined with gallstones is still controversial.The two most widely accepted techniques are one-stage laparoscopic cbd exploration plus laparoscopic cholecystectomy (lc) and two-stage preoperative endoscopic sphincterotomy plus lc.Considering that all current evidence comes from nonrandomized controlled trials, multicenter randomized controlled trials are needed to further establish the treatment strategy for elderly patients with cbd stones combined with gallstones.

Journal: Journal of minimally invasive surgery (2022)
Publication types: Editorial
Immune Microenvironment Landscape in CNS Tumors and Role in Responses to Immunotherapy.

Despite the important evolution of immunotherapeutic agents, brain tumors remain, in general, refractory to immune therapeutics.Recent discoveries have revealed that the glioma microenvironment includes a wide variety of immune cells in various states that play an important role in the process of tumorigenesis.Anti-tumor immune activity may be occurring or induced in immunogenic hot spots or at the invasive edge of central nervous system (cns) tumors.Understanding the complex heterogeneity of the immune microenvironment in gliomas will likely be the key to unlocking the full potential of immunotherapeutic strategies.An essential consideration will be the induction of immunological effector responses in the setting of the numerous aspects of immunosuppression and evasion.As such, immune therapeutic combinations are a fundamental objective for clinical studies in gliomas.Through immune profiling conducted on immune competent murine models of glioma and ex vivo human glioma tissue, we will discuss how the frequency, distribution of immune cells within the microenvironment, and immune modulatory processes, may be therapeutically modulated to lead to clinical benefits.

Journal: Cells (2021)
Publication types: Journal Article;Review
Evaluation of a pilot interprofessional Arclight™ workshop for healthcare students in Rwanda: promoting collaborative practice in eye health.

Preventable and treatable visual impairment affects more than 1 billion people worldwide.Rwanda has an estimated visual impairment prevalence of 3.7% amongst the 12 million inhabitants.Around one third of this demand could be addressed through a more integrated and collaborative approach, particularly in primary eye care services.Healthcare students, therefore, need to be prepared for collaborative practice in eye health through interprofessional learning.Interprofessional workshops were piloted with ophthalmic clinical officer, medical clinical officer, nursing and medical students from the university of rwanda.The aim was to promote collaborative practice by teaching students how to assess and recognize common eye conditions using the arclight; a low cost, solar powered, portable ophthalmoscope designed for use in low resource settings.Students reported that the workshop content was relevant to all professional groups.They valued the opportunity to learn interprofessionally, share their knowledge and perspectives, and acquire new knowledge and skills together.This pilot helped to identify the most relevant skills and knowledge for future interprofessional eye health training.It enabled the facilitators to reflect on how best to maintain a balance between a quality interprofessional experience and the more specific eye health related learning objectives.

Journal: Journal of interprofessional care (2021)
Publication types: Journal Article
Whole BodyIp6k1Deletion Protects Mice from Age-Induced Weight Gain, Insulin Resistance and Metabolic Dysfunction.

(1) background: we previously demonstrated that disruption of ip6k1 improves metabolism, protecting mice from high-fat diet-induced obesity, insulin resistance, and non-alcoholic fatty liver disease and steatohepatitis.Age-induced metabolic dysfunction is a major risk factor for metabolic diseases.The involvement of ip6k1 in this process is unknown.(2) methods: here, we compared body and fat mass, insulin sensitivity, energy expenditure and serum-, adipose tissue- and liver-metabolic parameters of chow-fed, aged, wild type (a wt) and whole body ip6k1knockout (a ko) mice.(3) results: ip6k1 was upregulated in the adipose tissue and liver ofa wtmice compared to young wtmice.Moreover,ip6k1deletion blocked age-induced increase in body- and fat-weight and insulin resistance in mice.a komice oxidized carbohydrates more efficiently.The knockouts displayed reduced levels of serum insulin, triglycerides, and non-esterified fatty acids.ip6k1deletion partly protected age-induced decline of the thermogenic uncoupling protein ucp1 in inguinal white adipose tissue.Targets inhibited by ip6k1 activity such as the insulin sensitivity- and energy expenditure-inducing protein kinases, protein kinase b (pkb/akt) and amp-activated protein kinase (ampk), were activated in the adipose tissue and liver ofa komice.(4) conclusions:ip6k1deletion maintains healthy metabolism in aging and thus, targeting this kinase may delay the development of age-induced metabolic dysfunction.

Journal: International journal of molecular sciences (2022)
Publication types: Journal Article