Miracle-dz/UniFAR-FTUs huggingface dataset:
Insight on the interaction between the scorpion toxin blocker Discrepin on potassium voltage-gated channel Kv4.3 by molecular dynamics simulations

Abstract Discrepin is a 38-residue α-toxin extracted from the venom of the Venezuelan scorpion Tityus discrepans, which inhibits ionic transit in the voltage-dependent potassium channels (Kv) of A-type current. The effect of specific residues on the IC50 between Discrepine and Kv4.3, the main component of A-type currents, is known; however, the molecular details of the toxin-channel interaction are not known. In this work, we present interaction models between Discrepin (wt) and two peptide variants (V6K/D20K and K13A) on the pore-forming domain of the Kv4.3 channel obtained from homology, docking, and molecular dynamics modeling techniques. The free energy calculations in these models correspond to the order of the experimentally determined IC50 values. Our studies shed light on the role of the K13 residue as responsible for occluding the Kv4.3 selectivity filter and the importance of the V6K mutation in the approach and stabilization of toxin-channel complex interactions. Communicated by Ramaswamy H. Sarma
Identification of a Novel Axon Regeneration Role for Noncanonical Wnt Signaling in the Adult Retina after Injury

Abstract Canonical and noncanonical Wnt signaling pathways are essential for development and maintenance of the CNS. Whereas the roles of canonical Wnt pathways in neuronal survival and axonal regeneration in adult CNS have been described, the functions of noncanonical Wnt pathways are not well understood. Furthermore, the role of noncanonical Wnt ligands in the adult retina has not been investigated. Noncanonical Wnt signaling shares receptors with canonical Wnt ligands but functions through calcium and c-Jun N-terminal kinase (JNK) signaling pathways. Noncanonical ligands, such as the prototypic ligand Wnt5a, have varying effects in the developing CNS, including inhibiting or promoting axonal growth. To identify a role for noncanonical Wnt signaling in the developed retina after injury, we characterized the effect of Wnt5a on neurite outgrowth in cultured retinal ganglion cell (RGC) neurons and on axonal regeneration in the injured optic nerve in the mouse. Endogenous Wnt5a was upregulated after injury and exogenous Wnt5a significantly enhanced neurite growth of primary RGCs and led to extensive axonal regeneration after optic nerve crush (ONC) injury. Wnt5a also significantly increased RGC survival. Furthermore, Wnt5a induced phosphorylation of CamKII and JNK and induced expression of their downstream pathway components. Therefore, these results demonstrate for the first time that Wnt5a promotes axonal growth and protects RGCs in the adult retina.
DNA Methylation in Gestational Diabetes and its Predictive Value for Postpartum Glucose Disturbances

Abstract Context DNA methylation in the diagnosis of gestational diabetes. Objective To assess the value of DNA methylation in the diagnosis of gestational diabetes (GDM) and in the prediction of maternal postpartum glucose disturbances. Methods Two-stage observational study performed between July 2006 and December 2010, at University Hospital. Forty-eight randomly selected pregnant women formed the discovery cohort (24 with GDM and 24 controls) and 252 pregnant women (94 with GDM and 158 controls) formed the replication cohort. GDM women were re-evaluated 4 years postpartum. The main outcome measures were GDM, type 2 diabetes or prediabetes at 4 years postpartum. Results We identified 3 CpG sites related to LINC00917, TRAPPC9, and LEF1 that were differentially methylated in women with GDM and abnormal glucose tolerance; and sites associated with LINC00917 and TRAPPC9 were independently associated with an abnormal glucose tolerance status 4 years postpartum after controlling for clinical variables. Moreover, the site associated with LINC00917 and the combination of the 3 sites had the highest predictive values. Conclusion Our results suggest that some of these sites may be implicated in the development of GDM and postpartum abnormal glucose tolerance.
Inhaled Pulmonary Vasodilators in COVID-19 Infection: A Systematic Review and Meta-Analysis

Introduction: Inhaled pulmonary vasodilators (IPVD) have been previously studied in patients with non-coronavirus disease-19 (COVID-19) related acute respiratory distress syndrome (ARDS). The use of IPVD has been shown to improve the partial pressure of oxygen in arterial blood (PaO2), reduce fraction of inspired oxygen (FiO2) requirements, and ultimately increase PaO2/FiO2 (P/F) ratios in ARDS patients. However, the role of IPVD in COVID-19 ARDS is still unclear. Therefore, we performed this meta-analysis to evaluate the role of IPVD in COVID-19 patients. Methods: Comprehensive literature search of PubMed, Embase, Web of Science and Cochrane Library databases from inception through April 22, 2022 was performed for all published studies that utilized IPVD in COVID-19 ARDS patients. The single arm studies and case series were combined for a 1-arm meta-analysis, and the 2-arm studies were combined for a 2-arm meta-analysis. Primary outcomes for the 1-arm and 2-arm meta-analyzes were change in pre- and post-IPVD P/F ratios and mortality, respectively. Secondary outcomes for the 1-arm meta-analysis were change in pre- and post-IPVD positive end-expiratory pressure (PEEP) and lung compliance, and for the 2-arm meta-analysis the secondary outcomes were need for endotracheal intubation and hospital length of stay (LOS). Results: 13 single arm retrospective studies and 5 case series involving 613 patients were included in the 1-arm meta-analysis. 3 studies involving 640 patients were included in the 2-arm meta-analysis. The pre-IPVD P/F ratios were significantly lower compared to post-IPVD, but there was no significant difference between pre- and post-IPVD PEEP and lung compliance. The mortality rates, need for endotracheal intubation, and hospital LOS were similar between the IPVD and standard therapy groups. Conclusion: Although IPVD may improve oxygenation, our investigation showed no benefits in terms of mortality compared to standard therapy alone. However, randomized controlled trials are warranted to validate our findings.
Selective engram coreactivation in idling brain inspires implicit learning

Significance A flexible interaction among memories is hypothesized to inform perception through extracting commonalities between the various life experiences and forming connections beyond those directly learned. It often occurs spontaneously after—rather than during—learning; we therefore studied the role of offline brain machinery, that is, during postlearning awake and sleep states, in generating these delayed associations. We found that this offline learning occurs through the coreactivation of cortical representations of an existing memory with that of a subtly related recent one as it gets consolidated during sleep. On the other hand, an early online association occurs when memories share obvious commonalities. Finally, disrupting these delayed offline cortical coreactivations, although not affecting individual memories, interfered with extracting their implicit relationship.
Identifying cellular cancer mechanisms through pathway-driven data integration

Abstract Motivation Cancer is a genetic disease in which accumulated mutations of driver genes induce a functional reorganization of the cell by reprogramming cellular pathways. Current approaches identify cancer pathways as those most internally perturbed by gene expression changes. However, driver genes characteristically perform hub roles between pathways. Therefore, we hypothesize that cancer pathways should be identified by changes in their pathway–pathway relationships. Results To learn an embedding space that captures the relationships between pathways in a healthy cell, we propose pathway-driven non-negative matrix tri-factorization. In this space, we determine condition-specific (i.e. diseased and healthy) embeddings of pathways and genes. Based on these embeddings, we define our ‘NMTF centrality’ to measure a pathway’s or gene’s functional importance, and our ‘moving distance’, to measure the change in its functional relationships. We combine both measures to predict 15 genes and pathways involved in four major cancers, predicting 60 gene–cancer associations in total, covering 28 unique genes. To further exploit driver genes’ tendency to perform hub roles, we model our network data using graphlet adjacency, which considers nodes adjacent if their interaction patterns form specific shapes (e.g. paths or triangles). We find that the predicted genes rewire pathway–pathway interactions in the immune system and provide literary evidence that many are druggable (15/28) and implicated in the associated cancers (47/60). We predict six druggable cancer-specific drug targets. Availability and implementation The code and data are available at: https://gitlab.bsc. es/swindels/pathway_driven_nmtf Supplementary information Supplementary data are available at Bioinformatics online.
Association Between Working Hours and Poor Glycemic Control in Patients With Diabetes

Long working hours were positively associated with an increased risk of poor glycemic control in patients with diabetes, aged over 40 years and undergoing treatment. Working hours for the workers with uncontrolled diabetes can be an important factor in glycemic control. Therefore, workers who work long hours may need more supervision and effort to glycemic control. Objective This study aimed to evaluate the relationship between working hours and glycemic control. Methods Study was performed among Korean participants who underwent at least two health screening examinations between 2012 and 2018. The study included 2169 participants who were older than 40 years and undergoing treatment for diabetes at baseline. A hemoglobin A1c level >9% at the follow-up visit was defined as poor glycemic control. The weekly working hours were divided into three groups for analysis. Results Compared with participants with 45–54 weekly working hours, multivariate-adjusted hazard ratios (95% confidence intervals) for incident poor glycemic control among participants with ≥55 and 35–44 working hours were 1.40 (1.01–1.96) and 1.51 (1.09–2.09), respectively. Conclusions Standard working hours and long working hours were independent risk factors for poor diabetes control in patients with diabetes.
Becoming by doing: How women in academic health sciences build a leadership identity through project experiences

Abstract Purpose Leadership development programs often use institutional projects to activate learning. We explored how project work shaped leadership identity formation in senior women leaders from one academic health science center who enrolled in The Hedwig von Ameringen Executive Leadership in Academic Medicine (ELAM®) program. Materials and methods We interviewed ELAM Fellows and conducted a qualitative analysis of transcripts. Our primary analysis focused on the influences of projects on Fellows and institutions. Leadership identity formation emerged as a distinct pattern, so this narrative content was separated for secondary analysis. All authors approved the final assignment of themes and codes. Results Participants described a multi-dimensional process for developing a leadership identity. Themes encompassed participants’ View of Self and One’s Image as a Leader, Interpersonal Relationships, and Commitment to a Value-based Goal. These internal factors grounded external influences, such as interactions with colleagues and institutional leaders, and the world beyond the institution. Conclusions We examined the process of leadership identity formation from the perspective of women leaders in academic health sciences who completed an institutional project during a leadership development program. Findings illustrate how internal and external forces, experienced in the context of project work, combine to influence leadership identity formation in women.
Validation of the Dutch Questionnaire on Emotional Labor (D-QEL) in Nurses and Teachers

This paper describes the validation of the Dutch Questionnaire on Emotional Labor (D-QEL) in a sample of 365 teachers and in a sample of 334 nurses. The D-QEL is a 13 item self-report questionnaire that measures surface acting, deep acting, suppression and emotional consonance. Confirmatory factor analysis provided support for the existence of four separate subscales. Evidence was also provided for convergent, discriminant and criterion validity
Psychometric evaluation of the tinnitus impact questionnaire using patients seeking help for tinnitus or tinnitus with hyperacusis

Abstract Objective To evaluate the psychometric properties of the Tinnitus Impact Questionnaire (TIQ), whose questions focus on assessing the impact of tinnitus on the patient’s day to day activities, mood, and sleep, and not on hearing difficulties. Design This was a retrospective cross-sectional study. Study sample Data were included for 172 adult patients who attended a tinnitus and hyperacusis clinic in the UK within a six-month period and who had completed the TIQ. Results Two items whose scores were very highly correlated with those for other items were removed, leaving seven items. Exploratory factor analysis suggested a single factor for the TIQ. A multiple causes multiple indicator model showed significant but very small direct effects of age on TIQ scores for two items, after adjustment for gender. The TIQ had excellent internal consistency, with Cronbach’s alpha = 0.89. The total TIQ score was moderately to strongly correlated with scores for the Tinnitus Handicap Inventory, Screening for Anxiety and Depression-Tinnitus questionnaire, Hyperacusis Questionnaire, and Hyperacusis Impact Questionnaire, indicating convergent validity. The TIQ score was weakly correlated with the pure-tone average hearing threshold, indicating discriminant validity. Conclusions The TIQ is a brief, valid and internally consistent questionnaire for assessing the impact of tinnitus.
Better preservation of erectile function in localized prostate cancer patients with modern proton therapy: Is it cost‐effective?

Stereotactic body radiation therapy (SBRT) has gradually been recognized as favorable curative treatment for localized prostate cancer (PC). However, the high rate of erectile dysfunction (ED) after traditional photon‐based SBRT remains an ongoing challenge that greatly impacts the quality of life of PC survivors. Modern proton therapy allows higher conformal SBRT delivery and has the potential to reduce ED occurrence but its cost‐effectiveness remains uninvestigated.
Genome Sequence of Erysipelothrix sp. Strain Poltava, Isolated from Acute Septic Erysipelas of Swine in Ukraine

The complete genome of Erysipelothrix sp. strain Poltava, isolated from fatal acute septic erysipelas of swine in Ukraine, was assembled using Nanopore sequences. One circular chromosome of 1,794,858 bp (N50, 1,794,858 bp) encodes 16 putative antibiotic resistance genes and secreted virulence factors, highlighting the risk of cross-species livestock and human infection. ABSTRACT The complete genome of Erysipelothrix sp. strain Poltava, isolated from fatal acute septic erysipelas of swine in Ukraine, was assembled using Nanopore sequences. One circular chromosome of 1,794,858 bp (N50, 1,794,858 bp) encodes 16 putative antibiotic resistance genes and secreted virulence factors, highlighting the risk of cross-species livestock and human infection.
Sequential ultrasound in arthralgia patients at risk for inflammatory arthritis: is it of added value in risk stratification?

Musculoskeletal ultrasound (MSUS) is often used to assess the presence of subclinical joint inflammation in arthralgia patients suspicious for progression to clinically apparent inflammatory arthritis (IA). Even though evidence-based guidelines for these patients are still absent, the presence or absence of subclinical joint inflammation often influences management decisions in daily practice (1). Indeed, subclinical inflammation has consistently shown to be a promising predictor for the development of IA in arthralgia patients and pro-vides the opportunity to improve risk stratification (1)
Role and Regulation of Hepatobiliary ATP-Binding Cassette Transporters during Chemical-Induced Liver Injury

Severity of drug-induced liver injury (DILI) ranges from mild, asymptomatic, and transient elevations in liver function tests to irreversible liver damage, often needing transplantation. Traditionally, DILI is classified mechanistically as high-frequency intrinsic DILI, commonly dose dependent or DILI that rarely occurs and is idiosyncratic in nature. This latter form is not dose dependent and has a pattern of histopathological manifestation that is not always uniform. Currently, a third type of DILI called indirect hepatotoxicity has been described that is associated with the pharmacological action of the drug. Historically, DILI was primarily linked to drug metabolism events; however, the impact of transporter-mediated rates of drug uptake and excretion has gained greater prominence in DILI research. This review provides a comprehensive view of the major findings from studies examining the contribution of hepatic ATP-binding cassette transporters as key contributors to DILI and how changes in their expression and function influence the development, severity, and overall toxicity outcome. SIGNIFICANCE STATEMENT Drug-induced liver injury (DILI) continues to be a focal point in drug development research. ATP-binding cassette (ABC) transporters have emerged as important determinants of drug detoxification, disposition, and safety. This review article provides a comprehensive analysis of the literature addressing: (a) the role of hepatic ABC transporters in DILI, (b) the influence of genetic mutations in ABC transporters on DILI, and (c) new areas of research emphasis, such as the influence of the gut microbiota and epigenetic regulation, on ABC transporters.
Outcomes reported in trials of treatments for severe malaria: The need for a core outcome set

Malaria is one of the most important parasitic infectious diseases worldwide. Despite the scale‐up of effective antimalarials, mortality rates from severe malaria (SM) remain significantly high; thus, numerous trials are investigating both antimalarials and adjunctive therapy. This review aimed to summarise all the outcome measures used in trials in the last 10 years to see the need for a core outcome set.
“A friend during troubled times”: Experiences of family caregivers to persons with dementia when receiving professional support via a mobile app

The number of adults living with dementia is increasing. In 2018, fifty million people worldwide were diagnosed with dementia and it is estimated that this figure will triple by 2050 [1]. The number of family members involved in providing care will increase accordingly and supporting them is crucial in order to increase the quality of life of persons with dementia. Although there have been advances in the treatment of dementia diseases, caregiving is still a challenging situation for the family. Across Europe, family caregivers are confronted with significant challenges regarding supportive care needs for persons with dementia living at home [2, 3]. These include personal care, housekeeping, logistics and financial problems, being responsible for medications, and contact with the healthcare authorities [4]. Such a caregiving role leads to a significant responsibility and little free time for the family caregiver to take care of themselves [5]. A meta-analysis focusing on stress and coping for family caregivers to persons with dementia shows that being a family caregiver is a significant risk factor which can lead to decreased physical health and increased psychological stress [6]. It is well known that family caregiving for persons with dementia is associated with negative consequences for the caregivers such as care burden [7], stress, strain [8], sadness, depression, and anxiety [9], feelings of loneliness and social isolation [10–12] and reduced quality of life [13]. Social isolation and lack of formal support have a negative impact on family caregivers’ personal and social life [10]. Evidence indicates a strong association between being a family caregiver of a person with dementia and symptoms of depression [14, 15]. Lower perceived health of family caregivers is associated with an increased risk for the institutionalisation of persons with dementia [16]. Even in terms of physical health, it has been reported that it is easier to be a caregiver to persons with other chronic diseases compared to persons with dementia [17]. The various types of support given to family caregivers to counteract their stress, burden, lack of subjective well-being and social isolation include organising support groups, education about dementia, social work services and face-to-face conversations [18, 19]. Different technical solutions can provide an alternative way and a platform for family caregivers to obtain support from care professionals or to exchange experiences with other family caregivers who are in similar situations [20]. The use of app-based technologies in smartphones is rapidly growing in all age groups. Mobile health (mHealth) applications have increased throughout the world and have been developed for a wide variety of health interventions, predominantly as mobile applications (app) for self-care such as for asthma [21] and diabetes [22]. mHealth is defined PLOS ONE
Diffuse Large B-Cell Lymphoma in the Public-Sector of Johannesburg, South Africa, in the Era of Widescale Antiretroviral Therapy Use

Background: Diffuse large B-cell lymphoma (DLBCL) is a high-grade non-Hodgkin lymphoma with increased incidence among people living with HIV-infection (PLWH). Although its frequency is reportedly attenuated by antiretroviral therapy (ART), we have previously shown a similar rate of DLBCL in the post-ART era (2017) in Johannesburg, South Africa compared with that observed when ART had only limited availability in the South Africa state-sector (2007). Here, we present a more detailed analysis of DLBCL in the pre-and post-ART eras in Johannesburg. Methods and Results: All cases of DLBCL diagnosed in the state-sector hospitals of Johannesburg in 2007 and 2017 were extracted from the laboratory information system, and factors of interest compared. Most (>85%) were observed among PLWH at both time-points; ART-coverage was significantly higher in 2017 compared with 2007, but with failed immunological recovery in 50% of cases. The immunohistochemically-defined cell of origin differed according to HIV-status; the germinal center (GC) and non-GC subtypes predominating in the PLWH and the HIV-negative group, respectively. MYC-gene rearrangement was more common than is reported elsewhere (22.1%), whereas BCL6 and BCL2 gene rearrangements were less so (14.6% and 0%, respectively). Slight improvement in survival was noted in the post-ART era, but remained poor, with bone marrow involvement and albumin levels ≤30 g/L independently associated with mortality. Conclusions: Although the frequency of DLBCL in Johannesburg has not dropped significantly in the post-ART era, a slight improvement in survival is observed. However, outcomes remain poor, indicating a need for further improvements in care.