Miracle-dz/UniFAR-FTUs huggingface dataset:
Excess of ovarian nerve growth factor impairs embryonic development and causes reproductive and metabolic dysfunction in adult female mice

Nerve growth factor (NGF) is critical for the development and maintenance of the peripheral sympathetic neurons. NGF is also involved in the ovarian sympathetic innervation and in the development and maintenance of folliculogenesis. Women with the endocrine disorder, polycystic ovary syndrome (PCOS), have an increased sympathetic nerve activity and increased ovarian NGF levels. The role of ovarian NGF excess in the PCOS pathophysiology and in the PCOS‐related features is unclear. Here, using transgenic mice overexpressesing NGF in the ovarian theca cells (17NF mice), we assessed the female embryonic development, and the reproductive and metabolic profile in adult females. Ovarian NGF excess caused growth restriction in the female fetuses, and a delayed gonocyte and primary oocyte maturation. In adulthood, the 17NF mice displayed irregular estrous cycles and altered ovarian expression of steroidogenic and epigenetic markers. They also exhibited an increased sympathetic output with increased circulating dopamine, and metabolic dysfunction reflected by aberrant adipose tissue morphology and function, impaired glucose metabolism, decreased energy expenditure, and hepatic steatosis. These findings indicate that ovarian NGF excess leads to adverse fetal development and to reproductive and metabolic complications in adulthood, mirroring common features of PCOS. This work provides evidence that NGF excess may be implicated in the PCOS pathophysiology.
Cognitive stimulation therapy for dementia: Provision in National Health Service settings in England, Scotland and Wales

Objectives: Cognitive stimulation therapy (CST) is a brief, non-pharmacological intervention for people with dementia, with an established evidence base for improving cognition and quality of life. It is widely implemented in National Health Service (NHS) settings, but little is known about its naturalistic use. The aim of this survey was to identify and explore inclusion criteria, dose and quality of CST across services in Great Britain (England, Scotland and Wales). Methods: All NHS memory clinics and services for people with dementia were contacted and asked to complete a mixed methods online survey on CST delivery in their service. Questions were centred on who provided CST, who received CST, the dose of CST and any outcomes that were routinely measured.Results: A total of 57/186 services responded, giving a response rate of 30.7%. While the majority reported offering CST (87.7%), there was variability in how this was delivered. Differing inclusion criteria included the use of varying cognitive and behavioural outcome measures, and CST was reported as being offered once and twice weekly. Services also differed in how they evaluated the quality of CST and how this evidence was incorporated for future sessions.Conclusion: While there was a low response rate, this survey indicates that there is significant variability in how CST is used in clinical practice, with many trusts not adhering to the evidence base. To ensure that people with dementia are consistently offered evidence-based, high-quality CST across NHS settings, further standardisation of inclusion criteria, dose and outcomes is needed.
The impact of the COVID-19 Pandemic on Patients with Chronic Rheumatic Diseases: A Study in 15 Arab Countries

Aim. To evaluate the impact of the Coronavirus Disease 2019 pandemic (COVID-19) on the access to rheumatology care for patients with chronic rheumatic diseases (CRD) in the Arab countries.Method. A web-based cross-sectional survey was designed by the Arab Adult Arthritis Awareness group (AAAA) consisting of 16 rheumatologists representing countries from the Arab League of Associations for Rheumatology (ArLAR), and was validated by the ArLAR scientific committee. The survey was disseminated through social media and patients' associations' channels between May 8 and May 22, 2020. The steering committee developed recommendations to improve the care of patients with CRD during the COVID-19 pandemic.Results. A total of 2163 patients were included in the analysis; 72% were females; mean age was 40 years (SD 11.9). The Levant, the Gulf, and North Africa contributed almost equally to the sample. The pandemic had a significant negative impact on rheumatology visits in 82% of cases, on access to hydroxychloroquine (47%), and on chronic medication persistency (28%). The negative impact on rheumatology visits was associated with female gender, country, medication non-persistency, isolation due to COVID-19, and impact on mental health. Sixty-one patients (2.8%) stated that they had COVID-19, 5% said that a close contact was infected, and 47% were in isolation because of COVID-19.Conclusion. The current study highlights the deleterious consequences of the COVID-19 pandemic on the continuity of rheumatology care. Therefore, an action plan, including establishing a telemedicine platform, securing drug availability, and promoting medication persistence through the appropriate communication channels, is strongly recommended.
Peptide‐mediated surface coatings for the release of wound‐healing cytokines

Supporting the wound healing process by sending the appropriate cytokine signals can shorten healing time and overcome chronic inflammation syndromes. Even though adhesion peptides consisting of Arg‐Gly‐Asp (RGD) are commonly used to enhance cell‐surface interactions, peptide‐mediated cytokine delivery has not been widely exploited so far. Cytokines interact with high affinity with their cognitive receptors but also with sulfated glycosaminoglycans (GAGs), both of which form a base for incorporation of cytokines into functional biomaterials. Here, we report on a mussel‐derived surface coating as a prospective cytokine delivery system using covalently bound heparin mimetics, receptor‐derived chemokine‐binding peptides, and heparin‐binding peptides (HBP). The latter enabled non‐covalent immobilization of heparin on the surface followed by chemokine binding and release, whereas the former allowed direct non‐covalent chemokine immobilization. The peptide displayed excellent binding to custom‐made polystyrene 96‐well plates, enabling convenient testing of several compounds. Released chemokine successfully induced migration in Jurkat cells, especially for the non‐covalent heparin immobilization approach using HBPs as evaluated in a transwell assay. In comparison, heparin‐mimetic coatings, comprised of sulfated peptides and GAG derivatives, proved less efficient with respect to amount of immobilized chemokine and migratory response. Thus, our study provides a roadmap for further rational optimization and translation into clinics.
Myocardial infarction or acute coronary syndrome with non-obstructive coronary arteries and sudden cardiac death: a missing connection

Abstract Myocardial infarction with non-obstructive coronary arteries or any acute coronary syndrome (ACS) with normal or near-normal (non-obstructive) coronary arteries (ACS-NNOCA) is an heterogeneous clinical entity, which includes different pathophysiology mechanisms and is challenging to treat. Sudden cardiac death (SCD) is a catastrophic manifestation of ACS that is crucial to prevent and treat urgently. The concurrence of the two conditions has not been adequately studied. This narrative review focuses on the existing literature concerning ACS-NNOCA pathophysiology, with an emphasis on SCD, together with risk and outcome data from clinical trials. There have been no large-scale studies to investigate the incidence of SCD within ACS-NNOCA patients, both early and late in the disease. Some pathophysiology mechanisms that are known to mediate ACS-NNOCA, such as atheromatous plaque erosion, anomalous coronary arteries, and spontaneous coronary artery dissection are documented causes of SCD. Myocardial ischaemia, inflammation, and fibrosis are probably at the core of the SCD risk in these patients. Effective treatments to reduce the relevant risk are still under research. ACS-NNOCA is generally considered as an ACS with more ‘benign’ outcome compared to ACS with obstructive coronary artery disease, but its relationship with SCD remains obscure, especially until its incidence and effective treatment are evaluated.
Part of pain labelled neuropathic in rheumatic disease might be rather nociplastic

Pain in rheumatic diseases is primarily due to mechanical or inflammatory mechanism, but neuropathic pain (NP) component is also occurring in many conditions and is probably underdiagnosed. The purpose of this article is to provide an overview of prevalence, pathophysiological and currently available treatment of NP in rheumatic diseases. When associated with clinical evaluation assessing neurological clinical signs and neuroanatomical distribution, Douleur Neuropathique 4 Questions, painDETECT, Leeds assessment of neuropathic symptoms and signs and Neuropathic Pain Questionnaire can detect NP component. Inflammatory or connective diseases, osteoarthritis, back pain or persistent pain after surgery are aetiologies that all may have a neuropathic component. Unlike nociceptive pain, NP does not respond to usual analgesics such as paracetamol and non-steroidal anti-inflammatory drugs. Entrapment neuropathy, peripheral neuropathy or small-fibre neuropathy are different aetiologies that can lead to NP. A part of the pain labelled neuropathic is rather nociplastic, secondary to a central sensitisation mechanism. Identifying the right component of pain (nociceptive vs neuropathic or nociplastic) could help to better manage pain in rheumatic diseases with pharmacological and non-pharmacological treatments.
The effect of coverage level and premium subsidy on farmers’ participation in forest insurance: An empirical analysis of forest owners in Hunan Province of China

ABSTRACT In forest insurance policy, coverage level and premium subsidy are two important factors that affect farmers’ decision to be insured. This paper uses data from a survey of farmers in Hunan Province of China. First, a single-bounded dichotomous-choice valuation method is used to estimate the average amount that the farmers are willing to pay (WTP) for forest insurance. The results show that farmers’ average WTP is 0.65 RMB/acre (Chinese currency is referred as RMB), which is lower than the premium level prescribed in the existing forest insurance implementation program. Second, an acreltiple-bound dichotomous-choice valuation method is used to study farmers’ WTP for acreltiple coverage levels. Results show that when coverage equals 500 RMB/acre, 1,000 RMB/acre, and 2,000 RMB/acre, the median value of the premium level of farmers’ WTP is 0.922 RMB/acre, 1.954 RMB/acre and 2.893 RMB/acre, respectively. In a situation where the current premium rates are unchanged, and the coverage level is 500 RMB/acre, 1,000 RMB/acre, or 2,000 RMB/acre, the models predict the subsidy ratio should be 53.90, 51.15 and 63.84%, respectively. Improving the coverage level of existing forest insurance policies can significantly increase farmers’ expected rate of insurance.
In silico and saturation transfer difference NMR approaches to unravel the binding mode of an andrographolide derivative to K-Ras oncoprotein.

Background: Andrographolide and its benzylidene derivatives, SRJ09 and SRJ23, potentially bind oncogenic K-Ras to exert anticancer activity. Their molecular interactions with K-Ras oncoproteins that lead to effective biological activity are of major interest. Methods & results: In silico docking and molecular dynamics simulation were performed using Glide and Desmond, respectively; while saturation transfer difference NMR was performed using GDP-bound K-RasG12V. SRJ23 was found to bind strongly and selectively to K-RasG12V, by anchoring to a binding pocket (namely p2) principally via hydrogen bond and hydrophobic interactions. The saturation transfer difference NMR analysis revealed the proximity of protons of functional moieties in SRJ23 to K-RasG12V, suggesting positive binding. Conclusion: SRJ23 binds strongly and interacts stably with K-RasG12V to exhibit its inhibitory activity.
Associations and risk factors for dental trauma: A systematic review of systematic reviews.

OBJECTIVE We sought to revise, qualify and summarize the body of evidence based on current information on the known associations and risk factors for traumatic dental injury (TDI) occurrence with an overview of systematic reviews. METHODS Electronic searches were performed with no language nor date restrictions.According to the PECO strategy, systematic reviews that investigated participants (P) with (E) and without (O) the presentation of factors relating to TDI and these factors' association with TDI episodes (O) as primary or secondary outcomes were included. Quality assessment and bias control were carried out according to the AMSTAR 2 checklist. In cases of systematic review results of discordance, the Jadad decision algorithm was applied. RESULTS After titles, abstracts and full texts were read, 19 systematic reviews were included in this overview. Four were classified with critically low, eleven with low and four with moderate methodological quality, respectively. In all studies, 249 cross-sectional, 34 epidemiological surveys, 22 cohort, 9 case-control, 4 longitudinal, 3 ecological and 30 unspecified studies were included. Male gender, child age, greater overjet, inadequate lip coverage, anterior open bite, caries in the permanent dentition, overweight, a previous history of TDI, tongue piercing, the use of alcoholic beverages and participation in sports were all associated with a greater chance of suffering TDI. CONCLUSIONS Sociodemographic, clinical and environmental factors are associated with a greater chance of TDI occurrence. However, most of the systematic reviews included were of a low quality and may not provide an accurate and comprehensive summary of the available research that addresses the question of interest. Well-designed primary studies on different aspects of TDI are encouraged to provide higher quality scientific evidence.
Colon Cancer and its Molecular Subsystems: Network Approaches to Dissecting Driver Gene Biology

by VISHAL N. PATEL The progression of colorectal cancer is driven by the accumulation of mutations in a number of key genes, which synergize with each other to promote tumor growth. These coregulatory genes are of particular importance as they provide alternative points for pharmacologic modulation of perturbed signaling pathways. In this work, we explored the signaling landscapes of three important regulatory genes – Hpgd, Apc, and Cdkn1a – using genetically engineered mice as models of colon cancer. We assayed the intestinal epithelium using genomic (mRNA arrays) and proteomic (2D gels and label-free proteomics) modalities. To identify genes with a potential regulatory role, we employed protein interaction networks and mRNA coexpression networks to extrapolate from the proteomic measurements. In the process, we introduced novel bioinformatic approaches for testing network-based hypotheses, for applications where the signaling pathway is known a priori. In addition, we also introduced a novel statistical framework for interpreting label-free proteomic data in a genomic context. With the objective of identifying new regulatory targets, we found that the sparsity of proteomic data is ameliorated by relying on inferences from interaction networks and that these inferences are greatly improved by coupling proteomic data with genomic measurements.
miR‐211‐5p is down‐regulated and a prognostic marker in bladder cancer

The micro RNA (miRNA)/histone deacetylase 9 (HDAC9) signaling axis has been reported to be involved in initiating and developing multiple malignant tumors. In the present study, we aimed to determine whether miR‐211‐5p serves as a post‐transcriptional regulator in bladder cancer (BCa) cell proliferation and apoptosis by targeting HDAC9.
Ecomorphological differences in foraging and pattering behavior among storm-petrels in the eastern Pacific Ocean

ABSTRACT For closely related species, differences in morphology can provide insight into the evolutionary history of a taxonomic group, as well as mechanisms for ecological segregation. Storm-petrels are among the smallest seabirds, and their greatest taxonomic diversity occurs in the eastern Pacific Ocean. Some storm-petrels exhibit a unique foraging behavior, known as “pattering” or “sea-anchor soaring,” in which they appear to walk on the surface of the ocean, but this behavior is used to a varying degree among species. We compared morphological traits related to the pattering behavior in 9 species of storm-petrels that breed in the eastern Pacific. Measurements on the wing (wing loading, aspect ratio), beak (size), and leg (length and foot size) were analyzed using a discriminant function analysis (DFA). A thin-plate spline/relative warp analysis was also used to detect subtle differences in wing shape. Species that patter the most have low wing loading, low foot loading, and a long tarsus and were distinct from the species that were classified as intermediate or least pattering. The DFA and a cluster analysis also identified putative pattering behavior of species based on morphology, for which there was little known observational data. A molecular phylogeny of the mitochondrial ND1 gene revealed that the 2 subfamilies of storm-petrels were not monophyletic. The phylogenetic tree shows that the pattering behavior has a strong evolutionary signal and arose early among storm-petrels.
Estimation on conditional restricted mean survival time with counting process

ABSTRACT In a comparative longitudinal clinical study, multiple clinical events of interest are typically collected in timing and occurrence during the follow-up period. These clinical events are often indicative of disease burden over the study period and provide overall evidence of benefit/risk of one treatment relative to another. While these clinical events are usually used to form a composite endpoint, only the first occurrence of the composite endpoint event is considered in primary efficacy analysis. This type of analysis is commonly performed but it may not be ideal. Most of the existing methods for analyzing multiple event-time data were developed, relying on certain model assumptions. However, the assumptions may greatly affect the inferences for treatment effect. In this paper, we propose a simple, non-parametric estimator of conditional mean survival time for multiple events to quantify treatment effect which has clinically meaningful interpretation. We use simulation studies to evaluate the performance of the new method. Further, we apply this method to analyze the data from a cardiovascular clinical trial as an illustration.
Efforts towards a COVID-19 vaccine.

To many scientists and political authorities, the development of a vaccine against SARS-CoV-2 will be will be the way to restore normality to civil life in this time of a devastating pandemic. Expectations for a vaccine are high while the case numbers continue to rise. As of mid-August 2020, more than 20 million people have been infected and more than 760'000 lives have been lost worldwide. The threat of this virus to health, the economy, and to society is so great that the wish for a fast track vaccine is understandable, but how realistic is it? This survey article tries to give an overview of vaccine candidates in development, including preclinical and clinical testing, and it also mentions some of the societal problems of vaccine acceptance. This article is protected by copyright. All rights reserved.
Can psychosocial working conditions help to explain the impact of shiftwork on health in male- and female-dominated occupations? A prospective cohort study

ABSTRACT Occupational factors are sometimes invoked to explain gender differences in the associations between shiftwork and health. We examined prospective associations between shiftwork and health, and between shiftwork and sick leave, separately for workers in female-dominated (FD) and male-dominated (MD) occupations; and whether the associations remained after controlling for psychosocial working conditions. Data from six waves of the Swedish Longitudinal Occupational Survey of Health were used to examine prospective associations with a four-year time lag between work schedule (daywork versus shiftwork involving nightwork; and daywork versus shiftwork not involving nightwork) and self-reports of depressive symptoms; incidents of short- and long-term sick leave; self-rated health; and sleep disturbance. Dynamic panel models with fixed effects were applied, using structural equation modeling. The analyses included adjustments for personal circumstances and employment conditions; and additional adjustments for psychosocial working conditions (psychological and emotional job demands; job control; worktime control; social support at work; persecution at work; and threats or violence at work). Within FD occupations, shiftwork that included night work (as compared to daytime work) predicted higher incidence of short-term sick leave (<1 week); within MD occupations, shiftwork that included nightwork predicted greater symptoms of mild depression. Despite notable differences in psychosocial working conditions between dayworkers and shiftworkers, both associations remained significant after adjustments. Thus, it was not confirmed that the associations between shiftwork and health reflected poorer working conditions of shiftworkers in either FD or MD occupations, although the possibility remains that the associations were due to other unmeasured aspects of the working environment.
RGFP966 inactivation of the YAP pathway attenuates cardiac dysfunction induced by prolonged hypothermic preservation

Oxidative stress and apoptosis are the key factors that limit the hypothermic preservation time of donor hearts to within 4–6 h. The aim of this study was to investigate whether the histone deacetylase 3 (HDAC3) inhibitor RGFP966 could protect against cardiac injury induced by prolonged hypothermic preservation. Rat hearts were hypothermically preserved in Celsior solution with or without RGFP966 for 12 h followed by 60 min of reperfusion. Hemodynamic parameters during reperfusion were evaluated. The expression and phosphorylation levels of mammalian STE20-like kinase-1 (Mst1) and Yes-associated protein (YAP) were determined by western blotting. Cell apoptosis was measured by the terminal deoxynucleotidyl-transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) method. Addition of RGFP966 in Celsior solution significantly inhibited cardiac dysfunction induced by hypothermic preservation. RGFP966 inhibited the hypothermic preservation-induced increase of the phosphorylated (p)-Mst1/Mst1 and p-YAP/YAP ratios, prevented a reduction in total YAP protein expression, and increased the nuclear YAP protein level. Verteporfin (VP), a small molecular inhibitor of YAP-transcriptional enhanced associate domain (TEAD) interaction, partially abolished the protective effect of RGFP966 on cardiac function, and reduced lactate dehydrogenase activity and malondialdehyde content. RGFP966 increased superoxide dismutase, catalase, and glutathione peroxidase gene and protein expression, which was abolished by VP. RGFP966 inhibited hypothermic preservation-induced overexpression of B-cell lymphoma protein 2 (Bcl-2)-associated X (Bax) and cleaved caspase-3, increased Bcl-2 mRNA and protein expression, and reduced cardiomyocyte apoptosis. The antioxidant and anti-apoptotic effects of RGFP966 were cancelled by VP. The results suggest that supplementation of Celsior solution with RGFP966 attenuated prolonged hypothermic preservation-induced cardiac dysfunction. The mechanism may involve inhibition of oxidative stress and apoptosis via inactivation of the YAP pathway.