Miracle-dz/UniFAR-FTUs huggingface dataset:
Delineation of functionally essential protein regions for 242 neurodevelopmental genes

Abstract Neurodevelopmental disorders (NDDs), including severe paediatric epilepsy, autism and intellectual disabilities are heterogeneous conditions in which clinical genetic testing can often identify a pathogenic variant. For many of them, genetic therapies will be tested in this or the coming years in clinical trials. In contrast to first-generation symptomatic treatments, the new disease-modifying precision medicines require a genetic test-informed diagnosis before a patient can be enrolled in a clinical trial. However, even in 2022, most identified genetic variants in NDD genes are ‘variants of uncertain significance’. To safely enrol patients in precision medicine clinical trials, it is important to increase our knowledge about which regions in NDD-associated proteins can ‘tolerate’ missense variants and which ones are ‘essential’ and will cause a NDD when mutated. In addition, knowledge about functionally indispensable regions in the 3D structure context of proteins can also provide insights into the molecular mechanisms of disease variants. We developed a novel consensus approach that overlays evolutionary, and population based genomic scores to identify 3D essential sites (Essential3D) on protein structures. After extensive benchmarking of AlphaFold predicted and experimentally solved protein structures, we generated the currently largest expert curated protein structure set for 242 NDDs and identified 14 377 Essential3D sites across 189 gene disorders associated proteins. We demonstrate that the consensus annotation of Essential3D sites improves prioritization of disease mutations over single annotations. The identified Essential3D sites were enriched for functional features such as intermembrane regions or active sites and discovered key inter-molecule interactions in protein complexes that were otherwise not annotated. Using the currently largest autism, developmental disorders, and epilepsies exome sequencing studies including >360 000 NDD patients and population controls, we found that missense variants at Essential3D sites are 8-fold enriched in patients. In summary, we developed a comprehensive protein structure set for 242 NDDs and identified 14 377 Essential3D sites in these. All data are available at https://es-ndd.broadinstitute. org for interactive visual inspection to enhance variant interpretation and development of mechanistic hypotheses for 242 NDDs genes. The provided resources will enhance clinical variant interpretation and in silico drug target development for NDD-associated genes and encoded proteins.
Does plantar skin abrasion affect cutaneous mechanosensation?

In humans, plantar cutaneous mechanoreceptors provide critical input signals for postural control during walking and running. Because these receptors are located within the dermis, the mechanical properties of the overlying epidermis likely affect the transmission of external stimuli. Epidermal layers are highly adaptable and can form hard and thick protective calluses, but their effects on plantar sensitivity are currently disputed. Some research has shown no effect of epidermal properties on sensitivity to vibrations, whereas other research suggests that vibration and touch sensitivity diminishes with a thicker and harder epidermis. To address this conflict, we conducted an intervention study where 26 participants underwent a callus abrasion while an age‐matched control group (n = 16) received no treatment. Skin hardness and thickness as well as vibration perception thresholds and touch sensitivity thresholds were collected before and after the intervention. The Callus abrasion significantly decreased skin properties. The intervention group exhibited no change in vibration sensitivity but had significantly better touch sensitivity. We argue that touch sensitivity was impeded by calluses because hard skin disperses the monofilament's standardized pressure used to stimulate the mechanoreceptors over a larger area, decreasing indentation depth and therefore stimulus intensity. However, vibration sensitivity was unaffected because the vibrating probe was adjusted to reach specific indentation depths, and thus stimulus intensity was not affected by skin properties. Since objects underfoot necessarily indent plantar skin during weight‐bearing, calluses should not affect mechanosensation during standing, walking, or running.
Omalizumab as a corticosteroid‐sparing agent in the treatment of bullous pemphigoid

Bullous pemphigoid (BP) is the most common autoimmune blistering skin disease, characterized by the development of autoantibodies against hemidesmosomal components BP180 and BP230. The mainstay of therapy is topical and systemic corticosteroids (CS) and immunosuppressors. As this pathology mainly involves the elderly, subjects often have numerous comorbidities that influence the clinical management. Omalizumab is a recombinant humanized monoclonal anti‐IgE antibody which has recently emerged as a promising treatment for BP in patients for whom CS are contraindicated or conventional treatments have failed to control the disease. For this study, we selected five patients who presented with corticosteroid‐dependent BP with a contraindication to the use of other immunosuppressive treatments. The objectives of our study were to evaluate the effectiveness of omalizumab in controlling BP and allowing to decrease the dosage of systemic CS, assessing the effects of omalizumab on the clinical manifestations and the titers of circulating anti‐BP180 and BP230 antibodies, IgE and eosinophils. A reduction in the dose of systemic CS was possible in 100% of the patients and complete resolution of the clinical picture was seen in 100% for skin lesions and in 40% for pruritus. A reduction of circulating IgE was found in 40%, anti‐BP180 and BP230 IgGs were decreased in 60% and eosinophils in 80%.
Higher sirt1 is associated with a better body composition in master sprinters and untrained peers

ABSTRACT Sirt1 is an enzyme involved in several anti-aging pathways. Associations between Sirt1, age, and body fat (BF) were assessed in master sprinters (MS; n = 35; 50.25 ±5.93 yr.), untrained young non-athletes (UY; n = 32; 23.78 ±3.98 yr.), and untrained middle-aged (UMA; n = 24; 47.29 ±8.04 yr.). BF was assessed using a skinfold protocol, and Sirt1 was measured in plasma by using commercial kits. Sirt1 of MS (17.18 ±4.77 ng/mL) was higher than UMA (6.36 ±2.29 ng/mL; p<0.0001) and did not differ from UY (20.26 ±6.20 ng/mL). Relative BF of MS was lower than UMA (12.71 ±4.07% vs. 22.13 ±4.18%; p<0.0001). Sirt1 was negatively correlated with chronological age (r = −0.735; p<0.0001) when combining UY and UMA in the analysis. However, when Sirt1 of MS and UY was analyzed together, no significant relationship between Sirt1 and chronological age was observed (r = −0.243; p = 0.083). Sirt1 correlated inversely with BF (r = −0.743; p<0.0001) for UY and UMA. Stepwise multiple regression revealed that being either a young or master athlete and body adiposity are possible predictors of Sirt1 levels. MS and UY were associated with higher levels of Sirt1, while UMA and increased BF were associated with lower levels of this enzyme. The relationships among Sirt1, BF, and chronological age of young and middle-aged non-athletes were not statistically significant when the middle-aged participants were MS. These findings suggest possible links between Sirt1 and body composition, which may play roles in the rate of biological aging. Highlights Lower levels of Sirt1 are associated with higher body fat. Master athlete lifestyle seems to promote higher Sirt1 Levels.
Adolescence in lockdown: The protective role of mentalizing and epistemic trust

Abstract Objective Mentalizing is the ability to interpret one's own and others' behavior as driven by intentional mental states. Epistemic trust (openness to interpersonally transmitted information) has been associated with mentalizing. Balanced mentalizing abilities allow people to cope with external and internal stressors. Studies show that social isolation imposed by the COVID‐19 pandemic was highly stressful for most people, especially for adolescents. Here we examine whether mentalizing and epistemic trust were protective factors in relation to emotional distress during the lockdown. Method A total of 131 nonclinical adolescents, aged between 12 and 18 years, were evaluated during the lockdown using the Reflective Functioning Questionnaire for Youth, Inventory of Parent and Peer Attachment, Perceived Stress Scale, and Difficulties in Emotion Regulation Scale. Results Results from network analysis showed that epistemic trust and mentalizing were negatively associated with perceived stress and emotion dysregulation. Epistemic trust in fathers was associated with level of perceived stress, and epistemic trust in mothers with emotion dysregulation. Conclusion These findings suggest that epistemic trust and the capacity to mentalize were low in adolescents during lockdown, and this was associated with high levels of stress. However, robust levels of epistemic trust and mentalizing may have acted as protective factors that buffered individuals from the risk of emotional dysregulation during the lockdown.
Phytase dose-dependent response of kidney inositol phosphate levels in poultry

Phytases, enzymes that degrade phytate present in feedstuffs, are widely added to the diets of monogastric animals. Many studies have correlated phytase addition with improved animal productivity and a subset of these have sought to correlate animal performance with phytase-mediated generation of inositol phosphates in different parts of the gastro-intestinal tract or with release of inositol or of phosphate, the absorbable products of phytate degradation. Remarkably, the effect of dietary phytase on tissue inositol phosphates has not been studied. The objective of this study was to determine effect of phytase supplementation on liver and kidney myo-inositol and myo-inositol phosphates in broiler chickens. For this, methods were developed to measure inositol phosphates in chicken tissues. The study comprised wheat/soy-based diets containing one of three levels of phytase (0, 500 and 6,000 FTU/kg of modified E. coli 6-phytase). Diets were provided to broilers for 21 D and on day 21 digesta were collected from the gizzard and ileum. Liver and kidney tissue were harvested. Myo-inositol and inositol phosphates were measured in diet, digesta, liver and kidney. Gizzard and ileal content inositol was increased progressively, and total inositol phosphates reduced progressively, by phytase supplementation. The predominant higher inositol phosphates detected in tissues, D-and/or L-Ins(3,4,5,6)P4 and Ins(1,3,4,5,6)P5, differed from those (D-and/or L-Ins(1,2,3,4)P4, D-and/or L-Ins(1,2,5,6)P4, Ins(1,2,3,4,6)P5, D-and/or L-Ins(1,2,3,4,5)P5 and D-and/or L-Ins(1,2,4,5,6)P5) generated from phytate (InsP6) degradation by E. coli 6-phytase or endogenous feed phytase, suggesting tissue inositol phosphates are not the result of direct absorption. Kidney inositol phosphates were reduced progressively by phytase supplementation. These data suggest that tissue inositol phosphate concentrations can be influenced by dietary phytase inclusion rate and that such effects are tissue specific, though the consequences for physiology of such changes have yet to be elucidated.
Genome‐wide association analysis identified consistent QTL for seed yield in a soybean diversity panel tested across multiple environments

Improving seed yield is one of the main targets of soybean [Glycine max (L.) Merr. ] breeding. Identification of loci that influence productivity and understanding their genetic mechanism will help marker‐assisted trait introgression. The present study evaluated a diverse panel of 541 soybean genotypes consisting of three maturity groups (MGs III–V) in four environments in Kansas, U.S. Data on seed yield, seed weight, shattering resistance, days to maturity, and plant height showed significant genotype, environmental, and genotype × environment interaction variations. Seed yield and shattering had moderate broad‐sense heritability (<85%), while the rest of the traits showed high broad‐sense heritability (>90%). The SoySNP50K iSelect BeadChip dataset was used to identify significantly associated loci via genome‐wide association studies (GWAS). A total of 19 single‐nucleotide polymorphisms (SNPs) were significantly associated with seed yield. Particularly, two stable seed yield quantitative trait loci (QTL) on chromosomes 9 and 17 were consistently detected in at least three out of four environments. Candidate gene analysis surrounding seed yield QTL on chromosome 9 showed that Glyma.09G048900, an oxygen binding protein, was the closest to the QTL peak. Similarly, Glyma.17G090200 and Glyma.17G090400 were within 20‐kb region of the seed yield QTL on chromosome 17. The candidate genes warrant further analysis to determine their functional mechanisms and develop markers for seed yield improvement.
BRMCF: Binary Relevance and MLSMOTE Based Computational Framework to Predict Drug Functions From Chemical and Biological Properties of Drugs

In silico machine learning based prediction of drug functions considering the drug properties would substantially enhance the speed and reduce the cost of identifying promising drug leads. The drug function prediction capability of different drug properties happens to be different. So assessing these is advantageous in drug discovery. The task of drug function prediction is multi-label in nature reason being, in case of several drugs, multiple functions are associated with a drug. A number of existing works have ignored this inherent multi-label nature of the problem in context of addressing the issue of class imbalance. In the present work, a computational framework named as BRMCF has been proposed for analysing the prediction capability of chemical and biological properties of drugs toward drug functions in view of multi-label nature of problem. It employs Binary Relevance (BR) approach along with five base classifiers for handling the multi-label prediction task and MLSMOTE for addressing the issue of class imbalance. The proposed framework has been validated and compared with BR, Classifier Chains (CC) and Deep Neural Network (DNN) method on four drug properties datasets: SMILES Strings (SS) dataset, 17 Molecular Descriptors (17MD) dataset, Protein Sequences (PS) dataset and drug perturbed Gene EXpression Profiles (GEX) dataset. The analysis of results shows that the proposed framework BRMCF has outperformed BR, CC and DNN method in terms of exact match ratio, precision, recall, F1-score, ROC-AUC which signifies the effectiveness of MLSMOTE. Further, assessment of prediction capability of different drug properties is done and they are ranked as SS <inline-formula><tex-math notation="LaTeX">$>$</tex-math><alternatives><mml:math><mml:mo>></mml:mo></mml:math><inline-graphic xlink:href="pal-ieq1-3215645.gif"/></alternatives></inline-formula> GEX <inline-formula><tex-math notation="LaTeX">$>$</tex-math><alternatives><mml:math><mml:mo>></mml:mo></mml:math><inline-graphic xlink:href="pal-ieq2-3215645.gif"/></alternatives></inline-formula> PS <inline-formula><tex-math notation="LaTeX">$>$</tex-math><alternatives><mml:math><mml:mo>></mml:mo></mml:math><inline-graphic xlink:href="pal-ieq3-3215645.gif"/></alternatives></inline-formula> 17MD. Additionally, the visualization and analysis of drug function co-occurrences signify the appropriateness of the proposed framework for drug function co-occurrence detection and in signaling the new possible drug leads where the detection rate varies from 94.34% to 99.61%.
Preclinical comparison of antinociceptive effects between ibuprofen, diclofenac, naproxen, and acetaminophen on acid-stimulated body stretching and acid-depressed feeding behaviors in rats

Pain is a major problem that burdens the health and economy of societies worldwide. Nonsteroidal anti-inflammatory drugs (NSAIDs) are over-the-counter medications that are widely indicated for mild to moderate pain conditions. Clinically, the selection of a medication among this class is mainly based according to both patient’s and doctor’s previous experiences. Herein, we studied differences in therapeutic efficacies among the most commonly prescribed NSAIDs and acetaminophen in inflammatory pain rat model. Body stretching and food consumption behaviors were assessed after intraperitoneal administration of lactic acid. Initially, different concentrations of lactic acid were evaluated in adult male rats in both behavioral models. Acid concentrations of 1.8 and 3.2% were selected to assess the effects of ibuprofen, diclofenac, naproxen, and acetaminophen in body stretching and feeding behaviors, respectively. In the feeding study, food restriction for 1–24 h prior to feeding studies was assessed at first, and 24 h was selected for further tests. Acetaminophen (100 mg/kg), diclofenac (10 mg/kg), ibuprofen (10–32 mg/kg), and naproxen (3.2–10 mg/kg) significantly decreased acid-stimulated body stretching. Likewise, acetaminophen (100 mg/kg), diclofenac (10 mg/kg), and ibuprofen (32 mg/kg) increased food consumption significantly after 3.2% lactic acid. There were no significant differences between different test drugs efficacies in both stretching and feeding behaviors. In conclusion, feeding behavior provides a good appraisal for pain and analgesic drugs in preclinical studies. There were comparable efficacies between all tested medications in both lactic acid-stimulated body stretching and -depressed feeding behaviors.
Perspectives on the success rate of current antidepressant pharmacotherapy

ABSTRACT Introduction There has been growing debate about the effectiveness of traditional antidepressants for the treatment of depression, and whether the clinical trials literature overstates the value of existing agents. Antidepressant efficacy is limited by suboptimal remission rates, lack of robust efficacy across diverse depressed subgroups, slow onset, and challenges managing tolerability. Clinicians can better navigate uncertainties in this area by recognizing patient-specific clinical and prognostic factors that influence the likelihood of antidepressant drug response. Areas covered The author summarizes pertinent literature regarding drug-placebo differences in antidepressant outcome as well as patient-specific factors that influence antidepressant drug responsivity across subtypes of depressive disorders. Expert opinion Standardized effect sizes for most monoaminergic antidepressants are relatively modest. At least one-third of treatment response derives from nonspecific (yet substantial) placebo effects, limiting the ability to compare antidepressant medication effects to that of ‘no treatment. ’ Patients with high baseline depressive symptom severity are less likely to respond to placebo but may be more responsive to antidepressant pharmacotherapy than is the case in mild forms of depression. Patient satisfaction with antidepressant response must take into consideration not only efficacy for reducing symptoms but also drug tolerability/acceptability and tangible improvement in functional outcome and quality of life.
Comparative evaluation of the antifungal efficacy of sodium hypochlorite, chlorhexidine, and silver nanoparticles against Candida albicans

Candida albicans is a microorganism that causes root canal infections. However, it cannot be eliminated with conventional irrigation solutions. Recently, silver nanoparticles (AgNPs) have become popular for their superior antimicrobial effects. The purpose of this study was to evaluate the antifungal effect of AgNPs to C. albicans comparing with 5.25% sodium hypochlorite (NaOCl) and 2% chlorhexidine (CHX). Silver nanoparticles were synthesized by chemical reduction method. Minimum inhibitory concentration and minimum fungicidal concentration of AgNPs against C. albicans strain were determined according to microdilution method reported by Clinical Laboratory Standards Institute. C. albicans biofilm layer was formed on the dentin blocks for 10 days. The biofilm structure was observed by scanning electron microscopy. Statistical analysis was performed with one way analysis of variance analysis and group comparisons were performed with Tukey test. AgNPs showed the highest antifungal effect among the groups. 5.25% NaOCl showed the lowest antifungal effect among the groups. While the 2% CHX solution had a statistically lower antifungal effect than AgNPs, it was found to have a higher effect than NaOCl (p < .016). Nanoparticles present a wide research field as an alternative irrigation solution in root canal treatment. The antifungal effect of AgNPs against C. albicans was confirmed in this study. Further in vivo studies should evaluate the conditions of use and long‐term prognosis of AgNPs.
The Difficulty of Gate Control in Molecular Transistors

The electrostatic gating effects on molecular transistors are investigated using the density functional theory (DFT) combined with the nonequilibrium Green's function (NEGF) method. When molecular energy levels are away from the Fermi energy they can be linearly shifted by the gate voltage, which is consistent with recent experimental observations [Nature 462, 1039 (2009)]. However, when they move near to the Fermi energy (turn-on process), the shifts become extremely small and almost independent of the gate voltage. The fact that the conductance may be beyond the gate control in the "ON" state will challenge the implementation of molecular transistors.
Autophagy activation can partially rescue proteasome dysfunction‐mediated cardiac toxicity

The ubiquitin–proteasome pathway and its functional interplay with other proteostatic and/or mitostatic modules are crucial for cell viability, especially in post‐mitotic cells like cardiomyocytes, which are constantly exposed to proteotoxic, metabolic, and mechanical stress. Consistently, treatment of multiple myeloma patients with therapeutic proteasome inhibitors may induce cardiac failure; yet the effects promoted by heart‐targeted proteasome dysfunction are not completely understood. We report here that heart‐targeted proteasome knockdown in the fly experimental model results in increased proteome instability and defective mitostasis, leading to disrupted cardiac activity, systemic toxicity, and reduced longevity. These phenotypes were partially rescued by either heart targeted‐ or by dietary restriction‐mediated activation of autophagy. Supportively, activation of autophagy by Rapamycin or Metformin administration in flies treated with proteasome inhibitors reduced proteome instability, partially restored mitochondrial function, mitigated cardiotoxicity, and improved flies' longevity. These findings suggest that autophagic inducers represent a novel promising intervention against proteasome inhibitor‐induced cardiovascular complications.
Questions to consider when caring for patients with ulcerative colitis

Abstract Although the management of patients with ulcerative colitis (UC) is well defined by national and international guidelines, there are many debates and open questions related to daily care of UC patients. Here, we aimed to review topics with high clinical relevance including therapy algorithms, potential biomarkers for disease prognosis and response to therapy, the role of interventions targeting the gut microbiota, insights from head-to-head trials, novel UC medications, exit strategies, the impact of COVID19 on UC, care of patients with acute severe disease, cancer screening, and the role of surgery.