Domestic species such as cattle (Bos taurus taurus and B. t. indicus) represent attractive biological models to characterize the genetic basis of short‐term evolutionary response to climate pressure ...induced by their post‐domestication history. Here, using newly generated dense SNP genotyping data, we assessed the structuring of genetic diversity of 21 autochtonous cattle breeds from the whole Mediterranean basin and performed genome‐wide association analyses with covariables discriminating the different Mediterranean climate subtypes. This provided insights into both the demographic and adaptive histories of Mediterranean cattle. In particular, a detailed functional annotation of genes surrounding variants associated with climate variations highlighted several biological functions involved in Mediterranean climate adaptation such as thermotolerance, UV protection, pathogen resistance or metabolism with strong candidate genes identified (e.g., NDUFB3, FBN1, METTL3, LEF1, ANTXR2 and TCF7). Accordingly, our results suggest that main selective pressures affecting cattle in Mediterranean area may have been related to variation in heat and UV exposure, in food resources availability and in exposure to pathogens, such as anthrax bacteria (Bacillus anthracis). Furthermore, the observed contribution of the three main bovine ancestries (indicine, European and African taurine) in these different populations suggested that adaptation to local climate conditions may have either relied on standing genomic variation of taurine origin, or adaptive introgression from indicine origin, depending on the local breed origins. Taken together, our results highlight the genetic uniqueness of local Mediterranean cattle breeds and strongly support conservation of these populations.
With the lack of effective therapy, chemoprevention, and vaccination against SARS-CoV-2, focusing on the immediate repurposing of existing drugs gives hope of curbing the COVID-19 pandemic. A recent ...unbiased genomics-guided tracing of the SARS-CoV-2 targets in human cells identified vitamin D among the three top-scoring molecules manifesting potential infection mitigation patterns. Growing pre-clinical and epidemiological observational data support this assumption. We hypothesized that vitamin D supplementation may improve the prognosis of COVID-19. The aim of this trial is to compare the effect of a single oral high dose of cholecalciferol versus a single oral standard dose on all-cause 14-day mortality rate in COVID-19 older adults at higher risk of worsening.
The COVIT-TRIAL study is an open-label, multicenter, randomized controlled superiority trial. Patients aged ≥ 65 years with COVID-19 (diagnosed within the preceding 3 days with RT-PCR and/or chest CT scan) and at least one worsening risk factor at the time of inclusion (i.e., age ≥ 75 years, or SpO2 ≤ 94% in room air, or PaO2/FiO2 ≤ 300 mmHg), having no contraindications to vitamin D supplementation, and having received no vitamin D supplementation > 800 IU/day during the preceding month are recruited. Participants are randomized either to high-dose cholecalciferol (two 200,000 IU drinking vials at once on the day of inclusion) or to standard-dose cholecalciferol (one 50,000 IU drinking vial on the day of inclusion). Two hundred sixty participants are recruited and followed up for 28 days. The primary outcome measure is all-cause mortality within 14 days of inclusion. Secondary outcomes are the score changes on the World Health Organization Ordinal Scale for Clinical Improvement (OSCI) scale for COVID-19, and the between-group comparison of safety. These outcomes are assessed at baseline, day 14, and day 28, together with the serum concentrations of 25(OH)D, creatinine, calcium, and albumin at baseline and day 7.
COVIT-TRIAL is to our knowledge the first randomized controlled trial testing the effect of vitamin D supplementation on the prognosis of COVID-19 in high-risk older patients. High-dose vitamin D supplementation may be an effective, well-tolerated, and easily and immediately accessible treatment for COVID-19, the incidence of which increases dramatically and for which there are currently no scientifically validated treatments.
ClinicalTrials.gov NCT04344041 . Registered on 14 April 2020 TRIAL STATUS: Recruiting. Recruitment is expected to be completed in April 2021.
Purpose
The aim was to assess long-term results and quality of life following anterior anal sphincter repair for anal incontinence.
Patients and methods
Twenty-three female patients underwent ...anterior anal sphincteroplasty over a 10-year period between January 1999 and January 2009 in a gynecological surgery department. Patients were asked to complete pre- and postoperative questionnaires comprising the Jorge and Wexner incontinence score. The secondary objective was to assess pre- and post-sphincteroplasty symptom severity and sexual quality of life. Mean follow-up was 87 months (median, 91.5 months). Kaplan-Meier time-to-event analysis was applied.
Results
Mean age was 52 years (±15.2), and mean postoperative Jorge and Wexner score, 7.5/20 (±4.1). Seventeen patients (85 %) declared themselves satisfied by the repair; 12 (60 %) showed good fecal continence. Fecal incontinence had a negative impact on quality of life for 15 % and on sexuality for 50 % of patients. Kaplan-Meier analysis showed 85 % conservation of anal continence correction at 1 year, 74 % at 48 months, 67 % at 60 months, and 48 % at 84 months.
Conclusions
Overlapping anterior anal sphincter repair provided lasting improvement in fecal incontinence, with satisfactory long-term functional results. At 84 months’ follow-up, 48 % of patients maintained good fecal continence, with a satisfaction rate of 85 %. Anal sphincteroplasty may be a first-line attitude in young female fecal incontinence patients with a recent sphincter defect following initially undiagnosed obstetric trauma and also restores perineal comfort.
Abstract The effects of nefopam and ketamine on pain control and rehabilitation after total knee replacement were compared in a prospective, double blinded study. Seventy-five patients were randomly ...assigned to receive a 0.2 mg kg−1 bolus of nefopam or ketamine, followed by a 120 μg kg−1 h−1 continuous infusion until the end of surgery, and 60 μg kg−1 h−1 until the second postoperative day, or an equal volume of saline considered as placebo. Pain scores measured on a visual analog scale at rest and on mobilization, and patient-controlled intravenous morphine consumption, were assessed during 48 h. We measured the maximal knee flexion on the third postoperative day, and the delay to obtain a 90° flexion. Ketamine and nefopam reduced morphine consumption ( p < 0.0001). Pain scores, were lower at rest and on mobilization in the ketamine group compared to the two other groups at all times of measurement. Pain score were lower in patients receiving nefopam compared to placebo, on arrival in the recovery room and at 2 h. Ketamine improved knee flexion on post operative day 3 (59° 33–63 vs. 50° 47–55 and 50° 44–55 in ketamine, placebo and nefopam groups, respectively, p < 0.0002) and decreased the delay to flex the knee at 90° (9.1 ± 4.2 vs. 12.3 ± 4.0 days, in ketamine and placebo groups, respectively, p = 0.01). Ketamine produces opioid-sparing, decreases pain intensity, and improves mobilization after total knee replacement. Nefopam achieves less significant results in that circumstances.
Cytochrome P450 (CYP) is a superfamily of enzymes responsible for the metabolism of drugs, xenobiotics and endogenous compounds. CYP2D6 metabolizes about 30% of drugs and predicting potential CYP2D6 ...inhibition is important in early-stage drug discovery.
We developed an original in silico approach for the prediction of CYP2D6 inhibition combining the knowledge of the protein structure and its dynamic behavior in response to the binding of various ligands and machine learning modeling. This approach includes structural information for CYP2D6 based on the available crystal structures and molecular dynamic simulations (MD) that we performed to take into account conformational changes of the binding site. We performed modeling using three learning algorithms--support vector machine, RandomForest and NaiveBayesian--and we constructed combined models based on topological information of known CYP2D6 inhibitors and predicted binding energies computed by docking on both X-ray and MD protein conformations. In addition, we identified three MD-derived structures that are capable all together to better discriminate inhibitors and non-inhibitors compared with individual CYP2D6 conformations, thus ensuring complementary ligand profiles. Inhibition models based on classical molecular descriptors and predicted binding energies were able to predict CYP2D6 inhibition with an accuracy of 78% on the training set and 75% on the external validation set.
Mo-based cluster compounds are an emerging class of potential candidates for thermoelectric applications because of several key crystallographic characteristics that drive their ability to transport ...heat close to that of amorphous systems. Here, we report on a detailed investigation of the crystal structure and high-temperature transport properties of the cluster compound K2Mo15Se19 and of its Ag-filled variant Ag3K2Mo15Se19. Single-crystal X-ray diffraction confirms that both compounds crystallize with a hexagonal crystal structure, successfully solved in the space group R 3 c, built by octahedral Mo6Se8 and bioctahedral Mo9Se11 clusters with K and Ag cations filling the large intercluster voids. In agreement with electronic band structure calculations, the electron transfer that occurs from the filling cations to the cluster subnetwork provides a simple guiding rule to predict the evolution of the transport properties upon filling with Ag. The metallic state observed in K2Mo15Se19 is turned into a more heavily doped semiconducting character in the presence of Ag resulting in enhanced thermopower values in Ag3K2Mo15Se19. The beneficial influence of Ag on the thermoelectric properties is also reflected by lowered lattice thermal conductivity values that reach 0.45 W m–1 K–1 at 750 K. These results indicate that inserting an additional element in the ternaries M 2Mo15Se19 is an interesting route to improving their thermoelectric properties.
In this letter, a cascaded loop force control is implemented on a robot while considering the flexibility of the force sensor connecting the end effector to the tool. A classical frequency approach ...using a bandwidth and a phase margin is used to tune this controller. The aim is to find an equivalence between the proposed control law and a classical impedance control law. The apparent impedance of this system is calculated and can be seen as the desired impedance for a classical impedance control law. Using this equivalence, the cascaded loop force controller can be tuned to an impedance controller, and can be shown to behave equivalently in simulations and experiments on a one degree of freedom robot.
SRSF1 (also known as ASF/SF2) is a non-small nuclear ribonucleoprotein (non-snRNP) that belongs to the arginine/serine (R/S) domain family. It recognizes and binds to mRNA, regulating both ...constitutive and alternative splicing. The complete loss of this proto-oncogene in mice is embryonically lethal. Through international data sharing, we identified 17 individuals (10 females and 7 males) with a neurodevelopmental disorder (NDD) with heterozygous germline SRSF1 variants, mostly de novo, including three frameshift variants, three nonsense variants, seven missense variants, and two microdeletions within region 17q22 encompassing SRSF1. Only in one family, the de novo origin could not be established. All individuals featured a recurrent phenotype including developmental delay and intellectual disability (DD/ID), hypotonia, neurobehavioral problems, with variable skeletal (66.7%) and cardiac (46%) anomalies. To investigate the functional consequences of SRSF1 variants, we performed in silico structural modeling, developed an in vivo splicing assay in Drosophila, and carried out episignature analysis in blood-derived DNA from affected individuals. We found that all loss-of-function and 5 out of 7 missense variants were pathogenic, leading to a loss of SRSF1 splicing activity in Drosophila, correlating with a detectable and specific DNA methylation episignature. In addition, our orthogonal in silico, in vivo, and epigenetics analyses enabled the separation of clearly pathogenic missense variants from those with uncertain significance. Overall, these results indicated that haploinsufficiency of SRSF1 is responsible for a syndromic NDD with ID due to a partial loss of SRSF1-mediated splicing activity.
Thanks to a large international data-sharing effort, in silico structural protein modeling, DNA methylation episignature analyses, and in vivo splicing assays in Drosophila, Bogaert et al. demonstrate that haploinsufficiency of SRSF1, which encodes a pre-mRNA splicing factor, causes a syndromic neurodevelopmental disorder with mild to moderate intellectual disability.
YajL is the closest prokaryotic homologue of Parkinson's disease-associated DJ-1, a protein of undefined function involved in the oxidative stress response. We reported recently that YajL and DJ-1 ...protect cells against oxidative stress-induced protein aggregation by acting as covalent chaperones for the thiol proteome, including the NuoG subunit of NADH dehydrogenase 1, and that NADH dehydrogenase 1 activity is negligible in the yajL mutant. We report here that this mutant compensates for low NADH dehydrogenase activity by utilizing NADH-independent alternative dehydrogenases, including pyruvate oxidase PoxB and d-amino acid dehydrogenase DadA, and mixed acid aerobic fermentations characterized by acetate, lactate, succinate and ethanol excretion. The yajL mutant has a low adenylate energy charge favouring glycolytic flux, and a high NADH/NAD ratio favouring fermentations over pyruvate dehydrogenase and the Krebs cycle. DNA array analysis showed upregulation of genes involved in glycolytic and pentose phosphate pathways and alternative respiratory pathways. Moreover, the yajL mutant preferentially catabolized pyruvate-forming amino acids over Krebs cycle-related amino acids, and thus the yajL mutant utilizes pyruvate-centred respiro-fermentative metabolism to compensate for the NADH dehydrogenase 1 defect and constitutes an interesting model for studying eukaryotic respiratory complex I deficiencies, especially those associated with Alzheimer's and Parkinson's diseases.
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