Miracle-dz/UniFAR-FTUs huggingface dataset:
Atomic-Level Mechanism of Pre-mRNA Splicing in Health and Disease.

ConspectusIntron removal from premature-mRNA (pre-mRNA splicing) is an essential part of gene expression and regulation that is required for the production of mature, protein-coding mRNA. The spliceosome (SPL), a majestic machine composed of five small nuclear RNAs and hundreds of proteins, behaves as an eminent transcriptome tailor, efficiently performing splicing as a protein-directed metallo-ribozyme. To select and excise long and diverse intronic sequences with single-nucleotide precision, the SPL undergoes a continuous compositional and conformational remodeling, forming eight distinct complexes throughout each splicing cycle. Splicing fidelity is of paramount importance to preserve the integrity of the proteome. Mutations in splicing factors can severely compromise the accuracy of this machinery, leading to aberrant splicing and altered gene expression. Decades of biochemical and genetic studies have provided insights into the SPL's composition and function, but its complexity and plasticity have prevented an in-depth mechanistic understanding. Single-particle cryogenic electron microscopy techniques have ushered in a new era for comprehending eukaryotic gene regulation, providing several near-atomic resolution structures of the SPL from yeast and humans. Nevertheless, these structures represent isolated snapshots of the splicing process and are insufficient to exhaustively assess the function of each SPL component and to unravel particular facets of the splicing mechanism in a dynamic environment.In this Account, building upon our contributions in this field, we discuss the role of biomolecular simulations in uncovering the mechanistic intricacies of eukaryotic splicing in health and disease. Specifically, we showcase previous applications to illustrate the role of atomic-level simulations in elucidating the function of specific proteins involved in the architectural reorganization of the SPL along the splicing cycle. Moreover, molecular dynamics applications have uniquely contributed to decrypting the channels of communication required for critical functional transitions of the SPL assemblies. They have also shed light on the role of carcinogenic mutations in the faithful selection of key intronic regions and the molecular mechanism of splicing modulators. Additionally, we emphasize the role of quantum-classical molecular dynamics in unraveling the chemical details of pre-mRNA cleavage in the SPL and in its evolutionary ancestors, group II intron ribozymes. We discuss methodological pitfalls of multiscale calculations currently used to dissect the splicing mechanism, presenting future challenges in this field. The results highlight how atomic-level simulations can enrich the interpretation of experimental results. We envision that the synergy between computational and experimental approaches will aid in developing innovative therapeutic strategies and revolutionary gene modulation tools to fight the over 200 human diseases associated with splicing misregulation, including cancer and neurodegeneration.
[Neonates treated with individualized parenteral nutrition who are candidates to receive standardized parenteral nutrition].

Objetive: to quantify the number of neonates treated with individualized parenteral nutrition (IPN) who were candidates to receive standardized parenteral nutrition (SPN), and to calculate their treatment duration. MATERIAL AND METHODS this was a prospective, observational, descriptive cohort study. Inclusion criteria were: neonates with indication of parenteral nutrition (PN) and individualized prescription. Exclusion criteria included: patients who had not started diuresis, with specific nutritional needs, altered acid-base balance, and/or contraindication to receive SPN. Included variables were patient-related (gender, weight, weeks of gestation, and days of life) and treatment-related regarding IPN composition. Setting the volume of PN as the conversion criterion, theoretical contributions were calculated with the SPN. The criterion for a patient to be a candidate to receive SPN was that all the theoretical contributions calculated were within the reference requirements range. RESULTS a total of 33 neonates (9 women) received IPN with 94 prescriptions. The median weight of the patients included in the study was 2.14 (IQR, 0.9) kg, and they were born at 35 (IQR, 3) weeks of gestation. PN began between 0 and 4 days of life. In all, 71 % (22/31) of the patients in 54.1 % of their (46/85) prescriptions were candidates to receive SPN via central administration for 1 to 8 days, whereas no patient was candidate to receive SPN via peripheral administration. CONCLUSIONS in our center, 71 % of neonates treated with central administration of NPI are candidates to receive NPE, thus promoting the normalization of nutritional support in this population.
Successful 18‐h acellular extracorporeal perfusion and replantation of porcine limbs ‐ Histology versus nerve stimulation

The current standard for composite tissue preservation is static cold storage (SCS) and is limited to 6 h until irreversible muscle damage occurs. Extracorporeal perfusion (ECP) is a promising technique for prolonged preservation, however, functional results have been scarcely researched. This article assessed neuromuscular function and compared results to histological alterations to predict muscle damage after ECP. Forelimbs of twelve Dutch landrace pigs were amputated and preserved by 4 h SCS at 4–6 °C (n = 6) or 18 h mid‐thermic ECP with University of Wisconsin solution (n = 6). Limbs were replanted and observed for 12 h. Sham surgery was performed on contralateral forelimbs (n = 12). Histology analysis scored four subgroups representing different alterations (higher score equals more damage). Muscle contraction after median nerve stimulation was comparable between ECP, SCS, and sham limbs (P = 0.193). Histology scores were higher in ECP limbs compared to SCS limbs (4.8 vs. 1.5, P = 0.013). This was mainly based on more oedema in these limbs. In‐vivo muscle contraction was well preserved after 18 h ECP compared to short SCS, although histology seemed inferior in this group. Histology, therefore, did not correlate to muscle function at 12 h after replantation. This leads to the question whether histology or neuromuscular function is the best predictor for transplant success.
Long-term efficacy and safety of oral semaglutide and the effect of switching from sitagliptin to oral semaglutide in patients with type 2 diabetes: a 52-week, randomized, open-label extension of the PIONEER 7 trial

Introduction The PIONEER 7 trial demonstrated superior glycemic control and weight loss with once-daily oral semaglutide with flexible dose adjustment versus sitagliptin 100 mg in type 2 diabetes. This 52-week extension evaluated long-term oral semaglutide treatment and switching from sitagliptin to oral semaglutide. Research design and methods A 52-week, open-label extension commenced after the 52-week main phase. Patients on oral semaglutide in the main phase continued treatment (n=184; durability part); those on sitagliptin were rerandomized to continued sitagliptin (n=98) or oral semaglutide (n=100; initiated at 3 mg) (switch part). Oral semaglutide was dose-adjusted (3, 7, or 14 mg) every 8 weeks based on glycated hemoglobin (HbA1c) (target <7.0% (<53 mmol/mol)) and tolerability. Secondary endpoints (no primary) included changes in HbA1c and body weight. Results In the durability part, mean (SD) changes in HbA1c and body weight from week 0 were –1.5% (0.8) and –1.3% (1.0) and –2.8 kg (3.8) and –3.7 kg (5.2) at weeks 52 and 104, respectively. In the switch part, mean changes in HbA1c from week 52 to week 104 were –0.2% for oral semaglutide and 0.1% for sitagliptin (difference –0.3% (95% CI –0.6 to 0.0); p=0.0791 (superiority not confirmed)). More patients achieved HbA1c <7.0% with oral semaglutide (52.6%) than sitagliptin (28.6%; p=0.0011) and fewer received rescue medication (9% vs 23.5%). Respective mean changes in body weight were –2.4 kg and –0.9 kg (difference –1.5 kg (95% CI –2.8 to –0.1); p=0.0321). Gastrointestinal adverse events were the most commonly reported with oral semaglutide. Conclusions Long-term oral semaglutide with flexible dose adjustment maintained HbA1c reductions, with additional body weight reductions, and was well tolerated. Switching from sitagliptin to flexibly dosed oral semaglutide maintained HbA1c reductions, helped more patients achieve HbA1c targets with less use of additional glucose-lowering medication, and offers the potential for additional reductions in body weight. Trial registration number NCT02849080.
Evaluation of Volatilomic Fingerprint from Apple Fruits to Ciders: A Useful Tool to Find Putative Biomarkers for Each Apple Variety

Aroma is a crucial criterion to assess the quality of apple fruits, juices, and ciders. The aim of this study was to explore similarities and differences in volatile profiles among apple fruits, juices, and ciders from different apple varieties (Festa, Branco, and Domingos) by headspace solid-phase microextraction gas chromatography–mass spectroscopy (HS–SPME/GC–MS). A total of 142 volatile organic compounds (VOCs) were identified, but only 9 were common in all analysed matrices and apple-tested varieties. Esters, alcohols, and aldehydes presented a higher concentration in apple fruits and juices, whereas esters, alcohols, and acids were dominant in ciders. Moreover, there were unique VOCs for each matrix and for each variety, highlighting the importance of the selection of apple varieties as an important factor to obtain good sensory and quality ciders, multiple benefits, and legal protection against the misuse of local products.
[Changes in adherence to the Mediterranean diet observed in a Spanish population during confinement for the SARS-CoV-2 pandemic].

INTRODUCTION home confinement due to the COVID-19 pandemic can influence the dietary profiles of the population, suddenly subjected to a stressful factor that implies important modifications in life habits. Among others, a restriction of mobility and a change in the way of carrying out work, going from being face-to-face to non-contact (teleworking). OBJECTIVE to get to know the usual dietary pattern prior to confinement, and to assess the evolution of adherence to the Mediterranean diet weekly until its conclusion. METHODS data were collected using a weekly anonymous online questionnaire that monitored adherence to the Mediterranean diet in real time in an initial sample of 490 adults from Spain. Adherence to the Mediterranean diet was assessed using the MEDAS (Mediterranean Diet Adherence Screener) and modified PREDIMED questionnaires. RESULTS confinement due to the COVID-19 pandemic influenced the eating habits of the participants, so that adherence to the Mediterranean diet increased at the end of the confinement period, which is of special interest, since it was based on a good initial adherence (MEDAS adherence: 10.03 ± 1.9 initial and 10.47 ± 2.1 final; p = 0.016; modified PREDIMED adherence: 9.26 ± 2.0 initial and 9.89 ± 2.1 final; p < 0.001), without observing clinically relevant changes in body composition as measured by body mass index (BMI) except in women (23.3 kg/m2 ± 2.9 initial and 23.4 kg/m2 ± 2.9 final; p < 0.001), with a slight increase in this parameter, but maintaining on average the healthy values recommended by the guidelines. CONCLUSIONS in the studied population we observed an improvement in adherence to the Mediterranean diet without observing clinically relevant changes in BMI.
Silencing of lncRNA MIAT alleviates LPS-induced pneumonia via regulating miR-147a/NKAP/NF-κB axis

Purpose: Pneumonia is a respiratory disease with an increasing incidence in recent years. More and more studies have revealed that lncRNAs can regulate the transcriptional expression of target genes at different stage. Herein, we aimed to explore the effect of lncRNA MIAT in LPS-induced pneumonia, and further illuminate the possible underlying mechanisms. Method and results: Mice were intraperitoneally injected with LPS, and the lung inflammation was evaluated. Microarray showed lncRNA MIAT was up-regulated in LPS-induced pulmonary inflammation. And qRT-PCR and FISH assay indicated that MIAT was increased in mice with LPS injection. Functional analysis showed sh-MIAT inhibited LPS-induced inflammation response, inhibited apoptosis level and protected lung function. As well, si-MIAT removed the injury of LPS on mouse lung epithelial TC-1 cells, and inhibited the activation of NF-κB signaling. Furthermore, MIAT acted as a sponge of miR-147a, and miR-147a directly targeted NKAP. Functionally, AMO-147a or NKAP remitted the beneficial effects of si-MIAT on LPS-induced inflammation response of TC-1 cells. Conclusion: Deletion of MIAT protected against LPS-induced lung inflammation via regulating miR-147a/NKAP, which might provide new insight for pneumonia treatment.
Alternative splicing transitions associate with emerging atrophy phenotype during denervation‐induced skeletal muscle atrophy

Alternative splicing (AS) presents a key posttranscriptional regulatory mechanism associated with numerous physiological processes. However, little is known about its role in skeletal muscle atrophy. In this study, we used a rat model of denervated skeletal muscle atrophy and performed RNA‐sequencing to analyze transcriptome profiling of tibialis anterior muscle at multiple time points following denervation. We found that AS is a novel mechanism involving muscle atrophy, which is independent changes at the transcript level. Bioinformatics analysis further revealed that AS transitions are associated with the appearance of the atrophic phenotype. Moreover, we found that the inclusion of multiple highly conserved exons of Obscn markedly increased at 3 days after denervation. In addition, we confirmed that this newly transcript inhibited C2C12 cell proliferation and exacerbated myotube atrophy. Finally, our study revealed that a large number of RNA‐binding proteins were upregulated when the atrophy phenotype appeared. Our data emphasize the importance of AS in this process.
Intrinsic viscosity-molecular weight relationships for dextran†

Intrinsic viscosities of dextrans of known branching ratio were measured in water formamide, and in a water-methanol mixture at two temperatures. Weight-average molecular weights (sedimentation equilibrium) ranged from 1.1 × 104 to 1.7 × 106. A model for the hydrolyzed dextran molecule was assumed. Using the methods of Zimm and Stockmayer, the g factor calculated from this model was compared with the g factor obtained from the intrinsic viscosity-molecular weight data through the use of the Flory-Fox theory (g = ratio of squares of radii of gyration of branched to unbranched polymer). The calculated branch lengths required to make consistent the g factors obtained by two different routes were of the same order of magnitude as those found by classical organic chemical methods for other dextran preparations. The intrinsic viscosity-molecular weight relation at 25°C. in water for linear dextran was predicted from the data. It is suggested that investigations of branched polymers of known constitution be carried out by these methods.
Significance of Hemodynamics Biomarkers, Tissue Biomechanics and Numerical Simulations in the Pathogenesis of Ascending Thoracic Aortic Aneurysms.

Guidelines for the treatment of aortic wall diseases are based on measurements of maximum aortic diameter. However aortic rupture or dissections do occur for small aortic diameters. Growing scientific evidence underlines the importance of biomechanics and hemodynamics in aortic disease development and progression. Wall shear stress (WWS) is an important hemodynamics marker which depends on aortic wall morphology and on the aortic valve function. WSS could be helpful to interpret aortic wall remodeling and define personalized risk criteria. The complementarity of Computational Fluid Dynamics and 4D Magnetic Resonance Imaging as tools for WSS assessment is a promising reality. The potentiality of these innovative technologies will provide maps or atlases of hemodynamics biomarkers to predict aortic tissue dysfunction. Ongoing efforts should focus on the correlation between these non-invasive imaging biomarkers and clinico-pathologic situations for the implementation of personalized medicine in current clinical practice.
Plant extracts in prevention of obesity

Abstract Obesity has become a worldwide issue and is accompanied by serious complications. Western high energy diet has been identified to be a major factor contributing to the current obesity pandemic. Thus, it is important to optimize dietary composition, bioactive substances, and agents to prevent and treat obesity. To date, extracts from plants, such as vegetables, tea, fruits, and Chinese herbal medicine, have been showed to have the abilities of regulating adipogenesis and attenuating obesity. These plant extracts mainly contain polyphenols, alkaloids, and terpenoids, which could play a significant role in anti-obesity through various signaling pathways and gut microbiota. Those reported anti-obesity mechanisms mainly include inhibiting white adipose tissue growth and lipogenesis, promoting lipolysis, brown/beige adipose tissue development, and muscle thermogenesis. In this review, we summarize the plant extracts and their possible mechanisms responsible for their anti-obesity effects. Based on the current findings, dietary plant extracts and foods containing these bioactive compounds can be potential preventive or therapeutic agents for obesity and its related metabolic diseases.
The longitudinal negative impact of early stressful events on emotional and physical well-being: The buffering role of cardiac vagal development.

Early stressful events negatively affect emotional and physical well-being. Cardiac vagal tone (CVT), which is associated with better emotional and physical well-being, usually gradually increase in early childhood. Nonetheless, children's CVT developmental trajectories are greatly variable, such that CVT can increase or decrease across the years. The present study examines the longitudinal effects of early stressful events and the role of 4 years CVT developmental trajectory on children's emotional and physical well-being. Forty-two 4-year-old children were enrolled. Number of stressful events and resting electrocardiogram (ECG) were collected at T1. ECG was registered again after one (T2), two (T3) and three (T4) years. Children's emotional and physical well-being were assessed at T4 through the Child Health and Illness Profile - Child Edition (CHIP-CE). CVT development was calculated as the angular coefficient, reflecting the developmental trajectory of CVT across the four timepoints. Results yielded that higher experienced stressful events predicted poorer emotional and physical well-being after 4 years. The interaction between the number of stressful events and CVT development emerged on physical well-being. Early stressful events negatively affect long-term children's emotional and physical well-being while a positive CVT development seems to mitigate the negative effects of early stressful events on physical well-being.
Determinants of household food security and dietary diversity during the COVID-19 pandemic in Bangladesh

Abstract Objectives: The study aimed to determine the associated factors of household food security (HFS) and household dietary diversity (HDD) during the COVID−19 pandemic in Bangladesh. Design: Both online survey and face-to-face interviews were employed in this cross-sectional study. The Household Food Security Scale and Household Dietary Diversity Score were used to access HFS and HDD, respectively. The HDD scores were derived from a 24-h recall of food intake from 12 groups. Setting: Bangladesh. Participants: A total sample of 1876 households were recruited. Results: The overall mean scores of HFS and HDD were 31·86 (sd 2·52) and 6·22 (sd 5·49), respectively. Being a rural resident, having no formal education, occupation of household head other than government job and low monthly income were potential determinants of lower HFS and HDD. Approximately 45 % and 61 % of Bangladeshi households did not get the same quantity and same type of food, respectively, as they got before the pandemic. Over 10 % of respondents reported that they lost their job or had to close their businesses, and income reduction was reported by over 70 % of household income earners during the COVID-19 pandemic, which in turn was negatively associated with HFS and HDD. Conclusion: Household socio-economic variables and COVID-19 effects on occupation and income are potential predictors of lower HFS and HDD scores. HFS and HDD deserve more attention during this pandemic particularly with reference to low-earning households and the households whose earning persons’ occupation has been negatively impacted during the COVID-19 pandemic.
Changes in Ion Selectivity Following the Asymmetrical Addition of Charge to the Selectivity Filter of Bacterial Sodium Channels

Voltage-gated sodium channels (NaVs) play fundamental roles in eukaryotes, but their exceptional size hinders their structural resolution. Bacterial NaVs are simplified homologues of their eukaryotic counterparts, but their use as models of eukaryotic Na+ channels is limited by their homotetrameric structure at odds with the asymmetric Selectivity Filter (SF) of eukaryotic NaVs. This work aims at mimicking the SF of eukaryotic NaVs by engineering radial asymmetry into the SF of bacterial channels. This goal was pursued with two approaches: the co-expression of different monomers of the NaChBac bacterial channel to induce the random assembly of heterotetramers, and the concatenation of four bacterial monomers to form a concatemer that can be targeted by site-specific mutagenesis. Patch-clamp measurements and Molecular Dynamics simulations showed that an additional gating charge in the SF leads to a significant increase in Na+ and a modest increase in the Ca2+ conductance in the NavMs concatemer in agreement with the behavior of the population of random heterotetramers with the highest proportion of channels with charge −5e. We thus showed that charge, despite being important, is not the only determinant of conduction and selectivity, and we created new tools extending the use of bacterial channels as models of eukaryotic counterparts.