Miracle-dz/UniFAR-FTUs huggingface dataset:
Dynamical changes of SARS‐CoV‐2 spike variants in the highly immunogenic regions impact the viral antibodies escaping

The prolonged circulation of the SARS‐CoV‐2 virus resulted in the emergence of several viral variants, with different spreading features. Moreover, the increased number of recovered and/or vaccinated people introduced a selective pressure toward variants able to evade the immune system, developed against the former viral versions. This process results in reinfections. Aiming to study the latter process, we first collected a large structural dataset of antibodies in complex with the original version of SARS‐CoV‐2 Spike protein. We characterized the peculiarities of such antibodies population with respect to a control dataset of antibody‐protein complexes, highlighting some statistically significant differences between these two sets of antibodies. Thus, moving our attention to the Spike side of the complexes, we identify the Spike region most prone to interaction with antibodies, describing in detail also the energetic mechanisms used by antibodies to recognize different epitopes. In this framework, fast protocols able to assess the effect of novel mutations on the cohort of developed antibodies would help establish the impact of the variants on the population. Performing a molecular dynamics simulation of the trimeric form of the SARS‐CoV‐2 Spike protein for the wild type and two variants of concern, that is, the Delta and Omicron variants, we described the physicochemical features and the conformational changes experienced locally by the variants with respect to the original version. Hence, combining the dynamical information with the structural study on the antibody‐spike dataset, we quantitatively explain why the Omicron variant has a higher capability of escaping the immune system than the Delta variant, due to the higher conformational variability of the most immunogenic regions. Overall, our results shed light on the molecular mechanism behind the different responses the SARS‐CoV‐2 variants display against the immune response induced by either vaccines or previous infections. Moreover, our analysis proposes an approach that can be easily extended to both other SARS‐CoV‐2 variants or different molecular systems.
Assessment of alcohol‐induced aggressive behavior in zebrafish (Danio rerio): A practical class

Ethanol (EtOH) is among the most consumed drugs in the world. The behavior of humans after ingestion of this drug is characteristic: At low doses it may be excitatory and at higher doses, it may induce depressant/sedative effects. Similar effects are observed in the zebrafish experimental model (Danio rerio), which has about 70% genetic similarity with humans and has been widely used in numerous research. With the objective of improving the learning of biochemistry students, this work aimed to develop a practical exercise in the laboratory for students to observe the behavioral repertoire of zebrafish under the effects of exposure to ethanol. Through this practical class, the students were able to observe the similarity of the behavior of the animal model with that of humans, showing its importance for the consolidation of knowledge, awakening in the students an interest in science and its applications in everyday life.
Threat of resurgence or hope for global eradication of poliovirus?

Purpose of review Recent outbreaks of poliomyelitis in countries that have been free of cases for decades highlight the challenges of eradicating polio in a globalized interconnected world beset with a novel viral pandemic. We provide an epidemiological update, advancements in vaccines, and amendments in public health strategy of poliomyelitis in this review. Recent findings Last year, new cases of wild poliovirus type 1 (WPV1) were documented in regions previously documented to have eradicated WPV1 and reports of circulating vaccine-derived poliovirus type 2 (cVDPV2) and 3 (cVDPV3) in New York and Jerusalem made international headlines. Sequencing of wastewater samples from environmental surveillance revealed that the WPV1 strains were related to WPV1 lineages from endemic countries and the cVDPV2 strains from New York and Jerusalem were not only related to each other but also to environmental isolates found in London. The evidence of importation of WPV1 cases from endemic countries, and global transmission of cVDPVs justifies renewed efforts in routine vaccination programs and outbreak control measures that were interrupted by the COVID-19 pandemic. After the novel oral poliovirus vaccine type 2 (nOPV2) received emergency authorization for containment of cVDPV2 outbreaks in 2021, subsequent reduced incidence, transmission rates, and vaccine adverse events, alongside increased genetic stability of viral isolates substantiates the safety and efficacy of nOPV2. The nOPV1 and nOPV3 vaccines, against type 1 and 3 cVDPVs, and measures to increase accessibility and efficacy of inactivated poliovirus vaccine (IPV) are in development. Summary A revised strategy utilizing more genetically stable vaccine formulations, with uninterrupted vaccination programs and continued active surveillance optimizes the prospect of global poliomyelitis eradication.
A small RNA system ensures accurate homologous pairing and unpaired silencing of meiotic chromosomes

During meiosis, chromosomes with homologous partners undergo synaptonemal complex (SC)‐mediated pairing, while the remaining unpaired chromosomes are heterochromatinized through unpaired silencing. Mechanisms underlying homolog recognition during SC formation are still unclear. Here, we show that the Caenorhabditis elegans Argonaute proteins, CSR‐1 and its paralog CSR‐2, interacting with 22G‐RNAs, are required for synaptonemal complex formation with accurate homology. CSR‐1 in nuclei and meiotic cohesin, constituting the SC lateral elements, were associated with nonsimple DNA repeats, including minisatellites and transposons, and weakly associated with coding genes. CSR‐1‐associated CeRep55 minisatellites were expressing 22G‐RNAs and long noncoding (lnc) RNAs that colocalized with synaptonemal complexes on paired chromosomes and with cohesin regions of unpaired chromosomes. CeRep55 multilocus deletions reduced the efficiencies of homologous pairing and unpaired silencing, which were supported by the csr‐1 activity. Moreover, CSR‐1 and CSR‐2 were required for proper heterochromatinization of unpaired chromosomes. These findings suggest that CSR‐1 and CSR‐2 play crucial roles in homology recognition, achieving accurate SC formation between chromosome pairs and condensing unpaired chromosomes by targeting repeat‐derived lncRNAs.
Comparative Effectiveness of Combined and Single Neurostimulation and Traditional Dysphagia Therapies for Post-Stroke Dysphagia: A Network Meta-Analysis

Background Comparative therapeutic benefits of combined and single neurostimulation therapies including neuromuscular electrical stimulation (NMES), pharyngeal electrical stimulation (PES), repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), and traditional dysphagia therapy (TDT) remain unknown in post-stroke dysphagia (PSD) rehabilitation. Therefore, we performed the first network meta-analysis (NMA) to determine comparative effectiveness of combined and single neurostimulation and traditional dysphagia therapies for PSD. Methods A frequentist NMA model was performed with therapy effect sizes presented as standardized mean differences (SMD) and corresponding 95% confidence interval (95% CI) for therapy comparisons while netrank function ranked the therapies in R-Software. Meta-regression models for study characteristics were analyzed using Bayesian NMA Model. Results Overall, 50 randomized controlled studies with 2250 participants were included. NMES + TDT 3.82 (95% CI, 1.62-6.01), tDCS + TDT 3.34 (95% CI, 1.09-5.59), rTMS + TDT 3.32 (95% CI, 1.18-5.47), NMES 2.69 (95% CI, 0.44-4.93), and TDT 2.27 (95% CI, 0.12-4.41) demonstrated very large effect in improving swallowing function. NMES + TDT −0.50 (95% CI, −0.68 to −0.32, rTMS + TDT −0.44 (95% CI, −0.67 to −0.21), TDT −0.28 (95% CI, −0.46 to −0.10), and NMES −0.19 (95% CI, −0.34 to −0.04) demonstrated medium to small effect in reducing pharyngeal transit time (PTT). rTMS −0.51 (95% CI, −0.93 to −0.08) demonstrated medium effect in reducing oral transit time (OTT). No significant therapy comparison differences were found for reducing aspiration/penetration. The highest ranked therapy was NMES + TDT for better swallowing function and reduction of PTT, rTMS for reduction of OTT, and tDCS + TDT for reduction of aspiration/penetration. Therapeutic effects of the therapies were moderated by frequency, sessions, and duration. Conclusion Combined therapies including NMES + TDT, tDCS + TDT, and rTMS + TDT demonstrate better therapeutic effect for improved swallowing function and reduction of PTT, OTT, and aspiration/penetration for PSD.
A multistate approach for the study of interventions on an intermediate time-to-event in health disparities research

We propose a novel methodology to quantify the effect of stochastic interventions for a non-terminal intermediate time-to-event on a terminal time-to-event outcome. Investigating these effects is particularly important in health disparities research when we seek to quantify inequities in the timely delivery of treatment and its impact on patients’ survival time. Current approaches fail to account for time-to-event intermediates and semi-competing risks arising in this setting. Under the potential outcome framework, we define causal contrasts relevant in health disparities research and provide identifiability conditions when stochastic interventions on an intermediate non-terminal time-to-event are of interest. Causal contrasts are estimated in continuous time within a multistate modeling framework and analytic formulae for the estimators of the causal contrasts are developed. We show via simulations that ignoring censoring in intermediate and/or terminal time-to-event processes or ignoring semi-competing risks may give misleading results. This work demonstrates that a rigorous definition of the causal effects and joint estimation of the terminal outcome and intermediate non-terminal time-to-event distributions are crucial for valid investigation of interventions and mechanisms in continuous time. We employ this novel methodology to investigate the role of delaying treatment uptake in explaining racial disparities in cancer survival in a cohort study of colon cancer patients.
Toward a Listening Training Paradigm: Evaluation in Normal-Hearing Young and Middle-Aged Adults

Objectives: Adults’ most common complaint relates to understanding speech in noisy environments. Hearing aids can compensate for sensory loss but do not restore hearing to normal. Listening training has the potential to partially remediate these problems. In this study, we propose and evaluate a Flemish version of a listening training paradigm, which involves the use of cognitive control as well as auditory perception. The paradigm entails a discrimination task where participants are cued to attend to one of two concurrent talkers with target speakers randomly varying between a female and a male voice. We evaluate learning effects, different scenarios, and masking types. Design: In total, 70 young and 54 middle-aged adults participated in this study. Each adult performed one or more conditions. Participants’ hearing was screened before participation, all middle-aged adults passed a cognitive screening task. Results: Analyses indicated learning effects across scenarios that were similar in terms of speech intelligibility. Our results indicated better speech intelligibility when the female speaker was the target, but speech intelligibility did not differ when the target was the male speaker. An unintelligible masker noise results in worse speech intelligibility than a competing talker masker. Our results suggest that listeners could use an intensity cue to identify and/or select the target speaker when presented at a lower signal to noise ratio (SNR). Error analysis suggested higher cognitive control demands when the target and masker were presented at similar levels (i.e., around 0 dB SNR). The addition of independent trials with the intensity of target and masker reversed improved speech intelligibility. Inhibitory control, but not task switching, was reliably correlated with listening performance. Conclusions: The proposed paradigm turned out to be feasible and practicable, demonstrating its potential for training speech intelligibility in noise. We believe that this training paradigm can generate real-life benefits including for persons with hearing loss. This latter application awaits future evaluation.
Regulatory and HTA Considerations for Development of Real‐World Data Derived External Controls

Regulators and Health Technology Assessment (HTA) bodies are increasingly familiar with, and publishing guidance on, external controls derived from real‐world data (RWD) to generate real‐world evidence (RWE). We recently conducted a systematic literature review (SLR) evaluating publicly available information on the use of RWD‐derived external controls to contextualize outcomes from uncontrolled trials submitted to the European Medicines Agency (EMA), the US Food and Drug Administration (FDA), and/or select HTA bodies. The review identified several key operational and methodological aspects for which more detailed guidance and alignment within and between regulatory agencies and HTA bodies is necessary. This paper builds on the SLR findings by delineating a set of key takeaways for the responsible generation of fit‐for‐purpose RWE. Practical methodological and operational guidelines for designing, conducting, and reporting RWD‐derived external control studies are explored and discussed. These considerations include: (i) early engagement with regulators and HTA bodies during the study planning phase; (ii) consideration of the appropriateness and comparability of external controls across multiple dimensions, including eligibility criteria, temporality, population representation, and clinical evaluation; (iii) ensuring adequate sample sizes, including hypothesis testing considerations; (iv) implementation of a clear and transparent strategy for assessing and addressing data quality, including data missingness across trials and RWD; (v) selection of comparable and meaningful endpoints that are operationalized and analyzed using appropriate analytic methods; and (vi) conduct of sensitivity analyses to assess the robustness of findings in the context of uncertainty and sources of potential bias.
Entospletinib with decitabine in acute myeloid leukemia with mutant TP53 or complex karyotype: A phase 2 substudy of the Beat AML Master Trial

Patients with acute myeloid leukemia (AML) who have tumor protein p53 (TP53) mutations or a complex karyotype have a poor prognosis, and hypomethylating agents are often used. The authors evaluated the efficacy of entospletinib, an oral inhibitor of spleen tyrosine kinase, combined with decitabine in this patient population.
Alveolar–arterial oxygen gradient nonlinearly impacts the 28‐day mortality of patients with sepsis: Secondary data mining based on the MIMIC‐IV database

Lung is often implicated in sepsis, resulting in acute respiratory distress syndrome (ARDS). The alveolar–arterial oxygen gradient [D(A‐a)O2] reflects lung diffusing capacity, which is usually compromised in ARDS. But whether D(A‐a)O2 impacts the prognosis of patients with sepsis remains to be explored. Our study aims to investigate the association between D(A‐a)O2 and 28‐day mortality in patients with sepsis using a large sample, multicenter Medical Information Mart for Intensive Care (MIMIC)‐IV database.
Numerical Modeling Of Microwave Heating OfDielectric Materials

Microwave heating has been established in industry for many years. The temperature distribution within irradiated materials is obtained by determining the electric field distribution. For this reason, modelling the geometry under the plane wave illumination is useful. To determine the temperature distribution, the transmission line analogy for plane wave propagation and reflection for normal incidence angle is used. The heating pattern in a multilayered slab material exposed to a uniform plane wave is obtained. The lossy dielectric object is modelled as an infinitive number of cascaded transmission lines terminated with a metal plate and the inner electric field is calculated.
A cross-sectional investigation of back pain beliefs and fear in physiotherapy and sport undergraduate students

Background Although low back pain (LBP) beliefs have been well investigated in mainstream healthcare discipline students, the beliefs within sports-related study students, such as Sport and Exercise Science (SES), Sports Therapy (ST), and Sport Performance and Coaching (SPC) programmes have yet to be explored. This study aims to understand any differences in the beliefs and fear associated with movement in students enrolled in four undergraduate study programmes–physiotherapy (PT), ST, SES, and SPC. Method 136 undergraduate students completed an online survey. All participants completed the Tampa Scale of Kinesiophobia (TSK) and Back Beliefs Questionnaire (BBQ). Two sets of two-way between-subjects Analysis of Variance (ANOVA) were conducted for each outcome of TSK and BBQ, with the independent variables of the study programme, study year (1st, 2nd, 3rd), and their interaction. Results There was a significant interaction between study programme and year for TSK (F(6, 124) = 4.90, P < 0.001) and BBQ (F(6, 124) = 8.18, P < 0.001). Post-hoc analysis revealed that both PT and ST students had lower TSK and higher BBQ scores than SES and SPC students particularly in the 3rd year. Conclusions The beliefs of clinicians and trainers managing LBP are known to transfer to patients, and more negative beliefs have been associated with greater disability. This is the first study to understand the beliefs about back pain in various sports study programmes, which is timely, given that the management of injured athletes typically involves a multidisciplinary team.
Extensive genome analysis identifies novel plasmid families in Clostridium perfringens

Globally, the anaerobic bacterium Clostridium perfringens causes severe disease in a wide array of hosts; however, C. perfringens strains are also carried asymptomatically. Accessory genes are responsible for much of the observed phenotypic variation and virulence within this species, with toxins frequently encoded on conjugative plasmids and many isolates carrying up to 10 plasmids. Despite this unusual biology, current genomic analyses have largely excluded isolates from healthy hosts or environmental sources. Accessory genomes, including plasmids, also have often been excluded from broader scale phylogenetic investigations. Here we interrogate a comprehensive collection of 464 C . perfringens genomes and identify the first putative non-conjugative enterotoxin (CPE)-encoding plasmids and a putative novel conjugative locus (Bcp) with sequence similarity to a locus reported from Clostridium botulinum . We sequenced and archived 102 new C. perfringens genomes, including those from rarely sequenced toxinotype B, C, D and E isolates. Long-read sequencing of 11 C . perfringens strains representing all toxinotypes (A–G) identified 55 plasmids from nine distinct plasmid groups. Interrogation of the 464 genomes in this collection identified 1045 plasmid-like contigs from the nine plasmid families, with a wide distribution across the C. perfringens isolates. Plasmids and plasmid diversity play an essential role in C. perfringens pathogenicity and broader biology. We have expanded the C. perfringens genome collection to include temporal, spatial and phenotypically diverse isolates including those carried asymptomatically in the gastrointestinal microbiome. This analysis has resulted in the identification of novel C. perfringens plasmids whilst providing a comprehensive understanding of species diversity.
Lyso-globotriaosylsphingosine induces endothelial dysfunction via autophagy-dependent regulation of necroptosis

Fabry disease is a lysosomal storage disorder characterized by the lysosomal accumulations of glycosphingolipids in a variety of cytotypes, which include endothelial cells. The disease is inherited and originates from an error in glycosphingolipid catabolism caused by insufficient α-galactosidase A activity, which causes uncontrolled progressive storage of intracellular globotriaosylceramide (Gb3) in the vasculature and extracellular accumulation of lyso-Gb3 (a deacetylated soluble form of Gb3). Necrosis can lead to inflammation, which exacerbates necrosis and creates a positive feedback loop that triggers necroinflammation. However, the role played by necroptosis, a form of programmed necrotic cell death, in the cell-to-cell inflammatory reaction between epithelial and endothelial cells is unclear. Thus, the present study was undertaken to determine whether lyso-Gb3 induces necroptosis and whether necroptosis inhibition protects endothelial dysfunction against lyso-Gb3 inflamed retinal pigment epithelial cells. We found lyso-Gb3 induced necroptosis of a retinal pigment epithelial cell line (ARPE-19) in an autophagy-dependent manner and that conditioned media (CM) from ARPE-19 cells treated with lyso-Gb3 induced the necroptosis, inflammation, and senescence of human umbilical vein endothelial cells. In addition, a pharmacological study showed CM from lyso-Gb3 treated ARPE-19 cells induced endothelial necroptosis, inflammation, and senescence were significantly inhibited by an autophagy inhibitor (3-MA) and by two necroptosis inhibitors (necrostatin and GSK-872), respectively. These results demonstrate lyso-Gb3 induces necroptosis via autophagy and suggest that lyso-Gb3 inflamed retinal pigment epithelial cells trigger endothelial dysfunction via the autophagy-dependent necroptosis pathway. This study suggests the involvement of a novel autophagy-dependent necroptosis pathway in the regulation of endothelial dysfunction in Fabry disease.
Drying behavior of a horizontal vibrated fluidized bed dryer for continuous manufacturing

Abstract Twin-screw wet granulation offers the possibility to granulate continuously. A drying step after wet granulation is required to realize a full continuous manufacturing line. Aim of this study was to gain insights into the drying behavior of a continuous vibrated fluidized bed dryer intended for pharmaceutical research and development. A Design of Experiment was conducted to examine the influence of process parameters during the drying of granules using drying temperature, air flow, and vibration acceleration as factors. The obtained temperature and humidity profiles during the drying of lactose-MCC and mannitol granules displayed the first and second drying stage which is spatially resolved. With a higher drying temperature or higher air flow, the second drying stage was achieved earlier. An increase in vibration acceleration shortened the residence time and by this, the second drying stage was reached later at a lower granule temperature and thus higher residual moisture of the granules. Formulation-dependent impact of the drying parameters was observed as lactose-MCC led to smaller granules when increasing the temperature or air flow.
COMPARISON BETWEEN MONOVARIABLE CONTROLLER AND MULTIVARIABLE CONTROLLER

This article describes the mathematical representation of two controllers which can be integrated in the Dynamic Regulation software closed loop module: - a monovariable controller suitable for delay systems (Smith predictor) which is synthesized by a pole placement technique, a multivariable controller (control by feedback state) the purpose of which is to minimize a quadratic criterion. The multivariable representation chosen reduces the matricial calculations (dimension 5).