Miracle-dz/UniFAR-FTUs huggingface dataset:
Global alternative splicing landscape of skeletal muscle atrophy induced by hindlimb unloading

Background Long-term exposure to microgravity will cause skeletal muscle atrophy, which can cause serious harm to astronauts in space travel. Therefore, it is important to explore skeletal muscle atrophy’s molecular mechanism for its prevention and treatment. However, as an important regulatory approach of skeletal muscle physiology, the role of alternative splicing in skeletal muscle atrophy, especially skeletal muscle atrophy caused by disuse, is unclear. Methods We established a rat hindlimb unloading model and performed RNA sequencing on soleus muscle, which was seriously atrophied during unloading. Several bioinformatics methods were used to identify alternative splicing events and determine their gene functions. Results Many alternative splicing events were found to occur at different time points (12 h, 24 h, 36 h, 3 days, and 7 days) after hindlimb unloading. These differential alternative splicing events mainly occurred in the gene's coding domain sequence region, and 59% of the alternative splicing events caused open reading frameshift. Bioinformatics analysis results showed that genes with different alternative splicing events were enriched in multiple pathways related to muscle atrophy, including the insulin signaling pathway, endocytosis, mitophagy, and ubiquitin-proteasome pathway. Moreover, alternative splicing of several deubiquitinase genes persisted during skeletal muscle atrophy induced by unloading. Additionally, we identified 10 differentially expressed RNA binding proteins during skeletal muscle atrophy induced by unloading, mainly containing Xpo4, Eif4e2, P4ha1, Lrrfip1, Zc3h14, Emg1, Hnrnp h1, Mbnl2, RBfox1, and Mbnl1. Hnrnp h1 and Mbnl2 were significantly downregulated, and RBfox1 and Mbnl1 were significantly upregulated during skeletal muscle atrophy caused by unloading. Conclusions To the best of our knowledge, the present study is the first to propose alternative splicing alterations related to disuse-induced muscle atrophy, emphasizing that alternative splicing is a new focus of attention in the occurrence of muscle atrophy.
Identification of recombinant Fabs for structural and functional characterization of HIV-host factor complexes

Viral infection and pathogenesis is mediated by host protein—viral protein complexes that are important targets for therapeutic intervention as they are potentially less prone to development of drug resistance. We have identified human, recombinant antibodies (Fabs) from a phage display library that bind to three HIV-host complexes. We used these Fabs to 1) stabilize the complexes for structural studies; and 2) facilitate characterization of the function of these complexes. Specifically, we generated recombinant Fabs to Vif-CBF-β-ELOB-ELOC (VCBC); ESCRT-I complex and AP2-complex. For each complex we measured binding affinities with KD values of Fabs ranging from 12–419 nM and performed negative stain electron microscopy (nsEM) to obtain low-resolution structures of the HIV-Fab complexes. Select Fabs were converted to scFvs to allow them to fold intracellularly and perturb HIV-host protein complex assembly without affecting other pathways. To identify these recombinant Fabs, we developed a rapid screening pipeline that uses quantitative ELISAs and nsEM to establish whether the Fabs have overlapping or independent epitopes. This pipeline approach is generally applicable to other particularly challenging antigens that are refractory to immunization strategies for antibody generation including multi-protein complexes providing specific, reproducible, and renewable antibody reagents for research and clinical applications. The curated antibodies described here are available to the scientific community for further structural and functional studies on these critical HIV host-factor proteins.
Prevalence and sociodemographic determinants of alcohol consumption among adults living with HIV in Eswatini

Aim: Alcohol consumption contributes to a significant burden of illnesses, health conditions and premature deaths globally. There is limited knowledge of alcohol consumption among people living with HIV (PLWH) in Eswatini. This study sought to determine the prevalence, and examine the sociodemographic determinants of alcohol consumption among adult people living with HIV in Eswatini. Methods: Using the Swaziland HIV Incidence Measurement Survey 2, a recent national representative cross-sectional survey conducted in Eswatini between August 2016 and March 2017, a subsample of 2 832 adults (aged 18 and older) living with HIV was extracted. Multinomial logistic regression was used to assess the sociodemographic factors associated with alcohol consumption (i.e. use or misuse). Results: The prevalence of alcohol misuse (hazardous drinking) was 10.9% (23% male v 4.5% female), whereas alcohol use (moderate drinking) was estimated at 8.5% (14.7% male v 5.2% female). Men were more likely to engage in alcohol use (adjusted relative risk ratio [aRRR] = 3.46 [95% CI 3.46–6.62]) and misuse (aRRR = 6.12 [95% CI 6.12–11.47]) than females. Those who reported HIV stigma had a higher likelihood of alcohol misuse compared to those who did not report HIV stigma (aRRR = 1.43 [95% CI 1.04–1.98]). Conclusion: Our findings highlight a notable prevalence of alcohol use or misuse among PLWH in Eswatini. Males, those with no education, never married and those who reported HIV stigma were more likely to report alcohol misuse. The study thus recommends innovative policies and strategies to curb alcohol-related harm in the Eswatini population, specifically among PLWH.
Survival after autologous versus allogeneic transplantation in patients with relapsed and refractory Hodgkin lymphoma

Abstract For relapsed Hodgkin lymphoma, salvage chemotherapy followed by auto-HCT is the standard of care. It is important to identify subpopulations who could benefit from allo-HCT. This retrospective analysis included 277 patients with rrHL who underwent first transplant with auto-HCT or allo-HCT between 2007–2017. Patients in the auto-HCT cohort (N = 218) were older, more likely to be in CR at the time of transplant and receive maintenance therapy post-transplant. Patients who underwent allo-HCT (N = 59) had a higher MSKCC relapse score. Factors associated with an inferior PFS and OS included early relapse, advanced stage, extranodal involvement and not achieving CR following salvage chemotherapy. After controlling for these 4 risk factors and MSKCC score, PFS (p = 0.112) or OS (p = 0.256) was not affected by the choice of transplant. In patients with ≥ 3 high risk features, the 4-year PFS was 51% in the allo-HCT vs. 39% (p = 0.107) in the auto-HCT cohort.
Physio-Chemicals Characteristics of Yoghurt from Camel’s Milk and Cow’s Milk in Different Ratios

This study was carried out to assessment yoghourt produced by camel's milk and cow's milk, From September to November (2014),Camel milk was collected from camel research center University of Khartoum ( Shambat),and cows milk are collected from animal production dairy farm college of agriculture studies, Sudan University of science and Technology (Shambat). Fresh camel and cows milk were analyzed and increased their total solids to 15% by skimmed powder milk to improve the coagulation characteristic and divided to 5 treatments pure camel milk portion and pure cow milk portion as a controls and camel milk mixed with cow milk by 75% , 50% and 25% respectively. After pasteurization at 85 for 30 min. Inoculation and incubation at 43 for 3h cow milk yoghurt and 4h for the mixed milk yoghurt between camel and cow milk 75% and 50% cow milk and 6h the camel milk yoghurt and 75%camel milk yoghurt, the physiochemical properties of yoghurt were analysis and pH , acidity analysis after incubation , 24h and after 10 days and panel taste was done. The results showed significant differences between camel and cow milk at (p≤ 0.05) in protein, SNF, and density But there were no significant differences (p≥0.05) in moisture, fat, ash, lactose, total soil (TS), Ph, acidity, Ca and phosphorus. Protein and SNF in cow milk were higher than that found in camel milk, while the density of camel milk is higher in comparison to the density of cow milk. The treatments effect of pure and mixture of camel and cow milk yoghurt on physiochemical characteristics result in highly significant differences at (p≤0.05). Pure cow milk yoghurt has higher percentage of protein, fat, lactose, SNF, Ph, Calcium and phosphorus. While Pure camel milk yoghurt showed high moisture, ash and acidity percentages,75% cow milk +25% camel milk yoghurt has superiority in protein ,fat ,lactose ,T.S and S.N. f percentages after pure cow milk yoghurt, followed by 50%cow milk +50% camel milk yoghurt . The effect of storage period for camel and cow milk yoghurt was highly significant on Ph acidity. The high value of Ph was observed after incubation followed by after 24hr then after 10 days while the acidity is higher after 10 days of storage followed by after 24 hr then after incubation. The sensory evaluation of pure and mixed camel and cow milk yoghurt treatments were appeared high significant (p≤0.05) on taste, flavor, smell, texture, and overall acceptability, but had no significant differences ( p≥0.05) recorded on the color. The best value for taste, flavor, smell, texture and overall acceptability were obtained by yoghurt made from pure cow milk followed by the 25% camel milk +75%cow milk yoghurt treatment then 50% camel milk + 50% cow milk yoghurt ,then 75% camel milk + 25%cow milk yoghurt and the last one was the pure camel milk yoghurt treatment.
Human transitional and IgMlow mature naïve B cells preserve permissive B‐cell receptors

The level of immunoglobulin M (IgM) displayed on the surface of peripheral blood B cells exhibits a broad dynamic range and has been associated with both development and selection. To determine whether IgM surface expression associates with distinct immunoglobulin heavy‐chain (IGH) repertoire properties, we performed deep IgM sequencing of peripheral blood transitional and mature naïve B cells in the upper and lower quartiles of surface IgM expression for 12 healthy donors. Mature naïve B cells within the lowest quartile for surface IgM expression displayed more diverse IGH features including increased complementarity‐determining region 3 length, IGHJ6 segment usage and aromatic amino acids compared with mature naïve B cells with high surface IgM. There were no differences between IGH repertoires for transitional B cells with high or low surface IgM. These findings suggest that a selection checkpoint during progression of transitional to mature naïve B cells reduces the breadth of the IGH repertoire among high surface IgM B cells but that diversity is preserved in B cells expressing low levels of surface IgM.
Cardiac Energy Metabolism in Heart Failure

Alterations in cardiac energy metabolism contribute to the severity of heart failure. However, the energy metabolic changes that occur in heart failure are complex and are dependent not only on the severity and type of heart failure present but also on the co-existence of common comorbidities such as obesity and type 2 diabetes. The failing heart faces an energy deficit, primarily because of a decrease in mitochondrial oxidative capacity. This is partly compensated for by an increase in ATP production from glycolysis. The relative contribution of the different fuels for mitochondrial ATP production also changes, including a decrease in glucose and amino acid oxidation, and an increase in ketone oxidation. The oxidation of fatty acids by the heart increases or decreases, depending on the type of heart failure. For instance, in heart failure associated with diabetes and obesity, myocardial fatty acid oxidation increases, while in heart failure associated with hypertension or ischemia, myocardial fatty acid oxidation decreases. Combined, these energy metabolic changes result in the failing heart becoming less efficient (ie, a decrease in cardiac work/O2 consumed). The alterations in both glycolysis and mitochondrial oxidative metabolism in the failing heart are due to both transcriptional changes in key enzymes involved in these metabolic pathways, as well as alterations in NAD redox state (NAD+ and nicotinamide adenine dinucleotide levels) and metabolite signaling that contribute to posttranslational epigenetic changes in the control of expression of genes encoding energy metabolic enzymes. Alterations in the fate of glucose, beyond flux through glycolysis or glucose oxidation, also contribute to the pathology of heart failure. Of importance, pharmacological targeting of the energy metabolic pathways has emerged as a novel therapeutic approach to improving cardiac efficiency, decreasing the energy deficit and improving cardiac function in the failing heart.
Sensitivity analyses of unmeasured and partially‐measured confounders using multiple imputation in a vaccine safety study

Sensitivity analyses have played an important role in pharmacoepidemiology studies using electronic health records data. Despite the existence of quantitative bias analysis in pharmacoepidemiologic studies, simultaneously adjusting for unmeasured and partially measured confounders is challenging in vaccine safety studies. Our objective was to develop a flexible approach for conducting sensitivity analyses of unmeasured and partially‐measured confounders concurrently for a vaccine safety study.
LncRNA AK020546 protects against cardiac ischemia–reperfusion injury by sponging miR-350-3p

Long non-coding RNAs (lncRNAs) have been implicated in the development of cardiovascular diseases. We observed that lncRNA AK020546 was downregulated following ischemia/reperfusion injury to the myocardium and following H2O2 treatment in H9c2 cardiomyocytes. In vivo and in vitro studies showed that AK020546 overexpression attenuated the size of the ischemic area, reduced apoptosis among H9c2 cardiomyocytes, and suppressed the release of reactive oxygen species, lactic acid dehydrogenase, and malondialdehyde. AK020546 served as a competing endogenous RNA for miR-350-3p and activated the miR-350-3p target gene ErbB3. MiR-350-3p overexpression reversed the effects of AK020546 on oxidative stress injury and apoptosis in H9c2 cardiomyocytes. Moreover, ErbB3 knockdown alleviated the effects of AK020546 on the expression of ErbB3, Bcl-2, phosphorylated AKT, cleaved Caspase 3, and phosphorylated Bad. These findings suggest lncRNA AK020546 protects against ischemia/reperfusion and oxidative stress injury by sequestering miR-350-3p and activating ErbB3, which highlights its potential as a therapeutic target for ischemic heart diseases.
Evaluation of high-resolution melt curve analysis for rapid differentiation of Campylobacter hepaticus from other species in birds

Spotty liver disease (SLD) is a bacterial disease of chicken, causing mortalities and reduction in egg production, hence, contributing to economic loss in the poultry industry. The causative agent of SLD has only recently been identified as a novel Campylobacter species, Campylobacter hepaticus. Specific primers were designed from the hsp60 gene of Campylobacter hepaticus and PCR followed by high-resolution melt curve analysis was optimised to detect and differentiate three species of Campylobacter (Campylobacter coli, Campylobacter jejuni and Campylobacter hepaticus). The three Campylobacter species produced a distinct curve profile and was differentiated using HRM curve analysis. The potential of the PCR-HRM curve analysis was shown in the genotyping of 37 Campylobacter isolates from clinical specimens from poultry farms. PCR-HRM curve analysis of DNA extracts from bile samples or cultures from bile samples, were identified as Campylobacter hepaticus and confirmed by DNA sequencing. The DNA sequence analysis of selected samples from each of the three HRM distinctive curves patterns showed that each DNA sequence was associated with a unique melt profile. The potential of the PCR-HRM curve analysis in genotyping of Campylobacter species was also evaluated using faecal specimens from 100 wild birds. The results presented in this study indicate that PCR followed by HRM curve analysis provides a rapid and robust technique for genotyping of Campylobacter species using either bacterial cultures or clinical specimens.
Sequencing toponymic change: A quantitative longitudinal analysis of street renaming in Sibiu, Romania

Recent scholarship in critical toponymy studies has refashioned the understanding of street names from innocent labels to nominal loci of historical memory and vectors of collective identity that are embroiled with power relations. Urban nomenclatures consist of more than mere linguistic signposts deployed onto space to facilitate navigation. Street names are also powerful signposts that indicate the political regime and its socio-cultural values. Drawing on these theoretical insights, this paper is focused on Sibiu (Romania) and explore the city’s shifting namescape in a longitudinal perspective spanning one century and a half of modern history (1875–2020). The analysis is based on a complete dataset of street names and street name changes registered across five political regimes (Habsburg Empire, Kingdom of Romania, Romanian People’s Republic, Socialist Republic of Romania, and post-socialist Romania). A series of multiple logistic regression models were carried out to determine the factors that influence toponymic change. The statistical results point out several significant predictors of street renaming: (1) the streets’ toponymic characteristics (politicized or neutral name); (2) artery rank (public squares and large avenues or ordinary streets and alleys); and (3) topographic features (a street’s size and centrality). Such a quantitative approach coupled with a longitudinal perspective contributes to the scholarly literature on place-naming practices in three major ways: firstly, by advancing an innovative methodological framework and analytical model for the study of street name changes; secondly, by delineating with statistical precision the factors that model toponymic change; and thirdly, by embedding these renaming practices observed especially after significant power shifts in the broader historical context of the changes brought in the city’s street nomenclature.
Toward Physics-Based Solubility Computation for Pharmaceuticals to Rival Informatics

We demonstrate that physics-based calculations of intrinsic aqueous solubility can rival cheminformatics-based machine learning predictions. A proof-of-concept was developed for a physics-based approach via a sublimation thermodynamic cycle, building upon previous work that relied upon several thermodynamic approximations, notably the 2RT approximation, and limited conformational sampling. Here, we apply improvements to our sublimation free-energy model with the use of crystal phonon mode calculations to capture the contributions of the vibrational modes of the crystal. Including these improvements with lattice energies computed using the model-potential-based Ψmol method leads to accurate estimates of sublimation free energy. Combining these with hydration free energies obtained from either molecular dynamics free-energy perturbation simulations or density functional theory calculations, solubilities comparable to both experiment and informatics predictions are obtained. The application to coronene, succinic acid, and the pharmaceutical desloratadine shows how the methods must be adapted for the adoption of different conformations in different phases. The approach has the flexibility to extend to applications that cannot be covered by informatics methods.
Enhanced detection of cortical atrophy in Alzheimer's disease using structural MRI with anatomically constrained longitudinal registration

Cortical atrophy is a defining feature of Alzheimer's disease (AD), often detectable before symptoms arise. In surface‐based analyses, studies have commonly focused on cortical thinning while overlooking the impact of loss in surface area. To capture the impact of both cortical thinning and surface area loss, we used anatomically constrained Multimodal Surface Matching (aMSM), a recently developed tool for mapping change in surface area. We examined cortical atrophy over 2 years in cognitively normal subjects and subjects with diagnoses of stable mild cognitive impairment, mild cognitive impairment that converted to AD, and AD. Magnetic resonance imaging scans were segmented and registered to a common atlas using previously described techniques (FreeSurfer and ciftify), then longitudinally registered with aMSM. Changes in cortical thickness, surface area, and volume were mapped within each diagnostic group, and groups were compared statistically. Changes in thickness and surface area detected atrophy at similar levels of significance, though regions of atrophy somewhat differed. Furthermore, we found that surface area maps offered greater consistency across scanners (3.0 vs. 1.5 T). Comparisons to the FreeSurfer longitudinal pipeline and parcellation‐based (region‐of‐interest) analysis suggest that aMSM may allow more robust detection of atrophy, particularly in earlier disease stages and using smaller sample sizes.
Development, implementation, and evaluation of a clinical decision support tool to improve naloxone coprescription within military health system pharmacies.

DISCLAIMER In an effort to expedite the publication of articles related to the COVID-19 pandemic, AJHP is posting these manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE To describe the development, implementation, and evaluation of a pharmacy clinical decision support tool designed to increase naloxone coprescription among people at risk for opioid overdose in a large healthcare system. SUMMARY The Military Health System Opioid Registry and underlying presentation layer were used to develop a clinical decision support capability to improve naloxone coprescription at the pharmacy point of care. Pharmacy personnel use a patient identification card barcode scanner or manually enter a patient's identification number to quickly visualize information on a patient's risk for opioid overdose and medical history related to pain and, when appropriate, receive a recommendation to coprescribe naloxone. The tool was made available to military treatment facility pharmacy locations. An interactive dashboard was developed to support monitoring, utilization, and impact on naloxone coprescription to patients at risk for opioid overdose. CONCLUSION Initial implementation of the naloxone tool was slow from a lack of end-user awareness. Efforts to increase utilization were, in part, successful owing to a number of enterprise-wide educational initiatives. In early 2020, the naloxone tool was used in 15% of all opioid prescriptions dispensed at a military pharmacy. Data indicate that the frequency of naloxone coprescription to patients at risk for opioid overdose was significantly higher when the naloxone tool was used than when the tool was not used.