Miracle-dz/UniFAR-FTUs huggingface dataset:
Biophysical and structural characterization of a multifunctional viral genome packaging motor

Abstract The large dsDNA viruses replicate their DNA as concatemers consisting of multiple covalently linked genomes. Genome packaging is catalyzed by a terminase enzyme that excises individual genomes from concatemers and packages them into preassembled procapsids. These disparate tasks are catalyzed by terminase alternating between two distinct states—a stable nuclease that excises individual genomes and a dynamic motor that translocates DNA into the procapsid. It was proposed that bacteriophage λ terminase assembles as an anti-parallel dimer-of-dimers nuclease complex at the packaging initiation site. In contrast, all characterized packaging motors are composed of five terminase subunits bound to the procapsid in a parallel orientation. Here, we describe biophysical and structural characterization of the λ holoenzyme complex assembled in solution. Analytical ultracentrifugation, small angle X-ray scattering, and native mass spectrometry indicate that 5 subunits assemble a cone-shaped terminase complex. Classification of cryoEM images reveals starfish-like rings with skewed pentameric symmetry and one special subunit. We propose a model wherein nuclease domains of two subunits alternate between a dimeric head-to-head arrangement for genome maturation and a fully parallel arrangement during genome packaging. Given that genome packaging is strongly conserved in both prokaryotic and eukaryotic viruses, the results have broad biological implications.
HetFCM: functional co-module discovery by heterogeneous network co-clustering

Abstract Functional molecular module (i.e., gene–miRNA co-modules and gene–miRNA–lncRNA triple-layer modules) analysis can dissect complex regulations underlying etiology or phenotypes. However, current module detection methods lack an appropriate usage and effective model of multi-omics data and cross-layer regulations of heterogeneous molecules, causing the loss of critical genetic information and corrupting the detection performance. In this study, we propose a heterogeneous network co-clustering framework (HetFCM) to detect functional co-modules. HetFCM introduces an attributed heterogeneous network to jointly model interplays and multi-type attributes of different molecules, and applies multiple variational graph autoencoders on the network to generate cross-layer association matrices, then it performs adaptive weighted co-clustering on association matrices and attribute data to identify co-modules of heterogeneous molecules. Empirical study on Human and Maize datasets reveals that HetFCM can find out co-modules characterized with denser topology and more significant functions, which are associated with human breast cancer (subtypes) and maize phenotypes (i.e., lipid storage, drought tolerance and oil content). HetFCM is a useful tool to detect co-modules and can be applied to multi-layer functional modules, yielding novel insights for analyzing molecular mechanisms. We also developed a user-friendly module detection and analysis tool and shared it at http://www.sdu-idea.cn/FMDTool.
Biomarkers of response to treatment in acromegaly

ABSTRACT Introduction Medical treatment of acromegaly is based in a `trial and error` approach. First-generation somatostatin receptor ligands (fg-SRL) are prescribed as first-line medical therapy to the vast majority of patients, despite lack of disease control in approximately 60% of patients. However, other drugs used in acromegaly treatment are available (cabergoline, pasireotide and pegvisomant). Areas covered In this article, we review and discuss the biomarkers of response to medical treatment in acromegaly. Expert opinion Biomarkers for fg-SRL that can already be applied in clinical practice are: gender, age, pretreatment GH and IGF-I levels, cytokeratin granulation pattern, and the expression of somatostatin receptor type 2. Using biomarkers of response could guide treatment towards precision medicine with greater efficacy and lower costs.
Dynamic behaviour of transition zones in soft soils during regular train traffic

Transition zones in railway tracks are of importance for infrastructure managers, due to the high maintenance required to maintain appropriate track geometry. To improve our understanding of the performance of transition zones, a research program was conducted in The Netherlands, in which a transition zone was extensively monitored during regular train traffic. This paper presents some of the results from the monitoring of this transition zone. The results highlight the poor performance of this transition zone compared to its expected design performance. The track was found to be hanging over the transition zone, exhibiting a rocking motion about a culvert. Track stiffness was found to reduce linearly with increasing train speed. The implications on the design of transition zones are discussed, with recommendations made.
Is inverse association between lipoprotein(a) and diabetes mellitus another paradox in cardiometabolic medicine?

ABSTRACT Introduction The impact of Type II Diabetes mellitus (T2DM) on cardiovascular disease (CVD) is well-established, while lipoprotein(a) [Lp(a)] has recently emerged as a recognized CVD risk factor. The rising prevalence of T2DM resulting from modern lifestyles and the development of specific Lp(a)-lowering agents brought the association between T2DM and Lp(a) in the forefront. Areas covered Despite advancements in T2DM treatment, diabetic patients remain at very-high risk of CVD. Lp(a) may, to some extent, contribute to the persistent CVD risk seen in diabetic patients, and the coexistence of T2DM and elevated Lp(a) levels appears to synergistically amplify overall CVD risk. The relationship between T2DM and Lp(a) is paradoxical. On one hand, high Lp(a) plasma concentrations elevate the risk of diabetic microvascular and macrovascular complications. On the other hand, low Lp(a) plasma concentrations have been linked to an increased risk of developing T2DM. Expert opinion Comprehending the association between T2DM and Lp(a) is critical due to the pivotal roles both entities play in overall CVD risk, as well as the unique aspects of their relationship. The mechanisms underlying the inverse association between T2DM and Lp(a) remain incompletely understood, necessitating further meticulous research.
Neurophobia among resident physicians in the emergency service

Introduction. Neurophobia is defined as the fear towards clinical neurology caused by the inability to apply theoretical knowledge to practical clinical situations. This phenomenon is not restricted to medical students and has never been studied before in the Emergency Department. We aimed to study how resident doctors perceive their knowledge in neurology and urgent neurological conditions as well as possible causes for said fears. Materials and methods. Cross-sectional multicentric study using self-administered surveys sent to medical residents within the Aragon Health Service. They were questioned about their fear of neurology and other medical specialties, possible causes, and perception of knowledge in neurological pathologies and subareas in the emergency service. Results. We obtained 134 responses. 27.6% (37) suffered from neurophobia. Despite neurology being considered the most difficult discipline, it did also arouse the third most interest among the students. The areas where they showed the most confidence were headaches and vascular pathology. The areas where they felt the most insecure were neuromuscular diseases, neuro-ophthalmology, and spinal cord injury. In none of the areas surveyed, the percentage of respondents who felt secure exceeded 50%. Conclusions. Neurophobia is prevalent among trainee doctors working in the emergency department. Their confidence correlates with the degree of exposure to patients. Neurologist must play an active role in the education of new specialist and promote the collaboration with emergency departments.
Association between endogenous plasma beta‐hydroxy‐beta‐methylbutyrate levels and frailty in community‐dwelling older people

Abstract Background Frailty is a key element in healthy ageing in which muscle performance plays a main role. Beta‐hydroxy‐beta‐methylbutyrate (HMB) supplementation has shown favourable effects in modulating protein synthesis, improving muscle mass and function in interventional studies. Decreased age‐related endogenous HMB levels have been shown in previous studies. The aim of the present study is to assess whether there is an association between endogenous plasma HMB levels and frailty. Methods Data from 1290 subjects (56.98% women; mean ± standard deviation age 74.6 ± 5.95 years) from the Toledo Study for Healthy Aging were obtained. Participants had their frailty status qualified according to Fried's Frailty Phenotype (FFP) score and the Frailty Trait Scale in its 12‐domain version (FTS‐12). Plasma HMB levels were analysed by an ultrahigh‐performance liquid chromatography tandem mass spectrometry. Differences between groups (frail vs. non‐frail) were tested using Mann–Whitney U test, Kruskal–Wallis test and chi‐squared test. The association between HMB and frailty was assessed by multivariate linear and logistic regressions when frailty was analysed as continuous and binary, respectively. Models were adjusted by age, gender, comorbidity, body composition and protein intake. Results HMB levels were lower in those aged ≥75 years than in those aged 65–74 years, with an inverse linear relationship between age and HMB levels (β = −0.031; P = 0.018), mainly accounted by males (β = −0.062; P = 0.002). HMB levels were higher in men (0.238 ± 0.065 vs. 0.193 ± 0.051 ng/mL; P ≤ 0.001). HMB levels were significantly lower in frail than in non‐frail individuals: 0.204 ± 0.058 versus 0.217 ± 0.063 ng/dL (P = 0.001) according to the FFP and 0.203 ± 0.059 versus 0.219 ± 0.063 ng/mL (P < 0.001) according to FTS‐12. These differences showed a dose‐dependent profile when we compared them by quintiles of HMB (P for trend: 0.022; 0.012 and 0.0004, respectively, for FFP, FTS‐12 binary and FTS‐12 continuous). Variables associated with low HMB levels were body mass index, strength, exhaustion and weight loss. Frailty was associated with HMB levels in all the adjusted models, including the fully adjusted ones, no matter the tool used (odds ratio: 0.45 [0.26, 0.77] for FFP and 0.36 [0.20, 0.63] for FTS‐12 binary; β = −4.76 [−7.29, −2.23] for FTS‐12 score). This association was also observed when the analyses were done by quintiles, showing such association since Q4 (FFP), Q2 (FTS‐12 binary) and Q3 (FTS‐12 score). The associations were observed in the whole sample and in each gender. Conclusions There is an inverse association between HMB levels and frailty status. These findings support the design of targeted clinical trials to evaluate the effect of HMB supplementation in older frail people with low HMB levels.
The Resolution of Civil Wars: Changing International Norms of Peace-Making and the Academic Consensus

ABSTRACT Since the end of the Cold War, the belief that the international community has a responsibility to support negotiated solutions to civil wars has exercised an enduring influence on research and policy making. However, this belief has relatively recent roots. This article looks at how changing international norms have influenced the way academic researchers view civil wars and expect them to end. The lack of interest in solving internal conflicts during the Cold War was matched among academics by a focus on other security issues and a belief that most civil wars could not be negotiated, although a minority of scholars disagreed. After the Cold War, a new international regime for solving civil wars has emerged, with the active support of a large share of the academic community. However, scholars have also criticised the way Western priorities have shaped liberal peace-making attempts and reflected on the assumptions underlying international conflict resolution. Paradoxically, while the academic community has become increasingly optimistic, the post-Cold War approach has fallen into crisis, due to geopolitical transformations and a change in the nature of contemporary insurgencies. At the end of this article, I suggest new avenues for research in the changing international order.
ICBcomb: a comprehensive expression database for immune checkpoint blockade combination therapy

Abstract The success of immune checkpoint blockade (ICB) promotes the immunotherapy to be a new pillar in cancer treatment. However, the low response rate of the ICB therapy limits its application. To increase the response rate and enhance efficacy, the ICB combination therapy has emerged and its clinical trials are increasing. Nevertheless, the gene expression profile and its pattern of ICB combination were not comprehensively studied, which limits the understanding of the ICB combination therapy and the identification of new drugs. Here, we constructed ICBcomb (http://bioinfo.life.hust.edu.cn/ICBcomb/), a comprehensive database, by analyzing the human and mouse expression data of the ICB combination therapy and comparing them between groups treated with ICB, other drugs or their combinations. ICBcomb contains 1399 samples across 29 cancer types involving 52 drugs. It provides a user-friendly web interface for demonstrating the results of the available comparisons in the ICB combination therapy datasets with five functional modules: [1, 2] the ‘Dataset/Disease’ modules for browsing the expression, enrichment and comparison results in each dataset or disease; [3] the ‘Gene’ module for inputting a gene symbol and displaying its expression and comparison results across datasets/diseases; [4] the ‘Gene Set’ module for GSVA/GSEA enrichment analysis on the built-in gene sets and the user-input gene sets in different comparisons; [5] the ‘Immune Cell’ module for immune cell infiltration comparison between different groups by immune cell abundance analysis. The ICBcomb database provides the first resource for gene expression profile and comparison in ICB combination therapy, which may provide clues for discovering the mechanism of effective combination strategies and new combinatory drugs.
Association of clinical symptoms and cardiometabolic dysregulations in patients with schizophrenia spectrum disorders

Background Patients with schizophrenia spectrum disorders (SSD) have a shortened life expectancy related to cardiovascular diseases. We investigated the association of cognitive, positive, and negative symptoms with cardiometabolic dysregulations in SSD patients. Methods Overall, 1,119 patients from the Genetic Risk and Outcome in Psychosis (GROUP) study were included. Cognitive function, positive and negative symptoms were assessed at baseline, 3-year, and 6-year. Cardiometabolic biomarkers were measured at 3-year follow-up. We used linear and multinomial logistic regression models to test the association between cardiometabolic biomarkers and clinical trajectories and performed mediation analyzes, while adjusting for clinical and demographic confounders. Results Cognitive performance was inversely associated with increased body mass index (mean difference [β], βhigh = −1.24, 95% CI = –2.28 to 0.20, P = 0.02) and systolic blood pressure (βmild = 2.74, 95% CI = 0.11 to 5.37, P = 0.04). The severity of positive symptoms was associated with increased glycated hemoglobin (HbA1c) levels (βlow = −2.01, 95% CI = −3.21 to −0.82, P = 0.001). Increased diastolic blood pressure (ORhigh-decreased = 1.04, 95% CI = 1.01 to 1.08, P = 0.02; ORhigh-increased = 1.04, 95% CI = 1.00 to 1.08, P = 0.048) and decreased high-density lipoprotein (OR high-increased = 6.25, 95% CI = 1.81 to 21.59, P = 0.004) were associated with more severe negative symptoms. Increased HbA1c (ORmoderate = 1.05, 95% CI = 1.01 to 1.10, P = 0.024; ORhigh = 1.08, 95% CI = 1.02 to 1.14, P = 0.006) was associated with more severe positive symptoms. These associations were not mediated by antipsychotics. Conclusions We showed an association between cardiometabolic dysregulations and clinical and cognitive symptoms in SSD patients. The observed associations underscore the need for early identification of patients at risk of cardiometabolic outcomes.
Macromolecular Complex Including MLL3, Carabin and Calcineurin Regulates Cardiac Remodeling

BACKGROUND: Cardiac hypertrophy is an intermediate stage in the development of heart failure. The structural and functional processes occurring in cardiac hypertrophy include extensive gene reprogramming, which is dependent on epigenetic regulation and chromatin remodeling. However, the chromatin remodelers and their regulatory functions involved in the pathogenesis of cardiac hypertrophy are not well characterized. METHODS: Protein interaction was determined by immunoprecipitation assay in primary cardiomyocytes and mouse cardiac samples subjected or not to transverse aortic constriction for 1 week. Chromatin immunoprecipitation and DNA sequencing (ChIP-seq) experiments were performed on the chromatin of adult mouse cardiomyocytes. RESULTS: We report that the calcium-activated protein phosphatase CaN (calcineurin), its endogenous inhibitory protein carabin, the STK24 (STE20-like protein kinase 3), and the histone monomethyltransferase, MLL3 (mixed lineage leukemia 3) form altogether a macromolecular complex at the chromatin of cardiomyocytes. Under basal conditions, carabin prevents CaN activation while the serine/threonine kinase STK24 maintains MLL3 inactive via phosphorylation. After 1 week of transverse aortic constriction, both carabin and STK24 are released from the CaN-MLL3 complex leading to the activation of CaN, dephosphorylation of MLL3, and in turn, histone H3 lysine 4 monomethylation. Selective cardiac MLL3 knockdown mitigates hypertrophy, and chromatin immunoprecipitation and DNA sequencing analysis demonstrates that MLL3 is de novo recruited at the transcriptional start site of genes implicated in cardiomyopathy in stress conditions. We also show that CaN and MLL3 colocalize at chromatin and that CaN activates MLL3 histone methyl transferase activity at distal intergenic regions under hypertrophic conditions. CONCLUSIONS: Our study reveals an unsuspected epigenetic mechanism of CaN that directly regulates MLL3 histone methyl transferase activity to promote cardiac remodeling.
Prevalence and temporal trend of gastric preneoplastic lesions in Asia: A systematic review with meta‐analysis

Abstract Background Gastric cancer is the fifth most common cancer globally, with about 75% of cases occurring in Asia. While chronic atrophic gastritis (CAG) and intestinal metaplasia (IM) are well‐recognized preneoplastic gastric lesions, we determined the prevalence and temporal trend of CAG and IM in Asia over the past 50 years. Methods In this systematic review and meta‐analysis, we searched PubMed, Embase, MEDLINE, Scopus, and Web of Science for studies reporting the prevalence of CAG and IM in Asia (according to the United Nations geoscheme) published between 1970 and 2022. Heterogeneity was assessed by the I 2 index and Cochran Q test. We adopted the random effects model to estimate the pooled prevalence and 95% confidence interval (CI). The slope of prevalence was estimated as a function of time in simple linear regression and weighted meta‐regression models to demonstrate the temporal trend. Studies that reported the odds ratio (OR) of Helicobacter pylori infection and CAG/IM were analyzed separately to compile a pooled OR with a 95% CI. This study was registered in INPLASY2022120028. Results Of the 81 studies from 19 Asian countries identified, the pooled prevalence for CAG and IM in Asia was 26.1% (95%CI: 22.7–30.0) and 22.9% (95%CI: 19.7–26.6), respectively. Over the past 5 decades, there was a significant decline in the prevalence of IM (slope in adjusted meta‐regression models: −0.79 [95%CI: −1.28 to −0.26], P = 0.003), but there was no significant change in the pooled prevalence of CAG. Within Asia, the prevalence varied significantly among different regions. Southern Asia reported the highest pooled prevalence of CAG (42.9%, 95%CI: 27.5%–67.1%), while Western Asia reported the lowest level (12.7%, 95%CI: 5.0%–32.3%). For IM, Eastern Asia reported the highest prevalence (27.1%, 95%CI: 21.1–34.9), with the lowest prevalence reported in Western Asia (3.1%; 95% CI 1.2%–8.0%). H. pylori infection was linked to CAG and IM with OR of 2.16 (95%CI: 2.09–2.22) and 1.64 (95%CI: 1.57–1.72), respectively. Conclusion This updated meta‐analysis showed that up to 26% of study individuals in Asia harbored preneoplastic gastric lesions. There was a declining temporal trend in the prevalence of IM, but not for CAG, in Asia.
Comparative effects of chemical and green zinc oxide nanoparticles in caprine testis: ultrastructural and steroidogenic enzyme analysis

ABSTRACT Recent advancements in nanotechnology has opened up enormous possibilities in diverse sectors such as industries, agriculture, environmental remediation, electronics, medicine and varied industries. Among metal oxide nanoparticles zinc oxide nanoparticles has gained considerable attention due to their fascinating physiochemical properties. Rapid growth in the use of zinc oxide nanoparticles (ZnONPs) in daily household products, food and feed additives, biological products, medicine, as antimicrobial agents, electronics and agriculture, creates serious toxic potential risks of these engineered nanoparticles on living organisms. The aim of present study was to assess the effects of synthesized chemical ZnONPs and green ZnONPs on testicular tissue of Capra hircus (goat) in vitro. The reproductive stress was analyzed by ultrastructural damage, change in frequency of apoptotic cells and alteration in steroidogenic enzyme activity. The transmission electron micrographs of testicular cells after treatment with chemical and green ZnONPs at three doses (10 µg/ml, 20 µg/ml and 30 µg/ml) for exposure duration 4 h and 8 h illustrated that chemical nanoparticles induced more alterations, identified as ruptured nuclear membrane, condensation and margination of chromatin material in somatic cells and germ cells in the seminiferous tubules, presence of apoptotic bodies in nucleus of spermatocytes and spermatids, reduction in number of cell organelles, vacuolization and hyalinization of cytoplasm. Maximum damage was observed after treatment of testicular tissues with 30 µg/ml of chemical ZnONPs for 8 h exposure duration. However, the green ZnONPs were found to be less toxic as evidenced by few apoptotic characteristics in testicular cells. The results of fluorescence assay by acridine orange staining showed significant increase in the percentage of apoptotic cells in chemical treated groups as compared to green and control groups. Decreased enzyme activity of 3β-Hydroxysteroid dehydrogenase and 17β-Hydroxysteroid dehydrogenase was assayed in chemical ZnONPs than green ZnONPs treated groups. Our results confirm that chemical ZnONPs are significantly more toxic in comparison to green ZnONPs and adversely affects the male fertility.