Miracle-dz/UniFAR-FTUs huggingface dataset:
Genome Size Evolution Differs Between Drosophila Subgenera with Striking Differences in Male and Female Genome Size in Sophophora

Genome size varies across the tree of life, with no clear correlation to organismal complexity or coding sequence, but with differences in non-coding regions. Phylogenetic methods have recently been incorporated to further disentangle this enigma, yet most of these studies have focused on widely diverged species. Few have compared patterns of genome size change in closely related species with known structural differences in the genome. As a consequence, the relationship between genome size and differences in chromosome number or inter-sexual differences attributed to XY systems are largely unstudied. We hypothesize that structural differences associated with chromosome number and X-Y chromosome differentiation, should result in differing rates and patterns of genome size change. In this study, we utilize the subgenera within the Drosophila to ask if patterns and rates of genome size change differ between closely related species with differences in chromosome numbers and states of the XY system. Genome sizes for males and females of 152 species are used to answer these questions (with 92 newly added or updated estimates). While we find no relationship between chromosome number and genome size or chromosome number and inter-sexual differences in genome size, we find evidence for differing patterns of genome size change between the subgenera, and increasing rates of change throughout time. Estimated shifts in rates of change in sex differences in genome size occur more often in Sophophora and correspond to known neo-sex events.
Developing an optimal short‐form of the PTSD Checklist for DSM‐5 (PCL‐5)

Although several short‐forms of the posttraumatic stress disorder (PTSD) Checklist (PCL) exist, all were developed using heuristic methods. This report presents the results of analyses designed to create an optimal short‐form PCL for DSM‐5 (PCL‐5) using both machine learning and conventional scale development methods.
Roles of T Follicular Helper Cells and T Follicular Regulatory Cells in Autoantibody Production in IL-2–Deficient Mice

Autoantibodies can result from excessive T follicular helper (Tfh) cell activity, whereas T follicular regulatory (Tfr) cells negatively regulate autoantibody production. IL-2 knockout (KO) mice on the BALB/c background have elevated Tfh responses, produce autoantibodies, and develop lethal autoimmunity. We analyzed Tfh and Tfr cells in IL-2 KO mice on the C57BL/6 (B6) genetic background. In B6 IL-2 KO mice, the spontaneous formation of Tfh cells and germinal center B cells was greatly enhanced, along with production of anti-DNA autoantibodies. IL-2 has been reported to repress Tfr cell differentiation; however, Tfr cells were not increased over wild-type levels in the B6 IL-2 KO mice. To assess Tfh and Tfr cell regulation of autoantibody production in IL-2 KO mice, we generated IL-2 KO mice with a T cell–specific deletion of the master Tfh cell transcription factor Bcl6. In IL-2 KO Bcl6 conditional KO (2KO-Bcl6TC) mice, Tfh cells, Tfr cells, and germinal center B cells were ablated. In contrast to expectations, autoantibody IgG titers in 2KO-Bcl6TC mice were significantly elevated over autoantibody IgG titers in IL-2 KO mice. Specific deletion of Tfr cells with Foxp3-cre Bcl6-flox alleles in IL-2 KO mice led to early lethality, before high levels of autoantibodies could develop. We found IL-2+/+ Tfr cell–deficient mice produce significant levels of autoantibodies. Our overall findings provide evidence that Tfh cells are dispensable for high-level production of autoantibodies and also reveal a complex interplay between Tfh and Tfr cells in autoantibody production and autoimmune disease.
CoBAMP: a Python framework for metabolic pathway analysis in constraint-based models

SUMMARY CoBAMP is a modular framework for the enumeration of pathway analysis concepts, such as elementary flux modes (EFM) and minimal cut sets in genome-scale constraint-based models of metabolism. It currently includes the K-shortest EFM algorithm and facilitates integration with other frameworks involving reading, manipulation and analysis of constraint-based models. AVAILABILITY The software is implemented in Python 3, supported on most operating systems and requires a mixed-integer linear programming optimizer supported by the optlang framework. Source-code is available at https://github.com/BioSystemsUM/cobamp.
Trends in modes of death in heart failure over the last two decades: less sudden death but cancer deaths on the rise

Better management of heart failure (HF) over the past two decades has improved survival, mainly by reducing the incidence of death due to cardiovascular (CV) causes. Deaths due to non‐CV causes, particularly cancer, may be increasing. This study explored the modes of death of consecutive patients who attended a HF clinic over 17 years.
How do stakeholders experience the adoption of electronic prescribing systems in hospitals? A systematic review and thematic synthesis of qualitative studies

Background Electronic prescribing (ePrescribing) or computerised provider/physician order entry (CPOE) systems can improve the quality and safety of health services, but the translation of this into reduced harm for patients remains unclear. This review aimed to synthesise primary qualitative research relating to how stakeholders experience the adoption of ePrescribing/CPOE systems in hospitals, to help better understand why and how healthcare organisations have not yet realised the full potential of such systems and to inform future implementations and research. Methods We systematically searched 10 bibliographic databases and additional sources for citation searching and grey literature, with no restriction on date or publication language. Qualitative studies exploring the perspectives/experiences of stakeholders with the implementation, management, use and/or optimisation of ePrescribing/CPOE systems in hospitals were included. Quality assessment combined criteria from the Critical Appraisal Skills Programme Qualitative Checklist and the Standards for Reporting Qualitative Research guidelines. Data were synthesised thematically. Results 79 articles were included. Stakeholders’ perspectives reflected a mixed set of positive and negative implications of engaging in ePrescribing/CPOE as part of their work. These were underpinned by further-reaching change processes. Impacts reported were largely practice related rather than at the organisational level. Factors affecting the implementation process and actions undertaken prior to implementation were perceived as important in understanding ePrescribing/CPOE adoption and impact. Conclusions Implementing organisations and teams should consider the breadth and depth of changes that ePrescribing/CPOE adoption can trigger rather than focus on discrete benefits/problems and favour implementation strategies that: consider the preimplementation context, are responsive to (and transparent about) organisational and stakeholder needs and agendas and which can be sustained effectively over time as implementations develop and gradually transition to routine use and system optimisation.
Association between invasively measured aortic pulse pressure and orthostatic hypotension in patients undergoing invasive coronary angiography.

OBJECTIVE Underlying pathophysiology of orthostatic hypotension has been poorly understood. We hypothesized that aortic pulse pressure (APP) reflecting aortic stiffness may be involved in the development of orthostatic hypotension. METHODS A total of 200 patients (age 64.3 ± 10.9 years, 62.5% men) who underwent invasive coronary angiography (ICA) were prospectively recruited. Orthostatic hypotension was defined as SBP drop at least 20 mmHg or DBP drop at least 10 mmHg within 3 min of the standing position compared with the supine position. Hemodynamic parameters were measured at the ascending aorta using a pig-tail catheter immediately before ICA. APP was calculated as a difference between the aortic peak systolic pressure and the end-diastolic pressure. RESULTS A total of 156 patients (78.0%) had obstructive coronary artery disease on ICA. Orthostatic hypotension was present in 58 patients (29.0%). Diabetes mellitus was more prevalent in patients with orthostatic hypotension than those without (48.3 vs. 23.2%; P < 0.001). Other clinical parameters including age, cardiovascular risk factors, laboratory findings and concomitant medications were not different between patients with and without orthostatic hypotension (P > 0.05 for each). In hemodynamic parameters, APP was higher in patients with orthostatic hypotension than those without (78.4 ± 25.8 vs. 68.3 ± 21.3 mmHg; P = 0.005). Higher APP was significantly associated with the presence of orthostatic hypotension even after controlling for potential confounders (odds ratio, 2.99; 95% confidence interval 1.15-7.78; P = 0.025). CONCLUSION In patients undergoing ICA, APP was associated with increased risk of orthostatic hypotension. Central aortic stiffness may play a role in the development of orthostatic hypotension.
Equine arteritis virus long-term persistence is orchestrated by CD8+ T lymphocyte transcription factors, inhibitory receptors, and the CXCL16/CXCR6 axis

Equine arteritis virus (EAV) has the unique ability to establish long-term persistent infection in the reproductive tract of stallions and be sexually transmitted. Previous studies showed that long-term persistent infection is associated with a specific allele of the CXCL16 gene (CXCL16S) and that persistence is maintained despite the presence of local inflammatory and humoral and mucosal antibody responses. Here, we performed transcriptomic analysis of the ampullae, the primary site of EAV persistence in long-term EAV carrier stallions, to understand the molecular signatures of viral persistence. We demonstrated that the local CD8+ T lymphocyte response is predominantly orchestrated by the transcription factors eomesodermin (EOMES) and nuclear factor of activated T-cells cytoplasmic 2 (NFATC2), which is likely modulated by the upregulation of inhibitory receptors. Most importantly, EAV persistence is associated with an enhanced expression of CXCL16 and CXCR6 by infiltrating lymphocytes, providing evidence of the implication of this chemokine axis in the pathogenesis of persistent EAV infection in the stallion reproductive tract. Furthermore, we have established a link between the CXCL16 genotype and the gene expression profile in the ampullae of the stallion reproductive tract. Specifically, CXCL16 acts as a “hub” gene likely driving a specific transcriptional network. The findings herein are novel and strongly suggest that RNA viruses such as EAV could exploit the CXCL16/CXCR6 axis in order to modulate local inflammatory and immune responses in the male reproductive tract by inducing a dysfunctional CD8+ T lymphocyte response and unique lymphocyte homing in the reproductive tract.
Personalized medicine and back–allogeneic exosomes for cancer immunotherapy

Extracellular vesicles, especially exosomes, have been explored for cancer immunotherapy. The initial studies made use of autologous B‐cell or dendritic cell‐derived exosomes, with the idea that MHC–peptide complexes on the exosomal surface would stimulate an MHC‐restricted cancer‐specific immune response. This was also verified in mouse systems, whilst the effects in human clinical systems were more modest. Several studies have explored the mechanisms for exosomal T‐cell activation, and a picture emerges where the antigen‐presenting cells, possibly both B cells and dendritic cells of the recipient, are needed to induce a potent T‐cell response to exosomes. Therefore, the exosomes function more as an adjuvant‐like delivery system of antigens, and we need to further understand the exact components that trigger the most broad and potent immune responses. Here, we describe the grounds for using allogeneic exosomes for cancer therapy, something that would greatly improve the feasibility of new exosome‐based immunotherapeutic approaches to cure cancer.
Quantitative Prediction of CYP3A4‐ and CYP3A5‐Mediated Drug Interactions

We verified a physiologically‐based pharmacokinetic (PBPK) model to predict cytochrome P450 3A4/5‐mediated drug‐drug interactions (DDIs). A midazolam (MDZ)–ketoconazole (KTZ) interaction study in 24 subjects selected by CYP3A5 genotype, and liquid chromatography and mass spectroscopy quantification of CYP3A4/5 abundance from independently acquired and genotyped human liver (n = 136) and small intestinal (N = 12) samples, were conducted. The observed CYP3A5 genetic effect on MDZ systemic and oral clearance was successfully replicated by a mechanistic framework incorporating the proteomics‐informed CYP3A abundance and optimized small intestinal CYP3A4 abundance based on MDZ intestinal availability (FG) of 0.44. Furthermore, combined with a modified KTZ PBPK model, this framework recapitulated the observed geometric mean ratio of MDZ area under the curve (AUCR) following 200 or 400 mg KTZ, which was, respectively, 2.7–3.4 and 3.9–4.7‐fold in intravenous administration and 11.4–13.4 and 17.0–19.7‐fold in oral administration, with AUCR numerically lower (P > 0.05) in CYP3A5 expressers than nonexpressers. In conclusion, the developed mechanistic framework supports dynamic prediction of CYP3A‐mediated DDIs in study planning by bridging DDIs between CYP3A5 expressers and nonexpressers.
The changing patterns and correlates of population-level polysubstance use in Australian youth: A multi-group latent class analysis of nationally representative samples spanning 12 year.

AIM To (1) identify population-level classes of polysubstance use among young Australians between 2004 and 2016, (2) test if these classes changed over the same period, in terms of class prevalence and probabilities of substance use within each class, and (3) identify demographic and health-related correlates of polysubstance use. DESIGN Repeated cross-sectional nationally representative household surveys. SETTING All Australian states/territories. PARTICIPANTS Young adult samples (Aged 18-30; 58% females) from the National Drug Strategy Household Surveys (N = 20,350) MEASUREMENTS: Outcomes: Extent of past year use of 10 licit (e.g. alcohol) and illicit substances (e.g. cannabis) were used to derive polysubstance use classes. Correlates: Gender, age, psychological distress, general health, language background, personal income, education level, remoteness of residence, and socio-economic index for area of residence. FINDINGS Three polysubstance use classes were consistently identified between 2004 and 2016 (SSABIC: 188349): Minimal users (MU, ~60%), Mainly tobacco, alcohol and cannabis users (TAC, ~30%) and Extended range polysubstance users (POLY, ~10%). There were substantial changes in use of different substances within each class over the study period. For example, smoking decreased in all classes (p < .05) while harmful alcohol use only decreased in the first two classes (p < .05). Factors associated with TAC and POLY were similar over the study period. These included: being male and having an English-speaking background, a high level of psychological distress, suboptimal health and high personal income. Living in an affluent area was associated with reduced likelihood of being TAC but an increased likelihood of being POLY. CONCLUSION At the population level among young Australians between 2004 and 2016, six in ten did not engage in polysubstance use; four in ten used a limited range of substances (mainly alcohol, tobacco, and cannabis), and one in ten used an extended range of substances. Over time, the types of substance within the extended polysubstance use class changed substantially.
Two Novel Negative-Sense RNA Viruses Infecting Grapevine Are Members of a Newly Proposed Genus within the Family Phenuiviridae

Two novel negative-stranded (ns)RNA viruses were identified by high throughput sequencing in grapevine. The genomes of both viruses, named grapevine Muscat rose virus (GMRV) and grapevine Garan dmak virus (GGDV), comprise three segments with each containing a unique gene. Based on sequence identity and presence of typical domains/motifs, the proteins encoded by the two viruses were predicted to be: RNA-dependent RNA polymerase (RdRp), nucleocapsid protein (NP), and putative movement protein (MP). These proteins showed the highest identities with orthologs in the recently discovered apple rubbery wood viruses 1 and 2, members of a tentative genus (Rubodvirus) within the family Phenuiviridae. The three segments of GMRV and GGDV share almost identical sequences at their 5′ and 3′ termini, which are also complementary to each other and may form a panhandle structure. Phylogenetics based on RdRp, NP and MP placed GMRV and GGDV in the same cluster with rubodviruses. Grapevine collections were screened for the presence of both novel viruses via RT-PCR, identifying infected plants. GMRV and GGDV were successfully graft-transmitted, thus, they are the first nsRNA viruses identified and transmitted in grapevine. Lastly, different evolutionary scenarios of nsRNA viruses are discussed.
Identification of key transcription factors in preeclampsia

ABSTRACT Objective: The aim of this study was to identify important transcription factors (TFs) in preeclampsia. Methods: Fisher’s test was applied to identify differentially expressed pathways. Functional principal component analysis (FPCA) was applied to identify differential expressed genes (DEGs). Topological characterizations of TFs were analyzed to identify key TFs. Results: From the DEG group, 37 genes were identified as TFs, and a total of 10 significant TFs with adjusted p<0.05 were identified. A total of 17 key TFs were identified from the TF network. Conclusions: Seventeen key TFs were identified, which may provide new insights into the mechanism of preeclampsia.
How Do Anticipated and Self Regulations and Information Sourcing Openness Drive Firms to Implement Eco-Innovation? Evidence from Korean Manufacturing Firms

Building upon institutional theory and the concept of openness to external sources in terms of breadth and depth, this study investigates the following three understudied drivers of eco-innovation in terms of external and internal factors: Anticipated regulation and self-regulation as external drivers, and information sourcing openness comprised of breadth and importance as internal drivers. Toward this end, this study employs a sample of 1824 Korean manufacturing firms collected from the Korean Innovation Survey 2010, which is compatible with the Oslo Manual and the Eurostat Community Innovation Survey (CIS). The current research adopts a multivariate probit model for the nine binary outcome variables and a zero-inflated negative binomial (ZINB) regression model for a count variable. It is found that, both anticipated regulation and self-regulation positively affect eco-process innovation and eco-product innovation across all of the nine eco-innovation types. The empirical findings on the effects of the breadth of external sources and the importance of used information acquired from external sources for innovative activities indicate that both the breadth and the importance have positive impacts on the number of types of eco-innovation with which a firm is engaged.
Roles of p53 Family Structure and Function in Non-Canonical Response Element Binding and Activation

The p53 canonical consensus sequence is a 10-bp repeat of PuPuPuC(A/T)(A/T)GPyPyPy, separated by a spacer with up to 13 bases. C(A/T)(A/T)G is the core sequence and purine (Pu) and pyrimidine (Py) bases comprise the flanking sequence. However, in the p53 noncanonical sequences, there are many variations, such as length of consensus sequence, variance of core sequence or flanking sequence, and variance in number of bases making up the spacer or AT gap composition. In comparison to p53, the p53 family members p63 and p73 have been found to have more tolerance to bind and activate several of these noncanonical sequences. The p53 protein forms monomers, dimers, and tetramers, and its nonspecific binding domain is well-defined; however, those for p63 or p73 are still not fully understood. Study of p63 and p73 structure to determine the monomers, dimers or tetramers to bind and regulate noncanonical sequence is a new challenge which is crucial to obtaining a complete picture of structure and function in order to understand how p63 and p73 regulate genes differently from p53. In this review, we will summarize the rules of p53 family non-canonical sequences, especially focusing on the structure of p53 family members in the regulation of specific target genes. In addition, we will compare different software programs for prediction of p53 family responsive elements containing parameters with canonical or non-canonical sequences.
Dissipation, residues and risk assessment of oxine-copper and pyraclostrobin in citrus

ABSTRACT An efficient, sensitive, simple and fast method for the simultaneous determination of oxine-copper and pyraclostrobin in citrus fruit was developed and validated. The method uses ethylene diamine tetra-acetic acid as a competitive ligand to convert oxine-copper to soluble 8-hydroxyquinoline for analysis by QuEChERS and LC-MS/MS. Linear relationships were determined with correlation coefficients ranging from 0.9904 to 0.9998. The limits of detection for the analytes were 0.012–0.8 μg kg−1, and the limits of quantitation were 0.04–2.6 μg kg−1 in citrus. The average recoveries were 79.1–114.9% with relative standard deviations of less than 7.4%. The analyses of dissipation indicated that the half-lives of oxine-copper and pyraclostrobin were 1.94–3.67 and 1.79–2.48 days and the terminal residues were <0.08–8.99 and <0.02–1.90 mg kg−1, respectively. The risk quotients of oxine-copper and pyraclostrobin were 0.026–0.199 and 0.003–0.022, respectively. This risk assessment provides a reference for the safe and reasonable use of oxine-copper and pyraclostrobin and may help to establish maximum residue limits for these pesticides in China. GRAPHICAL ABSTRACT
Brain endothelial specific gene therapy improves experimental Sandhoff disease

In Tay-Sachs and Sandhoff disease, a deficiency of the lysosomal enzyme β-hexosaminidase causes GM2 and other gangliosides to accumulate in neurons and triggers neurodegeneration. Although the pathology centers on neurons, β-hexosaminidase is mainly expressed outside of neurons, suggesting that gene therapy of these diseases should target non-neuronal cells to reconstitute physiological conditions. Here, we tested in Hexb−/− mice, a model of Sandhoff disease, to determine whether endothelial expression of the genes for human β-hexosaminidase subunit A and B (HEXA, HEXB) is able to reduce disease symptoms and prolong survival of the affected mice. The brain endothelial selective vectors AAV-BR1-CAG-HEXA and AAV-BR1-CAG-HEXB transduced brain endothelial cells, which subsequently released β-hexosaminidase enzyme. In vivo intravenous administration of the gene vectors to adult and neonatal mice prolonged survival. They improved neurological function and reduced accumulation of the ganglioside GM2 and the glycolipid GA2 as well as astrocytic activation. Overall, the data demonstrate that endothelial cells are a suitable target for intravenous gene therapy of GM2 gangliosidoses and possibly other lysosomal storage disorders.