Miracle-dz/UniFAR-FTUs huggingface dataset:
Adjuvant Imatinib in Patients with GIST Harboring Exon 9 KIT Mutations: Results from a Multi-institutional European Retrospective Study

Abstract Purpose: The effect of high-dose imatinib (800 mg/day) on survival in the adjuvant treatment of patients with resected KIT exon 9–mutated gastrointestinal stromal tumors (GIST) is not established. Here, the association of dose and other clinicopathologic variables with survival was evaluated in a large multi-institutional European cohort. Experimental Design: Data from 185 patients were retrospectively collected in 23 European GIST reference centers. Propensity score matching (PSM) and inverse-probability of treatment weighting (IPTW) were used to account for confounders. Univariate and multivariate unweighted and weighted Cox proportional hazard regression models were estimated for relapse-free survival (RFS), modified-RFS (mRFS) and imatinib failure-free survival (IFFS). Univariate Cox models were estimated for overall survival. Results: Of the 185 patients, 131 (70.8%) received a starting dose of 400 mg/d and the remaining 54 (29.2%) a dose of 800 mg/d. Baseline characteristics were partially unbalanced, suggesting a potential selection bias. PSM and IPTW analyses showed no advantage of imatinib 800 mg/d. In the weighted multivariate Cox models, high-dose imatinib was not associated with the survival outcomes [RFS: hazard ratio (HR), 1.24; 95% confidence interval (CI), 0.79–1.94; mRFS: HR, 1.69; 95% CI, 0.92–3.10; IFFS: HR, 1.35; 95% CI, 0.79–2.28]. The variables consistently associated with worse survival outcomes were high mitotic index and nongastric tumor location. Conclusions: In this retrospective series of patients with KIT exon 9–mutated GIST treated with adjuvant imatinib, a daily dose of 800 mg versus 400 mg did not show better results in terms of survival outcomes. Prospective evaluation of the more appropriate adjuvant treatment in this setting is warranted.
Complete Genome Sequence of Infectious Bronchitis Virus Strain JP/KH/64, Isolated in Japan

Here, we report the complete genome sequence of infectious bronchitis virus (IBV) strain JP/KH/64, which is the reference strain for the JP-I genotype in Japan. This information should be useful for an in-depth understanding of the evolution of the JP-I genotype. ABSTRACT Here, we report the complete genome sequence of infectious bronchitis virus (IBV) strain JP/KH/64, which is the reference strain for the JP-I genotype in Japan. This information should be useful for an in-depth understanding of the evolution of the JP-I genotype.
Context Matters: Stress for Minority Students Who Attend Minority-Majority Universities

Research on college student stress has typically focused on institutions where the student population is predominately White and continuing-generation. This study explored student stress in a unique context—a public regional university where the majority of students are Latinx, first-generation (FGCS), and of low socioeconomic status (SES). Of the 355 participants in the study, 72.4% self-identified as Latinx and 59.7% were FGCS. Additionally, on a subjective scale of socioeconomic status (1 = lowest, 10 = highest), the mean response was 5.76 (SD = 1.56). Participants (18 years old or older) who were enrolled in a first-year seminar course were recruited for this study. Through an online survey during Fall 2018, first-year students reported levels of perceived and experienced stress related to academic, economic, intrapersonal, and interpersonal concerns. Results of regression analyses indicated that most types of stress were predicted by students’ Latinx identity status and SES; FGCS status did not significantly predict stress. These findings highlight the need to explore solutions to address stress for Latinx and/or low SES students. Additionally, the study underscores the necessity of conducting research at educational institutions in which Latinx, FGC, and low SES students comprise the majority of the student body.
Communication Between Schools Nurses and Health Care Providers on Students with Asthma: An Integrative Review

School-based asthma programs have been proven to lessen the burden of pediatric asthma. There is a lack of successful care coordination between school nurses and primary care providers. This review examined strategies to increase communication and identified gaps in the literature. Databases, including PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Embase, and The Cochrane Library, were searched to identify relevant articles. This review included 12 articles consisting of randomized controlled trials, quasi-experimental studies, mixed method studies, qualitative studies, and other non-research articles. Four key findings emerged, including limited availability of asthma action plans, inclusion of parents in the communication triad, school nurse outreach to providers, and improved communication leads to positive outcomes for students with asthma including decreased use of emergency medication and increased self-management of asthma. Further research is needed to develop evidence-based interventions that can be implemented to improve communication between school nurses and primary care providers
Behaviour of Motor Units during Submaximal Isometric Contractions in Chronically Strength-Trained individuals.

Neural and morphological adaptations combine to underpin the enhanced muscle strength following prolonged exposure to strength training, although their relative importance remains unclear. We investigated the contribution of motor unit (MU) behaviour and muscle size to submaximal force production in chronically strength-trained athletes (ST) vs. untrained controls (UT). Sixteen ST (age, 22.9±3.5 yr; training experience, 5.9±3.5 yr) and fourteen UT (age, 20.4±2.3 yr) performed maximal voluntary isometric force (MViF) and ramp contractions (at 15, 35, 50, 70%MViF) with elbow flexors, whilst high-density surface EMG (HDsEMG) was recorded from the biceps brachii (BB). Recruitment thresholds (RT) and discharge rates (DR) of MUs identified from the submaximal contractions were assessed. The neural drive-to-muscle gain was estimated from the relation between changes in force (ΔFORCE, i.e. muscle output) relative to changes in MU DR (ΔDR, i.e. neural input). BB maximum anatomical cross-sectional area (ACSAMAX) was also assessed by MRI. MViF (+64.8% vs. UT, P<0.001) and BB ACSAMAX (+71.9%, P<0.001) were higher in ST. Absolute MU RT was higher in ST (+62.6%, P<0.001), but occurred at similar normalized forces. MU DR did not differ between groups at the same normalized forces. The absolute slope of the ΔFORCE-ΔDR relationship was higher in ST (+66.9%, P=0.002), whereas it did not differ for normalized values. We observed similar MU behaviour between ST athletes and UT controls. The greater absolute force-generating capacity of ST for the same neural input, demonstrates that morphological, rather than neural, factors are the predominant mechanism for their enhanced force generation during submaximal efforts.
A replication-linked mutational gradient drives somatic mutation accumulation and influences germline polymorphisms and genome composition in mitochondrial DNA

Abstract Mutations in mitochondrial DNA (mtDNA) cause maternally inherited diseases, while somatic mutations are linked to common diseases of aging. Although mtDNA mutations impact health, the processes that give rise to them are under considerable debate. To investigate the mechanism by which de novo mutations arise, we analyzed the distribution of naturally occurring somatic mutations across the mouse and human mtDNA obtained by Duplex Sequencing. We observe distinct mutational gradients in G→A and T→C transitions delimited by the light-strand origin and the mitochondrial Control Region (mCR). The gradient increases unequally across the mtDNA with age and is lost in the absence of DNA polymerase γ proofreading activity. In addition, high-resolution analysis of the mCR shows that important regulatory elements exhibit considerable variability in mutation frequency, consistent with them being mutational ‘hot-spots’ or ‘cold-spots’. Collectively, these patterns support genome replication via a deamination prone asymmetric strand-displacement mechanism as the fundamental driver of mutagenesis in mammalian DNA. Moreover, the distribution of mtDNA single nucleotide polymorphisms in humans and the distribution of bases in the mtDNA across vertebrate species mirror this gradient, indicating that replication-linked mutations are likely the primary source of inherited polymorphisms that, over evolutionary timescales, influences genome composition during speciation.
Fabrication of chitosan–alginate nanospheres for controlled release of cartap hydrochloride

Insecticide cartap hydrochloride (C) was fabricated as nanospheres by a two-step method of ionic gelification and polyelectrolyte complexation of alginate (ALG) and chitosan (CS) to undermine its adverse effects on environment. Nanospheres were characterized by field emission scanning electron microscope, Fourier transform infrared spectra and x-ray diffraction. The size of cartap hydrochloride entrapped chitosan alginate nanospheres (C-CS-ALG nps) was in range of 107.58–173.07 nm. Cartap hydrochloride nanospheres showed encapsulation efficiency of 76.19% and were stable for 30 d at ambient temperature. Release of cartap from nanospheres fitted best with first order linear kinetics followed by Hixson and Higuchi model suggesting super case II transport release. With the application of such control release nanoformulations, it is possible to reduce the frequency of field application of insecticide due to its slow release to the target organism, which is economical as well as environmentally safe.
Association of Primate Veterinarians Cranial Implant Care for Nonhuman Primates in Biomedical Research.

Use of nonhuman primates (NHPs) in biomedical research may include performing cranial surgeries with chronic implantation of research devices. The Association of Primate Veterinarians (APV) supports the responsible use of NHPs in neurobiological research. Such research must meet specific criteria, such as the Institutional Animal Care and Use Committee (IACUC) review and approval, verification of the surgeon's skill and experience
Estimating the correlation between semi‐competing risk survival endpoints

Time‐to‐event, bivariate, semi‐competing risk data occur when a terminal event can censor a non‐terminal event, but not vice versa. There are potential correlations between these endpoints as they are measured on the same individual. However, traditional methods to estimate the correlations cannot be used directly due to the censoring of time‐to‐event endpoints. We develop methods using a copula‐based approach to study the dependence structures between the two survival endpoints. We use a variety of copulas to estimate the correlation between endpoints and to acknowledge different dependence structures. The estimated association parameter in the copula function is transformed into Spearman's rank correlation coefficient. We conduct a simulation study to evaluate the estimation from the proposed models along with the effects of misspecification of the copula functions and survival distributions. The proposed methods are applied to two real‐life data sets.
Diversification along a benthic to pelagic gradient contributes to fish diversity in the world's largest lake (Lake Baikal, Russia)

Insights into the generation of diversity in both plants and animals have relied heavily on studying speciation in adaptive radiations. Russia's Lake Baikal has facilitated a putative adaptive radiation of cottid fishes (sculpins), some of which are highly specialized to inhabit novel niches created by the lake's unique geology and ecology. Here, we test evolutionary relationships and novel morphological adaptation in a piece of this radiation: the Baikal cottid genus, Cottocomephorus, a morphologically derived benthopelagic genus of three described species. We used a combination of mitochondrial DNA and restriction site associated DNA sequencing from all Cottocomephorus species. Analysis of mitochondrial cytochrome b haplotypes was only able to two resolve two lineages: C. grewingkii and C. comephoroides/inermis. Phylogenetic inference, principal component analysis, and faststructure of genome‐wide SNPs uncovered three lineages within Cottocomephorus: C. comephoroides, C. inermis and C. grewingkii. We found recent divergence and admixture between C. comephoroides and C. inermis and deep divergence between these two species and C. grewingkii. Contrasting other fish radiations, we found no evidence of ancient hybridization among Cottocomephorus species. Digital morphology revealed highly derived pelagic phenotypes that reflect divergence by specialization to the benthopelagic niche in Cottocomephorus. Among Cottocomephorus species, we found evidence of ongoing adaptation to the pelagic zone. This pattern highlights the importance of speciation along a benthic‐pelagic gradient seen in Cottocomephorus and across other adaptive fish radiations.
The Gambling Disorders Identification Test (GDIT): Psychometric Evaluation of a New Comprehensive Measure for Gambling Disorder and Problem Gambling

The novel gambling disorder identification test (GDIT) was recently developed in an international Delphi and consensus process. In this first psychometric evaluation, gamblers (N = 603) were recruited from treatment- and support-seeking contexts (n = 79 and n = 185), self-help groups (n = 47), and a population sample (n = 292). Participants completed self-report measures, a GDIT retest (n = 499), as well as diagnostic semistructured interviews assessing gambling disorder (GD; n = 203). The GDIT showed excellent internal consistency reliability (α = .94) and test–retest reliability (6-16 days, intraclass correlation coefficient = 0.93). Confirmatory factor analysis yielded factor loadings supporting the three proposed GDIT domains of gambling behavior, gambling symptoms, and negative consequences. Receiver operator curves and clinical significance indicators were used to estimate GDIT cut-off scores in relation to recreational (<15) and problem gambling (15-19), any GD (≥20), mild GD (20-24), moderate GD (25-29), and severe GD (≥30). The GDIT can be considered a valid and reliable measure to identify and predict GD severity, as well as problem gambling. In addition, the GDIT improves content validity in relation to an international research agreement concerning features of gambling outcome measures, known as the Banff Consensus Agreement.
Aqueous extracts of lingonberry and blackberry leaves identified by high-content screening beneficially act on cholesterol metabolism.

Decreasing circulating low-density lipoprotein (LDL) cholesterol levels leads to decreased risk of cardiovascular diseases. Natural compounds are capable of lowering LDL cholesterol even better than lifestyle modifications or medications. To identify novel plant-derived compounds to lower plasma LDL cholesterol levels, we performed high-content screening based on the transcriptional activation of the promoter of the LDL receptor (LDLR). The identified hits were thoroughly validated in human hepatic cell lines in terms of increasing LDLR mRNA and protein levels, lowering cellular cholesterol levels and increasing cellular LDL uptake. By means of this incremental validation process in vitro, aqueous extracts prepared from leaves of lingonberries (Vaccinium vitis-idaea) as well as blackberries (Rubus fruticosus) were found to have effects comparable to lovastatin, a prototypic cholesterol-lowering drug. When applied in vivo in mice, both extracts induced subtle increases in hepatic LDLR expression. In addition, a significant increase in high-density lipoprotein (HDL) cholesterol was observed. Taken together, aqueous extracts from lingonberry or blackberry leaves were identified and characterized as strong candidates to provide cardiovascular protection.
Paeonol assists fluconazole and amphotericin B to inhibit virulence factors and pathogenicity of Candida albicans

Abstract This study aimed to evaluate the mono- and dual- antifungal activities of paeonol (PAE) and fluconazole (FLZ)/amphotericin B (AmB). To this end, the effects of PAE and FLZ/AmB on cell surface hydrophobicity, hydrolase activity, morphological transition were investigated in vitro and in a Galleria mellonella infection model. The results showed a relatively high minimum inhibitory concentration (MIC) and sessile MIC (SMIC) of PAE alone. However, compared with the single drug, the combined use of PAE and FLZ/AmB had a potent synergistic potential to inhibit the virulence factors for Candida. The concomitant use of two drugs was consistently more effective than either drug alone for increasing survival rate, decreasing the fungal burden, and alleviating the pathological features of G. mellonella infected by the fungus. Taken together, these findings demonstrate the anti-Candida effects of PAE plus FLZ/AmB and their potential to increase the sensitivity of C. albicans to FLZ/AmB of PAE.
Streamlined CRISPR genome engineering in wild-type bacteria using SIBR-Cas

Abstract CRISPR-Cas is a powerful tool for genome editing in bacteria. However, its efficacy is dependent on host factors (such as DNA repair pathways) and/or exogenous expression of recombinases. In this study, we mitigated these constraints by developing a simple and widely applicable genome engineering tool for bacteria which we termed SIBR-Cas (Self-splicing Intron-Based Riboswitch-Cas). SIBR-Cas was generated from a mutant library of the theophylline-dependent self-splicing T4 td intron that allows for tight and inducible control over CRISPR-Cas counter-selection. This control delays CRISPR-Cas counter-selection, granting more time for the editing event (e.g. by homologous recombination) to occur. Without the use of exogenous recombinases, SIBR-Cas was successfully applied to knock-out several genes in three wild-type bacteria species (Escherichia coli MG1655, Pseudomonas putida KT2440 and Flavobacterium IR1) with poor homologous recombination systems. Compared to other genome engineering tools, SIBR-Cas is simple, tightly regulated and widely applicable for most (non-model) bacteria. Furthermore, we propose that SIBR can have a wider application as a simple gene expression and gene regulation control mechanism for any gene or RNA of interest in bacteria.
Bacteriophage Twort protein Gp168 is a β-clamp inhibitor by occupying the DNA sliding channel

Abstract Bacterial chromosome replication is mainly catalyzed by DNA polymerase III, whose beta subunits enable rapid processive DNA replication. Enabled by the clamp-loading complex, the two beta subunits form a ring-like clamp around DNA and keep the polymerase sliding along. Given the essential role of β-clamp, its inhibitors have been explored for antibacterial purposes. Similarly, β-clamp is an ideal target for bacteriophages to shut off host DNA synthesis during host takeover. The Gp168 protein of phage Twort is such an example, which binds to the β-clamp of Staphylococcus aureus and prevents it from loading onto DNA causing replication arrest. Here, we report a cryo-EM structure of the clamp–Gp168 complex at 3.2-Å resolution. In the structure of the complex, the Gp168 dimer occupies the DNA sliding channel of β-clamp and blocks its loading onto DNA, which represents a new inhibitory mechanism against β-clamp function. Interestingly, the key residues responsible for this interaction on the β-clamp are well conserved among bacteria. We therefore demonstrate that Gp168 is potentially a cross-species β-clamp inhibitor, as it forms complex with the Bacillus subtilis β-clamp. Our findings reveal an alternative mechanism for bacteriophages to inhibit β-clamp and provide a new strategy to combat bacterial drug resistance.
Clinical features and diagnosis of multiple myeloma: a population-based cohort study in primary care

Objectives Patients with multiple myeloma (MM) experience significant delays in diagnosis due to non-specific symptomatology. The aim of this study was to characterise the frequency and timing of clinical features in the primary care setting prior to MM diagnosis. Design Population-based cohort study. Setting Electronic health records data of approximately 17 million patients (2006–2016) within the UK Clinical Practice Research Datalink. Participants Patients aged ≥18 years with newly diagnosed MM (NDMM), no history of solid tumours and ≥2 years registration in a primary care practice prior to MM diagnosis. Main outcome measures Clinical features and symptoms including bone pain, skeletal-related events (SREs), investigation and confirmation of MM diagnostic CRAB criteria (hyperCalcaemia, Renal impairment, Anaemia, Bone lesions) during the 2 years prior to MM diagnosis; time between symptom manifestation and/or relevant investigation and diagnosis of MM. Results Among 2646 patients with NDMM, 47.5% had a bone pain record during the 2-year period prior to MM diagnosis, mainly affecting the back. Regardless of baseline bone pain, investigations for serum calcium level were used in 36.4% of patients prior to MM diagnosis, followed by haemoglobin (65.6%) or renal function (74.1%). Median (Q1, Q3) time from first-recorded bone pain to MM diagnosis was 220 (80, 476) days. Median (Q1, Q3) time from first-recorded hypercalcaemia, renal impairment or anaemia to MM diagnosis was 23 (12, 46), 58 (17, 254) and 73 days (28, 232), respectively. An imaging investigation or referral for imaging was recorded for 60.0% of patients with bone pain/SRE and 32% without. Conclusions Nearly half of patients diagnosed with NDMM presented with bone pain approximately 7 months prior to MM diagnosis. Investigations to evaluate all CRAB criteria, including targeted imaging, were underused. Early recognition of myeloma clinical features and optimised use of investigations in primary care may potentially expedite MM diagnosis.
G3BP1 binds to guanine quadruplexes in mRNAs to modulate their stabilities

Abstract RNA guanine quadruplexes (rG4) assume important roles in post-transcriptional regulations of gene expression, which are often modulated by rG4-binding proteins. Hence, understanding the biological functions of rG4s requires the identification and functional characterizations of rG4-recognition proteins. By employing a bioinformatic approach based on the analysis of overlap between peaks obtained from rG4-seq analysis and those detected in >230 eCLIP-seq datasets for RNA-binding proteins generated from the ENCODE project, we identified a large number of candidate rG4-binding proteins. We showed that one of these proteins, G3BP1, is able to bind directly to rG4 structures with high affinity and selectivity, where the binding entails its C-terminal RGG domain and is further enhanced by its RRM domain. Additionally, our seCLIP-Seq data revealed that pyridostatin, a small-molecule rG4 ligand, could displace G3BP1 from mRNA in cells, with the most pronounced effects being observed for the 3′-untranslated regions (3′-UTR) of mRNAs. Moreover, luciferase reporter assay results showed that G3BP1 positively regulates mRNA stability through its binding with rG4 structures. Together, we identified a number of candidate rG4-binding proteins and validated that G3BP1 can bind directly with rG4 structures and regulate the stabilities of mRNAs.