Miracle-dz/UniFAR-FTUs huggingface dataset:
Computational Investigation of Structural Basis for Enhanced Binding of Isoflavone Analogues with Mitochondrial Aldehyde Dehydrogenase

Isoflavone compounds are potent inhibitors against mitochondrial aldehyde dehydrogenase (ALDH2) for the treatment of alcoholism and drug addiction, and an in-depth understanding of the underlying structural basis helps design new inhibitors for enhanced binding. Here, we investigated the binding poses and strengths of eight isoflavone analogues (including CVT-10216 and daidzin) with ALDH2 via computational methods of molecular docking, molecular dynamics (MD) simulation, molecular mechanics Poisson–Boltzmann surface area (MM-PBSA), steered MD, and umbrella sampling. Neither the Vina scoring of docked and MD-sampled complexes nor the nonbonded protein–inhibitor interaction energy from MD simulations is able to reproduce the relative binding strength of the inhibitors compared to experimental IC50 values. Considering the solvation contribution, MM-PBSA and relatively expensive umbrella sampling yield good performance for the relative binding (free) energies. The isoflavone skeleton prefers to form π–π stacking, π–sulfur, and π–alkyl interactions with planar (Phe and Trp) or sulfur-containing (Cys and Met) residues. The enhanced inhibition of CVT-10216 originates from both end groups of the isoflavone skeleton offering strong van der Waals contacts and from the methylsulfonamide group at the 4′ position by hydrogen bonding (HB) with neighboring receptor residues. These results indicate that the hydrophobic binding tunnel of ALDH2 is larger than the isoflavone skeleton in length and thus an extended hydrophobic core is likely a premise for potent inhibitors.
Like I said, I would not have likely gotten up otherwise: patient experiences of using an Activity Board after abdominal cancer surgery

Abstract Purpose Most patients treated in a hospital setting are fully or partially immobilised. The Activity Board (Träningstavlan® Phystec) is a useful tool to enhance mobilisation after major abdominal cancer surgery. Knowledge of patient experiences of the mobilisation tool is crucial in implementing the Activity Board in health care. This study aimed to describe patient experiences of using the Activity Board after surgery for abdominal cancer. Materials and methods Semi-structured face-to-face interviews were conducted in 15 patients who underwent abdominal surgery due to colorectal, ovarian or urinary bladder cancer. All 15 patients (mean age 67.7 years, range 40–86) used the Activity Board postoperatively. The interviews were transcribed verbatim and analysed according to inductive content analysis. Results The overarching theme that emerged from the interviews was that “enabling participation facilitates empowerment over rehabilitation”. Three categories supported the theme: prerequisites for using the Activity Board, the value of using supportive behavioural techniques, and the possibility to influence the patients’ care. Conclusions These findings suggest that the Activity Board could be a viable tool that activates the person-centred postoperative rehabilitation process by cooperating with the medical team at the hospital ward. Implications for rehabilitation Patients who are in hospital due to cancer surgery are often immobilised, which increases the risk of complications. The Activity Board can stimulate the patients to participate in the rehabilitation process in a more active way. The Activity Board can be used to improve and clarify the person-centred approach in hospital settings.
Dose banding – Weighing up benefits, risks and therapeutic failure

Dose banding is a method of dose individualisation in which all patients with similar characteristics are allocated to the same dose. Dose banding results in some patients receiving less intensive treatment which risks a reduction in therapeutic benefit (iatrogenic therapeutic failure) because of variability not predicted by dose banding. This study aims to explore the effects of dose banding on therapeutic success and failure.
Bayesian adaptive randomization design incorporating propensity score‐matched historical controls

Incorporating historical control data to augment the control arm in randomized controlled trials (RCTs) is one way of increasing their efficiency and feasibility when adequate RCTs cannot be conducted. In recent work, a Bayesian adaptive randomization design incorporating historical control data has been proposed to reduce sample size according to the amount of information that could be borrowed, assessed at interim assessment in respect to prior‐data conflict. However, the approach does not distinguish between the two sources of prior‐data conflict: (1) imbalance in measured covariates, and (2) imbalance in unmeasured covariates. In this paper, we propose an extension of the Bayesian adaptive randomization design to incorporate propensity score‐matched historical controls. At interim assessment, historical controls similar to the concurrent controls in terms of measured covariates are selected using propensity score matching. Then, final sample size of the control arm is adjusted according to the extent of borrowing from the matched historical controls quantified by effective historical sample size. The conditional power prior approach and commensurate prior approach are adopted for designing the prior, and addressing prior‐data conflict due to unmeasured covariate imbalance. Simulation results show that the proposed method yields reduced bias in treatment effect estimates, type I error at the nominal level, and reduced sample size while maintaining statistical power. Even when residual imbalance exists due to unmeasured covariates, the proposed method borrowed more information without risking substantially inflated type I error and bias, providing meaningful implications for use of historical controls to facilitate the conduct of adequate RCTs.
Strong Parallel Differential Gene Expression Induced by Hatchery Rearing Weakly Associated with Methylation Signals in Adult Coho Salmon (O. kisutch)

Abstract Human activities and resource exploitation led to a massive decline of wild salmonid populations, consequently, numerous conservation programs have been developed to supplement wild populations. However, many studies documented reduced fitness of hatchery-born relative to wild fish. Here, by using both RNA sequencing and Whole Genome Bisulfite Sequencing of hatchery and wild-born adult Coho salmon (Oncorhynchus kisutch) originating from two previously studied river systems, we show that early-life hatchery-rearing environment-induced significant and parallel gene expression differentiation is maintained until Coho come back to their natal river for reproduction. A total of 3,643 genes differentially expressed and 859 coexpressed genes were downregulated in parallel in hatchery-born fish from both rivers relative to their wild congeners. Among those genes, 26 displayed a significant relationship between gene expression and the median gene body methylation and 669 single CpGs displayed a significant correlation between methylation level and the associated gene expression. The link between methylation and gene expression was weak suggesting that DNA methylation is not the only player in mediating hatchery-related expression differences. Yet, significant gene expression differentiation was observed despite 18 months spent in a common environment (i.e., the sea). Finally, the differentiation is observed in parallel in two different river systems, highlighting the fact that early-life environment may account for at least some of the reduced fitness of the hatchery salmon in the wild. These results illustrate the relevance and importance of considering both epigenome and transcriptome to evaluate the costs and benefits of large-scale supplementation programs.
Use of evidence‐based therapy in heart failure with reduced ejection fraction across age strata

In older patients, guideline‐directed medical therapy (GDMT) for heart failure (HF) with reduced ejection fraction (<40%; HFrEF) is not contraindicated, but adherence to guidelines is limited. We investigated the implementation of GDMT in HFrEF across different age strata in a large nationwide cohort.
Unsupervised and Semi-Supervised Robust Spherical Space Domain Adaptation

Adversarial domain adaptation has been an effective approach for learning domain-invariant features by adversarial training. In this paper, we propose a novel adversarial domain adaptation approach defined in the spherical feature space, in which we define spherical classifier for label prediction and spherical domain discriminator for discriminating domain labels. In the spherical feature space, we develop a spherical robust pseudo-label loss to utilize pseudo-labels robustly, which weights the importance of the estimated labels of target domain data by the posterior probability of correct labeling, modeled by the Gaussian-uniform mixture model in the spherical space. Our proposed approach can be generally applied to both unsupervised and semi-supervised domain adaptation settings. In particular, to tackle the semi-supervised domain adaptation setting where a few labeled target domain data are available for training, we propose a novel reweighted adversarial training strategy for effectively reducing the intra-domain discrepancy within the target domain. We also present theoretical analysis for the proposed method based on the domain adaptation theory. Extensive experiments are conducted on multiple benchmarks for object recognition, digit recognition, and face recognition. The results show that our method either surpasses or is competitive compared with the recent methods for both unsupervised and semi-supervised domain adaptation. Ablation studies also confirm the effectiveness of the spherical classifier, spherical discriminator, spherical robust pseudo-label loss, and reweighted adversarial training strategy.
Performance of chromoendoscopy and narrow-band imaging in the diagnosis of gastric intestinal metaplasia

Abstract Background/Aims Chromoendoscopy and narrow-band imaging (NBI) have been reported to aid in the diagnosis of gastric intestinal metaplasia (GIM). This study aimed to assess the diagnostic validity of chromoendoscopy combined with NBI in the diagnosis of GIM in Vietnamese. Methods A cross-sectional study was carried out on patients with dyspeptic symptoms who underwent esophagogastroduodenoscopy (EGD) at the University Medical Center at Ho Chi Minh City. We compared the detection rates of GIM in the group of patients examined with white-light endoscopy (WLE) alone and those examined with WLE in combination with chromoendoscopy and NBI. Results A total of 374 patients have been recruited. The additional GIM detection rate after chromoendoscopy combined with NBI was 8.6% (95% confidence interval [CI]: 4.3 − 12.8), p < . 005. The rate of GIM within the group of patients biopsied under the guidance of chromoendoscopy combined with NBI was statistically significantly higher than in the group with WLE alone with a distinct rate of 14.4% (95% CI: 6.3 − 2.6), p = . 001. Conclusions Chromoendoscopy combined with NBI helped to detect the GIM lesions missed by WLE and was a more reliable endoscopic method for the diagnosis of GIM.
Injury severity analysis of two-vehicle crashes at unsignalized intersections using mixed logit models

Abstract The severity of the two-vehicle crash is closely related to the characteristics of both the struck and striking vehicles. Ignoring vehicle roles may lead to biased results. Thus, this study used mixed logit models to determine the factors that influence injury severity in the two-vehicle crash, taking into account the vehicle characteristics of the different crash roles. The data used is collected from Pennsylvania Department of Transportation (PennDOT) Open Data Portal. First, the synthetic minority oversampling technique and nearest neighbors (SMOTE-ENN) strategy was selected to address the class imbalance problem of crash data. Then, two separated mixed logit models were developed for four- and three-legged unsignalized intersections. The results suggest that the type and movement of vehicles have significant effects on crash severity. For example, right-turn vehicles being struck can lead to more serious crashes than striking other vehicles. Large trucks striking other vehicles are found to increase crash severity, but being struck is found to decrease crash severity. Additionally, several factors were also identified to affect crash severity in both models and effective countermeasures suggestions were proposed to mitigate crash severity. Supplemental data for this article is available online at at .
Characterization of glutamate‐cysteine ligase and glutathione synthetase from the δ‐proteobacterium Myxococcus xanthus

Glutathione (GSH) is synthesized in two ATP‐dependent reactions by glutamate‐cysteine ligase (Gcl) and glutathione synthetase (Gs). Myxococcus xanthus, a gram‐negative bacterium belonging to δ‐proteobacteria, possesses mxGcl and mxGs, which have high sequence identity with the enzymes from plants and bacteria, respectively. MxGcl2 was activated by Mn2+, but not by Mg2+, and stabilized in the presence of 5 mM Mn2+ or Mg2+. Sequence comparison of mxGcl2 and Brassica juncea Gcl indicated that they have the same active site residues, except for Tyr330, which interacts with Cys and which in mxGcl2 is represented by Leu267. The substitution of Leu267 with Tyr resulted in the loss of mxGcl2 activity, but that with Met (found in cyanobacterial Gcls) increased the mxGcl2 affinity for Cys. GSH and its oxidized form GSSG equally inhibited the activity of mxGcl2; the inhibition was augmented by ATP at concentrations >3 mM. Buthionine sulfoximine inactivated mxGcl2 with Ki = 2.1 μM, which was lower than those for Gcls from other organisms. The mxGcl2 activity was also suppressed by pyrophosphate and polyphosphates. MxGs was a dimer, and its activity was induced by Mg2+ but strongly inhibited by Mn2+ even in the presence of 10 mM Mg2+. MxGs was inhibited by GSSG at Ki = 3.6 mM. Approximately 1 mM GSH was generated with 3 units of mxGcl2 and 6 units of mxGs from 5 mM Glu, Cys, and Gly, and 10 mM ATP. Our results suggest that GSH production in M. xanthus mostly depends on mxGcl2 activity.
Factors associated with intraoperative intravenous catheter extravasation in children

Summary This retrospective study aimed to determine the incidence of and factors associated with peripheral intravenous extravasation in paediatric patients in the intraoperative setting. We conducted a retrospective study of 56,777 patients who underwent general anaesthesia and had peripheral intravenous catheter placement at Cincinnati Children’s Hospital between 1 January 2015 and 1 January 2017. Data collected included age, American Society of Anesthesiologists Physical Status Classification, catheter site, number of cannulation attempts, ultrasound use for cannulation, surgery duration, and surgery class. Primary outcome was peripheral intravenous extravasation using an extravasation assessment tool. Some 64,814 peripheral venous catheters were placed in patients undergoing general anaesthesia. Significant extravasation was documented in 40 catheters with an estimated incidence of 1 in 1620 venous catheters (0.06%). Of those 40 catheters, 47.5% (n = 19) were placed using ultrasound and 37.5% (n = 15) required more than one cannulation attempt. In multivariable analysis, peripheral intravenous catheter extravasation was associated with American Society of Anesthesiologists Physical Status Classification (3, 4, 5) versus (1, 2) (odds ratio 2.42 (95% CI 1.08 to 5.41)), inpatient versus outpatient surgeries (odds ratio 2.99 (95% CI 1.31 to 6.81)), and intravenous catheters placed with ultrasound guidance (odds ratio 8.01 (95% CI 4.12 to 15.57)). Our study identified factors associated with intraoperative peripheral intravenous extravasation, and will help develop mitigation strategies to minimise harm to patients.
Quantification of Microbial Robustness in Yeast

Stable cell performance in a fluctuating environment is essential for sustainable bioproduction and synthetic cell functionality; however, microbial robustness is rarely quantified. Here, we describe a high-throughput strategy for quantifying robustness of multiple cellular functions and strains in a perturbation space. We evaluated quantification theory on experimental data and concluded that the mean-normalized Fano factor allowed accurate, reliable, and standardized quantification. Our methodology applied to perturbations related to lignocellulosic bioethanol production showed that the industrial bioethanol producing strain Saccharomyces cerevisiae Ethanol Red exhibited both higher and more robust growth rates than the laboratory strain CEN.PK and industrial strain PE-2, while a more robust product yield traded off for lower mean levels. The methodology validated that robustness is function-specific and characterized by positive and negative function-specific trade-offs. Systematic quantification of robustness to end-use perturbations will be important to analyze and construct robust strains with more predictable functions.
Cardiac arrest and coronavirus disease 2019

Purpose of review The impact of the coronavirus disease 2019 (COVID-19) on the cardiovascular system has been highlighted since the very first weeks after the severe acute respiratory syndrome coronavirus 2 identification. We reviewed the influence of COVID-19 pandemic on cardiac arrest, both considering those occurred out of the hospital (OHCA) and in the hospital (IHCA). Recent findings An increase in OHCA incidence occurred in different countries, especially in those regions most burdened by the COVID-19, as this seems to be bounded to the pandemic trend. A change of OHCA patients’ characteristics, with an increase of the OHCA occurred at home, a decrease in bystander cardiopulmonary resuscitation and automated external defibrillator use before Emergency Medical Service (EMS) arrival and an increase in non-shockable rhythms, have been highlighted. A dramatic drop in the OHCA patients’ survival was pointed out in almost all the countries, regardless of the high or low-incidence of COVID-19 cases. Concerning IHCA, a reduction in survival was highlighted in patients with COVID-19 who sustained a cardiac arrest. Summary Cardiac arrest occurrence and survival were deeply affected by the pandemic. Informative campaigns to the population to call EMS in case of need and the re-allocation of the prehospital resources basing on the pandemic trend are needed to improve survival.
Analysis of HIV‐1 integrase genotypes and polymorphisms among integrase inhibitors‐based antiretroviral treatment naïve patients in South Sudan

HIV‐1 genetic diversity and drug resistance mutations remain public health challenges especially in regions where treatment is limited. The aim of this study was to characterize the HIV‐1 integrase (IN) subtype and the possible occurrence of drug‐resistance mutations or polymorphisms in resource‐poor settings in South Sudan. Dried blood spots from integrase inhibitor treatment (Integrase strand transfer inhibitor [INSTI]) naïve HIV‐1 infected patients were subjected to DNA amplification and direct sequencing of integrase genes. The sequences were interpreted for drug resistance according to the Stanford algorithm and the International AIDS Society‐USA guidelines. Phylogenetic analysis revealed that HIV‐1 subtype D, C, G, A1, and recombinant forms accounted for 40%, 10%, 13.3%, 23.4%, and 13.3%, respectively. Furthermore, inter‐subtype recombinants were interspersed within viral strains sampled in other African countries, highlighting complex transmission dynamics within a mobile host population. A total of 78 of 288 (27%) amino acid IN positions presented at least one polymorphism each. Major INSTI resistance mutations were absent, however, polymorphic accessory mutations at positions M50ILR (26.6%) and L74I (3.3%) were detected. Despite the limited size of the study population, our findings underscore the need for monitoring minor and natural polymorphisms that may influence the outcome of treatment regimens.
The maturity status but not the relative age influences elite young football players’ physical performance

ABSTRACT Talent identification and selection process in young football is based on coaches’ decisions regarding the players’ performance at early ages. The aim of this study was to show how the maturity status and the relative age impact on young football players’ physical performance and their coaches’ efficacy expectations. The physical performance (1RM, Peak power output [PPO], 30-m sprint and t-test) of 118 young football players (U13 to U15; and their coaches’ efficacy expectations were assessed. Relative age was calculated according to the players’ date of birth within their selection year. The maturity status was estimated as the years from/to their peak height velocity (PHV). Linear regression analyses showed a significant relationship between players’ physical performance and their maturity status but not with their relative age. In contrast, the maturity status of players only was associated to the coaches’ efficacy expectations in the 1RM and PPO tests, whereas the relative age was a predictor of the coaches’ expectations about players’ performance in the t-test. These findings may be important for coaches and managers in young football academies since inter-individual differences in the maturity status but not in the relative age are related to physical performance despite the coaches’ expectations.
Immune-Desert Tumor Microenvironment in Thoracic SMARCA4-Deficient Undifferentiated Tumors with Limited Efficacy of Immune Checkpoint Inhibitors

Abstract Background Thoracic SMARCA4-deficient undifferentiated tumors (SMARCA4-UT) are aggressive neoplasms. Data linking BAF alterations with tumor microenvironment (TME) and efficacy of immune checkpoint inhibitors (ICI) are contradictory. The TME of SMARCA4-UT and their response to ICI are unknown. Materials and Methods Patients diagnosed with SMARCA4-UT in our institution were included. Immunostainings for tertiary lymphoid structures (TLS), immune cell markers, and checkpoints were assessed. Validation was performed using an independent transcriptome dataset including SMARCA4-UT, non–small cell lung cancers (NSCLC) with/without SMARCA4 mutations, and unclassified thoracic sarcomas (UTS). CXCL9 and PD-L1 expressions were assessed in NSCLC and thoracic fibroblast cell lines, with/without SMARCA4 knockdown, treated with/without interferon gamma. Results Nine patients were identified. All samples but one showed no TLS, consistent with an immune desert TME phenotype. Four patients received ICI as part of their treatment, but the only one who responded, had a tumor with a TLS and immune-rich TME. Unsupervised clustering of the validation cohort using immune cell scores identified 2 clusters associated with cell ontogeny and immunity (cluster 1 enriched for NSCLC independently of SMARCA4 status (n = 9/10; P = .001); cluster 2 enriched for SMARCA4-UT (n = 11/12; P = .005) and UTS (n = 5/5; P = .0005). SMARCA4 loss-of-function experiments revealed interferon-induced upregulation of CXCL9 and PD-L1 expression in the NSCLC cell line with no effect on the thoracic fibroblast cell line. Conclusion SMARCA4-UT mainly have an immune desert TME with limited efficacy to ICI. TME of SMARCA4-driven tumors varies according to the cell of origin questioning the interplay between BAF alterations, cell ontogeny and immunity.