Rhomboid proteases play a variety of physiological roles, but rhomboid protease inhibitors have been mostly developed for the E. coli model rhomboid GlpG. In this work, we screened different electrophilic scaffolds against the human mitochondrial rhomboid PARL and found 4-oxo-β-lactams as submicromolar inhibitors. Multifaceted computations suggest explanations for the activity at the molecular scale and provide models of covalently bound complexes. Together with the straightforward synthesis of the 4-oxo-β-lactam scaffold, this may pave the way toward selective, nonpeptidic PARL inhibitors.
- Publication type
- Journal Article MeSH
BACKGROUND: Acute kidney injury in deceased donors (D-AKI) is one of the common causes of donor kidney discard. The risk factors for D-AKI and its impact on kidney transplantation outcomes are not yet fully understood. METHODS: This single-center, retrospective cohort study included 388 donors referred between June 2021 and December 2022. D-AKI was defined and staged according to kidney disease: Improving global outcomes criteria, and donor clinical variables were analyzed to identify risk factors for D-AKI. Delayed graft function and estimated glomerular filtration rate (eGFR) at 6 mo were evaluated in 369 kidney grafts transplanted from donors with and without D-AKI. RESULTS: AKI was present in 171 deceased donors (44.1%), with 117 (30.2%) classified as AKI stage 1 and 54 (14%) as AKI stages 2 or 3. Donor history of hypertension (odds ratio [OR] 1.93; 95% confidence interval [CI], 1.21-3.10; P = 0.005), history of diabetes (OR 2.2; 95% CI, 1.21-3.98; P = 0.008), and anoxia as the cause of death (OR 2.61; 95% CI, 1.5-4.61; P < 0.001) were independently associated with an increased risk of D-AKI. Multivariable mixed models identified donor age (β -0.49; 95% CI, -0.71 to -0.28; P < 0.001) as the only independent risk factor for lower eGFR at 6 mo. D-AKI was not associated with delayed graft function or lower eGFR at 6 mo. CONCLUSIONS: Hypertension, diabetes, and anoxia as the cause of death were identified as risk factors for AKI in deceased donors. D-AKI should not be used as the sole criterion to assess the risk of poor graft outcomes. A broader range of donor variables should be considered when evaluating graft viability.
- Publication type
- Journal Article MeSH
Building reliable and robust quantitative structure-property relationship (QSPR) models is a challenging task. First, the experimental data needs to be obtained, analyzed and curated. Second, the number of available methods is continuously growing and evaluating different algorithms and methodologies can be arduous. Finally, the last hurdle that researchers face is to ensure the reproducibility of their models and facilitate their transferability into practice. In this work, we introduce QSPRpred, a toolkit for analysis of bioactivity data sets and QSPR modelling, which attempts to address the aforementioned challenges. QSPRpred's modular Python API enables users to intuitively describe different parts of a modelling workflow using a plethora of pre-implemented components, but also integrates customized implementations in a "plug-and-play" manner. QSPRpred data sets and models are directly serializable, which means they can be readily reproduced and put into operation after training as the models are saved with all required data pre-processing steps to make predictions on new compounds directly from SMILES strings. The general-purpose character of QSPRpred is also demonstrated by inclusion of support for multi-task and proteochemometric modelling. The package is extensively documented and comes with a large collection of tutorials to help new users. In this paper, we describe all of QSPRpred's functionalities and also conduct a small benchmarking case study to illustrate how different components can be leveraged to compare a diverse set of models. QSPRpred is fully open-source and available at https://github.com/CDDLeiden/QSPRpred .Scientific ContributionQSPRpred aims to provide a complex, but comprehensive Python API to conduct all tasks encountered in QSPR modelling from data preparation and analysis to model creation and model deployment. In contrast to similar packages, QSPRpred offers a wider and more exhaustive range of capabilities and integrations with many popular packages that also go beyond QSPR modelling. A significant contribution of QSPRpred is also in its automated and highly standardized serialization scheme, which significantly improves reproducibility and transferability of models.
- Publication type
- Journal Article MeSH
[This corrects the article DOI: 10.3389/fdgth.2024.1440986.].
- Publication type
- Published Erratum MeSH
BACKGROUND: Although evidence indicates that load carriage may have an influence on walking patterns, the specific impacts of progressively increased loads on spatial and temporal gait asymmetries remain underexplored. Therefore, the primary aim of this study was to examine whether an increased load carriage had an effect on spatiotemporal gait asymmetries among intervention police officers. METHODS: For the purpose of this study, 96 male intervention police officers were recruited and assessed under four load conditions: (i) "No load", (ii) "a 5 kg load", (iii) "a 25 kg load", and (iv) "a 45 kg load". Spatial and temporal gait parameters were measured using a pedobarographic platform (Zebris FDM). The spatial and temporal gait parameters, along with the ground reaction forces beneath different foot regions, were examined. The gait asymmetry for each parameter was calculated using the formula (xright - xleft)/0.5 × (xright + xleft)*100%, where "x" represents the numerical value of each parameter for the left and right sides of the body. RESULTS: The findings indicated no statistically significant differences in the spatiotemporal parameters, nor ground reaction force gait asymmetries between the left and right foot, during walking under a progressively increased load carriage. Additionally, the parameter values for both the left and right sides of the body remained consistent, with a high intercorrelation observed across all of the loading conditions. The gait speed and ground reaction forces, which served as covariates, did not significantly change the spatiotemporal gait asymmetries. CONCLUSIONS: In summary, this study demonstrates that an increased load carriage did not lead to a progressive rise in spatiotemporal gait asymmetries in professional intervention police officers. However, further examination using an advanced 3-D gait analysis and an assessment of physiological patterns and adaptations is recommended to identify and confirm the key factors influencing gait asymmetry.
- Publication type
- Journal Article MeSH
BACKGROUND: The updated Oslo Sports Trauma Research Questionnaire on Health Problems (OSTRC-H2) has been translated into a limited set of languages and lacks full validation of its new measures. PURPOSE: To (1) translate, cross-culturally adapt, and evaluate the measurement properties of the OSTRC-H2 for the Slovenian population and (2) investigate the construct validity for the severity score and time lost due to a health problem. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 3. METHODS: The OSTRC-H2 was translated from English to Slovenian (OSTRC-H2-SLO) according to international guidelines. A 15-week study was conducted among 188 elite athletes, with a test-retest performed in the 10th week. Internal consistency, reliability, content validity, feasibility, and potential ceiling effects were investigated. Internal consistency was measured using the Cronbach alpha coefficient, while reliability was measured with the intraclass correlation coefficient (ICC). Construct validity was measured with the Spearman rank correlation coefficient (rS). RESULTS: There was a 95% response rate and an 18% mean weekly prevalence of health problems. The OSTRC-H2-SLO showed excellent test-retest reliability (ICC, 0.94 [95% CI, 0.67-0.99]), with a Cronbach α of .93. A strong positive correlation was found between the OSTRC-H2-SLO severity score and days lost due to an acute injury (rS = 0.754), overuse injury (rS = 0.785), and illness (rS = 0.894) (P < .001 for all). Moderate to strong negative correlations were observed between severity score and total load (training and competition load in hours) as well as between days lost and total load (P < .001 for all). CONCLUSION: The OSTRC-H2-SLO was found to be valid, reliable, and well accepted among Slovenian athletes. The authors confirmed the questionnaire's construct validity and identified total load as an indicator of an increase in the severity score. REGISTRATION: NCT05471297 (ClinicalTrials.gov identifier).
- Publication type
- Journal Article MeSH
Ictal central apnoea is a feature of focal temporal seizures. It is implicated as a risk factor for sudden unexpected death in epilepsy (SUDEP). Here we study seizure-related apnoeas in two different models of experimental seizures, one chronic and one acute, in adult genetically-unmodified rats, to determine mechanisms of seizure-related apnoeas. Under general anaesthesia rats receive sensors for nasal temperature, hippocampal and/or neocortical potentials, and ECG or EMG for subsequent tethered video-telemetry. Tetanus neurotoxin (TeNT), injected into hippocampus during surgery, induces a chronic epileptic focus. Other implanted rats receive intraperitoneal pentylenetetrazol (PTZ) to evoke acute seizures. In chronically epileptic rats, convulsive seizures cause apnoeas (9.9 ± 5.3 s; 331 of 730 convulsive seizures in 15 rats), associated with bradyarrhythmias. Absence of EEG and ECG biomarkers exclude obstructive apnoeas. All eight TeNT-rats with diaphragm EMG have apnoeas with no evidence of obstruction, and have apnoea EMGs significantly closer to expiratory relaxation than inspiratory contraction during pre-apnoeic respiration, which we term "atonic diaphragm". Consistent with atonic diaphragm is that the pre-apnoeic nasal airflow is expiration, as it is in human ictal central apnoea. Two cases of rat sudden death occur. One, with telemetry to the end, reveals a lethal apnoea, the other only has video during the final days, which reveals cessation of breathing shortly after the last clonic epileptic movement. Telemetry following acute systemic PTZ reveals repeated seizures and seizure-related apnoeas, culminating in lethal apnoeas; ictal apnoeas are central - in 8 of 35 cases diaphragms initially contract tonically for 8.5 ± 15.0 s before relaxing, in the 27 remaining cases diaphragms are atonic throughout apnoeas. All terminal apnoeas are atonic. Differences in types of apnoea due to systemic PTZ in rats (mainly atonic) and mice (tonic) are likely species-specific. Certain genetic mouse models have apnoeas caused by tonic contraction, potentially due to expression of epileptogenic mutations throughout the brain, including in respiratory centres, in contrast with acquired focal epilepsies. We conclude that ictal apnoeas in the rat TeNT model result from atonic diaphragms. Relaxed diaphragms could be particularly helpful for therapeutic stimulation of the diaphragm to help restore respiration.
- MeSH
- Apnea physiopathology MeSH
- Diaphragm * physiopathology MeSH
- Chronic Disease MeSH
- Electroencephalography MeSH
- Rats MeSH
- Disease Models, Animal * MeSH
- Pentylenetetrazole toxicity MeSH
- Rats, Sprague-Dawley MeSH
- Muscle Relaxation physiology MeSH
- Tetanus Toxin toxicity MeSH
- Seizures * physiopathology MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
RATIONALE: Mescaline is a classical psychedelic compound with a phenylethylamine structure that primarily acts on serotonin 5-HT2A/C receptors, but also binds to 5-HT1A and 5-HT2B receptors. Despite being the first psychedelic ever isolated and synthesized, the precise role of different serotonin receptor subtypes in its behavioral pharmacology is not fully understood. OBJECTIVES: In this study, we aimed to investigate how selective antagonists of 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT1A receptors affect the behavioral changes induced by subcutaneous administration of mescaline (at doses of 10, 20, and 100 mg/kg) in rats. METHODS: We used adult male Wistar rats in all our experiments. We evaluated locomotor activity using the open field test, and assessed sensorimotor gating deficits by measuring prepulse inhibition (PPI) of acoustic startle reaction (ASR). RESULTS: While the highest dose of mescaline induced hyperlocomotion (p < 0.001), which almost all the other antagonists reversed (p < 0.05-0.001), the PPI deficits were selectively normalized by the 5-HT2A antagonist (p < 0.05-0.01). The 5-HT2C antagonist partially reversed the small PPI deficit induced by lower doses of mescaline (p = 0.0017). CONCLUSION: Our findings suggest that mescaline-induced changes in behavior are primarily mediated by the 5-HT2A receptor subtype, with less pronounced contributions from the 5-HT2C receptor. The other antagonists had limited effects.
- MeSH
- Serotonin 5-HT2 Receptor Antagonists pharmacology MeSH
- Serotonin Antagonists pharmacology MeSH
- Behavior, Animal * drug effects MeSH
- Hallucinogens pharmacology administration & dosage MeSH
- Rats MeSH
- Locomotion drug effects MeSH
- Mescaline * pharmacology MeSH
- Motor Activity drug effects MeSH
- Rats, Wistar * MeSH
- Prepulse Inhibition drug effects MeSH
- Receptor, Serotonin, 5-HT2A * metabolism drug effects MeSH
- Receptor, Serotonin, 5-HT2C * metabolism drug effects MeSH
- Reflex, Startle drug effects MeSH
- Dose-Response Relationship, Drug MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
The 37th International Conference on Antiviral Research (ICAR) was held in Gold Coast, Australia, May 20-24, 2024. ICAR 2024 featured over 75 presentations along with two poster sessions and special events, including those specifically tailored for trainees and early-career scientists. The meeting served as a platform for the exchange of cutting-edge research, with presentations and discussions covering novel antiviral compounds, vaccine development, clinical trials, and therapeutic advancements. A comprehensive array of topics in antiviral science was covered, from the latest breakthroughs in antiviral drug development to innovative strategies for combating emerging viral threats. The keynote presentations provided fascinating insight into two diverse areas fundamental to medical countermeasure development and use, including virus emergence at the human-animal interface and practical considerations for bringing antivirals to the clinic. Additional sessions addressed a variety of timely post-pandemic topics, such as the hunt for broad spectrum antivirals, combination therapy, pandemic preparedness, application of in silico tools and AI in drug discovery, the virosphere, and more. Here, we summarize all the presentations and special sessions of ICAR 2024 and introduce the 38th ICAR, which will be held in Las Vegas, USA, March 17-21, 2025.
- MeSH
- Antiviral Agents * therapeutic use pharmacology MeSH
- COVID-19 MeSH
- COVID-19 Drug Treatment MeSH
- Humans MeSH
- Drug Discovery MeSH
- Drug Development MeSH
- Vaccine Development MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Animals MeSH
- Publication type
- Congress MeSH
- Geographicals
- Australia MeSH
BACKGROUND: Subtle, prognostically important ECG features may not be apparent to physicians. In the course of supervised machine learning, thousands of ECG features are identified. These are not limited to conventional ECG parameters and morphology. We aimed to investigate whether neural network-derived ECG features could be used to predict future cardiovascular disease and mortality and have phenotypic and genotypic associations. METHODS: We extracted 5120 neural network-derived ECG features from an artificial intelligence-enabled ECG model trained for 6 simple diagnoses and applied unsupervised machine learning to identify 3 phenogroups. Using the identified phenogroups, we externally validated our findings in 5 diverse cohorts from the United States, Brazil, and the United Kingdom. Data were collected between 2000 and 2023. RESULTS: In total, 1 808 584 patients were included in this study. In the derivation cohort, the 3 phenogroups had significantly different mortality profiles. After adjusting for known covariates, phenogroup B had a 20% increase in long-term mortality compared with phenogroup A (hazard ratio, 1.20 [95% CI, 1.17-1.23]; P<0.0001; phenogroup A mortality, 2.2%; phenogroup B mortality, 6.1%). In univariate analyses, we found phenogroup B had a significantly greater risk of mortality in all cohorts (log-rank P<0.01 in all 5 cohorts). Phenome-wide association study showed phenogroup B had a higher rate of future atrial fibrillation (odds ratio, 2.89; P<0.00001), ventricular tachycardia (odds ratio, 2.00; P<0.00001), ischemic heart disease (odds ratio, 1.44; P<0.00001), and cardiomyopathy (odds ratio, 2.04; P<0.00001). A single-trait genome-wide association study yielded 4 loci. SCN10A, SCN5A, and CAV1 have roles in cardiac conduction and arrhythmia. ARHGAP24 does not have a clear cardiac role and may be a novel target. CONCLUSIONS: Neural network-derived ECG features can be used to predict all-cause mortality and future cardiovascular diseases. We have identified biologically plausible and novel phenotypic and genotypic associations that describe mechanisms for the increased risk identified.
- MeSH
- Time Factors MeSH
- Electrocardiography * MeSH
- Phenotype * MeSH
- Risk Assessment MeSH
- Cardiovascular Diseases diagnosis mortality genetics physiopathology MeSH
- Middle Aged MeSH
- Humans MeSH
- Neural Networks, Computer * MeSH
- Predictive Value of Tests * MeSH
- Prognosis MeSH
- Reproducibility of Results MeSH
- Risk Factors MeSH
- Aged MeSH
- Heart Rate MeSH
- Unsupervised Machine Learning MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
- Geographicals
- United States MeSH
