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Objectives: As a large language model (LLM) trained on a large data set, ChatGPT can perform a wide array of tasks without additional training. We evaluated the performance of ChatGPT on postgraduate UK medical examinations through a systematic literature review of ChatGPT's performance in UK postgraduate medical assessments and its performance on Member of Royal College of Physicians (MRCP) Part 1 examination., Methods: Medline, Embase and Cochrane databases were searched. Articles discussing the performance of ChatGPT in UK postgraduate medical examinations were included in the systematic review. Information was extracted on exam performance including percentage scores and pass/fail rates. MRCP UK Part 1 sample paper questions were inserted into ChatGPT-3.5 and -4 four times each and the scores marked against the correct answers provided., Results: 12 studies were ultimately included in the systematic literature review. ChatGPT-3.5 scored 66.4% and ChatGPT-4 scored 84.8% on MRCP Part 1 sample paper, which is 4.4% and 22.8% above the historical pass mark respectively. Both ChatGPT-3.5 and -4 performance was significantly above the historical pass mark for MRCP Part 1, indicating they would likely pass this examination. ChatGPT-3.5 failed eight out of nine postgraduate exams it performed with an average percentage of 5.0% below the pass mark. ChatGPT-4 passed nine out of eleven postgraduate exams it performed with an average percentage of 13.56% above the pass mark. ChatGPT-4 performance was significantly better than ChatGPT-3.5 in all examinations that both models were tested on., Conclusion: ChatGPT-4 performed at above passing level for the majority of UK postgraduate medical examinations it was tested on. ChatGPT is prone to hallucinations, fabrications and reduced explanation accuracy which could limit its potential as a learning tool. The potential for these errors is an inherent part of LLMs and may always be a limitation for medical applications of ChatGPT., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Vij et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

PKM2 is a rate-limiting enzyme in the glycolytic process and is involved in regulating tumor proliferation. Several amino acids (AAs) such as Asn, Asp, Val, and Cys have been shown to bind to the AA binding pocket of PKM2 and modulate its oligomeric state, substrate binding affinity, and activity. Although previous studies have attributed that the main chain and side chain of bound AAs are responsible for initiating signal to regulate PKM2, the signal transduction pathway remains elusive. To identify the residues involved in signal transfer process, N70 and N75 located at two ends of a β strand connecting the active site and AA binding pocket were altered. Biochemical studies of these variants with various AA ligands (Asn, Asp, Val, and Cys), illustrate that N70 and N75, along with β1 connecting these residues are part of the signal transduction pathway between the AA binding pocket and the active site. The results demonstrate that mutation of N70 to D prevents the transfer of the inhibitory signal mediated by Val and Cys, whereas N75 to L alteration blocks the activating signal initiated by Asn and Asp. Taken together, this study confirms that N70 is one of the residues responsible for transmitting the inhibitory signal and N75 is involved in the activation signal flow., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Nandi, Dey. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

MammoWave is a microwave imaging device for breast lesion detection, employing two antennas which rotate azimuthally (horizontally) around the breast. The antennas operate in the 1-9 GHz band and are set in free space, i.e., pivotally, no matching liquid is required. Microwave images, subsequently obtained through the application of Huygens Principle, are intensity maps, representing the homogeneity of the dielectric properties of the breast tissues under test. In this paper, MammoWave is used to realise tissues dielectric differences and localise lesions by segmenting microwave images adaptively employing pulse coupled neural network (PCNN). Subsequently, a non-parametric thresholding technique is modelled to differentiate between breasts having no radiological finding (NF) or benign (BF) and breasts with malignant finding (MF). Resultant findings verify that automated breast lesion localization with microwave imaging matches the gold standard achieving 81.82% sensitivity in MF detection. The proposed method is tested on microwave images acquired from a feasibility study performed in Foligno Hospital, Italy. This study is based on 61 breasts from 35 patients; performance may vary with larger number of datasets and will be subsequently investigated., Competing Interests: Lorenzo Sani, Alessandro Vispa and Giovanni Raspa are employed by UBT - Umbria Bioengineering Technologies. Gianluigi Tiberi and Lorenzo Sani are shareholders of UBT - Umbria Bioengineering Technologies. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Previous research on public stigma towards people with mental disorders has mostly targeted adult samples and focused on depression, schizophrenia or mental disorders in general. Hence, the present study aimed to investigate predictors of stigmatizing attitudes towards different mental disorders (including less researched ones) in a representative sample of adolescents and young adults., Methods: Data from the Swiss Youth Mental Health Literacy and Stigma Survey were used (analytical sample: n = 4,932). Each participant was randomly presented with one of five vignettes (depression; alcohol abuse; depression and alcohol abuse combined; schizophrenia; social anxiety). The structure of stigmatizing attitudes was assessed using confirmatory factor analysis. Regression models, implemented within a structural equation framework, were used to study predictors for the identified latent variables., Results: A three-factor model for stigmatizing attitudes-consisting of 'dangerous/unpredictable', 'weak-no-sick', and 'social distance' factors-best fitted the data. Female gender was associated with less stigmatizing attitudes. Associations in opposite directions with different latent factors were found for educational and migration background. Exposure to mental disorders (being personally affected, personally having received professional help or knowing someone close who has received treatment for a mental disorder) was either not or was negatively associated with stigmatizing attitudes. In contrast, current mental health symptoms (heightened levels of psychological distress, problematic alcohol use) were generally not or were positively associated with stigmatizing attitudes. Even though the included predictors had some predictive value, the variance explained by the models was rather small (the adjusted R2 varied between 0.03 and 0.26)., Conclusions: The current study indicates that contact with someone who has received treatment for a mental disorder might be an important component of programs aiming to decrease stigmatizing attitudes towards people with mental disorders, since this exposure variable predicted lower levels of stigmatizing attitudes. Furthermore, the findings suggest that target-group interventions for specific subgroups need to be considered, as the process leading to stigmatizing attitudes towards people with mental disorders appears to differ between specific sociodemographic subgroups., Competing Interests: The authors have declared that no competing interests exist.

The osmolyte dimethylsulfoniopropionate (DMSP) is a key nutrient in marine environments and its catabolism by bacteria through enzymes known as DMSP lyases generates dimethylsulfide (DMS), a gas of importance in climate regulation, the sulfur cycle, and signaling to higher organisms. Despite the environmental significance of DMSP lyases, little is known about how they function at the mechanistic level. In this study we biochemically characterize DddW, a DMSP lyase from the model roseobacter Ruegeria pomeroyi DSS-3. DddW is a 16.9 kDa enzyme that contains a C-terminal cupin domain and liberates acrylate, a proton, and DMS from the DMSP substrate. Our studies show that as-purified DddW is a metalloenzyme, like the DddQ and DddP DMSP lyases, but contains an iron cofactor. The metal cofactor is essential for DddW DMSP lyase activity since addition of the metal chelator EDTA abolishes its enzymatic activity, as do substitution mutations of key metal-binding residues in the cupin motif (His81, His83, Glu87, and His121). Measurements of metal binding affinity and catalytic activity indicate that Fe(II) is most likely the preferred catalytic metal ion with a nanomolar binding affinity. Stoichiometry studies suggest DddW requires one Fe(II) per monomer. Electronic absorption and electron paramagnetic resonance (EPR) studies show an interaction between NO and Fe(II)-DddW, with NO binding to the EPR silent Fe(II) site giving rise to an EPR active species (g = 4.29, 3.95, 2.00). The change in the rhombicity of the EPR signal is observed in the presence of DMSP, indicating that substrate binds to the iron site without displacing bound NO. This work provides insight into the mechanism of DMSP cleavage catalyzed by DddW.

Thioredoxins are small soluble proteins that contain a redox-active disulfide (CXXC). These disulfides are tuned to oxidizing or reducing potentials depending on the function of the thioredoxin within the cell. The mechanism by which the potential is tuned has been controversial, with two main hypotheses: first, that redox potential (Em) is specifically governed by a molecular 'rheostat'-the XX amino acids, which influence the Cys pKa values, and thereby, Em; and second, the overall thermodynamics of protein folding stability regulates the potential. Here, we use protein film voltammetry (PFV) to measure the pH dependence of the redox potentials of a series of wild-type and mutant archaeal Trxs, PFV and glutathionine-equilibrium to corroborate the measured potentials, the fluorescence probe BADAN to measure pKa values, guanidinium-based denaturation to measure protein unfolding, and X-ray crystallography to provide a structural basis for our functional analyses. We find that when these archaeal thioredoxins are probed directly using PFV, both the high and low potential thioredoxins display consistent 2H+:2e- coupling over a physiological pH range, in conflict with the conventional 'rheostat' model. Instead, folding measurements reveals an excellent correlation to reduction potentials, supporting the second hypothesis and revealing the molecular mechanism of reduction potential control in the ubiquitous Trx family.

Objective: The present study aimed to measure the prevalence of adult attention deficit hyperactivity disorder (ADHD) in a large, representative sample of young Swiss men and to assess factors associated with this disorder., Methods: Our sample consisted of 5656 Swiss men (mean age 20 years) who participated in the Cohort Study on Substance Use Risk Factors (C-SURF). ADHD was assessed with the World Health Organization (WHO) adult ADHD Self Report Screener (ASRS). Logistic regression analyses were conducted to assess the association between ADHD and several socio-demographic, clinical and familial factors., Results: The prevalence of ADHD was 4.0%, being higher in older and French-speaking conscripts. A higher prevalence also was identified among men whose mothers had completed primary or high school/university and those with a family history of alcohol or psychiatric problems. Additionally, adults with ADHD demonstrated impairment in their professional life, as well as considerable mental health impairment., Conclusion: Our results demonstrate that ADHD is common among young Swiss men. The impairments in function and mental health we observed highlight the need for further support and interventions to reduce burden in affected individuals. Interventions that incorporate the whole family also seem crucial.

Effective treatments for cancer are still needed, both for cancers that do not respond well to current therapeutics and for cancers that become resistant to available treatments. Herein we investigated the effect of a structure-selective d-amino acid peptide wrwycr that binds replication fork mimics and Holliday Junction (HJs) intermediates of homologous recombination (HR) in vitro, and inhibits their resolution by HJ-processing enzymes. We predicted that treating cells with HJ-binding compounds would lead to accumulation of DNA damage. As cells repair endogenous or exogenous DNA damage, collapsed replication forks and HJ intermediates will accumulate and serve as targets for the HJ-binding peptides. Inhibiting junction resolution will lead to further accumulation of DNA breaks, eventually resulting in amplification of the damage and causing cell death. Both peptide wrwycr and the related wrwyrggrywrw entered cancer cells and reduced cell survival in a dose- and time-dependent manner. Early markers for DNA damage, γH2AX foci and 53BP1 foci, increased with dose and/or time exposure to the peptides. DNA breaks persisted at least 48 h, and both checkpoint proteins Chk1 and Chk2 were activated. The passage of the cells from S to G2/M was blocked even after 72 h. Apoptosis, however, was not induced in either HeLa or PC3 cells. Based on colony-forming assays, about 35% peptide-induced cytotoxicity was irreversible. Finally, sublethal doses of peptide wrwycr (50-100 µM) in conjunction with sublethal doses of several DNA damaging agents (etoposide, doxorubicin, and HU) reduced cell survival at least additively and sometimes synergistically. Taken together, the results suggest that the peptides merit further investigation as proof-of-principle molecules for a new class of anti-cancer therapeutics, in particular in combination with other DNA damaging therapies.

Site-specific histone modifications are important epigenetic regulators of gene expression. As deregulation of genes often results in complex disorders, corrective modulation of site-specific histone marks could be a powerful therapeutic or disease-preventive strategy. However, such modulation by dietary compounds and the resulting impact on disease risk remain relatively unexplored. Here we examined phenethylisothiocyanate (PEITC), a common dietary compound derived from cruciferous vegetables with known chemopreventive properties under experimental conditions, as a possible modulator of histone modifications in human colon cancer cells. The present study reports novel, dynamic, site-specific chemical changes to histone H3 in a gene-promoter-specific manner, associated with PEITC exposure in human colon tumor-derived SW480 epithelial cells. In addition, PEITC attenuated cell proliferation in a concentration- and time-dependent manner, likely mediated by caspase-dependent apoptotic signalling. The effects of PEITC on histone modifications and gene expression changes were achieved at low, non-cytotoxic concentrations, in contrast to the higher concentrations necessary to halt cancer cell proliferation. Increased understanding of specific epigenetic alterations by dietary compounds may provide improved chemopreventive strategies for reducing the healthcare burden of cancer and other human diseases.

Phytochemicals are a rich source of chemoprevention agents but their effects on modulating the Wnt/β-catenin signaling pathway have remained largely uninvestigated. Aberrantly activated Wnt signaling can result in the abnormal stabilization of β-catenin, a key causative step in a broad spectrum of cancers. Here we report the modulation of lithium chloride-activated canonical Wnt/β-catenin signaling by phytochemicals that have antioxidant, anti-inflammatory or chemopreventive properties. The compounds were first screened with a cervical cancer-derived stable Wnt signaling reporter HeLa cell line. Positive hits were subsequently evaluated for β-catenin degradation, suppression of β-catenin nuclear localization and down-regulation of downstream oncogenic targets of Wnt/β-catenin pathway. Our study shows a novel degradation path of β-catenin protein in HeLa cells by Avenanthramide 2p (a polyphenol) and Triptolide (a diterpene triepoxide), respectively from oats and a Chinese medicinal plant. The findings present Avenanthramide 2p as a potential chemopreventive dietary compound that merits further study using in vivo models of cancers; they also provide a new perspective on the mechanism of action of Triptolide.