bluuebunny/crossref_metadata_2025_split huggingface dataset:
Therapeutic dose prediction of α5-GABA receptor modulation from simulated EEG of depression severity
Authors: Guet-McCreight Alexandre , Mazza Frank , Prevot Thomas D. , Sibille Etienne , Hay Etay 
Published: May 2024

AbstractTreatment for major depressive disorder (depression) often has partial efficacy and a large portion of patients are treatment resistant. Recent studies implicate reduced somatostatin (SST) interneuron inhibition in depression, and new pharmacology boosting this inhibition via positive allosteric modulators of α5-GABAAreceptors (α5-PAM) offers a promising effective treatment. However, testing the effect of α5-PAM on human brain activity is limited, meriting the use of detailed simulations. We utilized our previous detailed computational models of human depression microcircuits with reduced SST interneuron inhibition and α5-PAM effects, to simulate EEG of virtual subjects across depression severity and α5-PAM doses. We developed machine learning models that predicted optimal dose from EEG with high accuracy and recovered microcircuit activity and EEG. This study provides dose prediction models for α5-PAM administration based on EEG biomarkers of depression severity. Given limitations in doing the above in the living human brain, the results and tools we developed will facilitate translation of α5-PAM treatment to clinical use.
Genome-Wide Association Study Identifies Novel Genetic Variants Associated with Widespread Pain in the UK Biobank (N=172,230)
Authors: Pan Qi , Cai Tengda , Tao Yiwen , Compte Roger , Naeini Maryam Kazemi , Haque Mainul , Dottorini Tania , Williams Frances M.K. , Meng Weihua 
Published: May 2024

AbstractObjectivesWidespread pain is a hallmark characteristic of fibromyalgia, commonly affecting older individuals. This study aimed to identify novel genetic variants associated with widespread pain by utilizing the extensive UK Biobank dataset.MethodsWe conducted a primary genome-wide association study (GWAS) using a novel definition of widespread pain, defined as pain experienced all over the body during the past month. Sex-stratified GWAS analysis approach was also performed to analyze the impact of sex on widespread pain.ResultsThe primary GWAS identified one novel significant genetic locus (rs34691025,p= 1.76 × 10-8) on chromosome 5q13.2 within theARHGEF28gene and several loci that approached genome-wide significance. The sex-stratified GWAS outputs revealed biological difference widespread pain between males and females, with a novel locus identified in the female-specific analysis within theLRMDAgene on chromosome 10. Genetic Correlation analysis demonstrated significant genetic correlations between widespread pain and other phenotypes, including joint disorders and spondylosis. The PheWAS revealed associations between the significant genetic variants with hearing disorders and cardiovascular diseases.ConclusionsOur study advances the understanding of the genetic factors contributing to widespread pain, highlighting notable differences between males and females and identifying a novel genetic locus associated with this condition.
Assessing the environmental impact of medicines in Italy using data from the Italian Medicines Agency
Authors: Giunchi Valentina , Fusaroli Michele , Cangini Agnese , Fortinguerra Filomena , Zito Simona , Pierantozzi Andrea , Lunghi Carlotta , Poluzzi Elisabetta , Trotta Francesco 
Published: May 2024

AbstractAimThis study builds upon the environmental risk analysis presented in the 2022 National Report on Medicines Use in Italy by the Italian Medicines Agency and aims to assess the environmental risk posed by medicines in Italy and in its regions.MethodsThe analysis selected 90 medicines based on three criteria: high utilization, low PNEC, and inclusion or candidacy for the European Watch List. For each medicine, the environmental risk was computed as the ratio between the Predicted Environmental Concentration (PEC) and the Predicted No Effect Concentration (PNEC). PEC was derived following the approach of the Swedish Association of Pharmaceutical Industries and Italian drug utilization data. The risk was classified high if the ratio was greater than 10, and moderate if greater than 1.ResultsOverall, 13 medicines were identified as posing a high risk, including cardiovascular agents, antibiotics, analgesics, antidepressants, and antiparasitic agents. The high risk was driven by either a very low PNEC (e.g., estradiol and lacidipine), and high utilization (e.g., amoxicillin, ibuprofen, and diclofenac). Regional analysis showed higher risk due to high consumption for azithromycin and ofloxacin in Central and Southern Italy, and for levonorgestrel in Northern Italy.ConclusionThis study points to the need of prioritizing targeted sampling in surface waters for medicines estimated at high risk. To prevent and mitigate the risk, a more conscious clinical practice coupled with appropriate waste management are required.What is already known about this subjectMedicines represent a growing concern as a source of contamination in water systems.Traditional surface water samplings are resource-expensive and should be supported by estimation methods.The Italian Medicines Agency’s National report on medicines use included, for the first time in its 2022 version, an assessment of the environmental impact.What this study adds90 medicines with either high utilization, low Predicted No-Effect Concentration, or present in the European Watch List were included.13 medicines were at high environmental risk either because of their high toxicity to aquatic species or their high consumption in Italy.Regional differences potentially reflect various social and prescribing habits.
Supporting continuous glucose monitoring for people with serious mental illness and type 2 diabetes: Protocol for a co-design study
Authors: Brown Jennifer VE , Ajjan Ramzi , Siddiqi Najma , Kellar Ian , Coventry Peter A 
Published: May 2024

AbstractIntroductionCompared with the general population, people with serious mental illness (SMI) are 2-3 times more likely to develop type 2 diabetes, have poorer outcomes, and die 15 to 20 years younger, often as a result of long-term physical health conditions. Standard diabetes care does not meet the needs of people with SMI and they are frequently excluded from research, missing out on innovation. As diabetes care increasingly uses technology like continuous glucose monitoring (CGM) it is important to consider the views of people with SMI when new interventions are developed. This is a study protocol to identify candidate components of a structured CGM intervention for people with SMI, including the co-design of a logic model and programme theory.MethodsDrawing on experience-based co-design (EBCD) methods, we propose to collaborate with service-users, carers, and healthcare professionals to undertake early-phase development work for a novel intervention that maximises the potential of CGM to facilitate behaviour change. Fifteen participants will be recruited through existing cohorts and networks in England. The co-design will be informed by existing evidence and based on links between mechanisms of action and behaviour change techniques. Through a series of events (discovery sessions, co-design workshop, celebration event), we will identify candidate components for a prototype intervention ready for further development and testing. A logic model and programme theory will be developed and refined iteratively.DiscussionThe main output of this study will be a logic model and programme theory for a novel prototype intervention, ready for further testing following best practice intervention development, such as the Medical Research Council guidance for the development and evaluation of complex interventions. An intervention that makes CGM accessible for people with SMI has the potential to make a considerable contribution to reducing the profound health inequalities experienced by this population.
MiRNA encoded PTEN’s Impact on Clinical-Pathological Features and Prognosis in Osteosarcoma: a Systematic Review and Meta-Analysis
Authors: Limijadi Edward Kurnia Setiawan , Novriansyah Robin , Respati Danendra Rakha Putra , Tjandra Kevin Christian 
Published: May 2024

AbstractBackgroundOsteosarcoma (OSC) is considered one of the most common malignant bone tumours in adolescents. Due to OSC’s poor prognosis, a comprehensive approach to exploring these aspects is highly needed to improve the survival probability of OSC. In this study, we tried to explore the significance of miRNA-encoded PTEN for clinical-pathological features and prognostic value in OSC.MethodWe performed this systematic review and meta-analysis using articles and sources published between 2013 and 2023 from six databases (Scopus, PubMed, ProQuest, Science Direct, Sage Pub, and Cochrane). Included studies were clinical cross-sectional studies. Other study designs, articles not written in English, without full text, and not relevant—were excluded. Then, ROBINS-I is used to evaluate the distance. The results are constructed according to the PICOS criteria in a table. The expression of miRNA related to OSC is assessed in the meta-analysis as the main outcome to determine its ability as a diagnostic and prognostic agent for OSC. This systematic review followed the PRISMA guidelines.ResultsA total of 17 studies were included in the final screening. The meta-analysis showed significantly increased (p < 0.00001) miRNA expression in patients with osteosarcoma compared to healthy controlled with pooled md (2.85) (95% CI: 2.69, 3.02; I2= 22%, p= 0.20), the high inverse correlation (p < 0.001) between miRNA and PTEN expression was shown as mean effect size (−0.681) (95% CI: −0.787, −0.536; I2= 75%, p < 0.0001), and the prognostic evaluation of overall survival was significantly increased in low expression miRNA (p < 0.00001) with pooled OR.ConclusionFiveteen miRNAs from 17 studies were found, and together with PTEN expression, they may serve as potential prognostic biomarkers for OSC. High-level levels of miRNA expression are correlated with low PTEN expression, leading to a bad prognosis for OSC.
Stepping it up: A Longitudinal Assessment of Stair Negotiation Among ACL Reconstruction Patients Outside the Laboratory
Authors: Yona Tomer , Peskin Bezalel , Fischer Arielle 
Published: May 2024

AbstractIntroductionAnterior Cruciate Ligament Reconstruction (ACLR) is crucial for knee stability in ACL-injured individuals and for resuming pre-injury physical activities. Despite advancements, achieving symmetrical movement patterns during rehabilitation, particularly in stair negotiation, poses challenges. This study examines lower limb kinematics during stair negotiation at various rehabilitation stages post-ACLR, employing inertial measurement units (IMUs) and Statistical Parametric Mapping (SPM) for in-depth analysis outside the laboratory.MethodsThis cohort study longitudinally assessed stair ambulation kinematics in patients aged 18-40, three (n=26) and five months (n=18) post-ACLR, using IMUs to track sagittal plane movement during stair ascent and descent. The participants ambulated on a flight of 20 stairs outside the laboratory.ResultsAt three months post-ACLR, the injured knee was less flexed compared to the contralateral knee during stair ascent (mean difference = -11.3°, CI [-14.4, -8.1], p<.001) and descent (mean difference = -6.3°, CI [-10.2, -2.4], p=.002). SPM analysis identified clusters where the injured knee showed decreased flexion at 0-35% and 87-99% of the stair ascent cycle (p<.005). By five months, flexion differences during ascent improved (mean difference = -4.7°, CI [-8.1, -1.4], p=.008), but significant asymmetry persisted, with decreased flexion at 10-32% of the cycle during ascent and 20-29% during descent (p<.017). Improvements between three and five months were observed in knee flexion during ascent (mean increase = 6.1°, p<.001) and descent (mean increase = 9.3°, p=.004). Ankle and hip joint movements also exhibited persistent asymmetries, with minimal improvements over time.ConclusionsPersistent lower limb kinematic asymmetries remain five months post-ACLR during stair ascent and descent.
Patients’ perceptions of, emotional responses to, and disengagement from, physician-services for HIV: The relationship of trust and the mental and social effects of HIV to perceived service-adequacy
Authors: Whitaker R , Otis M 
Published: May 2024

AbstractAn exploratory, two-language, online survey assessed patients in relation to physician-services for HIV-infection. Most respondents had experienced primarily mental rather than physical illness due to HIV or its treatment, as well as a marked HIV-related impact on social networks. Mental and social factors were identified that predicted patients’ relationship to, and disengagement from, physicians’ services, including patients’ satisfaction, trust, physicians’ relational skills, time-pressure, the opportunity for clinical intimacy, physician-credibility; ‘heart-sink’ physicians, anxiety, passivity, self-efficacy, experience of HIV-related illness, experience of medication-toxicity, degree of loss in social networks, and ‘changing physician due to disagreement’, with ramifications for physicians’ concept of the ‘difficult patient’. The prevalence and significance of such issues and the related risk of distrust of, and disengagement from, physician-services confirm the still-remaining need for evidence-based treatment to be implemented for people with HIV, to include the delivery of integrated, multi-professional, and biopsychosocial health-services.What do we know already about this topic?Mental and social aspects of illness affect services’ ability to help patients to get well and stay well (i.e., health-effectiveness), but since the advent of HAART few clinics provide integrated, biopsychosocial services necessary to address these issues, despite the extensive evidence-base demonstrating such need.How does this research contribute to the field?This research: confirms the significance of biopsychosocial aspects of illness and identifies pervasive factors that intensify such challenges to the provision of health-effective services—and which can act as signal-events in quality-related service-audit—as well as analysing other factors, such as patients’ satisfaction, that have no value except to consumerism but relate to other variables, such as trust, that need to be used in service-evaluation.What are the implications of this research for theory, practice, or policy?The implications of this research are that each services needs a competent, multi-professional team to address the biopsychosocial factors identified, and to integrate the factors into the audit of services’ health-effectiveness, supported by specific policy such as treatment-guidelines that require the evidence-based formulation and delivery of health-services, not solely pharmaceuticals of choice.
Monomer-dimer structural comparison in quinol-dependent nitric oxide reductase reveals a functional basis for superior enzymatic activity in the dimer
Authors: Gopalasingam Chai C. , Egami Haruka , Shigematsu Hideki , Sakaue Masatora , Fukumoto Kouki , Gerle Christoph , Yamamoto Masaki , Shiro Yoshitsugu , Muramoto Kazumasa , Tosha Takehiko 
Published: May 2024

AbstractThe leading cause of bacterial meningitis,Neisseria meningitidis,deploys a quinol-dependent nitric oxide reductase (NmqNOR), belonging to the heme-copper oxidase superfamily. By detoxifying NO, an antimicrobial gas produced by host’s immune system, qNOR enables pathogen survival within hosts. Here, we determined cryoEM structures of the less active monomer and highly active dimer ofNmqNOR at resolutions of 2.25 and 1.89 Å, respectively, showing the structural elements responsible for effective NO reduction. Helical disorder at the dimer interface, associated with an altered conformation of the critical Glu563 near the heme/non-heme Fe active site, was observed in the monomer. These findings suggest that dimerization stabilizes the active conformation of Glu563 through the structural network between the dimerization site and the active site. Since other members of the heme-copper oxidases exhibit dimerization, the current data on qNOR helps us understand a regulatory mechanism related to the function of heme-copper oxidases upon oligomerization.TeaserCryoEM structures unveil a functional rationale for dimerization in nitric oxide detoxifying enzyme from a pathogen
TRIM52 is a primate-specific player in the DNA repair process under tight proteolytic control by a triad of giant E3 ligases
Authors: Shulkina Alexandra , Hacker Kathrin , Ehrmann Julian F. , Budroni Valentina , Mandlbauer Ariane , Bock Johannes , Grabarczyk Daniel B. , Cochella Luisa , Clausen Tim , Versteeg Gijs A. 
Published: May 2024

AbstractTripartite motif 52 (TRIM52) exhibits strong positive selection in humans, yet is lost in many other mammals. In contrast to what one would expect for such a non-conserved factor,TRIM52loss compromises cell fitness. We set out to determine the cellular function of TRIM52. Genetic and proteomic analyses revealed TRIM52’s involvement in resolving topoisomerase 2 (TOP2)-DNA cross-links, mitigating DNA damage and preventing cell-cycle arrest. Consistent with a fitness-promoting function, TRIM52 is upregulated in various cancers, prompting us to investigate its regulatory pathways. We found TRIM52 to be targeted for ultra-rapid proteasomal degradation by the giant E3 ubiquitin ligases BIRC6, HUWE1, and UBR4/KCMF1. BIRC6 mono-ubiquitinates TRIM52, with subsequent extension by UBR4/KCMF1. These findings underscore TRIM52’s pivotal role in DNA damage repair and regulation of its own abundance through multi-ligase degradation.
Tracing Homopolymers inOikopleura dioica’s mitogenome
Authors: Dierckxsens Nicolas , Watanabe Kosei , Tan Yongkai , Masunaga Aki , Mansfield Michael J. , Miao Jiashun , Luscombe Nicholas M. , Plessy Charles 
Published: May 2024

Oikopleura dioicais a planktonic tunicate (Appendicularia class) found extensively across the marine waters of the globe. The genome of a single male individual collected from Okinawa, Japan was sequenced using the single-molecule PacBio Hi-Fi method and assembled with NOVOLoci. The mitogenome is 39,268 bp long, featuring a large control region of around 22,000 bp. We annotated the proteins atp6, cob, cox1, cox2, cox3, nad1, nad4 and nad5, and found one more open reading frame that did not match any known gene. This study marks the first complete mitogenome assembly for an appendicularian, and reveals that A and T homopolymers cumulatively account for nearly half of its length. This reference sequence will be an asset for environmental DNA and phylogenetic studies.http://dx.doi.org/10.1364/ao.XX.XXXXXX
Cell invasive amyloid assemblies from SARS-CoV-2 peptides can form multiple polymorphs with varying neurotoxicity
Authors: Sanislav Oana , Tetaj Rina , Metali  , Ratcliffe Julian , Phillips William , Klein Annaleise , Sethi Ashish , Zhou Jiangtao , Mezzenga Raffaele , Saxer Sina , Charnley Mirren , Annesley Sarah , Reynolds Nicholas P 
Published: May 2024

AbstractThe neurological symptoms of COVID-19, such as memory loss, cognitive and sensory disruption (neuro-COVID) are well reported. These neurological symptoms frequently persist for months (post-acute sequalae of COVID-19 or PASC). The molecular origins of neuro-COVID and how it contributes to PASC are unknown, however a growing body of research highlights that the self-assembly of protein fragments from SARS-CoV-2 into amyloid nanofibrils may play a causative role. Previously, we identified two fragments from the proteins Open Reading Frame 6 (ORF6) and ORF10 that self-assemble into neurotoxic amyloid assemblies. Here we further our understanding of the self-assembly mechanisms and nano-architectures formed by these fragments as well as performing a more in-depth study of the biological responses of co-cultured neurons. By solubilising the peptides in a fluorinated solvent we eliminate insoluble aggregates in the starting materials (seeds) that change the polymorphic landscape of the assemblies. The resultant assemblies are dominated by structures with higher free energies (e.g. ribbons and amorphous aggregates) that are less toxic to cultured neurons. We also show the first direct evidence of cellular uptake by viral amyloids. This work highlights the importance of understanding the polymorphic behaviour of amyloids particularly in the context of neuro-COVID and PASC.Graphical Abstract for ToCThe neurological symptoms of COVID-19 are likely to be, in part, caused by the aggregation of viral proteins into neurotoxic amyloid nanofibrils. Changes in aggregation conditions alters the balance of fibril structures formed (polymorphism), influencing their toxicity to a neuronal cell line. These findings increase our understanding of viral amyloids and highlight the importance of careful choice of experimental protocol when studying these systems.
Preclinical evaluation of the novel [18F]CHDI-650 PET ligand for non-invasive quantification of mutant huntingtin aggregates in Huntington’s disease
Authors: Zajicek Franziska , Verhaeghe Jeroen , De Lombaerde Stef , Van Eetveldt Annemie , Miranda Alan , Munoz-Sanjuan Ignacio , Dominguez Celia , Khetarpal Vinod , Bard Jonathan , Liu Longbin , Staelens Steven , Bertoglio Daniele 
Published: May 2024

AbstractPurposePositron emission tomography (PET) imaging of mutant huntingtin (mHTT) aggregates is a potential tool to monitor disease progression as well as the efficacy of candidate therapeutic interventions for Huntington’s disease (HD). To date, the focus has been mainly on the investigation of11C radioligands; however, favourable18F radiotracers will facilitate future clinical translation. This work aimed at characterising the novel [18F]CHDI-650 PET radiotracer using a combination ofin vivoandin vitroapproaches in a mouse model of HD.MethodsAfter characterising [18F]CHDI-650 usingin vitroautoradiography, we assessedin vivoplasma and brain radiotracer stability as well as kinetics through dynamic PET imaging in the heterozygous (HET) zQ175DN mouse model of HD and wild-type (WT) littermates at 9 months of age. Additionally, we performed a head-to-head comparison study at 3 months with the previously published [11C]CHDI-180R radioligand.ResultsPlasma and brain radiometabolite profiles indicated a suitable metabolic profile forin vivoimaging of [18F]CHDI-650. Bothin vitroautoradiography andin vivo[18F]CHDI-650 PET imaging at 9 months of age demonstrated a significant genotype effect (p<0.0001) despite the poor test-retest reliability. [18F]CHDI-650 PET imaging at 3 months of age displayed higher differentiation between genotypes when compared to [11C]CHDI-180R.ConclusionOverall, [18F]CHDI-650 allows for discrimination between HET and WT zQ175DN mice at 9 and 3 months of age. [18F]CHDI-650 represents the first suitable18F radioligand to image mHTT aggregates in mice and its clinical evaluation is underway.