bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of Self-Reported Autonomic Symptoms With Sensor-Based Physiological Measures
Authors: Kolacz Jacek , Chen Xiwei , Nix Evan J. , Roath Olivia K. , Holmes Logan G. , Tokash Clarissa , Porges Stephen W. , Lewis Gregory F.
Published: September 2023

Objective

Autonomic regulation of organ and tissues may give rise to disruptions of typical functions. The Body Perception Questionnaire Short Form (BPQ-SF) includes items that were developed to assess autonomic symptoms in daily life. This pair of studies aimed to establish previously unexplored psychometric properties of the BPQ-SF autonomic symptoms scale, develop normative values for clinical and research use, and assess the convergence of self-reports with sensor-based measures.

Methods

Study 1 reports exploratory and confirmatory factor analysis on BPQ-SF autonomic symptom items from a large US population-based online study (n = 2048). In study 2, BPQ-SF scores were examined for associations with heart period, respiratory sinus arrhythmia, and skin conductance during seated leg lifts in a community sample (n = 62).

Results

Study 1 results supported a two-factor supradiaphragmatic and subdiaphragmatic autonomic symptom solution (confirmatory factor analysis: root mean squared error of approximation = 0.040, Comparative Fit Index = 0.99, Tucker-Lewis Index = 0.99), although a one-factor solution also fit the data well (root mean squared error of approximation = 0.080, Comparative Fit Index = 0.99, Tucker-Lewis Index = 0.99). In study 2, heart period responses to leg lifts and rests were demonstrated at all autonomic symptom levels. However, low autonomic symptoms were associated with optimal autonomic nervous system patterns of activation and recovery to baseline levels. Moderate symptoms were associated with prolonged sympathetic activation. The highest symptom levels were associated with impaired autonomic nervous system coordination across activation and recovery.

Conclusions

Results support the utility of self-reports of autonomic symptoms in research and clinical applications, with higher symptoms likely indicating autonomic impairment.
Associations of Germline Genetic Variants With Depression and Fatigue Among Hematologic Cancer Patients Treated With Allogeneic Hematopoietic Cell Transplantation
Authors: Hoogland Aasha I. , Gonzalez Brian D. , Park Jong Y. , Small Brent J. , Sutton Steven K. , Pidala Joseph A. , Smith Kristen S. , Bower Julienne E. , Jacobsen Paul B. , Jim Heather S.L.
Published: September 2023

Objective

Depression and fatigue are common among cancer patients and are associated with germline genetic variation. The goal of this pilot study was to examine genetic associations with depression and fatigue in the year after allogeneic hematopoietic cell transplant (HCT).

Methods

Blood was collected from patients and their donors before HCT. Patients completed self-report measures of depression and fatigue before HCT (T1), 90 days post-HCT (T2), and 1 year post-HCT (T3). Of the 384 genetic variants genotyped on a custom Illumina BeadChip microarray, 267 were retained for analysis based on quality control. Main effects of patient and donor variants as well as their interaction were examined using regression analyses. Significant variants were defined as those with a false discovery rate–adjusted p value of <.05.

Results

The sample consisted of 59 patient-donor pairs. Mean levels of depression and fatigue did not change significantly over time (p values of > .41). Increases in depression from T1 to T2 were associated with patient-donor interactions at rs1928040 (p = 3.0 × 10−4) and rs6311 (p = 2.0 × 10−4) in HTR2A. Increases in fatigue from T1 to T2 were associated with patient rs689021 in SORL1 (p = 6.0 × 10−5) and a patient-donor interaction at rs1885884 in HTR2A (p < 1.0 × 10−4).

Conclusions

Data suggest that variants in genes regulating the serotonergic system (HTR2A) and lipid metabolism (SORL1) are associated with changes in depression and fatigue in allogeneic HCT patients, implicating patients’ own genetic inheritance as well as that of donors. Additional studies are warranted to confirm these findings.
Effects of Music on Anxiety, Pain, and Comfort in Patients Undergoing Upper Endoscopy
Authors: Aksu Çiǧdem
Published: September 2023

Although upper gastrointestinal endoscopy is an important diagnostic procedure in the detection of diseases, it can cause discomfort and anxiety in patients. This study is a randomized controlled trial conducted to determine the effects of listening to music on the anxiety, pain, and comfort levels of patients undergoing upper gastrointestinal endoscopy. The patients were randomly divided into the intervention group (n = 40), who listened to music for 45 minutes before upper gastrointestinal endoscopy, and the control group (n = 40), which did not receive any intervention other than routine nursing care. It was observed that the pain and anxiety levels of the patients who listened to music before the procedure decreased, and their comfort levels and ease of the procedure increased. In order to reduce the pain and anxiety of patients who will undergo upper gastrointestinal endoscopy, increase the success of the procedure, and facilitate patient–doctor cooperation, encouraging patients to listen to music while awaiting the procedure can be effective.
Therapeutic developments for valosin-containing protein mediated multisystem proteinopathy
Authors: Boock Victoria , Roy Bhaskar , Pfeffer Gerald , Kimonis Virginia
Published: September 2023

Purpose of review

Missense mutations in valosin-containing protein (VCP) can lead to a multisystem proteinopathy 1 (MSP1) with any combination of limb-girdle distribution inclusion body myopathy (IBM) (present in about 90% of cases), Paget's disease of bone, and frontotemporal dementia (IBMPFD). VCP mutations lead to gain of function activity with widespread disarray in cellular function, with enhanced ATPase activity, increased binding with its cofactors, and reduced mitofusin levels.

Recent findings

This review highlights novel therapeutic approaches in VCP-MSP in in-vitro and in-vivo models. Furthermore, we also discuss therapies targeting mitochondrial dysfunction, autophagy, TDP-43 pathways, and gene therapies in other diseases with similar pathway involvement which can also be applicable in VCP-MSP.

Being a rare disease, it is challenging to perform large-scale randomized control trials (RCTs) in VCP-MSP. However, it is important to recognize potential therapeutic targets, and assess their safety and efficacy in preclinical models, to initiate RCTs for potential therapies in this debilitating disease.
Mesoterricola silvestris gen. nov., sp. nov., Mesoterricola sediminis sp. nov., Geothrix oryzae sp. nov., Geothrix edaphica sp. nov., Geothrix rubra sp. nov., and Geothrix limicola sp. nov., six novel members of Acidobacteriota isolated from soils
Authors: Itoh Hideomi , Sugisawa Yumi , Mise Kazumori , Xu Zhenxing , Kuniyasu Miyu , Ushijima Natsumi , Kawano Keisuke , Kobayashi Emiko , Shiratori Yutaka , Masuda Yoko , Senoo Keishi
Published: September 2023

Forty-eight

Acidobacteriota

strains were isolated from soils and sediments in Japan. Among them, six representative strains, designated W79T, W786T, Red222T, Red802T, Red803T, and Red804T, were subjected to the taxonomic classification. These six strains are Gram-stain-negative, non-spore-forming, rod-shaped, and facultative anaerobic bacterium that can reduce ferric iron. Phylogenetic and phylogenomic trees based on 16S rRNA genes and multiple single-copy gene sequences showed that strains Red222T, Red802T, Red803T, and Red804T formed a cluster with the type strains of

Geothrix

species, but strains W79T and W786T created an independent cluster from any other type strains. The former four strains shared 97.95–99.08% similarities of 16S rRNA gene sequence with the type strains of the genus

Geothrix

, whereas the latter two strains 94.86–95.49% similarities. The average amino acid identity of strains W79T and W786T were <63 % to any other type strains, which were below the genus delineation thresholds. Moreover, colonies of these two strains were white, while those of the other four isolated strains were reddish-yellow as well as the type strain

Geothrix fermentans

H-5T. Although the known type strains of

Geothrix

species have been reported to be non-motile, five strains (W79T, W786T, Red222T, Red803T, and Red804T) except for strain Red802T displayed motility. Furthermore, multiple genomic, phylogenetic, and phenotypic features supported the discrimination between these isolated strains. Based on the study evidence, we propose these six isolates as novel members within the

Acidobacteriota

/

Holophagae

/

Holophagales

/

Holophagaceae

, comprising two novel species of a novel genus, Mesoterricola silvestris gen. nov., sp. nov., and Mesoterricola sediminis sp. nov., and four novel species of the genus Geothrix: Geothrix oryzae sp. nov., Geothrix edaphica sp. nov., Geothrix rubra sp. nov., and Geothrix limicola sp. nov.
Evaluation of sequence hybridization for respiratory viruses using the Twist Bioscience Respiratory Virus Research panel and the OneCodex Respiratory Virus sequence analysis workflow
Authors: Kapel Natalia , Kalimeris Elizabeth , Lumley Sheila , Decano Arun , Rodger Gillian , Lopes Alves Marcela , Dingle Kate , Oakley Sarah , Barrett Lucinda , Barnett Sophie , Crook Derrick , Eyre David W. , Matthews Philippa C. , Street Teresa , Stoesser Nicole
Published: September 2023

Respiratory viral infections are a major global clinical problem, and rapid, cheap, scalable and agnostic diagnostic tests that capture genome-level information on viral variation are urgently needed. Metagenomic approaches would be ideal, but remain currently limited in that much of the genetic content in respiratory samples is human, and amplifying and sequencing the viral/pathogen component in an unbiased manner is challenging. PCR-based tests, including those which detect multiple pathogens, are already widely used, but do not capture information on strain-level variation; tests with larger viral repertoires are also expensive on a per-test basis. One intermediate approach is the use of large panels of viral probes or ‘baits’, which target or ‘capture’ sequences representing complete genomes amongst several different common viral pathogens; these are then amplified, sequenced and analysed with a sequence analysis workflow. Here we evaluate one such commercial bait capture method (the Twist Bioscience Respiratory Virus Research Panel) and sequence analysis workflow (OneCodex), using control (simulated) and patient samples head-to-head with a validated multiplex PCR clinical diagnostic test (BioFire FilmArray). We highlight the limited sensitivity and specificity of the joint Twist Bioscience/OneCodex approach, which are further reduced by shortening workflow times and increasing sample throughput to reduce per-sample costs. These issues with performance may be driven by aspects of both the laboratory (e.g. capacity to enrich for viruses present in low numbers), bioinformatics methods used (e.g. a limited viral reference database) and thresholds adopted for calling a virus as present or absent. As a result, this workflow would require further optimization prior to any implementation for respiratory virus characterization in a routine diagnostic healthcare setting.
A cross-sectional questionnaire-based landscaping of female infertility reveals genital Infections as a major contributor to reproductive tract anomalies, menstrual disorders, and infertility
Authors: Patnaik Naresh , Sarkar Uttam , Jojula Malathi , Vaddiraju Hema , Dey Ruchi Jain
Published: September 2023

Objectives

Female infertility is a global health concern. The association of genital infections with female infertility is neglected due to their chronic but asymptomatic nature. Lack of routine diagnosis and delay in treatment further causes intractable pathological sequalae and consequential infertility. This study aims to identify the most significant prognostic symptoms of genital infection(s) that correlate strongly with reproductive tract anomalies, menstrual disorders, and infertility.

Methods

We designed a detailed questionnaire and conducted a cross-sectional study with 100 female subjects, categorized into infertile (n1 = 62) and healthy groups (n2 = 38). The data collected was documented and statistically analyzed.

Results

This study highlights an early onset of infertility (21-30 years). Almost 27% of the infertile subjects are symptomatic for genital infections and ∼42% exhibit menstrual irregularities. Polycystic ovarian syndrome/disease (PCOS/PCOD, ∼30%), are observed to be the most predominant disorders followed by endometrial disorders (∼10%) and tubal damage (∼8%) in infertile subjects. A multivariate correlation analysis revealed a highly significant (p≤ 0.05) and strong association (0.15 < Φ ≤ 1.0) between menstrual disorders, endometrial disorders, uterine/tubal blockage, and hormonal disruption with infection-associated symptoms, such as vaginitis, cervicitis, pelvic inflammatory disorder (PID), dyspareunia, tuberculosis (TB), urinary tract infection (UTI), sperm, and semen abnormalities.

Conclusions

Our study reveals genital infections to be a significant contributor to female infertility. The questionnaire designed here offers a useful tool for self or clinical assessment and may help in timely prognosis/diagnosis of genital infections which may contribute to improved management of reproductive health and fertility.

Synopsis

The study reveals impact of genital infections on female infertility and offers a comprehensive questionnaire-based tool for an early self/clinical prognosis of infection induced infertility.
Single cell sequencing data identify distinct B cell and fibroblast populations in stricturing Crohn’s disease
Authors: Humphreys David T , Lewis Amy , Pan-Castillo Belen , Berti Giulio , Mein Charles , Wozniak Eva , Gordon Hannah , Gadhok Radha , Minicozzi Annamaria , ChinAleong Joanna , Feakins Roger , Giannoulatou Eleni , James Louisa K , Stagg Andy J , Lindsay James Oliver , Silver Andrew
Published: September 2023

We used human full thickness Crohn’s disease (CD) small bowel resection specimens and single cell RNA sequencing to identify potential therapeutic targets for stricturing (S)CD. Using an unbiased approach, 16 cell lineages were assigned within 14,539 sequenced cells from patient-matched SCD and non-stricturing (NSCD) preparations. SCD and NSCD contained identical cell types. Amongst immune cells, B cells and plasma cells were selectively increased in SCD samples. B cell subsets suggested formation of tertiary lymphoid tissue in SCD and compared with NSCD there was an increase in IgG, and a decrease in IgA plasma cells, consistent with their potential role in CD fibrosis. Two Lumican-positive fibroblast subtypes were identified and subclassified based on expression of selectively enriched genes as fibroblast clusters (C)12 and C9. Cells within these clusters expressed the profibrotic genesDecorin(C12) andJUN(C9). C9 cells expressedACTA2; ECM genesCOL4A1, COL4A2, COL15A1, COL6A3, COL18A1andADAMDEC1;LAMB1andGREM1. GO and KEGG Biological terms showed extracellular matrix, stricture organisation and regulation ofWNTpathway genes are associated with the C12 and C9 gene sets. Trajectory and differential gene analysis of C12 and C9 identified four sub-clusters. Intra sub-cluster gene analysis detected co-regulated gene modules that aligned along predicted pseudotime trajectories and identifiedCXCL14andADAMDEC1as key module markers. Our findings support further investigation of fibroblast heterogeneity and interactions with local and circulating immune cells at earlier time points in fibrosis progression. Breaking these interactions by targeting one or other population may improve therapeutic management for SCD.
Obesity Prediction in Young Adults from the Jerusalem Perinatal Study: Contribution of Polygenic Risk and Early Life Exposures
Authors: Hochner Hagit , Butterman Rachely , Margaliot Ido , Friedlander Yechiel , Linial Michal
Published: September 2023

We assessed whether adding early life exposures to a model based on polygenic risk score (PRS) improves prediction of obesity risk. We used a birth cohort with data at birth and BMI and waist circumference (WC) measured at age 32. The PRS was composed of SNPs identified in GWAS for BMI. Linear and logistic models were used to explore associations with obesity-related phenotypes. Improvement in prediction was assessed using measures of model discrimination (AUC), and net reclassification improvement (NRI). One SD change in PRS was associated with a significant increase in BMI and WC. These associations were slightly attenuated (13.7%-14.2%) with the addition of early life exposures to the model. Also, higher maternal pre-pregnancy BMI was associated with increase in offspring BMI and WC (p<0.001). For prediction obesity (BMI ≥ 30), the addition of early life exposures to the PRS model significantly increase the AUC from 0.69 to 0.73. At an obesity risk threshold of 15%, the addition of early life exposures to the PRS model provided a significant improvement in reclassification of obesity (NRI, 0.147; 95% CI 0.068-0.225). We conclude that inclusion of early life exposures to a model based on PRS improves obesity risk prediction in an Israeli population-sample.
Phonological Processing is Below Expectations and Linked to Word-Finding Difficulty in Multiple Sclerosis
Authors: Sumowski James F. , Dvorak Emily , Levy Sarah , Anderson Jordyn R.
Published: September 2023

Background

Word-finding difficulty is prevalent but poorly understood in persons with relapsing-remitting multiple sclerosis (RRMS).

Objective

Investigate our hypothesis that phonological processing ability is below expectations and related to word-finding difficulty in patients with RRMS.

Method

Data were analyzed from patients with RRMS (n=50) on patient-reported word-finding difficulty (PW-WFD) and objective performance on WIAT-4 Phonemic Proficiency (PP; analysis of phonemes within words), Word-Reading (WR, proxy of premorbid literacy and verbal ability), and Sentence Repetition (SR; auditory processing of word-level information).

Results

Performance (mean [95% CI]) was reliably lower than normative expectations for PP (− 0.41[-0.69, -0.13]) but not for WR (0.02[-0.21, 0.25]) or SR (0.08[-0.15, 0.31]. Within-subjects performance was worse on PP than both WR (t[49]=4.00, p<0.001, d=0.47) and SR (t[49]=3.76, p<0.001, d=0.54). Worse PR-WFD was specifically related to lower PP (F2,47=6.24, p=0.004, η2=0.21); worse PP performance at PR-WFD Often (n=13; -1.16[-1.49, -0.83]) than Sometimes (n=17; -0.14[-0.68, 0.41]) or Rarely (n=20; -0.16[-0.58, 0.27]. PR-WFD was unrelated to WR or SR (Ps>0.25).

Conclusion

Phonological processing was below expectations and specifically linked to word-finding difficulty in RRMS. Findings are consistent with early disease-related cortical changes within the posterior superior temporal / supramarginal region. Results inform our developing model of MS-related word-finding difficulty.
Characterizing the phenotypic and genetic structure of psychopathology in UK Biobank
Authors: Williams Camille M. , Peyre Hugo , Wolfram Tobias , Lee Younga H. , Ge Tian , Smoller Jordan W. , Mallard Travis T. , Ramus Franck
Published: September 2023

Mental conditions exhibit a higher-order transdiagnostic factor structure which helps to explain the widespread comorbidity observed in psychopathology. However, the phenotypic and genetic structures of psychopathology may differ, raising questions about the validity and utility of these factors. Here, we study the phenotypic and genetic factor structures of ten psychiatric conditions using UK Biobank and public genomic data. Although the factor structure of psychopathology was generally genetically and phenotypically consistent, conditions related to externalizing (e.g., alcohol use disorder) and compulsivity (e.g., eating disorders) exhibited cross-level disparities in their relationships with other conditions, plausibly due to environmental influences. Domain-level factors, especially thought disorder and internalizing factors, were more informative than a general psychopathology factor in genome-wide association and polygenic index analyses. Collectively, our findings enhance the understanding of comorbidity and shared etiology, highlight the intricate interplay between genes and environment, and offer guidance for psychiatric research using polygenic indices.
Assessing the Economic Burden of Alcohol Use in India Compared to Excise Taxes on Alcohol Sales
Authors: Zadey Siddhesh
Published: September 2023

Background

Alcohol use is among the topmost public health risk factors. There is a dearth of evidence on the broader impact of alcohol use on society, especially, for lower-middle-income countries like India. We retrospectively studied the economic burden of alcohol use and compared it with revenue from excise taxes on alcohol sales for India and its states in 2019.

Methods

For estimating the overall alcohol-attributable disease burden, disability-adjusted life-years or DALYs for India and its 30 states were extracted for all causes, all age groups, and both sexes with alcohol use as a risk factor from the Global Burden of Disease 2019 Study. Economic burden was calculated by the value of life-year (VLY) or full-income approach. National and state-level (top 10 revenue-earning states) data on excise taxes on alcohol sales were acquired from the Reserve Bank of India. Net losses were assessed by subtracting the revenue from the economic burden. All values are in Indian rupees (INR). Sensitivity analysis was conducted using different discount rates (0%, 3%, and 7%) for VLY values while uncertainty was propagated using 95% uncertainty intervals (UIs) for DALYs.

Results

The economic burden of alcohol use in India was 6.2 (95% UI: 4.8, 7.8) trillion INR in 2019. State-level burden varied from 7.3 (4.7, 10.4) billion INR in Mizoram to 1.1 (0.8, 1.4) trillion INR in Maharashtra. Nationally, revenue was 1.8 trillion INR depicting a net loss of 4.4 (3.1, 6.0) trillion. Net loss was largest in Maharashtra and smallest in Telangana. Sensitivity analyses confirmed that all ten states depicted losses in the case of a 3% discount rate, while five and seven states showed losses at 0% and 7% discount rates.

Conclusion

These are novel subnational estimates depicting annual net losses due to alcohol use in India with direct policy implications to disincentivize alcohol sales and raise taxes to an adequate level.

Highlights

The annual economic burden of alcohol use in India runs over six trillion rupees.

Economic burden exceeds revenue from excise taxes noting net loss.

Economic burden varies across states with Maharashtra having the largest burden.

All of the top ten revenue-earning states depict net losses in primary analysis.
Long-term longitudinal analysis of 4,187 participants reveals new insights into determinants of incident clonal hematopoiesis
Authors: Uddin Md Mesbah , Saadatagah Seyedmohammad , Niroula Abhishek , Yu Bing , Hornsby Whitney , Ganesh Shriienidhie , Lannery Kim , Shuermans Art , Honigberg Michael C. , Bick Alexander G. , Libby Peter , Ebert Benjamin L. , Ballantyne Christie M. , Natarajan Pradeep
Published: September 2023

Clonal hematopoiesis (CH), characterized by blood cells predominantly originating from a single mutated hematopoietic stem cell, is linked to diverse aging-related diseases, including hematologic malignancy and atherosclerotic cardiovascular disease (ASCVD). While CH is common among older adults, the underlying factors driving its development are largely unknown. To address this, we performed whole-exome sequencing on 8,374 blood DNA samples collected from 4,187 Atherosclerosis Risk in Communities Study (ARIC) participants over a median follow-up of 21 years. During this period, 735 participants developed incident CH. We found that age at baseline, sex, and dyslipidemia significantly influence the incidence of CH, while ASCVD and other traditional risk factors for ASCVD did not exhibit such associations. Our study also revealed associations between germline genetic variants and incident CH, prioritizing genes in CH development. Our comprehensive longitudinal assessment yields novel insights into the factors contributing to incident CH in older adults.
Evaluating the Potential Blood Coagulant Activity ofCaenothus americanus Compounds: Computational Analysis using Docking, Physicochemical, and ADMET Studies
Authors: Mashkani Zahra Sadat , Yali Zahra Pahlavan , Dorgalaleh Akbar , Shams Mahmood
Published: September 2023

Caenothus americanusis a common folk remedy for the treatment of wound bleeding. Certain compounds found in this plant have been shown to reduce clotting time. However, analyzing the effects of various compounds of a folk remedy is a time-consuming and expensive process, therefore, this study employed computational analyses using docking, physicochemical, and pharmacokinetic servers to identify potential clotting activity in C.americanus compounds. The ADMETlab, SwissADME web servers, Discovery Studio, and Autodock were used to study the proper binding to target proteins and predict the physicochemical and ADMET properties (adsorption, distribution, metabolism, excretion, and toxicity) of C. americanus compounds. Coagulation factors including activated factor (F) IIa, FVa, FVIIa, FVIIIa, FIXa, FXa, FXIa, FXIIa, and FXIIIa were chosen as target proteins. Docking studies revealed that malic acid, malonic acid, oxalic acid, and succinic acid were effective on coagulation factors, of which, malic acid had better binding to intrinsic pathway factors including FVIIa, FIIa, and FXIIIa (except FVIIIa), oxalic acid to FVIIIa, and malonic acid to FVa and FXa. Moreover, ADMET studies showed the safety profile of these compounds. In conclusion, carboxylic and alcoholic groups of malic acid, malonic acid, oxalic acid and succinic acid play a role in interaction with blood coagulation factors. Additionally, based on the ADMET characteristics and suitable pharmacokinetic potentials of these compounds, they can be introduced as blood coagulant candidates with fewer side effects in bleeding disorders. However, further studies are necessary to evaluate the precise components of theC. americanuswith the suability to bind coagulation factors.
The Quest to Identify USP8 Inhibitors for Parkinson’s Disease, a PAINful Experience
Authors: Lang Stuart , Bellany Fiona , Lin De , Barrett Denise S , Cartmill Kieran R. , Fletcher Daniel A. , Kerr Catrina , Plater Andrew , Forte Barbara , Baragaña Beatriz , Dixit Parul , Littleson Mairi M. , Wheldon Mary C. , Gray David W. , Cunningham Fraser
Published: September 2023

Pan Assay INterference compoundS (PAINS) are known to be a source of false positives in High Throughput Screening (HTS) campaigns. This has become a major problem in medicinal chemistry, often resulting in undesirable project outcomes and increased overall cost. Our recent campaign to identify inhibitors of USP8 that could be used in the treatment of Parkinson’s disease identified several PAINS that workedviaa variety of mechanisms. Herein, we discuss the process developed to identify not only the PAINS but also confirming the interference mechanism causing their activity. We found in this project that our USP8 assay was susceptible to multiple modes of interference, making it difficult to identify genuine hit molecules.

Abstract Figure
Vascular injury associated with ethanol intake is driven by AT1 receptor and mitochondrial dysfunction
Authors: Awata Wanessa M.C. , Alves Juliano V. , Costa Rafael M. , Bruder-Nascimento Ariane , Singh Shubhnita , Barbosa Gabriela S. , Tirapelli Carlos Renato , Bruder-Nascimento Thiago
Published: September 2023

Background

Renin-angiotensin (Ang II)-aldosterone system (RAAS) is crucial for the cardiovascular risk associated with excessive ethanol consumption. Disturbs in mitochondria have been implicated in multiple cardiovascular diseases. However, if mitochondria dysfunction contributes to ethanol-induced vascular dysfunction is still unknown. We investigated whether ethanol leads to vascular dysfunction via RAAS activation, mitochondria dysfunction, and mitochondrial reactive oxygen species (mtROS).

Methods

Male C57/BL6J or mt-keima mice (6–8-weeks old) were treated with ethanol (20% vol./vol.) for 12 weeks with or without Losartan (10 mg/kg).

Results

Ethanol induced aortic hypercontractility in an endothelium-dependent manner. PGC1α (a marker of biogenesis), Mfn2, (an essential protein for mitochondria fusion), as well as Pink-1 and Parkin (markers of mitophagy), were reduced in aortas from ethanol-treated mice. Disturb in mitophagy flux was further confirmed in arteries from mt-keima mice. Additionally, ethanol increased mtROS and reduced SOD2 expression. Strikingly, losartan prevented vascular hypercontractility, mitochondrial dysfunction, mtROS, and restored SOD2 expression. Both MnTMPyP (SOD2 mimetic) and CCCP (a mitochondrial uncoupler) reverted ethanol-induced vascular dysfunction. Moreover, L-NAME (NOS inhibitor) and EUK 134 (superoxide dismutase/catalase mimetic) did not affect vascular response in ethanol group, suggesting that ethanol reduces aortic nitric oxide (NO) and H2O2bioavailability. These responses were prevented by losartan.

Conclusion

AT1receptor modulates ethanol-induced vascular hypercontractility by promoting mitochondrial dysfunction, mtROS, and reduction of NO and H2O2bioavailability. Our findings shed a new light in our understanding of ethanol-induced vascular toxicity and open perspectives of new therapeutic approaches for patients with disorder associated with abusive ethanol drinking.
Evolutionarily conserved ovarian fluid proteins are responsible for extending egg viability in salmonid fish
Authors: Gueho Aurélie , Żarski Daniel , Rime Hélène , Guével Blandine , Com Emmanuelle , Lavigne Régis , Nguyen Thaovi , Montfort Jérôme , Pineau Charles , Bobe Julien
Published: September 2023

In contrast to most fish species, salmonids exhibit the unique ability to hold their eggs for several days after ovulation without significant loss of viability. During this period, eggs are held in the body cavity in a biological fluid, the coelomic fluid (CF) that is responsible for preserving egg viability. To identify CF proteins responsible for preserving egg viability, a proteomic comparison was performed using 3 salmonid species and 3 non-salmonid species to identify salmonid-specific highly abundant proteins. In parallel, rainbow trout CF fractions were purified and used in a biological test to estimate their egg viability preservation potential. The most biologically active CF fractions were then subjected to mass spectrometry analysis. We identified 50 CF proteins that are overabundant in a salmonid-specific manner and present in analytical fractions exhibiting the highest egg viability preservation potential. Here we show that salmonid CF is a complex biological fluid and that several proteins are responsible for preserving egg viability. Among these key players are proteins related to immunity, calcium binding, lipid metabolism, proteolysis, extracellular matrix and sialic acid metabolic pathway.
Unraveling the Structure of Meclizine Dihydrochloride with MicroED
Authors: Lin Jieye , Unge Johan , Gonen Tamir
Published: September 2023

Meclizine (Antivert, Bonine) is a first-generation H1 antihistamine used in the treatment of motion sickness and vertigo. Despite its wide medical use for over 70 years, its crystal structure and the details of protein-drug interactions remained unknown. In this study, we used microcrystal electron diffraction (MicroED) to determine the three-dimensional (3D) crystal structure of meclizine dihydrochloride directly from a seemingly amorphous powder. Two racemic enantiomers (R/S) were found in the unit cell, which packed as repetitive double layers in the crystal lattice. The packing was made of multiple strong N-H···Cl-hydrogen bonding interactions and weak interactions like C-H···Cl-and pi-stacking. Molecular docking revealed the binding mechanism of meclizine to the histamine H1 receptor. A comparison of the docking complexes between histamine H1 receptor and meclizine or levocetirizine (a second-generation antihistamine) showed the conserved binding sites. This research illustrates the combined use of MicroED and molecular docking in unraveling protein-drug interactions for precision drug design and optimization.
A common mechanism processes auditory and visual motion
Authors: Alais David , Folgueiras Uxía Fernández , Leung Johahn
Published: September 2023

We report behavioural findings implying common motion processing for auditory and visual motion. We presented brief translational motion stimuli drifting leftwards or rightwards in the visual or auditory modality at various speeds. Observers made a speed discrimination on each trial, comparing current speed against mean speed (i.e., method of single stimuli). Data were compiled into psychometric functions and means and slopes compared. Slopes between auditory and visual motion were identical, consistent with a common noise source, although mean speed for audition was veridical while visual speeds were significantly underestimated. An inter-trial analysis revealed clear motion priming in both audition and vision (i.e., faster perceived speed after a fast preceding speed, andvice versa– a positive serial dependence). Plotting priming as a function of preceding speed revealed the same slope for each modality. We also tested whether motion priming was modality specific. Whether vision preceded audition, or audition preceded vision, a positive serial bias (i.e., priming) was always observed. We conclude a common process underlies auditory and visual motion, and that this explains the closely matched data in vision and audition, as well as the crossmodal data showing equivalent motion priming regardless of the preceding trial’s modality.
Dynamics of associated microbiomes during algal bloom development: to see and to be seeing
Authors: Meirkhanova Ayagoz , Zhumakhanova Adina , Len Polina , Schoenbach Christian , Levi Eti E. , Jeppesen Erik , Davidson Thomas A. , Barteneva Natasha S.
Published: September 2023

Our understanding of the interactions between bacteria and phytoplankton in the freshwater phycosphere, including the development of algal blooms, is very limited. To identify the taxa and compositional variation within microbial communities, we performed 16S rRNA amplicon sequencing research on samples collected weekly through summer from mesocosms that differed in temperature and mixing regimes. We investigated, for the first time, the abundance diversity of microalgae, including Chlorophyta, Cryptophyta, and Cyanobacteria species, using visualization-based FlowCAM analysis and classification of microbial communities to species level by nanopore next-generation sequencing. We found that nanopore metagenomics, in parallel with complementary imaging flow cytometry, can depict the fine temporal dynamics of microbiomes associated with visually identifiedMicrocystismorphospecies, Chlorophyta, and Cryptophyta during algal bloom development. Our results showed that the temporal characteristics of microbiomes combined with a visual approach may be a key tool to predict the metacommunity structure and dynamics of algal blooms in response to anthropogenic effects and climate change.
Investigating a causal role for neutrophil count onP. falciparumsevere malaria: a Mendelian Randomization study
Authors: Constantinescu Andrei-Emil , Hughes David A. , Bull Caroline J. , Fleming Kathryn , Mitchell Ruth E. , Zheng Jie , Kar Siddhartha , Timpson Nicholas J. , Amulic Borko , Vincent Emma E.
Published: September 2023

Background

Malaria caused byP. falciparumimposes a tremendous public health burden on people living in sub-Saharan Africa. Severe malaria is associated with high morbidity and mortality and results from complications such as cerebral malaria, severe anaemia or respiratory distress. Individuals living in malaria endemic regions often have a reduced circulating neutrophil count due to a heritable phenomenon called ‘benign ethnic neutropenia’ (BEN). Neutrophils defend against bacterial infections but have been shown to be detrimental in pre-clinical malaria models, raising the possibility that reduced neutrophil counts modulate severity of malaria in susceptible populations. We tested this hypothesis by performing a genome-wide association study (GWAS) of circulating neutrophil count and a Mendelian randomization (MR) analysis of neutrophil counts on severe malaria in individuals of predominantly African ancestry.

Results

We carried out a GWAS of neutrophil count in individuals associated to an African continental ancestry group within UK Biobank (N=5,976). We identified previously unknown loci regulating neutrophil count in a non-European population. This was followed by a two-sample bi-directional MR analysis between neutrophil count and severe malaria (MalariaGEN, N=17,056). We identified 73 loci (r2=0.1) associated with neutrophil count, including the well-known rs2814778 variant responsible for BEN. The greatest evidence for an effect was found between neutrophil count and severe anaemia, although the confidence intervals crossed the null. MR analyses failed to suggest evidence for an effect of the combined severe malaria syndromes or individual subtypes (severe malaria anaemia, cerebral malaria, other severe malaria) on neutrophil count.

Conclusion

Our GWAS of neutrophil count revealed unique loci present in individuals of African ancestry. We note that a small sample-size reduced our power to identify variants with low allele frequencies and/or low effect sizes in our GWAS. Our work highlights the need for conducting large-scale biobank studies in Africa and for further exploring the link between neutrophils and severe malarial anemia.
Intragastric behavior of an experimental infant formula may better mimic intragastric behavior of human milk as compared to a control formula
Authors: Roelofs Julia J.M. , Tjoelker Reina S. , Lambers Tim T. , Smeets Paul A.M.
Published: September 2023

Background

During breastfeeding the macronutrient composition of breastmilk changes gradually from relatively low-fat (foremilk) to relatively high-fat (hindmilk), initially exposing the gastrointestinal tract to a relatively low fat concentration. In contrast, infant formulae (IF) are homogenous. Mild processing and addition of milk fat globule membrane (MFGM) may impact gastric emulsion instability, potentially impacting the phased release of nutrients as observed during breastfeeding.

Objective

To assess gastric emulsion stability, gastric emptying, and the postprandial plasma metabolome of an experimental minimally processed IF (EF) with an altered fat-globule interface and a control IF (CF).

Methods

Twenty healthy males participated in this double-blind randomized crossover trial. Gastric MRI scans and blood samples were obtained before and after consumption of 600 ml CF or EF over a 2-h period. Outcomes included gastric top layer formation, total gastric volume, and blood parameters (FFA, insulin, glucose, and NMR-metabolomics).

Results

EF showed an earlier onset (13.4 min, p=0.017), smaller maximum volume (49.0 ml, p= 0.033), and a shorter time to maximum top layer volume (13.9 min, p=0.022), but similar AUC (p=0.915) compared to CF. Total gastric volume did not show a treatment*time effect. Insulin concentrations were lower for EF. FFA and glucose did not differ. EF yielded higher serum concentrations of phospholipid-and cholesterol-related metabolites.

Conclusion

An EF displayed faster gastric creaming than a CF, thereby potentially better mimicking the behavior of breastmilk which leads to phased release of nutrients into the intestine. Overall physiological benefits of this difference in gastric behavior remain to be studied further in infants.
Social Context and Drug Cues Modulate Inhibitory Control in Cocaine Addiction: involvement of the STN evidenced through Functional Magnetic Resonance Imaging
Authors: Terenzi Damiano , Simon Nicolas , Gachomba Michael Joe Munyua , de Peretti Jeanne Laure , Nazarian Bruno , Sein Julien , Anton Jean-Luc , Grandjean Didier , Baunez Christelle , Chaminade Thierry
Published: September 2023

Background

Addictions often develop in a social context, although the influence of social factors did not receive much attention in the neuroscience of addiction. Recent animal studies suggest that peer presence can reduce cocaine intake, an influence potentially mediated, among others, by the subthalamic nucleus (STN). However, there is to date no such neurobiological study in humans.

Methods

This study investigated the impact of social context and drug cues on brain correlates of inhibitory control in individuals with and without cocaine use disorder (CUD) using functional Magnetic Resonance Imaging (fMRI). Seventeen CUD participants and 17 healthy controls (HC) performed a novel fMRI Stop-Signal task in the presence and absence of an observer while being exposed to cocaine-related and neutral pictures as cues.

Results

The results showed that CUD participants, while slower at stopping with neutral cues, recovered control level stopping abilities with cocaine cues, while HC did not show any difference. Neuroimaging revealed the involvement of frontal cortical regions and of the subthalamic nucleus (STN) in inhibitory control, which was modulated by both social context and drug cues in CUD participants but not in HC.

Conclusions

These findings highlight the impact of social context and drug cues on inhibitory control in CUD and suggest potential targets for intervention such as the STN, also emphasizing the importance of considering the social context in addiction research and treatment.
Super Bowl, an open platform for visual stimulation of insects
Authors: Prech Stefan , Groschner Lukas N. , Borst Alexander
Published: September 2023

To study how the nervous system processes visual information, experimenters must record neural activity while delivering visual stimuli in a controlled fashion. In animals with a nearly panoramic field of view, such as flies, precise stimulation of the entire visual field is challenging. We describe a projector-based device for stimulation of the insect visual system under a microscope. The device is based on a bowl-shaped screen that provides a wide and nearly distortion-free field of view. It is compact, cheap, easy to assemble, and easy to operate using the included open-source software for stimulus generation. We validate the virtual reality system technically and demonstrate its capabilities in a series of experiments at two levels: the cellular, by measuring the membrane potential responses of visual interneurons; and the organismal, by recording optomotor and fixation behavior ofDrosophila melanogasterin tethered flight. Our experiments reveal the importance of stimulating the visual system of an insect with a wide field of view, and we provide a simple solution to do so.
The structure of aC. neoformanspolysaccharide motif recognized by protective antibodies: A combined NMR and MD study
Authors: Hargett Audra A. , Azurmendi Hugo F. , Crawford Conor J. , Wear Maggie P. , Oscarson Stefan , Casadevall Arturo , Freedberg Darόn I.
Published: September 2023

Cryptococcus neoformansis a fungal pathogen responsible for cryptococcosis and cryptococcal meningitis. TheC. neoformanscapsular polysaccharide and shed exopolysaccharide functions both as a key virulence factor and to protect the fungal cell from phagocytosis. Currently, a glycoconjugate of these polysaccharides is being explored as a vaccine to protect againstC. neoformansinfection. In this combined NMR and MD study, experimentally determined NOEs andJ-couplings support a structure of the synthetic decasaccharide, GXM10-Ac3, obtained by MD. GXM10-Ac3was designed as an extension of glucuronoxylomannan (GXM) polysaccharide motif (M2) which is common in the clinically predominant serotype A strains and is recognized by protective forms of GXM-specific monoclonal antibodies. The M2 motif is characterized by a 6-residue α-mannan backbone repeating unit, consisting of a triad of α-(1→3)-mannoses, modified by β-(1→2)-xyloses on the first two mannoses and a β-(1→2)-glucuronic acid on the third mannose. The combined NMR and MD analyses reveal that GXM10-Ac3adopts an extended structure, with xylose/glucuronic acid branches alternating sides along the α-mannan backbone.O-acetyl esters also alternate sides and are grouped in pairs. MD analysis of a twelve M2-repeating unit polymer supports the notion that the GXM10-Ac3structure is uniformly represented throughout the polysaccharide. This experimentally consistent GXM model displays high flexibility while maintaining a structural identity, yielding new insights to further explore intermolecular interactions between polysaccharides, interactions with anti-GXM mAbs, and the cryptococcal polysaccharide architecture.

Significance Statement

This study utilized a combined NMR and MD approach to elucidate the structure of aCryptococcus neoformansGXM synthetic decasaccharide (GXM10-Ac3), recognized by protective anti-GXM mAbs. The data revealed an extended structure in which the xylose/glucuronic acid branches and pairs of 6-O-acetyl esters predominantly alternate sides along the α-mannan backbone. MD analysis of a GXM polysaccharide predicts that the decasaccharide structure is uniformly represented in the polysaccharide. Additionally, the GXM exhibits high flexibility while maintaining structural identity. These findings lay the foundation for future studies aimed at understanding anti-GXM antibody-polysaccharide interactions.
Structured RhoGEF recruitment drives myosin II organization on large exocytotic vesicles
Authors: Kamalesh Kumari , Segal Dagan , Avinoam Ori , Schejter Eyal D. , Shilo Ben-Zion
Published: September 2023

The Rho family of GTPases plays a crucial role in cellular mechanics, by regulating actomyosin contractility through the parallel induction of actin and myosin assembly and function. Using exocytosis of large vesicles in theDrosophilalarval salivary gland as a model, we followed the spatiotemporal regulation of Rho1, that in turn creates distinct organization patterns of actin and myosin. After vesicle fusion, low levels of activated Rho1 diffuse to the vesicle membrane and drive actin nucleation in an uneven, spread-out pattern. Subsequently, the Rho1 activator RhoGEF2 distributes as an irregular meshwork on the vesicle membrane, activating Rho1 in a corresponding punctate pattern and driving local myosin II recruitment, resulting in vesicle constriction. Vesicle membrane buckling and subsequent crumpling occur at local sites of high myosin II concentrations. These findings indicate that distinct thresholds for activated Rho1 create a biphasic mode of actomyosin assembly, inducing anisotropic membrane crumpling during exocrine secretion.