bluuebunny/crossref_metadata_2025 huggingface dataset:
Antigen receptor stimulation drives selection against pathogenic mtDNA variants that dysregulate lymphocyte responses
Authors: Zhang Jingdian , Koolmeister Camilla , Han Jinming , Filograna Roberta , Hanke Leo , Àdori Monika , Sheward Daniel J. , Teifel Sina , Liu Yong , Harris Robert A. , Murrell Ben , Mcinerney Gerald , Aoun Mike , Bäckdahl Liselotte , Holmdahl Rikard , Pekalski Marcin , Wedell Anna , Engvall Martin , Wredenberg Anna , Karlsson Hedestam Gunilla B. , Dopico Xaquin Castro , Rorbach Joanna
Published: October 2021

Pathogenic mitochondrial (mt)DNA molecules can exhibit heteroplasmy in single cells and cause a range of clinical phenotypes, although their contribution to immunity is poorly understood. Here, in mice carrying heteroplasmic C5024T in mt-tRNAAla– that impairs oxidative phosphorylation – we found a reduced mutation burden in peripheral T and B memory lymphocyte subsets, compared to their naïve counterparts. Furthermore, selection diluting the mutation was inducedin vitroby triggering T and B cell antigen receptors. While C5024T dysregulated naïve CD8+T cell respiration and metabolic remodeling post-activation, these phenotypes were partially ameliorated by selection. Analogous to mice, peripheral blood memory T and B lymphocyte subsets from human MELAS (Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like episodes) patients – carrying heteroplasmic A3243G in mt-tRNALeu– displayed a reduced mutation burden, compared to naïve cells. In both humans and mice, mtDNA selection was observed in IgG+antigen-specific B cells after SARS-CoV-2 Spike vaccination, illustrating an on-going processin vivo. Taken together, these data illustrate purifying selection of pathogenic mtDNA variants during the oxidative phosphorylation checkpoints of the naïve-memory lymphocyte transition.

Highlights

In human MELAS patients (A3243G in mt-tRNALeu) and a related mouse model (C5024T in mt-tRNAAla), T and B memory subsets displayed a reduced mtDNA mutation burden compared to their naïve counterparts.

Selection was observed in antigen-specific IgG+B cells after SARS-CoV-2 Spike protein vaccination.

T and B cell antigen receptor stimulation triggered purifying selectionin vitro, facilitating mechanistic studies of mtDNA selection.

Heteroplasmic pathogenic mutations in mtDNA dysregulated metabolic remodeling after lymphocyte activation and reduced macrophage OXPHOS capacity.
Serum but not mucosal antibody responses are associated with pre-existing SARS-CoV-2 spike cross-reactive CD4+T cells following BNT162b2 vaccination in the elderly
Authors: Meyer-Arndt Lil , Schwarz Tatjana , Loyal Lucie , Henze Larissa , Kruse Beate , Dingeldey Manuela , Gürcan Kübrah , Uyar-Aydin Zehra , Müller Marcel A. , Drosten Christian , Paul Friedemann , Sander Leif E. , Demuth Ilja , Lauster Roland , Giesecke-Thiel Claudia , Braun Julian , Corman Victor M. , Thiel Andreas
Published: October 2021

Advanced age is a main risk factor for severe COVID-19. However, low vaccination efficacy and accelerated waning immunity have been reported in this age group. To elucidate age-related differences in immunogenicity, we analysed human cellular, serological and salivary SARS-CoV-2 spike glycoprotein-specific immune responses to BNT162b2 COVID-19 vaccine in old (69-92 years) and middle-aged (24-57 years) vaccinees compared to natural infection (COVID-19 convalescents, 21-55 years). Serological humoral responses to vaccination exceeded those of convalescents but salivary anti-spike subunit 1 (S1) IgA and neutralizing capacity were less durable in vaccinees. In old vaccinees, we observed that pre-existing spike-specific CD4+T cells are associated with efficient induction of anti-S1 IgG and neutralizing capacity in serum but not saliva. Our results suggest pre-existing SARS-CoV-2 cross-reactive CD4+T cells as predictor of an efficient COVID-19 vaccine-induced humoral immune response in old individuals.
Relationship between five Epigenetic Clocks, Telomere Length and Functional Capacity assessed in Older Adults: Cross-sectional and Longitudinal Analyses
Authors: Vetter Valentin Max , Kalies Christian Humberto , Sommerer Yasmine , Spira Dominik , Drewelies Johanna , Regitz-Zagrosek Vera , Bertram Lars , Gerstorf Denis , Demuth Ilja
Published: October 2021

DNA methylation age acceleration (DNAmAA, derived from an epigenetic clock) and relative leukocyte telomere length (rLTL) are widely accepted biomarkers of aging. Nevertheless, it is still unclear which aspects of aging they represent best. Here we evaluated longitudinal associations between baseline rLTL and DNAmAA (estimated with 7-CpG clock) and functional assessments covering different domains of aging. Additionally, we made use of cross-sectional data on these assessments and examined their association with DNAmAA estimated by five different DNAm age measures.

Two-wave longitudinal data was available for 1,083 participants of the Berlin Aging Study II (BASE-II) who were re-examined on average 7.4 years after baseline as part of the GendAge study. Functional outcomes were assessed with Fried’s frailty score, Tinetti mobility test, falls in the past 12 months (yes/no), Finger-floor distance, Mini Mental State Examination (MMSE), Center for Epidemiologic Studies Depression Scale (CES-D), Activities of Daily Living (ADL), Instrumented ADL (IADL) and Mini Nutritional Assessment (MNA).

Overall, we found no evidence for an association between the molecular biomarkers measured at baseline, rLTL and DNAmAA (7-CpG clock), and functional assessments assessed at follow-up. Similarly, a cross-sectional analyses of follow-up data did also not show evidence for associations of the various DNAmAA measures (7-CpG clock, Horvath’s clock, Hannum’s clock PhenoAge, and GrimAge) with functional assessments.

In conclusion, neither rLTL nor 7-CpG DNAmAA were able to predict impairment in the analyzed assessments over a ∼7 year time-course. Similarly, DNAmAA as estimated by five epigenetic clocks was not a good cross-sectional marker of health deterioration either.
Feasibility and acceptability of daily testing at school as an alternative to self-isolation following close contact with a confirmed case of COVID-19: A qualitative analysis
Authors: Denford Sarah , Towler Lauren , Ali Behiye , Treneman-Evans Georgiana , Bloomer Rachael , Peto Tim , Young Bernadette C , Yardley Lucy
Published: October 2021

Background

Daily testing using a rapid Lateral Flow Device (LFD) has been suggested as an alternative to self-isolation. A randomised trial comparing daily contact testing (DCT) in schools with self-isolation found that SARS-CoV-2 transmission within school was comparable and low in both groups. However, if this approach is to be adopted widely, it is critical that we understand the perspective of those who will be delivering and receiving DCT. The aim of this qualitative process study embedded in the randomised controlled trial (RCT) was to improve understanding of a range of behavioural factors that could influence implementation.

Methods

Interviews were conducted with 63 participants, including staff, students, and parents of students who had been identified as being in close contact with someone with COVID-19. The topic guide explored perceptions of daily testing, understanding of positive and negative test results, and adherence to guidance. Data were analysed using an inductive thematic approach.

Results

Results were organised under three main headings: (1) factors influencing daily testing (2) interpretation of test results (3) behaviour during testing period. Participants recognized that daily testing may allow students to remain in school, which was viewed as necessary for both education and social needs. Whilst some felt safer as a result of daily testing, others raised concerns about safety. Participants did not always understand how to interpret and respond to test results, and although participants reported high levels of adherence to the guidance, improved communications were desired.

Conclusion

Daily testing may be a feasible and acceptable alternative to self-isolation among close contacts of people who test positive. However, improved communications are needed to ensure that all students and parents have a good understanding of the rationale for testing, what test results mean, how test results should be acted on, and how likely students are to test positive following close contact. Support is needed for students and parents of students who have to self-isolate and for those who have concerns about the safety of daily testing.
Enhancing Tele-Simulation during OSCE: Incorporating Feedback from Standardized Patients
Authors: Sudhir Meghana
Published: October 2021

Background

As COVID-19 impacted universities across the globe for over one year, the organization of OSCEs also demanded change. The traditional OSCEs had to transition to Tele simulation OSCEs. As the pandemic continues, there is possibility that this approach may continue for some time, it is imminent to capture feedback from the simulated patients so that we can explore ways to improve in future.

Objectives

To gather feedback from standardized patients doing Tele Simulation in OSCEs, To develop plans to improve Tele Simulation involving Standardized Patients based on the feedback gathered.

Method

Data were collected immediately after Tele simulation OSCE during debriefing from 18 Simulated Patients. This was followed up with an open-ended questionnaire and gathered additional information.

Results

The feedback from SPs included their feelings when they were introduced to Tele simulation OSCE, Tele simulation versus Face to Face OSCE and areas of improvement.

Conclusion

Tele simulation OSCE was a quick adaptation during COVID-19 pandemic. But the lessons learned, and the feedback received are pearls for future innovative approaches to assessments. It is encouraged to collect verbal and written feedback for the improvement of Tele simulation.
Adiposity and risk of prostate cancer death: a prospective analysis in UK Biobank and meta-analysis of published studies
Authors: Perez-Cornago Aurora , Dunneram Yashvee , Watts Eleanor L. , Key Timothy J. , Travis Ruth C.
Published: October 2021

Introduction

The association of adiposity with prostate cancer specific mortality remains unclear. We examined how adiposity and its distribution relates to fatal prostate cancer by analysing data from UK Biobank, and conducting a dose-response meta-analysis to integrate existing prospective evidence. We also described the cross-sectional associations in UK Biobank of commonly used adiposity measurements with indices of adiposity estimated by imaging.

Methods

218,246 men from UK Biobank who were free from cancer at baseline were included and participants were followed-up via linkage to health administrative datasets. Body mass index (BMI), total body fat percentage (using bioimpedance), waist circumference (WC) and waist-to-hip ratio (WHR) were collected at recruitment. Risk of dying from prostate cancer (primary cause) by the different adiposity measurements was estimated using multivariable-adjusted Cox proportional hazards models. Results from this and other prospective cohort studies were combined in a dose-response meta-analysis.

Results

In UK Biobank, 631 men died from prostate cancer over a mean follow-up of 11.5 years. The hazard ratios (HR) for prostate cancer death were 1.10 (95% confidence interval=1.00-1.21) per 5 kg/m2 higher BMI, 1.03 (0.96-1.11) per 5% increase in total body fat percentage, 1.09 (1.02-1.18) per 10 cm increase in WC, and 1.09 (1.02-1.16) per 0.05 increase in WHR. Our meta-analyses of prospective studies included 22,106 prostate cancer deaths for BMI, 642 for body fat percentage, 3,153 for WC and 1,611 for WHR, and the combined HRs for dying from prostate cancer for the increments above were 1.10 (1.08-1.13), 1.03 (0.96-1.11), 1.08 (1.04-1.12), and 1.07 (1.02-1.12), respectively. In up to 4,800 UK Biobank participants with magnetic resonance imaging and dual-energy X-ray absorptiometry, BMI and WC were strongly associated with imaging estimations of total and central adiposity (e.g. visceral fat, trunk fat), with associations marginally larger for WC. There might be ∼1000 fewer prostate cancer deaths per year in the UK if the mean BMI in men was reduced by 5 kg/m2.

Conclusion

Overall, we found that men with higher total and central adiposity had similarly higher risks of prostate cancer death, which may be biologically driven or due to differences in detection. In either case, these findings provide further reasons for men to maintain a healthy body weight.
Single-Molecule Detection of SARS-CoV-2 by Plasmonic Sensing of Isothermally Amplified Nucleic Acids
Authors: Ye Haihang , Nowak Chance , Liu Yaning , Li Yi , Zhang Tingting , Bleris Leonidas , Qin Zhenpeng
Published: October 2021

Single-molecule detection of pathogens such as SARS-CoV-2 is key to combat infectious diseases outbreak and pandemic. Currently colorimetric sensing with loop-mediated isothermal amplification (LAMP) provides simple readouts but suffers from intrinsic non-template amplification. Herein, we report that plasmonic sensing of LAMP amplicons via DNA hybridization allows highly specific and single-molecule detection of SARS-CoV-2 RNA. Our work has two important advances. First, we develop gold and silver alloy (Au-Ag) nanoshells as plasmonic sensors that have 4-times stronger extinction in the visible wavelengths and give 20-times lower detection limit for oligonucleotides than Au nanoparticles. Second, we demonstrate that the diagnostic method allows cutting the complex LAMP amplicons into short repeats that are amendable for hybridization with oligonucleotide-functionalized nanoshells. This additional sequence identification eliminates the contamination from non-template amplification. The detection method is a simple and single-molecule diagnostic platform for virus testing at its early representation.

Table of Content
Heterogeneity of acetylcholine receptor autoantibody-mediated complement activity in patients with myasthenia gravis
Authors: Obaid Abeer H. , Zografou Chryssa , Vadysirisack Douangsone D. , Munro-Sheldon Bailey , Fichtner Miriam L. , Roy Bhaskar , Philbrick William M. , Bennett Jeffrey L. , Nowak Richard J. , O’Connor Kevin C.
Published: October 2021

Background

Autoantibodies targeting the acetylcholine receptor (AChR), found in patients with myasthenia gravis (MG), mediate pathology through three mechanisms: complement-directed tissue damage, blocking of the acetylcholine binding site, and internalization of the AChR. Clinical assays, used to diagnose and monitor patients, measure only autoantibody binding. Consequently, they are limited in providing association with disease burden, understanding of mechanistic heterogeneity, and monitoring therapeutic response.

Objective

Develop a cell-based assay that measures AChR autoantibody-mediated complement membrane attack complex (MAC) formation.

Methods

An HEK293T cell line—modified using CRISPR/Cas9 genome editing to disrupt expression of the complement regulator genes (CD46, CD55 and CD59)—was used to measure AChR autoantibody-mediated MAC formation via flow cytometry.

Results

Serum samples (n=155) from 96 clinically confirmed AChR MG patients, representing a wide range of disease burden and autoantibody titer, were tested along with 32 healthy donor (HD) samples. AChR autoantibodies were detected in 139 of the 155 (89.7%) MG samples via a cell-based assay. Of the 139 AChR positive samples, autoantibody-mediated MAC formation was detected in 83 (59.7%), while MAC formation was undetectable in the HD group or AChR positive samples with low autoantibody levels. MAC formation was positively associated with autoantibody binding in most patient samples; ratios (MFI) of MAC formation to AChR autoantibody binding ranged between 0.27–48, with a median of 0.79 and interquartile range of 0.43 (0.58–1.1). However, the distribution of ratios was asymmetric and included extreme values; 16 samples were beyond the 10–90 percentile, with high-MAC to low-AChR autoantibody binding ratio or the reverse. Correlation between MAC formation and clinical disease scores suggested a modest positive association (rho=0.34, p=0.0023), which included a subset of outliers that did not follow this pattern. MAC formation did not associate with exposure to immunotherapy, thymectomy, or MG subtypes defined by age-of-onset.

Conclusions

A novel assay for evaluating AChR autoantibody-mediated complement activity was developed. A subset of patients that lack association between MAC formation and autoantibody binding or disease burden was identified. The assay may provide a better understanding of the heterogeneous autoantibody molecular pathology and identify patients expected to benefit from complement inhibitor therapy.
Correlation between leukocyte phenotypes and prognosis of amyotrophic lateral sclerosis: a longitudinal cohort study
Authors: Cui Can , Ingre Caroline , Yin Li , Li Xia , Andersson John , Seitz Christina , Ruffin Nicolas , Pawitan Yudi , Piehl Fredrik , Fang Fang
Published: October 2021

Background

Immune response changes have been reported in amyotrophic lateral sclerosis (ALS), but their clinical relevance remains undetermined. Therefore, we aim to evaluate the relationships between blood leukocyte subpopulations and prognosis of ALS.

Methods

A longitudinal cohort of 288 ALS patients with up to 5 years of follow-up during 2015-2020 were recruited at the only tertiary referral center for ALS in Stockholm, Sweden. Routine differential leukocyte counts, and determination of lymphocyte subpopulations including an extended T cell panel with flow cytometry, collected at diagnosis and at regular intervals thereafter. The primary outcome was risk of death (alternatively use of invasive ventilation) after diagnosis of ALS. The secondary outcomes included repeatedly measured functional status - through Amyotrophic Lateral Sclerosis Functional Rating Scale-revised (ALSFRS-R) score and disease progression rate. Cox model was used to evaluate the associations between leukocytes and risk of death. Generalized estimating equation model (GEE) was used to assess the correlation between leukocytes and ALSFRS-R score and disease progression rate.

Results

The counts of leukocytes, neutrophils and monocytes increased gradually over time since diagnosis and were negatively correlated with ALSFRS-R score, but not associated with risk of death or disease progression rate. Focusing on lymphocyte subpopulations, increasing counts of natural killer (NK) cells (HR=0.61, 95% CI= [0.42-0.88] per SD increase) and proportions of Th2-diffrentiated CD4+ central memory (CM) T cells (HR=0.64, 95% CI= [0.48-0.85] per SD increase) were correlated with a lower risk of death. Increasing proportions of CD4+ effector memory cells re-expressing CD45RA (EMRA) T cells (HR=1.39, 95% CI= [1.01-1.92] per SD increase) and CD8+ T cells (HR=1.38, 95% CI= [1.03-1.86] per SD increase) were associated with a higher risk of death. None of the lymphocyte subpopulations was correlated with ALSFRS-R score or disease progression rate.

Conclusion

Our findings suggest a dual role of immune responses in ALS prognosis, where neutrophils and monocytes primarily reflect functional status whereas NK cells and different T lymphocyte populations act as prognostic markers for survival. The findings also provide insights for cell-specific treatment for ALS.

Funding

This work was supported by the European Research Council (ERC) Starting Grant (MegaALS, No. 802091), the Swedish Research Council (No. 2019-01088), Karolinska Institutet (Strategic Research Area in Epidemiology and Senior Researcher Award), and China Scholarship Council.
Paretic upper extremity strength at acute rehabilitation evaluation predicts motor function outcome after stroke
Authors: da Silva Mary Alice Saltão , Cook Christine , Stinear Cathy M , Wolf Steven L , Borich Michael R
Published: October 2021

Objective

The primary objective of this study was to retrospectively assess current care practices to determine the routinely collected measures that are most predictive of paretic upper extremity (PUE) functional outcome post-stroke in patients undergoing acute inpatient rehabilitation (AR).

Methods

We conducted a longitudinal chart review of patients post-stroke who received care in the Emory University Hospital system for acute hospitalization, AR, and outpatient therapy in fiscal years 2016-2018. We identified eligible patients using previously established inclusion and exclusion criteria. We extracted demographics, stroke characteristics, and longitudinal documentation of post-stroke motor function from institutional electronic medical records. Serial assessments of PUE strength were estimated using available shoulder abduction and finger extension manual muscle test documentation (E-SAFE). Estimated Action Research Arm Test (E-ARAT) was used to quantify 3-month PUE functional outcome. Metric associations were explored through correlation and cluster analyses, Kruskal-Wallis tests, classification and regression tree (CART) analysis.

Results

Thirty-four patients met study eligibility criteria. E-SAFE assessments performed closest to acute hospitalization day-3 (Acute E-SAFE) and upon AR admission (AR E-SAFE) were correlated with E-ARAT. Cluster analysis produced three distinct outcome groups and aligned closely to previous outcome categories. Outcome groups significantly differed in Acute E-SAFE and AR E-SAFE. Exploratory CART analysis selected AR E-SAFE to classify patient outcome with 70.6% accuracy.

Conclusions

Current study findings reveal that: PUE E-SAFE, measured both acutely and at AR admission, is associated with PUE motor recovery outcome; categorizations of outcome are consistent with previous studies; and predictive models can identify recovery outcome category in patients undergoing AR.

Impact Statement

Our findings highlight the clinical utility of SAFE as an easy-to-acquire, readily implementable screening metric. Early, intentional use of SAFE in AR settings may improve clinical decision-making, enabling therapists to deliver precision-based interventions that serve to speed or enhance recovery outcome for patients post-stroke.
Comparison of MIS-C Related Myocarditis, Classic Viral Myocarditis, and COVID-19 Vaccine related Myocarditis in Children
Authors: Patel Trisha , Kelleman Michael , West Zachary , Peter Andrew , Dove Matthew , Butto Arene , Oster Matthew E.
Published: October 2021

Background

Although rare, myocarditis in the pediatric population is a disease process that carries significant morbidity and mortality. Prior to the SARS-CoV-2 related (COVID-19) pandemic, enteroviruses were the most common cause of classic myocarditis. However, since 2020, myocarditis linked to multisystem inflammatory syndrome in children (MIS-C) is now common. In recent months, myocarditis related to COVID-19 vaccines has also been described. This study aims to compare these three different types of myocarditis with regards to clinical presentation, course, and outcomes.

Methods

In this retrospective cohort study, we included all patients <21 years of age hospitalized at our institution with classic viral myocarditis from 2015-2019, MIS-C myocarditis from 3/2020-2/2021 and COVID-19 vaccine-related myocarditis from 5/2021-6/2021. We compared demographics, initial symptomatology, treatment, laboratory data, and echocardiogram findings.

Results

Of 201 total participants, 43 patients had classic myocarditis, 149 had MIS-C myocarditis, and 9 had COVID-19 vaccine-related myocarditis. Peak troponin was highest in the classic myocarditis group, whereas the MIS-C myocarditis group had the highest recorded brain natriuretic peptide (BNP). There were significant differences in time to recovery of normal left ventricular ejection fraction (LVEF) for the three groups: nearly all patients with MIS-C myocarditis (n=139, 93%) and all patients with COVID-19 vaccine-related myocarditis (n=9, 100%) had normal LVEF at the time of discharge, but a lower proportion of the classic myocarditis group (n=30, 70%) had a normal LVEF at discharge (p<0.001). Three months post-discharge, 18 of 40 children (45%) in the classic myocarditis group still required heart failure treatment, whereas only one of the MIS-C myocarditis patients and none of the COVID-19 vaccine-associated myocarditis patients did.

Conclusions

Compared to those with classic myocarditis, those with MIS-C myocarditis had more significant hematologic derangements and worse inflammation at presentation, but had better clinical outcomes, including rapid recovery of cardiac function. Patients with COVID-19 vaccine-related myocarditis had similar clinical presentation to patients with classic myocarditis, but their pattern of recovery was similar to those with MIS-C, with prompt resolution of symptoms and improvement of cardiac function. Long-term follow-up should focus on cardiac and non-cardiac consequences of myocarditis associated with COVID-19 illness and vaccination.
Burden of five healthcare associated infections in Australia
Authors: Lydeamore M. J. , Mitchell B.G. , Bucknall T. , Cheng A.C. , Russo P.L. , Stewardson A. J.
Published: October 2021

Healthcare associated infections (HAIs) are associated with increased morbidity and mortality, but there are few data that quantify the burden of infection nationally in Australia. We used data from an Australian national point prevalence survey to estimate the burden of HAIs amongst adults in Australian public hospitals. The incidence based appropach, introduced by the ECDC Burden of Comunicable Diseases in Europe was used. We estimate that 170,574 HAIs occur in adults admitted to public hospitals in Australia annually, resulting in 7583 deaths. Hospital acquired pneumonia is the most frequent HAI, followed by surgical site infections, and urinary tract infections. We find that blood stream infections contribute a small percentage of HAIs, but contribute the highest number of deaths (3512), more than twice that of the second largest, while pneumonia has the highert impact on years lived with disability. This study is the first time the national burden of HAIs has been estimated for Australia from point prevalence data. The estimated burden is high, and highlights the need for continued investment in HAI prevention.
Effect of workplace infection control practices on workers’ psychological distress: a large-scale cohort study during the COVID-19 second state of emergency in Japan
Authors: Kodama Toyohiko , Ishimaru Tomohiro , Tateishi Seiichiro , Hino Ayako , Tsuji Mayumi , Ogami Akira , Nagata Tomohisa , Matsuda Shinya , Fujino Yoshihisa
Published: October 2021

Background

The COVID-19 pandemic has dramatically transformed the work environment and work practices worldwide. Long-term infection control practices may increase the psychological stress on workers, and conversely, inadequate infection control practices at the working place may increase the fear of infection. This study aimed to determine the relationship between infection control practices at the workplace and employee mental health during the COVID-19 pandemic in Japan.

Methods

This study was conducted in December 2020 and February 2021. The participants had undergone a preliminary survey, which revealed that they were in good mental health. Their psychological distress was investigated via a second survey, and the factors associated with distress were studied using a logistic model.

Results

The results of the second survey indicated that 15.1% of participants demonstrated psychological distress. This was associated with leave-of-absence instructions, instructions for shortening business hours, and requests to avoid the workplace in case of any symptoms.

Conclusion

The study found that while some infection control practices reduce workers’ distress, others worsen it. Employers need to consider infection control practices as well as the worsening mental health of employees following a decrease in income caused by such measures. Follow-up studies may be necessary to clarify the long-term effects on workers’ mental health.
Pan-cancer imaging of TERT expression using deuterium magnetic resonance spectroscopy-based assessment of pyruvate metabolism
Authors: Batsios Georgios , Taglang Céline , Tran Meryssa , Stevers Nicholas , Barger Carter , Gillespie Anne Marie , Ronen Sabrina M , Costello Joseph F , Viswanath Pavithra
Published: October 2021

Telomerase reverse transcriptase (TERT) expression is indispensable for tumor immortality. Non-invasive methods of imaging TERT can, therefore, report on tumor proliferation and response to therapy. Here, we show that TERT expression is associated with elevated levels of the redox metabolite NADH in multiple cancers, including glioblastoma, oligodendroglioma, melanoma, neuroblastoma, and hepatocellular carcinoma. Mechanistically, TERT acts via the metabolic regulator FOXO1 to upregulate nicotinamide phosphoribosyl transferase, which is the key enzyme for NADH biosynthesis. Importantly, deuterium magnetic resonance spectroscopy (2H-MRS), which is a novel, clinically translatable metabolic imaging modality, can be leveraged for imaging TERT-linked NADH in preclinical tumor models in vivo. Since NADH is essential for pyruvate flux to lactate, 2H-MRS following administration of 2H-labeled pyruvate non-invasively visualizes TERT expression and reports on early response to therapy. Collectively, our study provides insights into the mechanisms of TERT-linked metabolic reprogramming and, importantly, establishes 2H-MRS as a pan-cancer strategy for imaging tumor immortality.
Fusion of quantitative susceptibility maps and T1-weighted images improve brain tissue contrast in primates
Authors: Dadarwal Rakshit , Ortiz-Rios Michael , Boretius Susann
Published: October 2021

Recent progress in quantitative susceptibility mapping (QSM) has enabled the accurate delineation of submillimeter scale subcortical brain structures in humans. The simultaneous visualization of cortical, subcortical, and white matter structure remains, however, challenging, utilizing QSM data solely. Here we present TQ-SILiCON, a fusion method that enhances the contrast of cortical and subcortical structures and provides an excellent white matter delineation by combining QSM and conventional T1-weighted (T1w) images. In this study, we first applied QSM in the macaque monkey to map iron-rich subcortical structures. Implementing the same QSM acquisition and analysis methods allowed a similar accurate delineation of subcortical structures in humans. However, the QSM contrast of white and cortical gray matter was not sufficient for an appropriate segmentation. Applying automatic brain tissue segmentation to TQ-SILiCON images of the macaque improved the classification of subcortical brain structures as compared to the single T1 contrast by maintaining a good white to cortical gray matter contrast. Furthermore, we validated our dual-contrast fusion approach in humans and similarly demonstrated improvements in automated segmentation of cortical and subcortical structures. We believe the proposed contrast will facilitate translational studies in nonhuman primates to investigate the pathophysiology of neurodegenerative diseases that affect subcortical structures such as the basal ganglia in humans.

Highlights

The subcortical gray matter areas of macaque monkeys are reliably mapped by QSM, much as they are in humans.

Combining T1w and QSM images improves the visualization and segmentation of white matter, cortical and subcortical structures in the macaque monkey.

The proposed dual contrast TQ-SILiCON provides a similar image quality also in humans.

TQ-SILiCON facilitates comparative and translational neuroscience studies investigating subcortical structures.
DiviSSR: Simple arithmetic for efficient identification of tandem repeats
Authors: Avvaru Akshay Kumar , Mishra Rakesh K , Sowpati Divya Tej
Published: October 2021

Numerical or vector representations of DNA sequences have been applied for identification of specific sequence characteristics and patterns which are not evident in their character (A, C, G, T) representations. These transformations often reveal a mathematical structure to the sequences which can be captured efficiently using established mathematical methods. One such transformation, the 2-bit format, represents each nucleotide using only two bits instead of eight for efficient storage of genomic data. Here we describe a mathematical property that exists in the 2-bit representation of tandemly repeated DNA sequences. Our tool, DiviSSR (pronounced divisor), leverages this property and subsequent arithmetic to achieve ultrafast and accurate identification of tandem repeats. DiviSSR can process the entire human genome in ∼30s, and short sequence reads at a rate of >1 million reads/s on a single CPU thread. Our work also highlights the implications of using simple mathematical properties of DNA sequences for faster algorithms in genomics.

Availability

DiviSSR can be installed directly using python pip. The source code and documentation of DiviSSR are available at https://github.com/avvaruakshay/divissr.git.
High fat diet exacerbates cognitive decline in mouse models of Alzheimer’s disease and mixed dementia in a sex-dependent manner
Authors: Gannon Olivia J. , Robison Lisa S. , Salinero Abigail E. , Abi-Ghanem Charly , Mansour Febronia , Tyagi Alvira , Brawley Rebekah , Ogg Jordan , Zuloaga Kristen L.
Published: October 2021

Approximately 70% of Alzheimer’s disease (AD) patients have co-morbid vascular contributions to cognitive impairment and dementia (VCID); this highly prevalent overlap of dementia subtypes is known as mixed dementia (MxD). AD is more prevalent in women, while VCID is slightly more prevalent in men. Sex differences in risk factors may contribute to sex differences in dementia subtypes. Unlike metabolically healthy women, diabetic women are more likely to develop VCID than diabetic men. Prediabetes is 3x more prevalent than diabetes and is linked to earlier onset of dementia in women, but not men. How prediabetes influences underlying pathology and cognitive outcomes across different dementia subtypes is unknown. To fill this gap in knowledge, we investigated the impact of diet-induced prediabetes and biological sex on cognitive function and neuropathology in mouse models of AD and MxD. Male and female 3xTg-AD mice received a sham (AD model) or unilateral common carotid artery occlusion surgery to induce chronic cerebral hypoperfusion (MxD model). Mice were fed a control or high fat (HF; 60% fat) diet for 3 months prior to behavior assessment. In both sexes, HF diet elicited a prediabetic phenotype (impaired glucose tolerance) and weight gain. In females, but not males, metabolic consequences of a HF diet were more severe in AD or MxD mice compared to WT. In both sexes, HF-fed AD or MxD mice displayed deficits in spatial memory in the Morris water maze (MWM). In females, but not males, HF-fed AD and MxD mice also displayed impaired spatial learning in the MWM. In females, but not males, AD or MxD caused deficits in activities of daily living, regardless of diet. Astrogliosis was more severe in AD and MxD females compared to males. Further, HF diet caused greater accumulation of amyloid beta in MxD females compared to MxD males. In females, but not males, more severe glucose intolerance (prediabetes) was correlated with increased hippocampal microgliosis. In conclusion, high fat diet had a wider array of metabolic, cognitive, and neuropathological consequences in AD and MxD females compared to males. These findings shed light on potential underlying mechanisms by which prediabetes may lead to earlier dementia onset in women.

Highlights

Created a mouse model of mixed dementia (MxD) with both AD + VCID pathology.

HF diet caused greater metabolic impairment in AD and MxD females, compared to males.

AD and MxD females showed a wider array of cognitive deficits, compared to males.

Astrogliosis and Aβ pathology were more severe in AD/MxD females, compared to males.

Metabolic impairment was more consistently associated with reductions in cognitive function in females.

More severe glucose intolerance was associated with worse microgliosis in females only.
Pan-cancer organoid validation of tumor outlier chromosomal amplification events
Authors: Salahudeen Ameen A. , Yuki Kanako , Seoane Jose A. , Mah Amanda T. , Smith Amber R. , Kolahi Kevin , De la O Sean M. , Hart Daniel J. , Ding Jie , Ma Zhicheng , Barkal Sammy , Shukla Navika D. , Zhang Chuck , Cantrell Michael A. , Batish Arpit , Usui Tatsuya , Root David , Hahn William , Curtis Christina , Kuo Calvin J
Published: October 2021

Somatic copy number gains are pervasive in many cancer types, yet their roles in oncogenesis are often poorly explored. This lack of understanding is in part due to broad extensions of copy gains across cancer genomes spanning large chromosomal regions, obscuring causal driver loci. Here we employed a multi-tissue pan-organoid modeling approach to validate candidate oncogenic loci identified within pan-cancer TCGA data by the overlap of extreme copy number amplifications with extreme expression dysregulation for each gene. The candidate outlier loci nominated by this integrative computational analysis were functionally validated by infecting cancer type-specific barcoded full length cDNA lentiviral libraries into cognate minimally transformed human and mouse organoids bearing initial oncogenic mutations from esophagus, oral cavity, colon, stomach, pancreas and lung. Presumptive amplification oncogenes were identified by barcode enrichment as a proxy for increased proliferation. Iterative analysis validatedDYRK2at 12q15, encoding a serine-threonine kinase, as an amplified head and neck squamous carcinoma oncogene inp53-/-oral mucosal organoids. Similarly,FGF3, amplified at 11q13 in 41% of esophageal squamous carcinomas, was validated inp53-/-esophageal organoids in vitro and in vivo with pharmacologic inhibition by small molecule and soluble receptor FGFR antagonists. Our studies establish the feasibility of pan-organoid contextual modeling of pan-cancer candidate genomic drivers, enabling oncogene discovery and preclinical therapeutic modeling.
NFkB-signaling promotes glial reactivity and suppresses Müller glia-mediated neuron regeneration in the mammalian retina
Authors: Palazzo Isabella , Todd Levi J. , Hoang Thanh V. , Reh Thomas A. , Blackshaw Seth , Fischer Andy J.
Published: October 2021

Müller glia (MG) in mammalian retinas are incapable of regenerating neurons after damage, whereas the MG in lower vertebrates regenerate functional neurons. Identification networks that regulate MG-mediated regeneration is key to harnessing the regenerative potential of MG. Here we study how NFkB-signaling influences glial responses to damage and reprogramming of MG into neurons in the rodent retina. We find activation of NFkB and dynamic expression of NFkB-associated genes in MG after damage, however NFkB activity is inhibited by microglia ablation. Knockout of NFkB in MG suppressed the accumulation of immune cells after damage. Inhibition of NFkB following NMDA-damage significantly enhanced the reprogramming of Ascl1-overexpressing MG into neuron-like cells. scRNA-seq of retinal glia following inhibition of NFkB reveals coordination with signaling via TGFβ2 and suppression of NFI and Id transcription factors. Inhibition of Smad3 or Id transcription factors increased numbers of neuron-like cells produced by Ascl1-overexpressing MG. We conclude that NFkB is a key signaling hub that is activated in MG after damage, mediates the accumulation of immune cells, and suppresses the neurogenic potential of MG.
Transient definitive host presence is sufficient to sustain avian schistosome populations
Authors: Rudko Sydney P , McPhail Brooke A , Reimink Ronald L , Froelich Kelsey , Turnbull Alyssa , Hanington Patrick C
Published: October 2021

To control swimmer’s itch in northern Michigan inland lakes, one species of bird, the common merganser (Mergus merganser), has been relocated from several lakes since 2015. Relocation efforts are driven by a desire to reduce the prevalence of the swimmer’s itch-causing parasite Trichobilharzia stagnicolae. The intention of this state-sponsored control effort was to interrupt the life cycle of T. stagnicolae and reduce parasite egg contribution into the environment from summer resident mergansers such that infections of the intermediate snail host Stagnicola emarginata declined. Reduced snail infection prevalence was expected to greatly reduce abundance of the swimmer’s itch-causing cercarial stage of the parasite in water. With no official program in place to assess the success of this relocation effort, we sought to study the effectiveness and impact of the removal of a single definitive host from a location with high definitive host and parasite diversity. This was assessed through a comprehensive, lake-wide monitoring study measuring longitudinal changes in the abundance of three species of avian schistosome cercariae in four inland Michigan lakes. Environmental measurements were also taken at these lakes to understand how they can affect swimmer’s itch incidence. Results from this study demonstrate that the diversity of avian schistosomes at the study lakes would likely make targeting of a single species of swimmer’s itch-causing parasite meaningless from a swimmer’s itch control perspective. Our data also suggest that removal of the common merganser is not an effective control strategy for the T. stagnicolae parasite, likely due to parasite contributions of migratory birds in the fall and spring. This suggests that only minimal contact time between the definitive host and the lake ecosystem is required to contribute sufficient parasite numbers to maintain a thriving population of parasite species with a high host-specificity.
MetAMDB: Metabolic Atom Mapping Database
Authors: Starke Collin , Wegner Andre
Published: October 2021

Abstract

MetAMDB (https://metamdb.tu-bs.de/) is an open source metabolic atom mapping database, providing atom mappings for around 75000 metabolic reactions. Each atom mapping can be inspected and downloaded either as a RXN file or as a graphic in SVG format. In addition, MetAMDB offers the possibility of automatically creating atom mapping models based on user-specified metabolic networks. These models can be of any size (small to genome scale) and can subsequently be used in standard 13C metabolic flux analysis software.
The kinectome: a comprehensive kinematic map of human motion in health and disease
Authors: Lopez Emahnuel Troisi , Sorrentino Pierpaolo , Liparoti Marianna , Minino Roberta , Carotenuto Anna , Amico Enrico , Sorrentino Giuseppe
Published: October 2021

Effective human movement requires the coordinated participation of the whole musculoskeletal system. Here we propose to represent the human body movements as a network (that we named “kinectome”), where nodes are body parts, and edges are defined as the correlations of the accelerations between each pair of body parts during gait. We apply this framework in healthy individuals and patients with Parkinson’s disease (PD). The network dynamics in Parkinson’s display high variability, as conveyed by the high variance and the modular structure in the patients’ kinectomes. Furthermore, our analysis identified a set of anatomical elements that are specifically related to the balance impairment in PD. Furthermore, each participant could be identified based on its kinectome patterns, akin to a “fingerprint” of movement, confirming that our approach captures relevant features of gait. We hope that applying network approaches to human kinematics yields new insights to characterize human movement.
Isotopic signatures induced by upwelling reveal regional fish populations in Lake Tanganyika
Authors: Ehrenfels Benedikt , Junker Julian , Namutebi Demmy , Callbeck Cameron M. , Dinkel Christian , Kalangali Anthony , Kimirei Ismael A. , Mbonde Athanasio S. , Mosille Julieth B. , Sweke Emmanuel A. , Schubert Carsten J. , Seehausen Ole , Wagner Catherine E. , Wehrli Bernhard
Published: October 2021

Lake Tanganyika’s pelagic fish sustain the second largest inland fishery in Africa and are under pressure from heavy fishing and global warming related increases in stratification. Only little is known about whether basin-scale hydrodynamics – including a more stratified north and an upwelling-driven south – induce ecological and genetic differences among populations of highly mobile, pelagic fish inhabiting these different areas. Here, we examine whether the basin-scale dynamics leave distinct isotopic imprints in the pelagic fish of Lake Tanganyika, which may reveal differences in habitat, diet, or lipid content. We conducted two lake-wide campaigns during different seasons and collected physical, nutrient, chlorophyll, phytoplankton and zooplankton data. Additionally, we analyzed the pelagic fish – the clupeids Stolothrissa tanganicae, Limnothrissa miodon and four Lates species – for their isotopic and elemental carbon (C) and nitrogen (N) compositions. The δ13C values were significantly higher in the productive south after the upwelling/mixing period across all trophic levels, implying that the fish have regional foraging grounds, and thus record these latitudinal isotope gradients. By combining our isotope data with genetics, we demonstrate that the fish form regional populations on a seasonal to multiannual time scale. Based on δ15N and C:N ratios, we found no strong evidence for varying diets or lipid contents between those regional populations.

Additional analyses revealed that isotopic variations between specimens from the same location are not linked to genetic differences. We suggest that the development of basinscale ecological differences in response to the prevailing hydrodynamic regimes may be inhibited by lake-wide gene flow on the long term. Our findings show that the pelagic fish species are genetically adapted to the whole lake, but they form regional populations on short time scales. This implies that sustainable management strategies may adopt basin-scale fishing quotas.