bluuebunny/crossref_metadata_2025 huggingface dataset:
Extensive polyploid clonality was a successful strategy for seagrass to expand into a newly submerged environment
Authors: Edgeloe Jane M. , Severn-Ellis Anita A. , Bayer Philipp E. , Mehravi Shaghayegh , Breed Martin F. , Krauss Siegfried L. , Batley Jacqueline , Kendrick Gary A. , Sinclair Elizabeth A.
Published: June 2022

Polyploidy has the potential to allow organisms to outcompete their diploid progenitor(s) and occupy new environments. Shark Bay, Western Australia, is a World Heritage Area dominated by temperate seagrass meadows including Poseidon's ribbon weed,
Posidonia australis
. This seagrass is at the northern extent of its natural geographic range and experiences extremes in temperature and salinity. Our genomic and cytogenetic assessments of 10 meadows identified geographically restricted, diploid clones (2
n
= 20) in a single location, and a single widespread, high-heterozygosity, polyploid clone (2
n
= 40) in all other locations. The polyploid clone spanned at least 180 km, making it the largest known example of a clone in any environment on earth. Whole-genome duplication through polyploidy, combined with clonality, may have provided the mechanism for
P. australis
to expand into new habitats and adapt to new environments that became increasingly stressful for its diploid progenitor(s). The new polyploid clone probably formed in shallow waters after the inundation of Shark Bay less than 8500 years ago and subsequently expanded via vegetative growth into newly submerged habitats.
Performance study of the anterior nasal AMP SARS-CoV-2 rapid antigen test in comparison with nasopharyngeal rRT-PCR
Authors: Leixner Georg , Voill-Glaninger Astrid , Krejci Isabella , Gaugeler-Kurzweil Julia , Kusstatscher Tanja , Krugluger Walter , Viveiros André
Published: June 2022

Introduction. The gold standard for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection is real-time reverse transcription PCR (rRT-PCR), which is expensive, has a long turnaround time and requires special equipment and trained personnel. Nasopharyngeal swabs are uncomfortable, not suitable for certain patient groups and do not allow self-testing. Convenient, well-tolerated rapid antigen tests (RATs) for SARS-CoV-2 detection are called for.

Gap statement. More real-life performance data on anterior nasal RATs are required.

Aim. We set out to evaluate the anterior nasal AMP RAT in comparison with rRT-PCR in a hospital cohort.

Methodology. The study included 175 patients, either hospitalized in a coronavirus disease 2019 (COVID-19) ward or screened in a preadmittance outpatient clinic. Two swabs were collected per patient: an anterior nasal one for the RAT and a combined naso-/oropharyngeal one for the rRT-PCR. Sixty-five patients (37%) were rRT-PCR-positive [cycle threshold (C
t) <40].

Results. The anterior nasal AMP RAT showed an overall sensitivity and specificity of 29.2 % (18.6–41.8, 95 % CI) and 100.0 % (96.7–100.0, 95 % CI) respectively. In patients with a C
t value <25, <30 and <33, higher sensitivities were observed. Time since symptom onset was significantly higher in patients with a false-negative RAT (P=0.02).

Conclusion. The anterior nasal AMP RAT showed low sensitivities in this cohort, especially in patients with a longer time since symptom onset. Further knowledge concerning the viral load and antigen expression over time and in different swabbing locations is needed to outline the usage time frame for SARS-CoV-2 RAT.
Comparison and critical assessment of single-cell Hi-C protocols
Authors: Gridina M. , Taskina A. , Lagunov T. , Nurislamov A. , Kulikova T. , Krasikova A. , Fishman V
Published: June 2022

Advances in single-cell sequencing technologies make it possible to study the genome architecture in single cells. The rapid growth of the field has been fueled by the development of innovative single-cell Hi-C protocols. However, the protocols vary considerably in their efficiency, bias, scale and costs, and their relative advantages for different applications are unclear.

Here, we compare the two most commonly used single-cell Hi-C protocols. We use long-read sequencing to analyze molecular products of the Hi-C assay and show that whole-genome amplification step results in increased number of artifacts, larger coverage biases, and increased amount of noise compared to PCR-based amplification. Our comparison provides guidance for researchers studying chromatin architecture in individual cells.
Evaluating the impact on clinical task efficiency of a natural language processing algorithm for searching medical documents: Prospective crossover study
Authors: Park Eunsoo H , Watson Hannah I , Mehendale Felicity V , O’Neil Alison Q
Published: June 2022

Background

Information retrieval (IR) from the free text within Electronic Health Records (EHRs) is time-consuming and complex. We hypothesise that Natural Language Processing (NLP)-enhanced search functionality for EHRs can make clinical workflows more efficient and reduce cognitive load for clinicians.

Objective

To evaluate the efficacy of three levels of search functionality (no search, string search, and NLP-enhanced search) in supporting IR for clinical users from the free text of EHR documents in a simulated clinical environment.

Methods

A clinical environment was simulated by uploading three sets of patient notes into an EHR research software application and presenting these alongside three corresponding IR tasks. Tasks contained a mixture of multiple choice and free text questions.

A prospective crossover study design was used, for which three groups of evaluators were recruited, comprised of doctors (n=19) and medical students (n=16). Evaluators performed the three tasks using each of the search functionalities in an order according to their randomly assigned group. The speed and accuracy of task completion was measured and analysed, and user perceptions of NLP-enhanced search were reviewed in a feedback survey.

Results

NLP-enhanced search facilitated significantly more accurate task completion than both string search (5.26%, p=0.01) and no search (7.44%, p=0.05). NLP-enhanced search and string search facilitated similar task speeds, both showing an increase in speed over no search function (15.9%/11.6%, p=0.05). 93% of evaluators agreed that NLP-enhanced search would make clinical workflows more efficient than string search, with qualitative feedback reporting that NLP-enhanced search reduced cognitive load.

Conclusions

To the best of our knowledge, this study is the largest evaluation to date of different search functionalities for supporting target clinical users in realistic clinical workflows, with a 3-way prospective crossover study design. NLP-enhanced search improved both accuracy and speed of clinical EHR IR tasks compared to browsing clinical notes without search. NLP-enhanced search improved accuracy and reduced the number of searches required for clinical EHR IR tasks compared to direct search term matching.
A multicenter, prospective, cross-sectional, genotype-phenotype and longitudinal natural history study of Andersen-Tawil syndrome
Authors: Rajakulendran Sanjeev , Tristani-Firouzi Martin , Sadjadi Reza , Cleland James , Tawil Rabi , Meola Giovanni , Sansone Valeria , Trivedi Jaya , Cannon Stephen C , Hanna Michael G , Griggs Robert C.
Published: June 2022

Objective

A multi-center, prospective, cross-sectional natural history study to define the clinical phenotype of Andersen-Tawil syndrome, validate its current diagnostic criteria, explore genotype-phenotype correlations, and establish clinically relevant endpoints for use in therapeutic trials.

Methods

Participants were followed at yearly intervals for two years. Outcome measures included attack frequency and duration, neurophysiological exercise testing and interictal muscle strength. Cardiac endpoints were QTc interval, presence of U-waves, frequency of ventricular ectopy and arrhythmias. Participants completed the SF-36 and underwent KCNJ2 gene analysis.

Results

28 participants were enrolled. The age range was 17 to 82 years. 23 participants harbored mutations in KCNJ2, including a new mutation, Y68D. All exhibited at least one skeletal feature with 26/28 exhibiting two or more. Common physical abnormalities were a small mandible (89%), low set ears (82%) and micromelia of hands or feet (71%). 26 participants reported periodic paralysis. The frequency of attacks varied from 12/week to 1/year, and duration from 12 minutes to 21 days. Common triggers for attacks were prolonged rest (85%) and exercise/exertion (73%). 20/25 had an abnormal long exercise test. A prolonged QTc interval was identified in 36% participants, U waves in 39% and ambulatory ECGs demonstrated runs of ventricular tachycardia in 32% and more than 10 000 ventricular couples in 14% of participants.

Interpretation

There is extensive heterogeneity in both the spectrum and severity of Andersen-Tawil syndrome. Overall, the symptoms result in a significant impairment in quality of life. The cardiac and neurophysiological data could serve as outcome measures in future treatment trials.
Pharmacogenomics of GLP-1 Receptor Agonists: A genome wide analysis of observational data and large randomized controlled trials
Authors: Dawed Adem Y , Mari Andrea , McDonald Timothy J , Li Lin , Wang Shuaicheng , Hong Mun-Gwan , Sharma Sapna , Robertson Neil R , Mahajan Anubha , Wang Xuan , Walker Mark , Gough Stephen , ‘t Hart Leen M , Zhou Kaixin , Forgie Ian , Ruetten Hartmut , Pavo Imre , Bhatnagar Pallav , Jones Angus G , Pearson Ewan R ,   DIRECT consortium
Published: June 2022

Background

In the treatment of type 2 diabetes (T2D), GLP-1 Receptor Agonists (GLP-1RA) lower glucose levels and body weight, and have cardiovascular benefits. GLP-1RA efficacy and side effects vary between people. Human pharmacogenomic studies of this inter-individual variation can provide both biological insight into drug action and provide biomarkers to inform clinical decision making. We therefore aimed to identify genetic variants associated with glycaemic response to GLP-1RA treatment.

Methods

We studied HbA1c reduction at 6 months after starting GLP-1RA in 4,571 subjects with T2D from four prospective observational cohorts and two randomized clinical trials. We evaluated variants in GLP-1R, then undertook a genome-wide association study (GWAS) and gene-based burden test.

Findings

Variation in HbA1c reduction with GLP-1RA treatment was associated with rs6923761G>A (Gly168Ser) in the GLP-1R (0.9 mmol/mol lower reduction in HbA1c per Serine, p=6.0×10−05) and low frequency variants in ARRB1 (pskato=6.72×10−08), largely driven by rs140226575G>A (Thr370Met) (2.7mmol/mol greater HbA1c reduction per Methionine, p=5.2×10−06). A similar effect size for the ARRB1 Thr370Met was seen in Hispanic and American Indian populations who have a higher frequency of this variant (6-11%) than in White populations. A genetic risk score derived from these two genes identified around 5% of the population who had a ∼30% greater reduction in HbA1c than the ∼43% of the population with the worse response.

Interpretation

This first genome wide pharmacogenomic study of GLP-1RA has provided novel biological and clinical insights. Clinically, when genotype is routinely available at the point of prescribing, individuals with ARRB1 variants may benefit from earlier initiation of GLP-1RA.

Funding

Innovative Medicines Initiative, Wellcome Trust
Identifying patients presenting in pain to the adult emergency department: A binary classification task and description of prevalence
Authors: Hughes J.A. , Douglas C. , Jones L. , Brown N.J. , Nguyen A. , Jarugula R. , Lyrstedt A. , Hazelwood S. , Wu Y. , Saleh F. , Chu K.
Published: June 2022

Background

Accurate, reliable and efficient measures of pain-related presentations are essential to evaluate and improve pain care in the ED. Estimates of pain prevalence on arrival to the emergency department (ED) vary depending on the methods used. Artificial intelligence (AI) approaches are likely to be the future for identifying patients in pain from electronic health records (EHR). However, we need a robust method to identify these patients before this can occur. This study aims to identify patients presenting in pain to the ED using binary classification and to describe the population, treatment and outcomes.

Methods

This study employs a cross-sectional design using retrospective data routinely collected in the EHR at a single ED. A random sample of 10 000 patients was selected for inclusion over three years. Triage nursing assessment underwent binary classification by three expert clinicians. The prevalence of pain on arrival is the primary outcome. Patients with pain were compared to those without pain on arrival regarding demographics, treatment and outcomes.

Results

The prevalence of pain on arrival was 55.2% (95%CI 54.2% - 56.2%). Patients who presented in pain differed from those without pain in terms of age, country of birth, socioeconomic status, mode of arrival, urgency and discharge destination. The median time to first analgesic medication was 65min (IQR 38 – 114 min), and 45.6% (95% CI 44.3% - 46.9%) of patients arriving in pain received analgesic medication.

Conclusions

The prevalence of pain on arrival compares well with previously reported figures using similar methods. Differences in the cohort presenting in pain compared to the population may represent differences in the prevalence or be an extension of previous bias seen in the documentation of pain. This work has set a rigorous methodology for identifying patients presenting with pain from the EHR. It will form the basis for future applications of AI to identify patients presenting in pain to the ED.
Sputum alarmin levels delineate distinct T2 cytokine pathways and patient subgroups in asthma
Authors: Gautam Samir , Chu Jen-Hwa , Cohen Avi J. , Kaur Ravdeep , Wilson Gabriella , Liu Qing , Gomez Jose , Rajaveen Haseena , Yan Xiting , Cohn Lauren , Clark Brian J. , Chupp Geoffrey
Published: June 2022

Rationale

Asthma is a chronic airway disease driven by multiple immunologic pathways that determine the clinical response to therapy. Current diagnostic methods are incapable of discriminating subtypes of asthma and guiding targeted treatment. We hypothesized that sputum cytokine profiles could help to identify immunologically-defined disease subtypes and individualize therapy in patients with severe asthma.

Objectives

Define asthma subtypes associated with sputum alarmin and cytokine levels.

Methods

Cross-sectional analysis of clinical features and sputum from 200 asthmatic patients was performed. 10 cytokines belonging to alarmin, T2, and non-T2 pathways were measured. Pearson correlation was used to identify cytokine modules. Latent class analysis was used to cluster patients by cytokine expression.

Measurements and Main Results

Three modules of highly correlated cytokines were identified including a non-T2 module, the IL-1βmod (IL-1β, IL-6, GCSF), and two distinct T2 modules: TSLPmod (TSLP, IL-4, IL-5, IL-9) and IL-33mod (IL-33, IL-13, IL-21). The TSLPmod was associated with asthma severity, airway obstruction, eosinophilia, and elevated FeNO. Patient clustering revealed three subgroups; two different subgroups showed expression of T2 modules.

Conclusions

Analysis of sputum cytokines revealed three discrete signaling modules in patients with asthma. Unexpectedly, the inclusion of alarmins led to separation of canonical T2 cytokines into two unique modules; IL-5 grouped with TSLP, while IL-13 grouped with IL-33. In addition, patient clustering revealed two distinct endotypes associated with T2 immune signaling. These findings indicate a new layer of immunologic heterogeneity within the T2 paradigm, and suggest that sputum cytokine profiling may hold diagnostic utility for patients with asthma.
Progressivity of out-of-pocket costs under Australia’s universal health care system: a national linked data study
Authors: Law HD , Marasinghe D , Butler D , Welsh J , Lancsar E , Banks E , Biddle N , Korda R
Published: June 2022

Background

In line with affordability and equity principles, Medicare—Australia’s universal health care program—has measures to contain out-of-pocket costs (OOPC), particularly for lower income households. This study examined the distribution of OOPC for Medicare-subsidised out-of-hospital services and prescription medicines in Australian households, according to their ability to pay.

Methods

OOPC for out-of-hospital services and medicines in 2017-18 were estimated for each household, using 2016 Australian Census data linked to Medicare Benefits Schedule (MBS) and Pharmaceutical Benefit Scheme (PBS) claims. We derived household disposable income by combining income information from the Census linked to income tax and social security data. We quantified OOPC as a proportion of equivalised household disposable income and calculated Kakwani progressivity indices (K).

Results

Using data from 85% (n=6,830,365) of all Census private households, OOPC as a percentage of equivalised household disposable income decreased from 1.16% in the poorest decile to 0.63% in the richest decile for MBS services, and from 1.35% to 0.35% for PBS medicines. The regressive trend was less pronounced for MBS services (K = −0.06), with percentage OOPC relatively stable between the 2nd and 9th income deciles; while percentage OOPC decreased substantially with increasing income for PBS medicines (K = −0.24).

Conclusion

OOPC for out-of-hospital Medicare services were mildly regressive while those for prescription medicines were distinctly regressive. Actions to reduce inequity in OOPC, particularly for medicines should be considered.
Multi-polygenic scores in psychiatry: from disorder-specific to transdiagnostic perspectives
Authors: Shi Yingjie , Sprooten Emma , Mulders Peter , Vrijsen Janna , Bralten Janita , Demontis Ditte , Børglum Anders D. , Walters G. Bragi , Stefansson Kari , van Eijndhoven Philip , Tendolkar Indira , Franke Barbara , Mota Nina Roth
Published: June 2022

The dense co-occurrence of psychiatric disorders questions the categorical classification tradition and motivates efforts to establish dimensional constructs with neurobiological foundations that transcend diagnostic boundaries. In this study, we examined the genetic liability for eight major psychiatric disorder phenotypes under both a disorder-specific and a transdiagnostic framework. In a deeply-phenotyped sample (n=513) consisting of 452 patients from tertiary care with mood disorders, anxiety disorders, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), and/or substance use disorders (SUD) and 61 unaffected comparison individuals, we derived subject-specific multi-base polygenic risk score (PRS) profiles and assessed their associations with psychiatric diagnoses, comorbidity status, as well as cross-disorder behavioral dimensions. High PRS for depression was unselectively associated with the diagnosis of SUD, ADHD, anxiety disorders, mood disorders, and the comorbidities among them. In the dimensional approach, four distinct functional domains were uncovered, namely the negative valence, social, cognitive, and regulatory systems, closely matching the major functional domains proposed by the Research Domain Criteria (RDoC) framework. Critically, the genetic predisposition for depression was selectively reflected in the functional aspect of negative valence systems but not others. This study highlights a misalignment between current psychiatric nosology and the underlying psychiatric genetic etiology, and underscores the effectiveness of the dimensional approach in both the functional characterization of psychiatric patients and the delineation of the genetic liability for psychiatric disorders.
The role of adolescent lifestyle habits in biological aging: A prospective twin study
Authors: Kankaanpää Anna , Tolvanen Asko , Heikkinen Aino , Kaprio Jaakko , Ollikainen Miina , Sillanpää Elina
Published: June 2022

Adolescence is a stage of fast growth and development. Exposures during puberty can have long-term effects on health in later life. This study aims to investigate the role of adolescent lifestyle in biological aging. The study participants originated from the longitudinal FinnTwin12 study (n = 5114). Adolescent lifestyle-related factors, including body mass index (BMI), leisure-time physical activity, smoking and alcohol use, were based on self-reports and measured at ages 12, 14 and 17 years. For a subsample, blood-based DNA methylation (DNAm) was used to assess biological aging with six epigenetic aging measures in young adulthood (21–25 years, n = 824). A latent class analysis was conducted to identify patterns of lifestyle behaviors in adolescence, and differences between the subgroups in later biological aging were studied. Genetic and environmental influences on biological aging shared with lifestyle behavior patterns were estimated using quantitative genetic modelling.

We identified five subgroups of participants with different adolescent lifestyle behavior patterns. When DNAm GrimAge, DunedinPoAm and DunedinPACE estimators were used, the class with the unhealthiest lifestyle and the class of participants with high BMI were biologically older than the classes with healthier lifestyle habits. The differences in lifestyle-related factors were maintained into young adulthood. Most of the variation in biological aging shared with adolescent lifestyle was explained by common genetic factors. These findings suggest that an unhealthy lifestyle during pubertal years is associated with accelerated biological aging in young adulthood. Genetic pleiotropy can largely explain the observed associations.
Comparative efficacy of different eating patterns in the management of type 2 diabetes and prediabetes: An arm-based Bayesian network meta-analysis
Authors: Zeng Ben-tuo , Pan Hui-qing , Li Feng-dan , Ye Zhen-yu , Liu Yang , Du Ji-wei
Published: June 2022

Aims/Introduction

Diet therapy is a vital approach to manage type 2 diabetes and prediabetes. However, the comparative efficacy of different eating patterns is not clear enough. We aimed to compare the efficacy of various eating patterns for glycemic control, anthropometrics, and serum lipid profiles in the management of type 2 diabetes and prediabetes.

Materials and Methods

We conducted a network meta-analysis using arm-based Bayesian methods and random effect models, and drew the conclusions using the partially contextualized framework. We searched twelve databases and yielded 9,534 related references, where 107 studies were eligible, comprising 8,909 participants.

Results

Eleven diets were evaluated for fourteen outcomes. Caloric restriction was ranked as the best pattern for weight loss (SUCRA 86.8%) and waist circumference (82.2%), low-carbohydrate diets for body mass index (81.6%) and high-density lipoprotein (84.0%), and low-glycemic-index diets for total cholesterol (87.5%) and low-density lipoprotein (86.6%). Other interventions showed some superiorities, but were of imprecision due to insufficient participants and needed further investigation. The attrition rates of interventions were similar. Meta-regression suggested that macronutrients, energy intake, and weight may modify outcomes differently. The evidence was of moderate-to-low quality, and 38.2% of the evidence items met the minimal clinically important differences.

Conclusions

The selection and development of dietary strategies for diabetic/prediabetic patients should depend on their holistic conditions, i.e., serum lipids profiles, glucometabolic patterns, weight and blood pressures. It is recommended to identify the most critical and urgent metabolic indicator to control for one specific patient, and then choose the most appropriate eating pattern accordingly.
Using a design-based research approach to develop a technology-supported physical education course to increase the physical activity levels of university students: Study protocol paper
Authors: Sultoni Kuston , Peralta Louisa , Cotton Wayne
Published: June 2022

Background

Promoting physical activity (PA) for university students is essential as PA levels decrease during the transition from secondary to higher education. Providing technology-supported university courses targeting students’ PA levels may be a viable option to combat the problem. However, it is still unclear how and what technologies should be implemented in university courses to promote PA. This study aims to create a series of design principles for technology-supported physical education courses that aim to increase university students’ PA knowledge, motivation and levels.

Method

The proposed methodology underpinning the research program is a seven-phase design-based research (DBR) approach, with the seven phases encompassed in four sequential studies. These four studies are a systematic review, a qualitative focus group study, a pilot study, and a randomised controlled trial (RCT) study. The protocol paper aims to detail the plan for conducting the four studies in a comprehensive and transparent manner, thus contributing to the methodological evidence base in this field.

Discussion

Design principles generated from this project will contribute to the growing evidence focusing on effective design and implementation features. Future practitioners can also use these to develop physical education courses that aim to promote university students’ physical activity levels, knowledge, and motivation.

Ethical consideration

This project has obtained ethical approval from the University of Sydney Human Research Ethics Committee (Project No. 2021/071; Project No. 2021/935). The randomised controlled trial protocol is registered at the Australian New Zealand Clinical Trials Registry (ANZCTR).

Trial registration

the RCT registry number: ACTRN12622000712707, 18/05/2022
Diagnostic delay of sarcoidosis: protocol for an integrated systematic review
Authors: Namsrai Tergel , Desborough Jane , Gregory Dianne , Kelly Elaine , Cook Matthew , Phillips Christine , Parkinson Anne
Published: June 2022

Sarcoidosis is a rare systemic inflammatory granulomatous disease with broad manifestation ranging from acute epileptic seizures to fatigue and pain syndromes that are subject to the organ involved. Delays in the diagnosis of sarcoidosis are attributed to the lack of a single diagnostic test or unified commonly used diagnostic criteria, and diagnosis based on exclusion of possible alternative diagnoses. We aim to systematically review the evidence about diagnostic delay in sarcoidosis to elucidate the causes and consequences of diagnostic delay, including people with sarcoidosis’ experiences. This will inform the development of interventions, tools, and health policies aiming to improve diagnostic efficiency and patients’ experiences of sarcoidosis.

Methods and analysis

A systematic search of the literature will be conducted using PubMed/Medline, Scopus, and ProQuest databases, and sources of grey literature, up to 25th of May 2022, with no limitations on publication date. We will include all study types (qualitative, quantitative, and mixed methods) except review articles, examining diagnostic delay, incorrect diagnosis, missed diagnosis or slow diagnosis of all types of sarcoidosis across all age groups. We will also examine evidence of patients’ experiences associated with diagnostic delay. Only studies in English, German and Indonesian will be included. The outcomes we examine will be diagnostic delay time, patients’ experiences, and causes and consequences associated with diagnostic delay in sarcoidosis. Two people will independently screen the titles and abstracts of search results, and then the remaining full-text documents against the inclusion criteria. Disagreements will be resolved with a third reviewer until consensus is reached. Selected studies will be appraised using the Mixed Methods Appraisal Tool (MMAT). A meta-analysis and subgroup analysis of quantitative data will be conducted. Meta-aggregation methods will be used to analyse qualitative data. If there is insufficient data for these analyses, a narrative synthesis will be conducted.

Ethics and dissemination

Ethical approval will not be required as no human recruitment or participation will be involved. Findings of the study will be disseminated through publications in peer-reviewed journals, conferences, and symposia.

Trial registration

PROSPERO Registration number: CRD42022307236 URL of the PROSPERO registration: https://www.crd.york.ac.uk/PROSPEROFILES/307236_PROTOCOL_20220127.pdf
Local genetic correlations exist among neurodegenerative and neuropsychiatric diseases
Authors: Reynolds Regina H. , Wagen Aaron Z. , Lona-Durazo Frida , Scholz Sonja W. , Shoai Maryam , Hardy John , Taliun Sarah A. Gagliano , Ryten Mina
Published: June 2022

Genetic correlation (rg) between traits can offer valuable insight into underlying shared biological mechanisms. Neurodegenerative diseases overlap neuropathologically and often manifest comorbid neuropsychiatric symptoms. However, globalrganalyses show minimalrgamong neurodegenerative and neuropsychiatric diseases. Importantly, localrgs can exist in the absence of global relationships. To investigate this possibility, we applied LAVA, a tool for localrganalysis, to genome-wide association studies of 3 neurodegenerative diseases (Alzheimer’s disease, Lewy body dementia and Parkinson’s disease) and 3 neuropsychiatric disorders (bipolar disorder, major depressive disorder and schizophrenia). We identified several localrgs missed in global analyses, including between (i) all 3 neurodegenerative diseases and schizophrenia and (ii) Alzheimer’s and Parkinson’s disease. For those localrgs identified in genomic regions containing disease-implicated genes, such asSNCA, CLUandAPOE, incorporation of expression quantitative trait loci identified genes that may drive genetic overlaps between diseases. Collectively, we demonstrate that complex genetic relationships exist among neurodegenerative and neuropsychiatric diseases, highlighting putative pleiotropic genomic regions and genes. These findings imply sharing of pathogenic processes and the potential existence of common therapeutic targets.
A series of pulses vaccination in SIR model – Understanding periodic orbits and irregular trajectories
Authors: Yang Hyun Mo
Published: June 2022

When a Susceptible-Infective-Recovered (SIR) model with a constant contact rate is used to describe the dynamics of directly transmitted infections, oscillations, which decay exponentially with time, are obtained. Due to damped oscillations, intermittent vaccination schemes can be designed in order to reduce or even eliminate the infection. A simple intermittent vaccination can be described by a series of pulses, i.e., a proportion of susceptible individuals is vaccinated intermittently at every fixed period of time. Analysis of the model is done by numerical simulations in order to determine the trajectories in the phase space. It is observed that as the proportion of vaccinated individuals increases, closed orbits with multiple cycles appear, even irregular trajectories arise occasionally. These results can be understood by comparing with bifurcations occurring in a discrete logistic model describing a single population. Further, bifurcations occurring in epidemiological models that use periodic functions to mimic seasonal variations in the disease transmission are discussed.
Preserved cognition in elderly with intact rhinal cortex
Authors: Sepehrband Farshid , Lynch Kirsten M. , Gasperi Andrea Sotelo , Bienkowski Michael S. , Wang Xinhui , Chui Helena C. , Toga Arthur W ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: June 2022

Alzheimer’s disease pathology leads to neurodegeneration within the memory-related structures of the medial temporal cortex and hippocampus. Neurodegeneration also occurs as a part of normative aging and it is unclear whether medial temporal lobe subregions are selectively intact in older adults with preserved cognitive function in comparison to adults who are cognitively impaired. In this study, we used T1-weighted and high-resolution T2-weighted magnetic resonance images to assess age-related volumetric changes to medial temporal lobe regions, including the hippocampal formation and rhinal cortex, in patients with mild cognitive impairment and cognitively normal controls in two independent cohorts. Our results show age was significantly associated with regional atrophy in the hippocampus, but not the rhinal cortex. Additionally, variability in regional medial temporal lobe volume was associated with tau uptake in the rhinal cortex, but not the hippocampus. Together, these results suggest that the rhinal cortex may be more indicative of Alzheimer’s disease pathology and can help differentiate from age-related neurodegeneration.
SARS-CoV-2 genomic surveillance in Rwanda: Introductions and local transmission of the B.1.617.2 (Delta) variant of concern
Authors: Butera Yvan , Hong Samuel L. , Semakula Muhammed , Bollen Nena , Hill Verity , O’Toole Áine Niamh , Potter Barney I. , Mutangana Dieudonné , Sindayiheba Reuben , Rutayisire Robert , Artesi Maria , Bours Vincent , Rujeni Nadine , Dellicour Simon , Durkin Keith , Mutesa Leon , Baele Guy
Published: June 2022

The emergence of the SARS-CoV-2 Delta variant of concern (lineage B.1.617.2) in late 2020 resulted in a new wave of infections in many countries across the world, where it often became the dominant lineage in a relatively short amount of time. We here report on a novel genomic surveillance effort in Rwanda in the time period from June to September 2021, leading to 201 SARS-CoV-2 genomes being generated, the majority of which were identified as the Delta variant of concern. We show that in Rwanda, the Delta variant almost completely replaced the previously dominant A.23.1 and B.1.351 (Beta) lineages in a matter of weeks, and led to a tripling of the total number of COVID-19 infections and COVID-19-related fatalities over the course of only three months. We estimate that Delta in Rwanda had an average growth rate advantage of 0.034 (95% CI 0.025-0.045) per day over A.23.1, and of 0.022 (95% CI 0.012-0.032) over B.1.351. Phylogenetic analysis reveals the presence of at least seven local Delta transmission clusters, with two of these clusters occurring close to the border with the Democratic Republic of the Congo, and another cluster close to the border with Tanzania. A smaller Delta cluster of infections also appeared close to the border with Uganda, illustrating the importance of monitoring cross-border traffic to limit the spread between Rwanda and its neighboring countries. We discuss our findings against a background of increased vaccination efforts in Rwanda, and also discuss a number of breakthrough infections identified during our study. Concluding, our study has added an important collection of data to the available genomes for the Eastern Africa region, with the number of Delta infections close to the border with neighboring countries highlighting the need to further strengthen genomic surveillance in the region to obtain a better understanding of the impact of border crossings on lowering the epidemic curve in Rwanda.
Estimating the replicability of highly cited clinical research (2004-2018)
Authors: da Costa Gabriel Gonçalves , Neves Kleber , Amaral Olavo B.
Published: June 2022

Introduction

Previous studies about the replicability of clinical research based on the published literature have suggested that highly cited articles are often contradicted or found to have inflated effects. Nevertheless, there are no recent updates of such efforts, and this situation may have changed over time.

Methods

We searched the Web of Science database for articles studying medical interventions with more than 2000 citations, published between 2004 and 2018 in high-impact medical journals. We then searched for replications of these studies in PubMed using the PICO (Population, Intervention, Comparator and Outcome) framework. Replication success was evaluated by the presence of a statistically significant effect in the same direction and by overlap of the replication’s effect size confidence interval (CIs) with that of the original study. Evidence of effect size inflation and potential predictors of replicability were also analyzed.

Results

A total of 89 eligible studies, of which 24 had valid replications (17 meta-analyses and 7 primary studies) were found. Of these, 21 (88%) had effect sizes with overlapping CIs. Of 15 highly cited studies with a statistically significant difference in the primary outcome, 13 (87%) had a significant effect in the replication as well. When both criteria were considered together, the replicability rate in our sample was of 20 out of 24 (83%). There was no evidence of systematic inflation in these highly cited studies, with a mean effect size ratio of 1.03 (95% CI [0.88, 1.21]) between initial and subsequent effects. Due to the small number of contradicted results, our analysis had low statistical power to detect predictors of replicability.

Conclusion

Although most studies did not have eligible replications, the replicability rate of highly cited clinical studies in our sample was higher than in previous estimates, with little evidence of systematic effect size inflation.
An in vivo biomarker to characterize ototoxic compounds and novel protective therapeutics
Authors: Bellairs Joseph A. , Redila Van A. , Wu Patricia , Tong Ling , Webster Alyssa , Simon Julian A. , Rubel Edwin W. , Raible David W.
Published: June 2022

There are no approved therapeutics for the prevention of hearing loss and vestibular dysfunction from drugs like aminoglycoside antibiotics. While the mechanisms underlying aminoglycoside ototoxicity remain unresolved, there is considerable evidence that aminoglycosides enter inner ear mechanosensory hair cells through the mechanoelectrical transduction (MET) channel. Inhibition of MET-dependent uptake with small molecules or modified aminoglycosides is a promising otoprotective strategy. To better characterize mammalian ototoxicity and aid in the translation of emerging therapeutics, a biomarker is needed. In the present study we propose that neonatal mice systemically injected with the aminoglycosides G418 conjugated to Texas Red (G418-TR) can be used as a histologic biomarker to characterize in vivo aminoglycoside toxicity. We demonstrate that postnatal day 5 mice, like older mice with functional hearing, show uptake and retention of G418-TR in cochlear hair cells following systemic injection. When we compare G418-TR uptake in other tissues, we find that kidney proximal tubule cells show similar retention. Using ORC-13661, an investigational hearing protection drug, we demonstrate in vivo inhibition of aminoglycoside uptake in mammalian hair cells. This work establishes how systemically administered fluorescently labeled ototoxins in the neonatal mouse can reveal important details about ototoxic drugs and protective therapeutics.
Physical activity increases neuronal activity in the circadian clock of diurnalArvicanthis ansorgei
Authors: Caputo Rosanna , Schoonderwoerd Robin A. , Ramkisoensing Ashna , Janse Jan A.M. , van Diepen Hester C. , Raison Sylvie , Pévet Paul , Derks Nienke A.V. , Sage-Ciocca Dominique , Deboer Tom , Challet Etienne , Meijer Johanna H.
Published: June 2022

2.

The central circadian clock, located in the suprachiasmatic nucleus (SCN) within the brain, regulates daily patterns of activity and physiology. Many studies indicate that exercise at specific times throughout the day can help maintain proper circadian rhythms. In nocturnal animals, even moderate levels of physical activity suppress the neuronal discharge rate of the SCN. Given that such a mechanism would likely be counter-effective in diurnal animals, we measured the firing rate of SCN neurons in freely moving diurnalArvicanthis ansorgeiusing implanted microelectrodes. We found that SCN firing was acutely increased rather than decreased both during brief (seconds) and long (hours) bouts of activity, and returned to baseline levels after behavioral activity ceased. We also found that daytime activity increases the strength of the SCN rhythm, as expected for day-active animals. To determine whether the acute increases in firing are produced within the SCN or in response to input from outside the SCN, we performedex vivorecordings in which afferent inputs are severed. We found no intrinsic increment occurring in the isolated SCN. These findings suggest that the excitatory effect on the SCN’s neuronal firing rate comes from areas that lie outside the SCN, presumably those that are affected by the animal’s activity. We conclude that exercise has opposite effects on the clock between nocturnal and diurnal rodents, and identified how exercise strengthens the neuronal discharge rhythm in the clock of a diurnal animal.

3.

Significance statement

Our biological clock controls behavioral activity rhythms by generating a 24-pattern of electrical activity. The electrical activity serves as output of the clock and is high during the day and low during the night. Physical activity, being under strong control of the clock, acts vice versa, and affects the electrical activity of the clock. In nocturnal animals, behavioral activity inhibits the clock’s firing rate. Here, we examined the effect of behavioral activity on the brain’s clock in the diurnal rodent,Arvicanthis. When the animal is active, the clock’s electrical activity is enhanced, rather than decreased. Thus, a diurnal animal can increase the strength of its own clock, by being active during the day.

Preprint Servers

The manuscript was deposited as a preprint in bioRxiv preprint doi:https://doi.org/10.1101/2022.05.31.493966; this version posted June 1, 2022. The copyright holder for this preprintin bioRxiv, made available under aCC-BY-NC-ND 4.0 International license (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license.

Classification

Biological Sciences, Physiology
A novel 3-miRNA network regulates tumour progression in oral squamous cell carcinoma
Authors: Patel Aditi , Patel Parina , Mandlik Dushyant , Patel Kaustubh , Malaviya Pooja , Johar Kaid , Swamy Krishna B.S , Patel Shanaya , Tanavde Vivek
Published: June 2022

Oral squamous cell carcinoma (OSCC) is often diagnosed late, leading to poor patient outcomes. This study aims to identify potential miRNA-based biomarkers for predicting disease progression using salivary exosomes derived from OSCC patients. Further, we identify crucial miRNA-mRNA networks involved in tumorigenesis and uncover the underlying mechanism responsible for OSCC progression.

Small RNA (n=23) sequencing analysis along with data available from The Cancer Genome Atlas (TCGA) (n=114) identified 12 differentially expressed miRNAs in OSCC patients as compared to controls. Validating these findings, miR-140-5p, miR-143-5p, and miR-145-5p were significantly downregulated in a larger cohort of OSCC patients (n=70). This 3-miRNA signature demonstrated higher efficacy of salivary exosomes (p<0.0001) in early detection and clinically correlated with disease progression and overall survival of OSCC patients (p<0.05). Further, analysis of the transcriptome, TCGA datasets and miRNA-mRNA networks, identified top hub genes (HIF1a,CDH1,CD44,EGFR, andCCND1) which were regulated by a 3-miRNA signature. Based on pathway analysis, these miRNA-mRNA interactions were found to be involved in regulating epithelial-mesenchymal transition (EMT). Further, transfection-mediated upregulation of the 3-miRNA signature significantly decreased cell proliferation, induced apoptosis, resulted in G2/M phase cell cycle arrest and reduced the invasive and migratory potential by reversing the EMT process in OECM-1 cell line.

Thus, this study identifies a 3-miRNA signature that can be utilized as a potential biomarker for early detection of OSCC and uncovers the underlying mechanisms responsible for converting a normal epithelial cell into a malignant phenotype.
A flexible, efficient, and scalable platform to produce circular RNAs as new therapeutics
Authors: Chen Chuyun , Wei Huanhuan , Zhang Kai , Li Zeyang , Wei Tong , Tang Chenxiang , Yang Yun , Wang Zefeng
Published: June 2022

Messenger RNA (mRNA) has recently emerged as a new drug modality with great therapeutic potential. However, linear mRNAs are relatively unstable and also require base modification to reduce their immunogenicity, imposing a limitation to the broad application. With improved stability, the circular RNA (circRNA) presents a better alternative for prolonged expression of the proteins, however the in vitro circularization of RNA at a large scale is technically challenging. Here we developed a new self-catalyzed system to efficiently produce circRNAs in a co-transcriptional fashion. By rational sequence design, we can efficiently produce scarless circRNAs that do not contain foreign sequences. The resulting circRNAs are very stable and have low immunogenicity, enabling prolonged protein translation in different cells without cellular toxicity. The circRNAs generated from this platform can be encapsulated in lipid nanoparticles and efficiently delivered into mice to direct robust protein expression. Finally, the circRNAs encoding RBD of SARS-CoV-2 S protein induced strong antibody productions, with neutralization antibody titers higher than the preclinical data from the linear mRNAs. Collectively, this study provided a general platform for efficient production of circRNAs, demonstrating the potential of circRNAs as the new generation of mRNA therapy.
The Value of Zero-filling in In Vivo MRS
Authors: Murali-Manohar Saipavitra , Oeltzschner Georg , Barker Peter B. , Edden Richard A.E.
Published: June 2022

Two opinions currently exist on the role of zero-filling in data processing for in vivo MRS: that it results in a purely cosmetic interpolation; or that it confers a benefit. Most commonly, in vivo MRS data are acquired as complex time-domain half-echoes, that are Fourier transformed to the give a real spectrum that is modeled for quantification. In this manuscript, we highlight that performing zero-filling draws the independent information from the imaginary part of the spectrum into the real spectrum, improving modeling accuracy. In order to demonstrate this, 10,000 time-domain datasets were simulated as decaying exponentials and noise was added. Data were then Fourier transformed with no-zero filling, 2x, 4x and 8x zero-filling. All spectra were then modeled using a simple single-Lorentzian frequency-domain model. It was demonstrated that 2x zero-filling results in a ∼√2 benefit in modeling accuracy, compared to no zero-filling. There was no additional advantage for further zero-filling.
Multiple Cullin-Associated E3 Ligases Regulate Cyclin D1 Protein Stability
Authors: Lu Ke , Zhang Ming , Xiao Guozhi , Tong Liping , Chen Di
Published: June 2022

Cyclin D1 is a key regulator of cell cycle progression, which forms a complex with CDK4/6 to regulate G1/S phase transition during cell cycle progression. Cyclin D1 has been recognized as an oncogene since it was upregulated in several different types of cancers. It is known that the post-translational regulation of cyclin D1 is controlled by ubiquitination/ proteasome degradation system in a phosphorylation-dependent manner. A few cullin-associated F-box E3 ligases have been shown to regulate cyclin D1 degradation; however, it is not known if additional cullin-associated E3 ligases participate in the regulation of cyclin D1 protein stability. In this study, we have screened a siRNA library containing siRNAs specific for 154 ligase subunits, including F-box, SOCS, BTB-containing proteins and DDB proteins. We found that multiple cullin-associated E3 ligases regulate cyclin D1 activity, including Keap1, DDB2, WSB2 and Rbx1. We found that these E3 ligases directly interact with cyclin D1, regulate cyclin D1 ubiquitination and proteasome degradation in a phosphorylation-dependent manner. These E3 ligases also control cell cycle progression and cell proliferation through regulation of cyclin D1 protein stability. Our study provides novel insights into regulatory mechanisms of cyclin D1 protein stability and function.