bluuebunny/crossref_metadata_2025 huggingface dataset:
Design and user experience testing of a polygenic score report: a qualitative study of prospective users
Authors: Brockman Deanna G. , Petronio Lia , Dron Jacqueline S. , Kwon Bum Chul , Vosburg Trish , Nip Lisa , Tang Andrew , O’Reilly Mary , Lennon Niall , Wong Bang , Ng Kenney , Huang Katherine H. , Fahed Akl C. , Khera Amit V.
Published: April 2021

Background

Polygenic scores – which quantify inherited risk by integrating information from many common sites of DNA variation – may enable a tailored approach to clinical medicine. However, alongside considerable enthusiasm, we and others have highlighted a lack of systematic approaches for score disclosure. Here, we review the landscape of polygenic score reporting and describe a generalizable approach for development of polygenic score disclosure tools for coronary artery disease.

Methods

First, we assembled a working group of clinicians, geneticists, data visualization specialists, and software developers. The group reviewed existing polygenic score reports and then designed a two-page mock polygenic score report for coronary artery disease. We then conducted a qualitative user-experience study with this report and an interview guide focused on comprehension, experience, and attitudes. Interviews were transcribed and thematically analyzed for themes identification.

Results

We conducted interviews with ten adult individuals (50% females, 70% without prior genetic testing experience, age range 20 to 70 years) recruited via an online platform. We identified three themes from interviews: (1) visual elements, such as color and simple graphics, enable participants to interpret, relate to, and contextualize their polygenic score, (2) word-based descriptions of risk and polygenic scores presented as percentiles were most often recognized and understood, (3) participants had varying levels of interest in understanding complex genomic information and therefore would benefit from additional resources that can adapt to their individual needs in real time. In response to user feedback, colors used for communicating risk were modified to minimize unintended color associations and odds ratios were removed. Of note, all 10 participants expressed interest in receiving this report based on their personal genomic information.

Conclusions

Our findings describe a generalizable approach to develop and test a polygenic score disclosure tool that is desired by the general public. These results are likely to inform ongoing efforts related to polygenic score disclosure within clinical practice.
A data-driven pipeline to extract potential side effects through co-prescription analysis: application to a cohort study of 2,010 patients taking hydroxychloroquine with an 11-year follow-up
Authors: Sabatier P. , Wack M. , Pouchot J. , Danchin N. , Jannot AS.
Published: April 2021

Context

Real-life data consist of exhaustive and unbiased data to study drug-safety profiles but are underused because of their complex temporality (i.e., safety depends on the dose, timing, and duration of treatment) and the considerable number of potential side effects to study. We aimed to create a pipeline that manages the complex temporality of real-life data using a data-driven strategy (i.e., without any hypothesis on the potential side effects to search for) to highlight the safety profile of a given drug. We used hydroxychloroquine (HCQ) and its co-prescription in a real-life database to illustrate this pipeline.

Methods

We incorporated a weighted cumulative exposure statistical model into a data-driven strategy. This pipeline makes it possible to highlight both long-term and short-term side effects, while avoiding false positives due to the natural course of the underlying disease. We applied the proposed pipeline to a cohort of 2,010 patients with a prescription of HCQ and used their drug prescription as the source of data to highlight the HCQ safety profile.

Results

The proposed pipeline introduces a bootstrap strategy into weighted cumulative-exposure statistics estimates to highlight significant drug signals. As applied to HCQ, the proposed pipeline showed nine drugs to be significantly associated with HCQ exposure. Of note, one of them has therapeutic indications for known HCQ side effects. Other associations could be explained by therapeutic indications linked to conditions associated with HCQ indications in France.

Conclusion

We propose a data-driven pipeline that makes it possible to provide a broad picture of the side effects of a given drug. It would be informative to pursue the development of this pipeline using other sources of data.
The evaluation of a novel tool to remotely assess visual acuity in chronic uveitis patients during the COVID-19 pandemic
Authors: Claessens J.L.J. , van Egmond J. , de Boer J.H. , Wisse R.P.L.
Published: April 2021

Background

Restrictions due to the recent COVID-19 pandemic catalysed the deployment of telehealth solutions. A novel web‐based visual acuity test, validated in a healthy population, may be of great value in the follow‐up of uveitis patients.

Objective

To determine the measurement accuracy of the unsupervised remote Easee web‐based visual acuity test in uveitis patients, when compared to a conventional in‐hospital assessment.

Methods

Cross‐sectional diagnostic accuracy study. Between April 2020 and September 2020, consecutive adult uveitis patients were invited for the web‐based visual acuity test (index test) within two weeks prior to their conventional in‐hospital assessment (reference test).

Results

A total of 269 patients were invited by mail, of whom 84 visited the website (31%). Ultimately 98 eyes met the criteria for statistical analysis. The mean difference between the two tests was low and non‐significant: 0.02 logMAR (SD 0.12, P = 0.085). The 95% limits of agreement ranged from ‐0.21 to 0.26 logMAR. No relevant differences were identified in clinical characteristics between subgroups with a good performance (i.e. difference between the tests 0.15 logMAR) or underperformance (i.e. difference >0.15 logMAR) on the web‐based test.

Conclusion

The web‐based visual acuity test is a promising tool to remotely assess visual acuity in the majority of uveitis patients, especially relevant when access to ophthalmic care is limited. No association between patient‐ or uveitis‐related variables and (under)performance of the test were identified. These outcomes underline the potential of remote vision testing in other common ophthalmic conditions. A proper implementation of this web‐based tool in health care could be of great value for revolutionizing teleconsultations.
Progressive dysmorphia of retinal pigment epithelium in age related macular degeneration revealed by fluorescence lifetime imaging
Authors: Hammer Martin , Jakob-Girbig Juliane , Schwanengel Linda , Curcio Christine A. , Hasan Somar , Meller Daniel , Schultz Rowena
Published: April 2021

Purpose

To observe changes of the retinal pigment epithelium (RPE) on the transition from dysmorphia to atrophy in age related macular degeneration (AMD) by fluorescence lifetime imaging ophthalmoscopy (FLIO).

Methods

Multimodal imaging including color fundus photography (CFP), optical coherence tomography (OCT), fundus autofluorescence (FAF) imaging, and FLIO was performed in 40 eyes of 37 patients with intermediate AMD and no evidence for geographic atrophy or macular neovascularization) (mean age: 74.2±7.0 years). Twenty-three eyes were followed for 28.3±18.3 months. Seven eyes had a second follow up after 46.6±9.0 months. Thickened RPE on OCT, hyperpigmentation on CFP, and migrated RPE, seen as hyperreflective foci (HRF) on OCT, were identified. Fluorescence lifetimes in two spectral channels (SSC: 500-560 nm, LSC: 560-720 nm) as well as emission spectrum intensity ratio (ESIR) of the lesions were measured by FLIO.

Results

As hyperpigmented areas form and RPE migrates into the retina, FAF lifetimes lengthen and ESRI of RPE cells increase. Thickened RPE showed lifetimes of 256±49 ps (SSC) and 336±35 ps (LSC) and an ESIR of 0.552±0.079. For hyperpigmentation, these values were 317±68 ps (p<0.001), 377±56 ps (p<0.001), and 0.609±0.081 (p=0.001), respectively, and for HRF 337±79 ps (p<0.001), 414±50 ps (p<0.001), and 0.654±0.075 (p<0.001).

Conclusions

In the process of RPE degeneration, comprising different steps of dysmorphia, hyperpigmentation, and migration, lengthening of FAF lifetimes and a hypsochromic shift of emission spectra can be observed by FLIO. Thus, FLIO might provide early biomarkers for AMD progression and contribute to our understanding of RPE pathology.
The risk of symptomatic reinfection during the second COVID-19 wave in individuals previously exposed to SARS-CoV-2
Authors: Manica Mattia , Pancheri Serena , Poletti Piero , Giovanazzi Giulia , Guzzetta Giorgio , Trentini Filippo , Marziano Valentina , Ajelli Marco , Zuccali Maria Grazia , Benetollo Pier Paolo , Merler Stefano , Ferro Antonio
Published: April 2021

To what extent infection with SARS-CoV-2 protects against subsequent reinfection or symptomatic reinfection is still unclear. In this cohort study, we analyzed surveillance records of COVID-19 cases identified between June 2020 and January 2021 in five Italian municipalities, where 77.7% of the entire population was screened for IgG antibodies in May 2020. We compared the risk of observing symptomatic infections in two mutually exclusive groups defined by the initial serological response. We estimated that the cumulative incidence of identified symptomatic infections in the IgG negative and positive cohorts was 2.67% (95%CI: 2.12% – 3.37%) and 0.14% (95%CI: 0.04% – 0.58%), respectively. The adjusted odd ratio of developing symptomatic infection in individuals previously exposed to SARS-CoV-2 was estimated at 0.054 (95%CI: 0.009 - 0.169). Quantifying protective immunity against COVID-19 disease elicited by natural infection with SARS-CoV-2 is essential to inform strategies for controlling the pandemic in the forthcoming months.
A seq2seq model to forecast the COVID-19 cases, deaths and reproductive R numbers in US counties
Authors: Zhang-James Yanli , Hess Jonathan , Salekin Asif , Wang Dongliang , Chen Samuel , Winkelstein Peter , Morley Christopher P , Faraone Stephen V
Published: April 2021

The global pandemic of coronavirus disease 2019 (COVID-19) has killed almost two million people worldwide and over 400 thousand in the United States (US). As the pandemic evolves, informed policy-making and strategic resource allocation relies on accurate forecasts. To predict the spread of the virus within US counties, we curated an array of county-level demographic and COVID-19-relevant health risk factors. In combination with the county-level case and death numbers curated by John Hopkins university, we developed a forecasting model using deep learning (DL). We implemented an autoencoder-based Seq2Seq model with gated recurrent units (GRUs) in the deep recurrent layers. We trained the model to predict future incident cases, deaths and the reproductive number, R. For most counties, it makes accurate predictions of new incident cases, deaths and R values, up to 30 days in the future. Our framework can also be used to predict other targets that are useful indices for policymaking, for example hospitalization or the occupancy of intensive care units. Our DL framework is publicly available on GitHub and can be adapted for other indices of the COVID-19 spread. We hope that our forecasts and model can help local governments in the continued fight against COVID-19.
Impaired antigen-specific memory B cell and plasma cell responses including lack of specific IgG upon SARS-CoV-2 BNT162b2 vaccination among Kidney Transplant and Dialysis patients
Authors: Rincon-Arevalo Hector , Choi Mira , Stefanski Ana-Luisa , Halleck Fabian , Weber Ulrike , Szelinski Franziska , Jahrsdörfer Bernd , Schrezenmeier Hubert , Ludwig Carolin , Sattler Arne , Kotsch Katja , Potekhin Alexander , Chen Yidan , Burmester Gerd R. , Eckardt Kai-Uwe , Guerra Gabriela Maria , Durek Pawel , Heinrich Frederik , Ferreira-Gomes Marta , Radbruch Andreas , Budde Klemens , Lino Andreia C. , Mashreghi Mir-Farzin , Schrezenmeier Eva , Dörner Thomas
Published: April 2021

Patients with kidney failure are at increased risk during the COVID-19 pandemic and effective vaccinations are needed. It is not known how efficient mRNA vaccines mount B and plasma cell responses in dialysis patients (DP) or kidney transplant recipients (KTR) compared to healthy controls (HC). We studied humoral and B cell responses of 25 HC, 44 DP and 40 KTR. Markedly impaired anti-BNT162b2 responses were identified among KTR and DP compared to 100% seroconversion in HC. In DP, the response was delayed (3-4 weeks after boost) and reduced with anti-S1 IgG positivity in 31 (70.5%) and anti-S1 IgA in 30 (68.2%) of 44, respectively. In contrast, KTR did not develop IgG response except one patient who had prior unrecognized infection and developed anti-S1 IgG. The majority of antigen-specific B cells (RBD+) were identified in the plasmablast or post-switch memory B cell compartments in HC, whereas these RBD+ B cells were enriched among pre-switch and naïve B cells from DP and KTR. Single cell transcriptome and CITE-seq analyses found reduced frequencies of plasmablasts, TCF7+CD27+GZMK+ T cells and proliferating MKI67-expressing lymphocytes among KTR non-responders. Importantly, the frequency and absolute number of antigen-specific circulating plasmablasts in the whole cohort correlated with the Ig response, a characteristic not reported for other vaccinations. In conclusion, this data indicate that lack of T cell help related to immunosuppression results in impaired germinal center differentiation of B and plasma cell memory. There is an urgent need to improve vaccination protocols in patients after kidney transplantation or on chronic dialysis.

One Sentence Summary

Kidney transplant recipients and dialysis patients show a markedly diminished humoral response and impaired molecular B cell memory formation upon vaccination with BNT162b2.
Patient-Specific Connectomic Models Correlate With, But Do Not Predict, Outcomes in Deep Brain Stimulation for Obsessive-Compulsive Disorder
Authors: Widge Alik S. , Zhang Fan , Gosai Aishwarya , Papadimitrou George , Wilson-Braun Peter , Tsintou Magdalini , Palanivelu Senthil , Noecker Angela M. , McIntyre Cameron C. , O’Donnell Lauren , McLaughlin Nicole C.R. , Greenberg Benjamin D. , Makris Nikolaos , Dougherty Darin D. , Rathi Yogesh
Published: April 2021

Background

Deep brain stimulation (DBS) of the ventral internal capsule/ventral striatum (VCVS) is an emerging treatment for obsessive-compulsive disorder (OCD). Recently, multiple studies using normative connectomes have correlated DBS outcomes to stimulation of specific white matter tracts. Those studies did not test whether these correlations are clinically predictive, and did not apply cross-validation approaches that are necessary for biomarker development. Further, they did not account for the possibility of systematic differences between DBS patients and the non-diagnosed controls used in normative connectomes.

Methods

We performed patient-specific diffusion imaging in 8 patients who underwent VCVS DBS for OCD. We delineated tracts connecting thalamus and subthalamic nucleus (STN) to prefrontal cortex via VCVS. We then calculated which tracts were likely activated by individual patients’ DBS settings. We fit multiple statistical models to predict both OCD and depression outcomes from tract activation. We further attempted to predict hypomania, a VCVS DBS complication. We assessed all models’ performance on held-out test sets.

Results

No model predicted OCD response, depression response, or hypomania above chance. Coefficient inspection partly supported prior reports, in that capture of tracts projecting to cingulate cortex was associated with both YBOCS and MADRS response. In contrast to prior reports, however, tracts connected to STN were not reliably correlated with response.

Conclusions

Patient-specific imaging and a guideline-adherent analysis were unable to identify a tractographic target with sufficient effect size to drive clinical decision-making or predict individual outcomes. These findings suggest caution in interpreting the results of normative connectome studies.
Asymptomatic or mild symptomatic SARS-CoV-2 infection elicits durable neutralizing antibody responses in children and adolescents
Authors: Garrido Carolina , Hurst Jillian H. , Lorang Cynthia G. , Aquino Jhoanna N. , Rodriguez Javier , Pfeiffer Trevor S. , Singh Tulika , Semmes Eleanor C. , Lugo Debra J. , Rotta Alexandre T. , Turner Nicholas A. , Burke Thomas W. , McClain Micah T. , Petzold Elizabeth A. , Permar Sallie R. , Moody M. Anthony , Woods Christopher W. , Kelly Matthew. S. , Fouda Genevieve G.
Published: April 2021

As SARS-CoV-2 continues to spread globally, questions have emerged regarding the strength and durability of immune responses in specific populations. In this study, we evaluated humoral immune responses in 69 children and adolescents with asymptomatic or mild symptomatic SARS-CoV-2 infection. We detected robust IgM, IgG, and IgA antibody responses to a broad array of SARS-CoV-2 antigens at the time of acute infection and 2 and 4 months after acute infection in all participants. Notably, these antibody responses were associated with virus neutralizing activity that was still detectable 4 months after acute infection in 94% of children. Moreover, antibody responses and neutralizing activity in sera from children and adolescents were comparable or superior to those observed in sera from 24 adults with mild symptomatic infection. Taken together, these findings indicate children and adolescents with mild or asymptomatic SARS-CoV-2 infection generate robust and durable humoral immune responses that are likely to protect from reinfection.
TheDrosophilaDCP2 is evolutionarily conserved in sequence and structure – insights fromin silicostudies of DmDCP2 orthologs and paralogs
Authors: Kunar Rohit , Roy Jagat Kumar
Published: April 2021

The mRNA decapping proteins (DCPs) function to hydrolyze the 7-methylguanosine cap at the 5’ end of mRNAs thereby, exposing the transcript for degradation by the exonuclease(s) and hence, play a pioneering role in the mRNA decay pathway. InDrosophila melanogaster, the mRNA decapping protein 2 (DCP2) is the only catalytically active mRNA decapping enzyme present. Despite its presence being reported across diverse species in the phylogenetic tree, a quantitative approach to the index of its conservation in terms of its sequence has not been reported so far. With structural and mechanistic insights being explored in the yeasts, the insect DCP2 has never been explored in the perspectives of structure and the indices of the conservation of its sequence and/or structurevis-à-vistopological facets. Being an evolutionarily conserved protein, the present endeavor aimed at deciphering the evolutionary relationship(s) and the pattern of conservation of the sequence of DCP2 across the phylogenetic tree as well as in sibling species ofD. melanogasterthrough a semi-quantitative approach relying on multiple sequence alignment and analyses of percentage identity matrices. Since NUDIX proteins are functionally diverse, an attempt to identify the other NUDIX proteins (or, DCP2 paralogs) inD. melanogasterand compare and align their structural features with that of DCP2 throughin silicoapproaches was endeavored in parallel. Our observations provide quantitative and structural bases for the observed evolutionary conservation of DCP2 across the diverse phyla and also, identify and reinforce the structural conservation of the NUDIX family inD. melanogaster.
Systematic discovery and perturbation of regulatory genes in human T cells reveals the architecture of immune networks
Authors: Freimer Jacob W. , Shaked Oren , Naqvi Sahin , Sinnott-Armstrong Nasa , Kathiria Arwa , Chen Amy F. , Cortez Jessica T. , Greenleaf William J. , Pritchard Jonathan K. , Marson Alexander
Published: April 2021

Complex gene regulatory networks ensure that important genes are expressed at precise levels. When gene expression is sufficiently perturbed it can lead to disease. To understand how gene expression disruptions percolate through a network, we must first map connections between regulatory genes and their downstream targets. However, we lack comprehensive knowledge of the upstream regulators of most genes. Here we developed an approach for systematic discovery of upstream regulators of critical immune factors – IL2RA, IL-2, and CTLA4 – in primary human T cells. Then, we mapped the network of these regulators’ target genes and enhancers using CRISPR perturbations, RNA-Seq, and ATAC-Seq. These regulators form densely interconnected networks with extensive feedback loops. Furthermore, this network is highly enriched for immune-associated disease variants and genes. These results provide insight into how immune-associated disease genes are regulated in T cells and broader principles about the structure of human gene regulatory networks.

Highlights

A systematic approach to identify upstream regulators of key immune genes in primary human cells

Comprehensive RNA-Seq and ATAC-Seq perturbation maps after KO of individual discovered regulators

Analysis uncovers a highly interconnected regulatory network of enhancers and genes in T cells

This network is highly enriched for immune disease variants and genes shedding light on the trans-regulatory connections among key immune genes in health and disease
ChIP-AP – An Integrated ChIP-Seq Analysis Pipeline
Authors: Suryatenggara Jeremiah , Yong Kol Jia , Tenen Danielle E. , Tenen Daniel G. , Bassal Mahmoud A.
Published: April 2021

ChIP-Seq is a technique used to analyse protein-DNA interactions. The protein-DNA complex is pulled down using a protein antibody, after which sequencing and analysis of the bound DNA fragments is performed. A key bioinformatics analysis step is “peak” calling - identifying regions of enrichment. Benchmarking studies have consistently shown that no optimal peak caller exists. Peak callers have distinct selectivity and specificity characteristics which are often not additive and seldom completely overlap in many scenarios. In the absence of a universal peak caller, we rationalized one ought to utilize multiple peak-callers to 1) gauge peak confidence as determined through detection by multiple algorithms, and 2) more thoroughly survey the protein-bound landscape by capturing peaks not detected by individual peak callers owing to algorithmic limitations and biases. We therefore developed an integrated ChIP-Seq Analysis Pipeline (ChIP-AP) which performs all analysis steps from raw fastq files to final result, and utilizes four commonly used peak callers to more thoroughly and comprehensively analyse datasets. Results are integrated and presented in a single file enabling users to apply selectivity and sensitivity thresholds to select the consensus peak set, the union peak set, or any sub-set in-between to more confidently and comprehensively explore the protein-bound landscape. (https://github.com/JSuryatenggara/ChIP-AP).
Aberrant Activation of the Mentalizing Brain System During Eye Gaze Discrimination in Bipolar Disorder
Authors: Tso Ivy F. , Burton Cynthia Z. , Lasagna Carly A. , Rutherford Saige , Yao Beier , Peltier Scott J. , Johnson Timothy D. , McInnis Melvin G. , Taylor Stephan F.
Published: April 2021

Bipolar disorder (BD) is associated with a range of social cognitive deficits. This study investigated the functioning of the mentalizing brain system in BD probed by an eye gaze perception task during fMRI. Compared with healthy controls (n = 21), BD participants (n = 14) showed reduced preferential activation for self-directed gaze discrimination in the medial prefrontal cortex (mPFC) and temporo-parietal junction (TPJ), which was associated with poorer cognitive and social functioning. Aberrant functions of the mentalizing system should be further investigated as marker of social dysfunction and treatment targets.

Highlights

Social dysfunction in bipolar disorder (BD) may be due to altered mentalizing.

Individuals with BD showed reduced activation in the mentalizing brain system.

Aberrant activity of the mentalizing system was associated with poorer functioning.
The Mental Health Under the COVID-19 Crisis in Africa: A Systematic Review and Meta-Analysis
Authors: Chen Jiyao , Farah Nusrat , Dong Rebecca Kechen , Chen Richard Z. , Xu Wen , Yin Allen , Chen Bryan Z. , Delios Andrew , Miller Saylor , Wan Xue , Zhang Stephen X.
Published: April 2021

Objective

In this paper, we aim to provide a systematic review and meta-analysis on the prevalence rates of mental health symptoms of anxiety, depression, and insomnia among the major populations during the COVID-19 pandemic in Africa.

Design

A systematic review and meta-analysis.

Data sources

We search and include articles using PubMed, Embase, Web of Science, PsycINFO, and medRxiv databases between Feb 202 and Feb 6th, 2021.

Eligibility criteria and data analysis

The meta-analysis targets the prevalence rates of mental health symptoms of major populations including frontline/general healthcare workers (HCWs), the general adult population, and medical students during the COVID-19 pandemic in Africa. To estimate the prevalence rates of anxiety, depression, and insomnia, we pooled data using random-effects meta-analyses.

Results

In this meta-analysis, we identify and include 28 studies and 32 independent samples from 12 countries with a total of 15,072 participants in Africa. Ethiopia (7) and Egypt (6) had the largest number of studies. While many countries including, but not limited to, Algeria, Kenya, and Ghana had a high number of COVID-19 cases, as many as three quarters of African countries have no studies. The pooled prevalence of anxiety in 27 studies was 37% (95%CI: 31-43%,I2= 99.0%) and that of depression in 24 studies was 45% (95%CI: 36-51%,I2= 99.5%) and that of insomnia in 9 studies was 28% (95%CI: 20-41%,I2= 99.2%). The pooled prevalence rates of anxiety, depression, and insomnia in North Africa (44%, 55%, and 31%, respectively) are higher than the rates in Sub-Saharan Africa (31%, 30%, and 24%, respectively). Our analysis indicated high heterogeneity and varying prevalence rates of mental health symptoms during the COVID-19 pandemic in Africa.

Discussion

We discuss our findings that a) a scarcity of studies in several African countries with a high number of COVID-19 cases, b) high heterogeneity among the studies, c) the extent of prevalence of mental health symptoms in Africa to be high, and d) the pattern of mental health symptoms in Africa differs from elsewhere, i.e., more African adults suffer from depression rather than anxiety and insomnia during COVID 19 compared to adult population in other countries or regions. Hence, our findings carry crucial implications for healthcare organizations and future research to enable evidence-based medicine in Africa. Our findings also call for increased scholarly attention on Africa, the least studied continent with a limited amount of research on mental health symptoms under the COVID 19 pandemic.

Trial registration

CRD42020224458
Babytwins Study Sweden (BATSS): A multi-method infant twin study of genetic and environmental factors influencing infant brain and behavioral development
Authors: Falck-Ytter Terje , Hamrefors Linnea , Sanchez Monica Siqueiros , Portugal Ana Maria , Taylor Mark , Li Danyang , Viktorsson Charlotte , Hardiansyah Irzam , Myers Lynnea , Westberg Lars , Bölte Sven , Tammimies Kristiina , Ronald Angelica
Published: April 2021

Twin studies can help us understand the relative contributions of genes and environment to phenotypic trait variation including attentional and brain activation measures. In terms of applying methodologies like electroencephalography (EEG) and eye tracking, which are key methods in developmental neuroscience, infant twin studies are almost non-existent. Here we describe the Babytwins Study Sweden (BATSS), a multi-method longitudinal twin study of 177 MZ and 134 DZ twin pairs (i.e. 622 individual infants) covering the 5 - 36 month time period. The study includes EEG, eye tracking and genetics, together with more traditional measures based on in-person testing, direct observation and questionnaires. The results show that interest in participation in research among twin parents is high, despite the comprehensive protocol. DNA analysis from saliva samples was possible in virtually all participants, allowing for both zygosity confirmation and polygenic score analyses. Combining a longitudinal twin design with advanced technologies in developmental cognitive neuroscience and genomics, BATSS represents a new approach in infancy research, which we hope to have impact across multiple disciplines in the coming years.
Cytoskeletal vimentin regulates cell size and autophagy through mTORC1 signaling
Authors: Mohanasundaram Ponnuswamy , Rato Leila S Coelho , Modi Mayank , Urbanska Marta , Lautenschläger Franziska , Cheng Fang , Eriksson John E
Published: April 2021

The nutrient-activated mTORC1 (mechanistic target of rapamycin kinase complex 1) signaling pathway determines cell size by controlling mRNA translation, ribosome biogenesis, protein synthesis, and autophagy. Here we show that vimentin, a cytoskeletal intermediate filament protein that we know to be important for wound healing and cancer progression, determines cell size through mTORC1 signaling, an effect that is also manifested at the organism level in mice. We found that vimentin maintains normal cell size by supporting mTORC1 activation and through inhibition of autophagic flux. This regulation is manifested at all levels of downstream target activation and regulation of protein synthesis. We show that vimentin controls mTORC1 mobility by allowing access to lysosomes. Vimentin inhibits the autophagic flux in normal fibroblasts even under starved conditions, indicating a growth factor-independent inhibition of autophagy at the level of mTORC1. Our findings demonstrate that vimentin couples cell size signaling and autophagy with the biomechanic, sensing, and kinetic functions of the cytoskeleton.
The association between Hfq and RNase E in long-term nitrogen starvedEscherichia coli
Authors: McQuail Josh , Carpousis Agamemnon J. , Wigneshweraraj Sivaramesh
Published: April 2021

Under conditions of nutrient adversity, bacteria adjust metabolism to minimise cellular energy usage. This is often achieved by controlling the synthesis and degradation of RNA. InEscherichia coli, RNase E is the central enzyme involved in RNA degradation and serves as a scaffold for the assembly of the multiprotein complex known as the RNA degradosome. The activity of RNase E against specific mRNAs can also be regulated by the action of small RNAs (sRNA). In this case, the ubiquitous bacterial chaperone Hfq bound to sRNAs can interact with the RNA degradosome for the sRNA guided degradation of target RNAs. The RNA degradosome and Hfq have never been visualised together in live bacteria. We now show that in long-term nitrogen starvedE. coli, both RNase E and Hfq co-localise in a single, large focus. This subcellular assembly, which we refer to as the H-body, forms by a liquid-liquid phase separation type mechanism and includes components of the RNA degradosome, namely, the helicase RhlB and the exoribonuclease polynucleotide phosphorylase. The results support the existence of an hitherto unreported subcellular compartmentalisation of a process(s) associated with RNA management in stressed bacteria.
Flexible Simultaneous Mesoscale Two-Photon Imaging Of Neural Activity at High Speeds
Authors: Clough Mitchell , Chen Ichun Anderson , Park Seong-Wook , Ahrens Allison M. , Stirman Jeffrey N. , Smith Spencer L. , Chen Jerry L.
Published: April 2021

Understanding brain function requires monitoring local and global brain dynamics. Two-photon imaging of the brain across mesoscopic scales has presented trade-offs between imaging area and acquisition speed. We describe a flexible cellular resolution two-photon microscope capable of simultaneous video rate acquisition of four independently targetable brain regions spanning an approximate five-millimeter field of view. With this system, we demonstrate the ability to measure calcium activity across mouse sensorimotor cortex at behaviorally relevant timescales.
Evolutionary transcriptomics implicates new genes and pathways in human pregnancy and adverse pregnancy outcomes
Authors: Mika Katie , Marinić Mirna , Singh Manvendra , Lynch Vincent J.
Published: April 2021

Evolutionary changes in the anatomy and physiology of the female reproductive system underlie the origins and diversification of pregnancy in Eutherian (“Placental”) mammals. This developmental and evolutionary history constrains normal physiological functions and biases the ways in which dysfunction contributes to reproductive trait diseases and adverse pregnancy outcomes. Here, we show that gene expression changes in the human endometrium during pregnancy are associated with the evolution of human-specific traits and pathologies of pregnancy. We found that hundreds of genes gained or lost endometrial expression in the human lineage. Among these are genes that may contribute to human-specific maternal-fetal communication (HTR2B) and maternal-fetal immunotolerance (PDCD1LG2) systems, as well as vascular remodeling and deep placental invasion (CORIN). These data suggest that explicit evolutionary studies of anatomical systems complement traditional methods for characterizing the genetic architecture of disease. We also anticipate our results will advance the emerging synthesis of evolution and medicine (“evolutionary medicine”) and be a starting point for more sophisticated studies of the maternal-fetal interface. Furthermore, the gene expression changes we identified may contribute to the development of diagnostics and interventions for adverse pregnancy outcomes.
Predicting Individual Task Contrasts From Resting-state Functional Connectivity using a Surface-based Convolutional Network
Authors: Ngo Gia H. , Khosla Meenakshi , Jamison Keith , Kuceyeski Amy , Sabuncu Mert R.
Published: April 2021

Task-based and resting-state represent the two most common experimental paradigms of functional neuroimaging. While resting-state offers a flexible and scalable approach for characterizing brain function, task-based techniques provide superior localization. In this paper, we build on recent deep learning methods to create a model that predicts task-based contrast maps from resting-state fMRI scans. Specifically, we propose BrainSurfCNN, a surface-based fully-convolutional neural network model that works with a representation of the brain’s cortical sheet. Our model achieves state of the art predictive accuracy on independent test data from the Human Connectome Project and yields individual-level predicted maps that are on par with the target-repeat reliability of the measured contrast maps. We also demonstrate that BrainSurfCNN can generalize remarkably well to novel domains with limited training data.
Genome Assembly of the Popular Korean Soybean Cultivar Hwangkeum
Authors: Kim Myung-Shin , Lee Taeyoung , Baek Jeonghun , Kim Ji Hong , Kim Changhoon , Jeong Soon-Chun
Published: April 2021

Massive resequencing efforts have been undertaken to catalog allelic variants in major crop species including soybean, but the scope of the information for genetic variation often depends on short sequence reads mapped to the extant reference genome. Additional de novo assembled genome sequences provide a unique opportunity to explore a dispensable genome fraction in the pan-genome of a species. Here, we report the de novo assembly and annotation of Hwangkeum, a popular soybean cultivar in Korea. The assembly was constructed using PromethION nanopore sequencing data and two genetic maps, and was then error-corrected using Illumina short-reads and PacBio SMRT reads. The 933.12 Mb assembly was annotated 79,870 transcripts for 58,550 genes using RNA-Seq data and the public soybean annotation set. Comparison of the Hwangkeum assembly with the Williams 82 soybean reference genome sequence revealed 1.8 million single-nucleotide polymorphisms, 0.5 million indels, and 25 thousand putative structural variants. However, there was no natural megabase-scale chromosomal rearrangement. Incidentally, by adding two novel groups, we found that soybean contains four clearly separated groups of centromeric satellite repeats. Analyses of satellite repeats and gene content suggested that the Hwangkeum assembly is a high-quality assembly. This was further supported by comparison of the marker arrangement of anthocyanin biosynthesis genes and of gene arrangement at the Rsv3 locus. Therefore, the results indicate that the de novo assembly of Hwangkeum is a valuable additional reference genome resource for characterizing traits for the improvement of this important crop species.
Demographics of COVID19 vaccine hesitancy during the second wave of COVID-19 pandemic: A cross-sectional web-based survey in Saudi Arabia
Authors: Al-Mohaithef Mohammed , Padhi Bijaya Kumar , Ennaceur Soukaina Abdulmajed
Published: April 2021

Background

The Coronavirus disease 2019 (COVID-19) pandemic is considered a major global public health threat affecting across the life course and socioeconomic aspects of life. Globally acceptance to an effective vaccine is the most anticipated resolution. This study aims to evaluate intent to be vaccinated among public in Saudi Arabia during the second wave of COVID-19 pandemic.

Methods

A cross-sectional web-based study was designed in Saudi Arabia. Study participants (N=658) were recruited through snowball sampling. SurveyMonkey platform was used to record the response. Cross-tabulation were performed by participants’ intention to vaccinate against COVID-19 virus with sociodemographic characteristics and respondents’ risk perception towards COVID-19, trust in the healthcare system, and their history of vaccine hesitancy behavior. Multivariable logistic regression analysis was performed to compute the predictors of vaccination intention among the study participants.

Results

658 participants were completed the survey (females = 47.4%). Of the 658 participants 351 (53.3%) have shown intent to be vaccinated. 519 (78.8%) of the participants were reported to be at high risk of COVID-19, and 307 (46.6%) were reported to trust the healthcare system in the country. The multivariable analysis shows respondents with a high-risk perception (OR: 2.27, 95% CI: 1.49-3.48); higher trust in the healthcare system (OR: 3.24, 95% CI: 2.32-4.61) was found to be the significant factor affecting the decision in acceptance of the COVID-19 vaccine in Saudi Arabia.

Conclusion

Participants reported high knowledge towards COVID-19 virus, and vaccine developments. About half (46.6%) of the study participant reported refusal/hesitancy towards the vaccine during the second wave of the pandemic in Saudi Arabia. The study highlighted that higher risk perception and higher trust in the healthcare system were found to be the main reasons for participant’s intentions behind the vaccination.
Central nervous system hypomyelination disrupts axonal conduction and behaviour in larval zebrafish
Authors: Madden Megan E , Suminaite Daumante , Ortiz Elelbin , Early Jason J , Koudelka Sigrid , Livesey Matthew R , Bianco Isaac H , Granato Michael , Lyons David A
Published: April 2021

Myelination is essential for central nervous system (CNS) formation, health and function. As a model organism, larval zebrafish have been extensively employed to investigate the molecular and cellular basis of CNS myelination, due to their genetic tractability and suitability for non-invasive live cell imaging. However, it has not been assessed to what extent CNS myelination affects neural circuit function in zebrafish larvae, prohibiting the integration of molecular and cellular analyses of myelination with concomitant network maturation. To test whether larval zebrafish might serve as a suitable platform with which to study the effects of CNS myelination and its dysregulation on circuit function, we generated zebrafish myelin regulatory factor (myrf) mutants with CNS-specific hypomyelination and investigated how this affected their axonal conduction properties and behaviour. We found that myrf mutant larvae exhibited increased latency to perform startle responses following defined acoustic stimuli. Furthermore, we found that hypomyelinated animals often selected an impaired response to acoustic stimuli, exhibiting a bias towards reorientation behaviour instead of the stimulus-appropriate startle response. To begin to study how myelination affected the underlying circuitry, we established electrophysiological protocols to assess various conduction properties along single axons. We found that the hypomyelinated myrf mutants exhibited reduced action potential conduction velocity and an impaired ability to sustain high frequency action potential firing. This study indicates that larval zebrafish can be used to bridge molecular and cellular investigation of CNS myelination with multiscale assessment of neural circuit function.
Life on the leaf: Seasonal activities of the phyllosphere microbiome of perennial crops
Authors: Howe Adina C. , Stopnisek Nejc , Dooley Shane K. , Yang Fan , Grady Keara L. , Shade Ashley
Published: April 2021

Plants and microorganisms form beneficial associations. Understanding plant-microbe interactions will inform microbiome management to enhance crop productivity and resilience to stress. Here, we apply a genome-centric approach to identify key leaf microbiome members on field-grown switchgrass and miscanthus, and quantify their activities for switchgrass over two growing seasons. We integrate metagenome and metatranscriptome sequencing from 192 leaf samples collected over key time points in crop phenology. We curated 40 focal metagenome-assembled-genomes (MAGs) and conservatively focus analysis on transcript recruitment to medium and high-quality MAGs that were <10% contaminated and >50% complete. Classes represented by these MAGs (Actinomycetia, Alpha- and Gamma-Proteobacteria, and Bacteroidota) were active and had seasonal dynamics in key functions, including enrichments in transcripts for of short chain dehydrogenase, molybdopterin oxioreductase, and polyketide cyclase in the late season. The majority of MAGs had activated stress-associated pathways, including trehalose metabolism, indole acetic acid degradation, betaine biosynthesis, and reactive oxygen species degradation, suggesting direct engagement with the host environment. We also detected seasonally activated biosynthetic pathways for terpenes (carotenoid and isoprenoids), and for various non-ribosomal peptide pathways that were poorly annotated. Overall, this study overcame laboratory and bioinformatic challenges associated with field-based leaf metatranscriptome analysis to inform potential key activities of these phyllosphere populations. These activities collectively support that leaf-associated bacterial populations are seasonally dynamic, responsive to host cues and interactively engage in feedbacks with the plant.
Comparison of Mucosal and Intramuscular Immunization against SARS-CoV-2 with Replication-Defective and Replicating Single-cycle Adenovirus Vaccines
Authors: Mudrick Haley E. , McGlinch Erin B. , Parrett Brian J. , Hemsath Jack R. , Barry Mary E. , Rubin Jeffrey D. , Uzendu Chisom , Hansen Michael J. , Erskine Courtney L. , VanKeulen Virginia P. , Drelich Aleksandra , Tseng Chien-Te Kent , Massey Shane , Fida Madiha , Suh Gina A. , Peikert Tobias , Block Matthew S. , Olivier Gloria R. , Barry Michael A.
Published: April 2021

SARS-CoV-2 enters the body at mucosal surfaces, such as the nose and lungs. These events involve a small number of virions at these mucosal barriers and are therefore a strategic point to stop a COVID-19 infection before it starts. Despite this, most vaccines against COVID-19 are being injected into the muscle where they will not generate the highest levels of mucosal protection. The vaccines that are approved for use in humans are all replication-defective (RD) mRNA, DNA, or adenovirus (Ad) vaccines that do not amplify antigen transgenes. We developed single cycle adenovirus (SC-Ad) vectors that replicate antigen genes up to 10,000-fold in human cells, but that are disabled from producing infectious Ad particles. We show here that SC-Ad expressing the full-length SARS-CoV-2 spike protein produces 100-fold more spike protein than a matched RD-Ad-Spike vector. When Ad-permissive hamsters were immunized with these vaccines by intranasal (IN) or intramuscular (IM) routes, SC-Ad produced significantly stronger antibody responses as compared to RD-Ad against the spike protein that rose over 14 weeks after one immunization. Single IN or IM immunizations generated significant antibody responses in serum and in bronchoalveolar lavages (BALs). IN priming, but not IM priming, generated HLA-restricted CD8 T cell responses in BALs. SC-Ad-Spike generated antibodies that retain binding to spike receptor binding domains (RBDs) with mutations from new viral variants. These data suggest empowering the genomes of gene-based vaccines with the ability to amplify antigen genes can increase potency. This may be particularly advantageous when applying mucosal vaccines to combat mucosal pathogens like SARS-CoV-2.

One Sentence Summary

Arming adenovirus vaccines with the ability to replicate vaccine antigen genes may increase potency for systemic, or more importantly, mucosal immunization against mucosal pathogens.
Extinction in complex communities as driven by adaptive dynamics
Authors: Nguyen Vu A.T. , Vural Dervis Can
Published: April 2021

In a complex community, species continuously adapt to each other. On rare occasions, the adaptation of a species can lead to the extinction of others, and even its own. “Adaptive dynamics” is the standard mathematical framework to describe evolutionary changes in community interactions, and in particular, predict adaptation driven extinction. Unfortunately, most authors implement the equations of adaptive dynamics through computer simulations, that require assuming a large number of questionable parameters and fitness functions. In this study we present analytical solutions to adaptive dynamics equations, thereby clarifying how outcomes depend on any computational input. We develop general formulas that predict equilibrium abundances over evolutionary time scales. Additionally, we predict which species will go extinct next, and when this will happen.