bluuebunny/crossref_metadata_2025 huggingface dataset:
Endemic HBV among hospital in-patients in Bangladesh, including evidence of occult infection
Authors: Chowdhury Fazle Rabbi , McNaughton Anna L. , Amin Mohammad Robed , Barai Lovely , Saha Mili Rani , Rahman Tanjila , Das Bikash Chandra , Hasan M. Rokibul , Islam K. M. Shahidul , Faiz M. A. , Al-Mahtab Mamun , Mokaya Jolynne , Kronsteiner Barbara , Jeffery Katie , Andersson Monique I. , de Cesare Mariateresa , Ansari M. Azim , Dunachie Susanna , Matthews Philippa C.
Published: July 2021

Bangladesh is one of the top-ten most heavily burdened countries for viral hepatitis, with hepatitis B (HBV) infections responsible for the majority of cases. Recombinant and occult HBV infections (OBI) have been reported previously in the region. We investigated an adult fever cohort (n=201) recruited in Dhaka, to determine the prevalence of HBV and OBI. A target-enrichment deep sequencing pipeline was applied to samples with HBV DNA >3.0 log10 IU ml−1. HBV infection was present in 16/201 (8 %), among whom 3/16 (19 %) were defined as OBI (HBsAg-negative but detectable HBV DNA). Whole genome deep sequences (WGS) were obtained for four cases, identifying genotypes A, C and D. One OBI case had sufficient DNA for sequencing, revealing multiple polymorphisms in the surface gene that may contribute to the occult phenotype. We identified mutations associated with nucleos(t)ide analogue resistance in 3/4 samples sequenced, although the clinical significance in this cohort is unknown. The high prevalence of HBV in this setting illustrates the importance of opportunistic clinical screening and DNA testing of transfusion products to minimise OBI transmission. WGS can inform understanding of diverse disease phenotypes, supporting progress towards international targets for HBV elimination.
Targeting cap-dependent translation to inhibit Chikungunya virus replication: selectivity of p38 MAPK inhibitors to virus-infected cells due to autophagy-mediated down regulation of phospho-ERK
Authors: Mudaliar Prashant , Pradeep Parvanendhu , Abraham Rachy , Sreekumar Easwaran
Published: July 2021

The 5′ capped, message-sense RNA genome of Chikungunya virus (CHIKV) utilizes the host cell machinery for translation. Translation is regulated by eIF2 alpha at the initiation phase and by eIF4F at cap recognition. Translational suppression by eIF2 alpha phosphorylation occurs as an early event in many alphavirus infections. We observe that in CHIKV-infected HEK293 cells, this occurs as a late event, by which time the viral replication has reached an exponential phase, implying its minimal role in virus restriction. The regulation by eIF4F is mediated through the PI3K-Akt-mTOR, p38 MAPK and RAS-RAF-MEK-ERK pathways. A kinetic analysis revealed that CHIKV infection did not modulate AKT phosphorylation, but caused a significant reduction in p38 MAPK phosphorylation. It caused degradation of phospho-ERK 1/2 by increased autophagy, leaving the PI3K-Akt-mTOR and p38 MAPK pathways for pharmacological targeting. mTOR inhibition resulted in moderate reduction in viral titre, but had no effect on CHIKV E2 protein expression, indicating a minimal role of the mTOR complex in virus replication. Inhibition of p38 MAPK using SB202190 caused a significant reduction in viral titre and CHIKV E2 and nsP3 protein expression. Furthermore, inhibiting the two pathways together did not offer any synergism, indicating that inhibiting the p38 MAPK pathway alone is sufficient to cause restriction of CHIKV replication. Meanwhile, in uninfected cells the fully functional RAS-RAF-MEK-ERK pathway can circumvent the effect of p38 MAPK inhibition on cap-dependent translation. Thus, our results show that host-directed antiviral strategies targeting cellular p38 MAPK are worth exploring against Chikungunya as they could be selective against CHIKV-infected cells with minimal effects on uninfected host cells.
Stakeholders’ perception of possible integration pathways for eye health into school health programme in Zanzibar: a qualitative health system research
Authors: Chan Ving Fai , Yard Elodie , Mashayo Eden , Mulewa Damaris , Drake Lesley , Omar Fatma
Published: July 2021

Purpose

To scope the potential for eye health programme to be integrated into Zanzibar School Health programme, through the lenses of stakeholders

Methods

Embedded into an operational research project integrating eye and School health, we elicited responses from 83 participants, purposefully selected from the Ministry of Health (n=7), Ministry of Education and Vocational Training (n=7), hospitals/eye centres (n=5), master trainers (4) and schools (n=60) participated in in-depth interviews. Their responses were analysed and grouped into four pre-determined themes of Human Resource Training, Resources Mobilisation, Acceptability, and Leadership and Governance. Quotations are presented to illustrate the findings.

Results

In line with the four research themes, i) The integrated school eye health programme training was satisfactory, with room for improvement, ii) Child eye health screening conducted by teachers was well-received, with concerns and suggestions to improve its effectiveness and efficiency, iii) Integration of eye health into the school health programme is perceived as a good initiative, but to increase referral, service uptake and spectacle usage, primary care units must be equipped, and eye health awareness needs to be improved, iv) Departmental roles, resources, gaps and synergies to ensure eye health is successfully integrated into the school health programme.

Conclusion

The concept of integrated school eye health delivery is generally well-received by beneficiaries and stakeholders within an operational research project in Zanzibar, with the caveat that investment is required for effective referral and update.
Ergonomics knowledge, attitude, and practice among biomedical scientists
Authors: Alwahaibi Nasar , Al Abri Ibrahim , Al Sadairi Mallak , Al Rawahi Samira
Published: July 2021

Biomedical scientists (BMSs) are important professionals for healthcare services as they help in the detection, diagnosis, and treatment of numerous diseases. To the best of our knowledge, this is the first study to assess ergonomics knowledge, attitude, and practice among BMSs. A cross-sectional study was carried out among BMSs using a self-constructed questionnaire. The association between these parameters and various risk factors was measured using the Chi-square test. The study included 110 BMSs. Females represented 68.2% and 45.5% were in the age of 25-34. Good ergonomics knowledge showed in 54.5% and 82.7% showed high positive attitude. However, poor ergonomics showed in 83.5%. There was no significant interrelation between the three parameters. A significant association was found between the male gender (0.040), more than 20 working experience (0.016), and good ergonomics practice. Biomedical scientists have good knowledge, high attitude but the poor practice of ergonomics. Ergonomics training and practice should be firmly enhanced among these healthcare professionals.
Statistical Analysis Plan for the Helmet Non-Invasive Ventilation for COVID-19 Patients (Helmet-COVID) Randomized Controlled Trial
Authors: Arabi Yaseen , Tlayjeh Haytham , Aldekhyl Sara , Al-Dorzi Hasan , Abdukahil Sheryl Ann , Jose Jesna , Al Harbi Mohammad Khulaif , Haji Husain Al , Mutairi Mohammed Al , Zumai Omar Al , Qasim Eman Al , Wehaibi Wedyan Al , Qahtani Saad Al , Alshahrani Mohammed , Albrahim Talal , Mady Ahmed , Bshabshe Ali Al , Aseri Zohair Al , Duhailib Zainab Al , Kharaba Ayman , Alqahtani Rakan , Algethamy Haifa , Alfaris Omar , Alnafel Omar , Al-Fares Abdulrahman A
Published: July 2021

Background and objective

Noninvasive respiratory support is frequently needed for patients with acute hypoxemic respiratory failure due to coronavirus disease 19 (COVID-19). Helmet noninvasive ventilation having multiple advantages over other support modalities but data about effectiveness are limited.

Methods

In this multicenter randomized trial of helmet non-invasive ventilation for COVID-19 patients (Helmet-COVID), 320 adult ICU patients with suspected or confirmed COVID-19 and acute hypoxemic respiratory failure (with a ratio of arterial oxygen partial pressure to fraction (percent) of inspired oxygen (PaO2/FiO2) <200 despite supplemental oxygen with a partial/non-rebreathing mask at a flow rate >10 L/min or above) will be randomized to helmet-noninvasive ventilation with usual care or usual care alone. The primary outcome is death from any cause within 28 days after randomization. The trial has 80% power to detect a 15% absolute risk reduction from 40% to 25%.

Conclusion

Consistent with international guidelines, we developed a detailed plan to guide the analysis of the Helmet-COVID trial. This plan specifies the statistical methods for the evaluation of primary and secondary outcomes to facilitate unbiased analyses of clinical data.

Trial registration

Clinicaltrials.gov: NCT04477668 (registered on July 20, 2020)
The final blink: intact eyeblink conditioning in isolated dystonia
Authors: Sadnicka Anna , Rocchi Lorenzo , Latorre Anna , Antelmi Elena , Teo James , Pareés Isabel , Hoffland Britt S , Brock Kristian , Kornysheva Katja , Edwards Mark J , Bhatia Kailash P , Rothwell John C
Published: July 2021

Structured Abstract

Background

Impaired eyeblink conditioning is often cited as evidence for cerebellar dysfunction in isolated dystonia yet the results from individual studies are conflicting and underpowered.

Objective

To systematically examine the influence of dystonia, dystonia subtype and clinical features over eyeblink conditioning within a statistical model which controlled for the covariates age and sex.

Methods

Original neurophysiological data from all published studies were shared to an age and sex matched control group. Two raters blinded to participant identity scored all recordings (6732 trials). After higher inter-rater agreement was confirmed, mean conditioning per block was entered into a mixed repetitive measures model.

Results

Much variability of eyeblink conditioning was seen in both groups. All dystonia versus controls showed no difference in conditioning (p=0.517). Analysis of dystonia subgroup, with age and sex as covariates did not reveal evidence that eyeblink conditioning is impaired in specific subtypes (cervical dystonia, DYT-TOR1A, DYT-THAP1 or focal hand dystonia). The presence of tremor did not significantly influence levels of eyeblink conditioning.

Conclusions

Collaborative efforts such as this article allow larger number of patients to be evaluated and provide more balanced estimates of disease effects over experimental outcomes. Intact eyeblink conditioning is against a global cerebellar learning deficit in isolated dystonia. Precise mechanisms for how the cerebellum interplays mechanistically with other key neuroanatomical nodes within the dystonic network remains an open research question.
Assessment of knowledge, attitude, and practices of Tuberculosis patients towards DOTs regimen in Jimma Health Center, Jimma zone, southwest Ethiopia
Authors: Amare Wudalem , Teshome Melese Sinaga , Dessie Gashaw , Malik Tabarak
Published: July 2021

Objective

Globally, tuberculosis (TB) is one of a chronic infectious disease, which has a major health burden. Thus, 9.4 million incidents and 14 million prevalent cases were reported in 2010. The high burden of TB is common in sub-Saharan Africa countries, including Ethiopia. The purpose of conducting this study was to assess the knowledge, attitude, and practices of TB patients towards DOTs regimen. The other objective of the study was to assess the attitude of patients towards causative factor and its treatment.

Results

The result of the study showed that 103 (68.7%) of patients scored high knowledge status, whereas 47 (31.3%) of them scored low. 25(16.7%) governmental employee had overall high knowledge status. 101 (67.3%) of the patient scored high overall attitude, while 49 (32.7%) of them scored low overall attitude. 85 (56.7%) of patients scored high overall practices, whereas 65(43.3%) of them scored low overall practices.In this study, the knowledge and attitude of patients about TB and its treatment was found within low level of perception. Therefore, implementation of health education and awareness creation are required to avoid the problem of patients.
The effect of sample medication use on subsequent anti-VEGF agent selection for neovascular age-related macular degeneration
Authors: Wai Karen M , Begaj Tedi , Patil Sachi , Chen Evan , Miller John B , Kylstra Jan , Aronow Mary E , Young Lucy H , Huckfeldt Rachel , Husain Deeba , Kim Leo A , Vavvas Demetrios G , Eliott Dean , Mukai Shizuo , Gragoudas Evangelos S , Patel Nimesh A , Sobrin Lucia , Miller Joan W , Parikh Ravi , Wu David M
Published: July 2021

Purpose: To examine the effect of medication sample use (ranibizumab or aflibercept) on future anti-vascular endothelial growth factor (VEGF) agent selection in neovascular age-related macular degeneration (nvAMD).
Design: Retrospective cohort study.
Methods: nvAMD patients who underwent an initial anti-VEGF injection with a sample medication were compared to nvAMD control patients who never received a medication sample. Charts from 2017 through 2020 were reviewed for data regarding demographics, anti-VEGF agent selection, and visual acuity outcomes for both groups. Anti-VEGF agent selection for the first four injections and at one year were examined in both the sample and control groups.
Results: Adherence to the initial agent was high between first and subsequent injections (2nd, 3rd, 4th injection, and 1 year) in both sample (96.2%, 95.9%, 91.9%, 93.4%, respectively) and control groups (98.1%, 94.2%, 94.9%, 87.8%, respectively). Bevacizumab usage was significantly lower among eyes receiving samples relative to controls at the second (1.9% vs. 38.7%, p<0.001), third (3.1% vs. 41.3%, p<0.001), fourth injections (4.7% vs. 40.4%, p<0.001), and at 1 year (0% vs. 33.8%, p<0.001). Aflibercept usage was significantly higher in sample eyes relative to controls at the second (78.3% vs. 43.4%, p<0.001), third (76.3% vs. 41.5%, p<0.001), and fourth injections (76.7% vs. 43.4%, p<0.001), and at 1 year (77.0% vs. 52.7%, p<0.001).
Conclusions: Eyes receiving a sample anti-VEGF agent (ranibizumab or aflibercept) for their initial injection were less likely to receive bevacizumab at future visits relative to eyes that did not receive an anti-VEGF sample, even after one year of treatment.
Development of a High-Performance Multiparametric MRI Oropharyngeal Primary Tumor Auto-Segmentation Deep Learning Model and Investigation of Input Channel Effects: Results from a Prospective Imaging Registry
Authors: Wahid Kareem A. , Ahmed Sara , He Renjie , van Dijk Lisanne V. , Teuwen Jonas , McDonald Brigid A. , Salama Vivian , Mohamed Abdallah S.R. , Salzillo Travis , Dede Cem , Taku Nicolette , Lai Stephen Y. , Fuller Clifton D. , Naser Mohamed A.
Published: July 2021

Background and Purpose

Oropharyngeal cancer (OPC) primary gross tumor volume (GTVp) segmentation is crucial for radiotherapy. Multiparametric MRI (mpMRI) is increasingly used for OPC adaptive radiotherapy but relies on manual segmentation. Therefore, we constructed mpMRI deep learning (DL) OPC GTVp auto-segmentation models and determined the impact of input channels on segmentation performance.

Materials and Methods

GTVp ground truth segmentations were manually generated for 30 OPC patients from a clinical trial. We evaluated five mpMRI input channels (T2, T1, ADC, Ktrans, Ve). 3D Residual U-net models were developed and assessed using leave-one-out cross-validation. A baseline T2 model was compared to mpMRI models (T2+T1, T2+ADC, T2+Ktrans, T2+Ve, all 5 channels [ALL]) primarily using the Dice similarity coefficient (DSC). Sensitivity, positive predictive value, Hausdorff distance (HD), false-negative DSC (FND), false-positive DSC, surface DSC, 95% HD, and mean surface distance were also assessed. For the best model, ground truth and DL-generated segmentations were compared through a Turing test using physician observers.

Results

Models yielded mean DSCs from 0.71 (ALL) to 0.73 (T2+T1). Compared to the T2 model, performance was significantly improved for HD, FND, sensitivity, surface DSC, and 95% HD for the T2+T1 model (p<0.05) and for FND for the T2+Ve and ALL models (p<0.05). There were no differences between ground truth and DL-generated segmentations for all observers (p>0.05).

Conclusion

DL using mpMRI provides high-quality segmentations of OPC GTVp. Incorporating additional mpMRI channels may increase the performance of certain evaluation metrics. This pilot study is a promising step towards fully automated MR-guided OPC radiotherapy.
HPV 51: A candidate for type-replacement following vaccination?
Authors: Bowden Sarah , Fiander Alison , Hibbitts Sam
Published: July 2021

Background: Human papilloma virus (HPV) infection is known to be a necessary cause of cervical cancer and is found in 99.7% of invasive cervical carcinomas. Current HPV vaccines protect against infection from strains 16 and 18. Baseline prevalence studies are important for the measurement of prophylactic vaccine impact and type-replacement monitoring. Between 2009-2010 the HPV research group in collaboration with Cervical Screening Wales conducted the Base HPV 2009 study to determine baseline prevalence in unvaccinated women aged 20-22 in Wales. Preliminary analysis of results showed that in single HPV infection, 16 was the most prevalent high-risk strain followed by 18 and 51. This high prevalence of HPV 51 has not been observed in previous studies from Wales and is not a common finding elsewhere.

Objectives: This study aims to determine whether the high prevalence of HPV 51 observed in the Base HPV 2009 study is a true finding and if HPV 51 should be considered a candidate for type-replacement post-vaccination.

Study population and design: The first 100 single and 100 multiple HPV 51 positive liquid-based cytology (LBC) samples from the Base HPV 2009 study were selected for re-analysis. Each sample underwent DNA extraction and was tested using two methods: 1) Repeat of original methodology using GP5+/6+ HPV 51 PCR-ELISA. 2) HPV 51 E7 PCR. Data were then correlated with age, social deprivation score and cytology. 5 samples were excluded from analysis.

Results: Direct repeat of HPV 51 PCR-EIA identified 146 of 195 (75.0%) samples as HPV 51 positive. E7 PCR identified 166 of 195 (85.1%) samples as HPV 51 positive. When classified by cytological grade, the prevalence of confirmed HPV 51 increased with grade.

Conclusions: This study confirms that the prevalence of HPV 51 observed in the Base HPV 2009 study population is truly high and warrants further consideration. There is limited evidence on the cross-protection for 51 offered by the current HPV vaccine and it represents a potential candidate for type-replacement following vaccination. This study highlights the need for further longitudinal investigation into the regional and global prevalence of HPV 51. The data would recommend HPV 51 to be considered in future multivalent vaccines.
Purifying selection determines the short-term time dependency of evolutionary rates in SARS-CoV-2 and pH1N1 influenza
Authors: Ghafari Mahan , du Plessis Louis , Raghwani Jayna , Bhatt Samir , Xu Bo , Pybus Oliver G , Katzourakis Aris
Published: July 2021

High throughput sequencing enables rapid genome sequencing during infectious disease outbreaks and provides an opportunity to quantify the evolutionary dynamics of pathogens in near real-time. One difficulty of undertaking evolutionary analyses over short timescales is the dependency of the inferred evolutionary parameters on the timespan of observation. Here, we characterise the molecular evolutionary dynamics of SARS-CoV-2 and 2009 pandemic H1N1 (pH1N1) influenza during the first 12 months of their respective pandemics. We use Bayesian phylogenetic methods to estimate the dates of emergence, evolutionary rates, and growth rates of SARS-CoV-2 and pH1N1 over time and investigate how varying sampling window and dataset sizes affects the accuracy of parameter estimation. We further use a generalised McDonald-Kreitman test to estimate the number of segregating non-neutral sites over time. We find that the inferred evolutionary parameters for both pandemics are time-dependent, and that the inferred rates of SARS-CoV-2 and pH1N1 decline by ∼50% and ∼100%, respectively, over the course of one year. After at least 4 months since the start of sequence sampling, inferred growth rates and emergence dates remain relatively stable and can be inferred reliably using a logistic growth coalescent model. We show that the time-dependency of the mean substitution rate is due to elevated substitution rates at terminal branches which are 2-4 times higher than those of internal branches for both viruses. The elevated rate at terminal branches is strongly correlated with an increasing number of segregating non-neutral sites, demonstrating the role of purifying selection in generating the time-dependency of evolutionary parameters during pandemics.
Genetic influences on the intrinsic and extrinsic functional organizations of the cerebral cortex
Authors: Zhao Bingxin , Li Tengfei , Smith Stephen M. , Fan Zirui , Yang Xiaochen , Yang Yilin , Shu Juan , Xiong Di , Wang Xifeng , Yang Yue , Luo Tianyou , Zhu Ziliang , Shan Yue , Li Yujue , Wu Zhenyi , Zhang Heping , Li Yun , Stein Jason L. , Zhu Hongtu
Published: July 2021

The human cerebral cortex is a vital component of brain function, but the genetic influences on cortical functional organization remain poorly understood. In this study, we used a parcellation-based approach to process resting-state and task-evoked functional magnetic resonance imaging (fMRI) from over 48,000 individuals in UK Biobank and ABCD studies. We identified 47 loci associated with functional areas and networks at rest, 15 of which also affected functional connectivity during task performance. We observed patterns of heritability and locus-specific genetic effects across different brain functional areas and networks. Our findings suggest that specific functional areas and networks share genetic influences with cognition, mental health, and major brain disorders such as Alzheimer’s disease and schizophrenia. For example, theAPOEε4 locus strongly associated with Alzheimer’s disease was particularly associated with the visual cortex in the secondary visual and default mode networks in both resting and task fMRI. This study contributes to our understanding of the genetic determinants of cerebral cortex function by analyzing biobank-scale fMRI data in high-resolution brain parcellation. Additionally, it prioritizes genetically associated fMRI traits for specific brain disorders.
COVID-19 in Londrina-PR-Brazil: SEIR Model with Parameter Optimization
Authors: Cirilo Eliandro R. , Natti Paulo L. , Romeiro Neyva M. L. , Godoi Pedro H. V. , Lerma Andina A. , Matias Vitor P.
Published: July 2021

The first cases of COVID-19 in Londrina-PR were manifested in March 2020 and the disease lasts until the present moment. We aim to inform citizens in a scientific way about how the disease spreads. The present work seeks to describe the behavior of the disease over time. We started from a compartmental model of ordinary differential equations like SEIR to find relevant information such as: transmission rates and prediction of the peak of infected people. We used the data released by city hall of Londrina to carry out simulations in periods of 14 days, applying a parameter optimization technique to obtain results with the greatest possible credibility.
Genomic epidemiology of SARS-CoV-2 divulge B.1, B.1.36, and B.1.1.7 as the most dominant lineages in first, second, and third wave of SARS-CoV-2 infections in Pakistan
Authors: Basheer Atia , Zahoor Imran
Published: July 2021

The present study aims to investigate the genomic variability and epidemiology of SARS-CoV-2 in Pakistan along with their role in the spread and severity of infection during the three waves of COVID-19. A total of 453 genomic sequences of Pakistani SARS-CoV-2 were retrieved from GISAID and subjected to MAFFT-based alignment and QC check which resulted in removal of 53 samples. The remaining 400 samples were subjected to Pangolin-based genomic lineage identification. And to infer our SARS-CoV-2 time-scaled and divergence phylogenetic trees, 3,804 selected global reference sequences plus 400 Pakistani samples were used for the Nextstrain analysis with Wuhan/Hu-1/2019, as reference genome. Finally, maximum likelihood based phylogenetic tree was built by using the Nextstrain & coverage map was created by employing Nextclade. And by using the amino acid subsitutions the maximum likelihood phylogenetic trees were developed for each wave, separately. Our results reveal the circulation of 29 lineages, belonging to following 7 clades G, GH, GR, GRY, L, O, & S in the three waves. From first wave, 16 genomic lineages of SARS-CoV-2 were identified with B.1(24.7%), B.1.36(18.8%), & B.1.471(18.8%) as the most prevalent lineages respectively. The second wave data showed 18 lineages, 10 of which were overlapping with the first wave suggesting that those variants could not be contained during the first wave. In this wave, a new lineage, AE.4, was reported from Pakistan for the very first time in the world. However, B.1.36 (17.8%), B.1.36.31 (11.9%), B.1.1.7 (8.5%) & B.1.1.1 (5.9%) were the major lineages in second wave. Third wave data showed the presence of 9 lineages with Alpha/B.1.1.7 (72.7%), Beta/B.1.351 (12.99%), & Delta/B.1.617.2 (10.39%) as the most predominant variants. It is suggested that these VOCs should be contained at the earliest in order to prevent any devastating outbreak of SARS-CoV-2 in the country.
Human brain anatomy reflects separable genetic and environmental components of socioeconomic status
Authors: Kweon Hyeokmoon , Aydogan Gökhan , Dagher Alain , Bzdok Danilo , Ruff Christian C. , Nave Gideon , Farah Martha J. , Koellinger Philipp D.
Published: July 2021

Recent studies report that socioeconomic status (SES) correlates with brain structure. Yet, such findings are variable and little is known about underlying causes. We present a well-powered voxel-based analysis of grey matter volume (GMV) across levels of SES, finding many small SES effects widely distributed across the brain, including cortical, subcortical and cerebellar regions. We also construct a polygenic index of SES to control for the additive effects of common genetic variation related to SES, which attenuates observed SES-GMV relations, to different degrees in different areas. Remaining variance, which may be attributable to environmental factors, is substantially accounted for by body mass index, a marker for lifestyle related to SES. In sum, SES affects multiple brain regions through measurable genetic and environmental effects.

One-sentence Summary

Socioeconomic status is linked with brain anatomy through a varying balance of genetic and environmental influences.
Population genomic consequences of novel life history and mating system adaptation to a geothermal soil mosaic in yellow monkeyflowers (Mimulus guttatus)
Authors: Kolis Kory M. , Berg Colette S. , Nelson Thomas C. , Fishman Lila
Published: July 2021

Local selection can promote phenotypic divergence despite gene flow across habitat mosaics, but adaptation itself may generate substantial barriers to genetic exchange. In plants, life-history, phenology, and mating system divergence have been particularly proposed to promote genetic differentiation in sympatry. In this study, we investigate phenotypic and genetic variation in Mimulus guttatus (yellow monkeyflowers) across a geothermal soil mosaic in Yellowstone National Park (YNP). Plants from thermal annual and nonthermal perennial habitats were heritably differentiated for life history and mating system traits, consistent with local adaptation to the ephemeral thermal-soil growing season. However, genome-wide genetic variation primarily clustered plants by geographic region, with little variation sorting by habitat. The one exception was an extreme thermal population also isolated by a 200m geographical gap. Individual inbreeding coefficients (FIS) were higher (and predicted by trait variation) in annual plants and annual pairs showed greater isolation by distance at local (<1km) scales. Finally, YNP adaptation does not re-use a widespread inversion polymorphism diagnostic of annual vs. perennial M. guttatus range-wide, suggesting a novel genetic mechanism. Overall, this work suggests that life history and mating system adaptation strong enough to shape individual mating patterns does not necessarily generate incipient speciation without geographical barriers.
Viruses of Asgard archaea
Authors: Medvedeva Sofia , Sun Jiarui , Yutin Natalya , Koonin Eugene V. , Nunoura Takuro , Rinke Christian , Krupovic Mart
Published: July 2021

Asgardarchaeota encode many eukaryotic signature proteins and are widely considered to represent the closest archaeal relatives of eukaryotes. Whether similarities between Asgard archaea and eukaryotes extend to their viromes remains unknown. Here we present 20 metagenome-assembled genomes of Asgardarchaeota from deep-sea sediments of the basin off the Shimokita Peninsula, Japan. By combining CRISPR spacer search of metagenomic sequences with phylogenomic analysis, we identify three family-level groups of viruses associated with Asgard archaea. The first group, Verdandiviruses, includes tailed viruses of the realmDuplodnaviria, the second one, Skuldviruses, consists of viruses with predicted icosahedral capsids that belong to the realmVaridnaviria, and the third group, Wyrdviruses, is related to spindle-shaped viruses previously identified in other archaea. More than 90% of the proteins encoded by these putative viruses of Asgard archaea show no sequence similarity to proteins encoded by other known viruses. Nevertheless, all three proposed families consist of viruses typical of prokaryotes, providing no indication of a specific evolutionary relationship between viruses infecting Asgard archaea and eukaryotes. Verdandiviruses and skuldviruses are likely to be lytic, whereas wyrdviruses, similar to all other known spindle-shaped viruses, probably establish chronic infection and are released without host cell lysis. All three groups of viruses were identified in sediment samples from distinct geographical locations and are expected to play important roles in controlling the Asgard archaea populations in deep-sea ecosystems.
The META tool optimizes metagenomic analyses across sequencing platforms and classifiers
Authors: Player Robert A. , Aguinaldo Angeline M. , Merritt Brian B. , Maszkiewicz Lisa N. , Adeyemo Oluwaferanmi E. , Forsyth Ellen R. , Verratti Kathleen J. , Chee Brant W. , Grady Sarah L. , Bradburne Christopher E.
Published: July 2021

A major challenge in the field of metagenomics is the selection of the correct combination of sequencing platform and downstream metagenomic analysis algorithm, or ‘classifier’. Here, we present the Metagenomic Evaluation Tool Analyzer (META), which produces simulated data and facilitates platform and algorithm selection for any given metagenomic use case. META-generated in silico read data are modular, scalable, and reflect user-defined community profiles, while the downstream analysis is done using a variety of metagenomic classifiers. Reported results include information on resource utilization, time-to-answer, and performance. Real-world data can also be analyzed using selected classifiers and results benchmarked against simulations. To test the utility of the META software, simulated data was compared to real-world viral and bacterial metagenomic samples run on four different sequencers and analyzed using 12 metagenomic classifiers. Lastly, we introduce ‘META Score’: a unified, quantitative value which rates an analytic classifier’s ability to both identify and count taxa in a representative sample.
Placental gene expression-based cell type deconvolution: Cell proportions drive preeclampsia gene expression differences
Authors: Campbell Kyle A , Colacino Justin A , Puttabyatappa Muraly , Dou John F , Elkin Elana R , Hammoud Saher S , Domino Steven E , Dolinoy Dana C , Goodrich Jaclyn M , Loch-Caruso Rita , Padmanabhan Vasantha , Bakulski Kelly M
Published: July 2021

The placenta mediates adverse pregnancy outcomes, including preeclampsia, which is characterized by gestational hypertension and proteinuria. Placental cell type heterogeneity in preeclampsia is not well-understood and limits mechanistic interpretation of bulk gene expression measures. We generated single-cell RNA-sequencing samples for integration with existing data to create the largest deconvolution reference of 19 fetal and 8 maternal cell types from placental villous tissue at term (n=15,532 cells). We deconvoluted eight published microarray case-control studies of preeclampsia (n=330). Deconvolution revealed excess extravillous trophoblasts and fewer mesenchymal cells. Adjustment for cellular composition reduced preeclampsia-associated differentially expressed genes (FDR<0.05) from 1,224 to 0, whereas pathway alterations exhibiting a metabolic adaptation to hypoxia were robust to cell type adjustment. Cellular composition explained 35.1% of the association between preeclampsia andFLT1overexpression. Our findings indicate substantial placental cellular heterogeneity in preeclampsia that predicts previously observed bulk gene expression differences. Our deconvolution reference lays the groundwork for cellular heterogeneity-aware investigation into placental dysfunction and adverse birth outcomes.
NEAT-seq: Simultaneous profiling of intra-nuclear proteins, chromatin accessibility, and gene expression in single cells
Authors: Chen Amy F , Parks Benjamin , Kathiria Arwa S , Ober-Reynolds Benjamin , Goronzy Jorg , Greenleaf William J
Published: July 2021

Oligonucleotide-conjugated antibodies1 have allowed for joint measurement of surface protein abundance and the transcriptome in single cells using high-throughput sequencing. Extending these measurements to gene regulatory proteins in the nucleus would provide a powerful means to link changes in abundance of trans-acting TFs to changes in activity of cis-acting elements and expression of target genes. Here, we introduce Nuclear protein Epitope, chromatin Accessibility, and Transcriptome sequencing (NEAT-seq), a technique to simultaneously measure nuclear protein abundance, chromatin accessibility, and the transcriptome in single cells. We apply this technique to profile CD4 memory T cells using a panel of master transcription factors (TFs) that drive distinct helper T cell subsets and regulatory T cells (Tregs) and identify examples of TFs with regulatory activity gated by three distinct mechanisms: transcription, translation, and regulation of chromatin binding. Furthermore, we identify regulatory elements and target genes associated with each TF, which we use to link a non-coding GWAS SNP within a GATA motif to both strong allele-specific chromatin accessibility in cells expressing high levels of GATA3 protein, and a putative target gene.
Optimizing large organ scale micro computed tomography imaging in pig and human hearts using a novel air-drying technique
Authors: Pallares-Lupon N. , Ramlugun G. , Ozenne V. , Duchâteau J. , Delgove A. , Bayer J. , Moreno A. , Constantin M. , Gerneke D. , Sands G.B. , Trew M.L. , Hocini M. , Haissaguerre M. , Vigmond E.J. , Quesson B. , Bernus O. , Walton R.D.
Published: July 2021

Underlying electrical propagation in the heart and potentially fatal arrhythmia is the cardiac microstructure. Despite the critical role of muscle architecture, a non-destructive approach to examine not only myocyte orientation, but cellular arrangement in to laminar organization is lacking in hearts from translational animal models and humans. X-ray micro computed tomography using contrast enhancing agents achieves three-dimensional images at near-histological resolutions. However, imaging large mammalian hearts presents challenges including X-ray over-attenuation and loss of image contrast. The goal of this study was to rethink tissue pre-treatment to optimize, and benefit from micro computed tomography imaging resolution in large tissues. Whole pig and human hearts were dehydrated and perfused with a tissue reinforcing agent, hexamethyldisilazane, and slowly air-dried. Heart morphology was conserved and temporally stable. This enabled direct air-mounting for micro computed tomography imaging. Moreover, the desiccated tissue density was significantly reduced compared to the initial hydrated state (P=0.04). Three-dimensional image reconstructions of air-dried hearts segmented using a single intensity threshold revealed detailed microstructural architecture of myolaminae. Conversely, one-step segmentation of hearts loaded with contrast agents poorly estimated the gross anatomical morphology of the heart and lacked identification of tissue microarchitecture. Air-drying large mammalian hearts optimizes X-ray imaging of cardiac microstructure.
Species-wide phylogenomics of the Staphylococcus aureus agr operon reveals convergent evolution of frameshift mutations
Authors: Raghuram Vishnu , Alexander Ashley M. , Loo Hui Qi , Petit Robert A. , Goldberg Joanna B. , Read Timothy D.
Published: July 2021

Staphylococcus aureus is a prominent nosocomial pathogen that causes several life-threatening diseases such as pneumonia and bacteremia. S. aureus modulates expression of its arsenal of virulence factors through sensing and integrating responses to environmental signals. The agr (accessory gene regulator) quorum sensing (QS) system is a major regulator of virulence phenotypes in S. aureus. There are four agr specificity groups each with a different autoinducer peptide sequence (encoded by the agrD gene). Though agr is critical for expression of many toxins, paradoxically, S. aureus strains often have non-functional agr activity due to loss-of-function mutations in the four-gene agr operon. To understand patterns in agr variability across S. aureus, we undertook a species-wide genomic investigation. We developed a software tool (AgrVATE; https://github.com/VishnuRaghuram94/AgrVATE) for typing and detecting frameshift mutations in the agr operon. In an analysis of over 40,000 S. aureus genomes, we showed close association between agr type and S. aureus clonal complex. We also found strong linkage between agrBDC alleles (encoding the peptidase, the autoinducing peptide itself, and the peptide sensor respectively) but not agrA (encoding the -response regulator). More than five percent of genomes were found to have frameshift mutations in the agr operon. Though most mutations occur only once in the entire species, we observed a small number of recurring mutations evolving convergently across different clonal lineages. Phylogenetic patterns suggested that strains with agr frameshifts were evolutionary dead ends. Overall, genomic analysis of agr operon suggests evolution through multiple processes with functional consequences that are not fully understood.

Importance

Staphylococcus aureus is a globally pervasive pathogen that produces a plethora of toxic molecules that can degrade, evade, or inhibit the host immune cells. Production of these toxins is mainly controlled by an active agr quorum sensing system, which senses and responds to bacterial cell density. However, there are many reports of S. aureus strains with genetic changes leading to impaired agr activity, often found during chronic bloodstream infections, and may be associated with increased disease severity. We developed an open-source software called AgrVATE to type agr systems and identify putative frameshifts. We used AgrVATE for a species-wide genomic survey of S. aureus, finding that more than 5 % of strains in the public database had non-functional agr systems. We also provide new insights into the evolution of these genetic mutations in the agr system. Overall, this study contributes to our understanding of a common but relatively understudied means of virulence regulation in S. aureus.
Widespread nociceptive maps in the human neonatal somatosensory cortex
Authors: Jones Laura , Verriotis Madeleine , Cooper Robert J. , Laudiano-Dray Maria Pureza , Rupawala Mohammed , Meek Judith , Fabrizi Lorenzo , Fitzgerald Maria
Published: July 2021

Topographic cortical maps are essential for spatial localisation of sensory stimulation and generation of appropriate task-related motor responses. Somatosensation and nociception are finely mapped and aligned in the adult somatosensory (S1) cortex, but in infancy, when pain behaviour is disorganised and poorly directed, nociceptive maps may be less refined. We compared the topographic pattern of S1 activation following noxious (clinically required heel lance) and innocuous (touch) mechanical stimulation of the same skin region in newborn infants (n=32) using multi-optode functional near-infrared spectroscopy (fNIRS). Signal to noise ratio and overall activation area did not differ with stimulus modality. Within S1 cortex, touch and lance of the heel elicit localised, partially overlapping increases in oxygenated haemoglobin (HbO), but while touch activation was restricted to the heel area, lance activation extended into cortical hand regions. The data reveals a widespread cortical nociceptive map in infant S1, consistent with their poorly directed pain behaviour.
Regulation of Mus81-Eme1 structure-specific endonuclease by Eme1 SUMO-binding and Rad3ATR kinase is essential in the absence of Rqh1BLM helicase
Authors: Giaccherini C. , Scaglione S. , Coulon S. , Dehé P.M. , Gaillard P.H.L.
Published: July 2021

The Mus81-Eme1 structure-specific endonuclease is crucial for the processing of DNA recombination and late replication intermediates. In fission yeast, stimulation of Mus81-Eme1 in response to DNA damage at the G2/M transition relies on Cdc2CDK1 and DNA damage checkpoint-dependent phosphorylation of Eme1 and is critical for chromosome stability in absence of the Rqh1BLM helicase. Here we identify Rad3ATR checkpoint kinase consensus phosphorylation sites and two SUMO interacting motifs (SIM) within a short N-terminal domain of Eme1 that is required for cell survival in absence of Rqh1BLM. We show that catalytic stimulation of Mus81-Eme1 depends entirely on direct phosphorylation of Eme1 by Rad3ATR and that while Eme1 also undergoes Chk1-mediated phosphorylation, this is not essential for catalytic modulation. Both Rad3ATR- and Chk1-mediated phosphorylation of Eme1 as well as the SIMs are independently critical for cell fitness in absence of Rqh1BLM and abrogating bimodal phosphorylation of Eme1 along with mutating the SIMs is incompatible with rqh1Δ cell viability. Our findings unravel an elaborate regulatory network that relies on the poorly structured N-terminal domain of Eme1 and which is essential for the vital functions Mus81-Eme1 fulfills in absence of Rqh1BLM.
Unique viruses that infect Archaea related to eukaryotes
Authors: Rambo Ian M. , de Anda Valerie , Langwig Marguerite V. , Baker Brett J.
Published: July 2021

Asgard archaea are newly described microbes that are related to eukaryotes. Asgards are diverse and globally distributed, however, their viruses have not been described. Here we characterize seven viral genomes that infected Lokiarchaeota, Helarchaeota, and Thorarchaeota in deep-sea hydrothermal sediments. These viruses code for structural proteins similar to those inCaudovirales, as well as proteins distinct from those described in archaeal viruses. They also have genes common in eukaryotic nucleocytoplasmic large DNA viruses (NCLDVs), and are predicted to be capable of semi-autonomous genome replication, repair, epigenetic modifications, and transcriptional regulation. Moreover, Helarchaeota viruses may hijack host ubiquitin systems similar to eukaryotic viruses. This first glimpse of Asgard viruses reveals they have features of both prokaryotic and eukaryotic viruses, and provides insights into their roles in the ecology and evolution of these globally distributed microbes.
Patterns of morphological diversification in the Ramphastoidea reveal the dramatic divergence of toucans from a conserved morphotype
Authors: Tamma Krishnapriya , Krishnan Anand , Reddy Sushma
Published: July 2021

Background

Morphological traits offer insights into an organism’s ecological niche, species interactions, and patterns of community organisation. Pantropical lineages - animals and plants distributed across the three tropical continental regions of Asia, Africa, and America - provide a way to test how different environments and communities influence morphological diversification. Here, we examined a monophyletic group of frugivorous birds, the barbets and toucans (Ramphastoidea), which diversified independently on three continents, to investigate whether clades in each region exhibit similar (phylogenetically constrained) or distinct (ecologically influenced) patterns of morphological diversification.

Results

Our results show that despite differences in community dynamics in these regions, lineage accumulation patterns through time on all three continents are broadly similar, putatively due to phylogenetic niche conservatism. We quantified morphological variation in light of phylogenetic relatedness to further reveal that all barbet lineages across continents occupy a conserved region of morphospace after correcting for variation in size. However, in the Neotropics, one lineage, the toucans, have diverged dramatically from typical barbet space and converged toward (yet are distinct from) the trait space occupied by the distantly related hornbills in Asia and Africa. Additionally, we found no link between climatic variables and morphological traits. We conclude that barbets exhibit a conserved morphotype across continents and have diversified by scaling mainly in body size. However, the absence of other large frugivorous birds may have allowed toucans to diversify into a different region of morphospace of increased bill/wing to tail/wing ratios.

Conclusions

A combination of photographic and specimen measurements enabled us to demonstrate the presence of a globally conserved barbet morphotype across three tropical continents. By examining different continental lineages of a single monophyletic bird group, we shed light on the contrasting effects of regional ecological factors and phylogenetic constraints on morphological diversification.
Endogenous protein tagging in medaka using a simplified CRISPR/Cas9 knock-in approach
Authors: Seleit Ali , Aulehla Alexander , Paix Alexandre
Published: July 2021

The CRISPR/Cas9 system has been used to generate fluorescently labelled fusion proteins by homology directed repair in a variety of species. Despite its revolutionary success, there remains an urgent need for increased simplicity and efficiency of genome editing in research organisms. Here, we establish a simplified, highly efficient and precise strategy for CRISPR/Cas9 mediated endogenous protein tagging in medaka (Oryzias latipes). We use a cloning-free approach that relies on PCR amplified donor fragments containing the fluorescent reporter sequences flanked by short homology arms (30-40bp), a synthetic sgRNA and streptavidin tagged Cas9. We generate six novel knock-in lines with high efficiency of F0 targeting and germline transmission. Whole Genome Sequencing (WGS) results reveal single-copy integration events only at the targetedloci. We provide an initial characterization of these fusion-protein lines, significantly expanding the repertoire of genetic tools available in medaka. In particular, we show that themScarlet-pcnaknock-in line has the potential to serve as an organismal-wide label for proliferative zones and an endogenous cell cycle reporter.