bluuebunny/crossref_metadata_2025 huggingface dataset:
The Prevalence of Mental Health Disorders in people with HIV and the effects on the HIV Care Continuum
Authors: Lang Raynell , Hogan Brenna , Zhu Jiafeng , McArthur Kristen , Lee Jennifer , Zandi Peter , Nestadt Paul , Silverberg Michael J. , Parcesepe Angela M. , Cook Judith A. , Gill M. John , Grelotti David , Closson Kalysha , Lima Viviane D. , Goulet Joseph , Horberg Michael A. , Gebo Kelly A. , Camoens Reena M. , Rebeiro Peter F. , Nijhawan Ank E. , McGinnis Kathleen , Eron Joseph , Althoff Keri N. ,   the North American AIDS Cohort Collaboration on Research and Design (NA-ACCORD) of the International Epidemiologic Databases to Evaluate AIDS (IeDEA)
Published: May 2022

Objective

To describe the prevalence of diagnosed depression, anxiety, bipolar disorder, and schizophrenia in people with HIV (PWH) and the differences in HIV care continuum outcomes in those with and without mental health disorders (MHD).

Design

Observational study of participants in the NA-ACCORD.

Methods

PWH (≥18 years) contributed data on prevalent schizophrenia, anxiety, depressive, and bipolar disorders from 2008-2018 based on ICD code mapping. MH multimorbidity was defined as having ≥ 2 MHD. Log binomial models with generalized estimating equations estimated adjusted prevalence ratios (aPR) and 95% confidence intervals for retention in care (≥ 1 visit/year) and viral suppression (HIV RNA ≤ 200 copies/mL) by presence vs. absence of each MHD between 2016-2018.

Results

Among 122,896 PWH, 67,643 (55.1%) were diagnosed with ≥ 1 MHD: 39% with depressive disorders, 28% with anxiety disorders, 10% with bipolar disorder, and 5% with schizophrenia. The prevalence of depressive and anxiety disorders increased between 2008-2018, while bipolar disorder and schizophrenia remained stable. MH multimorbidity affected 24% of PWH. From 2016-2018 (N=64,684), retention in care was marginally lower among PWH with depression or anxiety, however those with MH multimorbidity were more likely to be retained in care. PWH with bipolar disorder had marginally lower prevalence of viral suppression (aPR=0.98 [0.98-0.99]) as did PWH with MH multimorbidity (aPR=0.99 [0.99-1.00]) compared with PWH without MHD.

Conclusion

The prevalence of MHD among PWH was high, including MH multimorbidity. Although retention and viral suppression were similar to people without MHD, viral suppression was lower in those with bipolar disorder and MH multimorbidity.
A Statistical Argument Against Vaccine Injury
Authors: Balayla Jacques
Published: May 2022

Vaccine hesitancy is a major threat to public health. While the root causes of vaccine hesitancy are numerous, they largely revolve around some form of perceived risk to the self. In particular, the unknown long-term risks are amongst the most frequently cited concerns. In this work, we show that regardless of their peak onset following vaccination, the incidence of adverse outcomes will follow some distributionf(x|µ, σ2) of mean onsetµ, and standard deviationσ, and varianceσ2. Despite the small proportion of events at the tails of these distributions, the large-scale public deployment of vaccines would imply that any signal for a given adverse outcome would be observed soon after distribution begins, even in cases wheretx< tµ−3σ. The absence of such an early signal, however low, would suggest that long term effects are unlikely and that vaccine safety is therefore likely. Indeed, when enough individuals have been exposed to a new therapy - even if the majority of adverse outcomes only manifest at a future timetµ, the number of adverse outcomes given by the cumulative density function (CDF) neart0+dt >0. Otherwise stated:

We evoke the theory behind normal (Gaussian) and skew-normal distributions and use Chebyshev’s Theorem to evaluate the COVID-19 vaccine data as an example. The findings of this study are not vaccine-specific and can be applied to assess the health effects of the mass distribution of any good, treatment or policy at large.
Broadly neutralizing antibodies against Omicron variants of SARS-CoV-2 derived from mRNA-lipid nanoparticle-immunized mice
Authors: Lu Ruei-Min , Liang Kang-Hao , Chiang Hsiao-Ling , Hsu Fu-Fei , Lin Hsiu-Ting , Chen Wan-Yu , Ke Feng-Yi , Kumari Monika , Chou Yu-Chi , Wu Han-Chung
Published: May 2022

The COVID-19 pandemic continues to threaten human health worldwide, as new variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged. Currently, the predominant circulating strains around the world are Omicron variants, which can evade many therapeutic antibodies. Thus, the development of new broadly neutralizing antibodies remains an urgent need. In this work, we address this need by using the mRNA-lipid nanoparticle immunization method to generate a set of Omicron-targeting monoclonal antibodies. Five of our novel K-RBD-mAbs show strong binding and neutralizing activities toward all SARS-CoV-2 variants of concern (Alpha, Beta, Gamma, Delta and Omicron). Notably, the epitopes of these five K-RBD-mAbs are overlapping and localized around K417 and F486 of the spike protein receptor binding domain (RBD). Chimeric derivatives of the five antibodies (K-RBD-chAbs) neutralize Omicron sublineages BA.1 and BA.2 with low IC50 values that range from 5.7 to 12.9 ng/mL. Additionally, we performed antibody humanization on a broadly neutralizing chimeric antibody to create K-RBD-hAb-62, which still retains excellent neutralizing activity against Omicron. Our results collectively suggest that these five therapeutic antibodies may effectively combat current and emerging SARS-CoV-2 variants, including Omicron BA.1 and BA.2. Therefore, the antibodies can potentially be used as universal neutralizing antibodies against SARS-CoV-2.
Effects of multiple-dose intranasal oxytocin treatment on social responsiveness in children with autism: A randomized, placebo-controlled trial
Authors: Daniels Nicky , Moerkerke Matthijs , Steyaert Jean , Bamps Annelies , Debbaut Edward , Prinsen Jellina , Tang Tiffany , Van der Donck Stephanie , Boets Bart , Alaerts Kaat
Published: May 2022

In the past decade, intranasal administration of the neuropeptide oxytocin is increasingly explored as a new treatment for reducing the core symptoms of autism spectrum disorder (ASD). The efficacy of continual oxytocin treatment in school-aged children with ASD is, however, not well established. Using a double-blind, randomized, placebo-controlled, parallel design, the current trial explored the effects of four weeks of intranasal oxytocin treatment (12 IU, twice daily) on social functioning in pre-pubertal school-aged children (aged 8-12 years, 61 boys, 16 girls). The double-blind phase was followed by a four-week single-blind extension phase during which all participants received intranasal oxytocin. In the double-blind phase, no treatment-specific effects were identified in the primary outcome assessing social functioning (parent-rated Social Responsiveness Scale), as well as on secondary outcomes assessing repetitive behaviors, anxiety, and attachment. Exploratory moderator analyses revealed that children who received the oxytocin treatment in combination with concomitant psychosocial treatment displayed a greater benefit than those who received psychosocial treatment or oxytocin alone. A modulating effect of parents’ beliefs about allocated treatment was also identified, indicating that parents who believed their child assigned to the active treatment reported greater benefit than those who believed their child received placebo, particularly in the actual oxytocin group. Finally, participants who were allocated to receive the placebo treatment during the double-blind phase of the trial and later crossed-over to receive the active treatment during the single-blind extension phase, displayed a significant within-group improvement in social responsiveness, over and above the placebo-induced improvements noted in the first phase. While no overall treatment-specific improvements were identified, our results provide important indications that clinical efficacy can be augmented when oxytocin administration is paired with targeted psychosocial interventions that similarly stimulate socio-communicative behaviors. Future trials are urged to further elucidate the potential of embedding oxytocin treatment within a socially stimulating context.
Apurinic/apyrimidinic nuclease 1 drives genomic evolution contributing to chemoresistance and tumorigenesis in solid tumor
Authors: Kumar Subodh , Zhao Jiangning , Talluri Srikanth , Buon Leutz , Mu Shidai , Potluri Bhavani , Liao Chengcheng , Shi Jialan , Chakraborty Chandraditya , Gonzalez Gabriel B. , Tai Yu-Tzu , Patel Jaymin , Pal Jagannath , Mashimo Hiroshi , Samur Mehmet K. , Munshi Nikhil C. , Shammas Masood A.
Published: May 2022

Genomic instability fuels genomic alterations that befit cancer cells with necessary adaptations to keep proliferating and overcome the impact of host anti-tumor immunity and cytotoxic therapy. Since DNA breaks are required for genomic rearrangements to take place, we hypothesized that dysregulated nuclease activity mediates genomic instability in cancer. Using an integrated genomics protocol, we identified a four gene deoxyribonuclease signature correlating with genomic instability in six human cancers which included adenocarcinomas of esophagus (EAC), lung, prostate, stomach, pancreas and triple negative breast cancer. Functional screens confirmed the role of these nucleases in genomic instability and growth of cancer cells. Apurinic/apyrimidinic nuclease 1 (APE1), identified as top nuclease in functional screen, was further investigated in five cell lines representing four solid tumors (EAC, lung, prostate and breast cancer). We demonstrate that chemical as well as transgenic suppression of APE1 impaired growth/colony formation and increased cytotoxicity of chemotherapeutic agent, whereas inhibited spontaneous as well as chemotherapy-induced DNA breaks, homologous recombination (HR) activity and genomic instability in all cancer cell types tested. Treatment with APE1 inhibitor also impaired tumor growth and significantly increased efficacy of a chemotherapeutic agent in a subcutaneous mouse model of EAC. Overexpression of APE1 in normal esophageal epithelial cells increased DNA breaks and HR activity, leading to massive mutational, copy number as well as karyotypic instability. Evaluation of by whole genome sequencing identified HR as the top mutational process activated by APE1. Normal cells overexpressing APE1 grew as tumors in mice and tumors removed from mice displayed additional karyotypic changes, providing evidence of genomic instability in vivo. Overall, our data demonstrate that elevated APE1 dysregulates HR activity, G2/M checkpoint and genome stability thus contributing to tumorigenesis and chemoresistance in cancer. Therefore, inhibitors of APE1 have potential to inhibit growth and increase cytotoxicity of chemotherapeutic agents while minimizing spontaneous as well as chemotherapy-induced genomic damage and instability in EAC and other solid tumors.
Omics of an enigmatic marine amoeba uncovers unprecedented giant viruses gene trafficking and provides insights into its complex life cycle
Authors: Tekle Yonas I. , Tran Hanh , Wang Fang , Singla Mandakini , Udu Isimeme
Published: May 2022

Amoebozoa include lineages of diverse ecology, behavior and morphology. They are assumed to encompass members with the largest genome sizes of all living things, yet genomic studies in the group are limited. Trichosphaerium, a polymorphic, multinucleate, marine amoeba with a complicated life cycle has puzzled experts in the field for over a century. In an effort to explore the genomic diversity, and investigate extraordinary behavior observed among the Amoebozoa, we used integrated omics approaches to study this enigmatic marine amoeba. Omics data, including single-cell transcriptomics and cytological data, demonstrate that Trichosphaerium sp. possesses the complete meiosis toolkit genes. These genes are expressed in life stages of the amoeba including medium and large cells. The life cycle of Trichosphaerium sp. involves asexual processes via binary fission and multiple fragmentation of giant cells, and sexual-like processes involving genes implicated in sexual reproduction and polyploidization. These findings are in stark contrast to a life cycle previously reported for this amoeba. Despite the extreme morphological plasticity observed in Trichosphaerium, our genomic data showed populations maintain a species-level intragenomic variation. A draft genome of Trichosphaerium indicates elevated lateral gene transfer (LGT) from bacteria and giant viruses. Gene trafficking in Trichosphaerium is the highest within Amoebozoa, and among the highest in microbial eukaryotes.

Significance statement

Amoebozoa include various genome complexities and life cycles, however, the genomes of the vast diversity of amoebozoans remains unexplored. In this study an integrated omics approach is used to investigate the genome and life cycle of Trichophaerium, an enigmatic polymorphic marine amoeba. We uncovered elevated gene trafficking from giant viruses and presence of the complete meiosis gene toolkit. Despite the observed large morphological plasticity, the population of Trichophaerium maintains intragenomic variation of a species level.
JiangShi: a widely distributed Mucin-like protein essential for Drosophila development
Authors: Huang Yueping , Li LingLing , Rong Yikang S.
Published: May 2022

Epithelia exposed to elements of the environment are protected by a mucus barrier in mammals. This barrier also serves to lubricate during organ movements and to mediate substance exchanges between the environmental milieu and internal organs. A major component of the mucus barrier is a class of glycosylated proteins called Mucin. Mucin and mucin-related proteins are widely present in the animal kingdom. Mucin mis-regulation has been reported in many diseases such as cancers and ones involving the digestive and respiratory tracts. Although the biophysical properties of isolated Mucins have been extensively studied, in vivo models remain scarce for the study of their functions and regulations. Here we characterize the Mucin-like JiangShi (JS) protein and its mutations in the fruit fly Drosophila. JS is an extracellular glycoprotein with domain features reminiscent of mammalian non-membranous Mucins, and one of the most widely distributed Mucin-like proteins studied in Drosophila. Both loss and over-production of JS lead to terminal defects in adult structures and organismal death. Although the physiological function of JS remains poorly defined, we present a genetically tractable model system for the in vivo studies of Mucin-like molecules.
Adaptive plasticity in the healthy reading network investigated through combined neurostimulation and neuroimaging
Authors: Turker S. , Kuhnke P. , Schmid F. R. , Cheung V. K. M. , Zeidler B. , Seidel K. , Eckert L. , Hartwigsen G.
Published: May 2022

The reading network in the human brain comprises several regions, including the left inferior frontal cortex (IFC), ventral occipito-temporal cortex (vOTC) and dorsal temporo-parietal cortex (TPC). The left TPC is crucial for phonological decoding, i.e., for learning and retaining sound-letter mappings. Here, we tested the causal contribution of this area for reading with repetitive transcranial magnetic stimulation (rTMS) and explored the response of the reading network using functional magnetic resonance imaging (fMRI). 28 healthy adult readers overtly read simple and complex words and pseudowords during fMRI after effective or sham TMS over the left TPC. Behaviorally, effective stimulation slowed pseudoword reading. A multivariate pattern analysis showed a shift in activity patterns in the left IFC for pseudoword reading after effective relative to sham TMS. Furthermore, active TMS led to increased effective connectivity from the left vOTC to the left TPC, specifically for pseudoword processing. The observed changes in task-related activity and connectivity suggest compensatory reorganization in the reading network following TMS-induced disruption of the left TPC. Our findings provide first evidence for a causal role of the left TPC for overt pseudoword reading and emphasize the relevance of functional interactions in the healthy reading network for successful pseudoword processing.
Brain network integration, flexibility and quasicyclicity during task and rest
Authors: Fransson Peter , Strindberg Marika
Published: May 2022

Previous studies have shown that a re-organization of the brain’s functional connectome expressed in terms of integration and segregation may play a pivotal role. However, it has been proven difficult to capture both processes within a single network-based framework. In this study we apply a hierarchical, spatiotemporally flexible network perspective onto fMRI data to track changes in integration and segregation in time. Our results show that network integration and segregation occur simultaneously in the brain. During task performance, global changes in synchronization between networks arise which are tied to the underlying temporal design of the experiment. We show that a hallmark property of the dynamics of the brain’s functional connectome is a presence of quasiperiodic patterns of network activation and deactivation, which during task performance becomes intertwined with the underlying temporal structure of the experimental paradigm. The proposed approach to study spatiotemporal changes in network reconfiguration during rest as well as task performance could be useful to identify aberrant network motifs in disease.
Src42A is required for E-cadherin dynamics at cell junctions during Drosophila axis elongation
Authors: Chandran L. , Backer W. , Beati H.B. , Kong D. , Luschnig S. , Müller H.-Arno J.
Published: May 2022

Src kinases are important regulators of cell adhesion. Here we explored the function of Src42A in junction remodelling during Drosophila gastrulation. Src42A is required for tyrosine phosphorylation at bicellular and tricellular junctions in germband cells and localizes to hotspots of mechanical tension. The role of Src42A was investigated using maternal RNAi and by CRISPR-Cas9-induced germline mosaics. We find that during cell intercalations, Src42A is required for the contraction of junctions at anterior-posterior cell interfaces. The planar polarity of E-cadherin is compromised and E-cadherin accumulates at tricellular junctions after Src42A knock down. Furthermore, we provide evidence that Src42A acts in parallel to Abl, which has also been implicated in cell intercalations. Our data suggest that Src42A is involved in two related processes, one affecting tension generated by the planar polarity of MyoII and secondly, it can act as a signalling factor at tAJs in controlling E-cadherin residence time.
Loss of Tbx3 in mouse eye causes retinal angiogenesis defects reminiscent of human disease
Authors: Derbyshire M. , Akula S. , Wong A. , Rawlins K. , Voura E. , Brunken W.J. , Zuber M.E. , Fuhrmann S. , Moon A.M. , Viczian A.S
Published: May 2022

Purpose

In Retinopathy of Prematurity (ROP), infants often have incomplete vascularization, affecting the temporal region. A factor expressed in this region during retinal development is the T-box factor, Tbx3, which has not been studied in the mammalian eye. The purpose of this study was to determine if Tbx3 is required during eye formation for retinal angiogenesis.

Methods

Conditional removal of Tbx3 from both retinal progenitors and astrocytes was done using the optic cup-Cre recombinase driver, BAC-Dkk3-CRE and analyzed using standard immunohistochemical techniques.

Results

With Tbx3 loss, the retinas were hypovascular, as seen in patients with ROP and Familial Exudative Vitreoretinopathy (FEVR). Retinal vasculature failed to form the stereotypic tri-layered plexus in the dorsal-temporal region. Astrocyte precursors were reduced in number and failed to form a lattice at the dorsal-temporal edge. We next examined retinal ganglion cells, as they have been shown to play a critical role in retinal angiogenesis. We found that melanopsin expression and Islet1/2-positive retinal ganglion cells were reduced in the dorsal half of the retina. In previous studies, loss of melanopsin has been linked to hyaloid artery persistence, which we also observed in the Tbx3 cKO retina, as well as in infants with ROP or FEVR.

Conclusions

Together, these results show that TBX3 is required for normal mammalian eye formation for the first time. This potentially provides a new genetic model for retinal hypovascular diseases.
BiocMAP: A Bioconductor-friendly, GPU-Accelerated Pipeline for Bisulfite-Sequencing Data
Authors: Eagles Nicholas J , Wilton Richard , Jaffe Andrew E. , Collado-Torres Leonardo
Published: May 2022

Background

Bisulfite sequencing is a powerful tool for profiling genomic methylation, an epigenetic modification critical in the understanding of cancer, psychiatric disorders, and many other conditions. Raw data generated by whole genome bisulfite sequencing (WGBS) requires several computational steps before it is ready for statistical analysis, and particular care is required to process data in a timely and memory-efficient manner. Alignment to a reference genome is one of the most computationally demanding steps in a WGBS workflow, taking several hours or even days with commonly used WGBS-specific alignment software. This naturally motivates the creation of computational workflows that can utilize GPU-based alignment software to greatly speed up the bottleneck step. In addition, WGBS produces raw data that is large and often unwieldy; a lack of memory-efficient representation of data by existing pipelines renders WGBS impractical or impossible to many researchers.

Results

We present BiocMAP, a Bioconductor-friendly Methylation Analysis Pipeline consisting of two modules, to address the above concerns. The first module performs computationally-intensive read alignment using Arioc, a GPU-accelerated short-read aligner. The extraction module extracts and merges DNA methylation proportions - the fractions of methylated cytosines across all cells in a sample at a given genomic site. Since GPUs are not always available on the same computing environments where traditional CPU-based analyses are convenient, BiocMAP is split into two modules, with just the alignment module requiring an available GPU. Bioconductor-based output objects in R utilize an on-disk data representation to drastically reduce required main memory and make WGBS projects computationally feasible to more researchers.

Conclusions

BiocMAP is implemented using Nextflow and available at http://research.libd.org/BiocMAP/. To enable reproducible analysis across a variety of typical computing environments, BiocMAP can be containerized with Docker or Singularity, and executed locally or with the SLURM or SGE scheduling engines. By providing Bioconductor objects, BiocMAP’s output can be integrated with powerful analytical open source software for analyzing methylation data.
Fast, accurate antibody structure prediction from deep learning on massive set of natural antibodies
Authors: Ruffolo Jeffrey A. , Chu Lee-Shin , Mahajan Sai Pooja , Gray Jeffrey J.
Published: May 2022

Antibodies have the capacity to bind a diverse set of antigens, and they have become critical therapeutics and diagnostic molecules. The binding of antibodies is facilitated by a set of six hypervariable loops that are diversified through genetic recombination and mutation. Even with recent advances, accurate structural prediction of these loops remains a challenge. Here, we present IgFold, a fast deep learning method for antibody structure prediction. IgFold consists of a pre-trained language model trained on 558M natural antibody sequences followed by graph networks that directly predict backbone atom coordinates. IgFold predicts structures of similar or better quality than alternative methods (including AlphaFold) in significantly less time (under one minute). Accurate structure prediction on this timescale makes possible avenues of investigation that were previously infeasible. As a demonstration of IgFold’s capabilities, we predicted structures for 105K paired antibody sequences, expanding the observed antibody structural space by over 40 fold.
Waning of PCV13 vaccine-induced antibody levels within the first year of life, using a 3+0 schedule: an observational population-level serosurveillance study among children under 5 years old in Blantyre, Malawi
Authors: Swarthout Todd D , Henrion Marc Y R , Thindwa Deus , Meiring James E , Mbewe Maurice , Brown Comfort , Msefula Jacquline , Moyo Brewster , Mataya Andrew A , Barnaba Susanne , Pearce Emma , Gordon Melita , Goldblatt David , French Neil , Heyderman Robert S.
Published: May 2022

Background

Pneumococcal conjugate vaccines (PCVs) induce serotype-specific IgG antibody, effectively reducing vaccine-serotype (VT) carriage and invasive pneumococcal disease (IPD). IgG production wanes approximately 1 month after vaccination in absence of serotype-specific exposure. With uncertainty around correlate of protection (CoP) estimates and with persistent VT carriage and VT-IPD following PCV13 introduction, we undertook population-level immunogenicity profiling among children <5 years in Blantyre, Malawi.

Methods

For 638 children, capsule-specific IgG to PCV13 VTs, two non-VTs, and IgG to three pneumococcal proteins were measured using an enzyme-linked immunosorbent assay and a direct-binding electrochemiluminescence-based multiplex assay. A linear spline regression model estimated population-level, serotype-specific immunogenicity profiles. A linear regression model was used to validate putative CoPs.

Findings

Immunogenicity profiles revealed a consistent pattern among VTs except serotype 3: a vaccine-induced IgG peak followed by waning to a nadir and subsequent increase in titre. For serotype 3 there was no apparent vaccine-induced increase. Heterogeneity in parameters included age range at post-vaccination-nadir (11·2 [19F, 23F] to 27·3 [7F] months). Titres dropped below IPD CoPs among 9 VTs and below carriage CoPs for 10 VTs. Study data estimated a range of carriage CoPs (0·50μg/mL to 2·5μg/mL). Increasing antibody among older children and seroincident events were consistent with ongoing VT exposure.

Interpretation

A 3+0 PCV13 schedule with high uptake has not led to sustained population-level antibody immunity beyond the first year of life. Indeed, post-vaccine antibody concentrations dropped below putative CoPs for several VTs, potentially contributing to persistent VT carriage and residual VT-IPD in Malawi and other similar settings.

Funding

Bill & Melinda Gates Foundation, Wellcome UK, and National Institute for Health & Care Research.
Determinants of SARS-CoV-2 anti-spike antibody levels following BNT162b2 vaccination: cross-sectional analysis of 6,000 SIREN study participants
Authors: Otter Ashley David , D’Arcangelo Silvia , Whitaker Heather , Hewson Jacqueline , Foulkes Sarah , Atti Ana , Cole Michelle , Linley Ezra , Tonge Simon , Hettiarachchi Nipunadi , Sajedi Noshin , Calbraith Davina , Norman Chris , de Lacy Elen , Price Lesley , Stewart Sally , Cromey Lisa , Corrigan Diane ,   SIREN study group, Rowe Cathy , Brown Colin S , Islam Jasmin , Semper Amanda , Hopkins Susan , Hall Victoria , Brooks Tim
Published: May 2022

Background

Understanding immunological responses to SARS-CoV-2 vaccinations is integral to the management of SARS-CoV-2. We aimed to investigate determinants of antibody response to the BNT162b2 vaccine.

Methods

A cross-sectional analysis of anti-spike binding antibodies in serum samples from healthcare workers after one or two doses. Post-vaccination interval was restricted to ≥21 days after dose 1, ≥14 days after dose 2. The primary outcome was anti-S titres with explanatory variables dose, previous infection, dosing interval, age, ethnicity, and comorbidities. Multivariable linear regression was also conducted.

Results

Participants (n=5,871) included 3,989 post-dose 1, 1,882 post-dose 2. In SARS-CoV-2 infection naïve, 99.65% seroconverted after dose 1 and >99.9% seroconverted after dose 2. Geometric mean anti-S titre in the naïve cohort was 75.48 Binding Antibody Units/ml after dose 1, 7,049 BAU/ml after dose 2. Anti-S titres were higher in those with previous infection (2,111 BAU/ml post-dose 1, 16,052 BAU/ml post-dose 2), and increased with time between infection and vaccination: 3 months 1,970 (1,506-2,579) vs 9 months; 13,759 (8,097-23,379). Longer dosing intervals increased antibody response post-dose 2: 11-fold higher with a longer interval (>10 weeks) than those with shorter intervals, across all age-groups. Younger participants had higher mean titres (>2.2-fold higher). Multivariable regression modelling corroborated the above associations, and also found higher titres associated with being female or from an ethnic minority but lower titres among immunocompromised participants.

Conclusion

The number of antigen exposures and timing between vaccinations plays a significant role in the magnitude of the post-vaccination antibody response, with implications for long-term protection and post-booster antibody responses.
Epidemiological investigation of the COVID-19 outbreak in Vellore district in South India using Geographic Information Surveillance (GIS)
Authors: Murugesan Malathi , Venkatesan Padmanaban , Kumar Senthil , Thangavelu Premkumar , Rose Winsley , John Jacob , Castro Marx , T Manivannan , Mohan Venkata Raghava , Rupali Priscilla
Published: May 2022

Objectives

Geographical Information Surveillance (GIS) is an advanced digital technology tool that maps location-based data and helps in epidemiological modeling. We applied GIS to analyze patterns of spread and hotspots of COVID-19 cases in Vellore district in South India.

Methods

Laboratory-confirmed COVID-19 cases from the Vellore district and neighboring taluks from March 2020 to June 2021 were geo-coded and spatial maps were generated. Time trends exploring urban-rural burden with an age-sex distribution of cases and other variables were correlated with outcomes.

Results

A total of 45,401 cases of COVID-19 were detected with 20730 cases during the first wave and 24671 cases during the second wave. The overall incidence rates of COVID-19 were 462.8 and 588.6 per 100,000 populations during the first and second waves respectively. The pattern of spread revealed epicenters in densely populated urban areas with radial spread sparing rural areas in the first wave. The case fatality rate was 1.89% and 1.6% during the first and second waves that increased with advancing age.

Conclusions

Modern surveillance systems like GIS can accurately predict the trends and pattern of spread during future pandemics. A real-time mapping can help design risk mitigation strategies thereby preventing the spread to rural areas.
How time-scale differences in asymptomatic and symptomatic transmission shape SARS-CoV-2 outbreak dynamics
Authors: Harris Jeremy D. , Park Sang Woo , Dushoff Jonathan , Weitz Joshua S.
Published: May 2022

Asymptomatic and symptomatic SARS-CoV-2 infections can have different characteristic time scales of transmission. These time-scale differences can shape outbreak dynamics as well as bias population-level estimates of epidemic strength, speed, and controllability. For example, prior work focusing on the initial exponential growth phase of an outbreak found that larger time scales for asymptomatic vs. symptomatic transmission can lead to under-estimates of the basic reproduction number as inferred from epidemic case data. Building upon this work, we use a series of nonlinear epidemic models to explore how differences in asymptomatic and symptomatic transmission time scales can lead to changes in the realized proportion of asymptomatic transmission throughout an epidemic. First, we find that when asymptomatic transmission time scales are longer than symptomatic transmission time scales, then the effective proportion of asymptomatic transmission increases as total incidence decreases. Moreover, these time-scale-driven impacts on epidemic dynamics are enhanced when infection status is correlated between infector and infectee pairs (e.g., due to dose-dependent impacts on symptoms). Next we apply these findings to understand the impact of time-scale differences on populations with age-dependent assortative mixing and in which the probability of having a symptomatic infection increases with age. We show that if asymptomatic generation intervals are longer than corresponding symptomatic generation intervals, then correlations between age and symptoms lead to a decrease in the age of infection during periods of epidemic decline (whether due to susceptible depletion or intervention). Altogether, these results demonstrate the need to explore the role of time-scale differences in transmission dynamics alongside behavioural changes to explain outbreak features both at early stages (e.g., in estimating the basic reproduction number) and throughout an epidemic (e.g., in connecting shifts in the age of infection to periods of changing incidence).
Snotwatch COVID-Toes: An ecological study of chilblains and COVID-19 diagnoses in Victoria, Australia
Authors: Sawires Rana , Pearce Christopher , Fahey Michael , Clothier Hazel , Gardner Karina , Buttery Jim
Published: May 2022

Background

The COVID-19 pandemic has caused widespread illness with varying clinical manifestations. One less-commonly-reported presentation of COVID-19 infection is chilblain-like lesions.

Aims

We conducted an ecological analysis of chilblain presentations in comparison with confirmed and suspected COVID-19 infections in a primary care setting to establish that a relationship exists between the two.

Study Design

Our study collated data from three Primary Health Networks across Victoria, Australia, from 2017-2021, to understand patterns of chilblain presentations prior to and throughout the pandemic. Using a zero-inflated negative binomial regression analysis, we estimated the relationship between local minimum temperature, COVID-19 infections and the frequency of chilblain presentations.

Results

We found a 5.72 risk ratio of chilblain incidence in relation to COVID-19 infections and a 3.23 risk ratio associated with suspected COVID-19 infections. COVID-19 infections were also more strongly associated with chilblain presentations in 0-16-year-olds throughout the pandemic in Victoria.

Conclusion

Our study statistically demonstrates that chilblains are significantly associated with COVID-19 infections in a primary care setting. This has major implications for clinicians aiming to diagnose COVID-19 infections or determine the cause of a presentation of chilblains. Additionally, we demonstrate the utility of large-scale primary care data and its potential application to monitoring the spread of COVID-19 infections across the state, supporting current epidemiological efforts for COVID-19 tracking.
Resilience in soil bacterial communities of the boreal forest from one to five years after wildfire across a severity gradient
Authors: Whitman Thea , Woolet Jamie , Sikora Miranda , Johnson Dana B. , Whitman Ellen
Published: May 2022

Wildfires can represent a major disturbance to ecosystems, including soil microbial communities belowground. Furthermore, fire regimes are changing in many parts of the world, altering and often increasing fire severity, frequency, and size. The boreal forest and taiga plains ecoregions of northern Canada are characterized by naturally-occurring stand-replacing wildfires on a 40-350 year basis. We previously studied the effects of wildfire on soil microbial communities one year post-fire across 40 sites, spanning a range of burn severity. Here, we return to the same sites five years post-fire to test a series of hypotheses about the effects of fire on bacterial community composition. We ask the following questions: (1a) Do the fundamental factors structuring bacterial community composition remain the same five years post-fire? (1b) Do the effects of fire on bacterial community composition decrease between one and five years post-fire? (1c) Do shifts in bacterial community composition between one and five years post-fire suggest resilience? (2a) Does the importance of fast growth diminish between one and five years post-fire? (2b) Do short-term post-fire responders continue to dominate the community five years post-fire? We find the following: (1a) Five years post-fire, vegetation community, moisture regime, pH, total carbon, texture, and burned/unburned all remained significant predictors of bacterial community composition with similar predictive value (R2). (1b and 1c) Bacterial communities became more similar to unburned sites five years post-fire, across the range of severity, suggesting resilience, while general structure of co-occurrence networks remained similar one and five years post-fire. (2a) Fast growth potential, as estimated using predicted 16S rRNA copy numbers, was no longer significantly correlated with burn severity five years post-fire, indicating the importance of this trait for structuring bacterial community composition may be limited to relatively short timescales. (2b) Many taxa that were enriched in burned sites one year post-fire remained enriched five years post-fire, although the degree to which they were enriched generally decreased. Specific taxa of interest from the generaMassilia, Blastococcus, andArthrobacterall remained significantly enriched, suggesting that they may have traits that allow them to continue to flourish in the post-fire environment, such as tolerance to increased pH or ability to degrade pyrogenic organic matter. This hypothesis-based work expands our understanding of the post-fire recovery of soil bacterial communities and raises new hypotheses to test in future studies.
Isotopic reconstruction of the subsistence strategy for a Central Italian Bronze Age community (Pastena cave, 2nd millennium BCE)
Authors: Cortese F. , De Angelis F. , Achino K.F. , Bontempo L. , Di Cicco M.R. , Gatta M. , Lubritto C. , Salari L. , Silvestri L. , Rickards O. , Rolfo M.F.
Published: May 2022

The Pastena cave is located in central Italy and its best-preserved sector is Grotticella W2, which is dated radiometrically to the Early-Middle Bronze Age. The aim of this paper is to explore human diet, animal husbandry, and plant management analyzing the findings there discovered. Carbon and nitrogen stable isotope analysis have been carried out on 40 charred seeds, 6 faunal remains and 4 human specimens, investigating the whole bio-archaeological samples available. To the best of our knowledge, this is one of the first papers presenting stable isotope analysis on carpological remains dated to the Italian Early-Middle Bronze Age. The obtained results are consistent with a diet based on terrestrial protein, mainly on plants and secondly on meat and animal products. The data suggest that plants, especially broad beans, were partially subjected to human management, while livestock was managed through different husbandry strategies. The cooperation between archaeological studies and molecular analysis allows us to contribute to clarify the economic strategies for a Central Italian community in a scenario that is still poor in published data.
Oral rabies vaccination of dogs – experiences from a field trial in Namibia
Authors: Freuling Conrad M. , Busch Frank , Vos Ad , Ortmann Steffen , Lohr Frederic , Hedimbi Nehemia , Peter Josephat , Nelson Herman Adimba , Shoombe Kenneth , Shilongo Albertina , Gorejena Brighton , Kaholongo Lukas , Khaiseb Siegfried , van der Westhuizen Jolandie , Dietze Klaas , Geurtse Goi , Müller Thomas
Published: May 2022

Dog-mediated rabies is responsible for tens of thousands of human deaths annually, and in resource-constrained settings, vaccinating dogs to control the disease at source remains challenging. Currently, rabies elimination efforts rely on mass dog vaccination by the parenteral route. To increase the herd immunity, free-roaming and stray dogs need to be specifically addressed in the vaccination campaigns, with oral rabies vaccination (ORV) of dogs being a possible solution. Using a third-generation vaccine and a standardized egg-flavoured bait, bait uptake and vaccination was assessed under field conditions in Namibia. During this trial, both veterinary staff as well as dog owners expressed their appreciation to this approach of vaccination. Of 1,115 dogs offered a bait, 90% (n=1,006, 95%CI:91-94) consumed the bait and 72.9% (n=813, 95%CI:70.2-75.4) of dogs were assessed as being vaccinated, while for (11.7%, n=130, 95%CI:9.9-17.7) the status was recorded as “unkown” and 15.4% (n=172, 95%CI: 13.4-17.7) were considered as being not vaccinated. Smaller dogs and dogs offered a bait with multiple other dogs had significantly higher vaccination rates, while other factors, e.g. sex, confinement status and time had no influence.

The favorable results of this first large-scale field trial further support the strategic integration of ORV into dog rabies control programmes. Given the acceptance of the egg-flavored bait under various settings worldwide, ORV of dogs could become a game-changer in countries, where control strategies using parenteral vaccination alone failed to reach sufficient vaccination coverage in the dog population.
Maintenance of quantitative genetic variance in complex, multi-trait phenotypes: The contribution of rare, large effect variants in two Drosophila species
Authors: Hine Emma , Runcie Daniel E. , Allen Scott L. , Wang Yiguan , Chenoweth Stephen F. , Blows Mark W. , McGuigan Katrina
Published: May 2022

The interaction of evolutionary processes to determine quantitative genetic variation has implications for contemporary and future phenotypic evolution, as well as for our ability to detect causal genetic variants. While theoretical studies have provided robust predictions to discriminate among competing models, empirical assessment of these has been limited. In particular, theory highlights the importance of pleiotropy in resolving observations of selection and mutation, but empirical investigations have typically been limited to few traits. Here, we applied high dimensional Bayesian Sparse Factor Genetic modelling to 3,385 gene expression traits fromDrosophila melanogasterand fromD. serratato explore how genetic variance is distributed across high-dimensional phenotypic space. Surprisingly, most of the heritable trait covariation was due to few lines (genotypes) with extreme (>3 IQR from the median) values. This observation, in the two independently sampled species, suggests that the House of Cards (HoC) model might apply not only to individual expression traits, but also to emergent co-expression phenotypes. Intriguingly, while genotypes extreme for a multivariate factor also tended to have a higher proportion of individual traits that were extreme, we also observed genotypes that were outliers for multivariate factors but not for any individual traits. We observed other consistent differences between heritable multivariate factors with outlier lines versus those factors that conformed to a Gaussian distribution of genetic effects, including differences in gene functions. We use these observations to identify further data required to advance our understanding of the evolutionary dynamics and nature of standing genetic variation for quantitative traits.
Combining Stem Cell Rejuvenation and Senescence Targeting to Synergistically Extend Lifespan
Authors: Kaur Prameet , Otgonbaatar Agimaa , Ramamoorthy Anupriya , Zhen Chua Ellora Hui , Harmston Nathan , Gruber Jan , Tolwinski Nicholas S.
Published: May 2022

Why biological age is a major risk factor for many of the most important human diseases remains mysterious. We know that as organisms age, stem cell pools are exhausted while senescent cells progressively accumulate. Independently, induction of pluripotency via expression of Yamanaka factors (Oct4, Klf4, Sox2, c-Myc; OKSM) and clearance of senescent cells have each been shown to ameliorate cellular and physiological aspects of aging, suggesting that both processes are drivers of organismal aging. However, stem cell exhaustion and cellular senescence likely interact in the etiology and progression of age-dependent diseases because both undermine tissue and organ homeostasis in different if not complementary ways. Here, we combine transient cellular reprogramming (stem cell rejuvenation) with targeted removal of senescent cells to test the hypothesis that simultaneously targeting both cell-fate based aging mechanisms will maximize life and health span benefits. We show that these interventions protect the intestinal stem cell pool, lower inflammation, activate pro-stem cell signaling pathways, and synergistically improve health and lifespan. Our findings suggest that a combination therapy, simultaneously replacing lost stem cells and removing senescent cells, shows synergistic potential for anti-aging treatments. Our finding that transient expression of both is the most effective suggests that drug-based treatments in non-genetically tractable organisms will likely be the most translatable.
Explosive seed dispersal depends on SPL7 to ensure sufficient copper for localized lignin deposition via laccases
Authors: Pérez-Antón Miguel , Schneider Ilsa , Kroll Patrizia , Hofhuis Hugo , Metzger Sabine , Pauly Markus , Hay Angela
Published: May 2022

Exploding seed pods evolved in the Arabidopsis relative, Cardamine hirsuta, via morphomechanical innovations that allow the storage and rapid release of elastic energy. Asymmetric lignin deposition within endocarpb cell walls is one such innovation that is required for explosive seed dispersal and evolved in association with the trait. However, the genetic control of this novel lignin pattern is unknown. Here, we identify three lignin-polymerizing laccases, LAC4, 11 and 17, that precisely co-localize with, and are redundantly required for, asymmetric lignification of endocarpb cells. By screening for C. hirsuta mutants with less lignified fruit valves, we found that loss of function of the transcription factor gene SQUAMOSA PROMOTER BINDING PROTEIN-LIKE 7 (SPL7) caused a reduction in endocarpb cell wall lignification and a consequent reduction in seed dispersal range. SPL7 is a conserved regulator of copper homeostasis and is both necessary and sufficient for copper to accumulate in the fruit. Laccases are copper-requiring enzymes. We discovered that laccase activity in endocarpb cell walls depends on the SPL7 pathway to acclimate to copper deficiency and provide sufficient copper for lignin polymerization. Hence, SPL7 links mineral nutrition to efficient dispersal of the next generation.
Optimal burstiness in populations of spiking neurons facilitates decoding of decreases in tonic firing
Authors: Durian Sylvia C. L. , Agrios Mark , Schwartz Gregory W.
Published: May 2022

A stimulus can be encoded in a population of spiking neurons through any change in the statistics of the joint spike pattern, yet we commonly summarize single-trial population activity by the summed spike rate across cells: the population peri-stimulus time histogram (pPSTH). For neurons with low baseline spike rate that encode a stimulus with a rate increase, this simplified representation works well, but for populations with high baseline rates and heterogeneous response patterns, the pPSTH has limited utility in capturing the neural representation of the stimulus. We simulated populations of spiking neurons that varied in size, baseline rate, burst statistics, and correlation, and we measured how these populations represent decreases (gaps) in spike rate. We introduce a different representation of the population spike pattern which we call an “information train,” and we show that it is more flexible and robust than the pPSTH in capturing stimulus information across different types of neuronal populations. In particular, we use this tool to study populations with varying levels of burstiness in their spiking statistics. We find that there is an optimal level of burstiness for gap detection that is robust to several other parameters of the population. Next, we consider this theoretical result in the context of experimental data from different types of retinal ganglion cells and determine that the baseline spike statistics of a particular, recently identified type support nearly optimal detection of both the onset and strength of a contrast step.