bluuebunny/crossref_metadata_2025 huggingface dataset:
Neutralization of Omicron BA.4/BA.5 and BA.2.75 by Booster Vaccination or BA.2 Breakthrough Infection Sera
Authors: Wang Xun , Ai Jingwen , Li Xiangnan , Zhao Xiaoyu , Wu Jing , Zhang Haocheng , He Xing , Zhao Chaoyue , Qiao Rui , Li Minghui , Cui Yuchen , Chen Yanjia , Yang Lulu , Hu Zixin , Xu Chenqi , Zhang Wenhong , Wang Pengfei
Published: August 2022

Many new Omicron sub-lineages have been reported to evade neutralizing antibody response, including BA.2, BA.2.12.1, BA.4 and BA.5. Most recently, another emerging sub-lineage BA.2.75 has been reported in multiple countries. In this study, we constructed a comprehensive panel of pseudoviruses (PsVs), including wild-type, Delta, BA.1, BA.1.1, BA.2, BA.3, BA.2.3.1, BA.2.10.1, BA.2.12.1, BA.2.13, BA.2.75 and BA.4/BA.5, with accumulate coverage reached 91% according to the proportion of sequences deposited in GISAID database since Jan 1st, 2022. We collected serum samples from healthy adults at day14 post homologous booster with BBIBP-CorV, or heterologous booster with ZF2001, primed with two doses of BBIBP-CorV, or from convalescents immunized with three-dose inactivated vaccines prior to infection with Omicron BA.2, and tested their neutralization activity on this panel of PsVs. Our results demonstrated that all Omicron sub-lineages showed substantial evasion of neutralizing antibodies induced by vaccination and infection, although BA.2.75 accumulated the largest number of mutations in its spike, BA.4 and BA.5 showed the strongest serum escape. However, BA.2 breakthrough infection could remarkably elevated neutralization titers against all different variants, especially titers against BA.2 and its derivative sub-lineages.
Complex host/symbiont integration of a multi-partner symbiotic system in the eusocial aphid Ceratovacuna japonica
Authors: Yorimoto Shunta , Hattori Mitsuru , Maki Kondo , Shigenobu Shuji
Published: August 2022

Some hemipteran insects rely on multiple endosymbionts for essential nutrients. However, the evolution of multi-partner symbiotic systems is not well-established. Here, we report a co-obligate symbiosis in the eusocial aphid, Ceratovacuna japonica. 16S rRNA amplicon sequencing unveiled co-infection with a novel Arsenophonus sp. symbiont and Buchnera aphidicola, a common obligate endosymbiont in aphids. Both symbionts were housed within distinct bacteriocytes and were maternally transmitted. The Buchnera and Arsenophonus symbionts had streamlined genomes of 432,286 bp and 853,149 bp, respectively, and exhibited metabolic complementarity in riboflavin and peptidoglycan synthesis pathways. These anatomical and genomic properties were similar to those of independently evolved multi-partner symbiotic systems, such as Buchnera–Serratia in Lachninae and Periphyllus aphids, representing remarkable parallelism. Furthermore, symbiont populations and bacteriome morphology differed between reproductive and soldier castes. Our study provides the first example of co-obligate symbiosis in Hormaphidinae and gives insight into the evolutionary genetics of this complex system.
Ranging patterns of the rainforest-adapted lion-tailed macaque Macaca silenus in a human-dominated landscape in the Anamalai hills of the Western Ghats, India
Authors: Dhawale Ashni Kumar , Sinha Anindya
Published: August 2022

The ranging patterns of five lion-tailed macaque Macaca silenus troops, forming the Puthuthottam sub-population, were studied over a three year period to determine road/habitation visitation rate, home ranges and habitat preference. Each troop visited the road or human habitation at varying rates, with the largest troop visiting most frequently. Home ranges sizes were observed to be highly reduced when compared to wild populations, and also greatly varied across troops, with relatively low overlap given the macaque density in the available area. All five macaque troops showed a preference for human-modified habitats such as roads and human settlements where anthropogenic food was easily available. Our study shows an increasing dependence amongst members of the Puthuthottam troops on anthropogenic foods, which has led to many threats faced by individuals including fatal collisions with vehicular traffic and electrocutions.
Systematic delineation of signaling and epigenomic mechanisms underlying microglia inflammatory activity in acute and chronic brain pathologies
Authors: Xavier Andre Machado , Distéfano-Gagné Félix , Belhamiti Nesrine , Belhocine Sarah , Bitarafan Sara , Falle Alexia , Fiola S. , Rivest Serge , Gosselin David
Published: August 2022

Microglia promptly mount an inflammatory response following detection of infectious agents or injuries in the central nervous system. Such function fundamentally depends upon dynamic modulation of gene expression. However, the signaling and epigenomic mechanisms that regulate the transcriptional process underlying microglial inflammatory activity are not well understood. To address this, we used RNA-seq, ChIP-seq and ATAC-seq to delineate gene signatures and activity across the repertoire of genomic regulatory elements of microglia engaged in acute and chronic neuroinflammatory activity. Systematic interrogations of the microglial population over time during a systemic inflammatory response revealed a coordinated, sequential activation of multiple gene programs associated with defense response, translation and cell cycling. Activation of these programs occurred in parallel with gain and loss of activity at 4,080 and 3,119 genomic cis-regulatory elements, respectively. Furthermore, computational analyses identified key transcriptional regulators, including Ets, AP-1, C/epb, Nf-κB, Irf, Runx, c-Myc and E2f family members, that display differential propensity for activity at gene promoters and promoter-distal cis-regulatory elements. Gene expression analyses also suggested that the transcriptional process likely contribute to the effective activity of numerous transcriptional regulators through the modulation of their mRNA levels. Finally, characterization of CD11c-positive microglia that emerge with chronic demyelinating brain lesions suggested that Egr2, Mef2 members and E-box-binding factors such as Tfeb and Mitf contribute to the enhanced phagosomal activity of this inflammatory subset. Loss-of-function experiments validated that Mef2a in microglia is necessary for the acquisition of the CD11c-positive phenotype. Collectively, these results demonstrate that the inflammatory activity of microglia arises through an intricate, ultimately context-dependent, interplay between signaling pathways, genomic regulatory elements and the transcriptional machinery.
Filming space-time changes of gene expression with expressyouRcell
Authors: Paganin Martina , Tebaldi Toma , Lauria Fabio , Viero Gabriella
Published: August 2022

The last decade has witnessed massive advancements in high-throughput techniques capable of producing quantifications of transcript and protein levels across time and space, and at high resolution. Yet, the large volume of big data available and the complexity of experimental designs hamper an easy understanding and effective communication of the results.

Here we present expressyouRcell, a unique and easy-to-use R package to map the multi-dimensional variations of transcript and protein levels in cell-pictographs. These variations are outcomes of differential and gene set enrichment analysis across space and time. Our tool directly associates these results with up to twenty specific cellular compartments, visualising them as pictographic representations of four different cellular thematic maps. expressyouRcell visually reduces the complexity of displaying gene expression and protein level changes across multiple time-points by generating dynamic representations of cellular pictographs.

We applied expressyouRcell to six datasets, demonstrating its flexibility and usability in the visualization of simple and highly effective static and dynamic representations of time course variations in gene expression. Our approach complements classical plot-based methods for visualization and exploitation of biological data, improving the standard quantitative interpretation and communication of relevant results.
Tensorial Independent Component Analysis Reveals Social and Reward Networks Associated with Major Depressive Disorder
Authors: Dennison Jeff B. , Tepfer Lindsey J. , Smith David V.
Published: August 2022

Major depressive disorder (MDD) has been associated with changes in functional brain connectivity. Yet, typical analyses of functional connectivity, such as spatial ICA for resting-state data, often ignore sources of between-subject variability, which may be crucial for identifying functional connectivity patterns associated with MDD. Typically, methods like spatial ICA will identify a single component to represent a network like the default mode network (DMN), even if groups within the data show differential DMN coactivation. To address this gap, this project applies a tensorial extension of ICA (tensorial ICA)—which explicitly incorporates between-subject variability—to identify functionally connected networks using fMRI data from the Human Connectome Project (HCP). Data from the HCP included individuals with a diagnosis of MDD, a family history of MDD, and healthy controls performing a gambling and social cognition task. Based on evidence associating MDD with blunted neural activation to rewards and social stimuli, we predicted that tensorial ICA would identify networks associated with reduced spatio-temporal coherence and blunted social and reward-based network activity in MDD. Across both tasks, tensorial ICA identified three networks showing decreased coherence in MDD. All three networks included ventromedial prefrontal cortex (vmPFC), striatum, and cerebellum and showed different activation across the conditions of their respective tasks. However, MDD was only associated with differences in task-based activation in one network from the social task. Additionally, these results suggest that tensorial ICA could be a valuable tool for understanding clinical differences in relation to network activation and connectivity.
The Nested Hierarchy of Overt, Mouthed, and Imagined Speech Activity Evident in Intracranial Recordings
Authors: Soroush Pedram Z. , Herff Christian , Ries Stephanie K. , Shih Jerry J. , Schultz Tanja , Krusienski Dean J.
Published: August 2022

Recent studies have demonstrated that it is possible to decode and synthesize various aspects of acoustic speech directly from intracranial measurements of electrophysiological brain activity. In order to continue progressing toward the development of a practical speech neuroprosthesis for the individuals with speech impairments, better understanding and modeling of imagined speech processes are required. The present study uses intracranial brain recordings from participants that performed a speaking task with trials consisting of overt, mouthed, and imagined speech, representing various degrees of decreasing behavioral output. Speech activity detection models are constructed using spatial, spectral, and temporal brain activity features, and the features and model performances are characterized and compared across the three degrees of behavioral output. The results indicate there is a hierarchy in which the relevant channels for the lower behavioral output modes form nested subsets of the relevant channels from the higher behavioral output modes. This provides important insights for the elusive goal of developing more effective imagined speech decoding models with respect to the better-established overt speech decoding counterparts.
Pollinator and host sharing lead to hybridization and introgression in Panamanian free-standing figs, but not in their pollinator wasps
Authors: Satler Jordan D. , Herre Edward Allen , Heath Tracy A. , Machado Carlos A. , Zúñiga Adalberto Gómez , Jandér K. Charlotte , Eaton Deren A. R. , Nason John D.
Published: August 2022

Obligate pollination mutualisms, in which plant and pollinator lineages depend on each other for reproduction, often exhibit high levels of species-specificity. However, cases in which two or more pollinator species share a single host species (host sharing), or two or more host species share a single pollinator species (pollinator sharing), are known to occur in current ecological time. Further, evidence for host switching in evolutionary time is increasingly being recognized in these systems. The degree to which departures from strict specificity differentially affect the potential for hybridization and introgression in the associated host or pollinator is unclear. We addressed this question using genome-wide sequence data from five sympatric Panamanian free-standing fig species (Ficus subgenus Pharmacosycea, section Pharmacosycea) and their six associated fig pollinator wasp species (Tetrapus). Two of the five fig species, F. glabrata and F. maxima, were found to regularly share pollinators. In these species, ongoing hybridization was demonstrated by the detection of several first-generation (F1) hybrid individuals and historical introgression was indicated by phylogenetic network analysis. In contrast, although two of the pollinator species regularly share hosts, all six species were genetically distinct and deeply divergent, with no evidence for either hybridization or introgression. This pattern is consistent with results from other obligate pollination mutualisms, suggesting that, in contrast to their host plants, pollinators appear to be reproductively isolated, even when different species of pollinators mate in shared hosts.
Identification and prediction of Parkinson’s disease subtypes and progression using machine learning in two cohorts
Authors: Dadu Anant , Satone Vipul K. , Kaur Rachneet , Hashemi Sayed Hadi , Leonard Hampton , Iwaki Hirotaka , Makarious Mary B. , Billingsley Kimberley , Bandres-Ciga Sara , Sargent Lana J. , Noyce Alastair J. , Daneshmand Ali , Blauwendraat Cornelis , Marek Ken , Scholz Sonja W. , Singleton Andrew B. , Nalls Mike A. , Campbell Roy H. , Faghri Faraz
Published: August 2022

Background

The clinical manifestations of Parkinson’s disease (PD) are characterized by heterogeneity in age at onset, disease duration, rate of progression, and the constellation of motor versus non-motor features. There is an unmet need for the characterization of distinct disease subtypes as well as improved, individualized predictions of the disease course. The emergence of machine learning to detect hidden patterns in complex, multi-dimensional datasets provides unparalleled opportunities to address this critical need.

Methods and Findings

We used unsupervised and supervised machine learning methods on comprehensive, longitudinal clinical data from the Parkinson’s Disease Progression Marker Initiative (PPMI) (n = 294 cases) to identify patient subtypes and to predict disease progression. The resulting models were validated in an independent, clinically well-characterized cohort from the Parkinson’s Disease Biomarker Program (PDBP) (n = 263 cases). Our analysis distinguished three distinct disease subtypes with highly predictable progression rates, corresponding to slow, moderate, and fast disease progression. We achieved highly accurate projections of disease progression five years after initial diagnosis with an average area under the curve (AUC) of 0.92 (95% CI: 0.95 ± 0.01 for the slower progressing group (PDvec1), 0.87 ± 0.03 for moderate progressors, and 0.95 ± 0.02 for the fast progressing group (PDvec3). We identified serum neurofilament light (Nfl) as a significant indicator of fast disease progression among other key biomarkers of interest. We replicated these findings in an independent validation cohort, released the analytical code, and developed models in an open science manner.

Conclusions

Our data-driven study provides insights to deconstruct PD heterogeneity. This approach could have immediate implications for clinical trials by improving the detection of significant clinical outcomes that might have been masked by cohort heterogeneity. We anticipate that machine learning models will improve patient counseling, clinical trial design, allocation of healthcare resources, and ultimately individualized patient care.
Tensor Decomposition Discriminates Tissues Using scATAC-seq
Authors: Taguchi Y-h. , Turki Turki
Published: August 2022

ATAC-seq is a powerful tool for measuring the landscape structure of a chromosome. scATAC-seq is a recently updated version of ATAC-seq performed in a single cell. The problem with scATAC-seq is data sparsity and most of the genomic sites are inaccessible. Here, tensor decomposition (TD) was used to fill in missing values. In this study, TD was applied to massive scATAC-seq datasets generated by approximately 200 bp intervals, and this number can reach 13,627,618. Currently, no other methods can deal with large sparse matrices. The proposed method could not only provide UMAP embedding that coincides with tissue specificity, but also select genes associated with various biological enrichment terms and transcription factor targeting. This suggests that TD is a useful tool to process a large sparse matrix generated from scATAC-seq.
IFNγ and antibody synergize to enhance protective immunity againstChlamydiadissemination and female reproductive tract reinfections
Authors: Gann Jessica A. , Malaviarachchi Priyangi A. , Du Wuying , Mercado Miguel A.B. , Li Lin-Xi
Published: August 2022

CD4 T cell-dependent IFNγ production and antibody are the two best known effectors for protective immunity againstChlamydiafemale reproductive tract (FRT) infection. Nevertheless, mice lacking either IFNγ or B cells are capable of clearing vast majority ofChlamydiafrom the female reproductive tract (FRT), while suffering from varying degrees of disseminated infection. In this study, we investigated whether IFNγ and B cells play complimentary roles in host defense againstChlamydiaand evaluated their relative contributions in systemic and mucosal tissues. Using mice deficient in both IFNγ and B cells (IFNγ-/-x µMT), we showed that mice lacking both effectors are highly susceptible to lethal systemicChlamydiadissemination. Passive transfer of immune convalescent serum, but not recombinant IFNγ, reduced bacterial burden in both systemic and mucosal tissues in IFNγ-/-x µMT mice. Moreover, we observed a reduction of bacterial shedding of more than two orders of magnitude in IFNγ-/-x µMT mice following bothChlamydia muridarumandChlamydia trachomatisinfections. Lastly, protective immunity againstC. muridarumreinfection was completely abrogated in the absence of IFNγ and B cells. Our results suggest that IFNγ and B cells synergize to combat bacterial dissemination, while an IFNγ and B cell-independent mechanism exists for host resistance toChlamydiain the FRT.
The Association Between Cognitive Ability and Body Mass Index: A Sibling-Comparison Analysis in Four Longitudinal Studies
Authors: Wright Liam , Davies Neil M , Bann David
Published: August 2022

Background

Body mass index (BMI) and obesity rates have increased sharply since the 1980s. While multiple epidemiologic studies have found higher adolescent cognitive ability is associated with lower adult BMI, residual and unobserved confounding due to family background may explain these associations. We used a sibling design to test this association accounting for confounding factors shared within households.

Methods

We used data from four cohort studies: the National Longitudinal Study of Youth 1979 (NLSY-79), the NLSY-79 Children and Young Adult, the NLSY 1997 (NLSY-97) and the Wisconsin Longitudinal Study (WLS); a total of 12,250 siblings from 5,602 households. We used random effects within-between (REWB) and residualized quantile regression (RQR) models to compare between- and within-family estimates of the association between adolescent cognitive ability and adult BMI (20-64 years).

Results

In REWB models, moving from 0th to 100th percentile of adolescent cognitive ability was associated with −1.89 kg/m2 (95% CI = −2.41, −1.37) lower BMI between families. Adjusting for family socioeconomic position reduced the association to −1.23 (−1.79, −0.66) points. However, within families the association was just −0.13 (−0.70, 0.45) points. This pattern of results was found across multiple specifications, including analyses conducted in separate cohorts, models examining age-differences in association, and in RQR models examining the association across the distribution of BMI.

Conclusion

The association between high adolescent cognitive ability and low adult BMI was substantially smaller in within-family compared with between-family analysis. The well-replicated associations between cognitive ability and subsequent BMI may largely reflect confounding by family background factors.
Clinical and neurobiologic predictors of long-term outcome in schizophrenia
Authors: Nickl-Jockschat Thomas , Ho Beng-Choon , Andreasen Nancy
Published: August 2022

Background

Schizophrenia is a severe neuropsychiatric disorder accompanied by debilitating cognitive and psychosocial impairments over the course of the disease. As disease trajectories exhibit considerable inter-individual heterogeneity, early clinical and neurobiological predictors of long-term outcome are desirable for personalized treatment and care strategies.

Methods

In a naturalistic longitudinal approach, 381 schizophrenia patients from the Iowa Lon-gitudinal Study (ILS) cohort underwent an extensive characterization, including repeated magnetic resonance imaging (MRI) scans, over a mean surveillance period of 11.07 years. We explored whether pre-diagnostic markers, clinical markers at the first psychotic episode, or magnetic resonance imaging (MRI) measures at the onset of the disease were predictive of relapse or remission of specific symptom patterns later in life.

Results

We identified a set of clinical parameters - namely premorbid adjustment during adolescence, symptom patterns, and neuropsychological profiles at disease onset – that were highly correlated with future disease trajectories. In general, brain measures at baseline did not correlate with outcome. Progressive regional brain volume losses over the observation period, however, were highly correlated with relapse patterns and symptom severity.

Conclusions

Our findings provide clinicians with a set of highly robust, easily acquirable, and cost-effective predictors for long-term outcome in schizophrenia. These results can be directly translated to a clinical setting to improve prospective care and treatment planning for schizophrenia patients. (Funding sources: NIH MH68380, MH31593, MH40856, and MH43271).
A rapid review of what innovative workforce models have helped to rapidly grow capacity for community care to help older adults leave hospital
Authors: Morgan Helen , Weightman Alison , Lifford Kate J , Searchfield Lydia , Mann Mala K , Davies Freya , Lewis Ruth , Cooper Alison , Edwards Adrian G
Published: August 2022

Abstract: Older adults who have undergone treatment as hospital inpatients and are now medically fit for discharge back into the community may require additional care to support that transition. Prolonged hospital admissions can also have risks including functional decline, dependency and the risk of hospital acquired infections.
The aim of this rapid review was to review the research evidence for the effectiveness of workforce models in the community that may be able to rapidly grow capacity for community care and help older adults leave hospital.
19 studies were included: 11 systematic reviews and 8 UK primary studies not included in the reviews (4 quantitative study designs, 1 case study,1 mixed method study and 2 qualitative studies). The 19 studies evaluated 5 different intervention areas and a range of outcomes including: hospital length of stay; bed day rates, days to early supported discharge, delayed transfers of care (DTOCs); episode length of care; mortality; readmission; and carer, patient or staff perceptions.
Intervention areas that were studied the most were: Early Supported Discharge and Transitional care/Continuity of Care. Nine recent UK studies from the systematic reviews describing these interventions were analysed separately for data on outcomes and workforce components.
It is difficult to draw firm conclusions due to the limited evidence from a UK setting, and low quality of included studies. There is insufficient information to propose an optimum service design, but the evidence does suggest that interventions that are more comprehensive (covering a range of different components) and more intensive are more likely to be effective.
Further research is needed to evaluate the effectiveness of workforce models introduced to rapidly grow capacity for community care to help older adults leave hospital in the UK setting. The Early Supported Discharge and Transitional Care models hold some promise.
Sleep and seizure risk in epilepsy: Bed and wake times are more important than sleep duration
Authors: Stirling Rachel E. , Hidajat Cindy M. , Grayden David B. , D’Souza Wendyl J , Dell Katrina L. , Boston Ray , Schneider Logan D. , Nurse Ewan , Freestone Dean , Cook Mark J. , Karoly Philippa J.
Published: August 2022

Sleep duration, sleep deprivation and the sleep-wake cycle are thought to play an important role in the generation of epileptic activity and may also influence seizure risk. Hence, people diagnosed with epilepsy are commonly asked to maintain consistent sleep routines. However, emerging evidence paints a more nuanced picture of the relationship between seizures and sleep, with bidirectional effects between changes in sleep and seizure risk in addition to modulation by sleep stages and transitions between stages. We conducted a longitudinal study investigating sleep parameters and self-reported seizure occurrence in an ambulatory at-home setting using mobile and wearable monitoring.

Forty-four subjects wore a Fitbit smartwatch for at least 28 days while reporting their seizure activity in a mobile app. Multiple sleep features were investigated, including duration, oversleep and undersleep, and sleep onset and offset times. Sleep features in participants with epilepsy were compared to a large (n=37921) representative population of Fitbit users, each with 28 days of data. For participants with at least 10 seizure days (n=29), sleep features were analysed for significant changes prior to seizure days.

A total of 3894 reported seizures (M = 88, SD = 130) and 17078 recorded sleep nights (M = 388, SD = 351) were included in the study. Participants with epilepsy slept an average of 2 hours longer than the average sleep duration within the general population. Just 1 of 29 participants showed a significant difference in sleep duration the night before seizure days compared to seizure-free days. However, 11 of 29 subjects showed significant differences between either their sleep onset (bed) or offset (wake) times prior to seizure occurrence. In contrast to previous studies, the current study found oversleeping was associated with a 20% increased seizure risk in the following 48h (p < 0.01), likely due to nocturnal seizures driving increased sleep durations.

Nocturnal seizures were associated with both significantly longer sleep durations and increased risk of a seizure occurring in the following 48h. Oversleeping only significantly contributed to increased seizure risk when participants were already in a high-risk (rather than baseline- or low-risk) state, according to their endogenous cycles of seizure likelihood.

Overall, the presented results demonstrated that day-to-day changes in sleep-duration had a minimal effect on reported seizures, while bed- and wake-times were more important for identifying seizure risk the following day. Oversleeping was linked to seizure occurrence, most likely due to nocturnal seizures driving oversleep. Wearables can be utilised to identify these sleep-seizure relationships and guide clinical recommendations or improve seizure forecasting algorithms.
Direct and indirect effects of the COVID-19 pandemic on mortality in Switzerland: A population-based study
Authors: Riou Julien , Hauser Anthony , Fesser Anna , Althaus Christian L. , Egger Matthias , Konstantinoudis Garyfallos
Published: August 2022

The direct and indirect impact of the COVID-19 pandemic on population-level mortality is of concern to public health but challenging to quantify. We modelled excess mortality and the direct and indirect effects of the pandemic on mortality in Switzerland. We analyzed yearly population data and weekly all-cause deaths by age, sex, and canton 2010-2019 and all-cause and laboratory-confirmed COVID-19 deaths from February 2020 to April 2022 (study period). Bayesian models predicted the expected number of deaths. A total of 13,130 laboratory-confirmed COVID-19 deaths were reported. The model estimated that COVID-19-related mortality was underestimated by a factor of 0.72 [95% Credible Interval: 0.46-0.78] resulting in 18,140 [15,962-20,174] excess deaths. After accounting for COVID-19 deaths, the observed mortality was 3% [-1-7] lower than expected, corresponding to a deficit of 4,406 deaths, with a wide credibility interval [-1,776-10,700]. Underestimation of COVID-19 deaths was greatest for ages 70 years and older; the mortality deficit was most pronounced in age groups 40 to 69 years. We conclude that shortcomings in testing caused underestimation of COVID-19-related deaths in Switzerland, particularly in older people. Although COVID-19 control measures may have negative effects (e.g., delays in seeking care or mental health impairments), after subtracting COVID-19 deaths, there were fewer deaths in Switzerland during the pandemic than expected, suggesting that any negative effects of control measures on mortality were offset by the positive effects. These results have important implications for the ongoing debate about the appropriateness of COVID-19 control measures.
An empirical investigation into the impact of winner’s curse on estimates from Mendelian randomization
Authors: Jiang Tao , Gill Dipender , Butterworth Adam S. , Burgess Stephen
Published: August 2022

Introduction

Genetic associations for variants identified through genome-wide association studies (GWAS) tend to be overestimated in the original discovery dataset; as if the association was underestimated, the variant may not have been detected. This bias, known as winner’s curse, can affect Mendelian randomization estimates, but its severity and potential impact is unclear.

Methods

We performed an empirical investigation to assess the potential bias from winner’s curse in practice. We considered Mendelian randomization estimates for the effect of body mass index (BMI) on coronary artery disease risk. We randomly divided a UK Biobank dataset 100 times into three equal-sized subsets. The first subset was treated as the “discovery GWAS”. We compared genetic associations estimated in the discovery GWAS to those estimated in the other subsets for each of the 100 iterations.

Results

For variants associated with BMI at p<5×10−8 in at least one iteration, genetic associations with BMI were up to five-fold greater in iterations where the variant was statistically significantly associated with BMI compared to its mean association across all iterations. If the minimum p-value for association with BMI was p=10−13 or lower, then this inflation was less than 25%. Mendelian randomization estimates were affected by winner’s curse bias. However, bias did not materially affect results; all analyses indicated a deleterious effect of BMI on CAD risk.

Conclusions

Winner’s curse can bias Mendelian randomization estimates, although its practical impact may not be substantial. If avoiding sample overlap is infeasible, analysts should consider performing a sensitivity analysis based on variants strongly associated with the exposure.
Improving estimates of pertussis burden in Ontario, Canada 2010-2017 by combining validation and capture-recapture methodologies
Authors: McBurney Shilo H. , Kwong Jeffrey C. , Brown Kevin A. , Rudzicz Frank , Wilton Andrew , Crowcroft Natasha S.
Published: August 2022

An underestimation of pertussis burden has impeded understanding of transmission and disallows effective policy and prevention to be prioritized and enacted. Capture-recapture analyses can improve burden estimates; however, uncertainty remains around incorporating health administrative data due to accuracy limitations. The aim of this study is to explore the impact of pertussis case definitions and data accuracy on capture-recapture estimates. We used a dataset from March 7, 2010 to December 31, 2017 comprised of pertussis case report, laboratory, and health administrative data. We compared Chao capture-recapture abundance estimates using prevalence, incidence, and adjusted false positive case definitions. The latter was developed by removing the proportion of false positive physician billing code-only case episodes after validation. We calculated sensitivity by dividing the number of observed cases by abundance. Abundance estimates demonstrated that a high proportion of cases were missed by all sources. Under the primary analysis, the highest sensitivity of 78.5% (95% CI 76.2-80.9%) for those less than one year of age was obtained using all sources after adjusting for false positives, which dropped to 43.1% (95% CI 42.4-43.8%) for those one year of age or older. Most code-only episodes were false positives (91.0%), leading to considerably lower abundance estimates and improvements in laboratory testing and case report sensitivity using this definition. Accuracy limitations can be accounted for in capture-recapture analyses using different case definitions and adjustment. The latter enhanced the validity of estimates, furthering the utility of capture-recapture methods to epidemiological research. Findings demonstrated that all sources consistently fail to detect pertussis cases. This is differential by age, suggesting ascertainment and testing bias. Results demonstrate the value of incorporating real time health administrative data into public health surveillance if accuracy limitations can be addressed.
Rapid threat detection in SARS-CoV-2
Authors: Barrett Christopher L. , Huang Fenix W.D. , Li Thomas J.X. , Warren Andrew S. , Reidys Christian M.
Published: August 2022

This paper presents a novel virus surveillance framework, completely independent of phylogeny-based methods. The framework issues timely alerts with an accuracy exceeding 85% that are based on the co-evolutionary relations between sites of the viral multiple sequence array (MSA). This set of relations is formalized via a motif complex, whose dynamics contains key information about the emergence of viral threats without the referencing of strain prevalence. Our notion of threat is centered at the emergence of a certain type of critical cluster consisting of key co-evolving sites. We present three case studies, based on GISAID data from UK, US and New York, where we perform our surveillance. We alert on May 16, 2022, based on GISAID data from New York, to a critical cluster of co-evolving sites mapping to the Pango-designation, BA.5. The alert specifies a cluster of seven genomic sites, one of which exhibits D3N on the M (membrane) protein–the distinguishing mutation of BA.5, three encoding ORF6:D61L and the remaining three exhibiting the synonymous mutations C26858T, C27889T and A27259C. New insight is obtained: when projected onto sequences, this cluster splits into two, mutually exclusive blocks of co-evolving sites (m:D3N,nuc:C27889T) linked to the five reverse mutations (nuc:C26858T,nuc:A27259C,ORF6:D61L). We furthermore provide an in depth analysis of all major signaled threats, during which we discover a specific signature concerning linked reverse mutation in the critical cluster.
Two years of COVID-19 Pandemic: Framework of Health Interventions in a Brazilian City
Authors: Faiões Vanessa dos Santos , Póvoa Helvécio Cardoso Corrêa , Thurler Bruna Alves , Chianca Gabriela Ceccon , Assaf Andréa Videira , Iorio Natalia Lopes Pontes Póvoa
Published: August 2022

The COVID-19 pandemic and its effects on public health have urgently demanded effective health policies to avoid the spread of COVID-19. Thus, public administrators have implemented non-pharmacological and pharmacological interventions to mitigate the pandemic’s impacts and strengthen health services. The aim of this ecological study is to describe the scenario of COVID-19 pandemic in a Brazilian city, during two years. This ecological study was carried out in Nova Friburgo, a Brazilian city, for 105 weeks (two years), from March 29, 2020 (week 1) to April 02, 2022 (week 105). Data on COVID-19 cases and COVID-19 deaths, occupation of COVID-19 exclusive beds in hospitals, community mobility, vaccination, government regulation on the opening of city establishments and city risk assessment were collected from public datasets. Four waves of COVID-19 cases and deaths were observed during this period. The first case occurred in week 1 and first death in week 3 of this study. The highest peaks of cases and deaths were observed during the third wave with 1,131 cases (week 54) and 47 deaths (week 55) and where the highest occupation of COVID-19 exclusive beds in local hospitals occurred. Interventions from more restrictive to more flexible, were implemented throughout this study, including lockdown and gradual return in economic and social strata levels. Vaccination began on week 43 and at the end of this study 89.91% of the total population was vaccinated with at least one dose, being 83.22% fully vaccinated. A deep description of several interventions used to avoid COVID-19 spread in a Brazilian city during two years of this pandemic can help promote better decision-making in the future while it exposes the challenges of conducting public health policies in a pandemic scenario.
Atm loss does not radiosensitize a primary mouse model of Pten-deleted brainstem glioma
Authors: Stewart Connor E. , Guerra Garcia Maria E. , Luo Lixia , Williams Nerissa T. , Ma Yan , Regal Joshua A. , Ghosh Debosir , Sansone Patrick , Oldham Mark , Deland Katherine , Becher Oren J. , Kirsch David G. , Reitman Zachary J.
Published: August 2022

Diffuse midline gliomas arise in the brainstem and other midline brain structures and cause a large proportion of childhood brain tumor deaths. Radiation therapy is the most effective treatment option, but these tumors ultimately progress. Inhibition of the phosphoinositide-3-kinase (PI3K)-like kinase ataxia telangiectasia mutated (ATM), which orchestrates the cellular response to radiation-induced DNA damage, may enhance the efficacy of radiation therapy. Diffuse midline gliomas in the brainstem contain loss-of-function mutations in the tumor suppressor PTEN, or functionally similar alterations in the phosphoinositide-3-kinase (PI3K) pathway, at moderate frequency. Here, we sought to determine if Atm inactivation could radiosensitize a primary mouse model of brainstem glioma driven by Pten loss. Using Cre/loxP recombinase technology and the RCAS/TVA retroviral gene delivery system, we established a mouse model of brainstem glioma driven by Pten deletion. We find that Pten-null brainstem gliomas are relatively radiosensitive at baseline. In addition, we show that deletion of Atm in the tumor cells does not extend survival of mice bearing Pten-null brainstem gliomas after focal brain irradiation. These results characterize a novel primary mouse model of PTEN-mutated brainstem glioma and provide insights into the mechanism of radiosensitization by Atm deletion, which may guide the design of future clinical trials.

Brief Summary

We develop a mouse model of PTEN-mutated brainstem glioma and find that perturbation of the ATM does not enhance radiation efficacy in this model.
MAPK13 stabilization via m6A modification limits anti-cancer efficacy of rapamycin
Authors: Kim Joohwan , Chun Yujin , Ramirez Cuauhtemoc B. , Hoffner Lauren A. , Jung Sunhee , Jang Ki-Hong , Rubtsova Varvara I. , Jang Cholsoon , Lee Gina
Published: August 2022

N6-adenosine methylation (m6A) is the most abundant mRNA modification that controls gene expression through diverse mechanisms. m6A-dependent regulation of oncogenes and tumor suppressors indeed contribute to tumor development. However, the role of m6A-mediated gene regulation after drug treatment or resistance is poorly understood. Here, we report that m6A modification ofmitogen-activated protein kinase 13(MAPK13) determines the sensitivity of cancer cells to the mechanistic target of rapamycin complex 1 (mTORC1)- targeting chemotherapeutic agent rapamycin. mTORC1 induces m6A modification ofMAPK13mRNA at its 3’ untranslated region (3’UTR) through methyltransferase-like 3 (METTL3)-METTL14-Wilms’ tumor 1-associating protein (WTAP) methyltransferase complex, thereby stimulating its mRNA degradation via an m6A reader protein YTH domain family protein 2 (YTHDF2). Rapamycin blunts this process and stabilizesMAPK13. Unexpectedly,MAPK13silencing suppresses cell growth and enhances rapamycin’s anti-cancer effects, suggesting thatMAPK13is an oncogenic gene activated by rapamycin via a feedback regulation. Together, our data indicate that rapamycin-mediatedMAPK13mRNA stabilization may confer drug resistance, and it can thus be a therapeutic target to sensitize cancer cells to rapamycin.
ALT in Pediatric High-Grade Gliomas Can Occur withoutATRXMutation and is Enriched in Patients with Pathogenic Germline MMR Variants
Authors: Stundon Jennifer L. , Ijaz Heba , Gaonkar Krutika S. , Kaufman Rebecca S. , Jin Run , Karras Anastasios , Vaksman Zalman , Kim Jung , Corbett Ryan J. , Lueder Matthew R. , Miller Daniel P. , Guo Yiran , Santi Mariarita , Li Marilyn , Lopez Gonzalo , Storm Phillip B. , Resnick Adam C. , Waanders Angela J. , MacFarland Suzanne P. , Stewart Douglas R. , Diskin Sharon J. , Rokita Jo Lynne , Cole Kristina A.
Published: August 2022

Background

To achieve replicative immortality, most cancers develop a telomere maintenance mechanism, such as reactivation of telomerase or alternative lengthening of telomeres (ALT). There are limited data on the prevalence and clinical significance of ALT in pediatric brain tumors, and ALT-directed therapy is not available.

Methods

We performed C-circle analysis (CCA) on 579 pediatric brain tumors that had corresponding tumor/normal whole genome sequencing through the Open Pediatric Brain Tumor Atlas (OpenPBTA). We detected ALT in 6.9% (n=40/579) of these tumors and completed additional validation by ultrabright telomeric fociin situon a subset of these tumors. We used CCA to validateTelomereHunterfor computational prediction of ALT status and focus subsequent analyses on pediatric high-grade glioma (pHGG) Finally, we examined whether ALT is associated with recurrent somatic or germline alterations.

Results

ALT is common in pHGG (n=24/63, 38.1%), but occurs infrequently in other pediatric brain tumors (<3%). SomaticATRXmutations occur in 50% of ALT+ pHGG and in 30% of ALT-pHGG. Rare pathogenic germline variants in mismatch repair (MMR) genes are significantly associated with an increased occurrence of ALT. Conclusions: We demonstrate thatATRXis mutated in only a subset of ALT+ pHGG, suggesting other mechanisms ofATRXloss of function or alterations in other genes may be associated with the development of ALT in these patients. We show that germline variants in MMR are associated with development of ALT in patients with pHGG.

Key Points

ATRX alterations are frequent, but not required, for an ALT phenotype in pHGGs

pHGG patients with germline mismatch repair variants have higher rate of ALT + tumorsTelomereHunteris validated to predict ALT in pHGGs

Importance of the Study

We performed orthogonal molecular and computational analyses to detect the presence of alternative lengthening of telomeres in a highly characterized cohort of pediatric brain tumors. We demonstrate that many pHGG utilize ALT without a mutation in ATRX, suggesting either loss of function of ATRX via an alternative mechanism or an alternate means of development of ALT. We show that germline variants in MMR genes are significantly associated with ALT in pHGG. Our work adds to the biological understanding of the development of ALT and provides an approach to stratify patients who may benefit from future ALT-directed therapies in this patient population.
Plant species within Streptanthoid Complex associate with distinct microbial communities that shift to be more similar under drought
Authors: Igwe Allie N. , Pearse Ian S. , Aguilar Jessica M. , Strauss Sharon Y. , Vannette Rachel L.
Published: August 2022

Prolonged water stress can reduce plant growth and fitness and may shift rhizoplane microbial communities. Although drought affects microbial structure of many plant species, it is still poorly understood whether closely related plant species host distinct microbial communities or respond similarly to drought. To explore this question, eight members of the Streptanthus clade with varying affinity to serpentine were subjected to three watering regimes. Rhizoplane bacterial communities were described using 16S rRNA gene amplicon sequencing and we explored the impact of watering treatment and plant species on alpha diversity, differential abundance, and beta diversity of soil bacterial communities. Among most plant species, reduced watering also reduced alpha diversity, but plant species did not strongly impact alpha diversity. Drought treatment reduced microbial community dissimilarity among samples: bacterial communities were more similar when plants received less water. Watering altered the relative abundance of bacterial genera within Proteobacteria, Firmicutes, Bacteroidetes, Planctomycetes, and Acidobacteria, which responded similarly in the rhizoplane of most plant species. These results suggest that prolonged water stress in Streptanthus spp. can result in convergent microbial communities among plant species. We suggest the functional consequences of these shifts be examined to assess effects on plant and microbial fitness under drought conditions.
Selection on sperm size in response to promiscuity and variation in female sperm storage organs
Authors: Cramer Emily R. A. , Yilma Zelealem B. , Lifjeld Jan T.
Published: August 2022

Sperm cells are exceptionally morphologically diverse across taxa. However, morphology can be quite uniform within species, particularly for species where females copulate with many males per reproductive bout. Strong sexual selection in these promiscuous species is widely hypothesized to reduce intraspecific sperm variation. Conversely, we hypothesize that intraspecific sperm size variation may be maintained by high among-female variation in the size of sperm storage organs, assuming that paternity success improves when sperm are compatible in size with the sperm storage organ. We use individual-based simulations and an analytical model to evaluate how selection on sperm size depends on promiscuity level and variation in sperm storage organ size (hereafter, female preference variation). Simulated species with high promiscuity showed stabilizing selection on sperm when female preference variation was low, and disruptive selection when female preference variation was high, consistent with the analytical model results. With low promiscuity (2-3 mates per female), selection on sperm was stabilizing for all levels of female preference variation in the simulations, contrasting with the analytical model. Promiscuity level, or mate sampling, thus has a strong impact on the selection resulting from female preferences. Further, for species with low promiscuity, disruptive selection on male traits will occur under more limited circumstances than many previous models suggest. Variation in female sperm storage organs likely has strong implications for intraspecific sperm variation in highly promiscuous species, but likely does not explain differences in intraspecific sperm variation for less promiscuous taxa.