bluuebunny/crossref_metadata_2025 huggingface dataset:
Does cardiorespiratory fitness mediate or moderate the association between mid-life physical activity and cognitive function? Findings from the 1958 British birth cohort study
Authors: Norris Tom , Mitchell John J , Blodgett Joanna M , Pinto Pereira Mark Snehal M
Published: November 2023

Background

Physical activity (PA) is associated with a lower risk of cognitive decline and all-cause dementia in later life. Pathways underpinning this association are unclear but may involve either mediation and/or moderation by cardiorespiratory fitness (CRF).

Methods

Data on participation in PA (exposure) at 42y, non-exercise testing CRF (NETCRF, mediator/moderator) at 45y and overall cognitive function (outcome) at 50y were obtained from 9,385 participants in the 1958 British birth cohort study. We used a four-way decomposition approach to examine the relative contributions of mediation and moderation by NETCRF on the association between PA at 42y and overall cognitive function at 50y.

Results

In males, the estimated overall effect of 42y PA ≥once per week (vs. <once per week) was a 0.08 (95% confidence interval: 0.04,0.13) higher overall cognitive function z-score at 50y. The estimated controlled direct effect was similar (0.08 (0.03, 0.12)). Thus, the proportion of the estimated effect via mediation or moderation by NETCRF was small (∼3%), with confidence intervals straddling the null. In females, there was no estimated overall effect of PA on overall cognitive function.

Conclusion

We present the first evidence from a four-way decomposition analysis of the potential contribution that CRF plays in the relationship between mid-life PA and subsequent cognitive function. Our lack of evidence in support of CRF mediating or moderating the PA―cognitive function association suggests that other pathways underpin this association.
Benchmarking multi-omics integration algorithms across single-cell RNA and ATAC data
Authors: Xiao Chuxi , Chen Yixin , Wei Lei , Zhang Xuegong
Published: November 2023

Recent advancements in single-cell sequencing technologies have generated extensive omics data in various modalities and revolutionized cell research, especially in the single cell RNA and ATAC data. The joint analysis across scRNA-seq data and scATAC-seq data has paved the way to comprehending the cellular heterogeneity and complex cellular regulatory networks. Multi-omics integration is gaining attention as an important step in joint analysis, and the number of computational tools in this field is growing rapidly. In this paper, we benchmarked 12 multi-omics integration methods on three integration tasks via qualitative visualization and quantitative metrics, considering six main aspects that matter in multi-omics data analysis. Overall, we found that different methods have their own advantages on different aspects, while some methods outperformed other methods in most aspects. We therefore provided guidelines for selecting appropriate methods for specific scenarios and tasks to help obtain meaningful insights from multi-omics data integration.
Distinct mechanisms of plant immune resilience revealed by natural variation in warm temperature-modulated disease resistance amongArabidopsisaccessions
Authors: Rossi Christina A. M. , Patel Dhrashti N. , Castroverde Christian Danve M.
Published: November 2023

Elevated temperature suppresses production of the key plant defence hormone salicylic acid (SA). Heat-mediated SA suppression and resulting plant vulnerability are due to downregulated expression ofCALMODULIN BINDING PROTEIN 60-LIKE G(CBP60g) andSYSTEMIC ACQUIRED RESISTANCE DEFICIENT 1(SARD1), which encode master regulators of plant immunity. However, previous studies inArabidopsis thalianaplants have primarily focused on the accession Columbia-0 (Col-0), while the mechanisms governing the intraspecific variation inArabidopsisimmunity under elevated temperature have remained unknown. Here we show that BASIC HELIX LOOP HELIX 059 (bHLH059), a thermosensitive SA regulator at non-stress temperatures, does not regulate immune suppression under warmer temperatures. In agreement, temperature-resilient and -sensitiveArabidopsisaccessions based on disease resistance to the bacterial pathogenPseudomonas syringaepv.tomato(Pst) DC3000 did not correlate withbHLH059sequence polymorphisms. Instead, we found that different temperature-resilient accessions exhibit varyingCBP60gandSARD1expression profiles, potentially revealing bothCBP60g/SARD1-dependent and independent mechanisms of plant immune resilience to warming temperature. Collectively, this study has unveiled the intraspecific diversity ofArabidopsisimmune responses under warm temperatures. Our dissection of mechanisms underlying temperature-modulated plant immunity could aid in predicting plant responses to climate change and provide foundational knowledge for climate-resilient crop engineering.
Centrifuger: lossless compression of microbial genomes for efficient and accurate metagenomic sequence classification
Authors: Song Li , Langmead Ben
Published: November 2023

Centrifuger is an efficient taxonomic classification method that compares sequencing reads against a microbial genome database. In Centrifuger, the Burrows-Wheeler transformed genome sequences are losslessly compressed using a novel scheme called run-block compression. Run-block compression achieves sublinear space complexity and is effective at compressing diverse microbial databases like RefSeq while supporting fast rank queries. Combining this compression method with other strategies for compacting the Ferragina-Manzini (FM) index, Centrifuger reduces the memory footprint by half compared to other FM-index-based approaches. Furthermore, the lossless compression and the unconstrained match length help Centrifuger achieve greater accuracy than competing methods at lower taxonomic levels.
Epigenetic heritability of cell plasticity drives cancer drug resistance through one-to-many genotype to phenotype mapping
Authors: Oliveira Erica , Milite Salvatore , Fernandez-Mateos Javier , Cresswell George D , Yara-Romero Erika , Vlachogiannis Georgios , Chen Bingjie , James Chela , Patruno Lucrezia , Ascolani Gianluca , Acar Ahmet , Heide Timon , Spiteri Inma , Graudenzi Alex , Caravagna Giulio , Bertotti Andrea , Graham Trevor A , Magnani Luca , Valeri Nicola , Sottoriva Andrea
Published: November 2023

Cancer drug resistance is multi-factorial, driven by heritable (epi)genetic changes but also phenotypic plasticity. Here we dissect it by perturbing colorectal cancer patient-derived organoids longitudinally with drugs in sequence. Combining longitudinal tracking, single cell ’omics, evolutionary modelling, and machine leaning, we found that different targeted drugs select for distinct subclones, supporting rationally designed drug sequences. The cellular memory was encoded as a heritable epigenetic configuration, from which multiple transcriptional programmes could run, supporting a one-to-many (epi)genotype-to- phenotype map that explains how clonal expansions and plasticity manifest together. This may ensure drug resistance subclones can exhibit distinct phenotypes in changing environments while still preserving the cellular memory encoding for their selective advantage. Chemotherapies resistance was instead entirely driven by plasticity. Inducing further chromosomal instability before drug application changed clonal evolution but not convergent transcriptional programmes. Collectively, our data show how genetic and epigenetic alterations are selected to “permissive epigenome” enabling phenotypic plasticity.
Contrasting patterns of water use efficiency and annual radial growth among European beech forests along the Italian peninsula
Authors: Puchi Paulina F. , Dalmonech Daniela , Vangi Elia , Battipaglia Giovanna , Tognetti Roberto , Collalti Alessio
Published: November 2023

Tree mortality and forest dieback episodes are increasing due to drought and heat stress. Nevertheless, a comprehensive understanding of mechanisms enabling trees to withstand and survive droughts remains lacking. Our study investigated basal area increment (BAI), and δ13C- derived intrinsic water-use-efficiency (iWUE), to elucidate beech resilience across four healthy stands in Italy with varying climates and water availability. Additionally, fist-order autocorrelation (AR1) analysis was performed to detect early warning signals for potential tree dieback risks during extreme drought events.

Results reveal a negative link between BAI and vapour pressure deficit (VPD), especially in southern latitudes. After the 2003 drought, BAI decreased at the northern site, with an increase in δ13C andiWUE, indicating conservative water-use. Conversely, the southern sites showed increased BAI andiWUE, likely influenced by rising CO2and improved water availability. In contrast, the central site sustained higher transpiration rates due to higher soil water holding capacity (SWHC). Despite varied responses, most sites exhibited reduced resilience to future extreme events, indicated by increased AR1.

Temperature significantly affected beechiWUE and BAI in northern Italy, while VPD strongly influenced the southern latitudes. The observed increase in BAI andiWUE in southern regions might be attributed to an acclimation response.
Decoil: Reconstructing extrachromosomal DNA structural heterogeneity from long-read sequencing data
Authors: Giurgiu Mădălina , Wittstruck Nadine , Rodriguez-Fos Elias , González Rocío Chamorro , Brückner Lotte , Krienelke-Szymansky Annabell , Helmsauer Konstantin , Hartebrodt Anne , Euskirchen Philipp , Koche Richard P. , Haase Kerstin , Reinert Knut , Henssen Anton G.
Published: November 2023

Circular extrachromosomal DNA (ecDNA) is a form of oncogene amplification found across cancer types and associated with poor outcome in patients. EcDNA can be structurally complex and contain rearranged DNA sequences derived from multiple chromosome locations. As the structure of ecDNA can impact oncogene regulation and may indicate mechanisms of its formation, disentangling it at high resolution from sequencing data is essential. Even though methods have been developed to identify and reconstruct ecDNA in cancer genome sequencing, it remains challenging to resolve complex ecDNA structures, in particular amplicons with shared genomic footprints. We here introduce Decoil, a computational method which combines a breakpoint-graph approach withLASSOregression to reconstruct complex ecDNA and deconvolve co-occurring ecDNA elements with overlapping genomic footprints from long-read nanopore sequencing. Decoil outperformsde-novoassembly and alignment-based methods in simulated longread sequencing data for both simple and complex ecDNAs. Applying Decoil on whole genome sequencing data uncovered different ecDNA topologies and explored ecDNA structure heterogeneity in neuroblastoma tumors and cell lines, indicating that this method may improve ecDNA structural analyzes in cancer.
High-throughput profiling of metabolic responses to exogenous nutrients inSynechocystissp. PCC 6803
Authors: Haavisto Vilhelmiina , Landry Zachary , Pontrelli Sammy
Published: November 2023

Cyanobacteria fix carbon dioxide and release carbon-containing compounds into the wider ecosystem, yet they are sensitive to small metabolites that may impact their growth and physiology. Several cyanobacteria can grow mixotrophically, but we currently lack a molecular understanding of how specific nutrients may alter the compounds they release, limiting our knowledge of how environmental factors might impact primary producers and the ecosystems they support. In this study, we develop a high-throughput phytoplankton culturing platform and identify how the model cyanobacteriumSynechocystis sp.PCC 6803 responds to nutrient supplementation. We assess growth responses to 32 nutrients at two concentrations, identifying 15 that are utilized mixotrophically. Seven nutrient sources significantly enhance growth, while 19 elicit negative growth responses at one or both concentrations. High-throughput exometabolomics indicates that oxidative stress limits PCC 6803’s growth, but may be alleviated by antioxidant metabolites. Furthermore, glucose and valine induce strong changes in metabolite exudation in a possible effort to correct pathway imbalances or maintain intracellular elemental ratios. This study sheds light on the flexibility and limits of cyanobacterial physiology and metabolism, as well as how primary production and trophic food webs may be modulated by exogenous nutrients.

Importance

Cyanobacteria capture and release carbon compounds to fuel microbial food webs, yet we lack a comprehensive understanding of how external nutrients modify their behavior and what they produce. We developed a high throughput culturing platform to evaluate how the model cyanobacteriumSynechocystis sp.PCC 6803 responds to a broad panel of externally supplied nutrients. We found that growth may be enhanced by metabolites that protect against oxidative stress, and that growth and exudate profiles are altered by metabolites that interfere with central carbon metabolism and elemental ratios. This work contributes a holistic perspective of the versatile response of PCC 6803 to externally supplied nutrients, which may alter carbon flux into the wider ecosystem.
Hot springs viruses at Yellowstone National Park have ancient origins and are adapted to their thermophilic hosts
Authors: Benites L. Felipe , Stephens Timothy G. , Van Etten Julia , James Timeeka , Christian William C. , Barry Kerrie , Grigoriev Igor V. , McDermott Timothy R. , Bhattacharya Debashish
Published: November 2023

Geothermal springs in areas such as Yellowstone National Park (YNP), USA house unicellular red algae that dominate the microbial biomass. Little is known about the viruses that infect the biota. Here we used metagenomics to characterize the multi-kingdom infecting virus community associated with red algal mats in three neighboring habitats (creek, endolithic, soil) at Lemonade Creek, YNP to determine their taxonomic composition, predicted gene functions, extent of horizontal gene transfer, and potential links to hosts. We find that despite proximity, each habitat houses a unique collection of viruses, with the giant viruses, Megaviricetes, dominant in all three. The early branching phylogenetic position of genes encoded on metagenome assembled virus genomes (vMAGs) suggests that the YNP lineages are of ancient origins and not the result of multiple invasions from mesophilic habitats. The existence of genomic footprints of adaptation to thermophily in the vMAGs is consistent with this idea. Our study is the first analysis of viruses associated with polyextremophilic red algae that form extensive microbial mats in YNP and are common worldwide at geothermal sites. Although more recent than the earliest forms of prokaryotic life, these eukaryotic algal mats originated ca. 1.5 Bya, and therefore span a significant period of the planet’s history. Our data are therefore relevant to understanding biotic interactions on the early Earth.
Chronic activation of a negative engram induces behavioral and cellular abnormalities
Authors: Jellinger Alexandra L. , Suthard Rebecca L. , Yuan Bingbing , Surets Michelle , Ruesch Evan A. , Caban Albit J. , Liu Shawn , Shpokayte Monika , Ramirez Steve
Published: November 2023

Negative memories engage a brain and body-wide stress response in humans that can alter cognition and behavior. Prolonged stress responses induce maladaptive cellular, circuit, and systems-level changes that can lead to pathological brain states and corresponding disorders in which mood and memory are affected. However, it’s unclear if repeated activation of cells processing negative memories induces similar phenotypes in mice. In this study, we used an activity-dependent tagging method to access neuronal ensembles and assess their molecular characteristics. Sequencing memory engrams in mice revealed that positive (male-to-female exposure) and negative (foot shock) cells upregulated genes linked to anti- and pro-inflammatory responses, respectively. To investigate the impact of persistent activation of negative engrams, we chemogenetically activated them in the ventral hippocampus over three months and conducted anxiety and memory-related tests. Negative engram activation increased anxiety behaviors in both 6- and 14-month-old mice, reduced spatial working memory in older mice, impaired fear extinction in younger mice, and heightened fear generalization in both age groups. Immunohistochemistry revealed changes in microglial and astrocytic structure and number in the hippocampus. In summary, repeated activation of negative memories induces lasting cellular and behavioral abnormalities in mice, offering insights into the negative effects of chronic negative thinking-like behaviors on human health.
The MYC axis in advanced prostate cancer is impacted through concurrent targeting of ERβ and AR using a novel ERβ-selective ligand alongside Enzalutamide
Authors: Gray Jaimie S. , Wani Sajad A. , Hussain Shahid , Huang Phoebe , Nayak Debasis , Long Mark D. , Yates Clayton , Clinton Steven K. , Bennet Chad E. , Coss Christopher C. , Campbell Moray J.
Published: November 2023

We have dissected the role of Estrogen receptor beta (ERβ) in prostate cancer (PCa) with a novel ERβ ligand, OSU-ERb-12. Drug screens revealed additive interactions between OSU-ERB-12 and either epigenetic inhibitors or the androgen receptor antagonist, Enzalutamide (Enza). Clonogenic and cell biolody studies supported the potent additive effects of OSU-ERB-12 (100nM) and Enza (1µM). The cooperative behavior was in PCa cell lines treated with either OSU- ERB-12 plus Enza or combinations involving 17β-estradiol (E2). OSU-ERb-12 plus Enza uniquely impacted the transcriptiome, accessible chromatin, and the AR, MYC and H3K27ac cistromes. This included skewed transcriptional responses including suppression of the androgen and MYC transcriptomes, and repressed MYC protein. OSU-ERb-12 plus Enza uniquely impacted chromatin accessibility at approximately 3000 nucleosome-free sites, enriched at enhancers, enriched for basic Helix-Loop-Helix motifs. CUT&RUN experiments revealed combination treatment targeting of MYC, AR, and H3K27ac again shaping enhancer accessibility. Specifically, it repressed MYC interactions at enhancer regions enriched for bHLH motifs, and overlapped with publicly-available bHLH cistromes. Finally, cistrome-transcriptome analyses identified ∼200 genes that distinguished advanced PCa tumors in the SU2C cohort with high androgen and low neuroendocrine scores.

Statement of Implication

Targeting ERβ has potentially to augment AR antagonism to restrain MYC signaling and limit growth of advanced prostate cancer.
Unveiling the Emotional Turmoil: How Covid-19 impacted researchers and the pursuit of emotional well-being in academia
Authors: Weise Crista , Suñe-Soler Nuria , Corcelles Mariona , Sala-Bubaré Anna , Castelló Monsterrat
Published: November 2023

The Covid-19 crisis unprecedentedly required researchers to adapt to significant changes in their work and personal lives. Our study aims to fill this gap analysing the Covid-19 emotional impact and confinement potential disruptions on researchers’ activity (specifically, those related to working conditions, caring responsibilities, health, balance, and social support) considering the modulating role played by age, gender, and job position. An online survey was distributed during the first lockdown period of the Covid-19 pandemic, and answers from 1301 researchers (ECR %, senior researchers %) working in Sciences (28.1%), Social Sciences (25.9%), Humanities (16.2%), Health (16.2%) and in Engineering and Architecture (13.5%) were collected. The study highlights that the initial lockdown during the Covid-19 pandemic had a significant emotional impact on researchers, exacerbating pre-existing emotional distress and burnout within this group. Factors such as age, health, gender, and difficulties in balancing work and family life were associated with an increased risk of burnout and emotional distress. Lack of social support was identified as a significant risk factor, while the academic culture prioritizing productivity over well-being contributed to the issue. These findings underscore the need for greater support and cultural changes in academia to preserve researchers’ mental health and prevent the chronicization of mental health issues in young academics.
Identification and characterisationof Mansonella perstansin the Volta Region of Ghana
Authors: Opoku Millicent , de Souza Dziedzom K.
Published: November 2023

Mansonella spp. have been reported to have a wide global distribution. Despite the distribution and occurrence with other filarial parasites likeWuchereria bancrofti, Onchocerca volvulusandLao loa, it is given little attention. Hence, there is no surveillance programme for assessing the distribution or mansonellosis, with mild to no symptoms experienced by infected people. However, addressing this infection is critical to the onchocerciasis control program as current rapid diagnostic tools targetingO. volvulushave the tendency to cross react withMansonella species. In this study we identified and characterisedM. perstansfrom five sites in the Volta region of Ghana and compared them to samples from other regions. Night blood smears and filter blood blots were obtained from individuals as part of a study on lymphatic filariasis. The giemsa stained smears were screened by microscopy for the presence of filarial parasites. Genomic DNA was extracted from blood blots from 39 individuals that were positive forM. perstansand Nested PCR targeting the internal spacer 1 (ITS-1) was conducted. Of these, 30 were sequenced and 24 sequences were kept for further analysis. Phylogenetic analysis of 194 nucleotide positions showed no differences in the samples collected. Samples from Ghana clustered with samples from other reference sequences from Africa and Brazil, possibly supporting the introduction ofM. perstansfrom sub-Saharan Africa, during the trans-Atlantic slave trade. This study draws further attention to a neglected infection and presents the first characterisation ofM. perstansin Ghana and calls for more population-based studies across different geographical zones to ascertain species variations and disease distribution.
Whole genome profiling of short-term hypoxia induced genes and identification of HIF-1 binding sites provide insights into HIF-1 function inCaenorhabditis elegans
Authors: Feng Dingxia , Qu Long
Published: November 2023

Oxygen is essential to all the aerobic organisms. However, during normal development, disease and homeostasis, organisms are often challenged by hypoxia (oxygen deprivation). Hypoxia-inducible transcription factors (HIFs) are master regulators of hypoxia response and are evolutionarily conserved in metazoans. The homolog of HIF in the genetic model organismC. elegansis HIF-1. In this study, we aimed to understand short-term hypoxia response and to identify HIF-1 direct targets inC. elegans. The central research questions were: (1) which genes are differentially expressed in response to short-term hypoxia? (2) Which of these changes in gene expression are dependent upon HIF-1 function? (3) How do HIF-1-dependent hypoxia-responsive genes affect hypoxia adaptation? (4) Which genes are the direct targets of HIF-1? We combine whole genome gene expression analyses and chromatin immunoprecipitation sequencing (ChIP-seq) experiments to address these questions. In agreement with other published studies, we report that HIF-1-dependent hypoxia-responsive genes are involved in metabolism, oxidation-reduction process, and stress response. Some HIF-1-dependent hypoxia-responsive genes likeefk-1andphy-2dramatically impact survival in hypoxic conditions. HIF-1 co-immunoprecipitates with genomic regions proximal genes involved in stress response, protein processing in endoplasmic reticulum, and cell recognition. Further, some of these potential HIF-1 direct targets are differentially expressed under short-term hypoxia or are differentially regulated by mutations that enhance HIF-1 activity.
Suberoylanilide Hydroxamic Acid Attenuates Cognitive Impairment in Offspring Caused by Maternal Surgery during Mid-pregnancy
Authors: Feng Yunlin , Qin Jia , Lu Yanfei , Wang Mengdie , Wang Shengqiang , Luo Foquan
Published: November 2023

It is known that commonly-used anesthetics can cause long-term neurotoxicity in the developing brain. Some pregnant women have to experience non-obstetric surgery during pregnancy under general anesthesia. It is known that maternal exposure to sevoflurane, isoflurane, propofol and ketamine causes cognitive deficits in offspring. Histone acetylation has been implicated in synaptic plasticity, and abnormal histone acetylation contributes to the neonatal sevoflurane exposure induced deficits in hippocampus-dependent learning and memory. The HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) was shown to attenuate the sevoflurane-induced deficits. Propofol is commonly used in non-obstetric procedures on pregnant women. Recent evidence shows that propofol also causes neurotoxicity in developing brains. For example, previous studies in our laboratory showed that maternal propofol exposure in pregnancy impairs learning and memory in offspring by disturbing histone acetylation. The present study aims to investigate whether SAHA could also attenuate propofol-induced learning and memory deficits in offspring caused by maternal surgery during mid-pregnancy. Maternal rats were exposed to propofol or underwent abdominal surgery under propofol anesthesia during middle pregnancy. The learning and memory abilities of the offspring rats were assessed using Morris water maze (MWM) test. The protein levels of histone deacetylase 2 (HDAC2), phosphorylated cAMP response-element binding (p-CREB),brain derived neurotriphic factor (BDNF) and phosphorylated tyrosine kinase B (p-TrkB) in the hippocampus of the offspring rats were evaluated by immunofluorescence staining and western blot. Hippocampal neuroapoptosis was detected by TUNEL staining. Our results showed that maternal propofol exposure during middle pregnancy impaired the water-maze learning and memory of the offspring rats, increased the protein level of HDAC2 and reduced the protein levels of p-CREB,BDNF and p-TrkB in the hippocampus of the offspring, and such effects were exacerbated by surgery. SAHA alleviated the cognitive dysfunction and rescued the changes in the protein levels of p-CREB, BDNF and p-TrkB induced by maternal propofol exposure alone or maternal propofol exposure plus surgery. Therefore, SAHA could be a potential and promising agent for treating the learning and memory deficits in offspring caused by maternal nonobstetric surgery under propofol aneshtesia.
The proportion of Alzheimer’s disease attributable to apolipoprotein E
Authors: Williams Dylan M. , Davies Neil M. , Anderson Emma L.
Published: November 2023

INTRODUCTION

The extent to which genetic variation at theAPOElocus explains the burden of late-onset Alzheimer’s disease (AD) is poorly understood. We provide new estimates of the proportions of AD and all-cause dementia attributable to carriage of the ε3 and ε4APOEalleles.

METHODS

We conducted a cohort study using genetic and electronic health record data from 171,128 participants of UK Biobank, aged ≥60 years at baseline. AD and all-cause dementia were ascertained at baseline and during follow-up for up to 16.8 years.

RESULTS

74.0% (95% CI: 37.8, 89.1) of AD and 38.1% (95% CI: 9.8, 57.6%) of all-cause dementia burden were attributable to a combination of ε3 and ε4 carriage. Approximately 30% of AD was attributable to ε3 carriage specifically.

DISCUSSION

Differences in apolipoprotein E are responsible for most AD and a large fraction of all dementia. Research into this pathway should be prioritised to facilitate dementia prevention.
Potential Biases in Test-Negative Design Studies of COVID-19 Vaccine Effectiveness Arising from the Inclusion of Asymptomatic Individuals
Authors: Ortiz-Brizuela Edgar , Carabali Mabel , Jiang Cong , Merckx Joanna , Talbot Denis , Schnitzer Mireille E.
Published: November 2023

The test-negative design (TND) is a popular method for evaluating vaccine effectiveness (VE). A “classical” TND study includes symptomatic individuals tested for the disease targeted by the vaccine to estimate VE against symptomatic infection. However, recent applications of the TND have attempted to estimate VE against infection by including all tested individuals, regardless of their symptoms. In this article, we use directed acyclic graphs and simulations to investigate potential biases in TND studies of COVID-19 VE arising from the use of this “alternative” approach, particularly when applied during periods of widespread testing. We show that the inclusion of asymptomatic individuals can potentially lead to collider stratification bias, uncontrolled confounding by health and healthcare-seeking behaviors (HSBs), and differential outcome misclassification. While our focus is on the COVID-19 setting, the issues discussed here may also be relevant in the context of other infectious diseases. This may be particularly true in scenarios where there is either a high baseline prevalence of infection, a strong correlation between HSBs and vaccination, different testing practices for vaccinated and unvaccinated individuals, or settings where both the vaccine under study attenuates symptoms of infection and diagnostic accuracy is modified by the presence of symptoms.
Spatiotemporal Trends in Group A Streptococcal Pharyngitis in the United States
Authors: Kline Madeleine C. , Kissler Stephen M. , Whittles Lilith K. , Barnett Michael L. , Grad Yonatan H.
Published: November 2023

Background

Group AStreptococcus(GAS) causes an estimated 5.2 million outpatient visits for pharyngitis annually in the United States (U.S.) with incidence peaking in winter, but the annual spatiotemporal pattern of GAS pharyngitis across the U.S. is poorly characterized.

Methods

We used outpatient claims data from individuals with private medical insurance between 2010-2018 to quantify GAS pharyngitis visit rates across U.S. census regions, subregions, and states. We evaluated seasonal and age-based patterns of geographic spread and the association between school start dates and the summertime upward inflection in GAS visits.

Results

The South had the most visits per person (yearly average 39.11 visits per 1000 people, 95% CI: 36.21-42.01), and the West had the fewest (yearly average 17.63 visits per 1000 people, 95% CI: 16.76-18.49). Visits increased earliest in the South and in school-age children. Differences in visits between the South and other regions were most pronounced in the late summer through early winter. Visits peaked earliest in central southern states, in December to January, and latest on the coasts, in March. The onset of the rise in GAS pharyngitis visits correlated with, but preceded, average school start times.

Conclusions

The burden and timing of GAS pharyngitis varied across the continental U.S., with the South experiencing the highest overall rates and earliest onset and peak in outpatient visits. Understanding the drivers of these regional differences in GAS pharyngitis will help in identifying and targeting prevention measures.

The incidence of streptococcal pharyngitis varies across the U.S., with highest rates in the South and lowest in the West. On average, the yearly summer increase in cases begins in the South and progresses outwards to adjacent states.
Networks extracted from nonlinear fMRI connectivity exhibit unique spatial variation and enhanced sensitivity to differences between individuals with schizophrenia and controls
Authors: Kinsey Spencer , Kazimierczak Katarzyna , Camazón Pablo Andrés , Chen Jiayu , Adali Tülay , Kochunov Peter , Adhikari Bhim , Ford Judith , van Erp Theo G. M. , Dhamala Mukesh , Calhoun Vince D. , Iraji Armin
Published: November 2023

Functional magnetic resonance imaging (fMRI) studies often estimate brain intrinsic connectivity networks (ICNs) from temporal relationships between hemodynamic signals using approaches such as independent component analysis (ICA). While ICNs are thought to represent functional sources that play important roles in various psychological phenomena, current approaches have been tailored to identify ICNs that mainly reflect linear statistical relationships. However, the elements comprising neural systems often exhibit remarkably complex nonlinear interactions that may be involved in cognitive operations and altered in psychiatric conditions such as schizophrenia. Consequently, there is a need to develop methods capable of effectively capturing ICNs from measures that are sensitive to nonlinear relationships. Here, we advance a novel approach to estimate ICNs from explicitly nonlinear whole-brain functional connectivity (ENL-wFC) by transforming resting-state fMRI (rsfMRI) data into the connectivity domain, allowing us to capture unique information from distance correlation patterns that would be missed by linear whole-brain functional connectivity (LIN-wFC) analysis.

Our findings provide evidence that ICNs commonly extracted from linear (LIN) relationships are also reflected in explicitly nonlinear (ENL) connectivity patterns. ENL ICN estimates exhibit higher reliability and stability, highlighting our approach’s ability to effectively quantify ICNs from rsfMRI data. Additionally, we observed a consistent spatial gradient pattern between LIN and ENL ICNs with higher ENL weight in core ICN regions, suggesting that ICN function may be subserved by nonlinear processes concentrated within network centers. We also found that a uniquely identified ENL ICN distinguished individuals with schizophrenia from healthy controls while a uniquely identified LIN ICN did not, emphasizing the valuable complementary information that can be gained by incorporating measures that are sensitive to nonlinearity in future analyses. Moreover, the ENL estimates of ICNs associated with auditory, linguistic, sensorimotor, and self-referential processes exhibit heightened sensitivity towards differentiating between individuals with schizophrenia and controls compared to LIN counterparts, demonstrating the translational value of our approach and of the ENL estimates of ICNs that are frequently reported as disrupted in schizophrenia. In summary, our findings underscore the tremendous potential of connectivity domain ICA and nonlinear information in resolving complex brain phenomena and revolutionizing the landscape of clinical FC analysis.
Dynamic neuroinflammatory profiles predict Alzheimer’s disease pathology in microglia-containing cerebral organoids
Authors: Kuhn Madison K. , Kang Rachel Y. , Kim ChaeMin , Tagay Yerbol , Morris Nathan , Tabdanov Erdem D. , Elcheva Irina A. , Proctor Elizabeth A.
Published: November 2023

Neuroinflammation and the underlying dysregulated immune responses of microglia actively contribute to the progression and, likely, the initiation of Alzheimer’s disease (AD). Fine-tuned therapeutic modulation of immune dysfunction to ameliorate disease cannot be achieved without the characterization of diverse microglial states that initiate unique, and sometimes contradictory, immune responses that evolve over time in chronic inflammatory environments. Because of the functional differences between human and murine microglia, untangling distinct, disease-relevant reactive states and their corresponding effects on pathology or neuronal health may not be possible without the use of human cells. In order to profile shifting microglial states in early AD and identify microglia-specific drivers of disease, we differentiated human induced pluripotent stem cells (iPSCs) carrying a familial AD PSEN2 mutation or its isogenic control into cerebral organoids and quantified the changes in cytokine concentrations over time with Luminex XMAP technology. We used partial least squares (PLS) modeling to build cytokine signatures predictive of disease and age to identify key differential patterns of cytokine expression that inform the overall organoid immune milieu and quantified the corresponding changes in protein pathology. AD organoids exhibited an overall reduction in cytokine secretion after an initial amplified immune response. We demonstrate that reduced synapse density observed in the AD organoids is prevented with microglial depletion. Crucially, these differential effects of dysregulated immune signaling occurred without the accumulation of pathological proteins. In this study, we used microglia-containing AD organoids to quantitatively characterize an evolving immune milieu, made up of a diverse of collection of activation patterns and immune responses, to identify how a dynamic, overall neuroinflammatory state negatively impacts neuronal health and the cell-specific contribution of microglia.
Macrophage Depletion Protects Against Cisplatin-Induced Ototoxicity and Nephrotoxicity
Authors: Sung Cathy Yea Won , Hayase Naoki , Yuen Peter S.T. , Lee John , Fernandez Katharine , Hu Xuzhen , Cheng Hui , Star Robert A. , Warchol Mark E. , Cunningham Lisa L.
Published: November 2023

Cisplatin is a widely used and highly effective anti-cancer drug with significant side effects including ototoxicity and nephrotoxicity. Macrophages, the major resident immune cells in the cochlea and kidney, are important drivers of both inflammatory and tissue repair responses. To investigate the roles of macrophages in cisplatin-induced ototoxicity and nephrotoxicity, we used PLX3397, an FDA-approved inhibitor of the colony-stimulating factor 1 receptor (CSF1R), to eliminate tissue-resident macrophages during the course of cisplatin administration. Mice treated with cisplatin alone (cisplatin/vehicle) had significant hearing loss (ototoxicity) as well as kidney injury (nephrotoxicity). Macrophage ablation using PLX3397 resulted in significantly reduced hearing loss measured by auditory brainstem responses (ABR) and distortion-product otoacoustic emissions (DPOAE). Sensory hair cells in the cochlea were protected against cisplatin-induced death in mice treated with PLX3397. Macrophage ablation also protected against cisplatin-induced nephrotoxicity, as evidenced by markedly reduced tubular injury and fibrosis as well as reduced plasma blood urea nitrogen (BUN) and neutrophil gelatinase-associated lipocalin (NGAL) levels. Mechanistically, our data suggest that the protective effect of macrophage ablation against cisplatin-induced ototoxicity and nephrotoxicity is mediated by reduced platinum accumulation in both the inner ear and the kidney. Together our data indicate that ablation of tissue-resident macrophages represents a novel strategy for mitigating cisplatin-induced ototoxicity and nephrotoxicity.

Brief summary

Macrophage ablation using PLX3397 was protective against cisplatin-induced ototoxicity and nephrotoxicity by limiting platinum accumulation in the inner ear and kidney.
De novotranscriptome assembly and genome annotation of the fat-tailed dunnart (Sminthopsis crassicaudata)
Authors: Ibeh Neke , Feigin Charles Y. , Frankenberg Stephen R. , McCarthy Davis J. , Pask Andrew J. , Romero Irene Gallego
Published: November 2023

Marsupials exhibit highly specialized patterns of reproduction and development, making them uniquely valuable for comparative genomics studies with their sister lineage, eutherian (also known as placental) mammals. However, marsupial genomic resources still lag far behind those of eutherian mammals, limiting our insight into mammalian diversity. Here, we present a series of novel genomic resources for the fat-tailed dunnart (Sminthopsis crassicaudata), a mouse-like marsupial that, due to its ease of husbandry andex-uterodevelopment, is emerging as a laboratory model. To enable wider use, we have generated a multi-tissuede novotranscriptome assembly of dunnart RNA-seq reads spanning 12 tissues. This highly representative transcriptome is comprised of 2,093,982 assembled transcripts, with a mean transcript length of 830 bp. The transcriptome mammalian BUSCO completeness score of 93% is the highest amongst all other published marsupial transcriptomes. Additionally, we report an improved fat-tailed dunnart genome assembly which is 3.23 Gb long, organized into 1,848 scaffolds, with a scaffold N50 of 72.64 Mb. The genome annotation, supported by assembled transcripts andab initiopredictions, revealed 21,622 protein-coding genes. Altogether, these resources will contribute greatly towards characterizing marsupial biology and mammalian genome evolution.
The Wolfram-like variant WFS1E864Kdestabilizes MAM and compromises autophagy and mitophagy in human and mice
Authors: Patergnani Simone , Bataillard Méghane S. , Danese Alberto , Alves Stacy , Cazevieille Chantal , Valéro René , Tranebjærg Lisbeth , Maurice Tangui , Pinton Paolo , Delprat Benjamin , Richard Elodie M.
Published: November 2023

Dominant variants inWFS1, a gene coding for the mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) resident protein Wolframin, have been associated with Wolfram-like syndrome (WLS).In vitroandin vivo, WFS1 loss results in reduced ER to mitochondria calcium (Ca2+) transfer, mitochondrial dysfunction, and enhanced autophagy and mitophagy. However, in WLS pathological context, whether the mutant protein triggers the same cellular processes is unknown. Here, we show that, in human fibroblasts and murine neuronal cultures, WLS protein WFS1E864Kleads to decreases in mitochondria bioenergetics and Ca2+uptake, deregulation of the mitochondrial quality system mechanisms, and alteration of the autophagic flux. Moreover, in theWfs1E864Kmouse, these alterations are concomitant with a decrease of MAM number. These findings reveal pathophysiological similarities between WS and WLS, highlighting the importance of WFS1 for MAM’s integrity and functionality. It may open new treatment perspectives, until now non-existent, for patients with WLS.
Virus specificity and nucleoporin requirements for MX2 activity are affected by GTPase function and capsid-CypA interactions
Authors: Layish Bailey , Goli Ram , Flick Haley , Huang Szu-Wei , Zhang Robert Z. , Kvaratskhelia Mamuka , Kane Melissa
Published: November 2023

Human myxovirus resistance 2 (MX2/MXB) is an interferon-induced GTPase that inhibits human immunodeficiency virus-1 (HIV-1) infection by preventing nuclear import of the viral preintegration complex. The HIV-1 capsid (CA) is the major viral determinant for sensitivity to MX2, and complex interactions between MX2, CA, nucleoporins (Nups), cyclophilin A (CypA), and other cellular proteins influence the outcome of viral infection. To explore the interactions between MX2, the viral CA, and CypA, we utilized a CRISPR-Cas9/AAV approach to generate CypA knock-out cell lines as well as cells that express CypA from its endogenous locus, but with specific point mutations that would abrogate CA binding but should not affect enzymatic activity or cellular function. We found that infection of CypA knock-out and point mutant cell lines with wild-type HIV-1 and CA mutants recapitulated the phenotypes observed upon cyclosporine A (CsA) addition, indicating that effects of CsA treatment are the direct result of blocking CA-CypA interactions and are therefore independent from potential interactions between CypA and MX2 or other cellular proteins. Notably, abrogation of GTP hydrolysis by MX2 conferred enhanced antiviral activity when CA-CypA interactions were abolished, and this effect was not mediated by the CA-binding residues in the GTPase domain, or by phosphorylation of MX2 at position T151. We additionally found that elimination of GTPase activity also altered the Nup requirements for MX2 activity. Our data demonstrate that the antiviral activity of MX2 is affected by CypA-CA interactions in a virus-specific and GTPase activity-dependent manner. These findings further highlight the importance of the GTPase domain of MX2 in regulation of substrate specificity and interaction with nucleocytoplasmic trafficking pathways.

Author Summary

HIV-1 entry into the nucleus is an essential step in viral replication that involves complex interactions between the viral capsid and multiple cellular proteins, including the proline isomerase cyclophilin A. Nuclear entry of HIV-1 and other primate lentiviruses is inhibited by the antiviral protein MX2. Here, we show that direct interactions between capsid and cyclophilin A affect the antiviral activity and specificity of MX2, and that these interactions are altered when the enzymatic activity of MX2 is eliminated. We demonstrate that abolishing enzymatic activity of MX2 also alters the requirements for nuclear pore complex components for viral restriction. Our study provides new insights into how the enzymatic function of MX2 affects inhibition of lentiviral nuclear import.
A Computational Approach for Structural and Functional Analyses of Disease-associated Mutations in the HumanCYLDGene
Authors: Roy Arpita Singha , Feroz Tasmiah , Islam Md. Kobirul , Munim Md. Adnan , Supti Dilara Akhter , Antora Nusrat Jahan , Reza Hasan Al , Gosh Supriya , Bahadur Newaz Mohammad , Alam Mohammad Rahanur , Hossain Md Shahadat
Published: November 2023

Tumor suppressor Cylindromatosis protein (CYLD) regulates NF- κB and JNK signaling pathway by cleaving K63 linked poly-ubiquitin chain from its substrate molecules and thus preventing the progression of tumorigenesis and metastasis of the cancer cells. Mutations in CYLD can cause aberrant structure and abnormal functionality leading to tumor formation. In this study, we utilized several computational tools such as PANTHER, PROVEAN, PREDICT- SNP, POLYPHEN 2, PHD SNP, PON P2, and SIFT to find out deleterious nsSNPs. We also highlighted the damaging impact of those deleterious nsSNPs on the structure and function of the CYLD utilizing Consurf, I-Mutant, SDM, Phyre2, HOPE, Swiss PDB Viewer, and Mutation 3D. We shortlisted 18 high-risk nsSNPs from a total of 446 nsSNPs recorded in the NCBI database. Based on the conservation profile, stability status, and structural impact analysis we finalized 13nsSNPs. Molecular docking analysis and molecular dynamic simulation concluded the study with the findings of two significant nsSNPs (R830K, H827R) which have a remarkable impact on binding affinity, RMSD, RMSF, Radius of gyration, and hydrogen bond formation during CYLD-ubiquitin interaction. The principal component analysis compared native and two mutants R830K, H827R of CYLD that signifies structural and energy profile fluctuations during molecular dynamic (MD) simulation. Finally, the Protein-protein interaction network showed CYLD interacts with 20 proteins involved in several biological pathways that mutations can impair. Considering all these in silico analyses, our study recommended conducting large-scale association studies of nsSNPs of CYLD with cancer as well as designing precise medications against diseases associated with these polymorphisms.
Virtual Tissue Expression Analysis
Authors: Simeth Jakob , Hüttl Paul , Schön Marian , Nozari Zahra , Huttner Michael , Schmidt Tobias , Altenbuchinger Michael , Spang Rainer
Published: November 2023

Motivation

Bulk RNA expression data is widely accessible, whereas single-cell data is relatively scarce in comparison. However, single-cell data offers profound insights into the cellular composition of tissues and cell-type-specific gene regulation, both of which remain hidden in bulk expression analysis.

Results

Here, we present tissueResolver an algorithm designed to extract single-cell type information from bulk data, enabling us to attribute expression changes to individual cell types. The outcome is a virtual tissue that can be analyzed in a manner similar to single-cell RNA-seq data. When validated on simulated data tissueResolver outperforms competing methods. Additionally, our study demonstrates that tissueResolver reveals previously overlooked celltype specific regulatory distinctions between the activated B-cell-like (ABC) and germinal center B-cell-like (GCB) subtypes of diffuse large B-cell lymphomas (DLBCL).

Availability and Implementation

R package available athttps://github.com/spang-lab/tissueResolver. Code for reproducing the results of this paper is available athttps://github.com/spang-lab/tissueResolver-docs.

Contact

jakob.simeth@klinik.uni-regensburg.de