bluuebunny/crossref_metadata_2025 huggingface dataset:
Evolution of transient RNA structure–RNA polymerase interactions in respiratory RNA virus genomes
Authors: Rigby Charlotte V , Sabsay Kimberly R , Bisht Karishma , Eggink Dirk , Jalal Hamid , te Velthuis Aartjan J W
Published: September 2023

RNA viruses are important human pathogens that cause seasonal epidemics and occasional pandemics. Examples are influenza A viruses (IAV) and coronaviruses (CoV). When emerging IAV and CoV spill over to humans, they adapt to evade immune responses and optimize their replication and spread in human cells. In IAV, adaptation occurs in all viral proteins, including the viral ribonucleoprotein (RNP) complex. RNPs consist of a copy of the viral RNA polymerase, a double-helical coil of nucleoprotein, and one of the eight segments of the IAV RNA genome. The RNA segments and their transcripts are partially structured to coordinate the packaging of the viral genome and modulate viral mRNA translation. In addition, RNA structures can affect the efficiency of viral RNA synthesis and the activation of host innate immune response. Here, we investigated if RNA structures that modulate IAV replication processivity, so-called template loops (t-loops), vary during the adaptation of pandemic and emerging IAV to humans. Using cell culture-based replication assays and in silico sequence analyses, we find that the sensitivity of the IAV H3N2 RNA polymerase to t-loops increased between isolates from 1968 and 2017, whereas the total free energy of t-loops in the IAV H3N2 genome was reduced. This reduction is particularly prominent in the PB1 gene. In H1N1 IAV, we find two separate reductions in t-loop free energy, one following the 1918 pandemic and one following the 2009 pandemic. No destabilization of t-loops is observed in the influenza B virus genome, whereas analysis of SARS-CoV-2 isolates reveals destabilization of viral RNA structures. Overall, we propose that a loss of free energy in the RNA genome of emerging respiratory RNA viruses may contribute to the adaption of these viruses to the human population.
Viral community composition of hypersaline lakes
Authors: Le Lay Callum , Hamm Joshua N , Williams Timothy J , Shi Mang , Cavicchioli Ricardo , Holmes Edward C
Published: September 2023

Despite their widespread distribution and remarkable antiquity no RNA viruses definitively associated with the domain Archaea have been identified. In contrast, 17 families of DNA viruses are known to infect archaea. In an attempt to uncover more of the elusive archaeal virosphere, we investigated the metatranscriptomes of hypersaline lakes that are a rich source of archaea. We sequenced RNA extracted from water filter samples of Lake Tyrrell (Victoria, Australia) and cultures seeded from four lakes in Antarctica. To identify highly divergent viruses in these data, we employed a variety of search tools, including Hidden Markov models (HMMs) and position-specific scoring matrices (PSSMs). From this, we identified 12 highly divergent, RNA virus-like candidate sequences from the virus phyla Artverviricota, Duplornaviricota, Kitrinoviricota, Negarnaviricota, and Pisuviricota, including those with similarity to the RNA-dependent RNA polymerase (RdRp). An additional analysis with an artificial intelligence (AI)-based approach that utilises both sequence and structural information identified seven putative and highly divergent RdRp sequences of uncertain phylogenetic position. A sequence matching the Pisuviricota from Deep Lake in Antarctica had the strongest RNA virus signal. Analyses of the dinucleotide representation of the virus-like candidates in comparison to that of potential host species were in some cases compatible with an association to archaeal or bacterial hosts. Notably, however, the use of archaeal CRISPR spacers as a BLAST database failed to detect any RNA viruses. We also described DNA viruses from the families Pleolipoviridae, Sphaerolipoviridae, Halspiviridae, and the class Caudoviricetes. Although we were unable to provide definitive evidence the existence of an RNA virus of archaea in these hypersaline lakes, this study lays the foundations for further investigations of highly divergent RNA viruses in natural environments.
Sigma factors of RNA polymerase in the pathogenic spirochaete Leptospira interrogans, the causative agent of leptospirosis
Authors: Kędzierska‐Mieszkowska Sabina
Published: September 2023

The aim of this review is to summarize the current knowledge on the role of σ factors in a highly invasive spirochaete Leptospira interrogans responsible for leptospirosis that affects many mammals, including humans. This disease has a significant impact on public health and the economy worldwide. In bacteria, σ factors are the key regulators of gene expression at the transcriptional level and therefore play an important role in bacterial adaptative response to different environmental stimuli. These factors form a holoenzyme with the RNA polymerase core enzyme and then direct it to specific promoters, which results in turning on selected genes. Most bacteria possess several different σ factors that enable them to maintain basal gene expression, as well as to regulate gene expression in response to specific environmental signals. Recent comparative genomics and in silico genome‐wide analyses have revealed that the L. interrogans genome, consisting of two circular chromosomes, encodes a total of 14 σ factors. Among them, there is one putative housekeeping σ70‐like factor, and three types of alternative σ factors, i.e., one σ54, one σ28 and 11 putative ECF (extracytoplasmic function) σE‐type factors. Here, characteristics of these putative σ factors and their possible role in the L. interrogans gene regulation (especially in this pathogen's adaptive response to various environmental conditions, an important determinant of leptospiral virulence), are presented.
Chewing Gum Cannot Reduce Postoperative Abdominal Pain and Nausea After Posterior Spinal Fusions in Patients With Adolescent Idiopathic Scoliosis
Authors: Tong Bingdu , Chen Zefu , Li Gaoyang , Zhang Li , Chen Yaping
Published: September 2023

Study Design:

A systematic review and meta-analysis of randomized controlled trials.

Objective:

The aim of this study was to determine the effect of chewing gum on postoperative abdominal pain, nausea, and hospital stays after posterior spinal fusions (PSFs) in patients with adolescent idiopathic scoliosis (AIS).

Summary of Background Data:

Chewing gum had been extensively reported to improve bowel motility and is recommended to hasten bowel recovery following gastrointestinal surgery. However, there is no conclusive evidence regarding the effect of chewing gum on postoperative abdominal pain, nausea, and hospital stays after PSFs in AIS patients.

Methods:

A comprehensive literature search was performed for relevant randomized controlled trials using PubMed, Cochrane Central Register of Controlled Trials, Web of Science, and Embase. Studies were selected to compare the use of chewing gum versus standard care in the management of postoperative abdominal pain and nausea in AIS patients undergoing PSFs. Hospital stays were also investigated. The study was conducted using the checklist for PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses).

Results:

Three randomized controlled trials were included in the systematic review and the meta-analysis. No significant effect of chewing gum was highlighted concerning the postoperative abdominal pain scores at 24 and 48 hours [24 h: mean difference (MD)=0.45, 95% CI=−0.97 to 0.07, P=0.09; 48 h: MD=−0.24, 95% CI=−0.79 to 0.32, P=0.41]. No significant difference regarding the postoperative nausea scores was found at 24 and 48 hours (24 h: MD=0.26, 95% CI=−0.27 to 0.79, P=0.34; 48 h: MD=0.06, 95% CI=−0.36 to 0.48, P=0.77). No significant difference regarding hospital stays was found (MD=0.13, 95% CI=−0.02 to 0.28, P=0.09).

Conclusions:

Based on the current studies, chewing gum does not have a significant effect on postoperative abdominal pain, nausea, or hospital stays after PSFs in AIS patients. As the effect of chewing gum in reducing postoperative abdominal pain exhibits a tendency towards statistical significance (P=0.09), the effect of chewing gum in spinal surgery merits further studies with larger sample size.
Interpreting Meta-Analyses
Authors: Brush Parker L. , Sherman Matthew , Lambrechts Mark J.
Published: September 2023

Meta-analyses represent the best available medical evidence. Although a powerful tool, they are not without criticisms since any bias in the original studies are then compounded when they are pooled together for the meta-analysis. Funnel plots provide a useful graphical representation of the presence of bias, and forest plots represent the heterogeneity of findings within studies included in a meta-analysis. The purpose of this review is to help readers interpret these statistical tools to better understand the findings of a meta-analysis.
Fetal and Maternal Monitoring
Authors: Ledgerwood Chelsea , Angelides Mary , Idler Jay , Smith Bridget , DuMont Tiffany , Cheema Tariq , Barker Billie
Published: September 2023

Fetal monitoring in the intrapartum and peripartum periods is important for the well-being of both baby and mother. Electronic fetal monitoring was first designed over 50 years ago in an attempt to improve perinatal outcomes. Its purpose is to assess fetal oxygenation and acid-base status during the antepartum course when indicated and during labor. Maternal assessment begins early in gestation with blood pressure monitoring and urine protein excretion to diagnose potential complications, such as severe hypertension and preeclampsia/eclampsia.
Trauma in Pregnancy
Authors: Patel Samir , Qabbani Amjad , Sheridan Robyn , DuMont Tiffany , Kautza Benjamin , Arshad Hammad
Published: September 2023

Trauma in pregnancy can range from a mild injury, such as a fall from standing height, to a major injury, involving a penetrating injury or a high force motor vehicle collision. Providing care to a pregnant patient with trauma presents a unique challenge as 2 patients are at risk for complications, that is, the mother and the fetus, both of whom require evaluation and management. Health care professionals should be aware of and be prepared to manage complications of trauma in pregnancy, given its significant associated morbidity and mortality. This article details the epidemiology, etiology, assessment, diagnosis, and management of trauma in pregnancy.
Medical Emergencies in the Pregnant Patient
Authors: Nasrullah Adeel , Herrera Martin , Garbinski Ashley , DuMont Tiffany , Alhajhusain Ahmad
Published: September 2023

This review article provides a comprehensive overview of common medical emergencies that can occur in pregnant patients. We summarize the key diagnostic and management steps for each emergency to assist health care professionals in identifying and treating these potentially life-threatening conditions. The medical emergencies discussed in this article include postpartum hemorrhage; hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome; acute fatty liver of pregnancy; amniotic fluid embolism; pulmonary embolism; acute respiratory distress syndrome; and shock. Each condition is described in detail, with a focus on the clinical presentation, diagnostic workup, and treatment options. The information presented in this review article is based on current best practices and guidelines from leading medical organizations. We hope this article will serve as a valuable resource for health care professionals who care for pregnant patients and help improve outcomes for these patients in emergency situations.
Asthma in Pregnancy
Authors: Rao Sheldon , Modugula Sujith , Gaviglia Karen , Cheema Tariq , Dumont Tiffany , Balaan Marvin , DiSilvio Briana
Published: September 2023

Asthma is a common chronic respiratory condition that affects approximately 10% of adult women in the United States. Pregnancy can present unique challenges for women with asthma, as changes in the body can alter the severity and management of asthma-related respiratory symptoms. In this article, we review the current understanding of asthma during pregnancy, including the direct effects of the disease state on the pregnant woman and fetus, risk factors for poor control of disease, as well as current treatment recommendations.
Hypertension in Women and Pregnancy
Authors: Shah Aaisha , Kapcin Kyle , Deicke Matthew , Pappan Nikos , Holden Kyle , Routray Sujit Kumar , Schmetzer Amy , DuMont Tiffany , Nashar Khaled , Bajwa Omer , Ivanova Valentyna
Published: September 2023

Hypertension has been shown to have long-term cardiovascular effects if left untreated. Hypertension also has been shown to affect women during pregnancy, which can be detrimental not only to the patient but also to the fetus. Early identification and treatment are paramount to prevent adverse outcomes. This article details the epidemiology, clinical presentation, diagnosis, and treatment of essential hypertension in women, gestational hypertension, preeclampsia, and eclampsia.
A single-cell transcriptome analysis and prognostic model construction of stromal cells for renal cell carcinoma
Authors: Liao Kuo , Wang Yifan , Liu Shuangxin , Li Quhuan
Published: September 2023

Renal cell carcinoma (RCC) is among the top three cancers of the urinary system and its incidence keeps increasing worldwide in recent decades. However, methods for accurate prognosis evaluation and effective treatment are still lacking nowadays. Here, to explore the molecular expression features of RCC and establish a new RCC clinical prognosis evaluation model, a cell landscape of 187,263 renal cells obtained from eight patients with RCC was analyzed in this study. And by extracting and focusing on the main stromal cells from RCC tissues, innovative molecular characteristics and pathways of tumors were identified, like the well-known hypoxia pathway. By analyzing cell-cell communication, fibroblasts were found to promote tumor development by repressing natural killer cells. Based on Cox and least absolute shrinkage and selection operator regression analysis, four risk factors were screened and used to construct a reliable RCC clinical risk estimation model. In conclusion, our work provides new insights into the tumor microenvironment of RCC, as well as potential therapeutic targets and a clinical risk model for RCC invasiveness. Hopefully, these findings will be useful for cancer research and clinical treatment in future.
Critical Behavioral Traits Foster Peer Engagement in Online Mental Health Communities
Authors: Srivastava Aseem , Gupta Tanya , Cerezo Alison , (Grin) Lord Sarah Peregrine , Akhtar Md Shad , Chakraborty Tanmoy
Published: September 2023

Online Mental Health Communities (OMHCs), such as Reddit, have witnessed a surge in popularity as go-to platforms for seeking information and support in managing mental health needs. Platforms like Reddit offer immediate interactions with peers, granting users a vital space for seeking mental health assistance. However, the largely unregulated nature of these platforms introduces intricate challenges for both users and society at large. This study explores the factors that drive peer engagement within counseling threads, aiming to enhance our understanding of this critical phenomenon. We introduce BeCOPE, a novel behavior encoded Peer counseling dataset comprising over 10,118 posts and 58,279 comments sourced from 21 mental health-specific subreddits. The dataset is annotated using three major fine-grained behavior labels: (a) intent, (b) criticism, and (c) readability, along with the emotion labels. Our analysis indicates the prominence of “self-criticism” as the most prevalent form of criticism expressed by help-seekers, accounting for a significant 43% of interactions. Intriguingly, we observe that individuals who explicitly express their need for help are 18.01% more likely to receive assistance compared to those who present “surveys” or engage in “rants.” Furthermore, we highlight the pivotal role of well-articulated problem descriptions, showing that superior readability effectively doubles the likelihood of receiving the sought-after support. Our study emphasizes the essential role of OMHCs in offering personalized guidance and unveils behavior-driven engagement patterns.
Hemoglobin specific volume width might promote the prevalence and poor long-term prognosis of American cardiovascular disease adult patients: the NHANES 1999-2020
Authors: Zhang Lin , Chang Jun , Wang Kaiyue , Zhou Ying , Wang Liming , Zhang Lele , Zhang Xuemei , Fu Zhifei , Han Lifeng , Gao Xiumei
Published: September 2023

Background

Cardiovascular disease (CVD) patients are always accompanied by erythrocyte dysfunction. However, current erythrocyte-related indicators can’t explain the prevalence and long-term prognosis of CVD. Therefore, hemoglobin specific volume width (HSW) was first created to explain this phenomenon.

Methods

HSW’s quartiles were determined with Q1 [1.88,3.64] cL/g, Q2 (3.64,3.85] cL/g, Q3 (3.85,4.11] cL/g, and Q4 (4.11,11.74] cL/g. Among the 57,894 participants derived from National Health and Nutrition Examination Survey (NMAHES), 5,623 CVD patients had a whole following time (median 79 months). Logistic regression, Cox regression, Kaplan–Meier curves, and restricted cubic spline were utilized for analysis.

Results

Among the non-CVD (n=51,243) and CVD (n=6,651) individuals, the percentages of CVD in quartiles of HSW (Q1, Q2, Q3, and Q4) were 4.95%, 7.11%, 10.51%, and 16.14% (P< 0.0001). Adjusted odds ratio (OR) was still significant, 1.46 (95% CI 1.33, 1.60). Processing Q1 as reference, the adjusted ORs for Q3 and Q4 were 1.19(95% CI 1.05,1.35) and 1.54 (95% CI 1.36,1.73). Females had a higher risk (OR 1.49, 95% CI 1.32, 1.68) of CVD than males with increasing HSW. Diabetes mellitus (DM) patients had the highest risk of CVD (OR 1.54, 95% CI 1.30,1.84) than preDM or healthy individuals. Among dead (n=2,517) and alive CVD (n=3,106) patients, the adjusted HSW hazard ratio (HR) was 1.70 (95% CI 1.48,1.95). An inverse L-curve with an inflexion point of 3.96 was observed between HR and CVD. CVD patients with HSW > 3.96 had a poor prognosis than HSW <= 3.96.

Conclusions

HSW is a novel risk for CVD prevalence and long-term prognosis. Females and DM patients have a higher risk of CVD when HSW increases.
Core gene set of the speciesSaccharomyces cerevisiae
Authors: Dietrich Fred S. , Magwene Paul , McCusker John
Published: September 2023

Examination of the genome sequence ofSaccharomyces cerevisiaestrain S288c and 93 additional diverse strains allows identification of the 5873 genes that make up the core set of genes in this species and gives a better sense of the organization and plasticity of this genome.S. cerevisiaestrains each contain dozens to hundreds of strain specific genes. In addition to a variable content of retrotransposons, some strains contain a novel transposable element, Ty7. Examination further shows that some annotated putative protein coding genes are likely artifacts. We propose altering approximately 5% of the current annotations in the widely used reference strain S288c. Potential null alleles are common and found in all 94 strains examined, with these potential null alleles typically containing a single stop codon or frameshift. There are also gene remnants, pseudogenes, and variable arrays of genes. Among the core genes there are now only 373 protein coding genes of unknown function, classified as uncharacterized in the Saccharomyces Genome Database. This work suggests that there is a role for carefully edited and annotated genome sequences in understanding the genome organization and content of a species. We propose that gene remnants be added to the repertoire of features found in theS. cerevisiaegenome, and likely other fungal species.
MacaqueNet: big-team research into the biological drivers of social relationships
Authors: De Moor Delphine ,   MacaqueNet, Skelton Macaela , Schülke Oliver , Ostner Julia , Neumann Christof , Duboscq Julie , Brent Lauren J. N.
Published: September 2023

For many animals, social relationships are a key determinant of fitness. However, major gaps remain in our understanding of the adaptive function, ontogeny, evolution, and mechanistic underpinnings of social relationships. There is a vast and ever-accumulating amount of social behavioural data on individually recognised animals, an incredible resource to shed light onto the biological basis of social relationships. Yet, the full potential of such data lies in comparative research across taxa with distinct life histories and ecologies. Substantial challenges impede systematic comparisons, one of which is the lack of persistent, accessible, and standardised databases.

Here, we advocate for the creation of big-team collaborations and comparative databases to unlock the wealth of behavioural data for research on social relationships by introducing MacaqueNet (https://macaquenet.github.io/).

As a global collaboration of over 100 researchers, the MacaqueNet database encompasses data from 1981 to the present on 14 species and is the first publicly searchable and standardised database on affiliative and agonistic animal social networks. With substantial inter-specific variation in ecology and social structure and the first published record on macaque behaviour dating back to 1956, macaque research has already contributed to answering fundamental questions on the biological bases and evolution of social relationships. Building on these strong foundations, we believe that MacaqueNet can further promote collaborative and comparative research on social behaviour.

We believe that big-team approaches to building standardised databases, bringing together data contributors and researchers, will aid much-needed large-scale comparative research in behavioural ecology and beyond. We describe the establishment of MacaqueNet, from starting a large-scale collective to the creation of a cross-species collaborative database and the implementation of data entry and retrieval protocols. As such, we hope to provide a functional example for future endeavours of large-scale collaborative research into the biology of social behaviour.
Tissue-resident uterine regulatory T cells support fetal growth
Authors: Florez Laura Maria , Fourcade Gwladys , Darrassse-Jèze Guillaume , Barennes Pierre , Gan-Fernandez Karina , Régnier Paul , Nehar-Belaid Djamel , Courau Tristan , Ruocco Maria Grazia , Zacchigna Serena , Giacca Mauro , Lion Julien , Mooney Nuala , Tchitchek Nicolas , Mariotti-Ferrandiz Encarnita , Klatzmann David
Published: September 2023

Regulatory T cells (Tregs) are known to contribute to successful allogeneic pregnancy by promoting maternal-fetal tolerance. Here, phenotypic studies and parabionts identified a population of uterine tissue-resident Tregs (uTregs) with trophic functions in the non-pregnant mouse endometrium. Phenotypically, uTregs are CD25-/loand they present characteristic phenotypic attributes of tissue-resident memory T cells with effector functions. Transcriptionally, uTregs are distinguishable from other peripheral or tissue-resident Tregs by their expression of genes related to extracellular matrix remodeling and vasculogenesis, and they express a polyclonal T cell receptor (TCR) repertoire. Pregnancy triggers the expansion of uTregs, which remain CD25-/lo, retain their polyclonal TCR repertoire, and increase the expression of genes involved in regulation of hypoxia and vasculogenesis. Functionally, we show that uTregs support the proliferation of primary uterine microvascular endothelial cellsin vitroand that a specific depletion of uTregs in pregnant mice leads to fetal intra-uterine growth retardation (IUGR). Thus, a previously unidentified population of CD25-/louTregs promotes uterine tissue remodeling before and during pregnancy, and contributes to fetal growth.
Development of a cellular reporter assay to measure activity of MutSβ, a therapeutic target for Huntington’s disease
Authors: An Jian , Towle Theresa , Aksit Melis Atalar , Mohiuddin Mohiuddin , Castaneda Samantha , Nakashima Reiko , Moccia Rob , Bulawa Christine , Fleming James
Published: September 2023

Genetic modifiers of age of onset in Huntington’s disease (HD) provide compelling evidence that somatic expansion of the CAG repeats is a critical driver of pathogenesis and demonstrate that repeat instability is modulated by DNA mismatch repair (MMR). A component of this pathway, MutSβ, a heterodimer comprised of MSH2 and MSH3, has emerged as a potential target for small-molecule therapeutic intervention. However, a robust cellular assay to interrogate genetic and pharmacological modifiers of MutSβ has not been reported. We have repurposed and optimized a tetranucleotide reporter assay to measure MutSβ activity in MMR-competent cells. We show that repeat instability is modulated by MSH3 protein levels and by its ATPase activity. In addition, we show that an inhibitor of HDAC3 modulates repeat instability, demonstrating the utility of the assay for pharmacological studies.
Toward a synthesis of phytoplankton community composition methods for global-scale application
Authors: Kramer Sasha J. , Bolaños Luis M. , Catlett Dylan , Chase Alison P. , Behrenfeld Michael J. , Boss Emmanuel S. , Crockford E. Taylor , Giovannoni Stephen J. , Graff Jason R. , Haëntjens Nils , Karp-Boss Lee , Peacock Emily E. , Roesler Collin S. , Sosik Heidi M. , Siegel David A.
Published: September 2023

The composition of the marine phytoplankton community has been shown to impact many biogeochemical processes and marine ecosystem services. A variety of methods exist to characterize phytoplankton community composition (PCC), with varying degrees of taxonomic resolution. Accordingly, the resulting PCC determinations are dependent on the method used. Here, we use surface ocean samples collected in the North Atlantic and North Pacific Oceans to compare high performance liquid chromatography (HPLC) pigment-based PCC to four other methods: quantitative cell imaging, flow cytometry, and 16S and 18S rRNA amplicon sequencing. These methods allow characterization of both prokaryotic and eukaryotic PCC across a wide range of size classes. PCC estimates of many taxa resolved at the class level (e.g., diatoms) show strong positive correlations across methods, while other groups (e.g., dinoflagellates) are not well captured by one or more methods. Since variations in phytoplankton pigment concentrations are related to changes in optical properties, this combined dataset expands the potential scope of ocean color remote sensing by associating PCC at the genus- and species-level with group- or class-level PCC from pigments. Quantifying the strengths and limitations of pigment-based PCC methods compared to PCC assessments from amplicon sequencing, imaging, and cytometry methods is the first step toward the robust validation of remote sensing approaches to quantify PCC from space.
Non-feature-specific elevated responses and feature-specific backward replay in human brain induced by visual sequence exposure
Authors: He Tao , Gong Xizi , Wang Qian , Zhu Xinyi , Liu Yunzhe , Fang Fang
Published: September 2023

The ability of cortical circuits to adapt in response to experience is a fundamental property of the brain. After exposure to a moving dot sequence, flashing a dot as a cue at the starting point of the sequence can elicit successive elevated responses even in the absence of the sequence. These cue-triggered elevated responses have been shown to play a crucial role in predicting future events in dynamic environments. However, temporal sequences we are exposed typically contain rich feature information. It remains unknown whether the elevated responses are feature specific and, more crucially, how the brain organizes sequence information after exposure. To address these questions, participants were exposed to a predefined sequence of four motion directions for about 30 min, followed by the presentation of the start or end motion direction of the sequence as a cue. Surprisingly, we found that cue-triggered elevated responses were not specific to any motion direction. Interestingly, motion direction information was spontaneously reactivated, and the motion sequence was backward replayed in a time-compressed manner. These effects were observed even after brief exposure. Notably, no replay events were observed when the second or third motion direction of the sequence served as a cue. Further analyses revealed that activity in the medial temporal lobe (MTL) preceded the ripple power increase in visual cortex at the onset of replay, implying a coordinated relationship between the activities in the MTL and visual cortex. Together, these findings demonstrate that visual sequence exposure induces two-fold brain plasticity that may simultaneously serve for different functional purposes. The non-feature-specific elevated responses may facilitate general processing of upcoming stimuli, whereas the feature-specific backward replay may underpin passive learning of visual sequence.
WITHDRAWN: How antimicrobial heteroresistance promotes bacterial adaptation to antimicrobial therapy – or not
Authors: Liao Junqi , Nyhoegen Christin , Uecker Hildegard , Schulenburg Hinrich
Published: September 2023

Withdrawal Statement

The authors have withdrawn their manuscript owing to inconsistencies of results during a re-assessment of the experimental work, which now question main conclusions drawn and which require additional experiments. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author
Clonal stochasticity in early NK cell response to mouse cytomegalovirus is generated by mature subsets of varying proliferative ability
Authors: Wethington Darren , Ahmad Saeed , Potempa Marc , Giuliani Giuseppe , Aguilar Oscar A. , Poudel Maheshwor , Grassmann Simon , Stewart William , Adams Nicholas M. , Sun Joseph C. , Lanier Lewis L. , Das Jayajit
Published: September 2023

Natural killer (NK) cells are classically defined as innate immune cells, but experiments show that mouse cytomegalovirus (MCMV) infection in C57BL/6 mice can cause NK cells to undergo antigen-specific proliferation and memory formation, similar to adaptive CD8+ T cells. One shared behavior between CD8+ T cells and NK cells is clonal expansion, where a single stimulated cell proliferates rapidly to form a diverse population of cells. For example, clones derived from single cells are most abundant during expansion when they are primarily CD27- for NK cells and CD62L- for T cells, phenotypes derived from precursor CD27+ and CD62L+ cells, respectively. Here we determined the mechanistic rules involving proliferation, cell death, and differentiation of endogenous and adoptively transferred NK cells in the expansion phase of the response to MCMV infection. We found that the interplay between cell proliferation and cell death of mature CD27- NK cells and a highly proliferative CD27-Ly6C- mature subtype and intrinsic stochastic fluctuations in these processes play key roles in regulating the heterogeneity and population of the NK cell subtypes. Furthermore, we estimate rates for maturation of endogenous NK cells in homeostasis and in MCMV infection and found that only NK cell growth rates, and not differentiation rates, are appreciably increased by MCMV. Taken together, these results quantify the differences between the kinetics of NK cell antigen-specific expansion from that of CD8+ T cells and unique mechanisms that give rise to the observed heterogeneity in NK cell clones generated from single NK cells in the expansion phase.
Sound elicits stereotyped facial movements that provide a sensitive index of hearing abilities
Authors: Clayton Kameron K. , Stecyk Kamryn S. , Guo Anna A. , Chambers Anna R. , Chen Ke , Hancock Kenneth E. , Polley Daniel B.
Published: September 2023

Sound elicits rapid movements of muscles in the face, ears, and eyes that protect the body from injury and trigger brain-wide internal state changes. Here, we performed quantitative facial videography from mice resting atop a piezoelectric force plate and observed that broadband sounds elicit rapid, small, and highly stereotyped movements of a facial region near the vibrissae array. Facial motion energy (FME) analysis revealed sensitivity to far lower sound levels than the acoustic startle reflex and greater reliability across trials and mice than sound-evoked pupil dilations or movement of other facial and body regions. FME tracked the low-frequency envelope of sounds and could even decode speech phonemes in varying levels of background noise with high accuracy. FME growth slopes were disproportionately steep in mice with autism risk gene mutations and noise-induced sensorineural hearing loss, providing an objective behavioral measure of sensory hyper-responsivity. Increased FME after noise-induced cochlear injury was closely associated with the emergence of excess gain in later waves of the auditory brainstem response, suggesting a midbrain contribution. Deep layer auditory cortex units were entrained to spontaneous facial movements but optogenetic suppression of cortical activity facilitated – not suppressed – sound-evoked FME, suggesting the auditory cortex is a modulator rather than a mediator of sound-evoked facial movements. These findings highlight a simple involuntary behavior that is more sensitive and integrative than other auditory reflex pathways and captures higher-order changes in sound processing from mice with inherited and acquired hearing disorders.
PAN-GWES: Pangenome-spanning epistasis and co-selection analysis via de Bruijn graphs
Authors: Kuronen Juri , Horsfield Samuel , Pöntinen Anna K. , Arredondo-Alonso Sergio , Thorpe Harry , Gladstone Rebecca , Willems Rob J.L. , Bentley Stephen D. , Croucher Nicholas J , Pensar Johan , Lees John A. , Tonkin-Hill Gerry , Corander Jukka
Published: September 2023

Studies of bacterial adaptation and evolution are hampered by the difficulty of measuring traits such as virulence, drug resistance and transmissibility in large populations. In contrast, it is now feasible to obtain high-quality complete assemblies of many bacterial genomes thanks to scalable and affordable long-read sequencing technology. To exploit this opportunity we introduce a phenotype- and alignment-free method for discovering co-selected and epistatically interacting genomic variation from genome assemblies covering both core and accessory parts of genomes. Our approach uses a compact coloured de Bruijn graph to approximate the intra-genome distances between pairs of loci for a collection of bacterial genomes to account for the impacts of linkage disequilibrium (LD). We demonstrate the versatility of our approach to efficiently identify associations between loci linked with drug resistance and adaptation to the hospital niche in the major human bacterial pathogensStreptococcus pneumoniaeandEnterococcus faecalis.
Phase separation of S-RNase promotes self-incompatibility inPetunia hybrida
Authors: Tian Huayang , Zhang Hongkui , Huang Huaqiu , Zhang Yu’e , Xue Yongbiao
Published: September 2023

Self-incompatibility (SI) is an intraspecific reproductive barrier widely present in angiosperms. The SI system with the broadest occurrence in angiosperms is based on anS-RNaselinked to a cluster of multipleS-locus F-box(SLF) genes found in the Solanaceae, Plantaginaceae, Rosaceae, and Rutaceae. Recent studies reveal that non-self S-RNase is degraded by the SCFSLF-mediated ubiquitin-proteasome system in a collaborative manner inPetunia, but how self-RNase functions largely remains mysterious. Here, we show that S-RNases form S-RNase condensates (SRCs) in the self-pollen tube cytoplasm through phase separation and their disruption breaks SI in self-incompatiblePetunia hybrida.We further find that the pistil SI factors of a small asparagine-rich protein HT-B and thioredoxin h (Trxh) together with a reduced state of the pollen tube all promote the expansion of SRCs, which then sequester several actin binding proteins, including the actin polymerization factor PhABRACL, whose actin polymerization activity is reduced by S-RNase in vitro. Meanwhile, we find that S-RNase variants lacking condensation ability fail to recruit PhABRACL and are unable to induce actin foci formation required for the pollen tube growth inhibition. Taken together, our results demonstrate that phase separation of S- RNase promotes SI response inP. hybrida, revealing a new mode of S-RNase action.
Disease trajectories in hospitalized COVID-19 patients are predicted by clinical and peripheral blood signatures representing distinct lung pathologies
Authors: Da Silva Filho João , Herder Vanessa , Gibbins Matthew P. , dos Reis Monique Freire , Melo Gisely Cardoso , Haley Michael J. , Judice Carla Cristina , Val Fernando Fonseca Almeida , Borba Mayla , Tavella Tatyana Almeida , de Sousa Sampaio Vanderson , Attipa Charalampos , McMonagle Fiona , de Lacerda Marcus Vinicius Guimaraes , Costa Fabio Trindade Maranhão , Couper Kevin N. , Monteiro Wuelton Marcelo , de Lima Ferreira Luiz Carlos , Moxon Christopher Alan , Palmarini Massimo , Marti Matthias
Published: September 2023

Linking clinical biomarkers and lung pathology still is necessary to understand COVID-19 pathogenesis and the basis of progression to lethal outcomes. Resolving these knowledge gaps enables optimal treatment approaches of severe COVID-19. We present an integrated analysis of longitudinal clinical parameters, blood biomarkers and lung pathology in COVID-19 patients from the Brazilian Amazon. We identified core signatures differentiating severe recovered patients and fatal cases with distinct disease trajectories. Progression to early death was characterized by rapid and intense endothelial and myeloid activation, presence of thrombi, mostly driven by SARS-CoV-2+macrophages. Progression to late death was associated with systemic cytotoxicity, interferon and Th17 signatures and fibrosis, apoptosis, and abundant SARS-CoV-2+epithelial cells in the lung. Progression to recovery was associated with pro-lymphogenic and Th2-mediated responses. Integration of ante-mortem clinical and blood biomarkers with post-mortem lung-specific signatures defined predictors of disease progression, identifying potential targets for more precise and effective treatments.
How immunity shapes the long-term dynamics of seasonal influenza
Authors: Eales Oliver , Shearer Freya , McCaw James
Published: September 2023

Since its emergence in 1968, influenza A H3N2 has caused yearly epidemics in temperate regions. While infection confers immunity against antigenically similar strains, new antigenically distinct strains that evade existing immunity regularly emerge (‘antigenic drift’). Immunity at the individual level is complex, depending on an individual’s lifetime infection history. An individual’s first infection with influenza typically elicits the greatest response with subsequent infections eliciting progressively reduced responses (‘antigenic seniority’). The combined effect of individual-level immune responses and antigenic drift on the epidemiological dynamics of influenza are not well understood. Here we develop an integrated modelling framework of influenza transmission, immunity, and antigenic drift to show how individual-level exposure, and the build-up of population level immunity, shape the long-term epidemiological dynamics of H3N2. Including antigenic seniority in the model, we observe that following an initial decline after the pandemic year, the average annual attack rate increases over the next 80 years, before reaching an equilibrium, with greater increases in older age-groups. Our analyses suggest that the average attack rate of H3N2 is still in a growth phase. Further increases, particularly in the elderly, may be expected in coming decades, driving an increase in healthcare demand due to H3N2 infections.

We anticipate our findings and methodological developments will be applicable to other antigenically variable pathogens. This includes the recent pandemic pathogens influenza A H1N1pdm09, circulating since 2009, and SARS-CoV-2, circulating since 2019. Our findings highlight that following the short-term reduction in attack rates after a pandemic, if there is any degree of antigenic seniority then a resurgence in attack rates should be expected over the longer-term. Designing and implementing studies to assess the dynamics of immunity for H1N1pdm09, SARS-CoV-2, and other antigenically variable pathogens may help anticipate any long-term rises in infection and health burden.
UK and US risk factors for hearing loss in neonatal intensive care unit infants
Authors: Thornton Sally K , Hoare Derek J , Yates Alice M , Willis Karen R , Scutt Polly , Kitterick Padraig T , Dixit Abhijit , Jayasinghe Dulip S
Published: September 2023

Importance

Early detection and intervention of hearing loss may mitigate negative effects on children’s development. Children who were admitted to the neonatal intensive care unit (NICU) as babies are particularly susceptible to hearing loss and risk factors are vital for surveillance.

Design, Setting and Participants

This single-centre retrospective cohort study included data from 142 inborn infants who had been admitted to the NICU in a tertiary regional referral centre. Data were recorded for 71 infants with confirmed permanent congenital hearing loss hearing loss. To determine impact of NICU admission independently of prematurity babies were individually matched with 71 inborn infants on gestational age, birthweight, and sex.

Main Outcomes and Measures

Neonatal indicators were recorded for all children with permanent congenital hearing loss. Presence of UK and US risk factors for hearing loss were collected on the neonatal population with hearing loss and for the matched controls.

Results

A fifth (21%) of babies with hearing loss had one or more UK risk factors whereas most (86%) had at least one US risk factor. False positives would be evident if US factors were used whereas the matched controls had no UK risk factors. Ten babies who at birth had no UK or US risk factors did not have any significant neonatal indicators identified in their records, one was ventilated for one day and two had a genetic anomaly.

Conclusions and Relevance

Current risk factors for hearing loss we identified for follow-up in this high-risk group are highly specific for congenital hearing loss. UK risk factors were highly specific for hearing loss but not sensitive and conversely, US risk factors are sensitive but not specific so false positives would be recorded. A national study of neonatal indicators could provide the utility to test which combinations of risk factors provide high sensitivity without losing specificity.

Key points

Current risk factors listed in UK guidance were highly specific for congenital hearing loss but not sensitive meaning cases would be missed. US risk factors were more sensitive for hearing loss but not very specific indicating false positives would be made in this population.

Neonates with hearing loss who wouldnothave been identified solely according to US or UK risk factors were born close to term and had few neonatal indicators identified.
Inhibition of Replication Origins and ATR Synergistically Activates the Innate Immune System in Cancer Cells
Authors: Doberstein Kai , Panther Johannes , Berlit Sebastian , Tuschy Benjamin , Sütterlin Marc , Marmé Frederik
Published: September 2023

Sufficient numbers of activated replication origins are essential for successful DNA replication. While normal cells load replication origins in abundance to the genome, cancer cells often load fewer origins of replication due to genomic alterations such asCCNE1amplifications.

Here we exploit this feature to sensitize cancer cells to ATR inhibition.

We show by using siRNA and small molecules that the inhibition of origin activation as well as the reduction of replication origins itself sensitizes ovarian cancer cell lines against ATR inhibition by inducing genomic instability. We further show that in ovarian cancer cells this combinatorial approach leads to an increased genomic instability which manifests in an increase of micronuclei that consequently activate the innate immune system through the cGAS-STING pathway. Notably, no activation of the innate immune system was observed in immortalized fallopian tube cells. However, overexpression of Cyclin E1 in this model leads to a marked increase in genomic instability and innate immune activation.

Here we provide preclinical evidence to increase the therapeutic efficacy of ATR inhibitors. Additionally, this approach could help to activate innate immunity and increase T-cell immune infiltration in tumors, providing a rationale for a combination with immune checkpoint inhibitors.
“Surviving and Thriving”: Evidence for Cortical GABA Stabilization in Cognitively-Intact Oldest-Old Adults
Authors: Britton MK , Jensen G , Edden RA , Puts NA , Nolin SA , Merritt SS , Rezaei RF , Forbes M , Johnson KJ , Bharadwaj PK , Franchetti MK , Raichlen DA , Jessup CJ , Hishaw GA , Van Etten EJ , Gudmundson AT , Murali-Manohar S , Cowart H , Trouard TP , Geldmacher DS , Wadley VG , Alperin N , Levin BE , Rundek T , Visscher KM , Woods AJ , Alexander GE , Cohen RA , Porges EC
Published: September 2023

Cortical GABA levels are reduced in older age; age-related differences in GABA may be associated with age-related cognitive change. The nature of age-related GABA differences in the highest-functioning stratum of the oldest-old (85+) population is not yet known. We extend our previously-reported Individual Participant Data Meta-Analysis of GABA levels (Porges et al., 2021) across the lifespan with four novel datasets sampling the cognitively-intact oldest-old. The slope of age-related GABA differences in cognitively-intact oldest-old adults flattens after roughly age 80. We interpret these findings as an effect of survivorship: inclusion in the study required intact cognition, and too great a reduction of GABA levels may not be compatible with neurophysiological function needed for intact cognition. This work contributes to a growing body of evidence suggesting that successful cognitive aging may require intact GABAergic function, as well as further characterizing successful aging amongst oldest-old adults.