bluuebunny/crossref_metadata_2025 huggingface dataset:
Brain oscillatory processes related to sequence memory in healthy older adults
Authors: Ehrhardt Nina M. , Flöel Agnes , Li Shu-Chen , Lucchese Guglielmo , Antonenko Daria
Published: September 2023

Sequence memory is subject to age-related decline, but the underlying processes are not yet fully understood. We analyzed electroencephalography (EEG) in 21 healthy older (60-80 years) and 26 young participants (20-30 years) and compared time-frequency spectra and theta-gamma phase-amplitude-coupling (PAC) during encoding of the order of visually presented items. In older adults, desynchronization in theta (4-8 Hz) and synchronization in gamma (30-45 Hz) power did not distinguish between subsequently correctly and incorrectly remembered trials, while there was a subsequent memory effect for young adults. Theta-gamma PAC was modulated by item position within a sequence for older but not young adults. Specifically, position within a sequence was coded by higher gamma amplitude for successive theta phases for later correctly remembered trials. Thus, deficient differentiation in theta desynchronization and gamma oscillations during sequence encoding in older adults may reflect neurophysiological correlates of age-related memory decline. Furthermore, our results indicate that sequences are coded by theta-gamma PAC in older adults, but that this mechanism might lose precision in aging.
Brain Glutathione and GABA+ levels in autistic children
Authors: Song Yulu , Hupfeld Kathleen E. , Davies-Jenkins Christopher W. , Zöllner Helge J. , Murali-Manohar Saipavitra , Abdul-Nashirudeen Mumuni , Crocetti Deana , Yedavalli Vivek , Oeltzschner Georg , Alessi Natalie , Batschelett Mitchell A. , Puts Nicolaas A.J. , Mostofsky Stewart H. , Edden Richard A.E.
Published: September 2023

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by social communication challenges and repetitive behaviors. Altered neurometabolite levels, including glutathione (GSH) and gamma-aminobutyric acid (GABA), have been proposed as potential contributors to the biology underlying ASD. This study investigated whether cerebral GSH or GABA levels differ between a large cohort of children aged 8-12 years with ASD (n=52) and typically developing children (TDC, n=49). A comprehensive analysis of GSH and GABA levels in multiple brain regions, including the primary motor cortex (SM1), thalamus (Thal), medial prefrontal cortex (mPFC), and supplementary motor area (SMA), was conducted using single-voxel HERMES MR spectroscopy at 3T. The results revealed no significant differences in cerebral GSH or GABA levels between the ASD and TDC groups across all examined regions. These findings suggest that the concentrations of GSH (an important antioxidant and neuromodulator) and GABA (a major inhibitory neurotransmitter) do not exhibit marked alterations in children with ASD compared to TDC. A statistically significant positive correlation was observed between GABA levels in the SM1 and Thal regions with ADHD inattention scores. No significant correlation was found between metabolite levels and hyper/impulsive scores of ADHD, measures of core ASD symptoms (ADOS-2, SRS-P) or adaptive behavior (ABAS-2). While both GSH and GABA have been implicated in various neurological disorders, the current study provides valuable insights into the specific context of ASD and highlights the need for further research to explore other neurochemical alterations that may contribute to the pathophysiology of this complex disorder.

Lay summary

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by social communication challenges and repetitive behaviors. Altered glutathione (GSH, an important antioxidant and neuromodulator) and gamma-aminobutyric acid (GABA, a major inhibitory neurotransmitter) levels have been proposed as potential contributors to the biology underlying ASD. Here, we used advanced edited Magnetic Resonance Spectroscopy (MRS) to measure levels of these low-concentration metabolites in four brain regions of a pediatric cohort. Contrary to our hypothesis, no significant difference was found between ASD and control subjects in either GSH or GABA levels in any brain region.
The spread ofAedes albopictusin the islands of São Tomé and Príncipe
Authors: Rader Jonathan A. , Serrato-Capuchina Antonio , Anspach Tayte , Matute Daniel R.
Published: September 2023

The mosquitoAedes albopictusis a vector species of Dengue, yellow fever, and Zika among other diseases. The species originated in Southeast Asia and has spread widely and rapidly in the last century. The species has been reported in localities from the Gulf of Guinea since the early 2000s, but systematic sampling has been scant. We sampledAe. albopictusbetween 2013 and 2023 across the altitudinal gradient in São Tomé and found that the species was present in all sampled years at altitudes up to 680 meters. We also find some evidence of increases in proportional representation compared toAe. aegyptiover time. We report the presence of the species in Príncipe for the first time, suggesting that the range ofAe. albopictusis larger than previously thought. Finally, we use bioclimatic niche modeling to infer the potential range ofAe. albopictusand infer that the species has the potential to spread across a large portion of São Tomé and Príncipe. Our results suggest thatAe. albopictushas established itself as a resident species of the islands of the Gulf of Guinea and should be incorporated into the list of potential vectors that need to be surveyed and controlled.
CO2Response Screen in GrassBrachypodiumReveals Key Role of a MAP-Kinase in CO2-Triggered Stomatal Closure
Authors: Lopez Bryn N. K. , Ceciliato Paulo H. O. , Rangel Felipe J. , Salem Evana A. , Kernig Klara , Takahashi Yohei , Chow Kelly , Zhang Li , Sidhom Morgana A. , Seitz Christian G. , Sibout Richard , Laudencia-Chingcuanco Debbie L. , Woods Daniel P. , McCammon J. Andrew , Vogel John P. , Schroeder Julian I.
Published: September 2023

Plants respond to increased CO2concentrations through rapid stomatal closure which can contribute to increased water use efficiency. Grasses display faster stomatal responses than eudicots due to dumbbell-shaped guard cells flanked by subsidiary cells working in opposition. However, forward genetic screening for stomatal CO2signal transduction mutants in grasses has not been reported. The grass modelBrachypodium distachyonis closely related to agronomically important cereal crops, sharing largely collinear genomes. To gain insights into CO2control mechanisms of stomatal movements in grasses, we developed a forward genetics screen with an EMS-mutagenizedBrachypodium distachyonM5 generation population using infrared imaging to identify plants with altered canopy leaf temperature at elevated CO2. Among isolated mutants, a “chill1” mutant exhibited cooler leaf temperatures than wildtype Bd21-3 parent control plants after exposure to increased [CO2].chill1plants showed strongly impaired high CO2-induced stomatal closure, despite retaining a robust abscisic acid-induced stomatal closing response. Through bulked segregant whole-genome-sequencing analyses followed by analyses of further backcrossed F4 generation plants and generation and characterization of CRISPR-cas9 mutants,chill1was mapped to a protein kinase,BdMPK5. Thechill1mutation impaired BdMPK5 protein-mediated CO2/HCO3-sensingin vitro. Furthermore, AlphaFold2-directed structural modeling suggests that the identified BdMPK5-D90Nchill1mutant residue is located at the interface with the HT1 Raf-like kinase. BdMPK5 is a key signaling component involved in CO2-induced stomatal movements, potentially functioning as a component of the CO2sensor in grasses.
Autosomal suppression of sex-ratio meiotic drive influences the dynamics of X and Y chromosome coevolution
Authors: Gupta Anjali , Unckless Robert L.
Published: September 2023

Sex-ratio meiotic drivers are selfish genes or gene complexes that bias the transmission of sex chromosomes resulting in skewed sex ratios. Existing theoretical models have suggested the maintenance of a four-chromosome equilibrium (with driving and standard X and suppressing and susceptible Y) in a cyclic dynamic, studies of natural populations have failed to capture this pattern. Although there are several plausible explanations for this lack of cycling, interference from autosomal suppressors has not been studied using a theoretical population genetic framework even though autosomal suppressors and Y-linked suppressors coexist in natural populations of some species. In this study, we use a simulation-based approach to investigate the influence of autosomal suppressors on the cycling of sex chromosomes. Our findings demonstrate that the presence of an autosomal suppressor can hinder the invasion of a Y-linked suppressor under some parameter space, thereby impeding the cyclic dynamics, or even the invasion of Y-linked suppression. Even when a Y-linked suppressor invades, the presence of an autosomal suppressor can prevent cycling. Our study demonstrates the potential role of autosomal suppressors in preventing sex chromosome cycling and provides insights into the conditions and consequences of maintaining both Y-linked and autosomal suppressors.
B-cell specific expression of the murineMyd88L252Pmutation correlates with the establishment of an immunosuppressive microenvironnement in Waldenström macroglobulinemia lymphoplasmacytic lymphoma
Authors: Lemasson Quentin , Téteau Ophélie , Chabaud Mina , Jeanson Laurie , Feuillard Jean , Vincent-Fabert Christelle
Published: September 2023

Waldenström macroglobulinemia is a rare and indolent lymphoproliferative disorder genetically characterized by the presence of the L265P mutation in theMYD88gene in nearly each case. Despite its slow progression, Waldenström macroglobulinemia remain incurable due to the lack of specific treatments. The importance of the tumour microenvironment was well documented since the last decade especially concerning the study of solid tumours, but the failures of the immune microenvironment are also experiencing growing interest for B cell lymphomas. In this study, we investigated the implication of some dysregulations of the immune microenvironment in Waldenström macroglobulinemia through ourMyd88L252Pmutated transgenic model, which may explain its progression. In essence, we highlighted the existence of multiple immune escape mechanisms that lead to T-cell exhaustion and participate to Waldenström disease progression. This work in animals opens up new prospects for the development of new therapeutic combinations in WM targeting reactivation of the immune system.
INAEME: Integral Neoantigen Analysis with Entirety of Mutational Events
Authors: Kovacevic Vladimir , Milicevic Ognjen S. , Ilic Raicevic Nevena M. , Kojicic Milica , Mijalkovic Lazic Ana , Skundric Nikola , DiGiovanna Jack
Published: September 2023

Neoantigens are peptides on the surface of cancer cells presented to the immune system. Multiple novel therapeutic approaches involve the administration of neoantigens to trigger immunity-induced tumor regression. Identification of neoantigens includes a personalized approach consisting of detailed analyses of the sequenced tumor tissue and its comparison with wild type to identify somatic mutations. Alternated peptides are translated from nucleotides around somatic mutations and their binding affinity and immunogenicity need to be further evaluated. Still, the entire bioinformatics analysis is very complex, and accurate prediction of the neoantigen candidates represents a true challenge. Here, we present the novel, integral bioinformatic analysis workflow for neoantigen discovery, denoted INAEME (Integral Neoantigen Analysis with Entirety of Mutational Events). The workflow performs integral processing of an individual’s DNA tumor-normal and RNA tumor raw reads to output prioritized neoantigen candidates. Our evaluation analysis includes a wide scope of mutational events so far not considered in the existing solutions, including phasing of variants, influence of both somatic and germline variants, positions of all transcripts, neighboring variants, and frameshifts. The influence of each mutational event on the accuracy of predicted neoantigen candidates is tested across 300 TCGA samples from multiple cancer types. The obtained results have demonstrated the significance of considering the entirety of mutational events to obtain an accurate set of strong neoantigen candidates for cancer immunotherapy targets or vaccines. The adaption of the described methods in the bioinformatics analysis minimizes the existence of false positives which are only later discovered in a laboratory environment using expensive methods such as mass spectrometry or microscopy.
Thermal suppression of gametogenesis can explain historical collapses in larval recruitment
Authors: Okamoto Daniel K. , Spindel Nathan B. , Mustermann Maya J. , Karelitz Sam , Collicutt Brenna , Gimenez Iria , Rolheiser Kate , Cronmiller Evan , Foss Megan , Mahara Natalie , Swezey Dan , Ferraro Rachele , Rogers-Bennett Laura , Schroeter Stephen
Published: September 2023

Projections for population viability under climate change are often made using estimates of thermal lethal thresholds. These estimates vary across life history stages and can be valuable for explaining or forecasting shifts in population viability. However, sublethal temperatures can also depress vital rates and shape fluctuations in the reproductive viability of populations. For example, heatwaves may suppress reproduction, leading to recruitment failure before lethal temperatures are reached. Despite a growing awareness of this issue, tying sublethal effects to observed recruitment failure remains a challenge especially in marine environments. We experimentally show that sublethal suppression of female gametogenesis by marine heatwaves can partially explain historical collapses in urchin recruitment. These responses differ by sex but are similar between animals from warmer or cooler regions of their range. Overall, we show sublethal thermal sensitivities of reproduction can narrow the thermal envelope for population viability compared to predictions from lethal limits.
WITHDRAWN: HER2 Cellular Localization, Cell-Cell Contacts, and Cell Density Regulate Cancer Cell Plasticity in HER2+ Breast Cancer
Authors: Sameri Saba , Das Durdam , Shahrivari Shabnam , Milosevic Vladan , Sarhadi Shamim , Koerkel-Qu Huiqin , Fisch Carolina , Kokal Miriam , Schletter Michael , Hahn Paul S. , Seider Lisa , Schübel Marisa , Michaelis Stefanie , Wegener Joachim , Weber Florian , Hoffmann Martin , Werno Christian , Weidele Kathrin , Bruckmann Astrid , Östman Arne , Tamm Ernst R. , Li Yuting , Klein Christoph A. , Hosseini Hedayatollah
Published: September 2023

Withdrawal statement

The authors have withdrawn this manuscript due to a conflict of interest among the authors. 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.
Single-cell transcription mapping of murine and human mammary organoids responses to female hormones
Authors: Ortiz Jenelys Ruiz , Lewis Steven M. , Ciccone Michael F. , Chatterjee Deeptiman , Henry Samantha , Siepel Adam , dos Santos Camila O.
Published: September 2023

During female adolescence and pregnancy, rising levels of hormones result in a cyclic source of signals that control the development of mammary tissue. While such alterations are well understood from a whole-gland perspective, the alterations that such hormones bring to organoid cultures derived from mammary glands have yet to be fully mapped. This is of special importance given that organoids are considered suitable systems to understand cross species breast development. Here we utilized single-cell transcriptional profiling to delineate responses of murine and human normal breast organoid systems to female hormones across evolutionary distinct species. Collectively, our study represents a molecular atlas of epithelial dynamics in response to estrogen and pregnancy hormones.
The delayed kinetics of Myddosome formation explains why Aβ aggregates trigger TLR4 less efficiently than LPS
Authors: Li Bing , Suresh Prasanna , Brelstaff Jack , Kedia Shekhar , Bryant Clare , Klenerman David
Published: September 2023

The Myddosome is a key innate immune signalling platform. It forms at the cell surface and contains MyD88 and IRAK proteins which ultimately coordinate the production of pro-inflammatory cytokines. Toll-like receptor 4 signals via the Myddosome when triggered by Lipopolysaccharide (LPS) or Amyloid-Beta (Aβ) aggregates but the magnitude and time duration of the response are very different for reasons that are unclear. Here we followed the formation of Myddosomes in live macrophages using local delivery of TLR4 agonist to the cell surface and visualisation with 3D rapid light sheet imaging. This was complemented by super-resolution imaging of Myddosomes in fixed macrophages to determine the size of the signalling complex at different times after triggering. Myddosomes formed more rapidly after LPS than in response to sonicated Aβ 1-42 fibrils (80 seconds vs 372 seconds). The mean lifetimes of the Myddosomes was also shorter when triggered by LPS compared to sonicated Aβ fibrils (170 and 220 s) respectively. In both cases a range of Myddosome of different sizes (50-500 nm) were formed. In particular, small round Myddosomes around 100 nm in size formed at early time points, then reduced in proportion over time. Collectively our data suggests that compared to LPS the multivalency of Aβ fibrils leads to the formation of larger Myddosomes which form more slowly and, due to their size, take longer to disassemble. This explains why sonicated Aβ fibrils results in less efficient triggering of TLR4 signalling and may be a general property of protein aggregates.
Improvisation and Live Accompaniment Increase Motor Response and Reward During a Music Playing Task
Authors: Palumbo Anna , Groves Karleigh , Muñoz Vidal Eva Luna , Turry Alan , Codio Robert , Raghavan Preeti , Schambra Heidi , Voelbel Gerald T. , Ripollés Pablo
Published: September 2023

Music provides an abstract reward that can enhance learning and motivation in humans. While music is often combined with exercise to improve performance and to upregulate mood, the relationship between music-induced reward and motor output is poorly understood. Here, we study music reward and motor output at the same time by capitalizing on music playing. Specifically, we investigate the effects of music improvisation and live accompaniment on motor, autonomic, and affective responses. Thirty adults performed a rhythm tapping task while (i) improvising or maintaining the beat and (ii) with live or recorded accompaniment. Motor response was characterized by acceleration of hand movements (accelerometry), wrist flexor and extensor muscle activation (electromyography), and the number of beats played. Autonomic arousal was measured by tonic response of electrodermal activity (EDA) and heart rate (HR). Affective responses were measured by a 12-item Likert scale. The combination of improvisation and live accompaniment, as compared to all other conditions, significantly increased acceleration of hand movements and muscle activation, as well as participant reports of enjoyment during music-playing. Improvisation, regardless of type of accompaniment, increased the number of beats played and autonomic arousal (including tonic EDA responses and several measures of HR), as well as participant reports of challenge. Importantly, increased motor response was associated with increased enjoyment during music improvisation only and not while participants were maintaining the beat. The increased motor responses achieved with improvisation and live accompaniment have important implications for enhancing dose of movement during music-based interventions for stroke rehabilitation.

Significance Statement

Music provides a rewarding stimulus and improves motor performance and learning. However, the relationship between music reward and motor output is poorly understood. Here, we show that music improvisation with live accompaniment increased acceleration and muscle activation during movement, and that this increase in motor response was associated with increased enjoyment only when improvising. These findings are important for developing music interventions that target improved motor performance and learning in exercise and physical rehabilitation.
Decoding of columnar-level organization across cortical depth using BOLD- and CBV-fMRI at 7 T
Authors: Haenelt Daniel , Chaimow Denis , Nasr Shahin , Weiskopf Nikolaus , Trampel Robert
Published: September 2023

Multivariate pattern analysis (MVPA) methods are a versatile tool to retrieve information from neurophysiological data obtained with functional magnetic resonance imaging (fMRI) techniques. Since fMRI is based on measuring the hemodynamic response following neural activation, the spatial specificity of the fMRI signal is inherently limited by contributions of macrovascular compartments that drain the signal from the actual location of neural activation, making it challenging to image cortical structures at the spatial scale of cortical columns and layers. By relying on information from multiple voxels, MVPA has shown promising results in retrieving information encoded in fine-grained spatial patterns. We examined the spatial specificity of the signal exploited by MVPA. Over multiple sessions, we measured ocular dominance columns (ODCs) in human primary visual cortex (V1) with different acquisition techniques at 7 T. For measurements with blood oxygenation level dependent contrast (BOLD), we included both gradient echo- (GE-BOLD) and spin echo-based (SE-BOLD) sequences. Furthermore, we acquired data using the vascular-space-occupancy (VASO) fMRI technique, which is sensitive to cerebral blood volume (CBV) changes. We used the data to decode the eye-of-origin across cortical depth. While ocularity information can be decoded with all imaging techniques, the macrovascular contributions in GE- and SE-BOLD limit their use for discriminating signals between cortical layers. However, the cortical profile of decoded ocularity information from VASO measurements better reflects the expected profile of neural activity, suggesting the combination of VASO and MVPA to be a promising approach for investigating the mesoscopic circuitry of the human cerebral cortex.
HI-FISH: WHOLE BRAIN IN SITU MAPPING OF NEURONAL ACTIVATION IN DROSOPHILA DURING SOCIAL BEHAVIORS AND OPTOGENETIC STIMULATION
Authors: Watanabe Kiichi , Chiu Hui , Anderson David J.
Published: September 2023

Monitoring neuronal activity at single-cell resolution in freely movingDrosophilaengaged in social behaviors is challenging because of their small size and lack of transparency. Extant methods, such as Flyception, are highly invasive. Whole-brain calcium imaging in head-fixed, walking flies is feasible but the animals cannot perform the consummatory phases of social behaviors like aggression or mating under these conditions. This has left open the fundamental question of whether neurons identified as functionally important for such behaviors using loss- or gain-of-function screens are actually active during the natural performance of such behaviors, and if so during which phase(s). Here we perform brain-wide mapping of active cells expressing the Immediate Early Genehr38using a high-sensitivity/low background FISH amplification method called HCR-3.0. Using double-labeling for hr38 mRNA and for GFP, we describe the activity of several classes of aggression-promoting neurons during courtship and aggression, including P1acells, an intensively studied population of male-specific interneurons. Using HI-FISH in combination with optogenetic activation of aggression-promoting neurons (opto-HI-FISH) we identify candidate downstream functional targets of these cells in a brain-wide, unbiased manner. Finally we compare the activity of P1aneurons during sequential performance of courtship and aggression, using intronic vs. exonichr38probes to differentiate newly synthesized nuclear transcripts from cytoplasmic transcripts synthesized at an earlier time. These data provide evidence suggesting that different subsets of P1aneurons may be active during courtship vs. aggression. HI-FISH and associated methods may help to fill an important lacuna in the armamentarium of tools for neural circuit analysis inDrosophila.
Heat Shock Factor 1 forms nuclear condensates and restructures the yeast genome before activating target genes
Authors: Rubio Linda S. , Mohajan Suman , Gross David S.
Published: September 2023

In insects and mammals, 3D genome topology has been linked to transcriptional states yet whether this link holds for other eukaryotes is unclear. Using both ligation proximity and fluorescence microscopy assays, we show that inSaccharomyces cerevisiae,Heat Shock Response(HSR) genes dispersed across multiple chromosomes and under the control of Heat Shock Factor (Hsf1) rapidly reposition in cells exposed to acute ethanol stress and engage in concerted, Hsf1-dependent intergenic interactions. Accompanying 3D genome reconfiguration is equally rapid formation of Hsf1-containing condensates. However, in contrast to the transience of Hsf1-driven intergenic interactions that peak within 10-20 min and dissipate within 1 h in the presence of 8.5% (v/v) ethanol, transcriptional condensates are stably maintained for hours. Moreover, under the same conditions, Pol II occupancy ofHSRgenes, chromatin remodeling, and RNA expression are detectable only later in the response and peak much later (>1 h). This contrasts with the coordinate response ofHSRgenes to thermal stress (39°C) where Pol II occupancy, transcription, histone eviction, intergenic interactions, and formation of Hsf1 condensates are all rapid yet transient (peak within 2.5-10 min and dissipate within 1 h). Therefore, Hsf1 forms condensates, restructures the genome and transcriptionally activatesHSRgenes in response to both forms of proteotoxic stress but does so with strikingly different kinetics. In cells subjected to ethanol stress, Hsf1 forms condensates and repositions target genes before transcriptionally activating them.

Graphical Abstract
Widespread human exposure to ledanteviruses in Uganda – a population study
Authors: Shepherd James G. , Ashraf Shirin , Salazar-Gonzalez Jesus F. , Salazar Maria G. , Downing Robert , Bukenya Henry , Jerome Hanna , Mpanga Joseph T. , Davis Chris , Tong Lily , Sreenu Vattipally B. , Atiku Linda A. , Logan Nicola , Kajik Ezekiel , Mukobi Yafesi , Mungujakisa Cyrus , Olowo Michael V. , Tibo Emmanuel , Wunna Fred , Ireland Hollie Jackson , Blunsum Andrew E. , Owolabi Iyanuoluwani , da Silva Filipe Ana , Bwogi Josephine , Willett Brian J. , Lutwama Julius J. , Streicker Daniel G. , Kaleebu Pontiano , Thomson Emma C.
Published: October 2023

Le Dantec virus (LDV), type species of the genusLedanteviruswithin theRhabdoviridaehas been associated with human disease but has gone undetected since the 1970s. We describe the detection of LDV in a human case of undifferentiated fever in Uganda by metagenomic sequencing and demonstrate a serological response using ELISA and pseudotype neutralisation. By screening a cohort of 997 individuals sampled in 2016, we show frequent exposure to ledanteviruses with 76% of individuals seropositive in Western Uganda, but lower seroprevalence in other areas. Serological cross-reactivity as measured by pseudotype-based neutralisation was confined toLedantevirus,indicating population seropositivity may represent either exposure to LDV or related ledanteviruses. We also describe the discovery of a closely related ledantevirus, Odro virus, in the synanthropic rodentMastomys erythroleucus.Ledantevirusinfection is common in Uganda but is geographically heterogenous. Further surveys of patients presenting with acute fever are required to determine the contribution of these emerging viruses to febrile illness in Uganda.
Protection of second booster vaccinations and prior infection against SARS-CoV-2 in the UK SIREN healthcare worker cohort
Authors: Kirwan Peter D , Hall Victoria , Foulkes Sarah , Otter Ashley , Munro Katie , Sparkes Dominic , Howells Anna , Platt Naomi , Broad Jonathan , Crossman David , Norman Chris , Corrigan Diane , Jackson Christopher H , Cole Michelle , Brown Colin S , Atti Ana , Islam Jasmin ,   SIREN Study Group, Presanis Anne M , Charlett Andre , De Angelis Daniela , Hopkins Susan
Published: October 2023

Background

The protection of fourth dose mRNA vaccination against SARS-CoV-2 is relevant to current global policy decisions regarding ongoing booster roll-out. We estimate the effect of fourth dose vaccination, prior infection, and duration of PCR positivity in a highly-vaccinated and largely prior-COVID-19 infected cohort of UK healthcare workers.

Methods

Participants underwent fortnightly PCR and regular antibody testing for SARS-CoV-2 and completed symptoms questionnaires. A multi-state model was used to estimate vaccine effectiveness (VE) against infection from a fourth dose compared to a waned third dose, with protection from prior infection and duration of PCR positivity jointly estimated.

Results

1,298 infections were detected among 9,560 individuals under active follow-up between September 2022 and March 2023. Compared to a waned third dose, fourth dose VE was 13.1% (95%CI 0.9 to 23.8) overall; 24.0% (95%CI 8.5 to 36.8) in the first two months post-vaccination, reducing to 10.3% (95%CI - 11.4 to 27.8) and 1.7% (95%CI -17.0 to 17.4) at 2-4 and 4-6 months, respectively. Relative to an infection >2 years ago and controlling for vaccination, 63.6% (95%CI 46.9 to 75.0) and 29.1% (95%CI 3.8 to 43.1) greater protection against infection was estimated for an infection within the past 0-6, and 6-12 months, respectively. A fourth dose was associated with greater protection against asymptomatic infection than symptomatic infection, whilst prior infection independently provided more protection against symptomatic infection, particularly if the infection had occurred within the previous 6 months. Duration of PCR positivity was significantly lower for asymptomatic compared to symptomatic infection.

Conclusions

Despite rapid waning of protection, vaccine boosters remain an important tool in responding to the dynamic COVID-19 landscape; boosting population immunity in advance of periods of anticipated pressure, such as surging infection rates or emerging variants of concern.

Funding

UK Health Security Agency, Medical Research Council, NIHR HPRU Oxford, and others.
Association Between Psychiatric Polygenic Scores, Healthcare Utilization and Comorbidity Burden
Authors: Kirchner H. Lester , Rocha Daniel , Linner Richard K , Wilimitis Drew , Walsh Colin G , Ripperger Michael , Lee Hyunjoon , Liu Zhaowen , Davis Lea , Hu Yirui , Chabris Christopher F , Smoller Jordan W
Published: September 2023

Purpose

To estimate the association of psychiatric polygenic scores with healthcare utilization and comorbidity burden.

Methods

Observational cohort study (N = 118,882) of adolescent and adult biobank participants with linked electronic health records (EHRs) from three diverse study sites; (Massachusetts General Brigham, Vanderbilt University Medical Center, Geisinger). Polygenic scores (PGS) were derived from the largest available GWAS of major depressive depression, bipolar disorder, and schizophrenia at the time of analysis. Negative binomial regression models were used to estimate the association between each psychiatric PGS and healthcare utilization and comorbidity burden. Healthcare utilization was measured as frequency of emergency department (ED), inpatient (IP), and outpatient (OP) visits. Comorbidity burden was defined by the Elixhauser Comorbidity Index and the Charlson Comorbidity Index.

Results

Participants had a median follow-up duration of 12 years in the EHR. Individuals in the top decile of polygenic score for major depressive disorder had significantly more ED visits (RR=1.22, 95% CI; 1.17, 1.29) compared to those the lowest decile. Increases were also observed with IP and comorbidity burden. Among those diagnosed with depression and in the highest decile of the PGS, there was an increase in all utilization types (ED: RR=1.56, 95% CI 1.41, 1.72; OP: RR=1.16, 95% CI 1.08, 1.24; IP: RR=1.23, 95% CI 1.12, 1.36) post-diagnosis. No clinically significant results were observed with bipolar and schizophrenia polygenic scores.

Conclusions

Polygenic score for depression is modestly associated with increased healthcare resource utilization and comorbidity burden, in the absence of diagnosis. Following a diagnosis of depression, the PGS was associated with further increases in healthcare utilization. These findings suggest that depression genetic risk is associated with utilization and burden of chronic disease in real-world settings.
All-cause and infection-attributable mortality amongst adults with bloodstream infection – a population-based study
Authors: Underwood Jonathan , Griffiths Rowena , Gillespie David , Akbari Ashley , Ahmed Haroon
Published: September 2023

Background

Bloodstream infections (BSI), are common, life threatening infections. However, it remains unclear whether deaths following BSI are primarily due to uncontrolled infection or underlying comorbidities. We aimed to determine the overall mortality, infection-attributable mortality, and causes of death for four leading BSI pathogens.

Methods

This retrospective cohort study was conducted within the SAIL Databank, containing anonymised population-scale electronic health record data for Wales, UK. We included adults withEscherichia coli, Klebsiella sp, Pseudomonas aeruginosaandStaphylococcus aureusBSI between 2010-2022 using linked data from Public Health Wales and the Office for National Statistics. 30-day all-cause and sepsis-specific mortality, as a proxy for infection-attributable mortality, were compared using Cox proportional hazards and competing risk regression respectively.

Findings

We identified 35,691 adults with BSI.E. coliwas the most prevalent (59.6%). Adjusted analyses revealed that all organisms had a higher 30-day mortality vs.E. coliwith MRSA the highest (HR: 2.04 [1.83-2.37], p<0.001).

Cancer was the leading cause of death following BSI for all organisms, particularly deaths occurring between 30-90 days (35.9%). 25.5% of deaths within 30 days involved sepsis. MRSA was associated with the highest sepsis mortality vs.E. coli(HR: 2.45 [2.12-2.82], p<0.001). Peak CRP was positively associated with increased sepsis mortality (p<0.001).

Interpretation

This population-level study challenges the assumption that most deaths following BSI are directly attributable to uncontrolled infection. Our findings underscore the need for re-evaluating clinical trial design and developing better preventative strategies for BSI.

Funding

This work is funded by the Medical Research Council [grant number MR/T023791/1].
Interplay Of Serum Bilirubin and Tobacco Smoking with Lung and Head and Neck Cancers in a Diverse, EHR-linked Los Angeles Biobank
Authors: Venkateswaran Vidhya , Petter Ella , Boulier Kristin , Ding Yi , Bhattacharya Arjun , Pasaniuc Bogdan
Published: October 2023

Structured Abstract

Background

Bilirubin is a potent antioxidant with a protective role in many diseases. We examined the relationships between serum bilirubin (SB) levels, tobacco smoking (a known cause of low SB), and aerodigestive cancers, grouped as lung (LC) and head and neck (HNC).

Methods

We examined the associations between SB, LC and HNC using data from 393,210 participants from UCLA Health, employing regression models, propensity score matching, and polygenic scores.

Results

Current tobacco smokers showed lower SB (-0.04mg/dL, 95% CI: [-0.04, -0.03]), compared to never-smokers. Lower SB levels were observed in HNC and LC cases (-0.10 mg/dL, [-0.13, -0.09] and -0.09 mg/dL, CI [-0.1, -0.07] respectively) compared to cancer-free controls with the effect persisting after adjusting for smoking. SB levels were inversely associated with HNC and LC risk (ORs per SD change in SB: 0.64, CI [0.59,0.69] and 0.57, CI [0.43,0.75], respectively). Lastly, a polygenic score (PGS) for SB was associated with LC (OR per SD change of SB-PGS: 0.71, CI [0.67, 0.76]).

Conclusions

Low SB levels are associated with an increased risk of both HNC and LC, independent of the effect of tobacco smoking with tobacco smoking demonstrating a strong interaction with SB on LC risk. Additionally, genetically predicted low SB (from polygenic scores) is negatively associated with LC.

Impact

These findings suggest that SB could serve as a potential early biomarker for LC and HNC.
Stomata, a vulnerability in the plant defence against phytophagous mites that ABA can overcome
Authors: Rosa-Diaz Irene , Rowe James , Cayuela-Lopez Ana , Arbona Vicent , Diaz Isabel , Jones Alexander M.
Published: September 2023

Arthropod herbivory possess a significant threat to crop yield, prompting plants to employ intricate defense mechanisms against pest feeding. The generalist pest,Tetranychus urticae, inflicts rapid damage and remains a challenge due to its broad target range. In this study, we exploredArabidopsis thaliana’sresponse toT. urticaeinfestation, revealing the induction of abscisic acid (ABA), a hormone typically associated with abiotic stress adaptation, including stomatal closure during water stress. Leveraging a FRET-based ABA biosensor (nlsABACUS2-400n), we observed elevated ABA levels in various leaf cell types post-mite feeding. While ABA’s role in pest resistance or susceptibility has been debated, an ABA-deficient mutant exhibited increased mite infestation, alongside intact canonical biotic stress signalling, indicating an independent function of ABA in mite defense. Through genetic and pharmacological interventions targeting ABA levels, ABA signalling, stomatal aperture, and density, we established that ABA-triggered stomatal closure effectively hinders mite feeding and minimizes leaf cell damage. This study underscores the critical interplay between biotic and abiotic stresses in plants, highlighting how the vulnerability to mite infestation arising from open stomata, crucial for transpiration and photosynthesis, underscores the intricate relationship between these two stress types.
Optimizing data integration improves Gene Regulatory Network inference in Arabidopsis thaliana
Authors: Cassan Océane , Lecellier Charles-Henri , Martin Antoine , Bréhélin Laurent , Lèbre Sophie
Published: September 2023

Motivations

Gene Regulatory Networks (GRN) are traditionnally inferred from gene expression profiles monitoring a specific condition or treatment. In the last decade, integrative strategies have successfully emerged to guide GRN inference from gene expression with complementary prior data. However, datasets used as prior information and validation gold standards are often related and limited to a subset of genes. This lack of complete and independent evaluation calls for new criteria to robustly estimate the optimal intensity of prior data integration in the inference process.

Results

We address this issue for two common regression-based GRN inference models, an integrative Random Forest (weigthedRF) and a generalized linear model with stability selection estimated under a weighted LASSO penalty (weightedLASSO). These approaches are applied to data from the root response to nitrate induction inArabidopsis thaliana. For each gene, we measure how the integration of transcription factor binding motifs influences model prediction. We propose a new approach, DIOgene, that uses model prediction error and a simulated null hypothesis for optimizing data integration strength in a hypothesis-driven, gene-specific manner. The resulting integration scheme reveals a strong diversity of optimal integration intensities between genes. In addition, it provides a good trade-off between prediction error minimization and validation on experimental interactions, while master regulators of nitrate induction can be accurately retrieved.

Availability and implementation

The R code and notebooks demonstrating the use of the proposed approaches are available in the repositoryhttps://github.com/OceaneCsn/integrative_GRN_N_induction.
A size principle for bistability in mouse spinal motoneurons
Authors: Harris-Warrick Ronald M , Pecchi Emilie , Drouillas Benoît , Brocard Frédéric , Bos Rémi
Published: September 2023

Bistability in spinal motoneurons supports tonic spike activity in the absence of excitatory drive. Earlier work in adult preparations suggested that smaller motoneurons innervating slow antigravity muscle fibers are more likely to generate bistability for postural maintenance. However, whether large motoneurons innervating fast-fatigable muscle fibers display bistability related to postural tone is still controversial. To address this, we examined the relationship between soma size and bistability in lumbar ventrolateral α-motoneurons of ChAT-GFP and Hb9-GFP mice across different developmental stages: neonatal (P2-P7), young (P7-P14) and mature (P21-P25). We found that as neuron size increases, the prevalence of bistability rises. Smaller α-motoneurons lack bistability, while larger fast α-motoneurons (MMP-9+/Hb9+) with a soma area ≥ 400µm2exhibit significantly higher bistability. Ionic currents associated with bistability, including the persistent Nav1.6 current, thermosensitive Trpm5 Ca2+-activated Na+current and the slowly inactivating Kv1.2 current, also scale with cell size. Serotonin evokes full bistability in large motoneurons with partial bistable properties, but not in small motoneurons. Our study provides important insights into the neural mechanisms underlying bistability and how motoneuron size dictates this process.

New and Noteworthy

Bistability is not a common feature of all mouse spinal motoneurons. It is absent in small, slow motoneurons but present in most large, fast motoneurons. This difference results from differential expression of ionic currents that enable bistability, which are highly expressed in large motoneurons but small or absent in small motoneurons. These results support a possible role for fast motoneurons in maintenance of tonic posture in addition to their known roles in fast movements.
In vivodissection of the mouse tyrosine catabolic pathway with CRISPR-Cas9 identifies modifier genes affecting hereditary tyrosinemia type 1
Authors: Rivest Jean-François , Carter Sophie , Goupil Claudia , Cyr Denis , Ung Roth-Visal , Soglio Dorothée Dal , Mac-Way Fabrice , Waters Paula J. , Paganelli Massimiliano , Doyon Yannick
Published: September 2023

Hereditary tyrosinemia type 1 is an autosomal recessive disorder caused by mutations (pathogenic variants) in fumarylacetoacetate hydrolase, an enzyme involved in tyrosine degradation. Its loss results in the accumulation of toxic metabolites that mainly affect the liver and kidneys and can lead to severe liver disease and liver cancer. Tyrosinemia type 1 has a global prevalence of approximately 1 in 100,000 births but can reach up to 1 in 1,500 births in some regions of Québec, Canada. Mutating functionally related ‘modifier’ genes (i.e., genes that, when mutated, affect the phenotypic impacts of mutations in other genes) is an emerging strategy for treating human genetic diseases.In vivosomatic genome editing in animal models of these diseases is a powerful means to identify modifier genes and fuel treatment development. In this study, we demonstrate that mutating additional enzymes in the tyrosine catabolic pathway through liver-specific genome editing can relieve or worsen the phenotypic severity of a murine model of tyrosinemia type 1. Neonatal gene delivery using recombinant adeno-associated viral vectors expressingStaphylococcus aureusCas9 under the control of a liver-specific promoter led to efficient gene disruption and metabolic rewiring of the pathway, with systemic effects that were distinct from the phenotypes observed in whole-body knockout models. Our work illustrates the value of usingin vivogenome editing in model organisms to study the direct effects of combining pathological mutations with modifier gene mutations in isogenic settings.
Changes in the urinary proteome of rats after short-term intake of magnesium threonate
Authors: Shen Ziyun , Yang Minhui , Wang Haitong , Liu Yuqing , Gao Youhe
Published: September 2023

Magnesium is an important mineral in living organisms and has multiple functions in the human body, wherein it plays an important therapeutic and preventive role in a variety of diseases. In the present study, urine samples of rats before and after gavage of magnesium threonate were collected, and the urinary proteome was identified using the LC-MS/MS technique and analyzed using various databases. The results illustrated that the urinary proteome of rats was significantly altered after short-term intake of magnesium supplements and that the differential proteins and the biological functions were related to magnesium. This study innovatively establishes a method to study nutrients from the perspective of urine proteomics. This work demonstrates that the urinary proteome is capable of reflecting the effects of nutrient intake on the organism in a more systematic and comprehensive manner and has the potential to provide clues for clinical nutrition research and practice.
Resident memory T cell development is associated with AP-1 transcription factor upregulation across anatomical niches
Authors: Smith Neal P. , Yan Yu , Pan Youdong , Williams Jason B. , Manakongtreecheep Kasidet , Pant Shishir , Zhao Jingxia , Tian Tian , Pan Timothy , Stingley Claire , Wu Kevin , Zhang Jiang , Kley Alexander L. , Sorger Peter K. , Villani Alexandra-Chloé , Kupper Thomas S.
Published: October 2023

Tissue-resident memory T (TRM) cells play a central role in immune responses to pathogens across all barrier tissues after infection. However, the underlying mechanisms that drive TRMdifferentiation and priming for their recall effector function remains unclear. In this study, we leveraged both newly generated and publicly available single-cell RNA-sequencing (scRNAseq) data generated across 10 developmental time points to define features of CD8 TRMacross both skin and small-intestine intraepithelial lymphocytes (siIEL). We employed linear modeling to capture temporally-associated gene programs that increase their expression levels in T cell subsets transitioning from an effector to a memory T cell state. In addition to capturing tissue-specific gene programs, we defined a consensus TRMsignature of 60 genes across skin and siIEL that can effectively distinguish TRMfrom circulating T cell populations, providing a more specific TRMsignature than what was previously generated by comparing bulk TRMto naïve or non-tissue resident memory populations. This updated TRMsignature included the AP-1 transcription factor family membersFos, FosbandFosl2. Moreover, ATACseq analysis detected an enrichment of AP-1-specific motifs at open chromatin sites in mature TRM.CyCIFtissue imaging detected nuclear co-localization of AP-1 membersFosbandJunbin resting CD8 TRM>100 days post-infection. Taken together, these results reveal a critical role of AP-1 transcription factor members in TRMbiology and suggests a novel mechanism for rapid reactivation of resting TRMin tissue upon antigen encounter.