bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractDuring 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

AbstractThe 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

AbstractMusic 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 StatementMusic 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

AbstractMultivariate 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

AbstractMonitoring 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

AbstractIn 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

AbstractLe 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

AbstractBackgroundThe 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.MethodsParticipants 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.Results1,298 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.ConclusionsDespite 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.FundingUK 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

AbstractPurposeTo estimate the association of psychiatric polygenic scores with healthcare utilization and comorbidity burden.MethodsObservational 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.ResultsParticipants 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.ConclusionsPolygenic 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

AbstractBackgroundBloodstream 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.MethodsThis 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.FindingsWe 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).InterpretationThis 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.FundingThis 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 AbstractBackgroundBilirubin 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).MethodsWe 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.ResultsCurrent 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]).ConclusionsLow 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.ImpactThese 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

AbstractArthropod 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.