bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inference of infectious disease transmission using multiple genomes per host
Authors: Carson Jake , Keeling Matt , Wyllie David , Ribeca Paolo , Didelot Xavier 
Published: July 2023

ABSTRACTIn recent times, pathogen genome sequencing has become increasingly used to investigate infectious disease outbreaks. When genomic data is sampled densely enough amongst infected individuals, it can help resolve who infected whom. However, transmission analysis cannot rely solely on a phylogeny of the genomes but must account for the within-host evolution of the pathogen, which blurs the relationship between phylogenetic and transmission trees. When only a single genome is sampled for each host, the uncertainty about who infected whom can be quite high. Consequently, transmission analysis based on multiple genomes of the same pathogen per host has a clear potential for delivering more precise results, even though it is more laborious to achieve. Here we present a new methodology that can use any number of genomes sampled from a set of individuals to reconstruct their transmission network. We use simulated data to show that our method becomes more accurate as more genomes per host are provided, and that it can infer key infectious disease parameters such as the size of the transmission bottleneck, within-host growth rate, basic reproduction number and sampling fraction. We demonstrate the usefulness of our method in applications to real datasets from an outbreak ofPseudomonas aeruginosaamongst cystic fibrosis patients and a nosocomial outbreak ofKlebsiella pneumoniae.
Epidermal IL-33 drives inflammation in necroptosis-induced skin inflammation by recruiting TNF-producing immune cells
Authors: Fernandez-Nasarre Africa , Srivastava Vikas , Bennett Ffion , Michel Laurence , Bensussan Armand , Choy Ernest H. , Bagot Martine , Bonnet Marion C. 
Published: July 2023

AbstractCaspase-8 deficiency in the epidermis (caspase-8EKO) results in cutaneous inflammation resembling pustular psoriasis, triggered by necroptotic cell death of keratinocytes. Necroptosis is a highly proinflammatory form of programmed necrosis due to the release of intracellular molecules called alarmins, which can act as inflammatory mediators. However, their role in necroptosis-induced skin inflammation remains unexplored. Here, we demonstrate that alarmin IL-33 and its receptor ST2 are essential early mediators of necroptosis-induced skin inflammation. Genetic ablation ofIl-33orSt2dramatically delays lesion development and improves survival of caspase-8EKOanimals. IL-33 is highly expressed in necroptotic epidermis of caspase-8EKOmice and induces immune cell recruitment in the skin upon keratinocyte necroptosis. Impairment of the IL33-ST2 axis does not affect epidermal necroptosis but reduces the recruitment of TNF-producing infiltrating immune cells and subsequent amplification of cutaneous inflammation. Collectively, our findings highlight a pivotal role for IL-33 and ST2 in necroptosis-induced skin inflammation.TeaserInhibition of IL-33/ST2 axis alleviates necroptosis-induced skin inflammation by reducing TNF production in the dermis.
Rho-associated kinase regulates Langerhans cell morphology and responsiveness to tissue damage
Authors: Peterman Eric , Quitevis Elgene J.A. , Goo Camille E.A. , Rasmussen Jeffrey P. 
Published: July 2023

ABSTRACTSkin is often the first physical barrier to encounter invading pathogens and physical damage. Damage to the skin must be resolved quickly and efficiently to maintain organ homeostasis. Epidermal-resident immune cells known as Langerhans cells use dendritic protrusions to dynamically surveil the skin microenvironment, which contains epithelial keratinocytes and somatosensory peripheral axons. The mechanisms governing Langerhans cell dendrite dynamics and responses to tissue damage are not well understood. Using skin explants from adult zebrafish, we show that Langerhans cells maintain normal surveillance activity following axonal degeneration and use their dynamic dendrites to engulf small axonal debris. By contrast, a ramified-to-rounded shape transition accommodates the engulfment of larger keratinocyte debris. We find that Langerhans cell dendrites are richly populated with actin and sensitive to a broad spectrum actin inhibitor. We further show that Rho-associated kinase (ROCK) inhibition leads to elongated dendrites, perturbed clearance of large debris, and reduced Langerhans cell migration to tissue-scale wounds. Altogether, our work describes the unique dynamics of Langerhans cells and involvement of the ROCK pathway in immune cell responses to damage of varying magnitude.
A genetic screen to uncover molecular mechanisms underlying lipid transfer protein function at membrane contact sites and neurodegeneration
Authors: Mishra Shirish , Manohar Vaishnavi , Chandel Shabnam , Manoj Tejaswini , Bhattacharya Subhodeep , Hegde Nidhi , Nath Vaisaly R , Krishnan Harini , Wendling Corinne , Di Mattia Thomas , Martinet Arthur , Chimata Prasanth , Alpy Fabien , Raghu Padinjat 
Published: July 2023

AbstractLipid transfer proteins mediate the transfer of lipids between organelle membranes in eukaryotes and loss of function in these has been linked to neurodegenerative disorders. However, the mechanism by which loss of lipid transfer protein function leads to neurodegeneration is not understood. InDrosophilaphotoreceptors, depletion of Retinal Degeneration B (RDGB), a phosphatidylinositol transfer protein localized to endoplasmic reticulum-plasma membrane contact sites leads to defective phototransduction and retinal degeneration but the mechanism by which RDGB function is regulated and the process by which loss of this activity leads to retinal degeneration is not understood. RDGB is localized to membrane contact sites (MCS) and this depends in the interaction of its FFAT motif with the ER integral protein VAP. To identify regulators of RDGB functionin vivo, we depleted more than 300 VAP interacting proteins and identified a set of 52 suppressors ofrdgB. The molecular identity of these suppressors indicates a role for novel lipids in regulating RDGB function and for transcriptional and ubiquitination processes in mediating retinal degeneration inrdgB. The human homologs of several of these molecules have been implicated in neurodevelopmental diseases underscoring the importance of VAP mediated processes in these disorders.
Apically localized PANX1 impacts neuroepithelial expansion in human cerebral organoids
Authors: Noort Rebecca J. , Flemmer Robert T. , Moore Craig S. , Belbin Thomas J. , Esseltine Jessica L. 
Published: July 2023

AbstractDysfunctional paracrine signaling through Pannexin 1 (PANX1) channels is linked to several adult neurological pathologies and emerging evidence suggests that PANX1 plays an important role in human brain development. It remains unclear how early PANX1 influences brain development, or how loss of PANX1 alters the developing human brain. Using a cerebral organoid model of early human brain development, we find that PANX1 is expressed at all stages of organoid development from neural induction through to neuroepithelial expansion and maturation. Interestingly, PANX1 cellular distribution and subcellular localization changes dramatically throughout cerebral organoid development. During neural induction, PANX1 becomes concentrated at the apical membrane domain of neural rosettes where it co-localizes with several apical membrane adhesion molecules. During neuroepithelial expansion,PANX1-/- organoids are significantly smaller than control and exhibit significant gene expression changes related to cell adhesion, Wnt signaling and non-coding RNAs. As cerebral organoids mature, PANX1 expression is significantly upregulated and is primarily localized to neuronal populations outside of the ventricular-like zones. Ultimately, PANX1 protein can be detected in all layers of a 21-22 post conception week human fetal cerebral cortex. Together, these results show that PANX1 is dynamically expressed by numerous cell types throughout embryonic and early fetal stages of human corticogenesis and loss of PANX1 compromises neuroepithelial expansion due to dysregulation of cell-cell and cell-matrix adhesion, perturbed intracellular signaling, and changes to gene regulation.
Identification of state-specific proteomic and transcriptomic signatures of microglia-derived extracellular vesicles
Authors: Santiago Juliet V. , Natu Aditya , Ramelow Christina C. , Rayaprolu Sruti , Xiao Hailian , Kumar Vishnu , Seyfried Nicholas T. , Rangaraju Srikant 
Published: July 2023

AbstractMicroglia are resident immune cells of the brain that play important roles in mediating inflammatory responses in several neurological diseases via direct and indirect mechanisms. One indirect mechanism may involve extracellular vesicle (EV) release, so that the molecular cargo transported by microglia-derived EVs can have functional effects by facilitating intercellular communication. The molecular composition of microglia-derived EVs, and how microglial activation states impacts EV composition and EV-mediated effects in neuroinflammation, remain poorly understood. We hypothesize that microglia-derived EVs have unique molecular profiles that are determined by microglial activation state. Using size-exclusion chromatography to purify EVs from BV2 microglia, combined with proteomic (label-free quantitative mass spectrometry or LFQ-MS) and transcriptomic (mRNA and non-coding RNA seq) methods, we obtained comprehensive molecular profiles of microglia-derived EVs. LFQ-MS identified several classic EV proteins (tetraspanins, ESCRT machinery, and heat shock proteins), in addition to over 200 proteins not previously reported in the literature. Unique mRNA and microRNA signatures of microglia-derived EVs were also identified. After treating BV2 microglia with lipopolysaccharide (LPS), interleukin-10, or transforming growth factor beta, to mimic pro-inflammatory, anti-inflammatory, or homeostatic states, respectively, LFQ-MS and RNA seq revealed novel state-specific proteomic and transcriptomic signatures of microglia-derived EVs. Particularly, LPS treatment had the most profound impact on proteomic and transcriptomic compositions of microglia-derived EVs. Furthermore, we found that EVs derived from LPS-activated microglia were able to induce pro-inflammatory transcriptomic changes in resting responder microglia, confirming the ability of microglia-derived EVs to relay functionally-relevant inflammatory signals. These comprehensive microglia-EV molecular datasets represent important resources for the neuroscience and glial communities, and provide novel insights into the role of microglia-derived EVs in neuroinflammation.
Method for Depletion of Mitochondria DNA in Human Bronchial Epithelial Cells
Authors: Novotny Michael V. , Xu Weiling , Mulya Anny , Janocha Allison J. , Erzurum Serpil C. 
Published: July 2023

AbstractIntroductionMitochondria are increasingly recognized to play a role in the airway inflammation of asthma. Model systems to study the role of mitochondrial gene expression in bronchial epithelium are lacking. Here, we create custom bronchial epithelial cell lines derived from primary airway epithelium that are depleted of mitochondrial DNA.MethodsWe treated BET-1A and BEAS-2B cells with ethidium bromide (EtBr) with or without 2’,3’-dideoxycytidine (ddC) to create cells lacking mitochondrial DNA (mtDNA). Cells’ mtDNA copy number were verified by quantitative polymerase chain reaction (qPCR) in comparison to nuclear DNA (nDNA). Cells were also assessed for oxidative phosphorylation by measures of oxygen consumption using the Seahorse analyzer.ResultsOne week of EtBr treatment led to ∼95% reduction of mtDNA copy number (mtDNA-CN) in cells (mtDNA-CN, mean±SE, baseline vs. treatment: BEAS-2B, 820 ± 62 vs. 56 ± 9; BET-1A, 957 ± 52 vs. 73 ± 2), which was further reduced by addition of 25 μM ddC (mtDNA-CN: BEAS-2B, 2.8; BET-1A, 47.9). Treatment for up to three weeks with EtBr and ddC led to near complete loss of mtDNA (mtDNA-CN: BEAS-2B, 0.1; BET-1A, 0.3). The basal oxygen consumption rate (OCR) of mtDNA-depleted BET-1A and BEAS-2B cells dropped to near zero. Glycolysis measured by extracellular acidification rate (ECAR) increased ∼two-fold in cells when mtDNA was eliminated [ECAR (mpH/min/103cells), baseline vs. treatment: BEAS-2B, 0.50 ± 0.03 vs. 0.94 ± 0.10P=0.005; BET-1A, 0.80 ± 0.04 vs. 1.14 ± 0.06P=0.001].ConclusionMitochondrial DNA–depleted BET-1A ρ0 and BEAS-2B ρ0 cell lines are viable, lack the capacity for aerobic respiration, and increase glycolysis. This cell model system can be used to further test mitochondrial mechanisms of inflammation in bronchial epithelial cells.
Impact of sickle cell trait hemoglobin inPlasmodium falciparum-infected erythrocytes
Authors: Seidu Zakaria , Ofori Michael F. , Hviid Lars , Lopez-Perez Mary 
Published: July 2023

AbstractSickle cell trait (HbAS) confers protection against severePlasmodium falciparummalaria but has little effect on infection ratesper se. The reason for this is not fully understood. However, it appears to involve impaired parasite survival at the low oxygen tensions prevailing in the postcapillary venules whereP. falciparum-infected erythrocytes (IEs) often accumulate. This IE sequestration is mediated by parasite-encoded IE surface ligands, primarily PfEMP1. Different variants of this family of proteins bind to host receptors with different tissue distributions. We hypothesized thatP. falciparumparasites modulate PfEMP1 expression to enhance their survival by altering IE tissue distribution in HbAS hosts. To test this, we studied PfEMP1 expression in parasites maintained in vitro in HbAS and HbAA erythrocytes. We found that parasite survival and PfEMP1 expression were reduced in HbAS IEs, particularly at low oxygen tensions, without obvious qualitative differences in PfEMP1 expression between HbAA and HbAS IEs. In contrast, parasites growing in HbAS erythrocytes increased their transcription ofpfsa2, a parasite gene hypothesized to be under HbS-dependent selection. Taken together, our findings support the hypothesis of quantitative but not qualitative modulation of PfEMP1 expression as a parasite strategy for coping with HbAS-related host resistance. Moreover, it provides a hint at the role ofPfsa2in parasite adaptation to HbAS and highlights the importance of further research.
Genetic Evidence for Geographic Structure within the Neanderthal Population
Authors: Rogers Alan R. 
Published: July 2023

AbstractPSMC estimates of Neanderthal effective population size (Ne) exhibit a roughly 5-fold decline across the most recent 20 ky before the death of each fossil. To explain this pattern, this article develops new theory relating genetic variation to geographic population structure and local extinction. It argues that the observed pattern results from subdivision and gene flow. If two haploid genomes are sampled from the same subpopulation, their recent ancestors are likely to be geographic neighbors and therefore coalesce rapidly. By contrast, remote ancestors are likely to be far apart, and their coalescent rate is lower. Consequently,Neis larger in the distant past than in the recent past.New theoretical results show that modest rates of extinction cause substantial reductions in heterozygosity, Wright’sFST, andNe.
Neural Correlates of High-Level Visual Saliency Models
Authors: Kroner Alexander , Senden Mario , Goebel Rainer 
Published: July 2023

AbstractVisual saliency highlights regions in a scene that are most relevant to an observer. The process by which a saliency map is formed has been a crucial subject of investigation in both machine vision and neuroscience. Deep learning-based approaches incorporate high-level information and have achieved accurate predictions of eye movement patterns, the overt behavioral analogue of a saliency map. As such, they may constitute a suitable surrogate of cortical saliency computations. In this study, we leveraged recent advances in computational saliency modeling and the Natural Scenes Dataset (NSD) to examine the relationship between model-based representations and the brain. Our aim was to uncover the neural correlates of high-level saliency and compare them with low-level saliency as well as emergent features from neural networks trained on different tasks. The results identified hV4 as a key region for saliency computations, informed by semantic processing in ventral visual areas. During natural scene viewing, hV4 appears to serve a transformative role linking low- and high-level features to attentional selection. Moreover, we observed spatial biases in ventral and parietal areas for saliency-based receptive fields, shedding light on the interplay between attention and oculomotor behavior.
Incremental Self-Organization of Spatio-Temporal Spike Pattern Detection
Authors: Dehghani-Habibabadi Mohammad , Müller Lenny , Pawelzik Klaus 
Published: July 2023

ABSTRACTBrains learn new information while retaining already acquired contents. It is not known by what mechanisms synapses preserve previously stored memories while they are plastic and contribute to further learning. To understand how this notorious stability-plasticity dilemma might be resolved, we investigate a one layer self-supervised neural network that incrementally learns to detect new spatio-temporal spike patterns without loosing existing selectivities. A plausible combination of Hebbian mechanisms, hetero-synaptic plasticity, and synaptic scaling enables unsupervised learning of spatio-temporal input patterns by single neurons. In networks acquisition of different patterns one after the other is achieved by including pre-synaptic hetero-synaptic plasticity which enforces differentiation of the neurons’ selectivities. We found, however, that only when additionally the training spikes are both, jittered and stochastic past memories persist despite ongoing learning. This input variability selects a subset of weights and drives them into a regime where synaptic scaling induces self-stabilization. Thereby our model provides a novel explanation for the stability of synapses related to preexisting contents despite ongoing plasticity, and suggests how nervous systems could incrementally learn and exploit temporally precise Poisson rate codes.Significance StatementActivity-dependent changes in synaptic efficacy are thought to underlie learning. While ongoing synaptic plasticity is necessary for learning new content, it is detrimental to the traces of previously acquired memories. Here, we show how memories for spatio-temporal patterns can be protected from overwriting. A combination of biologically plausible synaptic plasticity mechanisms turns single neurons into robust detectors of statistically dominant input patterns. For networks, we find that memory stability is achieved when the patterns to be learned are temporally sloppy and noisy, as opposed to being frozen. This variability drives the relevant synaptic weights to large efficacies, where they become self-reinforcing and continue to support the initially learned patterns. As a result, such a network can incrementally learn one pattern after another.
Motor Improvement in Neurological Conditions (MINC): Multiple Sclerosis Design and methods of a single-arm feasibility study
Authors: van der Groen Onno , Learmonth Yvonne , van Rijn Kirsten , Smith James , Edwards Dylan 
Published: August 2023

AbstractIntroductionMultiple sclerosis (MS) is a chronic progressive neurological disease. There is ample evidence that exercise can be beneficial. The advancement of modern technology led to improvements in the way therapy can be offered and can make it more motivating, thereby increasing adherence. The primary objective of this two site single blinded randomized control trial (RCT) is to explore the feasibility of conducting a multicentre definite RCT trial with a neuroanimation intervention of high-dose practice in people with mild-to-moderate MS. The secondary objective is to collect data on the variability of outcome measures to inform sample size calculations for a RCT. The tertiary outcome is to assess if this intervention changes exercise behaviour.Methods and analysisThis study is in preparation for a future definitive randomised control trial (RCT) where the efficacy compared to a dose matched control therapy will be assessed. The setting for this study is a research laboratory at Edith Cowan University (ECU) and a neurological service provider, Multiple Sclerosis Society of Western Australia (MSWA). This feasibility study will recruit people with MS who have mild to moderate disability. Subjects will participate in 24 session, 2 times a week, of 60 minutes time-on-task intense arm training, using an exergaming system. Participants will undergo a follow up within 3 days and at 6 months after the final study visit.Ethics and disseminationThis study was approved by the local Ethics Committee of Edith Cowan University. Subjects will be included after signing informed consent. Study outcomes will be disseminated through presentations at scientific conferences and through peer-reviewed journals.Trial registrationACTRN12622000281796Strengths and limitations of this studyThe study intervention is a newly developed exercise intervention protocol designed to be engaging and motivatingNext to investigating primary efficacy in order to determine sample size for a larger trial, the study also uses implementation science to assess future obstacles in a follow up randomized control trialThe feasibility of conducting a larger trial will be based on standardised criteria regarding process, resource, and management metricsThis study without a control group demonstrates feasibility rather than efficacy
Early Sport Specialization Impact on Rates of Injury in Collegiate and Professional Sport Participation: A Systematic Review and Meta-analysis
Authors: Adlou Bahman , Weimar Wendi , Wilburn Christopher , Wilson Alan 
Published: August 2023

AbstractEarly sport specialization (ESS) is common among adolescent athletes due to desire of reaching elite status; however, the long-term impact of ESS on sports injury (SI) rates is not fully understood. We performed a systematic review and meta-analysis of the literature to evaluate the effect of ESS on SI rates during elite sport participation. Search included PubMed, Web of Science, SPORTDiscus, EMBASE, Cochrane, CINAHL, ERIC, and Medline databases. Preferred Reporting Items for Systematic Reviews and MetaAnalyses (PRISMA) guidelines were followed to identify published peer-reviewed articles from inception to 23 March 2023. Eligible studies reported numbers of elite athletes in collegiate, national, and professional teams in ESS and their counterpart category, as well as the portion of each group with at least one SI. Studies on concussion or non-contact injuries, or without explicit injury reports during elite sprot participation were excluded. Five articles were included in the review; 3 reported SIs on collegiate and 2 reported on professional athletes. A total of 3087 athletes were included (ESS = 45%). The overall effect was not significant and demonstrated that ESS athletes had a lower odd (OR=0.7) of a SI during elite sport participation. Articles with clear reports are scarce, and thus limit the impact of the findings in this study. High heterogeneity was evident in this analysis, largely due to lack of standardized terminology, evaluation, and data representation. Prospective studies that consider diverse athlete population of the same sport are warranted.