bluuebunny/crossref_metadata_2025_split huggingface dataset:
A cross-species approach using an in vivo evaluation platform in mice demonstrates that sequence variation in the human RABEP2 gene modulates ischemic stroke outcomes
Authors: Lee Han Kyu , Kwon Do Hoon , Marchuk Douglas A. 
Published: July 2022

AbstractIschemic stroke, caused by vessel blockage, results in cerebral infarction; the death of brain tissue. Previously, quantitative trait locus mapping (QTL) of cerebral infarct volume and collateral vessel number identified a single, strong genetic locus regulating both phenotypes. Additional studies identified the causative gene, encoding RAB GTPase Binding Effector Protein 2 (Rabep2). However, there is yet no evidence that variation in the human ortholog of this gene plays any role in ischemic stroke outcomes. We established an in vivo evaluation platform in mice using adeno-associated virus (AAV) gene replacement and verified that both mouse and human RABEP2 rescue the mouse Rabep2 KO ischemic stroke volume and collateral vessel phenotypes. Importantly, this cross-species complementation enabled us to experimentally investigate the functional effects of coding sequence variation in the human RABEP2 gene. We chose four coding variants from the human population that are predicted by multiple in silico algorithms to be damaging to RABEP2 function. In vitro and in vivo analyses verify that all four led to decreased collateral vessel connections and increased infarct volume. Thus, there are naturally occurring loss-of-function alleles. This cross-species approach will expand the number of targets for therapeutics development for ischemic stroke.
A scalable open-source framework for machine learning based image collection, annotation and classification: a case study for automatic fish species identification
Authors: Silva Catarina NS , Dainys Justas , Simmons Sean , Vienožinskis Vincentas , Audzijonyte Asta 
Published: July 2022

AbstractCitizen science platforms, social media and multiple smart phone applications enable collection of large amounts of georeferenced images. This provides a huge opportunity in biodiversity and ecological research, but also creates challenges for efficient data handling and processing. Recreational and small-scale fisheries is one of the fields that could be revolutionised by efficient, widely accessible and machine learning based processing of georeferenced images. The majority of non-commercial inland and coastal fisheries are considered data poor and are rarely assessed, yet they provide multiple societal benefits and can have large ecological impacts. Given that large quantities of fish observations and images are being collected by fishers every day, artificial intelligence (AI) and computer vision applications offer a great opportunity to improve data collection, automate analyses and inform management. Yet, to date, many AI image analysis applications in fisheries are focused on the commercial sector and are not publicly available for community use. In this study we present an open-source modular framework for large scale image storage, handling, annotation and automatic classification, using cost- and labour-efficient methodologies. The tool is based on TensorFlow Lite Model Maker library and includes data augmentation and transfer learning techniques, applied to different convolutional neural network models. We demonstrate the implementation of this framework in an example case study for automatic fish species identification from images taken through a recreational fishing smartphone application. The framework presented here is highly customisable for further advancement and community based image collection and annotation.
Natural occurrence and analysis of Nosema sp. infection in the adult population of western bean cutworm in Michigan
Authors: Bunn Dakota C. , Miller Nicholas 
Published: July 2022

AbstractAn understanding of population dynamics and insect biology is important for effective crop management strategies. Biotic factors such as pathogens play a large role on the fitness and dynamics of insect populations. Microsporidia are obligate intracellular parasites that infect more than 150 insect species and range from sublethal and chronic to fast acting and deadly. The western bean cutworm, Striacosta albicosta (Smith) (Lepidoptera: Noctuidae), is a pest of both corn (Zea maize L.) and dry beans (Phaseolus sp L.) that is infected by a microsporidian parasite from the genus Nosema. Unfortunately, little is known about the interactions between the Nosema sp. infecting the western bean cutworm and its prevalence and effects on the host population. This is especially true for the western bean cutworm population that has settled in the Great Lakes region over the last two decades. Using field caught samples and phase contrast microscopy, we found a 100% prevalence of infection in the adult western bean cutworm population in Michigan. No consistent trends in pathogen load were observed over the course of the western bean cutworm flight season. A weak, but statistically significant relationship was observed between male body weight and pathogen load.
Reactive Bergmann glia play a central role in Spinocerebellar ataxia inflammation via the JNK pathway
Authors: Edamakanti Chandrakanth Reddy , Mohan Vishwa , Opal Puneet 
Published: July 2022

AbstractThe spinocerebellar ataxias (SCAs) are devastating neurological diseases characterized by progressive cerebellar incoordination. While neurons bear the brunt of the pathology, a growing body of evidence suggests that glial cells are also affected. It has, however, been difficult to understand the role of glia, given the diversity of subtypes, each with their individual contributions to neuronal health. Using human SCA autopsy samples we have discovered that Bergmann glia—the radial glia of the cerebellum, which form intimate functional connections with cerebellar Purkinje neurons—display inflammatory JNK-dependent c-Jun phosphorylation. This phosphorylation defines a signaling pathway not observed in other activated glial populations, providing an opportunity to specifically isolate the role of Bergmann glia in SCA inflammation. Turning to an SCA1 mouse model as a paradigmatic SCA, we demonstrate that inhibiting the JNK pathway reduces Bergmann glia inflammation accompanied by improvements in the SCA1 phenotype both behaviorally and pathologically. These findings demonstrate the causal role for Bergmann glia inflammation in SCA1 and point to a novel therapeutic strategy that could span several ataxic syndromes where Bergmann glia inflammation is a major feature.Significance StatementWe have identified a Bergmann-glia specific signaling pathway that contributes to cerebellar degeneration in the spinocerebellar ataxias. This pathway is defined by activation of JNK that phosphorylates the transcription factor c-Jun leading to the release of IL-1β and potentially other cytokines from Bergmann glia. Inhibiting c-Jun phosphorylation with pharmacological JNK inhibition could serve as therapeutic approach to treating cerebellar degeneration.
Life history strategies and niches of soil bacteria emerge from interacting thermodynamic, biophysical, and metabolic traits
Authors: Marschmann Gianna L. , Tang Jinyun , Zhalnina Kateryna , Karaoz Ulas , Cho Heejung , Le Beatrice , Pett-Ridge Jennifer , Brodie Eoin L. 
Published: July 2022

AbstractEfficient biochemical transformation of belowground carbon by microorganisms plays a critical role in determining the long-term fate of soil carbon. As plants assimilate carbon from the atmosphere, up to 50% is exuded into the area surrounding growing roots, where it may be transformed into microbial biomass and subsequently stabilized through mineral associations. However, due to a hierarchy of interacting microbial traits, it remains elusive how emergent life-history strategies of microorganisms influence the processing of root exudate carbon. Here, by combining theory-based predictions of substrate uptake kinetics for soil bacteria and a new genome-informed trait-based dynamic energy budget model, we predicted life history traits and trade-offs of a broad range of soil bacteria growing on 82 root exudate metabolites. The model captured resource-dependent trade-offs between growth rate (power) and growth efficiency (yield) that are fundamental to microbial fitness in communities. During early phases of plant development, growth rates of bacteria were largely constrained by maximum growth potential, highlighting the predictive power of genomic traits during nutrient-replete soil conditions. In contrast, selection for efficiency was important later in the plant growing season, where the model successfully predicted microbial substrate preferences for aromatic organic acids and plant hormones. The predicted carbon-use efficiencies for growth on organics acids were much higher than typical values observed in soil. These predictions provide mechanistic underpinning for the apparent efficiency of the microbial route to mineral stabilization in the rhizosphere and add an additional layer of complexity to rhizosphere microbial community assembly.
Neutrophils infiltrate sensory ganglia and mediate chronic widespread pain in fibromyalgia
Authors: Caxaria Sara , Bharde Sabah , Fuller Alice M. , Evans Romy , Thomas Bethan , Celik Petek , Dell’Accio Francesco , Yona Simon , Gilroy Derek , Voisin Mathieu-Benoit , Wood John N. , Sikandar Shafaq 
Published: July 2022

AbstractFibromyalgia is a debilitating widespread chronic pain syndrome that occurs in 2-4% of the population. The prevailing view that fibromyalgia results from central nervous system dysfunction has recently been challenged with data showing changes in peripheral nervous system activity. Using a mouse model of chronic widespread pain through hyperalgesic priming of muscle, we show that neutrophils invade sensory ganglia and confer mechanical hypersensitivity on recipient mice, whilst adoptive transfer of immunoglobulin, serum, lymphocytes or monocytes have no effect on pain behaviour. Neutrophil depletion abolishes the establishment of chronic widespread pain in mice. Neutrophils from patients with fibromyalgia also confer pain on mice. A link between neutrophil derived mediators and peripheral nerve sensitisation is already established. These observations suggest new approaches for targeting fibromyalgia pain through an understanding of the mechanisms that cause altered neutrophil activity and interactions with sensory neurons.Significance statementWe used a back-translational model in mice to demonstrate the pro-nociceptive role of neutrophils in fibromyalgia. Adoptive transfer of neutrophils from mice with chronic widespread pain or from patients with fibromyalgia can confer mechanical pain to recipient naïve mice, sensitise evoked action potential firing of spinal cord neurons and produce phenotypic changes in cell surface expression of neutrophil proteins that cause infiltration of neutrophils into dorsal root ganglia. These data provide the framework for an immunological basis of chronic widespread pain in fibromyalgia mediated by polymorphonuclear granulocytes.
The SCN1A Philadelphia variant – a gain-of-function mutation causing an early-onset epileptic encephalopathy
Authors: Clatot Jérôme , Parthasarathy Shridhar , Cohen Stacey , McKee Jillian , Massey Shavonne , Somarowthu Ala , Goldberg Ethan M. , Helbig Ingo 
Published: July 2022

AbstractObjectiveLoss-of-function variants in SCN1A cause Dravet Syndrome, the most common genetic developmental and epileptic encephalopathy (DEE). However, emerging evidence suggests separate entities of SCN1A-related disorders due to gain-of-function variants. Here, we aim to refine the clinical, genetic, and functional electrophysiological features of a recurrent p.R1636Q gain-of-function variant, identified in four individuals at a single center.MethodsIndividuals carrying the recurrent SCN1A p.R1636Q variant were identified through diagnostic testing. Whole-cell voltage-clamp electrophysiological recording in HEK-293T cells was performed to compare the properties of sodium channels containing wild-type Nav1.1 or Nav1.1-R1636Q along with both Navβ1 and Navβ2 subunits, including response to oxcarbazepine. To delineate differences to other SCN1A-related epilepsies, we analyzed electronic medical records.ResultsAll four individuals had an early-onset DEE characterized by focal tonic seizures and additional seizure types starting in the first few weeks of life. Electrophysiological analysis showed a mixed gain-of-function effect with normal current density, a leftward (hyperpolarized) shift of steady-state inactivation, and slower inactivation kinetics leading to a prominent late sodium current (INa). The observed functional changes closely paralleled effects of pathogenic variants in SCN3A and SCN8A at corresponding positions. Both wildtype and variant exhibited sensitivity to block by oxcarbazepine, partially correcting electrophysiological abnormalities of the SCN1A p.R1636Q variant. Clinically, a single individual responded to treatment with oxcarbazepine. Across 51 individuals with SCN1A-related epilepsies, those with the recurrent p.R1636Q variants had the earliest ages of onset.InterpretationThe recurrent SCN1A p.R1636Q variant causes a clinical entity with a wider clinical spectrum than previously reported, characterized by ultra early-onset epilepsy and absence of prominent movement disorder. Functional consequences of this variant lead to mixed loss- and gain-of-function that is partially corrected by oxcarbazepine. The recurrent p.R1636Q variant represents one of the most common causes of early-onset SCN1A-related epilepsies with separate treatment and prognosis implications.Key PointsLoss-of-function variants in SCN1A cause Dravet syndrome, but gain-of-function variants have an emerging clinical spectrum.The SCN1A p.R1636Q variant shows similar overall gain-of-function effects to identical missense variants in other voltage-gated sodium channels.Features of four unreported individuals with SCN1A p.R1636Q from a single center expand the SCN1A gain-of-function phenotype.Individuals with this variant are recognizable by their ultra early-onset seizures in contrast to Dravet syndrome.
An independent external validation of the QRISK3 cardiovascular risk prediction model applied to UK Biobank participants
Authors: Parsons Ruth E. , Liu Xiaonan , Collister Jennifer A. , Clifton David A. , Cairns Benjamin J. , Clifton Lei 
Published: July 2022

ABSTRACTBackgroundThe QRISK3 cardiovascular disease (CVD) risk prediction model was derived using primary care data; however, it is frequently used outside of clinical settings. The use of QRISK3 in epidemiological studies without external validation may lead to inaccurate results, however it has been used multiple times on data from UK Biobank. We aimed to externally evaluate the performance of QRISK3 for predicting 10-year risk of cardiovascular events in the UK Biobank cohort.MethodsWe used data from the UK Biobank, a large-scale prospective cohort study of 403,370 participants aged 40-69 years recruited between 2006 and 2010 in the United Kingdom (UK). We included participants with no previous history of CVD or statin treatment and the outcome was the first occurrence of coronary heart disease, ischaemic stroke or transient ischaemic attack, derived from linked hospital episode statistics (HES) and death registration data (DRD).ResultsOur study population included 233,233 females and 170,137 males, with 9295 and 13,028 incident cardiovascular events, respectively. The overall median follow-up time after recruitment was 11.7 years. The discrimination measure of QRISK3 in the overall population was reasonable (Harrell’s C-Index 0.722 in females and 0.697 in males), this was poorer in older participants (<0.62 in all participants aged 65 or older). QRISK3 had systematic over-prediction of CVD risk in UK Biobank, particularly in older participants, by as much as 20%.ConclusionsQRISK3 had reasonable overall discrimination for the whole study population, which was best in younger participants. The observed CVD risk in UK Biobank participants was lower than that predicted by QRISK3, particularly for older participants. The UK Biobank cohort is known to be healthier than the general population and therefore it is necessary to recalibrate QRISK3 before using it to predict absolute CVD risk in the UK Biobank cohort.
Low back pain service utilization and costs: association with timing of first-line services for individuals initially contacting a primary care provider. A retrospective cohort study
Authors: Elton David , Zhang Meng 
Published: July 2022

AbstractBackgroundLow back pain (LBP) is prevalent, costly, and a common reason for a visit to a primary care provider (PCP). Clinical practice guidelines (CPG) recommend a stepped approach to management.ObjectiveFor individuals with LBP initially contacting a PCP, examine the association between the incorporation of first-line therapies, use of second- and third-line services and total episode cost.DesignRetrospective cohort studySetting/PatientsNational sample of individuals with non-surgical LBP occurring in 2017-2019.MeasurementsIndependent variables were initial contact with a PCP, and the timing of incorporation of 5 types of first-line therapies. Dependent measures included use of 13 types of health care services and total episode cost.Results8.5% of 118,503 PCPs initially contacted by 308,790 individuals with 347,627 episodes of non-surgical LBP were associated with an episode including any first-line service at any time. 17.5% of episodes included any first-line service at any time. Active care (11.6% of episodes), manual therapy (8.0%) and chiropractic manipulative therapy (7.0%) were the most common first-line services. 5.4% of episodes included a first-line service during the first 7 days with these episodes associated with a modest reduction (risk ratio 0.34 to 0.89) in the use of prescription pharmaceuticals. First-line services were associated with an increase in total episode cost with the smallest increase associated with chiropractic and osteopathic manipulation. Younger individuals from ZIP codes with higher adjusted gross income were more likely to receive a first-line service in the first 7 days of an episode.LimitationsAs a retrospective observational analysis of associations there are numerous potential confounders and limitations.ConclusionsIndividuals with non-surgical LBP initially contacting a PCP infrequently receive a first-line service, and if received, it is typically in addition to second- and third-line pharmaceutical, imaging, and interventional services. There is an opportunity to improve concordance with the stepped approach to management described in LBP CPGs.
Increased disparity in routine infant vaccination during COVID-19
Authors: Righolt Christiaan H. , Pabla Gupreet , Mahmud Salaheddin M. 
Published: July 2022

AbstractBackgroundCOVID-19 restrictions and its impact on healthcare resources have reduced routine infant vaccine uptake, although some report that this effect was short-lived. These prior studies mostly described entire populations, but disparities in uptake may have changed during the pandemic due to differential access to healthcare.ObjectivesWe aimed to examine disparities in the reduction in routine infant vaccine uptake during the COVID-19 pandemic in Manitoba, Canada.MethodsWe assessed vaccine uptake for routine infant vaccines for a pre-pandemic and pandemic subcohort. We assessed how the reduction in vaccine uptake differed by gender, neighborhood income quintile and region of residence. For each evaluation age, we limited the pandemic subcohort to children reaching this milestone age on/before November 30, 2021.ResultsVaccine uptake was about 5-10% lower during the pandemic. The groups most vulnerable to COVID-19 saw the largest reductions in vaccine uptake, with an ongoing downward trend throughout the pandemic. Children in the lowest income neighborhoods saw a 17% reduction in diphtheria, tetanus, and acellular pertussis dose 4 uptake at 24 months, 4.4-fold that of high-income neighborhoods, and an 11% reduction in measles, mumps, rubella (MMR) vaccine uptake at 24 months, 5.6-fold that of high-income neighborhoods. The largest reductions were for low-income Northern residents and smallest for high-income Winnipeg residents, e.g. 16-fold larger for MMR at 24 months (79:94 pre-pandemic to 65:93 during the pandemic).ConclusionsWhile privileged children have similar high vaccine uptake as before the pandemic, children in populations hardest hit by COVID-19 continue seeing concerning reductions in routine infant vaccination. It is imperative that infant vaccination rates are increased, especially in communities with lower socioeconomic status, as a failure to do so could lead to persistent rebound epidemics in the most vulnerable populations.SynopsisStudy questionHow did COVID-19 and its restrictions affect routine infant vaccine uptake?What’s already knownWe know that vaccine uptake in infants decreased during the pandemic. We do not know whether this affected everyone equally or whether the pandemic worsened existing disparities in vaccine uptake.What this study addsAlthough vaccine uptake was not affected in wealthy urban neighborhoods, the reduction in uptake was largest, and continued on a downward trend, for groups with the lowest baseline vaccine uptake. Only two-thirds of children, instead of the 4/5th before the pandemic, in the remote, predominantly Indigenous Northern region received a measles vaccine by their second birthday.
Predicting infectious disease for biopreparedness and response: A systematic review of machine learning and deep learning approaches
Authors: Keshavamurthy Ravikiran , Dixon Samuel , Pazdernik Karl T. , Charles Lauren E. 
Published: July 2022

AbstractDespite the complex and unpredictable nature of pathogen occurrence, substantial efforts have been made to better predict infectious diseases (IDs). Following PRISMA guidelines, we conducted a systematic review to investigate the advances in ID prediction capabilities for human and animal diseases, focusing on Machine Learning (ML) and Deep Learning (DL) techniques. Between January 2001 and May 2021, the number of relevant articles published steadily increased with a significantly influx after January 2019. Among the 237 articles included, a variety of IDs and locations were modeled, with the most common being COVID-19 (37.1%) followed by Influenza/influenza-like illnesses (8.9%) and Eastern Asia (32.5%) followed by North America (17.7%), respectively. Tree-based ML models (38.4%) and feed-forward DL neural networks (26.6%) were the most frequent approaches taking advantage of a wide variety of input features. Most articles contained models predicting temporal incidence (66.7%) followed by disease risk (38.0%) and spatial movement (31.2%). Less than 10% of studies addressed the concepts of uncertainty quantification, computational efficiency, and missing data, which are essential to operational use and deployment. Our study summarizes the broad aspects and current status of ID prediction capabilities and provides guidelines for future works to better support biopreparedness and response.