bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical features and outcomes of hospitalised patients with COVID-19 and Parkinsonian disorders: a multicentre UK-based study
Authors: Sorrell Lexy , Leta Valentina , Barnett Anton , Stevens Kara , King Angela , Inches Jemma , Kobylecki Christopher , Walker Richard , Chaudhuri K Ray , Martin Hannah , Rideout Jane , Sneyd J Robert , Campbell Sarah , Carroll Camille 
Published: April 2023

AbstractBackgroundParkinson’s disease has been identified as a risk factor for severe Coronavirus disease 2019 (COVID-19) outcomes. However, whether the significant high risk of death from COVID-19 in people with Parkinson’s disease is specific to the disease itself or driven by other concomitant and known risk factors such as comorbidities, age, and frailty remains unclear.ObjectiveTo investigate clinical profiles and outcomes of people with Parkinson’s disease and atypical parkinsonian syndromes who tested positive for COVID-19 in the hospital setting in a multicentre UK-based study.MethodsA retrospective cohort study of Parkinson’s disease patients with a positive COVID-19 test admitted to hospital between February 2020 and July 2021. An online survey was used to collect data from clinical care records, recording patient, Parkinson’s disease and COVID-19 characteristics. Associations with time-to-mortality and severe outcomes were analysed using either the Cox proportional hazards model or logistic regression models, as appropriate.ResultsData from 552 admissions were collected: 365 (66%) male; median (inter-quartile range) age 80 (74-85) years. The 34-day mortality rate was 38.4%; male sex, increased age and frailty, Parkinson’s dementia syndrome, requirement for respiratory support and no vaccination were associated with increased mortality risk. Community-acquired COVID-19 and co-morbid chronic neurological disorder were associated with increased odds of requiring respiratory support. Hospital-acquired COVID-19 and delirium were associated with requiring an increase in care level post-discharge.ConclusionsThis first, multicentre, UK-based study on people with Parkinson’s disease or atypical parkinsonian syndromes, hospitalised with COVID-19, adds and expands previous findings on clinical profiles and outcomes in this population.
Genetic associations of risk behaviours and educational attainment
Authors: Spano Michelle Arellano , Morris Tim , Davies Neil M , Hughes Amanda 
Published: April 2023

AbstractRisk behaviours such as alcohol use, smoking, and physical inactivity are common in adolescence and persist into adulthood. People who engage in more risk behaviour are more likely to have lower educational attainment. Genome-wide association studies show that participation in risk behaviours and level of education are both heritable and have a highly polygenic architecture, suggesting an important role of many variants across the genome. The extent to which risk behaviours and educational attainment have shared genetic overlap is unknown, yet knowledge of this could help understand how these traits co-occur and influence each other. In the ALSPAC cohort, we used genome-based restricted maximum likelihood (GREML) to estimate the genetic covariance between risk behaviours and educational achievement. We found a strong genetic component of educational achievement and a modest genetic component of the risk behaviours. Whereby children who have a higher genetic liability for education also have a lower genetic liability for risky behaviours.
Depressive symptoms are associated with DNA methylation age acceleration in a cross-sectional analysis of adults over age 50 in the United States
Authors: Wang Herong , Bakulski Kelly M. , Blostein Freida , Porath Brittany R. , Dou John , Tejera Cesar Higgins , Ware Erin B. 
Published: April 2023

AbstractBackgroundMajor depressive disorder affects mental well-being and accelerates DNA methylation age, a marker of biological aging. Subclinical depressive symptoms and DNA methylation aging have not been explored.ObjectiveTo assess the cross-sectional association between depressive symptoms and accelerated DNA methylation aging among United States adults over age 50.MethodsWe included 3,793 participants from the 2016 wave of the Health and Retirement Study. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression scale and operationalized as high versus low/no. Blood DNA methylation GrimAge was regressed on chronologic age to obtain acceleration. Multiple linear regression assessed the relationship between high depressive symptoms and GrimAge acceleration, controlling for demographic factors, health behaviors, and cell type proportions. We investigated sex and race/ethnicity stratified associations.ResultsParticipants were 42% male, 14% had high depressive symptoms, 44% had accelerated GrimAge, and were mean age 70 years. In our fully adjusted model, those with high depressive symptoms had 0.40 (95%CI: 0.06, 0.73) years accelerated GrimAge, compared to those with low/no depressive symptoms. The association between depressive symptoms and GrimAge acceleration was larger in male participants (P= 0.04).ConclusionHigher depressive symptoms were associated with accelerated DNA methylation age among older adults.
The evaluation of the quality of life in survivors of critical illness after discharge from Intensive Care Unit (ICU): A prospective cohort study
Authors: Papageorgiou Dimitrios , Triantafyllou Christos , Stavropoulou Areti , Kelesi Martha , Kaba Evridiki , Evgenikos Konstantinos , Liveri Athanasia , Stroumpouki Theodora 
Published: April 2023

AbstractIntroductionAdmission to the Intensive Care Unit (ICU) constitutes a substantial psychophysical burden for both patients and their relatives. Individuals who are critically ill and receive care in the ICU frequently exhibit numerous physical and mental issues stemming from the primary ailment, its complications, and subsequent treatments. This study aimed to assess the quality of life (QoL) for ICU patients in the first and third month after ICU discharge and identify any issues arising from their ICU hospitalization.Material and methodsThis was a prospective cohort study. The study participants were adult medical or surgical patients admitted to Intensive Care Units (ICUs) in three public hospitals in the region of Attica in Greece, from August 2020 to December 2021. The short form (SF)-36 was used to measure QoL. Data collection was performed through telephone interviews during the first and third month after ICU discharge.ResultsThe study included 43 patients, 34 men and nine women. The mean age was 59.63±13.06 years. The average value of the two main categories in the 1st month was: Physical health: 53.72 ± 15.92, and Mental health: 69.03 ± 26.02, while in the 3rdmonth, it was 62.42 ± 20.45 and 72.81 ± 16.47, respectively. The duration of mechanical ventilation, high-flow oxygen therapy, and spontaneous breathing in days seemed to be correlated with the “Physical Functioning”, “Pain”, and “Limitation of the role due to Physical health” subscales of SF-36, respectively (p-value <0.05). The total length of hospitalization seemed to have a statistically significant negative correlation with “Physical Function” and “Physical Health” subscales (p-value<0.05).ConclusionsAn improvement in patients’ QoL was demonstrated three months after discharge from the ICU. Factors such as gender, cause of ICU admission, occurrence or non-occurrence of cardiac arrest, the performance of a tracheostomy, and type of ventilation support should always be considered when assessing the quality of life after ICU hospitalization.
Neural stem and progenitor cells support and protect adult hippocampal function via vascular endothelial growth factor secretion
Authors: Denninger Jiyeon K. , Miller Lisa N. , Walters Ashley E. , Hosawi Manal , Sebring Gwendolyn , Rieskamp Joshua D. , Ding Tianli , Rindani Raina , Chen Kelly S. , Senthilvelan Sakthi , Volk Abigail , Zhao Fangli , Askwith Candice , Kirby Elizabeth D. 
Published: April 2023

AbstractAdult neural stem and progenitor cells (NSPCs) reside in the dentate gyrus (DG) of the hippocampus throughout the lifespan of most mammalian species. In addition to generating new neurons, NSPCs may alter their niche via secretion of growth factors and cytokines. We recently showed that adult DG NSPCs secrete vascular endothelial growth factor (VEGF), which is critical for maintaining adult neurogenesis. Here, we asked whether NSPC-derived VEGF alters hippocampal function independent of adult neurogenesis. We found that loss of NSPC-derived VEGF acutely impaired hippocampal memory, caused neuronal hyperexcitability and exacerbated excitotoxic injury. We also found that NSPCs generate substantial proportions of total DG VEGF and VEGF disperses broadly throughout the DG, both of which help explain how this anatomically-restricted cell population could modulate function broadly. These findings suggest that NSPCs actively support and protect DG function via secreted VEGF, thereby providing a non-neurogenic functional dimension to endogenous NSPCs.
Chromosome-Level Genome Assembly and Circadian Gene Repertoire of the Patagonia blennieEleginops maclovinus- the closest ancestral proxy of Antarctic cryonotothenioids
Authors: Cheng C.-H. Christina , Rivera-Colón Angel G. , Minhas Bushra Fazal , Wilson Loralee , Rayamajhi Niraj , Vargas-Chacoff Luis , Catchen Julian M. 
Published: April 2023

AbstractThe basal S. American notothenioidEleginops maclovinus(Patagonia blennie) occupies a uniquely important phylogenetic position in Notothenioidei as the singular closest sister species to the Antarctic cryonotothenioid fishes. Its genome and the traits encoded therein would be nearest representatives of the temperate ancestor from which the Antarctic clade arose, providing an ancestral reference for deducing polar derived changes. In this study, we generated a gene- and chromosome-complete assembly ofE. maclovinusgenome using long read sequencing and HiC scaffolding. We compared its genome architecture with the more basally divergentCottoperca gobioand the derived genomes of nine cryonotothenioids representing all five Antarctic families. We additionally curated its repertoire of circadian rhythm genes, ascertained their functionality by transcriptome sequencing, and compared its pattern of gene retention withC. gobioand the derived cryonotothenioids. Both analyses foundE. maclovinusto share greater conservation with the Antarctic clade, solidifying its evolutionary status as direct sister and best suited ancestral proxy of cryonotothenioids. The high quality genome ofE. maclovinuswill facilitate inquiries into cold derived traits in temperate to polar evolution, as well as inform on the paths of readaptation to non-freezing habitats in various secondarily temperate cryonotothenioids through comparative genomic analyses.
Chemical screens in aging-relevant human motor neurons identify MAP4Ks as therapeutic targets for amyotrophic lateral sclerosis
Authors: Liu Meng-Lu , Ma Shuaipeng , Tai Wenjiao , Zhong Xiaoling , Ni Haoqi , Zou Yuhua , Wang Jingcheng , Zhang Chun-Li 
Published: April 2023

ABSTRACTEffective therapeutics is much needed for amyotrophic lateral sclerosis (ALS), an adult-onset neurodegenerative disease mainly affecting motor neurons. By screening chemical compounds in human patient-derived and aging-relevant motor neurons, we identify a neuroprotective compound and show that MAP4Ks may serve as therapeutic targets for treating ALS. The lead compound broadly improves survival and function of motor neurons directly converted from human ALS patients. Mechanistically, it works as an inhibitor of MAP4Ks, regulates the MAP4Ks-HDAC6-TUBA4A-RANGAP1 pathway, and normalizes subcellular distribution of RANGAP1 and TDP-43. Finally, in an ALS mouse model we show that inhibiting MAP4Ks preserves motor neurons and significantly extends animal lifespan.
Whole Body PBPK Model of Nasal Naloxone Administration to Measure Repeat Dosing Requirements During Fentanyl Overdose
Authors: Baird Austin , White Steven A. , Das Rishi , Tatum Nathan , Bisgaard Erika K 
Published: April 2023

AbstractOpioid use in the United States and abroad is an endemic part of culture with yearly increases in overdose rates and deaths. As rates of overdose incidence increases, the use of the safe and effective reversal agent, naloxone, in the form of a nasal rescue spray is being fielded and used by emergency medical technicians (EMTs) at a greater and greater rate. Despite advances in deployment of these rescue products, deaths are continuing to increase. There is evidence that repeated dosing of a naloxone nasal spray (such as Narcan) is becoming more common due to the amount and type of opiate being abused. Despite the benefits of naloxone related to opioid reversals, we lack repeated dosing guidelines as a function of opiate and amount the patient has taken. Goal directed dosing is promising, where respiratory markers are being used as an indication of the patient recovery but require time and understanding by the EMT. We construct a whole-body model of the pharmacokinetics and dynamics of an opiate, fentanyl on respiratory depression. We then construct a model of nasal deposition and administration of naloxone to investigate repeat dosing requirements for large overdoses. We demonstrate that naloxone is highly effective at reversing respiratory symptoms of the patient and recommend dosing requirements as a function of opiate amount administered. By designing the model to include circulation and respiration we investigate physiological markers that may be used in goal directed therapy rescue treatments.
Resolving exit strategies of mycobacteria by combining high-pressure freezing with 3D-correlative light and electron microscopy
Authors: Franzkoch Rico , Anand Aby , Breitsprecher Leonhard , Psathaki Olympia E. , Barisch Caroline 
Published: April 2023

AbstractThe infection course ofMycobacterium tuberculosisis highly dynamic and comprises sequential stages that require damaging and crossing of several membranes to enable the translocation of the bacteria into the cytosol or their escape from the host. Many important breakthroughs such as the restriction of vacuolar and cytosolic mycobacteria by the autophagy pathway and the recruitment of sophisticated host repair machineries to theMycobacterium-containing vacuole have been gained in theDictyostelium discoideum/M. marinumsystem. Despite the availability of well-established light and advanced electron microscopy techniques in this system, a correlative approach that integrates both methodologies with almost native ultrastructural preservation is still lacking at the moment. This is most likely due to the low ability ofD. discoideumto adhere to surfaces, which results in cell loss even after fixation. To address this problem, we improved the adhesion of cells and developed a straightforward and convenient workflow for 3D-correlative light and electron microscopy. This approach includes high-pressure freezing, which is an excellent technique for preserving membranes. Thus, our method allows to monitor the ultrastructural aspects of vacuole escape which is of central importance for the survival and dissemination of bacterial pathogens.
Learning shapes neural geometry in the prefrontal cortex
Authors: Wójcik Michał J. , Stroud Jake P. , Wasmuht Dante , Kusunoki Makoto , Kadohisa Mikiko , Buckley Mark J. , Myers Nicholas E. , Hunt Laurence T. , Duncan John , Stokes Mark G. 
Published: April 2023

AbstractThe relationship between the geometry of neural representations and the task being performed is a central question in neuroscience1–6. The primate prefrontal cortex (PFC) is a primary focus of inquiry in this regard, as under different conditions, PFC can encode information with geometries that either rely on past experience7–13or are experience agnostic3,14–16. One hypothesis is that PFC representations should evolve with learning4,17,18, from a format that supports exploration of all possible task rules to a format that minimises the encoding of task-irrelevant features4,17,18and supports generalisation7,8. Here we test this idea by recording neural activity from PFC when learning a new rule (‘XOR rule’) from scratch. We show that PFC representations progress from being high dimensional, nonlinear and randomly mixed to low dimensional and rule selective, consistent with predictions from constrained optimised neural networks. We also find that this low-dimensional representation facilitates generalisation of the XOR rule to a new stimulus set. These results show that previously conflicting accounts of PFC representations can be reconciled by considering the adaptation of these representations across different stages of learning.
Analysis of antennal responses to motion stimuli in the honey bee by automated tracking using DeepLabCut
Authors: Kohno Hiroki , Kamata Shuichi , Kubo Takeo 
Published: April 2023

AbstractConsidering recent developments in gene manipulation methods for honey bees, establishing simple, robust, and indoor assay systems which can analyze behavioral components in detail is important for the rise of honey bee behavioral genetics. We focused on the movements of antennae of the honey bee, which are used for not only multimodal sensory perception but also interactions between individuals. We developed an experimental system for analyzing the antennal responses (ARs) of the honey bee using DeepLabCut, a markerless posture-tracking tool using deep learning. The tracking of antennal movements during the presentation of vertical (downward and upward) motion stimuli using DeepLabCut successfully detected the ARs reported in the previous studies, where bees tilted their antennae in the direction opposite to the motion stimuli. In addition, we successfully detected ARs in response to horizontal (forward and backward) motion stimuli. An investigation of the developmental maturation of honey bee ARs showed that ARs to motion stimuli were not detected in bees immediately after emergence but became detectable through post-emergence development in an experience-independent manner. Furthermore, unsupervised clustering analysis using multidimensional data created by processing tracking data using DeepLabCut classified antennal movements into different clusters, suggesting that data-driven behavioral classification can apply to AR paradigms. These results reveal novel AR to visual stimuli and developmental maturation of ARs and suggest the efficacy of data-driven analysis for behavioral classification in behavioral studies of the honey bee.Summary statementAutomated tracking using DeepLabCut was successfully applied to measure the antennal response to motion stimuli and unsupervised classification of antennal movements in honey bees.
A guide to thein vitroreconstitution of Cdc42 GTPase activity and its regulation
Authors: Tschirpke Sophie , van Opstal Frank , van der Valk Ramon , Daalman Werner K-G. , Laan Liedewij 
Published: April 2023

AbstractCdc42 is a small Rho-type GTPase and the main regulator of cell division in eukaryotes. It is surrounded by a large network of regulatory proteins. To understand the processes around cell division, in-depth understanding of Cdc42 and its regulation is required.In vitroreconstitutions are a suitable tool for such detailed mechanistic studies, as they allow a high level of control over the conditions and components used and. For these Cdc42 and its regulators need to be expressed, purified, and tested for their activity. There are many methods described for this, but their details, possible difficulties, and points of failure are rarely discussed. This makesin vitrostudies on Cdc42 less accessible to scientists that have a background different from biochemistry. We here present our experience with working with Cdc42in vitro. We describe the recombinant expression and purification behaviour of 12 Cdc42, six Cdc42-mNeonGreenSWand four Cdc42-sfGFPSWconstructs inE. coli. We explore Cdc42 dimerisationin vitroand assess its activity using GTPase Glo assays and Flag-pulldown assays. GTPase Glo assays turn out to be a reliable tool to quantitatively asses GTPase activities, wheareas pulldown experiments are more error prone. We find that most Cdc42 constructs, with the exception of those with an N-terminal Twin-Step-tag, show a similar GTPase activity and interaction with the GDP/GTP exchange factor Cdc24. We close with using enterokinase and TEV protease to generate untagged Cdc42. Enterokinase also cuts Cdc42 in an undesired position. TEV protease leads to the desired product, which retains its GTPase activity but shows a reduced Cdc24 interaction. The work presented here acts as a guide for scientists desiring to work with Cdc42in vitrothrough describing Cdc42’s properties in detail and examining assays that can be used to study its behaviour or act as activity checks.Graphical abstract
Refined Tamoxifen Administration in Mice by Encouraging Voluntary Consumption of Palatable Formulations
Authors: Vanhecke Dominique , Bugada Viola , Buch Thorsten 
Published: April 2023

AbstractDrug administration in preclinical rodent models is essential for research and development of novel therapies. Compassionate administration methods have been developed, but these are mostly incompatible with water-insoluble drugs such as tamoxifen or do not allow for precise timing or dosing of the drugs. For more than two decades, tamoxifen has been administered by oral gavage or injection to CreERT2/loxP gene-modified mouse models to spatiotemporally control gene expression, with the numbers of such models steadily increasing in recent years. Animal-friendly procedures for accurately administering tamoxifen or other water-insoluble drugs would therefore have an important impact on animal welfare. Based on a previously published micropipette feeding protocol, we developed palatable formulations to encourage voluntary consumption of tamoxifen. We evaluated the acceptance of the new formulations by mice during training and treatment and assessed the efficacy of tamoxifen-mediated induction of CreERT2/loxP dependent reporter genes. Both sweetened milk and syrup-based formulations encouraged mice to consume tamoxifen voluntarily, but only sweetened milk formulations were statistically non-inferior to oral gavage in inducing CreERT2-mediated gene expression. Serum concentrations of tamoxifen metabolites, quantified using an in-house developed cell assay, confirmed the lower efficacies of syrup- as compared to sweetened milk-based formulations. We found dosing with a micropipette to be more accurate, with the added advantage that the method requires little training for the experimenter. The new palatable solutions encourage voluntary consumption of tamoxifen without loss of efficacy compared to oral gavage and thus represent a refined administration method.