bluuebunny/crossref_metadata_2025_split huggingface dataset:
Levamisole suppresses activation and proliferation of human T cells by the induction of a p53-dependent DNA damage response
Authors: Khan Gerarda H. , Veltkamp Floor , Scheper Mirte , Hoebe Ron A. , Claessen Nike , Butter Loes , Bouts Antonia H.M. , Florquin Sandrine , Guikema Jeroen E.J. 
Published: May 2023

AbstractLevamisole (LMS) is a small molecule used in the treatment of idiopathic nephrotic syndrome (INS). The pathogenesis of INS remains unknown, but most evidence points towards an immunological basis of the disease. Recently, LMS has been shown to increase the relapse-free survival in INS patients treated in combination with corticosteroids with relatively few side effects. While LMS has been hypothesized to exert an immunomodulatory effect, its mechanism of action remains unknown. To provide insight into the working mechanism of LMS, we studied its immunomodulatory activity on in vitro activated human T cells. We show here that treatment with LMS decreased activation and proliferation of human CD4+ and CD8+ T cells. In addition, production of T cell activation-associated cytokines such as IL-2, TNF-α and IFN-γ were reduced upon LMS treatment, whereas IL-4 and IL-13 production was increased. Gene expression profiling confirmed the suppressive effects of LMS on proliferation as numerous genes involved in cell cycle progression were downregulated. Furthermore, genes associated with p53 activation and cell cycle arrest were upregulated by LMS. In agreement, LMS treatment resulted in p53 phosphorylation and increased expression of the p53 target gene FAS. Accordingly, LMS sensitized activated T cells for Fas-mediated apoptosis. Cell cycle analysis showed that LMS induced a mid-S phase arrest indicating the activation of a replication stress-associated checkpoint. In support, LMS treatment resulted in γH2AX-foci formation and phosphorylation of CHK1. Our findings indicate that LMS acts as an immunosuppressive drug that directly affects the activation and proliferation of human T cells by induction of DNA damage and the activation of a p53-dependent DNA damage response.
Phage display assisted discovery of a pH-dependent anti-α-cobratoxin antibody from a natural variable domain library
Authors: Tulika Tulika , Pedersen Rasmus W. , Rimbault Charlotte , Ahmadi Shirin , Ledsgaard Line , Bohn Markus-Frederik , Ljungars Anne , Voldborg Bjørn G. , Ruso-Julve Fulgencio , Andersen Jan Terje , Laustsen Andreas H. 
Published: May 2023

AbstractRecycling antibodies can bind to their target antigen at neutral pH in the blood stream and release them upon endocytosis when pH levels drop, allowing the antibodies to be recycled into circulation via FcRn-mediated pathway, while the antigens undergo lysosomal degradation. This enables recycling antibodies to achieve the same therapeutic effect at lower doses than their non-recyclable counterparts. The development of such antibodies is typically achieved by histidine doping of the variable regions of specific antibodies or by performingin vitroantibody selection campaigns utilizing histidine doped libraries. While often successful, these strategies may introduce sequence liabilities, as they often involve mutations that may render the resultant antibodies to be non-natural. Here, we present a methodology that employs a naïve antibody phage display library, consisting of natural variable domains, to discover antibodies that bind α-cobratoxin from the venom ofNaja kaouthiain a pH-dependent manner. Upon screening of the discovered antibodies with immunoassays and bio-layer interferometry, a pH-dependent antibody was discovered that exhibits an 8-fold higher dissociation rate at pH 5.5 than 7.4. Interestingly, the variable domains of the pH-dependent antibody were found to be entirely devoid of histidines, demonstrating that pH-dependency may not always be driven by this amino acid. Further, given the high diversity available in a naïve antibody library, the methodology presented here can likely be applied to discover pH-dependent antibodies against different targetsab initiowithout the need of histidine doping.For broader audienceHere, we present the discovery of an α-cobratoxin targeting pH-dependent antibody, with a variable region devoid of histidines, from a naïve antibody library with natural variable domains. Our findings suggest that the commonly taken approach of histidine doping to find pH-dependent antibodies may not always be required, and thus offer an alternative strategy for the discovery of pH-dependent antibodies.
Ade novolong-read genome assembly of the sacred datura plant (Datura wrightii) reveals a role of tandem gene duplications in the evolution of herbivore-defense response
Authors: Goldberg Jay K , Olcerst Aaron , McKibben Michael , Hare J Daniel , Barker Michael S , Bronstein Judith 
Published: May 2023

AbstractThe sacred datura plant (Solanales: Solanaceae:Datura wrightii) has been used to study plant-herbivore interactions for decades. The wealth of information that has resulted leads it to have potential as a model system for studying the ecological and evolutionary genomics of these interactions. We present ade novo Datura wrightiigenome assembled using PacBio HiFi long-reads. Our assembly is highly complete and contiguous (N50 = 179Mb, BUSCO Complete = 97.6%). We successfully detected a previously documented ancient whole genome duplication using our assembly and have classified the gene duplication history that generated its coding sequence content. We use it as the basis for a genome-guided differential expression analysis to identify the induced responses of this plant to one of its specialized herbivores (Coleoptera: Chrysomelidae:Lema daturaphila). We find over 3000 differentially expressed genes associated with herbivory and that elevated expression levels of over 200 genes last for several days. We also combined our analyses to determine the role that different gene duplication categories have played in the evolution ofDatura-herbivore interactions. We find that tandem duplications have expanded multiple functional groups of herbivore responsive genes with defensive functions, including UGT-glycosyltranserases, oxidoreductase enzymes, and peptidase inhibitors. Overall, our results expand our knowledge of herbivore-induced plant transcriptional responses and the evolutionary history of the underlying herbivore-response genes.
Attenuation of muscle spindle firing with artificially increased series compliance during stretch of relaxed muscle
Authors: Abbott Emily M , Stephens Jacob D , Simha Surabhi N , Wood Leo , Nardelli Paul , Cope Timothy C , Sawicki Gregory S , Ting Lena H 
Published: May 2023

AbstractMuscle spindles relay vital mechanosensory information for movement and posture, but muscle spindle feedback is coupled to skeletal motion by a compliant tendon. Little is known about the effects of tendon compliance on muscle spindle feedback during movement, and the complex firing of muscle spindles make these effects difficult to predict. Our goal was to investigate changes in muscle spindle firing using added series elastic elements (SEEs) to mimic a more compliant tendon, and to characterize the accompanying changes in firing with respect to muscle-tendon unit (MTU) and muscle fascicle displacements (recorded via sonomicrometry). Sinusoidal, ramp-hold-release, and triangular stretches were analyzed to examine potential changes in muscle spindle instantaneous firing rates (IFRs) in locomotor-and perturbation-like stretches as well as history dependence. Added SEEs effectively reduced overall MTU stiffness and generally reduced muscle spindle firing rates, but the effect differed across stretch types. During sinusoidal stretches, peak firing rates were reduced and IFR was strongly correlated with fascicle velocity. During ramp stretches, SEEs reduced the dynamic and static responses of the spindle during lengthening but had no effect on initial bursts at the onset of stretch. Notably, IFR was negatively related to fascicle displacement during the hold phase. During triangular stretches, SEEs reduced the mean IFR during the first and second stretches, affecting the history dependence of mean IFR. Overall, these results demonstrate that tendon compliance may attenuate muscle spindle feedback during movement, but these changes cannot be fully explained by reduced muscle fascicle length and velocity.New FindingsWhat is the central question of the study?Little is known about the effects of tendon compliance on muscle spindle function. We asked whether increasing the series compliance the muscle-tendon unit muscle spindle Ia responses to stretch. We also test the relationship between muscle spindle firing rates and muscle fascicle biomechanics.What is the main finding and its importance?Muscle spindle firing was generally attenuated with added series compliance, with the exception of the initial burst at the onset of stretch. Overall, the changes depended upon stretch profiles, and could not be fully explained by muscle fascicle length and velocity.
Transition from Transient DNA Rereplication to Inherited Gene Amplification Following Prolonged Environmental Stress
Authors: Wright Gregory M , Menzel Johannes , Tatman Philip D. , Black Joshua C. 
Published: May 2023

ABSTRACTCells require the ability to adapt to changing environmental conditions, however, it is unclear how these changes elicit stable permanent changes in genomes. We demonstrate that, in response to environmental metal exposure, the metallothionein (MT) locus undergoes DNA rereplication generating transient site-specific gene amplifications (TSSGs). Chronic metal exposure allows transition from MT TSSG to inherited MT gene amplification through homologous recombination within and outside of the MT locus. DNA rereplication of the MT locus is suppressed by H3K27me3 and EZH2. Long-term ablation of EZH2 activity eventually leads to integration and inheritance of MT gene amplifications without the selective pressure of metal exposure. The rereplication and inheritance of MT gene amplification is an evolutionarily conserved response to environmental metal from yeast to human. Our results describe a new paradigm for adaptation to environmental stress where targeted, transient DNA rereplication precedes stable inherited gene amplification.
Curbing zoonotic disease spread in multi-host-species systems will require integrating novel data streams and analytical approaches: evidence from a scoping review of bovine tuberculosis
Authors: Conteddu Kimberly , English Holly M. , Byrne Andrew W. , Amin Bawan , Griffin Laura L. , Kaur Prabhleen , Morera-Pujol Virginia , Murphy Kilian J. , Salter-Townshend Michael , Smith Adam F. , Ciuti Simone 
Published: May 2023

AbstractBackgroundZoonotic diseases represent a significant societal challenge in terms of their health and economic impacts. One Health approaches to managing zoonotic diseases are becoming more prevalent, but require novel thinking, tools and cross-disciplinary collaboration. Bovine tuberculosis (bTB) is one example of a costly One Health challenge with a complex epidemiology involving human, domestic animal, wildlife and environmental factors, which require sophisticated collaborative approaches.ObjectiveWe undertook a scoping review of multi-host bTB epidemiology to identify recent trends in species publication focus, methodologies, scales and One Health approaches. We aimed to identify research gaps where novel research could provide insights to inform control policy, for bTB and other zoonoses.ResultsThe review included 167 articles. We found different levels of research attention across episystems, with a significant proportion of the literature focusing on the badger-cattle-TB episystem, with far less attention given to the multi-host episystems of southern Africa. We found a limited number of studies focusing on management solutions and their efficacy, with very few studies looking at modelling exit strategies. Surprisingly, only a small number of studies looked at the effect of human disturbances on the spread of bTB involving wildlife hosts. Most of the studies we reviewed focused on the effect of badger vaccination and culling on bTB dynamics with few looking at how roads, human perturbations and habitat change may affect wildlife movement and disease spread. Finally, we observed a lack of studies considering the effect of weather variables on bTB spread, which is particularly relevant when studying zoonoses under climate change scenarios.ConclusionsSignificant technological and methodological advances have been applied to bTB episystems, providing explicit insights into its spread and maintenance across populations. We identified a prominent bias towards certain species and locations. Generating more high-quality empirical data on wildlife host distribution and abundance, high-resolution individual behaviours and greater use of mathematical models and simulations are key areas for future research. Integrating data sources across disciplines, and a “virtuous cycle” of well-designed empirical data collection linked with mathematical and simulation modelling could provide additional gains for policy-makers and managers, enabling optimised bTB management with broader insights for other zoonoses.
Invariant relationship unites REM and NonREM sleep
Authors: Zhdanova Irina V. , Kharchenko Vasili 
Published: May 2023

AbstractEstablishing structural and functional links between two distinct types of sleep, rapid-eye-movement (REM) and non-REM (NREM), that alternate and form several sleep cycles per night, has posed a significant challenge. Here we demonstrate a simple invariant relationship where the product of the duration of NREM sleep episode and intensity of subsequent REM sleep episode remains constant over successive sleep cycles of normal human sleep. This Sleep Cycle Invariant (SCI), previously predicted by a quantitative model of sleep dynamics, supports the structural and functional unity of NREM and REM sleep. The significance of SCI for understanding normal sleep and sleep disorders is highlighted by alterations in REM sleep intensity and NREM sleep episode duration being a hallmark of major depression.One-Sentence SummaryThe duration of NREM sleep and intensity of REM sleep have an invariant relationship across normal sleep cycles of one night.
Elucidation of multiple high-resolution states of human MutSβ by cryo-EM reveals interplay between ATP/ADP binding and heteroduplex DNA recognition
Authors: Lee Jung-Hoon , Thomsen Maren , Daub Herwin , Thieulin-Pardo Gabriel , Steinbacher Stefan C. , Sztyler Agnieszka , Dahiya Vinay , Neudegger Tobias , Dominguez Celia , Iyer Ravi R. , Wilkinson Hilary A. , Monteagudo Edith , Plotnikov Nikolay V. , Felsenfeld Dan P. , Haque Tasir S. , Finley Michael , Boudet Julien , Vogt Thomas F. , Prasad Brinda C. 
Published: May 2023

AbstractHuman and mouse genetic studies have demonstrated a role for DNA mismatch repair (MMR) molecular machines in modulating the rate of somatic expansion of the huntingtin (HTT)CAG repeats, and onset and progression of Huntington’s Disease (HD). MutSβ, a key component of the MMR pathway, is a heterodimeric protein of MSH2 and MSH3 that recognizes and initiates the repair of extrahelical DNA extrusions. Loss-of-function of mouseMsh3and reduced-expression alleles of humanMSH3lead to slower rates of somatic expansion and delayed disease onset in humans, signifying MSH3 as a promising therapeutic target for HD. Here we report biochemical and cryo-electron microscopy analyses of human MutSβ, demonstrating MutSβ undergoes conformational changes induced by nucleotide and DNA binding. We present multiple conformations of MutSβ including the DNA-free MutSβ compatible with homoduplex DNA binding, two distinct structures of MutSβ bound to (CAG)2DNA, a sliding clamp form and a DNA-unbound, ATP-bound conformation. Along with evidence for novel conformational states adopted by MutSβ to initiate the MMR cascade, these structures provide a foundation for structure-guided drug discovery.
Investigating the causal effects of childhood and adulthood adiposity on later life mental health outcome: a Mendelian randomisation study
Authors: Pathak Sweta , Richardson Tom G , Sanderson Eleanor , Åsvold Bjørn Olav , Bhatta Laxmi , Brumpton Ben 
Published: May 2023

AbstractBackgroundObesity particularly during childhood is considered a global public health crisis and has been linked with later life health consequences including mental health.However, there is lack of causal understanding if childhood adiposity has a direct effect on mental health or has an indirect effect after accounting for adulthood body size.ObjectiveTo investigate the total and direct effect of childhood adiposity on later life anxiety and depression.MethodTwo-sample Mendelian randomization (MR) was performed to estimate the total effect and direct effect (accounting for adulthood body size) of childhood body size on anxiety and depression. We used summary statistics from a genome-wide association study (GWAS) of UK Biobank (n=453,169) and large-scale consortia of anxiety (Million Veteran Program) and depression (Psychiatric Genomics Consortium) (n=175,163 and n=173,005, respectively).ResultUnivariable MR did not indicate genetically predicted effects of childhood body size with later life anxiety (beta=-0.05, 95% CI=-0.13, 0.02), and depression (OR=1.06, 95% CI=0.94, 1.20). However, using multivariable MR, we observed that the higher body size in childhood reduced the risk of later life anxiety (beta=-0.19, 95% CI=-0.29, -0.08) and depression (OR=0.83, 95% CI=0.71, 0.97). Both univariable and multivariable MR indicated that higher body size in adulthood increased the risk of later life anxiety and depression.ConclusionOur findings suggest that the higher body size in childhood has a protective effect on later life anxiety and depression, if obesity is not present into adulthood. Higher body size in adulthood was a risk factor for later life anxiety and depression.
Wildfire exposure and academic performance in Brazil: a causal inference approach for spatiotemporal data
Authors: McGrath Sean , Mukherjee Rajarshi , Réquia Weeberb J. , Lee Wan-Chen 
Published: May 2023

AbstractAs the frequency and intensity of wildfires are projected to globally amplify due to climate change, there is a growing need to quantify the impact of exposure to wildfires in vulnerable populations such as adolescents. In our study, we applied rigorous causal inference methods to estimate the effect of wildfire exposure on academic performance of high school students in Brazil between 2009 and 2015. Using longitudinal data from 8,183 high schools across 1,571 municipalities in Brazil, we estimated that the average performance in most academic subjects decreases under interventions that increase wildfire exposure, e.g., a decrease of 1.8% (p= 0.01) in the natural sciences when increasing the wildfire density from 0.0035 wildfires/km2(first quantile in the sample) to 0.0222 wildfires/km2(third quartile). Furthermore, these effects considerably worsened over time and were worse in regions with lower income. Our findings highlight the adverse impact of wildfires on educational outcomes.
Effects of Equine-Assisted Therapy on Recovery after Stroke – A Systematic Review
Authors: Trunk Bettina Hanna , Gharabaghi Alireza 
Published: May 2023

AbstractBackgroundEquine-Assisted Therapy (EAT) can boost well-being and recovery of patients with neurological or psychiatric disorders.ObjectiveThe goal of this systematic review is to gain a better understanding of the effects of EAT on recovery after stroke.MethodsA systematic literature search was performed in the following databases: PubMed, Web of Science and Scopus. Furthermore, reference lists from the articles included were screened. English-written articles published between 2000-2023 that reported on health-related effects of EAT (applied with both horses and riding simulators) on stroke recovery in patients aged between 18 and 85 were included. Methodological quality was assessed by the Mixed Methods Appraisal Tool.ResultsFollowing the screening of 2030 and retrieval of 33 articles respectively, 14 studies were included in this systematic review (437 patients, mean age range: 40 – 70 years). Since several of these studies lacked important methodological information, the overall methodological quality varied. Thirteen studies reported physical findings (balance, gait, postural coordination, activities of daily living, lower extremity motor impairment, motor function and hand strength), and seven studies reported further health-related outcomes (cognition, quality of life, depression and perception of the intervention, muscle thickness and trunk muscle activity). The findings suggest positive effects of EAT on stroke recovery in different health-related outcomes, whereas the most consistent beneficial effects were reported for balance and gait.ConclusionEAT appears to be a promising multimodal intervention for the recovery of different functions after stroke. However, evidence is sparse and methodological quality limited. Future research should investigate the effects of EAT on stroke recovery more systematically.
Surveillance strategies for the detection of new SARS-CoV-2 variants across epidemiological contexts
Authors: Oliveira Roster Kirstin I. , Kissler Stephen M. , Omoregie Enoma , Wang Jade C. , Amin Helly , Di Lonardo Steve , Hughes Scott , Grad Yonatan H. 
Published: May 2023

AbstractRapid identification of new SARS-CoV-2 variants is a critical component of the public health response to the COVID-19 pandemic. However, we lack a quantitative framework to assess the expected performance of sampling strategies in varying epidemic contexts. To address this gap, we used a multi-patch stochastic model of SARS-CoV-2 spread in New York City to evaluate the impact of the volume of testing and sequencing, geographic representativeness of sampling, location and timing of variant emergence, and relative variant transmissibility on the time to first detection of a new variant. The strategy of targeted sampling of likely emergence locations offered the most improvement in detection speed. Increasing sequencing capacity reduced detection time more than increasing testing volumes. The relative transmissibility of the new variant and the epidemic context of variant emergence also influenced detection times, showing that individual surveillance strategies can result in a wide range of detection outcomes, depending on the underlying dynamics of the circulating variants. These findings help contextualize the design, interpretation, and trade-offs of genomic surveillance strategies.