bluuebunny/crossref_metadata_2025_split huggingface dataset:
Aging-related olfactory loss is associated with olfactory stem cell transcriptional alterations in humans
Authors: Oliva Allison D. , Issa Khalil , Hachem Ralph Abi , Jang David , Gupta Rupali , Moseman E. Ashley , Matsunami Hiroaki , Goldstein Bradley J. 
Published: August 2021

AbstractPresbyosmia, or aging related olfactory loss, occurs in a majority of humans over age 65 years, yet remains poorly understood, with no specific treatment options. The olfactory epithelium (OE) in the nasal fossa is the peripheral organ for olfaction, and is subject to acquired damage, suggesting a likely site of pathology in aging. OE basal stem cells reconstitute the neuroepithelium in response to cell loss under normal conditions. In aged OE, patches of respiratory-like metaplasia have been observed histologically, consistent with a failure in normal neuroepithelial homeostasis or repair. Accordingly, we have focused on identifying cellular and molecular changes in presbyosmic OE. Combining psychophysical testing with olfactory mucosa biopsy analysis, single cell RNA-sequencing (scRNA-seq), and human olfactory culture studies, we identified evidence for inflammation-associated changes in the OE stem cells of presbyosmic patients. The presbyosmic basal stem cells exhibited increased expression of genes involved in response to cytokines or stress, or the regulation of proliferation and differentiation. To facilitate further study of human OE stem cells, we developed an adult human basal cell culture model. Characterization of cultures using scRNA-seq confirmed maintenance of a reserve stem cell-like phenotype, and brief cytokine exposure in basal cell cultures resulted in increased expression of TP63, a transcription factor acting to prevent OE stem cell differentiation. Our data are consistent with a process by which aging-related inflammatory changes in OE stem cells may contribute to presbyosmia, via the disruption of normal epithelial homeostasis, suggesting that OE stem cells may represent a rational therapeutic target for restoration of olfaction.One Sentence SummarySingle cell profiling suggests that inflammatory-associated olfactory epithelial stem cell dysfunction is associated with presbyosmia in humans.
Dose-dependent dissociation of pro-cognitive effects of donepezil on attention and cognitive flexibility in rhesus monkeys
Authors: Hassani Seyed A. , Lendor Sofia , Neumann Adam , Roy Kanchan Sinha , Boroujeni Kianoush Banaie , Hoffman Kari L. , Pawliszyn Janusz , Womelsdorf Thilo 
Published: August 2021

ABSTRACTBACKGROUNDDonepezil exerts pro-cognitive effects by non-selectively enhancing acetylcholine (ACh) across multiple brain systems. The brain systems that mediate pro-cognitive effects of attentional control and cognitive flexibility are the prefrontal cortex and the anterior striatum which have different pharmacokinetic sensitivities to ACh modulation. We speculated that these area-specific ACh profiles lead to distinct optimal dose-ranges for donepezil to enhance the cognitive domains of attention and flexible learning.METHODSTo test for dose-specific effects of donepezil on different cognitive domains we devised a multi-task paradigm for nonhuman primates (NHPs) that assessed attention and cognitive flexibility. NHPs received either vehicle or variable doses of donepezil prior to task performance. We measured donepezil intracerebral and how strong it prevented the breakdown of ACh within prefrontal cortex and anterior striatum using solid-phase-microextraction neurochemistry.RESULTSThe highest administered donepezil dose improved attention and made subjects more robust against distractor interference, but it did not improve flexible learning. In contrast, only a lower dose range of donepezil improved flexible learning and reduced perseveration, but without distractor-dependent attentional improvement. Neurochemical measurements confirmed a dose-dependent increase of extracellular donepezil and decreases in choline within the prefrontal cortex and the striatum.CONCLUSIONSThe donepezil dose for maximally improving attention functions differed from the dose range that enhanced cognitive flexibility despite the availability of the drug in the major brain systems supporting these cognitive functions. Thus, the non-selective acetylcholine esterase inhibitor donepezil inherently trades improvement in the attention domain for improvement in the cognitive flexibility domain at a given dose range.
Natural reassortment of a segmented RNA arbovirus illustrates plasticity of phenotype in the arthropod vector and mammalian hostin vivo
Authors: Sanders Christopher , Veronesi Eva , Rajko-Nenow Paulina , Mertens Peter Paul Clement , Batten Carrie , Gubbins Simon , Darpel Karin , Carpenter Simon 
Published: August 2021

ABSTRACTSegmented RNA viruses are a taxonomically diverse group of 11 families that can infect plant, wildlife, livestock and human hosts. A shared feature of these viruses is the ability to exchange genome segments during co-infection of a host by a process termed ‘reassortment’. Reassortment enables rapid evolutionary change, but in the case of segmented RNA viruses utilising an arthropod vector is set against the constraint of purifying selection and genetic bottlenecks imposed by replication in two evolutionarily distant hosts. In this study, we use anin vivohost: arbovirus: vector model to investigate the impact of reassortment on two phenotypic traits: vector competence and virulence in the host. Bluetongue virus (BTV) (Reoviridae) is the causative agent of bluetongue (BT), an economically important disease of domestic and wild ruminants and deer. The genome of BTV is comprised of 10 linear segments of dsRNA and the virus is transmitted between ruminants byCulicoidesbiting midges (Diptera: Ceratopogonidae). Five strains of BTV representing three serotypes (BTV-1, BTV-4 and BTV-8) were isolated from naturally infected ruminants in Europe and parental/reassortant lineage status assigned through full genome sequencing. Each strain was then assessed in parallel for the ability to infectCulicoidesand to cause BT in sheep. Our results demonstrate that two reassortment strains, which themselves became established in the field, had obtained high replication ability inC. sonorensisfrom one of the parental virus strains which allowed inferences of the genome segments conferring this phenotypic trait.IMPORTANCEReassortment between strains can lead to major shifts in the transmission parameters and virulence of segmented RNA viruses with consequences for spread, persistence and impact. The ability of these pathogens to change their phenotypes rapidly in response to selection pressure in new environments presents a major challenge in understanding factors driving emergence. Utilising a natural mammalian host-insect vector infection and transmission model, we demonstrated for the first time the genetic basis for a phenotypic trait of BTV within strains directly isolated from the field and, hence, selected and relevant for natural transmission.
Beyond Black vs White: Racial/Ethnic Disparities in Chronic Pain including Hispanic, Asian, Native American, and Multiracial U.S. Adults
Authors: Zajacova Anna , Grol-Prokopczyk Hanna , Fillingim Roger 
Published: August 2021

ABSTRACTPrevious literature on race/ethnicity and pain has rarely included all major U.S. racial groups or examined the sensitivity of findings to different pain operationalizations. Using data from the 2010-2018 National Health Interview Surveys on adults 18+ (N=273,972), we calculate the weighted prevalence of six definitions of pain to provide a detailed description of chronic pain in White, Black, Hispanic, Asian, Native American, and multiracial groups. We also estimate logistic models to obtain relative disparities, including net of demographic and socioeconomic (SES) factors; finally, we calculate average predicted probabilities to show prevalence disparities in absolute terms. We find that Asian Americans have the lowest pain prevalence across all pain definitions or model specifications. In contrast, Native American and multiracial adults have the highest pain prevalence. This pain excess is due to the lower SES among Native Americans but remains significant and unexplained among multiracial adults. Whites, Blacks, and Hispanics fall in between. In this trio, Hispanics have the lowest prevalence, an advantage not attributable to immigrant status or SES. While most prior research focused on Black-White comparisons, these two groups differ relatively little. Blacks report lower prevalence of less severe pain definitions than Whites, but higher prevalence of severe pain. Net of SES, however, Blacks have significantly lower pain across all definitions. Overall, racial disparities are larger than previously recognized once all major racial groups are included, and these disparities are largely consistent across different operationalizations of pain.
Hierarchical control of visually-guided movements in a 3D-printed robot arm
Authors: Matić Adam , Valerjev Pavle , Gomez-Marin Alex 
Published: August 2021

AbstractThe control architecture guiding simple movements such as reaching toward a visual target remains an open problem. The nervous system needs to integrate different sensory modalities and coordinate multiple degrees of freedom in the human arm to achieve that goal. The challenge increases due to noise and transport delays in neural signals, nonlinear and fatigable muscles as actuators, and unpredictable environmental disturbances. Here we examined the capabilities of a previously proposed hierarchical feedback control model (Powers 1999, 2008), so far only testedin silico. We built a robot arm system with four degrees of freedom, including a visual system for locating the planar position of the hand, joint angle proprioception, and pressure sensing in one point of contact. We subjected the robot to various human-inspired reaching and tracking tasks and found features of biological movement, such as isochrony and bell-shaped velocity profiles in straight-line movements, and the speed-curvature power law in curved movements. These behavioral properties emerge without trajectory planning or explicit optimization algorithms. We then applied static structural perturbations to the robot: we blocked the wrist joint, tilted the writing surface, extended the hand with a tool, and rotated the visual system. For all of them, we found that the armin machinaadapts its behavior without being reprogrammed. In sum, while limited in speed and precision (by the nature of the do-it-yourself inexpensive components we used to build the robot from scratch), when faced with the noise, delays, nonlinearities, and unpredictable disturbances of the real world, the embodied control architecture shown here balances biological realism with design simplicity.
Characterization of the composition and functioning of the Crumbs complex in C. elegans
Authors: Castiglioni Victoria G , Ramalho João J , Kroll Jason , Stucchi Riccardo , van Beuzekom Hanna , Schmidt Ruben , Altelaar Maarten , Boxem Mike 
Published: August 2021

AbstractThe apical domain of epithelial cells can acquire a diverse array of morphologies and functions, which is critical for the function of epithelial tissues. The Crumbs proteins are evolutionary conserved transmembrane proteins with essential roles in promoting apical domain formation in epithelial cells. The short intracellular tail of Crumbs proteins interacts with a variety of proteins, including the scaffolding protein Pals1 (protein associated with LIN7, Stardust in Drosophila). Pals1 in turn binds to a second scaffolding protein termed PATJ (Pals1-associated tight junction protein), to form the core Crumbs/Pals1/PATJ Crumbs complex. While essential roles in epithelial organization have been shown for Crumbs proteins in Drosophila and mammalian systems, the three Caenorhabditis elegans crumbs genes are dispensable for epithelial polarization and animal development. Moreover, the presence and functioning of orthologs of Pals1 and PATJ has not been investigated. Here, we identify MAGU-2 and MPZ-1 as the C. elegans orthologs of Pals1 and PATJ, respectively. We show that MAGU-2 interacts with all three Crumbs proteins as well as MPZ-1, and localizes to the apical membrane domain in a Crumbs-dependent fashion. Similar to crumbs mutants, a magu-2 null mutant shows no developmental or epithelial polarity defects. Finally, we show that overexpression of the Crumbs proteins EAT-20 or CRB-3 in the C. elegans intestine can lead to apical membrane expansion. Our results shed light into the composition of the C. elegans Crumbs complex and indicate that the role of Crumbs proteins in promoting apical domain formation is conserved.
Mucin induces CRISPR-Cas defence in an opportunistic pathogen
Authors: Almeida Gabriel MF , Hoikkala Ville , Ravantti Janne , Rantanen Noora , Sundberg Lotta-Riina 
Published: August 2021

AbstractParasitism by bacteriophages has led to the evolution of a variety of defense mechanisms in their host bacteria. However, it is unclear what factors lead to specific defenses being deployed upon phage infection. To explore this question, we exposed the bacterial fish pathogenFlavobacterium columnareto its virulent phage V156 in the presence of a eukaryotic host signal (mucin). All tested conditions led to some level of innate immunity, but the presence of mucin led to a dramatic increase in CRISPR spacer acquisition, especially in low nutrient conditions where over 60% of colonies had obtained at least one new spacer. Additionally, we show that the presence of a competitor bacterium further increases CRISPR spacer acquisition inF. columnare. These results suggest that ecological factors are important in determining defense strategies against phages, and that the concentration of phages on metazoan surfaces may select for the diversification of bacterial immune systems.
Mammal virus diversity estimates are unstable due to accelerating discovery effort
Authors: Gibb Rory , Albery Gregory F. , Mollentze Nardus , Eskew Evan A. , Brierley Liam , Ryan Sadie J. , Seifert Stephanie N. , Carlson Colin J. 
Published: August 2021

AbstractHost-virus association data form the backbone of research into eco-evolutionary drivers of viral diversity and host-level zoonotic risk. However, knowledge of the wildlife virome is inherently constrained by historical discovery effort, and there are concerns that the reliability of ecological inference from host-virus data may be undermined by taxonomic and geographical sampling biases. Here, we evaluate whether current estimates of host-level viral diversity in wild mammals are stable enough to be considered biologically meaningful, by analysing a comprehensive dataset of discovery dates of 6,571 unique mammal host-virus associations between 1930 and 2018. We show that virus discovery rates in mammal hosts are still either constant or accelerating, with little evidence of declines towards viral richness asymptotes in even highly-sampled hosts. Consequently, inference of relative viral richness across host species has been unstable over time, particularly in bats, where intensified surveillance since the early 2000s caused a rapid rearrangement of species’ ranked viral richness. Our results show that comparative inference of host-level virus diversity across mammals is highly sensitive to even short-term changes in sampling effort. We advise caution to avoid overinterpreting patterns in current data, since our findings suggest that an analysis conducted today could feasibly draw quite different conclusions than one conducted only a decade ago.
A novel approach to evaluate alpha-synuclein seeding shows a wide heterogeneity in multiple system atrophy
Authors: Martinez-Valbuena Ivan , Visanji Naomi P. , Kim Ain , Lau Heather H. C. , So Raphaella W. L. , Alshimemeri Sohaila , Gao Andrew , Seidman Michael , Luquin Maria R. , Watts Joel C. , Lang Anthony E. , Kovacs Gabor G. 
Published: August 2021

AbstractSeveralin vitroandin vivofindings have consistently shown that α-synuclein derived from multiple system atrophy (MSA) subjects has more seeding capacity than Parkinson’s disease-derived α-synuclein. However, reliable detection of α-synuclein derived from MSA using seeded amplification assays, such as the Real-Time Quaking-induced Conversion, has remained challenging. Here we demonstrate that the interaction of the Thioflavin T dye with α-synuclein from MSA and Parkinson’s disease patients can be modulated by the type of salt, pH, and ionic strength used to generate strain-specific reaction buffers. Employing this novel approach, we have generated a streamlined Real-Time Quaking-induced Conversion assay capable of categorizing MSA brains according to their α-synuclein seeding behavior, and to unravel a previously unrecognized heterogeneity in seeding activity between different brain regions of a given individual that goes beyond immunohistochemical observations and provide a framework for future molecular subtyping of MSA.
Reservoir host studies of Lloviu virus: first isolation, sequencing and serology in Schreiber’s bats in Europe
Authors: Kemenesi Gábor , Tóth Gábor Endre , Mayora-Neto Martin , Scott Simon , Temperton Nigel , Wright Edward , Mühlberger Elke , Hume Adam J. , Zana Brigitta , Boldogh Sándor András , Görföl Tamás , Estók Péter , Lanszki Zsófia , Somogyi Balázs A. , Nagy Ágnes , Pereszlényi Csaba István , Dudás Gábor , Földes Fanni , Kurucz Kornélia , Madai Mónika , Zeghbib Safia , Maes Piet , Vanmechelen Bert , Jakab Ferenc 
Published: August 2021

IntroductoryFiloviruses are prime examples of emerging human pathogens that are transmitted to humans by zoonotic spillover events. Since their initial discovery, filovirus outbreaks have occured with increasing frequency and intensity. There is an urgent need to better understand their enzootic ecology and pathogenic potential, given recent zoonotic virus spillover events including the 2013-2016 West African Ebola virus (EBOV) epidemic. Several novel filoviruses have been discovered with a markedly wider geographic distribution than previously described. One of these novel filoviruses, Lloviu virus (LLOV), was first identified in 2002 in Schreiber’s bats (Miniopterus schreibersii) in Spain, Portugal, and southern France. Subsequently, in 2016, LLOV was detected during the passive monitoring of bats in Hungary.Here we report the first isolation of infectious Lloviu virus; from the blood of an asymptomatic Schreiber’s bat, subsequently cultivated in the Miniopterus sp. kidney cell line SuBK12-08. We also show that LLOV is able to infect monkey and human cells, suggesting that LLOV might have spillover potential. We performed a multi-year surveillance of LLOV and detected LLOV RNA in both deceased and asymptomatic live animals as well as in coupled ectoparasites from the families Nycteribiidae and Ixodidae. We present data on the natural infection and seropositivity of Schreiber’s bats and provide novel LLOV genomic sequence information from a bat host and an arthropod parasite. Our data support the role of bats, specificallyMiniopterus schreibersiias natural reservoirs for the LLOV filovirus in Europe. We also suggest that bat-associated parasites might play a role in the natural ecology of filoviruses in temperate climate regions compared to filoviruses in the tropics. These results raise the possibility of cross-species transmission events via bat-human interactions.
Generation of iPSCs from endangered Grevy’s zebra and comparative transcriptomic analysis of mammalian PSCs
Authors: Endo Yoshinori , Kamei Ken-ichiro , Hasegawa Koichi , Okita Keisuke , Ito Hideyuki , Terada Shiho , Inoue-Murayama Miho 
Published: August 2021

AbstractInduced pluripotent stem cells (iPSCs) can provide a biological resource for functional and conservation research in various species. This expectation has led to generation of iPSCs from various species, including those identified as endangered species. However, the understanding of species variation in mammalian iPSCs is largely unknown. Here, to gain insight into the species variation in iPSCs, we the first generated iPSCs from the endangered species Grevy’s zebra (Equus grevyi; gz-iPSCs) for the first time in the world. We isolated primary fibroblasts cell from an individual that had died of natural causes at a zoo and reprogrammed the fibroblasts into iPSCs. We confirmed their pluripotency and differentiation potential and performed RNA sequencing analysis. The gz-iPSC transcriptome showed that the generated gz-iPSCs robustly expressed genes associated with pluripotency and reprogramming processes, including epithelial-to-mesenchymal and mesenchymal-to-epithelial transitions. Comparative transcriptomics with other species revealed patterns of gene expression among mammalian PSCs and detected evolutionary conservation of pluripotency-associated genes and the plausible importance of the translation process. This study provides new insights into the evolution of mammalian PSCs, and the species conservation and variation of PSCs will advance our understanding of the early development of mammals.
RNA X-ray footprinting reveals the consequences of anin vivoacquired determinant of viral infectivity
Authors: Chandler-Bostock Rebecca , Bingham Richard J. , Clark Sam , Scott Andrew J. P. , Wroblewski Emma , Barker Amy , White Simon J. , Dykeman Eric C. , Mata Carlos P. , Bohon Jen , Farquhar Erik , Twarock Reidun , Stockley Peter G. 
Published: August 2021

AbstractThe secondary structures of the bacteriophage MS2 ssRNA genome, frozen in defined states, were determined with minimal perturbation using constraints from X-ray synchrotron footprinting (XRF). The footprints of the gRNA in the virion and as transcript are consistent with single, dominant but distinct conformations, and reveal the presence of multiple Packaging Signals potentially involved in assembly regulation that have not been detected by other techniques. XRF also reveals the dramatic effect of the unique Maturation Protein (MP) on both the capsid lattice, and the gRNA conformation inside the phage compared with a virus-like-particle composed only of coat protein subunits. Aspects of genome organisation in the phage, their impacts on the capsid shell, and the distortion of lattice geometry by MP, are hallmarks of molecular frustration. Phage assembly therefore appears to prepare the particle for the next step of the infectious cycle.
Lung injury induces alveolar type 2 cell hypertrophy and polyploidy with implications for repair and regeneration
Authors: Weng Anthea , Maciel-Herrerias Mariana , Watanabe Satoshi , Welch Lynn , Flozak Annette S. , Grant Rogan , Aillon Raul Piseaux , Dada Laura , Han Seung Hye , Hinchcliff Monique , Misharin Alexander , Budinger GR Scott , Gottardi Cara J. 
Published: August 2021

AbstractEpithelial polyploidization post-injury is a conserved phenomenon, recently shown to improve barrier restoration during wound healing. Whether lung injury can induce alveolar epithelial polyploidy is not known. We show that bleomycin injury induces AT2 cell hypertrophy and polyploidy. AT2 polyploidization is also seen in short term ex vivo cultures, where AT2-to-AT1 trans-differentiation is associated with substantial binucleation due to failed cytokinesis. Both hypertrophic and polyploid features of AT2 cells can be attenuated by inhibiting the integrated stress response (ISR) using the small molecule ISRIB. These data suggest that AT2 hypertrophic growth and polyploidization may be a feature of alveolar epithelial injury. As AT2 cells serve as facultative progenitors for the distal lung epithelium, a propensity for injury-induced binucleation has implications for AT2 self-renewal and regenerative potential upon reinjury, which may benefit from targeting the ISR.