bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rhesus macaques as a tractable physiological model of human ageing
Authors: Chiou Kenneth L. , Montague Michael J. , Goldman Elisabeth A. , Watowich Marina M. , Sams Sierra N. , Song Jeff , Horvath Julie E. , Sterner Kirstin N. , Ruiz-Lambides Angelina V. , Martínez Melween I. , Higham James P. , Brent Lauren J. N. , Platt Michael L. , Snyder-Mackler Noah 
Published: September 2020

Research in the basic biology of ageing is increasingly identifying mechanisms and modifiers of ageing in short-lived organisms such as worms and mice. The ultimate goal of such work is to improve human health, particularly in the growing segment of the population surviving into old age. Thus far, few interventions have robustly transcended species boundaries in the laboratory, suggesting that changes in approach are needed to avoid costly failures in translational human research. In this review, we discuss both well-established and alternative model organisms for ageing research and outline how research in nonhuman primates is sorely needed, first, to translate findings from short-lived organisms to humans, and second, to understand key aspects of ageing that are unique to primate biology. We focus on rhesus macaques as a particularly promising model organism for ageing research owing to their social and physiological similarity to humans as well as the existence of key resources that have been developed for this species. As a case study, we compare gene regulatory signatures of ageing in the peripheral immune system between humans and rhesus macaques from a free-ranging study population in Cayo Santiago. We show that both mRNA expression and DNA methylation signatures of immune ageing are broadly shared between macaques and humans, indicating strong conservation of the trajectory of ageing in the immune system. We conclude with a review of key issues in the biology of ageing for which macaques and other nonhuman primates may uniquely contribute valuable insights, including the effects of social gradients on health and ageing. We anticipate that continuing research in rhesus macaques and other nonhuman primates will play a critical role in conjunction with the model organism and human biodemographic research in ultimately improving translational outcomes and extending health and longevity in our ageing population.
This article is part of the theme issue ‘Evolution of the primate ageing process’.
Broad frequency sensitivity and complex neural coding in the larval zebrafish auditory system
Authors: Poulsen Rebecca E. , Sholz Leandro A. , Constantin Lena , Favre-Bulle Itia , Vanwalleghem Gilles C. , Scott Ethan K. 
Published: September 2020

SUMMARYMost animals have complex auditory systems that identify salient features of the acoustic landscape to direct appropriate responses. In fish, these features include the volume, frequency, complexity, and temporal structure of auditory stimuli transmitted through water. Larval fish have simple brains compared to adults, but swim freely and depend on sophisticated sensory processing for survival. Zebrafish larvae, an important model for studying brain-wide neural networks, have thus far been found to possess a rudimentary auditory system, sensitive to a narrow range of frequencies and without evident sensitivity to auditory features that are salient and ethologically important to adult fish. Here, we have combined a novel method for delivering water-borne sounds, a diverse assembly of acoustic stimuli, and whole-brain calcium imaging to describe the responses of individual auditory neurons across the brains of zebrafish larvae. Our results reveal responses to frequencies ranging from 100Hz to 4kHz, with evidence of frequency discrimination from 100Hz to 2.5kHz. Frequency-selective neurons are located in numerous regions of the brain, and neurons responsive to the same frequency are spatially grouped in some regions. Using functional clustering, we identified categories of neurons that are selective for pure tones of a single frequency, white noise, the sharp onset of auditory stimuli, and stimuli involving a gradual crescendo. These results suggest a more nuanced auditory system than has previously been described in larval fish and provide insights into how a young animal’s auditory system can both function acutely and serve as the scaffold of a more complex adult system.
Spatial information transfer in hippocampal place cells depends on trial-to-trial variability, symmetry of place-field firing and biophysical heterogeneities
Authors: Roy Ankit , Narayanan Rishikesh 
Published: September 2020

ABSTRACTThe relationship between the feature-tuning curve and information transfer profile of individual neurons provides vital insights about neural encoding. However, the relationship between the spatial tuning curve and spatial information transfer of hippocampal place cells remains unexplored. Here, employing a stochastic search procedure spanning thousands of models, we arrived at 127 conductance-based place-cell models that exhibited signature electrophysiological characteristics and sharp spatial tuning, with parametric values that exhibited neither clustering nor strong pairwise correlations. We introduced trial-to-trial variability in responses and computed model tuning curves and information transfer profiles, using stimulus-specific (SSI) and mutual (MI) information metrics, across locations within the place field. We found spatial information transfer to be heterogeneous across models, but to reduce consistently with increasing degrees of variability. Importantly, whereas reliable low-variability responses implied that maximal information transfer occurred at high-slope regions of the tuning curve, increase in variability resulted in maximal transfer occurring at the peak-firing location in a subset of models. Moreover, experience-dependent asymmetry in place-field firing introduced asymmetries in the information transfer computed through MI, but not SSI, and the impact of activity-dependent variability on information transfer was minimal compared to activity-independent variability. Biophysically, we unveiled a many-to-one relationship between different ion channels and information transfer, and demonstrated critical roles forN-methyl-D-aspartate receptors, transient potassium and dendritic sodium channels in regulating information transfer. Our results emphasize the need to account for trial-to-trial variability, tuning-curve shape and biological heterogeneities while assessing information transfer, and demonstrate ion-channel degeneracy in the regulation of spatial information transfer.
Expression of a modified astrocytic glutamate transporter alleviates Huntington’s hypokinesia, promotes synaptic glutamate clearance and counteracts potentially adverse EAAT2 interactions
Authors: Hirschberg Stefan , Dvorzhak Anton , Rasooli-Nejad Seyed M. A. , Angelov Svilen , Kirchner Marieluise , Mertins Philip , Lättig-Tünnemann Gilla , Harms Christoph , Schmitz Dietmar , Grantyn Rosemarie 
Published: September 2020

SUMMARYRapid removal of glutamate from the sites of glutamate release is an essential step in excitatory synaptic transmission. Despite many years of research, the molecular mechanisms underlying the intracellular regulation of glutamate transport at tripartite synapses have remained unclear. This limits the options for pharmacological treatment of motor disorders associated with glutamate excitotoxicity. Therefore, using the Q175 mouse model of Huntington’s disease (HD), we explored the effects of structural changes in the astrocytic excitatory amino acid transporter type 2 (EAAT2). We report that expression of a C-terminal-modified variant of EAAT2 can alleviate the symptoms of hypokinesia in mice with already advanced HD. At a cellular level, this beneficial outcome correlated with faster synaptic glutamate clearance, higher astrocytic glutamate uptake and larger amounts of native EAAT2 protein. Proteomics data indicate a partial reversal of HD-induced changes in the EAAT2 interactor spectrum. Thus, astrocytic glutamate transport remains a target for therapeutic intervention.
The gut microbiome and its metabolites are necessary for morphine reward
Authors: Hofford Rebecca S. , Mervosh Nicholas L. , Euston Tanner J. , Meckel Katherine R. , Orr Amon T. , Kiraly Drew D. 
Published: September 2020

AbstractRecent evidence has demonstrated that the gut microbiome has marked effects on neuronal function and behavior. Disturbances to microbial populations within the gut have been linked to myriad models of neuropsychiatric disorders. However, the role of the microbiome in substance use disorders remains understudied. Here we show that animals with their gut microbiome depleted by non-absorbable antibiotics (Abx) exhibit decreased formation of morphine conditioned place preference and demonstrate marked changes in gene expression within the nucleus accumbens (NAc) in response to morphine. Replacement of short-chain fatty acid (SCFA) metabolites, which are reduced by microbiome knockdown, reversed the behavioral and transcriptional effects of microbiome depletion. This identifies SCFA as the crucial mediators of microbiome-brain communication responsible for the effects on morphine reward caused by microbiome knockdown. These studies add important new behavioral, molecular, and mechanistic insight to the role of gut-brain signaling in substance use disorders.
A step-by-step sequence-based analysis of virome enrichment protocol for freshwater and sediment samples
Authors: Pinto Federica , Zolfo Moreno , Beghini Francesco , Armanini Federica , Asnicar Francesco , Silverj Andrea , Boscaini Adriano , Salmaso Nico , Segata Nicola 
Published: September 2020

AbstractCultivation-free metagenomic analysis afforded unprecedented details on the diversity, structure and potential functions of microbial communities in different environments. When employed to study the viral fraction of the community that is recalcitrant to cultivation, metagenomics can shed light into the diversity of viruses and their role in natural ecosystems. However, despite the increasing interest in virome metagenomics, methodological issues still hinder the proper interpretation and comparison of results across studies. Virome enrichment experimental protocols are key multi-step processes needed for separating and concentrating the viral fraction from the whole microbial community prior to sequencing. However, there is little information on their efficiency and their potential biases. To fill this gap, we used metagenomic and amplicon sequencing to examine the microbial community composition through the serial filtration and concentration steps commonly used to produce viral-enriched metagenomes. The analyses were performed on water and sediment samples from an Alpine lake. We found that, although the diversity of the retained microbial communities declined progressively during the serial filtration, the final viral fraction contained a large proportion (from 10% to 40%) of non-viral taxa, and that the efficacy of filtration showed biases based on taxonomy. Our results quantified the amount of bacterial genetic material in viromes and highlighted the influence of sample type on the enrichment efficacy. Moreover, since viral-enriched samples contained a significant portion of microbial taxa, computational sequence analysis should account for such biases in the downstream interpretation pipeline.ImportanceFiltration is a commonly used method to enrich viral particles in environmental samples. However, there is little information on its efficiency and potential biases on the final result. Using a sequence-based analysis on water and sediment samples, we found that filtration efficacy is dependent on sample type and that the final virome contained a large proportion of non-viral taxa. Our finding stressed the importance of downstream analysis to avoid biased interpretation of data.
Modeling physician variability to prioritize relevant medical record information
Authors: Tajgardoon Mohammadamin , Cooper Gregory F , King Andrew J , Clermont Gilles , Hochheiser Harry , Hauskrecht Milos , Sittig Dean F , Visweswaran Shyam 
Published: September 2020

AbstractObjectivePatient information can be retrieved more efficiently in electronic medical record (EMR) systems by using machine learning models that predict which information a physician will seek in a clinical context. However, information-seeking behavior varies across EMR users. To explicitly account for this variability, we derived hierarchical models and compared their performance to non-hierarchical models in identifying relevant patient information in intensive care unit (ICU) cases.Materials and MethodsCritical care physicians reviewed ICU patient cases and selected data items relevant for presenting at morning rounds. Using patient EMR data as predictors, we derived hierarchical logistic regression (HLR) and standard logistic regression (LR) models to predict their relevance.ResultsIn 73 pairs of HLR and LR models, the HLR models achieved an area under the ROC curve of 0.81, 95% CI [0.80, 0.82], which was statistically significantly higher than that of LR models (0.75, 95% CI [0.74-0.76]). Further, the HLR models achieved statistically significantly lower expected calibration error (0.07, 95% CI [0.06-0.08]) than LR models (0.16, 95% CI [0.14-0.17]).DiscussionThe physician reviewers demonstrated variability in selecting relevant data. Our results show that HLR models perform significantly better than LR models with respect to both discrimination and calibration. This is likely due to explicitly modeling physician-related variability.ConclusionHierarchical models can yield better performance when there is physician-related variability as in the case of identifying relevant information in the EMR.
Anti-androgens induce Rab11a-exosome secretion in prostate cancer by suppressing amino acid-sensitive PAT4-mTORC1 signalling
Authors: McCormick Kristie , Sanitt Poohrawind , Fan Shih-Jung , Mason John D , Harris Adrian L , Hamdy Freddie C , Verrill Clare , Bryant Richard J , Goberdhan Deborah C I 
Published: September 2020

AbstractAdvanced prostate cancer is typically treated with anti-androgens to reduce cancer growth, but patients almost inevitably develop treatment resistance and castration-resistant disease. Recently, extracellular vesicles known as exosomes, which are secreted from the endosomal compartments in which they are formed, have been implicated in drug resistance mechanisms. Here we investigate whether growth regulation by the amino acid-dependent kinase complex, mechanistic Target of Rapamycin Complex 1 (mTORC1), and associated extracellular vesicle secretion might be involved in the adaptive responses to anti-androgens. We show that expression and intracellular localisation of the glutamine-sensing PAT4 (SLC36A4) amino acid transporter is increased in malignant versus benign prostatic tissue, mirroring earlierin vivofly studies suggesting that these transporters are more effective at promoting growth from internal versus cell surface membranes. Furthermore, androgens induce PAT4 expression in prostate cancer cell lines and PAT4 is required for a proportion of androgen-stimulated mTORC1 activation and growth. Consistent with previous studies in other cancer cell lines, we find that glutamine depletion, PAT4 knockdown and mTORC1 inhibition all independently increase the production of a specific exosome subtype, Rab11a-exosomes, which has recently been implicated in pro-tumorigenic signalling responses to mTORC1 inhibition. Furthermore, we show that these exosomes are also induced by anti-androgens. We hypothesise that the uptake of Rab11a-exosomes by cells with higher PAT4 levels could provide a growth-promoting boost, enabling them to out-compete others with lower PAT4 expression, resulting in tumours that are more resistant to nutrient-deprivation and anti-androgen treatment.
Functional diversity of microboringOstreobiumalgae isolated from corals
Authors: Massé A. , Tribollet A. , Meziane T. , Bourguet-Kondracki M.L. , Yéprémian C. , Sève C. , Thiney N. , Longeon A. , Couté A. , Domart-Coulon I. 
Published: September 2020

AbstractThe filamentous chlorophyteOstreobiumsp. dominates shallow marine carbonate microboring communities, and is one of the major agents of reef bioerosion. While its large genetic diversity has emerged, its physiology remains little known, with unexplored relationship between genotypes and phenotypes (endolithicversusfree-living growth forms). Here, we isolated 9 strains affiliated to 2 lineages ofOstreobium(>8% sequence divergence of the plastid generbcL), one of which was assigned to the family Odoaceae, from the fast-growing coral hostPocillopora acutaLamarck 1816. Free-living isolates maintained their bioerosive potential, colonizing pre-bleached coral carbonate skeletons. We compared phenotypes, highlighting shifts in pigment and fatty acid compositions, carbon to nitrogen ratios and stable isotope compositions (δ13C and δ15N). Our data show a pattern of higher chlorophyllband lower arachidonic acid (20:4ω6) content in endolithicversusfree-livingOstreobium. Photosynthetic carbon fixation and nitrate uptake, quantified via 8h pulse-labeling with13C-bicarbonate and15N-nitrate, showed lower isotopic enrichment in endolithic compared to free-living filaments. Our results highlight the functional plasticity ofOstreobiumphenotypes. The isotope tracer approach opens the way to further study the biogeochemical cycling and trophic ecology of these cryptic algae at coral holobiont and reef scales.
PARP inhibition in Ewing sarcoma: impact of germline DNA damage repair defects and activation of immunoregulatory pathways
Authors: Maurer Lisa M. , Venier Rosemarie E. , Mukherjee Elina , Julian Claire M. , Daley Jessica D. , Bailey Nathanael G. , Jacobs Michelle F. , Kumar-Sinha Chandan , Raphel Haley , Weiss Kurt , Janeway Katherine A. , Mody Rajen , Lucas Peter C. , McAllister-Lucas Linda M. , Bailey Kelly M. 
Published: September 2020

ABSTRACTEwing sarcoma, an oncofusion-driven primary bone tumor, can occur in the setting of various germline mutations in DNA damage repair pathway genes. We recently reported our discovery of a germline mutation in the DNA damage repair proteinBARD1(BRCA1-associated RING domain-1) in a patient with Ewing sarcoma. BARD1 is recruited to the site of DNA double stranded breaks via the poly(ADP-ribose) polymerase (PARP) protein and plays a critical role in DNA damage response pathways including homologous recombination. PARP inhibitors (PARPi) are effective against Ewing sarcoma cellsin vitro, though have demonstrated limited success in clinical trials to date. In order to assess the impact of BARD1 loss on Ewing sarcoma sensitivity to PARP inhibitor therapy, we generated the novel PSaRC318 patient-derived Ewing tumor cell from our patient with a germlineBARD1mutation and then analyzed the response of these cells to PARPi. We demonstrate that PSaRC318 cells are sensitive to PARP inhibition and by testing the effect of BARD1 depletion in additional Ewing sarcoma cell lines, we confirm that loss of BARD1 enhances PARPi sensitivity. In certain malignancies, DNA damage can activate the IRF1 (interferon response factor 1) immunoregulatory pathway, and the activation of this pathway can drive immunosuppression through upregulation of the immune checkpoint protein PD-L1. In order to determine the ability of PARPi to alter Ewing tumor immunoregulation, we evaluated whether PARPi results in upregulation of the IRF1-PDL1 pathway. Indeed, we now demonstrate that PARPi leads to increased PD-L1 expression in Ewing sarcoma. Together, these data thus far suggest that while Ewing tumors harboring germline mutations in DNA damage repair proteins may in respond to PARPiin vitro, in vivobenefit of PARPi may only be demonstrated when counteracting the immunosuppressive effects of DNA damage by concurrently targeting immune checkpoint proteins.
Using cortical neuron markers to target cells in the dorsal cochlear nucleus
Authors: Malfatti Thawann , Ciralli Barbara , Hilscher Markus M. , Edwards Steven J. , Kullander Klas , Leao Richardson N. , Leao Katarina E. 
Published: September 2020

AbstractThe dorsal cochlear nucleus (DCN) is the first auditory region that integrates somatosensory and auditory inputs. The region is of particular interest for auditory research due to the large incidence of somatic tinnitus and increased aberrant activity in other forms of tinnitus. Yet, the lack of useful genetic markers for in vivo manipulations hinders the elucidation of the DCN contribution to tinnitus pathophysiology. In this work, we assessed whether adeno-associated viral vectors (AAV) containing the calcium/calmodulin-dependent protein kinase 2 alpha (CaMKIIα) promoter and our mouse line of nicotinic acetylcholine receptor alpha 2 subunit (Chrna2)-Cre can be used to target specific DCN populations. The CaMKIIαpromoter is usually applied in studies of principal neurons of neo and paleocortex while Chrna2-cre mice express Cre recombinase in cortical dendrite inhibiting interneurons. We found that CaMKIIαcannot be used to specifically target excitatory fusiform DCN neurons. EYFP expression driven by the CaMKIIαpromoter was stronger in the fusiform layer but labelled cells showed a diverse morphology indicating that they belong to different classes of DCN neurons. Light stimulation after driving Channelrhodopsin2 (ChR2) by the CaMKIIαpromoter generated spikes in some units but firing rate decreased when light stimulation coincide with sound presentation. Expression and activation of eArch3.0 (CaMKIIαdriven) in the DCN produced spike inhibition in some units but, most importantly, sound-driven spikes were delayed by concomitant light stimulation. We explored the existence of Cre+ cells in the DCN of Chrna2-Cre mice by hydrogel embedding technique (CLARITY). There were almost no Cre+ cell bodies in the DCN; however, we observed profuse projections arising from the ventral cochlear nucleus (VCN). Anterograde labeling Cre dependent AAV injected in the VCN revealed two main projections: one arising in the ipsilateral superior olive and the contralateral medial nucleus of the trapezoid body (bushy cells) and a second bundle terminating in the DCN, suggesting the latter to be excitatory Chrna2+ T-stellate cells). Stimulating ChR2 expressing terminals (light applied on the DCN) of VCN Chrna2+ cells increased firing of sound responding and nonresponding DCN units. This work shows that molecular tools intensively used in cortical studies may be useful for manipulating the DCN especially in tinnitus studies.
CRISPR-Cas systems restrict horizontal gene transfer inPseudomonas aeruginosa
Authors: Wheatley Rachel M. , MacLean R. Craig 
Published: September 2020

AbstractCRISPR-Cas systems provide bacteria and archaea with an adaptive immune system that targets foreign DNA. However, the xenogenic nature of immunity provided by CRISPR-Cas raises the possibility that these systems may constrain horizontal gene transfer. Here we test this hypothesis in the opportunistic pathogenPseudomonas aeruginosa, which has emerged an important model system for understanding CRISPR-Cas function. Across the diversity ofP. aeruginosa, active CRISPR-Cas systems are associated with smaller genomes and a reduced GC content, suggesting that CRISPR-Cas inhibits the acquisition of foreign DNA. Although phage are the major target of CRISPR-Cas spacers, more than 80% of isolates with an active CRISPR-Cas system have spacers that target integrative conjugative elements (ICE) or the conserved conjugative transfer machinery used by plasmids and ICE. Consistent with these results, genomes containing active CRISPR-Cas systems harbor a lower abundance of both prophage and ICE. Crucially, spacers in genomes with active CRISPR-Cas systems map to ICE and phage that are integrated into the chromosomes of closely related genomes lacking CRISPR-Cas immunity, providing direct evidence that CRISPR-Cas constrains horizontal gene transfer in these lineages. In conclusion, we find that CRISPR-Cas acts as an important constraint to horizontal gene transfer, suggesting that CRISPR-Cas may constrain the ability of this pathogen to adapt to new niches and stressors.