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Smith, A. C.

Publications and source records attributed to Smith, A. C..

At least 19 recordsLinked to original sources

Interspecies synergism and antagonism induce differential and potentially exploitable susceptibility to various classes of antibiotics in a wound-like polymicrobial community

Chronic wounds are persistent and difficult to treat. Often this is because they are colonized by polymicrobial communities which contribute to changes in antimicrobial susceptibilities, making these infections harder to effectively clear. We explored the role a community can play in individual members survival when challenged by antibiotics, specifically looking at a community consisting of Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecalis, and Acinetobacter baumannii. Our data shows that communities can contribute to both increases and decreases in susceptibilities depending on the species and the antibiotic. The changes in susceptibilities can be due to interspecies cooperation or competition, with identifiable mechanisms. We also demonstrated that current antimicrobial susceptibility testing (AST) methods used in hospitals, which focus on determining the minimum inhibitory concentration (MIC) via determination of visible turbidity breakpoints, are not able to truly indicate the clearance of bacteria, as species can persist in higher antibiotic concentrations after visible turbidity is gone. To combat decreases in antibiotic susceptibilities contributed to by the community, we used our data from individual antibiotics to determine a potentially effective antibiotic combination, similar to combinatorial therapy used in hospitals to treat recalcitrant infections. Our data proved useful, as the combination of gentamicin and cephalexin was able to overcome polymicrobial synergism and clear the desired bacteria. This demonstrates that it is possible to determine effective antibiotic treatments for polymicrobial infections, whether they be combinatorial in nature or not. One simply must account for the role of the community in order to prescribe the most effective treatment.

microbiology↗

Hyper-dominant species drive unexpected functional shifts in North American birds

Global environmental changes have led to widespread intraspecific shifts in functional traits across large numbers of widely distributed taxa. However, how within-species functional shifts predict community-level changes is unknown. We summarized seven key traits that are hypothesized to shift adaptively under environmental changes using local community-weighted means across North American bird communities. We find that communities shifted toward larger body mass and smaller appendage sizes over time, the opposite of widely observed within-species temporal changes in North American birds. These unexpected patterns arise from changes in the relative abundance of a very small number of hyper-dominant species, with 23 out of 470 (5%) species explaining the community-level trajectories in functional traits. These species are known to be heavily impacted--both positively and negatively--by human activities, and the idiosyncratic drivers of population sizes result in weak associations between community-level functional shifts and major bioclimatic variables but strong associations with human-induced land use changes. Our results illustrate the complexity in scaling from within-species responses to global change to community-level responses and highlight the importance of species-specific responses to the environment beyond climate when predicting functional and taxonomic diversity under global change.

ecology↗

Mapping Hand Function with Simultaneous Brain-Spinal Cord Functional MRI

INTRODUCTIONHand motor control depends on intricate brain-spinal cord interactions that regulate muscle activity. Hand function can be disrupted by injury to the brain, spinal cord, and peripheral nerves leading to weakness and impaired coordination. Functional MRI (fMRI) can map motor-related neural activity and potentially characterize the mechanisms underlying hand weakness and diminished coordination. Although brain motor control has been extensively studied, spinal cord mechanisms remain less explored. Here we use simultaneous brain-spinal cord fMRI to map neural activity related to hand strength and dexterity across the central nervous system using force matching and finger tapping tasks. This study pioneers the use of simultaneous brain-spinal cord fMRI to comprehensively map hand function, offering novel insights into coordinated motor processing across the central nervous system. METHODSWe performed simultaneous brain-spinal cord fMRI in 28 right-handed healthy volunteers (age: 40.0 {+/-} 13.8 years, 14 females, 14 males) using a 3T GE SIGNA Premier scanner equipped with a 21-channel head-neck coil. Participants performed a force-matching task at 10%, 20%, and 30% of maximum voluntary contraction using a hand dynamometer. For the finger tapping task, participants completed button-presses at 1 Hz with a 5-button response pad for three task levels: single-digit response with the second digit only (low), single-digit response with all digits in a sequential order (medium), single-digit response with all digits in a random order (high). Visual cues and feedback were provided during the tasks. Brain and spinal cord images were processed separately using FSL and the Spinal Cord Toolbox, with motion correction, physiological noise filtering, and spatial normalization to standard templates. Subject level activity maps were generated and entered into group level analyses to explore both activations and deactivations. For the brain, we used a mixed effect design with a voxelwise threshold of Z score > 3.10 and cluster threshold of p < 0.05. For the spinal cord, we used a fixed effect design with a voxelwise threshold of Z score > 1.64 and cluster threshold of p < 0.05. Region of interest (ROI) analyses were conducted to examine localized changes in activation across task levels RESULTSBoth tasks elicited activation in motor and sensory regions of the brain and spinal cord, with graded responses in the left primary motor (M1), left primary sensory (S1) cortex, and right spinal cord gray matter across task levels. Deactivation of the right M1 and S1 was also present for both tasks. Deactivation of the left spinal cord gray matter was present in the high task level of the force matching task. The ROI analysis findings complemented the group level activity maps. DISCUSSIONOur study provides a detailed map of brain-spinal cord interactions in hand function, revealing graded neural activation and inhibition patterns across motor and sensory regions. Interhemispheric inhibition, reflected in right M1 deactivation, likely restricts extraneous motor output during unilateral tasks. For force matching, the deactivation of the left ventral and dorsal horns of the spinal cord, provides the first evidence that the inhibition of motor areas during a unilateral motor task extends to the spinal cord. Whether this inhibition results from direct descending modulation from the brain or interneuronal inhibition in the cord remains to be interrogated. These findings expand our understanding of central motor control mechanisms and could inform rehabilitation strategies for individuals with motor impairments. CONCLUSIONSOur simultaneous brain-spinal cord fMRI approach provides novel insights into the neural coordination of hand function, enhancing our understanding of motor control and its modulation. This approach may offer a foundation for studying motor dysfunction in conditions such as stroke, spinal cord injury, and neurodegenerative diseases.

neuroscience↗

An anterior hypothalamic circuit gates stress vulnerability

Prior adversity increases susceptibility to subsequent stressful events, but the causal underlying changes in brain circuitry are poorly understood. We harnessed unbiased whole-brain activity mapping to identify circuits that are functionally remodeled by prior adversity. This revealed that the anterior hypothalamic nucleus (AHN) displays heightened stress reactivity in previously stressed mice. This was accompanied by increased functional connectivity between the AHN and a threat-related limbic network. Using in vivo Miniscope imaging, we found that neuronal activity in the AHN encodes stressor valence. Moreover, stimulating AHN neurons enhanced, and inhibiting their activity mitigated, reactivity to stressful events. Lastly, silencing amygdala inputs to the AHN abolished the ability of prior adversity to increase stress sensitivity. These findings define a key role of the AHN in gating stress vulnerability by scaling valence signals from the amygdala.

neuroscience↗

Accumbens Nitrergic Interneurons Drive the Cell Type-Specific Synaptic Plasticity Required for Cue-Induced Cocaine Seeking

Cocaine use disorder (CUD) remains a serious public health crisis, with relapse vulnerability continuing to pose the largest impediment to effective clinical treatment. Relapse to cocaine seeking is often triggered by drug craving evoked by exposure to drug-associated environmental cues. Data from preclinical models of rodent self-administration (SA) and cue-induced reinstatement demonstrate that exposure to drug predictive cues following a period of withdrawal engages a large induction of glutamate release in the nucleus accumbens core (NAc), not observed during cued sucrose seeking. This profound glutamate release engages neuronal nitric oxide synthase (nNOS) expressing interneurons likely through activation of metabotropic glutamate receptor 5 (mGluR5), leading to increased production of nitric oxide (NO). Importantly, cue-induced glutamate and NO production have been linked to activation of matrix metalloproteinases (MMPs) and induction of the transient synaptic plasticity in medium spiny neurons (MSNs) required for cued cocaine seeking. Recent evidence suggests that cue-induced structural and synaptic plasticity occurs predominantly in D1 Dopamine receptor expressing MSNs, yet despite these findings, how cue-induced glutamate release is translated into D1 MSN plasticity has yet to be elucidated. We show here that knockdown of nNOS is sufficient to block cue-induced reinstatement to cocaine and prevents cue-induced functional and structural synaptic adaptions specifically in D1 receptor containing MSNs. Next, we demonstrate that knockdown of mGluR5, selectively on nitrergic interneurons in the NAc, is sufficient to block both conditioned place preference (CPP) and cue-induced reinstatement to cocaine, mechanistically linking cue-associated glutamate release to NO signaling. Finally, we demonstrate that downstream of glutamate-mediated activation of mGluR5 on nitrergic interneurons and MMP activation, expression of {beta}3 integrin receptors on D1 MSNs is required for cued cocaine seeking. Taken together, our data provide a mechanistic link between cocaine cue-induced glutamate release, activation of nitrergic interneurons and the D1 MSN plasticity required for cued cocaine seeking, Significance StatementRelapse vulnerability to cocaine is a persistent challenge to successful treatment of CUD. Relapse precipitated by drug-associated environment cues requires synaptic plasticity in MSNs. Here, we show that knockdown of nNOS, or mGluR5 on nitrergic interneurons, or {beta}3 integrin receptors on D1 MSNs is sufficient to block cue-induced cocaine seeking. Taken together our data support the following cocaine seeking signaling cascade. {square}Cocaine cues [->] PrL driven NAc glutamate release [->] mGluR5-mediated Activation of NAc nitrergic neurons [->] Activation of B3 integrins [->] D1 MSN plasticity [->] Reinstated Cocaine seeking.

neuroscience↗

High quality, high throughput, and low-cost simultaneous video recording of 60 animals in operant chambers using PiRATeMC

BackgroundThe development of Raspberry Pi-based recording devices for video analyses of drug self-administration studies has shown to be promising in terms of affordability, customizability, and capacity to extract in-depth behavioral patterns. Yet, most video recording systems are limited to a few cameras making them incompatible with large-scale studies. New MethodWe expanded the PiRATeMC (Pi-based Remote Acquisition Technology for Motion Capture) recording system by increasing its scale, modifying its code, and adding equipment to accommodate large-scale video acquisition, accompanied by data on the throughput capabilities, video fidelity, synchronicity of devices, and comparisons between the Raspberry Pi 3B+ and 4B models. ResultsUsing PiRATeMC default recording parameters resulted in minimal storage ([~]350MB/h), high throughput (< [~]120 seconds/Pi), high video fidelity, and synchronicity within [~]0.02 seconds, affording the ability to simultaneously record 60 animals in individual self-administration chambers at a fraction of current commercial costs. No consequential differences were found between Raspberry Pi 3B+ and 4B models. Comparison with Existing Method(s)This system allows greater acquisition of video data simultaneously than other video recording systems by an order of magnitude with less storage needs and lower costs. Additionally, we report in-depth quantitative assessments of throughput, fidelity, and synchronicity, displaying real-time system capabilities. ConclusionsThe system presented is able to be fully installed in a months time by a single technician and provides a scalable, low cost, and quality-assured procedure with a high-degree of customization and synchronicity between recording devices, capable of recording a large number of subjects with high turnover in a variety of species and settings.

neuroscience↗

Development of a polymicrobial checkerboard assay as a tool for determining combinatorial antibiotic effectiveness in polymicrobial communities

AIMSTo establish a methodology for identifying the effects of combinatorial antibiotic treatment on individual members of a polymicrobial community. METHODS AND RESULTSBoth gentamicin and ceftazidime were diluted to concentrations ranging from 0.06 g ml-1 to 128 g ml-1. An equal ratio polymicrobial community of Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus faecalis, and Acinetobacter baumannii was inoculated into the combined antibiotics in the checkerboard and incubated for 18 hours in static conditions. After incubation, visible turbidity of the overall community was recorded, and bacteria from the wells were diluted to 10-3 and then spot plated on selective and differential media. After 24 hours, colony-forming unit (CFU) counts were obtained for each species. CONCLUSIONSVisible turbidity is not truly indicative of cell viability, and the polymicrobial community can decrease the antibiotic susceptibility of P. aeruginosa, rendering the clinically-established beneficial combination of gentamicin and ceftazidime ineffective. SIGNIFICANCEPrevious checkerboard methodology which focuses on using visible turbidity to determine monomicrobial antibiotic susceptibility fails to account for polymicrobial cooperation that has been shown to reduce antibiotic efficacy. Our new methodology could be implemented in clinical microbiology laboratories with minimal impact on the overall time for diagnosis.

microbiology↗

Diversity-stability relationships become decoupled across spatial scales: a synthesis of organism and ecosystem types

The relationship between biodiversity and stability, or its inverse, temporal variability, is multidimensional and complex. Temporal variability in aggregate properties, like total biomass or abundance, is typically lower in communities with higher species diversity (i.e., the diversity-stability relationship or DSR). Recent work has shown that, at broader spatial extents, regional-scale aggregate variability is also lower with higher regional diversity (in plant systems) and with lower spatial synchrony. However, it is not yet clear whether regional DSRs hold across a broad range of organisms and ecosystem types. Furthermore, focusing exclusively on aggregate properties of communities may overlook potentially destabilizing compositional shifts. To test these questions, we compiled a large collection of long-term spatial metacommunity data spanning a wide range of taxonomic groups (e.g., birds, fish, plants, invertebrates) and ecosystem types (e.g., deserts, forests, oceans). We applied a newly developed quantitative framework for jointly analyzing aggregate and compositional variability across scales. We quantified DSRs for composition and total abundance in local communities and metacommunities. At the local scale, compositional DSRs suggested that higher local () diversity was associated with lower variability in animal populations but higher variability in plant populations, while aggregate DSRs supported the classic stabilizing effects of diversity. Spatial synchrony differed among taxa (birds had the lowest, plants the highest), suggesting differences in stabilization by spatial processes. Spatial synchrony declined with higher diversity among sites ({beta}) for both compositional and aggregate properties. However, at the regional ({gamma}) scale, we found no aggregate DSR, but a positive compositional DSR. Across a broader range of taxa, our results suggest that high {gamma}-diversity does not consistently stabilize aggregate properties at regional scales without sufficient spatial {beta}-diversity to reduce spatial synchrony. Open research statementAll data sets are accessible via the Environmental Data Initiative, and a specific data package of the data sets used in this analysis will be made publicly available (doi: pending). Citations to original sources are included in Appendix S1. Code to reproduce the analyses is found in a Zenodo archive (doi: pending) of the GitHub repository for this project (https://github.com/sokole/ltermetacommunities/tree/master/Manuscripts/MS3).

ecology↗

Conformation of HIV-1 Envelope governs rhesus CD4 usage and simian-human immunodeficiency virus replication

Infection of rhesus macaques with simian-human immunodeficiency viruses (SHIVs) is the preferred model system for vaccine development because SHIVs encode HIV-1 envelope glycoproteins (Env) - a key target of HIV-1 neutralizing antibodies. Since the goal of vaccines is to prevent new infections, SHIVs encoding circulating HIV-1 Env are desired as challenge viruses. Development of such biologically relevant SHIVs has been challenging as they fail to infect rhesus macaques, mainly because most circulating HIV-1 Env do not use rhesus CD4 (rhCD4) receptor for viral entry. Most primary HIV-1 Env exist in a closed conformation and occasionally transit to downstream, open conformation through an obligate intermediate conformation. Here, we provide genetic evidence that open Env conformations can overcome the rhCD4 entry barrier and increase replication of SHIVs in rhesus lymphocytes. Consistent with prior studies, we found that circulating HIV-1 Env do not use rhCD4 efficiently for viral entry. However, using HIV-1 Env with single amino acid substitutions that alter their conformational state, we found that transitions to intermediate and open Env conformation allow usage of physiological levels of rhCD4 for viral entry. We engineered these single amino acid substitutions in the transmitted/founder HIV-1BG505 Env encoded by SHIV-BG505 and found that open Env conformation enhances SHIV replication in rhesus lymphocytes. Lastly, CD4-mediated SHIV pull-down, sensitivity to soluble CD4, and fusogenicity assays indicated that open Env conformation promotes efficient rhCD4 binding and viral-host membrane fusion. These findings identify conformational state of HIV-1 Env as a major determinant for rhCD4 usage, viral fusion, and SHIV replication. ImportanceRhesus macaques are critical animal model for preclinical testing of HIV-1 vaccine and prevention approaches. However, HIV-1 does not replicate in rhesus macaques, and thus chimeric simian-human immunodeficiency viruses (SHIVs), which encode HIV-1 envelope glycoproteins, are used as surrogate challenge viruses to infect rhesus macaques for modeling HIV-1 infection. Development of SHIVs encoding envelope from clinically relevant, circulating HIV-1 variants has been extremely challenging as such SHIVs replicate poorly, if at all, in rhesus lymphocytes. This is because most circulating HIV-1 envelope do not use rhesus CD4 efficiently for viral entry. In this study, we identify conformational state of HIV-1 envelope as a key determinant for rhesus CD4 usage, viral-host membrane fusion, and SHIV replication in rhesus lymphocytes.

microbiology↗

PiRATeMC: A highly flexible, scalable, and affordable system for obtaining high quality video recordings for behavioral neuroscience.

With the recent development and rapidly accelerating adoption of machine-learning based rodent behavioral tracking tools such as DeepLabCut, there is an unmet need for a method of acquiring video data that is scalable, flexible, and affordable. Many experimenters use webcams, GoPros, or other commercially available cameras that are not only relatively expensive, but offer very little flexibility over recording parameters. These cameras are not ideal for recording many types of behavioral experiments, and can lead to suboptimal video quality. Furthermore when using relatively affordable commercially available products, it is a challenge, if not impossible, to synchronize multiple cameras with each other, or to interface with third-party equipment (for example, receiving a simple trigger to simultaneously start recording, or acting as a microcontroller for closed-loop experiments). We have developed an affordable ecosystem of behavioral recording equipment, PiRATeMC (Pi-based Remote Acquisition Technology for Motion Capture), that relies on Raspberry Pi Camera Boards that are able to acquire high quality recordings in bright light, low light, or dark conditions under infrared light. PiRATeMC offers users control over nearly every recording parameter, and can be fine-tuned to produce optimal video data in any behavioral arena. This setup can easily be scaled up and synchronously controlled in clusters via a self-contained network to record a large number of simultaneous behavioral sessions without burdening institutional network infrastructure. Furthermore, the Raspberry Pi is an excellent platform for novice and inexperienced programmers interested in using an open-source recording system, with a large online community that is very active in developing novel open-source tools. It easily interfaces with Arduinos and other microcontrollers, allowing simple synchronization and interfacing of video recording with nearly any behavioral equipment using GPIO pins to send or receive 3.3V or 5V (TTL) signals, I2C, or serial communication.

neuroscience↗

Divergent sex differences in functional brain connectivity networks in excessively drinking C57BL/6J mice

Individuals with alcohol use disorder continue to drink in excess despite the health and societal consequences, and the rate of problematic drinking and alcohol-related harms is increased in women. Clinical imaging studies report widespread adaptations in brain structure after chronic, heavy drinking, and alcohol-related cues enhance brain reactivity in reward-related regions. In rodents, alcohol drinking induces expression of the immediate early gene c-Fos, which can be a marker of cellular activity, across multiple brain regions. Recent evidence also suggests that abstinence from chronic intermittent alcohol exposure can produce mesoscale changes in c-Fos expression. However, there is a substantial gap in our understanding of how excessive drinking affects functional connectivity networks to influence alcohol-seeking behaviors. For this study, male and female C57BL/6J mice were given access to either water or a choice between water and ethanol in the intermittent access drinking model for 4 weeks. After a short-access drinking session, whole brains from high alcohol drinking male and female mice and water drinking controls were then subjected to c-Fos immunolabeling, iDISCO+ clearing, light sheet imaging, and whole-brain c-Fos mapping. Correlation matrices were then generated and graph theoretical statistical approaches were used to determine changes in functional connectivity across sex and drinking condition. We observed robust sex differences in the network of c-Fos+ cells in water drinking mice, and excessive alcohol drinking produce divergent and robust changes in functional network connectivity in male and female mice. In addition, these analyses identified novel hub regions in excessively drinking mice that were unique for each sex. In conclusion, the whole-brain c-Fos mapping analysis identified sex difference in functional network connectivity and unique and understudied regions that may play a critical role in controlling excessive ethanol drinking in male and female mice.

neuroscience↗

Hierarchical Bayesian Model for Estimating Migratory Bird Harvest in Canada

The Canadian Wildlife Service (CWS) requires reliable estimates of the harvest of migratory game birds, including waterfowl, to effectively manage populations of these hunted species. The National Harvest Survey is an annual survey of hunters who purchase Canadas mandatory migratory game bird hunting permit, integrating information from a survey of hunting activity with information from a separate survey of species composition in the harvest. We use these survey data to estimate the number of birds harvested for each species, as well as hunting activity metrics such as the number of active hunters and days spent hunting. The analytical methods used to generate these estimates have not changed since the survey was first designed in the early 1970s. Here we describe a new hierarchical Bayesian integrated model, which replaces the series of ratio estimators that comprised the old model. We are now using this new model to generate estimates for migratory bird harvests as of the 2019-2020 hunting season, and to generate updated estimates for all earlier years. The hierarchical Bayesian model uses over-dispersed Poisson distributions to model mean hunter activity and harvest (zero inflated Poisson and zero truncated Poisson, respectively). It also includes multinomial distributions to model some key components including, variation in total harvest across periods of the hunting season, the species composition of the harvest within each of those periods, and the age and sex composition in the harvests of a given species. We estimated the parameters of the Poisson and the multinomial distributions for each year as random effects using first-difference time-series. This time-series component allows the model to share information across years and reduces the sensitivity of the estimates to annual sampling noise. The new model estimates are generally very similar to those from the old model, particularly for the species that occur most commonly in the harvest, and so the results do not suggest any major changes to harvest management decisions and regulations. However, estimates for all species from the new model are more precise and less susceptible to annual sampling error, particularly for species that occur less commonly in the harvest (e.g., sea ducks and other species of conservation concern). This new model, with its hierarchical Bayesian framework, will also facilitate future improvements and elaborations, allowing the incorporation of prior information from the rich literature and knowledge in game bird management and biology.

ecology↗

Host defense mechanisms induce genome instability in an opportunistic fungal pathogen

The ability to generate genetic variation facilitates rapid adaptation in stressful environments. The opportunistic fungal pathogen Candida albicans frequently undergoes large-scale genomic changes, including aneuploidy and loss-of heterozygosity (LOH), following exposure to physiological stressors and host environments. However, the specific host factors that induce C. albicans genome instability remains largely unknown. Here, we leveraged genetically-tractable nematode hosts to specifically investigate the innate immune components driving host-associated C. albicans genome instability, which include host production of antimicrobial peptides (AMPs) and reactive oxygen species (ROS). C. albicans associated with wildtype, immunocompetent hosts carried multiple large-scale genomic changes including LOH, whole chromosome, and segmental aneuploidies. In contrast, C. albicans associated with immunocompromised hosts deficient in AMPs or ROS production had reduced LOH frequencies and fewer, if any, additional genomic changes. We also found that C. albicans cap1{Delta}/{Delta} strains deficient in ROS detoxification, were more susceptible to host-produced ROS genome instability compared to wildtype C. albicans. Further, genomic perturbations resulting from host-produced ROS are mitigated by the addition of antioxidants. Taken together, this work suggests that host-produced ROS and AMPs induces genotypic plasticity in C. albicans which may facilitate rapid adaptation and lead to phenotypic changes.

genomics↗

Allopregnanolone mediates affective switching through modulation of oscillatory states in the basolateral amygdala

Brexanolone (allopregnanolone), was recently approved by the FDA for the treatment of post-partum depression, demonstrating long-lasting antidepressant effects. Despite our understanding of the mechanism of action of neurosteroids as positive allosteric modulators (PAMs) of GABAO_SCPLOWAC_SCPLOW receptors, we still do not fully understand how allopregnanolone exerts these persistent antidepressant effects. Here, we demonstrate that allopregnanolone and similar synthetic neuroactive steroid analogs, SGE-516 (tool-compound) and zuranolone (SAGE-217, investigational-compound), are capable of modulating oscillatory states across species, which we propose may contribute to long-lasting changes in behavioral states. We identified a critical role for interneurons in generating oscillations in the basolateral amygdala (BLA) and a role for delta-containing GABAO_SCPLOWAC_SCPLOWRs in mediating the ability of neurosteroids to modulate network and behavioral states. Actions of allopregnanolone in the BLA is sufficient to alter behavioral states and enhance BLA high-theta oscillations (6-12Hz) through delta-containing GABAO_SCPLOWAC_SCPLOW receptors, a mechanism distinct from other GABAO_SCPLOWAC_SCPLOW PAMs, such as benzodiazepines. Moreover, treatment with the allopregnanolone analog SGE-516 induces long-lasting protection from chronic stress-induced disruption of network states, which correlates with improved behavioral outcomes. Our findings demonstrate a novel molecular and cellular mechanism mediating the well-established anxiolytic and antidepressant effects of neuroactive steroids.

neuroscience↗

Establishment and characterisation of primary skeletal muscle cell cultures from patients with advanced Chronic Kidney Disease

Skeletal muscle wasting and dysfunction is a common characteristic of non-dialysis dependent chronic kidney disease (NDD-CKD). The mechanisms by which this occurs are not clearly understood and one reason for this is a lack of well controlled in-vitro methodologies to simulate NDD-CKD induced muscle wasting for mechanistic investigation at the cellular level. Here we sought to conduct the initial investigations into developing a CKD-induced skeletal muscle model for use as a mechanistic analysis tool as well as a test bed for potential novel therapeutics in this population. Human derived muscle cells (HDMCs) were isolated from n=5 NDD-CKD patients and n=3 matched healthy controls (HC) and taken through proliferation and differentiation phases in cell culture. Upon comparison of the 2 donor types, significantly greater mRNA expression of myogenic markers was noted in the NDD-CKD cultures in comparison to HC cultures, which was carried through to greater mRNA expression of myosin heavy chains (MyHCs) post differentiation. However, this was not carried over to protein expression where Pax7 and MyoD were seen to be expressed to a greater extent in HC cultures. mRNA expression markers of protein degradation were noted to be elevated in NDD-CKD cultures in comparison to HC cultures. In light of our findings, future work should seek to investigate the role of the CKD environment as well as mechanisms implicated in transcription regulation to further advance the current model development as well as the mechanistic understanding of skeletal muscle wasting in CKD.

cell biology↗

bbsBayes: An R Package for Hierarchical Bayesian Analysis of North American Breeding Bird Survey Data

The North American Breeding Bird Survey (BBS) is the primary ecological monitoring program used to assess the population, status, and trend of North American birds. As such, accessible analysis of BBS data is crucial to wildlife conservation/management and ecological science in North America. The R package bbsBayes was developed as a wrapper for the analysis of BBS data using hierarchical Bayesian models, including the models currently used by the Canadian Wildlife Service and the United States Geological Survey. The goal of bbsBayes is to provide an accessible package for anyone in the conservation community to estimate population trajectories (time-series) and trends (rates of change) for any of the 400+ bird species monitored by the BBS, and to allow more advance users to easily access the data and model-templates necessary to customize an analysis for their research.

ecology↗

Host association induces genome changes in Candida albicans which alters its virulence

Candida albicans is an opportunistic fungal pathogen of humans that is typically diploid yet, has a highly labile genome that is tolerant of large-scale perturbations including chromosomal aneuploidy and loss-of-heterozygosity events. The ability to rapidly generate genetic variation is crucial for C. albicans to adapt to changing or stress environments, like those encountered in the host. Genetic variation occurs via stress-induced mutagenesis or can be generated through its parasexual cycle, which includes mating between diploids or stress-induced mitotic defects to produce tetraploids and non-meiotic ploidy reduction. However, it remains largely unknown how genetic background contributes to C. albicans genome instability in vitro or in vivo. Here, we tested how genetic background, ploidy and host environment impact C. albicans genome stability. We found that host association induced both loss-of-heterozygosity events and genome size changes, regardless of genetic background or ploidy. However, the magnitude and types of genome changes varied across C. albicans strains. We also assessed whether host-induced genomic changes resulted in any consequences on growth rate and virulence phenotypes and found that many host derived isolates had significant changes compared to their parental strains. Interestingly, host derivatives from diploid C. albicans predominantly displayed increased virulence, whereas host derivatives from tetraploid C. albicans had mostly reduced virulence. Together, these results are important for understanding how host-induced genomic changes in C. albicans alter the relationship between the host and C. albicans.

microbiology↗

Improved status and trend estimates from the North American Breeding Bird Survey using a hierarchical Bayesian generalized additive model

The status and trend estimates derived from the North American Breeding Bird Survey (BBS), are critical sources of information for bird conservation. However, the estimates are partly dependent on the statistical model used. Therefore, multiple models are useful because not all of the varied uses of these estimates (e.g. inferences about long-term change, annual fluctuations, population cycles, recovery of once declining populations) are supported equally well by a single statistical model. Here we describe Bayesian hierarchical generalized additive models (GAM) for the BBS, which share information on the pattern of population change across a species range. We demonstrate the models and their benefits using data a selection of species; and we run a full cross-validation of the GAMs against two other models to compare predictive fit. The GAMs have better predictive fit than the standard model for all species studied here, and comparable predictive fit to an alternative first difference model. In addition, one version of the GAM described here (GAMYE) estimates a population trajectory that can be decomposed into a smooth component and the annual fluctuations around that smooth. This decomposition allows trend estimates based only on the smooth component, which are more stable between years and are therefore particularly useful for trend-based status assessments, such as those by the IUCN. It also allows for the easy customization of the model to incorporate covariates that influence the smooth component separately from those that influence annual fluctuations (e.g., climate cycles vs annual precipitation). For these reasons and more, this GAMYE model is a particularly useful model for the BBS-based status and trend estimates. LAY SUMMARYO_LIThe status and trend estimates derived from the North American Breeding Bird Survey are critical sources of information for bird conservation, but they are partly dependent on the statistical model used. C_LIO_LIWe describe a model to estimate population status and trends from the North American Breeding Bird Survey data, using a Bayesian hierarchical generalized additive mixed-model that allows for flexible population trajectories and shares information on population change across a species range. C_LIO_LIThe model generates estimates that are broadly useful for a wide range of common conservation applications, such as IUCN status assessments based on trends or changes in the rates of decline for species of concern; and the estimates have better or similar predictive accuracy to other models., and C_LI

ecology↗