Biology subjects

Smith, A. R.

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

At least 19 recordsLinked to original sources

bioRxiv2025

Systemic infections alter cortical transcriptional signatures in Alzheimer's disease

Alzheimers disease (AD) is characterized by neuroinflammation, yet the impact of concurrent systemic infections on the AD brain remains poorly understood. We investigated the molecular mechanisms underlying the central nervous system response to systemic infections in AD by analyzing RNA sequencing data generated in the prefrontal cortex from 202 post-mortem donors (113 AD, 89 controls), where we stratified by the presence of a respiratory infection at the time of death. We identified 763 significantly differentially expressed genes (DEGs) between AD and controls without infection, which were enriched for oxidative phosphorylation and neurodegenerative pathways. In contrast, 122 DEGs distinguished AD from controls during infection, with 57 genes uniquely altered in AD in the presence of infection, including MAPK4, VAV3, and POU3F4, implicating infection-dependent mechanisms of vascular and immune regulation. Pathway activity analysis revealed that infection in AD suppresses some immune and vascular pathways, while enhancing transcriptional and developmental programs. Weighted gene co-expression network analysis uncovered three key modules: one module strongly associated with AD, enriched for aging and signal transduction; one module linked to both AD and infection, highlighting cytoskeletal remodelling and host-pathogen interactions; and one module specific to infection, enriched in astrocytes, pericytes, and endothelial cells, implicating blood-brain barrier dysfunction. These findings suggest that systemic respiratory infections reshape transcriptional programs in the AD brain, dampening immune effector pathways and engaging vascular and host-pathogen processes in blood-brain-barrier-associated cell types. Our results highlight the complex interplay between systemic infection, neuroinflammation, and vascular responses in AD.

neuroscience↗

bioRxiv2025

Cytokine Regulation of Human Antibody Responses to Influenza Vaccines

Studies show that human vaccine responses widely vary. Here, we analyzed data measuring 66 cytokines from 4 different inactivated influenza vaccine (IIV) cohorts over 5 seasons (N=581) and identified a significant correlation between baseline/day 0 serum IL-18 and IFN-{beta} concentrations and the vaccine-specific antibody response on day 28, suggesting these factors may have an adjuvant-like effect. To investigate this further, we tested the impact of 19 cytokines on the development of anti-influenza antibody response when administered together with the IIV vaccine in human tonsil and spleen organoids. We found that Type I IFNs (IFN-{beta} and others), IL-21, IL-12, IL-10, but not IL-18 or IFN-{gamma}, enhanced the antibody response. The live attenuated influenza vaccine (LAIV) induced a stronger antibody response than the inactivated one in organoids. Adding a single cytokine, IFN-{beta}, to IIV stimulation recapitulated most of the live vaccine-specific cytokine activation program. It increased the antibody response of the inactivated vaccine to that of the LAIV. Two other antibody-boosting cytokines, IL-12 and IL-21, were induced by LAIV but not by Type I IFNs, indicating different cytokines can affect different pathways leading to a robust antibody response. We then generated cytokine mRNA lipid nanoparticles (LNPs) to test the effect of cytokines on IIV response in a mouse model of immunization. We found that IL-21-LNPs augmented the quantity and breadth of the antibody responses, while IFN-{beta} LNPs enhanced durability. These findings identified parallel cytokine pathways regulating human vaccine responses and provide a rationale for using cytokines as adjuvants to mimic the effectiveness of live-attenuated vaccines without the risk of viral replication.

immunology↗

bioRxiv2025

Methylomic signatures of tau and amyloid-beta in transgenic mouse models of Alzheimer's disease neuropathology

Alzheimers disease (AD) is characterized by progressive neurodegeneration driven by tau and amyloid-{beta} (A{beta}) pathology. Emerging evidence implicates a role for epigenetic modifications, particularly altered DNA methylation (DNAm), in AD pathogenesis. However, few studies have comprehensively investigated DNAm in experimental models. Here, we profile DNAm dynamics in two widely used transgenic mouse models of tau (rTg4510) and A{beta} (J20) neuropathology, focusing on variation in the entorhinal cortex and hippocampus. Using reduced representation bisulfite sequencing (RRBS) and methylation arrays across multiple disease stages, we identified widespread DNAm alterations associated with genotype and neuropathological burden. In rTg4510 mice, tau accumulation was linked to extensive DNAm remodeling at genes involved in neuronal plasticity and apoptosis (including Dcaf5, Creb3l4, and As3mt). J20 mice exhibited more modest changes annotated to immune-related genes, notably at Grk2, Ncam2, and Prmt8. Of note, tau-associated DNAm changes were more consistent across brain areas than those associated with A{beta} pathology. Comparison with DNAm data from human studies revealed that a subset of DNAm sites mirrored those observed in the human AD cortex, including hypermethylation at Ank1 and Prdm16. These findings provide evidence for pathology-associated epigenetic alterations in AD, highlight shared and distinct DNAm signatures of tau and A{beta}, and offer insight into molecular mechanisms that may precede overt neurodegeneration. Our work underscores the utility of epigenomic profiling in transgenic models and provides a foundation for identifying novel targets for early intervention in AD.

neuroscience↗

bioRxiv2025

A Cell Type Enrichment Analysis Tool for Brain DNA Methylation Data (CEAM)

DNA methylation signatures are highly cell type-specific, yet most epigenome-wide association studies (EWAS) are performed on bulk tissue, potentially obscuring critical cell type-specific patterns. Existing computational tools for detecting cell type-specific DNAm changes are often limited by the accuracy of cell type deconvolution algorithms. Here, we introduce CEAM (Cell-type Enrichment Analysis for Methylation), a robust and interpretable framework for cell type enrichment analysis in DNA methylation data. CEAM applies over-representation analysis with cell type-specific CpG panels from Illumina EPIC arrays derived from nuclei-sorted cortical post-mortem brains from neurologically healthy aged individuals. The constructed CpG panels were systematically evaluated using both simulated datasets and published EWAS results from Alzheimers disease, Lewy body disease, and multiple sclerosis. CEAM demonstrated resilience to shifts in cell type composition, a common confounder in EWAS, and remained accurate across a wide range of differentially methylated positions, underscoring its flexibility. Application to existing EWAS findings generated in neurodegenerative diseases revealed enrichment patterns concordant with established disease biology, confirming CEAMs biological relevance. The workflow is publicly available as an interactive Shiny app (https://um-dementia-systems-biology.shinyapps.io/CEAM/) enabling rapid, interpretable analysis of cell type-specific DNAm changes from bulk EWAS.

genomics↗

bioRxiv2025

Epigenomic subtypes of late-onset Alzheimer's disease reveal distinct microglial signatures

Growing evidence suggests that clinical, pathological, and genetic heterogeneity in late-onset Alzheimers disease contributes to variable therapeutic outcomes, potentially explaining many trial failures. Advances in molecular subtyping through proteomic and transcriptomic profiling reveal distinct patient subgroups, highlighting disease complexity beyond amyloid-beta plaques and tau tangles. This insight underscores the need to expand molecular subtyping across new molecular layers, to identify novel drug targets for different patient subgroups. In this study, we analyzed genome-wide DNA methylation data from three independent postmortem brain cohorts (n = 831) to identify epigenetic subtypes of late-onset Alzheimers disease. Unsupervised clustering approaches were employed to identify distinct DNA methylation patterns, with subsequent cross-cohort validation to ensure robustness and reproducibility. To explore the cell-type specificity of the identified epigenomic subtypes, we characterized their methylation signatures utilizing DNA methylation profiles derived from purified brain cells. Transcriptomic data from bulk and single-cell RNA sequencing were integrated to examine the functional impact of epigenetic subtypes on gene expression profiles. Finally, we performed statistical analyses to investigate associations between these DNA methylation-defined subtypes and clinical or neuropathological features, aiming to elucidate their biological significance and clinical implications. We identified two distinct epigenomic subtypes of late-onset Alzheimers disease, each defined by reproducible DNA methylation patterns across three cohorts. Both subtypes exhibit cell-type-specific DNA methylation profiles. Subtype 1 and subtype 2 show significant microglial methylation enrichment, with odds ratios (OR) of 1.6 and 1.3, respectively. The minimal overlap between them suggests distinct microglial states. Additionally, subtype 2 displays strong neuronal (OR = 1.6) and oligodendrocyte (OR = 3.6) enrichment. Bulk transcriptomic analyses further highlighted divergent biological mechanisms underpinning these subtypes, with subtype 1 enriched for immune-related processes, and subtype 2 characterized predominantly by neuronal and synaptic functional pathways. Single-cell transcriptional profiling of microglia revealed subtype-specific inflammatory states: subtype 1 represented a state of chronic innate immune hyperactivation with impaired resolution, while subtype 2 exhibited a more dynamic inflammatory profile balancing pro-inflammatory signaling with reparative and regulatory mechanisms. This study highlights the molecular heterogeneity of late-onset Alzheimers disease by identifying two epigenetic subtypes with distinct cell-type-specific DNA methylation patterns. Their alignment with previously defined molecular classifications underscores their relevance in disease pathogenesis. By linking these subtypes to inflammatory microglial activity, our findings provide a foundation for future precision medicine approaches in Alzheimers research and treatment.

genomics↗

bioRxiv2025

A new Paramoeba Isolate from Florida Exhibits a Microtubule-Bound Endosymbiont Closely Associated with the Host Nucleus

The genera Paramoeba and Neoparamoeba, within the family Paramoebidae (order Dactylopodida), are distinguished by their dactylopodial pseudopodia and the presence of an intracellular eukaryotic symbiont, the Perkinsela-like organism (PLO). Taxonomic classification within these genera has been challenging due to overlapping morphological traits and close phylogenetic relationships. Most species are marine, with some acting as significant parasites, contributing to sea urchin mass mortality and serving as causative agents of Amoebic Gill Disease (AGD). Despite their ecological and economic importance, many aspects of their diversity, biology, evolution, and host interactions remain poorly understood. In this study, we describe a novel amoeba species, Paramoeba daytoni n. sp., isolated from Daytona Beach, Florida. Morphological and molecular analyses confirm its placement within the Paramoeba clade, closely related to P. eilhardi, P. karteshi, and P. aparasomata. Phylogenetic assessments using 18S and COI markers demonstrate the limitations of 18S gene for species delineation, highlighting COI as a more reliable genetic marker for this group. Additionally, observations on PLO morphology, movement, and microtubule association provide insights into the endosymbiotic relationship, reinforcing the need for further research into this unique eukaryote-eukaryote symbiosis.

microbiology↗

bioRxiv2024

Brain-body circuit by which midbrain dopamine neuronal activity modulates splenic immunity

Midbrain dopamine neurons are well-known to shape central nervous system function, yet there is growing evidence for their influence on the peripheral immune system. Here we demonstrate that midbrain dopamine neurons form a circuit to the spleen via a multi-synaptic pathway from the dorsal vagal complex (DVC) through the celiac ganglion. Midbrain dopamine neurons modulate the activity of D1- and D2-like dopamine receptor-expressing DVC neurons. In vivo activation of midbrain dopamine neurons induced dopamine release in the DVC and increased immediate early gene expression in both the DVC and celiac ganglion. Activation of this midbrain-to-spleen circuit reduced spleen weight and decreased naive CD4+ T-cell populations without affecting total T-cell numbers. These findings unveil a functional midbrain- DVC-celiac ganglion-spleen pathway, through which midbrain dopamine neurons modulate splenic immunity. These novel insights into the neural regulation of the immune system have important implications for diseases involving altered dopamine neurotransmission and highlight potential targets for immunotherapeutic interventions.

neuroscience↗

bioRxiv2024

AAV-based delivery of RNAi targeting Ataxin-2 improves survival, strength, and pathology in mouse models of rapidly and slowly progressive sporadic ALS

Amyotrophic lateral sclerosis (ALS) is characterized by motor neuron death due to nuclear loss and cytoplasmic aggregation of the splice factor TDP-43. Pathologic TDP-43 associates with stress granules (SGs) and downregulating the SG-associated protein Ataxin-2 (Atxn2) using antisense oligonucleotides (ASO) prolongs survival in the TAR4/4 sporadic ALS mouse model, a strategy now in clinical trials. Here, we used AAV-mediated RNAi delivery to achieve lasting and targeted Atxn2 knockdown after a single injection. To achieve this, a novel AAV with improved transduction potency of our target cells was used to deliver Atxn2-targeting miRNAs. Mouse dosing studies demonstrated 55% Atxn2 knockdown in frontal cortex and 25% knockdown throughout brainstem and spinal cord after intracerebroventricular injection at a dose 40x lower than used in other recent studies. In TAR4/4 mice, miAtxn2 treatment increased mean and median survival by 54% and 45% respectively (p<0.0003). Mice showed robust improvement across strength-related measures ranging from 24-75%. Interestingly, treated mice showed increased vertical activity above wildtype, suggesting unmasking of an FTD phenotype with improved strength. Histologically, lower motor neuron survival improved with a concomitant reduction in CNS inflammatory markers. Additionally, phosphorylated TDP-43 was reduced to wildtype levels. Bulk RNA sequencing revealed correction of 153 genes in the markedly dysregulated transcriptome of mutant mice, several of which are described in the human ALS literature. In slow progressing hemizygous mice, treatment rescued weight loss and improved gait at late time points. Cumulatively the data support the utility of AAV-mediated RNAi against Atxn2 as a robust and translatable treatment strategy for sporadic ALS.

neuroscience↗

bioRxiv2024

Transient growth factor expression via mRNA in lipid nanoparticles promotes hepatocyte cell therapy to treat murine liver diseases

Primary human hepatocyte (PHH) transplantation is a promising alternative to liver transplantation, whereby liver function could be restored by partial repopulation of the diseased organ with healthy cells. However, currently PHH engraftment efficiency is low and benefits are not maintained long-term. Here we refine two mouse models of human chronic and acute liver diseases to recapitulate compromised hepatocyte proliferation observed in nearly all human liver diseases by overexpression of p21 in hepatocytes. In these clinically relevant contexts, we demonstrate that transient, yet robust expression of human hepatocyte growth factor and epidermal growth factor in the liver via nucleoside-modified mRNA in lipid nanoparticles, whose safety was validated with mRNA-based COVID-19 vaccines, drastically improves PHH engraftment, reduces disease burden, and improves overall liver function. This novel strategy may overcome the critical barriers to clinical translation of cell therapies with primary or stem cell-derived hepatocytes for the treatment of liver diseases.

cell biology↗

bioRxiv2023

Epigenetic insights into neuropsychiatric and cognitive symptoms in Parkinson's disease: A DNA co-methylation network analysis

Parkinsons disease is a highly heterogeneous disorder, encompassing a complex spectrum of clinical presentation including motor, sleep, cognitive and neuropsychiatric symptoms. We aimed to investigate genome-wide DNA methylation networks in post-mortem Parkinsons disease brain samples and test for region-specific association with common neuropsychiatric and cognitive symptoms. Of traits tested, we identify a co-methylation module in the substantia nigra with significant correlation to depressive symptoms and with ontological enrichment for terms relevant to neuronal and synaptic processes. Notably, expression of the genes annotated to the methylation loci present within this module are found to be significantly enriched in neuronal subtypes within the substantia nigra. These findings highlight the potential involvement of neuronal-specific changes within the substantia nigra with regard to depressive symptoms in Parkinsons disease.

neuroscience↗

bioRxiv2023

VEGFA mRNA-LNP promotes biliary epithelial cell-to-hepatocyte conversion in acute and chronic liver diseases and reverses steatosis and fibrosis

The liver is known for its remarkable regenerative ability through proliferation of hepatocytes. Yet, during chronic injury or severe hepatocyte death, proliferation of hepatocytes is exhausted. To overcome this hurdle, we propose vascular-endothelial-growth-factor A (VEGFA) as a therapeutic means to accelerate biliary epithelial cell (BEC)-to-hepatocyte conversion. Investigation in zebrafish establishes that blocking VEGF receptors abrogates BEC-driven liver repair, while VEGFA overexpression promotes it. Delivery of VEGFA via non-integrative and safe nucleoside-modified mRNA encapsulated into lipid-nanoparticles (mRNA-LNP) in acutely or chronically injured mouse livers induces robust BEC-to-hepatocyte conversion and reversion of steatosis and fibrosis. In human and murine diseased livers, we further identified VEGFA-receptor KDR-expressing BECs associated with KDR-expressing cell-derived hepatocytes. This defines KDR-expressing cells, most likely being BECs, as facultative progenitors. This study reveals novel therapeutic benefits of VEGFA delivered via nucleoside-modified mRNA-LNP, whose safety is widely validated with COVID-19 vaccines, for harnessing BEC-driven repair to potentially treat liver diseases. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=156 SRC="FIGDIR/small/537186v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@8ce1bdorg.highwire.dtl.DTLVardef@1385103org.highwire.dtl.DTLVardef@4ec496org.highwire.dtl.DTLVardef@14c9295_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIComplementary mouse and zebrafish models of liver injury demonstrate the therapeutic impact of VEGFA-KDR axis activation to harness BEC-driven liver regeneration. C_LIO_LIVEGFA mRNA LNPs restore two key features of the chronic liver disease in humans such as steatosis and fibrosis. C_LIO_LIIdentification in human cirrhotic ESLD livers of KDR-expressing BECs adjacent to clusters of KDR+ hepatocytes suggesting their BEC origin. C_LIO_LIKDR-expressing BECs may represent facultative adult progenitor cells, a unique BEC population that has yet been uncovered. C_LI

pathology↗

bioRxiv2023

Growth Hormone Accelerates Recovery From Acetaminophen-Induced Murine Liver Injury

Background and AimsAcetaminophen (APAP) overdose is the leading cause of acute liver failure, with one available treatment, N-acetyl cysteine (NAC). Yet, NAC effectiveness diminishes about ten hours after APAP overdose, urging for therapeutic alternatives. This study addresses this need by deciphering a mechanism of sexual dimorphism in APAP-induced liver injury, and leveraging it to accelerate liver recovery via growth hormone (GH) treatment. GH secretory patterns, pulsatile in males and near-continuous in females, determine the sex bias in many liver metabolic functions. Here, we aim to establish GH as a novel therapy to treat APAP hepatotoxicity. Approach and ResultsOur results demonstrate sex-dependent APAP toxicity, with females showing reduced liver cell death and faster recovery than males. Single-cell RNA sequencing analyses reveal that female hepatocytes have significantly greater levels of GH receptor expression and GH pathway activation compared to males. In harnessing this female-specific advantage, we demonstrate that a single injection of recombinant human GH protein accelerates liver recovery, promotes survival in males following sub-lethal dose of APAP, and is superior to standard-of-care NAC. Alternatively, slow-release delivery of human GH via the safe nonintegrative lipid nanoparticle-encapsulated nucleoside-modified mRNA (mRNA-LNP), a technology validated by widely used COVID-19 vaccines, rescues males from APAP-induced death that otherwise occurred in control mRNA-LNP-treated mice. ConclusionsOur study demonstrates a sexually dimorphic liver repair advantage in females following APAP overdose, leveraged by establishing GH as an alternative treatment, delivered either as recombinant protein or mRNA-LNP, to potentially prevent liver failure and liver transplant in APAP-overdosed patients.

pathology↗

bioRxiv2022

Engineered extracellular matrices reveal stiffness-mediated chemoresistance in patient-derived pancreatic cancer organoids

Pancreatic ductal adenocarcinoma (PDAC) is characterized by its fibrotic and stiff extracellular matrix (ECM); however, the role that altered cell-ECM signaling may play in driving PDAC phenotype has historically been difficult to dissect. Here, we design an engineered matrix that recapitulates key hallmarks of the tumor ECM and show that patient-derived PDAC organoids develop gemcitabine chemoresistance when cultured within high stiffness matrices mechanically matched to in vivo tumors. Using genetic barcoding, we find that while matrix-specific clonal selection occurs, cellular heterogeneity is not the main driver of chemoresistance. Instead, stiffness-induced chemoresistance occurs due to the development of a plastic cancer stem cell phenotype - mediated by hyaluronan mechanosignaling - with increased expression of drug efflux transporters. Moreover, PDAC chemoresistance is reversible following transfer from high to low stiffness matrices, suggesting that mechanotherapeutics targeting the fibrotic ECM may sensitize chemoresistant tumors. Overall, we demonstrate the power of engineered matrices and patient-derived organoids to elucidate how ECM properties influence human disease pathophysiology.

cancer biology↗

bioRxiv2021

Pan-cancer organoid validation of tumor outlier chromosomal amplification events

Somatic copy number gains are pervasive in many cancer types, yet their roles in oncogenesis are often poorly explored. This lack of understanding is in part due to broad extensions of copy gains across cancer genomes spanning large chromosomal regions, obscuring causal driver loci. Here we employed a multi-tissue pan-organoid modeling approach to validate candidate oncogenic loci identified within pan-cancer TCGA data by the overlap of extreme copy number amplifications with extreme expression dysregulation for each gene. The candidate outlier loci nominated by this integrative computational analysis were functionally validated by infecting cancer type-specific barcoded full length cDNA lentiviral libraries into cognate minimally transformed human and mouse organoids bearing initial oncogenic mutations from esophagus, oral cavity, colon, stomach, pancreas and lung. Presumptive amplification oncogenes were identified by barcode enrichment as a proxy for increased proliferation. Iterative analysis validated DYRK2 at 12q15, encoding a serine-threonine kinase, as an amplified head and neck squamous carcinoma oncogene in p53-/- oral mucosal organoids. Similarly, FGF3, amplified at 11q13 in 41% of esophageal squamous carcinomas, was validated in p53-/- esophageal organoids in vitro and in vivo with pharmacologic inhibition by small molecule and soluble receptor FGFR antagonists. Our studies establish the feasibility of pan-organoid contextual modeling of pan-cancer candidate genomic drivers, enabling oncogene discovery and preclinical therapeutic modeling.

cancer biology↗

bioRxiv2021

Hyperbolic trade-off: the importance of balancing trial and subject sample sizes in neuroimaging

Here we investigate the crucial role of trials in task-based neuroimaging from the perspectives of statistical efficiency and condition-level generalizability. Big data initiatives have gained popularity for leveraging a large sample of subjects to study a wide range of effect magnitudes in the brain. On the other hand, most taskbased FMRI designs feature a relatively small number of subjects, so that resulting parameter estimates may be associated with compromised precision. Nevertheless, little attention has been given to another important dimension of experimental design, which can equally boost a studys statistical efficiency: the trial sample size. The common practice of condition-level modeling implicitly assumes no cross-trial variability. Here, we systematically explore the different factors that impact effect uncertainty, drawing on evidence from hierarchical modeling, simulations and an FMRI dataset of 42 subjects who completed a large number of trials of cognitive control task. We find that, due to the hyperbolic relationship between trial and subject sample sizes and the presence of relatively large cross-trial variability, 1) trial sample size has nearly the same impact as subject sample size on statistical efficiency; 2) increasing both the number of trials and subjects improves statistical efficiency more effectively than focusing on subjects alone; 3) trial sample size can be leveraged alongside subject sample size to improve the cost-effectiveness of an experimental design; 4) for small trial sample sizes, trial-level modeling, rather than condition-level modeling through summary statistics, may be necessary to accurately assess the standard error of an effect estimate. We close by making practical suggestions for improving experimental designs across neuroimaging and behavioral studies.

neuroscience↗

bioRxiv2021

Protistan grazing impacts microbial communities and carbon cycling at deep-sea hydrothermal vents

Microbial eukaryotes (or protists) in marine ecosystems are a link between microbial primary producers and all higher trophic levels. The rate at which heterotrophic protistan grazers consume microbial prey and recycle organic matter is an important factor that influences marine microbial food webs and carbon cycling. At deep-sea hydrothermal vents, chemosynthetic bacteria and archaea form the base of a food web that functions in the absence of sunlight, but the role of protistan grazers in these highly productive ecosystems is largely unexplored. Here, we pair grazing experiments with a molecular survey to quantify protistan grazing and to characterize the composition of vent-associated protists in low-temperature venting fluids from Gorda Ridge in the North East (NE) Pacific Ocean. Results reveal protists exert higher predation pressure at vents compared to the surrounding deep seawater environment and may account for consuming 28-62% of the daily stock of prokaryotic biomass within the hydrothermal vent food web. The vent-associated protistan community was more species rich relative to the background deep sea, and patterns in the distribution and co-occurrence of vent microbes provide additional insights into potential predator-prey interactions. Ciliates, followed by dinoflagellates, Syndiniales, rhizaria, and stramenopiles dominated the vent protist community and included bacterivorous species, species known to host symbionts, and parasites. Our findings provide an estimate of protistan grazing pressure within hydrothermal vent food webs, highlighting the role that diverse deep-sea protistan communities have in carbon cycling. SignificanceHeterotrophic protists are ubiquitous in all aquatic ecosystems and represent an important ecological link because they transfer organic carbon from primary producers to higher trophic levels. Here, we quantify the predator-prey trophic interaction among protistan grazers and microbial prey at multiple sites of hydrothermal venting near the Gorda Ridge spreading center in the NE Pacific Ocean. Grazing pressure was higher at the site of active diffuse flow and was carried out by a highly diverse assemblage of protistan species; elevated grazing rates are attributed to higher concentrations of chemosynthetic microorganisms and biological diversity localized to hydrothermal vent environments.

microbiology↗

bioRxiv2021

Beyond the intraclass correlation: A hierarchical modeling approach to test-retest assessment

The concept of test-retest reliability indexes the consistency of a measurement across time. High reliability is critical for any scientific study, but specifically for the study of individual differences. Evidence of poor reliability of commonly used behavioral and functional neuroimaging tasks is mounting. Reports on low reliability of task-based fMRI have called into question the adequacy of using even the most common, well-characterized cognitive tasks with robust population-level effects, to measure individual differences. Here, we lay out a hierarchical framework that estimates reliability as a correlation divorced from trial-level variability, and show that reliability estimates tend to be higher compared to the conventional framework that adopts condition-level modeling and ignores across-trial variability. We examine how estimates from the two frameworks diverge and assess how different factors (e.g., trial and subject sample sizes, relative magnitude of cross-trial variability) impact reliability estimates. We also show that, under specific circumstances, the two statistical frameworks converge. Results from the two approaches are approximately equivalent if (a) the trial sample size is sufficiently large, or (b) cross-trial variability is in the same order of magnitude as, or less than, cross-subject variability. As empirical data indicate that cross-trial variability is large in most tasks, this work highlights that a large number of trials (e.g., greater than 100) may be required to achieve precise reliability estimates. We reference the tools TRR and 3dLMEr for the community to apply trial-level models to behavior and neuroimaging data and discuss how to make these new measurements most useful for current studies.

neuroscience↗

bioRxiv2020

Prevention and Treatment of SHIVAD8 Infection in Rhesus Macaques by a Potent D-peptide HIV Entry Inhibitor

Cholesterol-PIE12-trimer (CPT31) is a potent D-peptide HIV entry inhibitor that targets the highly conserved gp41 N-peptide pocket region. CPT31 exhibited strong inhibitory breadth against diverse panels of primary virus isolates. In a SHIV macaque model, CPT31 prevented infection from a single high-dose rectal challenge. In chronically infected animals, CPT31 monotherapy rapidly reduced viral load by ~2 logs before rebound occurred due to the emergence of drug resistance. In chronically infected animals with viremia initially controlled by combination antiretroviral therapy (cART), CPT31 monotherapy prevented viral rebound after discontinuation of cART. These data establish CPT31 as a promising new candidate for HIV prevention and treatment.

microbiology↗