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Murray, K.

Publications and source records attributed to Murray, K..

18 recordsLinked to original sources

Comprehensive Phylogenomic Inference of Eucalypts Reveals Taxonomic Limits through Gene Tree Concordance

Speciation can be a slow process for long-lived organisms with large populations due to persistent incomplete lineage sorting, while hybridisation can further obscure species boundaries through admixture. In eucalypts, there is tremendous morphological and environmental variation with almost a thousand described species, subspecies, and hybrid taxa falling into multiple subgenera and intermediate sections. Multilocus molecular studies have generated concatenated species trees supporting deeper divergence between the Corymbia + Blakella + Angophora clade with the rest of eucalypts. However, the proportion of gene trees that recover the concatenated tree topology, including the taxonomic relationships among individual subgenera and sections, remains underappreciated. In this study, we assessed the predictive power of current eucalypt taxonomy - represented as a concatenated tree - in explaining topological variation across gene trees. To do this, we first extracted 1,187 BUSCO loci from short-read data of 701 samples representing roughly 500 described species using CAPTUS. We then inferred individual gene trees and a concatenated species tree using IQ-TREE2. Finally, we calculated the concordance factors for every described subgenus and section on the concatenated tree, and developed a taxonomic consistency test that tracks the taxonomic placement of each sample across gene trees. We show that, even though most taxonomic groups are monophyletic on the concatenated tree with 100% bootstrap support, several groups exhibit very low concordance, indicating that most gene trees do not recover their relationships as represented by the concatenated tree. These results highlight important considerations for current eucalypt taxonomic classification and provide a phylogenomic inference pipeline that can be applied not only to future eucalypt studies, but also to other evolutionarily complex groups of taxa.

evolutionary biology↗

In vivo cellular localisation and nanoscale organisation of NLRP3 inflammasomes

The NLRP3 inflammasome is a critical regulator of inflammation, yet the localisation, organisation, and cellular sources of endogenous NLRP3 inflammasomes remain incompletely understood. Here, we generated NLRP3-mScarlet-I endogenous reporter mice enabling visualisation of NLRP3 at physiological levels in primary cells and in vivo. We show that activated NLRP3 associated with PI4P-positive membranes from multiple organelles, supporting a model where diverse membrane platforms act as a scaffold to nucleate inflammasome assembly. Super-resolution imaging revealed that NLRP3 and ASC occupy distinct nanoscale architectures within the inflammasome, with NLRP3 displaying marked structural heterogeneity and stimulus-dependent organisation. Unexpectedly, circulating monocytes and neutrophils, rather than tissue-resident populations, emerged as the dominant NLRP3-expressing cells in vivo which rapidly infiltrated tissues following systemic inflammation, highlighting an underappreciated cellular source of rapid inflammasome-driven responses. These findings reveal previously unrecognised insights into inflammasome organisation and localisation, establishing a powerful resource for investigating endogenous NLRP3 biology in health and disease.

immunology↗

The Endocannabinoid System's Contribution to Placebo Analgesia

Placebo analgesia--pain reduction from inert treatments--varies widely across individuals, yet its neurochemical basis remains poorly understood. While endogenous opioids, specifically {beta}-endorphin, contribute to placebo effects, mu-opioid receptor blockade does not fully abolish analgesia, implicating additional systems. Here, we investigate the endogenous cannabinoid (eCB) systems contribution to placebo analgesia in 48 healthy adults using a validated placebo paradigm with blood sampling. We quantified circulating levels of eCB ligands and {beta}-endorphin at baseline, as well as before and after placebo and control conditions to determine condition-related changes. Individual differences in placebo analgesia were associated with increases in fatty acid amide hydrolase (FAAH) substrates--a composite of anandamide, palmitoylethanolamide, and oleoylethanolamide--but not 2-arachidonoylglycerol or {beta}-endorphin alone. Critically, {beta}-endorphin moderated this relationship: FAAH substrates were strongly associated with pain reduction only when {beta}-endorphin levels were low. These findings provide evidence that eCB and opioid systems interact in a state-dependent manner during placebo analgesia in humans, with implications for understanding individual variability in treatment responses.

neuroscience↗

mRNA and Protein Expression of Fetal Insulin Receptor in Breast Cancer Cell Lines

The insulin receptor (IR) is expressed in breast cancer cells and plays a role in regulating tumor biology. There are two IR isoforms generated from the same gene. Alternate splicing with exclusion or inclusion of exon 11accounts for the two isoforms. The exon 11 excluded isoform (IR-A) is expressed during fetal development while the full-length adult IR (IR-B) is the primary form expressed during adult life. This splice variant results in a 12 amino acid variation in peptide sequence. Breast cancer cells overexpress IR-A with an increased IR-A:IR-B ratio. Most of these data were obtained by examining mRNA expressions. In this work, we examined over 40 breast cancer cell lines and patient tumor samples for mRNA expression of the IR isoforms to show that most cells overexpressed IR-A compared to IR-B. Further we used mass spectrometry to demonstrate IR-A protein expression in the Du4475 cell line which has a high level of IR-A mRNA expression. To our knowledge, this is the first demonstration of IR-A protein expression. Thus, IR-A mRNA and protein expression demonstrate a potential role for this insulin receptor isoform in breast cancer biology.

cancer biology↗

The Dishevelled C-terminus interacts with the centrosomal protein Kizuna to regulate microtubule organization during ciliogenesis.

Microtubules (MTs) serve as dynamic scaffolds that support diverse cellular processes, including cell division, intracellular transport, and epithelial morphogenesis. In ciliated cells, MTs not only form the axonemal backbone of cilia but also work in tandem with actin to build an apical meshwork that anchors and orients basal bodies. However, the mechanisms regulating apical MT organization during ciliogenesis remain poorly understood. Here, we identify the centrosomal protein Kizuna (Kiz) as a critical regulator of apical MT architecture. Kiz interacts with the C-terminus of Dishevelled 2 (Dvl-C), inducing an open conformation and enabling the recruitment of Protein Kinase C delta (PKC{delta}) to stabilize the apical MT meshwork. This Dvl2-Kiz-PKC{delta} signaling axis is essential for ciliogenesis across multiple contexts, including the formation of primary cilia in the eye, multicilia in the mucociliary epidermis (MCE), and mono-motile cilia in the left-right organizer, the gastrocoel roof plate (GRP). These findings reveal a conserved molecular mechanism linking Dvl2 conformational dynamics to MT organization and highlight Kizuna as a key mediator coupling non-canonical Wnt signaling to ciliogenesis, left-right patterning, and the organization of the apical actin microtubule meshwork in ciliated cells of embryos.

developmental biology↗

Impaired Lung BCAA Metabolism Promotes Ferroptosis and Resultant Pulmonary Arterial Hypertension-Associated Hepatopathy

BackgroundDysregulated branched chain amino acid (BCAA) homeostasis occurs in pulmonary arterial hypertension (PAH) as BCAA metabolites accumulate and cause metabolic alterations in pulmonary artery smooth muscle cells (PASMC). In other cells, altered BCAA metabolism promotes ferroptosis, a PAH-inducing metabolic pathway. However, the interplay between BCAAs, lung ferroptosis, and PAH is unexplored, as is the impact of PAH severity on liver molecular regulation, a key unknown as recent clinical data highlight the importance of the lung-right heart-liver axis in PAH outcomes. MethodsHuman metabolomic and transcriptomic studies examined BCAA metabolism and ferroptosis pathways. The relationship between BCAAs and ferroptotic-phenotypes in PASMCs was evaluated. Multi-omics and physiological analyses evaluated how modulation of BCAA catabolism impacted preclinical PAH multi-organ physiology. Confocal microscopy and proteomic analyses assessed hepatic alterations in human PAH. ResultsMetabolomic analyses identified alterations in BCAA metabolites across multiple physiological gradients in patients with pulmonary vascular disease. RNA sequencing demonstrated deficits in the BCAA catabolic and ferroptosis pathways in PAH lungs and smooth muscle cells. In vitro, excess BCAAs induced mitochondrial fragmentation, reactive oxygen species generation, and lipid peroxidation in PASMC. Moreover, BCAAs promoted PASMC death, which ferrostatin-1, a ferroptosis antagonist, rescued. BT2, a small-molecule inducer of BCAA catabolism, reduced PAH severity, improved RV function, and enhanced maximal exercise capacity in monocrotaline rats. BT2 blunted pro-ferroptotic changes in lung metabolites and proteins, and combatted peri-vascular complement deposition. In the liver, BT2 blocked mechanical shear stress phenotypes including hepatocyte nuclear expansion and restructured mitochondrial protein regulation and the metabolomic signature. Additionally, a low BCAA diet modestly combatted preclinical PAH severity. Finally, human PAH livers exhibited increased hepatocyte nuclear size and derangements in liver metabolic regulation. ConclusionsImpaired BCAA metabolism promotes PAH via ferroptosis. PAH severity is associated with hepatic pathological shear stress phenotypes and metabolic alterations, which are combatted by a BCAA-targeted therapy. Graphical Abstract/Summary Figure O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=152 SRC="FIGDIR/small/672819v1_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@1649980org.highwire.dtl.DTLVardef@199c40aorg.highwire.dtl.DTLVardef@1586fdorg.highwire.dtl.DTLVardef@15166c1_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

The Contribution of Circulating Endocannabinoid Tone to Individual Differences in Human Pain Sensitivity: A Quantitative Sensory Testing Study

The endocannabinoid (eCB) system--comprising cannabinoid receptors, eCBs (anandamide-- AEA, 2-arachidonoylglycerol--2-AG) and related N-acylethanolamines (NAEs; N-palmitoylethanolamide--PEA, and N-oleoylethanolamide--OEA), and metabolizing enzymes (e.g., fatty acid amide hydrolase; FAAH)--modulates nociceptive circuits in rodents. In humans, the FAAH C385A polymorphism is associated with reduced pain sensitivity, suggesting eCB tone influences individual pain differences, but this has yet to be tested. Here, we determined whether the eCB system is associated with somatosensory and pain sensitivity measured with quantitative sensory testing (QST) in 91 healthy participants (39 males, 52 females). We tested three hypotheses: (1) FAAH C385A polymorphism, cannabis use, and sex affect serum eCB/NAE concentrations; (2) FAAH C385A carriers show altered pain sensitivity versus non-carriers; and (3) baseline serum eCB/NAE concentrations are associated with QST measures. eCB/NAE concentrations were not statistically different based on sex (p > .05), based on FAAH genotype (p > .05), and based on cannabis use (p > .05). To address collinearity of AEA, OEA and PEA, we performed a principal components analysis, which identified a single component of FAAH substrates. Linear regressions found that FAAH genotype did not affect QST measures and that baseline 2-AG and FAAH substrate concentrations were not associated with QST measures, except pressure pain thresholds (PPT; p = 0.003), which were associated with AEA and OEA. Baseline eCB/NAE levels and FAAH genotype are not associated with the outcome measures of standard QST tests that rely on point estimates in healthy adult humans; nonetheless, circulating FAAH substrate levels were associated with PPT.

neuroscience↗

Proteomic and Metabolomic Profiling Nominates Druggable Targets and Biomarkers forPulmonary Arterial Hypertension-Associated Myopathy and Exercise Intolerance

BackgroundPulmonary arterial hypertension (PAH) is a rare but debilitating condition that causes exercise intolerance and ultimately death. Skeletal muscle derangements contribute to depressed exercise capacity in PAH, but the mechanisms underlying muscle dysfunction including the changes in muscle biology based on fiber type are understudied. MethodsWe evaluated exercise capacity, muscle histopathology, mitochondrial density, mitochondrial proteomics, and metabolomics/lipidomics of quadriceps (predominately fast fibers) and soleus (predominately slow fibers) muscles in the monocrotaline (MCT) rat model of PAH. ResultsMCT rats exhibited impaired exercise capacity. Surprisingly, there were divergent atrophic and metabolic remodeling in the quadriceps and soleus muscles of MCT rats. In the quadriceps, there was a mild atrophic response only in type II fibers. In contrast, both type I and II fibers atrophied in the soleus. Both muscles exhibited fibrotic infiltration, but mitochondrial density was reduced in the quadriceps only. Mitochondrial proteomics and tissue metabolomics/lipidomics profiling demonstrated the two muscles exhibited distinct responses as the quadriceps had impairments in oxidative phosphorylation/fat metabolism and storage of triacylglycerides. However, the soleus showed signs of proteasome deficiencies and alterations in phosphatidylcholine/phosphatidylethanolamine homeostasis. Finally, profiling of metabolites/lipids in the serum identified potential novel biomarkers of exercise intolerance in PAH including the dimethylarginine pathway, cysteine, and triacylglycerides. ConclusionOur data suggests differential cachectic and metabolic responses occur in PAH-induced myopathy. We nominate mitochondrial biogenesis and proteasome activation as potential druggable targets for PAH-myopathy.

systems biology↗

Inhibition of acute lung inflammation by a neuroimmune circuit induced by vagal nerve stimulation.

Vagus nerve stimulation (VNS) has been shown to limit immune cell activity across several pathologies ranging from sepsis to auto-immune diseases. While stimulation of vagal efferent neurons has been previously demonstrated to reduce maladaptive host responses during endotoxemia, only selective stimulation of vagal afferent neurons was able to inhibit TLR7-induced macrophage activation and neutrophil recruitment in the lung. These anti-inflammatory actions are facilitated by systemic increases in epinephrine, as VNS significantly increased epinephrine in the serum and bronchoalveolar lavage fluid, and inhibition of epinephrine production eliminated the protection afforded by VNS. Selective afferent VNS induced activation in the nucleus tractus solitarius and the rostral ventrolateral medulla. Inhibition of neuronal activity in this brain region that controls peripheral sympathetic nervous system activity rendered VNS ineffective. Activation of the {beta}2-adrenergic receptor ({beta}2AR) is critical for innate immune cell suppression, as the anti-inflammatory effects of VNS were eliminated in {beta}2AR-knock out mice, and with pharmacological inhibition of the {beta}2AR. Analysis of the immune cells responding to R848 critically identified that plasmacytoid dendritic cells were refractive to inhibition by VNS, and this corresponded to lack of {beta}2AR expression. These findings demonstrate a novel neuro-immune circuit elicited by VNS that can control acute lung inflammation. SummaryWe have identified a novel neuro-immune circuit activated by afferent vagus nerve stimulation to reduce acute lung inflammation. This effect was dependent on vagal-induced adrenal gland-derived epinephrine release that initiates anti-inflammatory {beta}2-adrenergic receptor signaling in innate immune cells within the lung.

immunology↗

Substance P receptor signaling contributes to host maladaptive responses during enteric bacterial infection.

Immune responses in the intestine are intricately balanced to prevent pathogen entry without inducing immunopathology. The nervous system is well-established to interface with the immune system to fine-tune immunity in various organ systems including the gastrointestinal tract. Specialized sensory neurons can detect bacteria, bacterial products, and the resulting inflammation, to coordinate the immune response in the gastrointestinal tract. These sensory neurons release peptide neurotransmitters such as Substance P (SP), to induce both neuronal signaling and localized responses in non-neuronal cells. With this in mind, we assessed the immunoregulatory roles of SP receptor signaling during enteric bacterial infection with the non-invasive pathogen Citrobacter rodentium. Pharmacological antagonism of the SP receptor significantly reduced bacterial burden and prevented colonic crypt hyperplasia. Mice with SP receptor signaling blockade had significantly reduced inflammation and recruitment of T-cells in the colon. Reduced colonic T-cell recruitment is due to reduced expression of adhesion molecules on colonic endothelial cells in SP receptor antagonist-treated mice. Using SP receptor T-cell conditional knockout mice, we further confirmed SP receptor signaling enhanced select aspects of T-cell responses. Our data demonstrates that SP receptor signaling can significantly reduce inflammation and prevent host-maladaptive responses without impinging upon host protection.

immunology↗

Potential climate change effects on the distribution of urban and sylvatic dengue and yellow fever vectors

Climate change may increase the risk of dengue and yellow fever transmission by urban and sylvatic mosquito vectors. Previous research primarily focused on Aedes aegypti and Aedes albopictus. However, these diseases involve a complex transmission cycle in which sylvatic vectors are also involved. Our aim was to analyse which mosquito species could contribute to the increased risk of transmission of these diseases due to climate change, and to identify where the risk increase could most likely occur. Using a biogeographical approach, we mapped areas where mosquito favourability could increase, decrease or remain stable in the near (2041-2060) and distant (2061-2080) future. Models predict dengue vectors expanding in West and Central Africa and in South-East Asia, reaching Borneo. Yellow fever vectors could spread in West and Central Africa and in the Amazon. In Europe, the models suggest a re-establishment of Ae. aegypti, while Ae. albopictus will continue to find new favourable areas. The results underline the need to focus more on vectors Ae. vittatus, Ae. luteocephalus and Ae. africanus in West and Central sub-Saharan Africa, especially Cameroon, Central Africa Republic, and northern Democratic Republic of Congo; and suggest the need for a protocol to prevent dengue and yellow fever that include surveillance of neglected sylvatic vectors.

ecology↗

Plant genome evolution in the genus Eucalyptus driven by structural rearrangements that promote sequence divergence

Genomes have a highly organised architecture (non-random organisation of functional and non-functional genetic elements within chromosomes) that is essential for many biological functions, particularly, gene expression and reproduction. Despite the need to conserve genome architecture, a surprisingly high level of structural variation has been observed within species. As species separate and diverge, genome architecture also diverges, becoming increasingly poorly conserved as divergence time increases. However, within plant genomes, the processes of genome architecture divergence are not well described. Here we use long-read sequencing and de novo assembly of 33 phylogenetically diverse, wild and naturally evolving Eucalyptus species, covering 1-50 million years of diverging genome evolution to measure genome architectural conservation and describe architectural divergence. The investigation of these genomes revealed that following lineage divergence genome architecture is highly fragmented by rearrangements. As genomes continue to diverge, the accumulation of mutations and subsequent divergence beyond recognition of rearrangements becomes the primary driver of genome divergence. The loss of syntenic regions also contribute to genome divergence, but at a slower pace than rearrangements. We hypothesise that duplications and translocations are potentially the greatest contributors to Eucalyptus genome divergence.

genomics↗

Specific subcellular localization drives the different functions of CDC42 isoforms during migration

The small G-protein CDC42 is an evolutionary conserved polarity protein and a key regulator of numerous polarized cell functions, including directed cell migration. In vertebrates, alternative splicing gives rise to two CDC42 proteins: the ubiquitously expressed isoform (CDC42u) and the brain isoform (CDC42b), whose specific roles are not fully elucidated. The two isoforms only differ in their carboxy-terminal sequence, which includes the CAAX motif essential for CDC42 interaction with membrane. Here we show that these divergent sequences do not directly affect the range of CDC42s potential binding partners, but indirectly influence CDC42-driven signaling by controlling the specific subcellular localization of the two isoforms. In astrocytes and neural precursors, which naturally express both variants, CDC42u is mainly cytosolic and associates with the leading-edge plasma membrane of migrating cells where it recruits the Par6-PKC{zeta} complex to fulfill its polarity function. In contrast, CDC42b mainly localizes to intracellular membrane compartments, where it interacts with N-WASP. CDC42b does not participate in cell polarization but embodies the major isoform regulating endocytosis. Both CDC42 isoforms act in concert by contributing their specific functions to promote chemotaxis of neural precursors, demonstrating that the expression pattern of the two isoforms is decisive for the tissue-specific behavior of cells.

cell biology↗

New climatically specialized lineages of Batrachochytrium dendrobatidis and their sub-lethal effects on amphibians establish the Asiatic origins of the pathogen

Chytridiomycosis, a highly significant global wildlife disease, has caused unprecedented amphibian population declines and species extinctions worldwide. In contrast, mass die-offs due to chytridiomycosis have not been observed in Asia, which is thought to be the ancestral region of origin and a hyper-diversity hotspot of the known causal pathogens, Batrachochytrium dendrobtidis (Bd) and B. salamndrivorans (Bsal). It has been hypothesized that Asian amphibians may have evolved immunity to clinical Batrachochytrium infection. However, limited knowledge of endemic lineages, evolutionary history, and climate-related infection patterns limits our ability to explore this hypothesis. Here, we investigated the genetic diversity and infection patterns of the frog-infecting species, Bd, in Chinas poorly-explored Guangxi region. We used the internal transcribed spacer (ITS) marker and the nested PCR method to survey prevalence and haplotype diversity of Bd across 17 forest sites. A generalized linear model was used to evaluate associations between numerous variables and Bd prevalence within native amphibians. Our results identified seven new haplotypes, four of which are closely related to the early-emerging BdASIA-1 lineage recovered from South Korea. We also identified a unique Asian haplotype, close to the BdASIA-3 lineage, as the most prevalent (64.6% of Bd-infected adult individuals) in 11 out of 15 infected species. This haplotype was also detected in a salamander individual, which exhibited non-lethal skin lesions on the abdomen. The infection of Bd within amphibians was found to be positively associated with temperature and elevation. Our findings suggest that there is significant undiscovered genetic diversity of Asian Bd lineages in this region. Longer-term studies are required to further investigate Bd diversity, prevalence, seasonality and impact on native species and populations in Southern China and across the region of origin in Asia. Author SummaryChytridiomycosis is a disease which is responsible for the sharp decline of amphibian populations and species extinctions around the world. Surprisingly, it has not yet been well-studied in Asia, the region where the two causal pathogens of the disease, Batrachochytrium dendrobatidis (Bd) and B. salamandrivorans (Bsal) originated. In order to better understand the lack of mass die-offs in Asia, we recently conducted a study in south Chinas Guangxi region to investigate the genetic diversity and infection patterns of Bd. Through the use of internal transcribed spacer (ITS) markers and nested PCR, we discovered seven new types of Bd, four of which were closely related to the early-emerging BdASIA-1 lineage from South Korea. The highest prevalence of Bd infection was observed in 11 species of amphibians, including a salamander which had non-lethal skin lesions. It was also noted that infection of Bd in amphibians was associated with temperature and elevation. This study has provided important information on Bd diversity and prevalence in the region, and further research is needed to explore Asia as the putative region of origin for this disease.

evolutionary biology↗

Genomic constraints to drought adaptation

Global shifts in climate and precipitation patterns are altering the diversity and structure of forests. The ability for species to adapt is especially difficult for long lived foundation species with unknown genetic and trait diversity. We harnessed genomic, physiological, and climate data to determine adaptation constraints. We used denovo assembly and 6.5 million genomic variants with drought related traits from 432 individuals sourced from across the complete range of the foundation tree species Corymbia calophylla. We found genomic variants determining traits predominantly in gene regulatory regions. The ability for populations to adapt was limited by within population genetic diversity associated with traits, and epistatic interactions within traits and pleiotropic interactions among traits. Nevertheless, we could accurately predict adaptive traits using genomic and climate data to guide reforestation. Our study indicated that some populations may contain variation sufficient for the species to adapt to the effects of drought, while other populations will need increased variability from those sources.

evolutionary biology↗

Regarding the F-word: the effects of data Filtering on inferred genotype-environment associations

Genotype-environment association (GEA) methods have become part of the standard landscape genomics toolkit, yet, we know little about how to filter genotype-by-sequencing data to provide robust inferences for environmental adaptation. In many cases, default filtering thresholds for minor allele frequency and missing data are applied regardless of sample size, having unknown impacts on the results. These effects could be amplified in downstream predictions, including management strategies. Here, we investigate the effects of filtering on GEA results and the potential implications for adaptation to environment. Using empirical and simulated datasets derived from two widespread tree species to assess the effects of filtering on GEA outputs. Critically, we find that the level of filtering of missing data and minor allele frequency affect the identification of true positives. Even slight adjustments to these thresholds can change the rate of true positive detection. Using conservative thresholds for missing data and minor allele frequency substantially reduces the size of the dataset, lessening the power to detect adaptive variants (i.e. simulated true positives) with strong and weak strength of selections. Regardless, strength of selection was a good predictor for GEA detection, but even SNPs under strong selection went undetected. We further show that filtering can significantly impact the predictions of adaptive capacity of species in downstream analyses. We make several recommendations regarding filtering for GEA methods. Ultimately, there is no filtering panacea, but some choices are better than others, depending largely on the study system, availability of genomic resources, and desired objectives of the study.

genomics↗

Multiomic Immunophenotyping of COVID-19 Patients Reveals Early Infection Trajectories

Host immune responses play central roles in controlling SARS-CoV2 infection, yet remain incompletely characterized and understood. Here, we present a comprehensive immune response map spanning 454 proteins and 847 metabolites in plasma integrated with single-cell multi-omic assays of PBMCs in which whole transcriptome, 192 surface proteins, and T and B cell receptor sequence were co-analyzed within the context of clinical measures from 50 COVID19 patient samples. Our study reveals novel cellular subpopulations, such as proliferative exhausted CD8+ and CD4+ T cells, and cytotoxic CD4+ T cells, that may be features of severe COVID-19 infection. We condensed over 1 million immune features into a single immune response axis that independently aligns with many clinical features and is also strongly associated with disease severity. Our study represents an important resource towards understanding the heterogeneous immune responses of COVID-19 patients and may provide key information for informing therapeutic development.

immunology↗

Alterations in retrotransposition, synaptic connectivity, and myelination implicated by transcriptomic changes following maternal immune activation in non-human primates

BackgroundMaternal immune activation (MIA) is a proposed risk factor for multiple neurodevelopmental and psychiatric disorders, including schizophrenia. However, the molecular and neurobiological mechanisms through which MIA imparts risk for these disorders remain poorly understood. A recently developed nonhuman primate model of exposure to the viral mimic poly:ICLC during pregnancy shows abnormal social and repetitive behaviors and elevated striatal dopamine, a molecular hallmark of human psychosis, providing an unprecedented opportunity for mechanistic dissection. MethodsWe performed RNA-sequencing across four psychiatrically-relevant brain regions (prefrontal cortex, anterior cingulate, hippocampus, and primary visual cortex) from 3.5-4-year old male MIA-exposed and control offspring--an age comparable to mid adolescence in humans. ResultsWe identify 266 unique genes differentially expressed (DE) in at least one brain region with the greatest number observed in hippocampus. Co-expression networks identified region-specific alterations in synaptic signaling and oligodendrocytes. Across regions, we observed temporal and regional differences, but transcriptomic changes were largely similar across 1st or 2nd trimester MIA exposures, including for the top DE genes--PIWIL2 and MGARP. In addition to PIWIL2, several other known regulators of retrotransposition, as well as endogenous transposable elements were dysregulated in MIA offspring. ConclusionsTogether, these results begin to elucidate the brain-level molecular mechanisms through which MIA may impart risk for psychiatric disease.

neuroscience↗