Biology subjects

Murphy, K.

Publications and source records attributed to Murphy, K..

At least 19 recordsLinked to original sources

bioRxiv2026

Characterization of Resolved, Localized, and Progressing Infections at the Maternal-Fetal Interface in a Nonhuman Primate Model

Background: Inflammation and infection are responsible for the majority of early preterm births. Host innate immune responses at the maternal-fetal interface that contribute to sterile intra-amniotic inflammation (SIAI), bacterial clearance, or invasive infection remain poorly understood. Group B Streptococcus (Streptococcus agalactiae) is a leading cause of preterm birth, stillbirth, and invasive neonatal disease. Objective: To determine the host innate immune factors and transcriptional profiles that characterize the persistence versus resolution of a Group B Streptococcus infection at the maternal-fetal interface in a nonhuman primate (pigtail macaque, Macaca nemestrina) model. We hypothesized that a highly inflammatory profile, associated with interleukin-1 signaling, is linked to progression, whereas a mild or non-inflammatory signature is associated with infection resolution. Study Design: In a chronically catheterized pregnant pigtail macaque model, Group B Streptococcus was inoculated into the choriodecidual space. Infections were classified as progressing (invasive into the amniotic fluid), localized (bacteria persisting at the inoculation site), or resolved (minimal to no bacteria detected). Temporal and spatial RNA and protein profiles in the chorioamniotic membranes and decidua and in the myometrium were assessed by histopathology, multiplex protein assays, total RNA-sequencing, Nanostring nCounter, and spatial transcriptomics (digital spatial profiling). Differential gene expression was analyzed with limma using moderated t-tests and by gene set enrichment analysis. Results: A GBS infection at the maternal-fetal interface produced three infection outcomes: progressing infections that disseminated into the amniotic fluid (AF, N=5), low-titer localized infections remaining at the inoculation site (N=6), and resolved infections (N=5), compared with saline controls (N=3). Preterm labor occurred frequently regardless of infection outcome (40-80%). In resolved infections, SIAI occurred in the AF and lymphocytes infiltrated the myometrium. Total RNA-Seq of the chorioamniotic membranes demonstrated that 99 genes separated progressing from resolved infections, 98 of them were upregulated and dominated by IL-1 signaling and granulocyte recruitment (i.e., IL1B, CXCL8, TLR2, CLEC4A). Histone deacetylase 10 (HDAC10) was the only significantly downregulated gene in the progressing versus resolved contrast (p<0.05). An exploratory spatial transcriptomics experiment localized the progressing inflammatory response to the chorion. In the myometrium, zinc and RING finger 3 (ZNRF3) was significantly downregulated in localized versus control and resolved versus control and was also the only differentially expressed gene. Downregulated WNT signaling and upregulated lymphocyte-mediated immunity gene sets in the myometrium were a signature of resolved infections. Conclusion: A GBS infection at the maternal-fetal interface can result in a spectrum of progressing, localized and resolved outcomes. An early IL-1 and granulocyte response in the chorion layer of the chorioamniotic membranes marks bacterial dissemination, with loss of HDAC10 suggesting epigenetic regulation within the membranes with progressing infections. In the myometrium, ZNRF3 and downregulation of WNT signaling persisted even after infection resolution, reflecting an infectious exposure. Unexpectedly, resolved infections were associated with SIAI and a myometrial inflammatory response, offering a possible explanation for preterm labor associated with SIAI.

systems biology↗

bioRxiv2026

Neuroendocrine influences on dynamic cerebrovascular function and implications for functional MRI

To fully profile how ovarian hormones interact with cerebrovascular function, it is vital to consider, not just resting physiology, but also dynamic aspects of cerebrovasculature that support neural activity. This study uses hypercapnic cerebrovascular reactivity (CVR) and the visually-evoked haemodynamic response function (HRF) to investigate the influence of menstrual-related changes in oestradiol and progesterone on dynamic aspects of the cerebrovascular system. 20 menstruating females (age mean[SD]=23.01[4.01]years) completed a 3T MRI scanning session during the early follicular, late follicular, and mid-luteal phases of their menstrual cycle. Circulating hormones were measured via blood samples. Simultaneous blood oxygen level dependant (BOLD)-CVR and cerebral blood flow (CBF)-CVR data were collected using a pseudocontinuous arterial spin labelling (pCASL) acquisition using a dual-excitation (DEXI) readout during periods of hypercapnia (5% CO2). The HRF was estimated using a whole brain EPI scan during high-contrast radial checkerboard presentation. Both oestradiol and additional progesterone variance were associated with increased CVR (both BOLD-CVR and CBF-CVR; p<0.001) and altered HRF shape (p<0.005). No statistically significant regional effects were found. A secondary experiment investigated the impact of using either canonical or individually mapped HRF in a standard fMRI processing pipeline; namely, population receptive field (pRF) mapping. Results across phases suggest that neither hormone was associated with pRF size when modelled using a canonical HRF (both p>0.05). However, a significant neuroendocrine influence on pRF sizes was discovered when using individually measured HRFs (p<0.001). This study found evidence that dynamic cerebrovascular functions are sensitive to menstrual-related ovarian hormones, which may be a potential mechanism underlying menstrual symptomatology and has implications for fMRI studies that assume intact neurovascular coupling processes in women, regardless of menstrual staging, to make inferences about neural activity.

neuroscience↗

bioRxiv2026

Social attachment shapes interbrain synchrony

Neural synchrony, or correlated neural activity across interacting individuals, scales with relationship quality in humans, yet how it evolves during social bond formation remains unknown. Using fiber photometry in monogamous prairie voles, we track prefrontal cortex synchrony across pair bond formation. Bonded voles show stronger synchrony with partners than strangers, mirroring human findings. A linear mixed model reveals that synchrony is jointly shaped by bond strength, inter-animal distance, and time since interaction onset, with relationship type modulating how each factor contributes. Using a machine-learning behavioral classification pipeline we developed for freely interacting voles, we demonstrate that the coupling between specific behaviors and synchrony depends on the nature of the dyadic relationship. These findings establish that neural synchrony is not a simple function of proximity or interaction time but is fundamentally shaped by relationship history--a conclusion with direct implications for understanding the synchrony in human social attachment.

neuroscience↗

bioRxiv2025

Unilateral online ultrasound stimulation of early visual cortex suppresses responses to contralateral visual stimuli

Transcranial ultrasound stimulation (TUS) shows great promise for inducing neuroplastic changes that persist long after stimulation. Evidence of stimulation-locked neural changes would enable closed-loop application of TUS, but such responses have not yet been clearly dissociated from the coincident neural response to auditory and peripheral stimulation associated with TUS. We leveraged the contralateral retinotopic organization of the early visual cortex to isolate online TUS effects from peripheral confounds in 19 subjects. Using a hemifield visual stimulation paradigm combined with high-precision, functional MRI guided TUS, we applied TUS to the left early visual cortex while participants viewed checkerboards presented in the left or right visual field. TUS was delivered randomly on half of the trials, enabling within-subject comparisons of pattern-locked visual evoked potentials (VEPs) across hemispheres and against no stimuli. We observed a reduction in VEPs in the contralateral, but not ipsilateral, hemifield, consistent with genuine online neuromodulatory effects. Furthermore, online suppression was positively correlated with the TUS dose delivered to the target, as estimated by modelling TUS field-target overlap and differential attenuation through heterogeneous skulls. Collectively, these findings provide a robust framework for future studies aiming to map the TUS parameter space in real time by leveraging topographic organization to control for peripheral confounds.

neuroscience↗

bioRxiv2025

Genetic modulation of immune gene co-expression in the aged mouse hippocampus by the Apbb1ip locus

Ageing is a major risk factor for many neurodegenerative diseases, and the hippocampus is particularly vulnerable to the effects of ageing. To define the transcriptomic changes related to ageing and the impact of genetic variation, we analysed hippocampal gene expression data generated from a genetically diverse panel of inbred mouse strains belonging to the BXD Family. We applied a combination of differential expression, differential correlation, and weighted gene co-expression network analyses, followed by genetic mapping to delineate age-associated transcriptomic patterns and genetic modulators. This study revealed an upregulation in immune response and microglial genes. We identified a key age-associated co-expression module enriched in immune related genes, and quantitative trait locus mapping of this module uncovered a genetic regulatory locus in which Apbb1ip was the primary candidate gene. Additionally, gene level differential correlation analysis identified a substantial restructuring of the hippocampal transcriptome during ageing. Notably, Ywhab, an important signalling chaperone displayed altered gene expression correlations with >70 genes, between young and aged mice. These results provide novel insights into transcriptional dynamics of hippocampal ageing and identified the immune gene Apbb1ip as a potential modulator of immune response and microglial gene upregulation with implications for neurodegenerative disease pathogenesis. HighlightsO_LIComplementary gene expression analyses indicated an upregulation of immune responses in the ageing hippocampus of a genetically diverse mouse cohort, likely driven by microglia subtypes. C_LIO_LIA systems genetics approach revealed the Apbb1ip locus as a modulator of immune gene co-expression, highlighting a novel candidate regulator of age-associated neuroimmune dynamics. C_LIO_LISignalling chaperone Ywhab gene expression was highly differentially correlated with other transcripts during ageing which may underlie widespread age-associated molecular perturbations in the hippocampus. C_LI

bioinformatics↗

bioRxiv2025

Neutralizing Activity of Cervicovaginal Secretions against Herpes Simplex Virus is Mediated by Mucosal IgG and Viral Glycoprotein E and Adversely Impacted by Vaginal Dysbiosis

Genital herpes simplex virus (HSV) recurrences are more common in women with bacterial vaginosis (BV). Prior studies demonstrated that genital tract secretions exhibit variable neutralizing activity against HSV, independent of serostatus, but the relationship of this activity to the vaginal microbiome and underlying mechanisms have not been defined. To test the hypothesis that cervicovaginal antiviral activity is lower in women with BV, we took advantage of cervicovaginal lavage (CVL) available from two studies conducted among women with symptomatic BV and healthy controls. CVL obtained from women with BV had significantly less antiviral activity than controls (p< 0.001). Inhibitory activity correlated negatively and most strongly with Shannon diversity index (p<0.0001). The innate activity did not differ comparing HSV-seropositive versus seronegative participants and no HSV-specific antibodies were detected in CVL. Activity was enriched in the immunoglobulin fraction but was lost when IgG (but not IgA) was depleted. Increasing doses of an anti-glycoprotein E (gE) monoclonal antibody overcame the neutralizing activity, suggesting that interactions between the Fc region of IgG and gE, a viral Fc gamma receptor (Fc{gamma}R), contribute. Consistent with this notion, CVL had less HSV inhibitory activity against a gE-null virus. Glycan analysis demonstrated a decrease in mature glycans in IgG from CVL with low antiviral activity and treatment of CVL with peptide N-glycanase F, which cleaves N-glycans in IgG, resulted in a loss of HSV inhibitory activity. We speculate that glycosidases elaborated by anaerobic bacteria cleave Fc glycans, resulting in decreased affinity for gE and a reduction in protective activity. IMPORTANCE: This study provides a mechanistic link for the increased risk of HSV infection and replication in the setting of symptomatic bacterial vaginosis and asymptomatic vaginal dysbiosis. Independent of Fab antigen specificity, the Fc region of mucosal IgG may neutralize HSV by binding to glycoprotein E, a viral Fc receptor. Vaginal dysbiosis leads to a loss of Fc glycans and a concomitant decrease in this innate antiviral activity. These findings suggest that viral Fc receptors, previously thought to function only in immune evasion, may also play a protective role. The results highlight the importance of developing and implementing strategies to protect against vaginal dysbiosis.

microbiology↗

bioRxiv2025

NodoMap: a spatio-cellular map of the mouse nodose ganglia

The vagus nerve is a key component of the parasympathetic nervous system, innervating multiple abdominal organs to monitor and regulate their function. It forms the main neural pathway between the gastrointestinal tract and the brain, playing a major role in the regulation of energy homeostasis. The cell bodies for vagal sensory neurons reside in the nodose ganglia, with the left and right ganglia reported to have distinct roles in food intake and reward. Here, we have integrated our own single nucleus RNA sequencing data with multiple publicly available datasets to create a database of 108,482 nuclei and cells, and combined this with spatial transcriptomics to present a spatio-cellular transcriptional map of the mouse nodose ganglia, the NodoMap. Nodose ganglia neuronal cells clustered into twenty-two different subtypes, all found in both left and right nodose ganglia, but with significant differences in gene expression between left and right ganglia across multiple neuronal subtypes. Overnight fasting modulated gene expression across specific neuronal subtypes, including nutrient responsive pathways. Spatial transcriptomics showed that while vagal neuronal types were highly interspersed, patterns of organisation into cellular neighbourhoods could be observed, with neighbourhoods identified of predominantly non-neuronal cells and of different neuronal populations accompanied by glial-like cells. Thus, NodoMap provides a detailed atlas of the mouse nodose ganglia in a spatial context, providing a platform for vagovagal neurocircuit analysis, and serving as an important resource to identify targets for pharmacotherapies for metabolic disease.

physiology↗

bioRxiv2025

A selective inhibitor of oncogenic JNK signalling perturbs metastatic outgrowth of triple-negative breast cancer through metabolic blockade

Although c-Jun N-terminal Kinase (JNK) represents an attractive anti-cancer target, its pleiotropic functionality limits the use of direct JNK inhibitors. Here, we identify a distinct subcellular pattern of JNK activity as a therapeutic vulnerability in breast cancer, where cytoplasmic JNK activity predicts poor survival outcomes, is elevated in triple-negative breast cancers (TNBC) and is essential for metastatic outgrowth. Mechanistic analyses reveal cytoplasmic JNK acts through multiple mechanisms, with downstream targets involved in cellular metabolism and cytoskeletal regulation. On this basis, we leveraged actin-based phenotypic drug-screening and identified K12, an indirect but selective inhibitor of cytoplasmic JNK that blocks TNBC metastatic outgrowth in vivo. We reveal that K12 inhibits glutaminase-1 and the pyruvate dehydrogenase complex, and that this poly-pharmacology overcomes pyruvate anaplerosis, a known resistance mechanism of existing glutaminase inhibitors. These findings demonstrate the potential of selectively targeting the oncogenic function of JNK, offering new treatment options for early-stage metastatic TNBC.

cancer biology↗

bioRxiv2025

LC-MS analysis of RNA through hydrogen bonding of alkylamines

Nucleic acid oligonucleotides represent a promising therapy for treating disease. Production of these biopolymers happens synthetically which can produce impurities concomitant with the desired product. The use of liquid chromatography coupled to high resolution mass spectrometry is a robust analytical technique for determination of sample purity. Traditionally, ion pairing reagents are used to facilitate chromatography separation before sampling with the mass spectrometer. The choice of reagent for analysis can impact the analysis as the length of the oligonucleotide increases. This is in part due to the thermodynamics of transitioning the oligonucleotide from the liquid phase to the gas phase. Here we show that the use of a hydrogen bond donating alkylamine assists with overcoming the energy barrier of phase transition by bonding to the nucleobase as well as the phosphodiester backbone. By increasing the relative hydrophobicity of the oligonucleotide, the transition to the gas phase is increased producing a cleaner mass spectrum. Furthermore, we show that by using a hydrogen bond donating alkylamine, we can remove the fluoroalcohol reagent commonly used in ion pairing mass spectrometry of nucleic acids.

biochemistry↗

bioRxiv2024

Endocrine modulation of cortical and retinal blood flow across the menstrual cycle

The ovarian hormones, oestrogen and progesterone, have vaso- and neuroprotective effects, likely due to interactions with the cerebrovascular system. This study investigates their neuroendocrine influence on a range of cerebral and retinal vascular functions across a healthy menstrual cycle. Twenty-six healthy, menstruating females completed imaging sessions and assessment of circulating hormone levels during their early follicular, late follicular, and mid-luteal phase (1-4, 10-12 and 20-22 days after menses onset). Cerebral blood flow (CBF), arterial arrival time (AAT), global oxygen extraction fraction (OEF), cerebrovascular metabolic rate of oxygen (CMRO2), carotid artery radius and carotid pulsatility index (PI) were measured using 3T MRI. Retinal vessel density and blood flow resistance were assessed with optical coherence tomography angiography (OCT-A). Assessed with linear models, increased oestradiol was related to increased global CBF ({chi}2(1)=41.682; p=1.074x10-10). An independent progesterone increase was also associated with increased global CBF ({chi}2(1)=14.979; p=0.0001). In the retina, a relationship was found between oestradiol and decreased retinal blood flow resistance ({chi}2(1)=5.28; p=0.0215), which was primarily driven by centrally localised vessels. This study finds that circulating oestrogen increases blood flow in the eye and brain, while progesterone significantly impacts the brain alone. These effects suggest a potential pathway for neuroprotective mechanisms.

neuroscience↗

bioRxiv2024

The Condensin II Complex Regulates the Expression of Essential Gene Expression Programs During Erythropoiesis

Erythropoiesis is characterized by dramatic changes in gene expression in the context of a cell that is rapidly proliferating while simultaneously condensing its nucleus in anticipation of enucleation. The mechanisms that maintain high level expression of erythroid genes and promote nuclear condensation remain poorly understood. Condensin II is a ring-like complex that promotes mitotic chromatin condensation and has roles in regulating interphase chromatin architecture and gene expression. We interrogated the role of Condensin II in erythropoiesis using an erythroid-specific deletion of the Condensin II subunit, Ncaph2. Ncaph2 loss resulted in severe embryonic anemia with lethality at embryonic day 13.5. Ncaph2 mutant erythroid cells had dysregulated maturation and disrupted cell cycle progression, but surprisingly Ncaph2 was dispensable for nuclear condensation. Genomic studies revealed that Ncaph2 occupied the promoter of key erythroid and cell cycle genes that were downregulated following Ncaph2 loss. Together, our results demonstrate an essential role for Ncaph2 in the gene expression programs that regulate cell cycle progression and erythroid differentiation, and identify a key role for the Condensin II complex in the regulation of a lineage-specific differentiation program. Summary StatementThe Condensin II complex regulates cell cycle progression and erythroid differentiation, but is dispensable for nuclear condensation during terminal erythroid maturation.

genomics↗

bioRxiv2024

Flight-Scope: microscopy with microfluidics in microgravity

With the European Space Agency (ESA) and NASA working to return humans to the moon and onwards to Mars, it has never been more important to study the impact of altered gravity conditions on biological organisms. These include astronauts but also useful micro-organisms they may bring with them to produce food, medicine, and other useful compounds by synthetic biology. Parabolic flights are one of the most accessible microgravity research platforms but present their own challenges: relatively short periods of altered gravity ([~]20s) and aircraft vibration. Live-imaging is necessary in these altered-gravity conditions to readout any real-time phenotypes. Here we present Flight-Scope, a new microscopy and microfluidics platform to study dynamic cellular processes during the short, altered gravity periods on parabolic flights. We demonstrated Flight-Scopes capability by performing live and dynamic imaging of fluorescent glucose uptake by yeast, S. cerevisiae, on board an ESA parabolic flight. Flight-Scope operated well in this challenging environment, opening the way for future microgravity experiments on biological organisms.

biophysics↗

bioRxiv2024

Velocity-selective arterial spin labelling bolus duration measurements: Implications for consensus recommendations

Velocity-selective arterial spin labelling (VSASL) MRI is insensitive to arterial transit time. This is an advantage over other perfusion measurements, where long arterial transit times can lead to bias. Therefore, VSASL can be used to study perfusion in the presence of long arterial transit times, such as in the ageing brain, in vascular pathologies, and cancer, or where arterial transit time changes, such as during measurement of cerebrovascular reactivity (CVR). However, when calculating perfusion (cerebral blood flow, CBF, in the brain) from VSASL signal, it is assumed that images are acquired before the trailing edge of the labelled blood has arrived in the imaging slice. The arrival of the trailing edge of the labelled bolus of blood will cause an underestimation of perfusion. Here we measure bolus duration in young, healthy human brains, both at rest and during elevated CBF. Grey matter bolus duration was 1.61 {+/-} 0.31 s, but there was a large spatial heterogeneity, with bolus duration being lower in anterior brain regions, with some areas having bolus duration < 1.2 s. We place these results in context of recommendations from a recent consensus paper, which recommends imaging 1.4 s after the label, potentially underestimating CBF in anterior regions. Further, we observed a 0.23 {+/-} 0.12 s reduction in grey matter bolus duration with 5% CO2 inhalation. These results can be used to inform the experimental design of future VSASL studies, to avoid underestimating perfusion by imaging after the arrival of the trailing edge of the labelled bolus.

neuroscience↗

bioRxiv2024

Imaging brain vascular function in Cystic Fibrosis: an MRI study of cerebral blood flow and brain oxygenation

Cystic fibrosis (CF) is a progressive inherited disorder that primarily affects the lungs. With recent breakthroughs in effective treatments for CF that increase life-expectancy, a higher prevalence of age-related comorbidities have been reported including cardiovascular disease, stroke and cognitive decline. Despite the known relationship between cardiovascular health and cerebrovascular function, very little is known about brain blood flow and oxygen metabolism in patients with CF (PwCF). In 14 PwCF and 56 healthy age / sex matched controls, we used pseudo-continuous arterial spin labelling (pCASL) to quantify cerebral perfusion in grey-matter and T2-Relaxation-Under-Spin-Tagging (TRUST) to estimate global oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen consumption (CMRO2). Compared to healthy controls, PwCF showed elevated CMRO2 (p = 0.015). There were no significant between-group differences in grey-matter CBF (p = 0.342), or whole brain OEF (p = 0.091). However, regional analysis showed certain areas with higher CBF in PwCF (p < .05, FDR). This is the first study to characterise cerebrovascular function and brain oxygen metabolism in PwCF. Our findings highlight the need for early cardiovascular monitoring procedures to help maintain cerebrovascular function and combat accelerated aging effects in the brains of PwCF.

neuroscience↗

bioRxiv2024

BMI1 regulates human erythroid self-renewal through both gene repression and gene activation

The limited proliferative capacity of erythroid precursors is a major obstacle to generate sufficient numbers of in vitro-derived red blood cells (RBC) for clinical purposes. We and others have determined that BMI1, a member of the polycomb repressive complex 1 (PRC1), is both necessary and sufficient to drive extensive proliferation of self-renewing erythroblasts (SREs). However, the mechanisms of BMI1 action remain poorly understood. BMI1 overexpression led to 10 billion-fold increase BMI1-induced (i)SRE self-renewal. Despite prolonged culture and BMI1 overexpression, human iSREs can terminally mature and agglutinate with typing reagent monoclonal antibodies against conventional RBC antigens. BMI1 and RING1B occupancy, along with repressive histone marks, were identified at known BMI1 target genes, including the INK-ARF locus, consistent with an altered cell cycle following BMI1 inhibition. We also identified upregulated BMI1 target genes with low repressive histone modifications, including key regulator of cholesterol homeostasis. Functional studies suggest that both cholesterol import and synthesis are essential for BMI1-associated self-renewal. These findings support the hypothesis that BMI1 regulates erythroid self-renewal not only through gene repression but also through gene activation and offer a strategy to expand the pool of immature erythroid precursors for eventual clinical uses.

cell biology↗

bioRxiv2023

Sex-Specific Development of ssRNA Virus Receptor Gene Expression in the Human Brain

Neurotropic single-stranded RNA (ssRNA) viruses can disrupt brain function, yet little is known about how host virus receptor expression develops across the human lifespan or whether these trajectories differ between females and males. We focused on postnatal development using postmortem transcriptomic data from 33 human donors (4 months-82 years; both sexes), comprising 52 cerebral hemispheres and 15 brain areas, to characterize developmental patterns of 67 host receptor genes that mediate entry of major ssRNA viral families. Using sex-specific LOESS trajectory modelling, hierarchical clustering, and sliding-window differential expression analyses, we identified multiple non-linear developmental programs governing virus receptor expression. About half of female-male gene-area trajectory pairs exhibited divergent developmental patterns. Sex differences were most pronounced in the cortex, where high-dimensional receptor expression profiles were sufficient to predict the sex of individual cases. Sex differential expression was most frequent during early childhood, coinciding with sensitive periods of cortical circuit refinement. A targeted prenatal analysis revealed that virus receptor expression was predominantly male-biased before birth, contrasting with the predominantly female-biased expression observed during the early postnatal period. Although receptors from most viral families were broadly distributed across developmental programs, a subset of sex-by-age expression clusters showed some enrichment for specific viral lineages and glial-associated cell-type signatures. Together, these findings reveal that virus receptor expression in the human brain is organized into structured, sex-biased trajectories that dynamically reorganize over development, providing the first developmental atlas of viral entry receptors in the human brain. Significance StatementMany viruses that affect the brain use host receptors to enter cells, yet it is unclear how these receptors are expressed across the human lifespan or whether their expression differs between females and males. Using human postmortem brain transcriptomic data spanning infancy to older adulthood, we show that virus receptor genes follow dynamic, sex-biased developmental trajectories, particularly in the cortex. These patterns are strongest during early childhood and are sufficient to distinguish female and male expression profiles at the individual level. Rather than acting as static entry points, virus receptors are embedded within developmental and neuroimmune programs. These findings provide a developmental framework for understanding why vulnerability to neuroinfectious disease may vary by age, brain area, and sex.

neuroscience↗

bioRxiv2023

Mitochondrial fusion and altered beta-oxidation drive muscle wasting in a Drosophila cachexia model

Cancer cachexia is a tumour-induced wasting syndrome, characterised by extreme loss of skeletal muscle. Defective mitochondria can contribute to muscle wasting; however, the underlying mechanisms remain unclear. Using a Drosophila larval model of cancer cachexia, we observed enlarged and dysfunctional muscle mitochondria. Morphological changes were accompanied by upregulation of beta-oxidation proteins and depletion of muscle glycogen and lipid stores. Muscle lipid stores were also decreased in Colon-26 adenocarcinoma mouse muscle samples, and expression of the beta-oxidation gene CPT1A was negatively associated with muscle quality in cachectic patients. Mechanistically, mitochondrial defects result from reduced muscle insulin signalling, downstream of tumour-secreted insulin growth factor binding protein (IGFBP) homolog ImpL2. Strikingly, muscle-specific inhibition of Forkhead box O (FOXO), mitochondrial fusion, or beta-oxidation in tumour-bearing animals preserved muscle integrity. Finally, dietary supplementation with nicotinamide or lipids, improved muscle health in tumour-bearing animals. Overall, our work demonstrates that muscle FOXO, mitochondria dynamics/beta-oxidation and lipid utilisation are key regulators of muscle wasting in cancer cachexia.

developmental biology↗

bioRxiv2023

Comprehensive Characterization of tRNA by Ultra High-Performance Liquid Chromatography High-Resolution Accurate Mass Spectrometry

Transfer ribonucleic acid (tRNA) are the smallest RNA in the translational triune and contain the greatest density of post-transcriptional modifications than any other RNA types in the cell. Due to the size of tRNA studying these modifications usually entails enzymatic digestion followed by liquid chromatography tandem mass spectrometry (LC-MS/MS). Here we report an advancement in Intact Mass Analysis for identification of tRNA through deconvolution of high resolution accurate mass spectrometry facilitated using a secondary alkylamine as an ion pairing reagent during reverse phase chromatography. We identify in isolated and total S. cerevisiae tRNA 3 CCA variations and show that most tRNA lack a 3 adenosine with the lesser abundant species having the expected CCA termini. We identify a previously unknown stable demethylated Wybutosine intermediate for tRNAPHE and identify low abundant contaminating tRNAs in an isolated tRNAPHE sample. Confirmation of identities was verified through traditional mass spectrometric nucleoside and mass mapping experiments.

biochemistry↗