Biology subjects

Nguyen, H. D.

Publications and source records attributed to Nguyen, H. D..

18 recordsLinked to original sources

bioRxiv2026

A genome-wide catalog of sites where peripheral DNA methylation reflects the brain

Epigenetic studies of psychiatric and neurological disorders rely largely on peripheral tissues, yet where peripheral DNA methylation (DNAm) reflects the brain remains unclear. We generated a paired brain and peripheral DNAm dataset from 148 donors in three cohorts and combined it with five published cohorts for consensus brain-peripheral correlations. By cross-validation across cohorts, we defined brain epigenome shared sites (BrESS), more than 100,000 CpGs per tissue at which peripheral DNAm reproducibly predicts brain DNAm. BrESS lay at promoters active in both brain and periphery and in housekeeping genes, and most were not explained by genetic effects. BrESS did not contribute to the heritability of seven disorders, and CpGs from epigenome-wide association studies of these disorders were not enriched at BrESS. Peripheral DNAm reflects the brain mainly in a regulatory compartment shared across tissues, outside which disease signals largely lie, and BrESS separate peripheral signals attributable to the brain from others.

neuroscience↗

bioRxiv2026

Zuranolone mitigates delirium-like bispectral EEG changes, behavioral deficits, and neuroinflammation across surgical and inflammatory mouse models and age groups

Delirium is an acute, fluctuating brain dysfunction that commonly follows surgery and systemic inflammation, disproportionately affects older adults, and remains difficult to quantify continuously over time and treat pharmacologically. Here, we tested whether the neuroactive steroid zuranolone, a positive allosteric modulator of synaptic and extrasynaptic GABA_A receptors, mitigates delirium-like abnormalities across two complementary murine delirium models, a lipopolysaccharide-induced systemic inflammation (LPS) model and a postoperative delirium (POD) model, primarily in young and aged mice, with selected analyses in super-aged mice. Using continuous EEG with a validated bispectral EEG (BSEEG) metric, we found that zuranolone attenuated delirium-like EEG slowing in the LPS model in young mice in a dose-dependent manner and retained efficacy in aged mice. In the POD model, prophylactic dosing provided limited benefit in young mice, whereas post-surgery treatment reduced postoperative BSEEG elevations. In aged mice, prophylactic dosing suppressed POD-associated BSEEG abnormalities, and in super-aged mice, prophylactic zuranolone improved survival after POD induction. In parallel, zuranolone reduced microglial density and activation markers (IBA1 and CD68 immunoreactivity) at 24 h after POD surgery and after LPS challenge, with effects that were particularly evident in peri-screw site tissue in young POD mice and more broadly distributed across regions in aged mice. Finally, in young mice, zuranolone improved a composite behavioral severity score in the LPS model, whereas behavioral effects in the POD model were modest and domain-specific. Together, these findings support zuranolone as a candidate strategy to reduce delirium-like electrophysiological and neuroimmune abnormalities, with the strongest effects in inflammation-driven and age-vulnerable contexts.

neuroscience↗

bioRxiv2026

Variable transmission efficiency of mammalian origin HPAI D1.1 H5N1 strains in ferrets

Highly pathogenic avian influenza H5N1 2.3.4.4b genotype D1.1 lineage continues to predominate in the United States wild bird population and has spilled over into dairy cattle three independent times. To assess the transmission risk of this sublineage, we performed direct-contact transmission experiments for three distinct D1.1 strains in ferrets. Two of these strains were isolated from humans and one from a lethal cat infection. We found that only one human isolate (A/NV/10/2025) was able to transmit efficiently between ferrets. Compared to the other strains, this isolate harbored the mammalian adaptive PB2 D701N mutation, suggesting this mutation may be critical for D1.1 transmission as opposed to the PB2 E627K substitution present in the lethal cat isolate. Based on these data we conclude that the transmission fitness of D1.1 strains is modest but that special attention should be paid to emergence of adaptation at the PB2 701 position.

microbiology↗

bioRxiv2026

ONETest PathoGenome: A Multi-Cohort Evaluation of an Optimized NGS Assay for Detection of Lower Respiratory Pathogens in Bronchoalveolar Lavage

BackgroundLower respiratory tract infections (LRTIs) remain diagnostically challenging when culture and molecular assays are negative or delayed. We evaluated ONETest Pathogenome (OT), an automated hybrid-capture metagenomic assay with core-genome enrichment probes, for direct pathogen detection in bronchoalveolar lavage (BAL). MethodsAnalytical performance (LoD, precision, continuity) was assessed using whole-cell spike-ins into culture-negative BAL fluid. Technical performance was assessed in 119 specimens profiled by OT and whole-metagenome shotgun sequencing (WmGS, cohort 1). Clinical accuracy was evaluated in 360 specimens (cohort 2) benchmarked against routine bacterial and acid-fast bacillus (AFB) culture. Laboratory-developed test (LDT) validation included 43 specimens (cohort 3) benchmarked to bacterial and AFB culture. ResultsOT uses 6.2 million probes covering core genomes across 50 microbial families (>250 respiratory pathogens). In BAL specimens, OT increased normalized on-target microbial abundance 26-fold versus that of WmGS while preserving within-sample microbial diversity. In cohort 2, OT achieved species-level sensitivity of 80% and specificity of 99% across culture-confirmed isolates and detected [≥]1 culture-confirmed organism in 100/115 culture-positive specimens (87%), while applying species-specific background baselines to mitigate overcalling. Additive yield was 21% (76/360), with 7.5% (27/360) of specimens having [≥]1 additional finding supported by orthogonal testing. In LDT validation, OT identified [≥]1 culture-confirmed organism in 34/40 culture-positive specimens (85%) with one OT-positive/culture-negative specimen. ConclusionsOT is an assay with a turnaround time <24 h complementary to culture that improves pathogen detection and expands microbiologic findings through additional detections and co-detections, including slow-growing organisms that may require prolonged incubation by conventional methods.

microbiology↗

bioRxiv2025

Linking Pain and Delirium via Microglial Activation: A Mouse Study Using BSEEG, Behavioral Assays, Immunohistochemistry, and RNA Sequencing

BackgroundThe rising incidence of delirium in surgical and critical care settings, especially in older patients, calls for improved preventative and management strategies. Chronic pain is increasingly recognized as a key risk factor for delirium, and microglial activation may be the central mediator linking these two conditions. MethodsWe used a spared nerve injury (SNI) model of persistent neuropathic pain in tandem with a postoperative delirium (POD) mouse model. Pain assessments, electroencephalography (EEG) recording, and immunofluorescence were performed to characterize pain and delirium-like states. Microglia were isolated for RNA-seq to elucidate gene expression changes comprehensively. ResultsSNI mice showed persistent mechanical hypersensitivity from Day 7 onwards and demonstrated disrupted sleep-wake patterns in EEG indices. Immunofluorescence revealed sustained microglial activation in both the hippocampus and cortex following SNI. RNA-seq analyses indicated the upregulation of pro-inflammatory pathways (e.g., interleukin-6 production, NF-{kappa}B signaling) in SNI mice that also underwent head-mount surgery. Notably, the coincidence of persistent pain and an acute delirium-like state further exacerbated neuroinflammation. ConclusionOur findings suggest that neuropathic pain-induced microglial activation primes the brain for exaggerated inflammatory responses under additional surgical stress, potentially worsening delirium. Further investigations into microglia-focused therapies may inform novel strategies for mitigating delirium in patients with neuropathic pain.

neuroscience↗

bioRxiv2025

A Yeast-Based High-Throughput Screening Platform for the Discovery of Novel pre-mRNA Splicing Modulators

Pre-mRNA splicing is a crucial process in eukaryotic gene expression, and splicing dysregulation has been linked to various diseases. However, very few small molecules have been discovered that can modulate spliced mRNA formation or inhibit the splicing machinery itself. This study presents a novel high-throughput screening (HTS) platform for identifying compounds that modulate splicing. Our platform comprises a two-tiered screening approach: a primary screen measuring growth inhibition in sensitized in S. cerevisiae (yeast) strains and a secondary screen that relies on production of a fluorescent protein as a readout for splicing inhibition. Using this approach, we identified 4 small molecules that cause accumulation of unspliced pre-mRNA in vivo in yeast. In addition, cancer cells expressing a myelodysplastic syndrome-associated splicing factor mutation (SRSF2P95H) are more sensitive to one of these compounds than those expressing the wild-type version of the protein. Transcriptome analyses showed that this compound causes widespread changes in gene expression in sensitive SRSF2P95H-expressing cells. Our results demonstrate the utility of using a yeast-based HTS to identify compounds capable of changing pre-mRNA splicing outcomes.

biochemistry↗

bioRxiv2025

Characterization of immunosenescent alveolar macrophages in rhesus macaques

As the global population ages, understanding the mechanisms underlying age-related diseases becomes increasingly important. Inflammaging, a state of chronic inflammation and immune dysregulation, is a key feature of aging. Macrophages, as master regulators of inflammation, are critical to this process. However, the effects of natural aging on alveolar macrophages (AMs) in the lungs remain poorly understood. In this study, we evaluated AM biology in older compared with young rhesus macaques. We compared cytokine profiles in plasma and bronchoalveolar lavage (BAL) fluid between young and aged macaques and performed single-cell RNA sequencing (scRNA-seq) to characterize age-related transcriptional and functional changes in AMs. Compared to young animals, AMs from aged animals exhibited similar cytokine inflammaging profile observed in the plasma of elderly humans. However, the general decrease of chemokine levels in BAL fluid relative to plasma suggest BAL may not reflect AM status in the lung tissues of rhesus macaques. scRNA-seq data corroborated plasma inflammaging findings, revealing increased inflammatory cytokine responses in AMs from older macaques. The consistent elevation of macrophage migration inhibitory factor (MIF) across plasma, AMs, and BAL fluid marks it as a promising biomarker and potential therapeutic target for age-associated inflammation. scRNA-seq further identified genes and pathways linked to macrophage senescence and turnover, suggesting potential targets for therapeutic intervention. Overall, our findings highlight the essential role of tissue-resident macrophages in pulmonary aging and underscores the need to further investigate their role in age-associated lung disease.

immunology↗

bioRxiv2025

Contribution of HMGB1 to Keratinocyte inflammation in Recessive Dystrophic Epidermolysis Bullosa

Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited skin disorder characterized by fragile skin, blistering, and chronic wounds. Keratinocytes, the primary cells in the epidermis, are directly affected by persistent injury in RDEB, contributing to chronic inflammation. High mobility group box 1 (HMGB1) is elevated in the serum of individuals with RDEB. However, its role in keratinocyte inflammation remains unclear. Here, we report an increase in HMGB1 expression in keratinocytes at chronic wound sites compared to matched non-wounded skin from an RDEB individual, suggesting a potential link to local inflammation. Pharmacological inhibition of HMGB1 using inflachromene reduced lipopolysaccharide (LPS)-induced inflammatory responses in a keratinocyte cell line, supporting a role for keratinocyte-specific HMGB1 in inflammation. Surprisingly, deletion of HMGB1 alone or together with its paralogue HMGB2 did not suppress the inflammatory response to LPS. Furthermore, inflachromene still reduced inflammation in these knockout cells. This unexpected discrepancy between genetic deletion and pharmacologic inhibition points to a more complex role for HMGB1 or off-target effects of the compound. These findings suggest that HMGB1 may contribute to inflammation in keratinocytes, but its exact function needs further investigation.

molecular biology↗

bioRxiv2025

Spatial transcriptomic analysis of muscle biopsy from treatment-naive juvenile dermatomyositis patients reveals mitochondrial abnormalities despite disease-related interferon driven signature

ObjectivesThis study aimed to investigate the spatial transcriptomic landscape of muscle tissue from treatment-naive juvenile dermatomyositis (JDM) patients in comparison to healthy paediatric muscle tissue. MethodsMuscle biopsies from three JDM patients and three age-matched controls were analysed using the Nanostring GeoMx(R) Digital Spatial Profiler. Regions of interest were selected based on muscle fibres without immune cells, immune cell infiltration and CD68+ macrophage enrichment. Differential gene expression, pathway analysis and pathways clustering analysis were conducted. Key findings were validated in 19 cases of JDM using immunohistochemistry and chemical stains, and a bulk RNAseq dataset of four cases of JDM. ResultsJDM muscle tissues exhibited significant interferon pathway activation and mitochondrial dysfunction compared to controls. A 15-gene interferon signature was significantly elevated in JDM muscle and macrophage-enriched regions, correlating with clinical weakness. In contrast, mitochondrial dysregulation, characterized by downregulated respiratory chain pathways, was present regardless of interferon activity or muscle strength. The interferon-driven and mitochondrial signatures were replicated in an independent RNAseq dataset from JDM muscle; lack of association between interferon signature and mitochondrial dysregulation was validated in 19 cases by conventional staining methods. Clustering analysis revealed distinct transcriptomic profiles between JDM and control tissues, as well as between JDM patients with varying clinical phenotypes. ConclusionsThis study highlights mitochondrial dysfunction as a consistent pathological feature in JDM muscle, which may be independent of interferon-driven inflammation. These findings highlight the potential for mitochondrial-targeted therapies in JDM management and emphasise the need for further studies to explore their therapeutic value. KEY MESSAGESWhat is already known on this topic O_LIJuvenile dermatomyositis (JDM) involves interferon-driven inflammation and immune-mediated muscle damage. C_LIO_LIMitochondrial abnormalities in blood immune cells persist despite treatment and contribute to disease pathology. C_LI What this study adds O_LIMitochondrial dysfunction is present in both muscle fibres and tissue-infiltrating immune cells within JDM muscle. C_LIO_LIThese abnormalities are detectable even in clinically less severe muscle weakness. C_LIO_LIDegree of mitochondrial abnormality at transcript and protein level may be independent of strength of IFN-driven signal. C_LIO_LIMitochondrial dysregulation detected at transcriptional level correlates with abnormal transcription of muscle (sarcomere) and the subcellular peroxisome organelle. C_LI How this study might affect research, practice, or policy O_LITargeting mitochondrial dysfunction could enhance treatment outcomes for JDM, especially in patients whose disease is refractory to current therapies. C_LIO_LIInsights from this study support the development of stratification tools to detect aspects of pathology which are not tightly correlated with IFN-driven pathology. C_LI

immunology↗

bioRxiv2025

Non-linear Age-related Change in Human Interleukin-11 and the receptor subunit alpha DNA Methylation

IntroductionInterleukin-11 (IL-11) is a cytokine involved in inflammatory processes and a previous study showed that blocking or knocking down IL11 in mice prolongs a healthy lifespan. This study investigates DNA methylation (DNAm) changes in the IL11 and IL-11 receptor subunit alpha (IL-11RA) gene across ages to reveal how aging might influence IL-11 production and sensitivity. MethodsA genome-wide DNAm database focusing on Cytosine-phosphate-Guanine (CpG) sites within the IL11 and IL11RA was analyzed. Hierarchical regression analyses examined the relationship between DNAm, age, and the squared age term for quadratic associations. ResultsThe database comprised 10,297 samples (5,156 males and 5,141 females) with a mean age of 53.9 years (SD = 14.1 years). The majority of IL11 and IL11RA CpG sites in the TSS1500 and 3UTR regions exhibited significant inverse U-shaped associations with age. DNAm levels were low during youth, increased in middle age (40s-50s), and decreased again in older age. ConclusionThe observed inverse U-shaped DNAm patterns in the IL11 and IL11RA suggest n non-linear, age-related regulation of IL-11 expression and sensitivity. These findings indicate that IL-11 may have different roles across life stages and suggest that therapeutic interventions targeting IL-11 should consider age-specific effects.

genetics↗

bioRxiv2025

Glial Contribution to the Pathogenesis of Post-Operative Delirium Revealed by Multi-omic Analysis of Brain Tissue from Neurosurgery Patients

Post-operative delirium (POD) is a common complication after surgery especially in elderly patients, characterized by acute disturbances in consciousness and cognition, which negatively impacts long-term outcomes. Effective treatments remain elusive due to the unclear pathophysiology of POD. To address the knowledge gap, we investigated DNA methylation profiles and gene expression changes in brain cells from POD and non-POD patients who underwent brain resection surgery for medication refractory epilepsy. DNA methylation analysis revealed alteration in epigenetic status of immune and inflammation-related genes. Single-nucleus RNA sequencing (snRNAseq) identified POD-specific glial cell alterations, particularly in microglia, where neuroinflammation was strongly enhanced, consistent with epigenetic findings. Astrocytes exhibited changes in synapse-related functions and migration. Furthermore, downstream analysis indicated similarities between POD-associated glial cell states and pathologies such as encephalitis and dementia. Overall, this study--the first multi-omics analysis of brain tissue from POD patients--provides direct evidence of glial cell contributions to POD pathogenesis, and highlights potential therapeutic targets.

neuroscience↗

bioRxiv2025

The age-related susceptibility to postoperative delirium quantified by bispectral electroencephalography (BSEEG) correlates with postoperative delirium-like behavior in mice

Postoperative delirium (POD) is a severe neuropsychiatric state characterized by acute fluctuating various mental symptoms. Despite its prevalence, the underlying mechanisms of POD remain largely unknown, and effective biomarkers for its detection are lacking. We have successfully developed a novel delirium detection method, the bispectral electroencephalography (BSEEG) method, which has shown excellent performance in delirium detection and outcome prediction. From there, similar to the clinical situation, we hypothesize that BSEEG scores can serve as indicators of POD-like states in mice. This study investigated the correlation between POD-like behavior and BSEEG score in a mouse model following EEG head mount implantation surgery. 2-3 and 22-23 month-old male C57BL/6J mice underwent EEG head-mount implantation surgery, followed by EEG monitoring and a battery of behavioral tests, including Buried Food Test, Open Field Test, and Y-maze, to assess POD-like behavior. We measured BSEEG scores and analyzed the correlation between these scores and the behavior measurements. The results showed that BSEEG scores correlated with attention deficit and decreases in locomotor activity in young mice, whilst BSEEG scores only correlated with a decrease in locomotor activity in aged mice. Notably, composite Z scores representing delirium severity also showed a correlation with BSEEG scores in young mice. Our findings indicate that the BSEEG method can be an indicator of POD-like states consistent with those measured by behavior tests. This study provides a novel preclinical framework for understanding the pathophysiology of POD and underscores the potential of BSEEG as a valuable tool for delirium detection and severity assessment.

animal behavior and cognition↗

bioRxiv2025

Developing the Computational Image Processing Methodfor Quantitative Analysis of Nanopore Structure Obtained from HS-AFM (AFMnanoQ)

High-Speed Atomic Force Microscopy (HS-AFM) enables imaging of biological structures and dynamics with nanometer spatial and millisecond temporal resolution. AFM images contain three-dimensional (3D) surface information, comprising two-dimensional (2D) lateral (x-y) and one-dimensional (1D) height (z) encoded in pixel intensity. This dynamic structure poses significant challenges for instance boundary detection and morphological analysis. To address this, we develop AFMnanoSALQ, a feature-driven computational framework for semi-automatic labeling and quantitative (SALQ) detection and morphological measurement of HS-AFM data. Unlike conventional methods that rely solely on either visual or geometric features for 2D boundary detection, AFM- nanoSALQ integrates both to extract 3D morphology. It requires neither annotated data nor intensive training, enabling fast deployment at minimal cost. With performance comparable to typical deep-learning models, AFMnanoSALQ facilitates semi-automatic labeling, making it a practical tool for preliminary data inspection and accelerating the creation of training datasets. As a case study, we focus on -hemolysin (HL), a {beta}-barrel pore-forming toxin secreted by Staphylococcus aureus, using both synthetic and experimental AFM data. AFMnanoSALQ provides a foundation for future deep learning studies, enabling both dataset generation and cross-validation between feature-driven and data-driven approaches.

bioinformatics↗

bioRxiv2024

Targeted H3K9 acetylation at lncSox1 promoter by cell type-specific epigenome editing promotes intermediate progenitor proliferation in developing mouse cortex

The distribution and level of epigenetic (chromatin) marks have implications for differential regulatory effects at specific gene loci. Herein, we applied a protocol which combines in vivo electroporation and a CRISPR-dead (d)Cas9 system to probe and edit a specific chromatin mark in the epigenome of intermediate progenitor cells (IPCs) in developing mouse cortex. We found that the promoter of lncSox1, a long non-coding gene, is a key genomic locus for H3K9 acetylation (H3K9ac) during IPC amplification. CRISPR-dCas9-mediated addition of H3K9ac at lncSox1 promoter resulted in lncSox1 upregulation, with attendant increase in IPC pool and augmented neurogenesis. Thus, we have identified dynamic regulation of lncSox1 as a major downstream target of H3 acetylation, and as part of an epigenetic mechanism involved in IPC proliferation during neocortex expansion. This finding is a proof-of-concept that our epigenome editing-based method can be used for manipulating specific epigenetic effectors to determine their (neuro)biological significance. MOTIVATIONThe abundance of basal progenitors is critical for cortical neurogenesis during brain development. There is growing interest in identifying how specific epigenetic factors regulate the genesis and expansion of basal progenitor cell sub-populations, including intermediate progenitor cells. We established a protocol that allowed us to identify the involvement of a long non-coding RNA (lncSox1) in regulating the proliferation of intermediate progenitor cells under the influence of H3K9 acetylation (H3K9ac). By enhancing H3K9ac at the promoter region of lncSox1 using a CRISPR-dCas9-mediated gene-editing tool, we were able to determine that lncSox1 upregulation is a downstream effect of H3K9ac acetylation and is necessary for intermediate progenitor pool amplification during cortical development. Highlights- Identification of H3 acetylation-dependent expression of ncRNAs in developing cortex. - Establishment of cell Cre/LoxP and CRISPR-dCas9-dependent H3K9ac epigenome editing. - CRISPR-dCas9-mediated addition of H3K9ac at lncSox1 promoter resulted in lncSox1 upregulation. - H3K9 acetylation at lncSox1 promoter enhances proliferation of TBR2-expressing IPCs. - Targeted epigenome editing revealed lncSox1 as a key regulator of cortical development.

neuroscience↗

bioRxiv2024

A novel variant in ADPRS disrupts ARH3 stability and subcellular localization in childrenwith neurodegeneration and respiratory failure

PurposeADP-ribosylation is a post-translational modification involving the transfer of one or more ADP-ribose units from NAD+ to target proteins. Dysregulation of ADP-ribosylation is implicated in neurodegenerative diseases. Here we report a novel homozygous variant in the ADPRS gene (c.545A>G, p.His182Arg) encoding the mono(ADP-ribosyl) hydrolase ARH3 found in 2 patients with childhood-onset neurodegeneration with stress-induced ataxia and seizures (CONDSIAS). MethodsGenetic testing via exome sequencing was used to identify the underlying disease cause in two siblings with developmental delay, seizures, progressive muscle weakness, and respiratory failure following an episodic course. Studies in a cell culture model uncover biochemical and cellular consequences of the identified genetic change. ResultsThe ARH3H182R variant affects a highly conserved residue in the active site of ARH3, leading to protein instability, degradation, and reduced expression. ARH3H182R additionally fails to localize to the nucleus. The combination of reduced expression and mislocalization of ARH3H182R resulted in accumulation of mono-ADP ribosylated species in cells. ConclusionsThe childrens clinical course combined with the biochemical characterization of their genetic variant develops our understanding of the pathogenic mechanisms driving CONDSIAS and highlights a critical role for ARH3-regulated ADP ribosylation in nervous system integrity.

molecular biology↗

bioRxiv2023

Saracatinib synergizes with enzalutamide to downregulate androgen receptor activity in castration resistant prostate cancer

Prostate cancer (PCa) remains the most diagnosed non-skin cancer amongst the American male population. Treatment for localized prostate cancer consists of androgen deprivation therapies (ADTs), which typically inhibit androgen production and the androgen receptor (AR). Though initially effective, a subset of patients will develop resistance to ADTs and the tumors will transition to castration-resistant prostate cancer (CRPC). Second generation hormonal therapies such as abiraterone acetate and enzalutamide are typically given to men with CRPC. However, these treatments are not curative and typically prolong survival only by a few months. Several resistance mechanisms contribute to this lack of efficacy such as the emergence of AR mutations, AR amplification, lineage plasticity, AR splice variants (AR-Vs) and increased kinase signaling. Having identified SRC kinase as a key tyrosine kinase enriched in CRPC patient tumors from our previous work, we evaluated whether inhibition of SRC kinase synergizes with enzalutamide or chemotherapy in several prostate cancer cell lines expressing variable AR isoforms. We observed robust synergy between the SRC kinase inhibitor, saracatinib, and enzalutamide, in the AR-FL+/AR-V+ CRPC cell lines, LNCaP95 and 22Rv1. We also observed that saracatinib significantly decreases AR Y534 phosphorylation, a key SRC kinase substrate residue, on AR-FL and AR-Vs, along with the AR regulome, supporting key mechanisms of synergy with enzalutamide. Lastly, we also found that the saracatinib-enzalutamide combination reduced DNA replication compared to the saracatinib-docetaxel combination, resulting in marked increased apoptosis. By elucidating this combination strategy, we provide pre-clinical data that suggests combining SRC kinase inhibitors with enzalutamide in select patients that express both AR-FL and AR-Vs.

cancer biology↗

bioRxiv2020

Reproducible functional connectivity endophenotype confers high risk of ASD diagnosis in a subset of individuals

Functional connectivity (FC) analyses of individuals with autism spectrum disorder (ASD) have established robust alterations of brain connectivity at the group level. Yet, the translation of these imaging findings into robust markers of individual risk is hampered by the extensive heterogeneity among ASD individuals. Here, we report an FC endophenotype that confers a greater than 7-fold risk increase of ASD diagnosis, yet is still identified in an estimated 1 in 200 individuals in the general population. By focusing on a subset of individuals with ASD and highly predictive FC alterations, we achieved a greater than 3-fold increase in risk over previous predictive models. The identified FC risk endophenotype was characterized by underconnectivity of transmodal brain networks and generalized to independent data. Our results demonstrate the ability of a highly targeted prediction model to meaningfully decompose part of the heterogeneity of the autism spectrum. The identified FC signature may help better delineate the multitude of etiological pathways and behavioural symptoms that challenge our understanding of the autism spectrum.

neuroscience↗

bioRxiv2020

Subtypes of functional connectivity associate robustly with ASD diagnosis

Our understanding of the changes in functional brain organization in autism is hampered by the extensive heterogeneity that characterizes this neurodevelopmental disorder. Data driven clustering offers a straightforward way to decompose this heterogeneity into subtypes of distinguishable connectivity types and promises an unbiased framework to investigate behavioural symptoms and causative genetic factors. Yet the robustness and generalizability of these imaging subtypes is unknown. Here, we show that unsupervised functional connectivity subtypes are moderately associated with the clinical diagnosis of autism, and that these associations generalize to independent replication data. We found that subtypes identified robust patterns of functional connectivity, but that a discrete assignment of individuals to these subtypes was not supported by the data. Our results support the use of data driven subtyping as a data dimensionality reduction technique, rather than to establish clinical categories.

neuroscience↗