Biology subjects

He, M.

Publications and source records attributed to He, M..

At least 91 records · Page 5Linked to original sources

bioRxiv2024

Unraveling the Genetic Comorbidity Landscape of Alzheimer's Disease

Alzheimers disease (AD) has emerged as the most prevalent and complex neurodegenerative disorder among the elderly population. However, the genetic comorbidity etiology for AD remains poorly understood. In this study, we conducted pleiotropic analysis for 41 AD phenotypic comorbidities, identifying ten genetic comorbidities with 16 pleiotropy genes associated with AD. Through biological functional and network analysis, we elucidated the molecular and functional landscape of AD genetic comorbidities. Furthermore, leveraging the pleiotropic genes and reported biomarkers for AD genetic comorbidities, we identified 50 potential biomarkers for AD diagnosis. Our findings deepen the understanding of the occurrence of AD genetic comorbidities and provide new insights for the search for AD diagnostic markers. HighlightsThe present study has focused on the comorbidities associated with Alzheimers disease (AD) by constructing a landscape of these comorbidities at various levels, including diseases, genetics, and pathways. O_LIThe study findings reveal novel and significant pathways that contribute to the etiology of AD and its comorbidities. C_LIO_LIBy exploring pleiotropic genes and reported biomarkers of AD comorbidities, the study has identified several potential diagnostic biomarker candidates for AD. C_LI O_FIG O_LINKSMALLFIG WIDTH=192 HEIGHT=200 SRC="FIGDIR/small/583453v1_figG1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@2fc040org.highwire.dtl.DTLVardef@f6d801org.highwire.dtl.DTLVardef@1df65a4org.highwire.dtl.DTLVardef@18a307e_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphic abstract.C_FLOATNO Study pipeline. C_FIG

neuroscience↗

bioRxiv2024

Individualized temporal patterns dominate cortical upstate and sleep depth in driving human sleep spindle timing

Sleep spindles are critical for memory consolidation and strongly linked to neurological disease and aging. Despite their significance, the relative influences of factors like sleep depth, cortical up/down states, and spindle temporal patterns on individual spindle production remain poorly understood. Moreover, spindle temporal patterns are typically ignored in favor of an average spindle rate. Here, we analyze spindle dynamics in 1008 participants from the Multi-Ethnic Study of Atherosclerosis using a point process framework. Results reveal fingerprint-like temporal patterns, characterized by a refractory period followed by a period of increased spindle activity, which are highly individualized yet consistent night-to-night. We observe increased timing variability with age and distinct gender/age differences. Strikingly, and in contrast to the prevailing notion, individualized spindle patterns are the dominant determinant of spindle timing, accounting for over 70% of the statistical deviance explained by all of the factors we assessed, surpassing the contribution of slow oscillation (SO) phase ([~]14%) and sleep depth ([~]16%). Furthermore, we show spindle/SO coupling dynamics with sleep depth are preserved across age, with a global negative shift towards the SO rising slope. These findings offer novel mechanistic insights into spindle dynamics with direct experimental implications and applications to individualized electroencephalography biomarker identification.

neuroscience↗

bioRxiv2024

Dual Targeting of STING and PI3Kγ Eliminates Regulatory B Cells to Overcome STING Resistance for Pancreatic Cancer Immunotherapy

The immune suppression in tumors and lymph nodes of pancreatic ductal adenocarcinoma (PDAC), regulated by suppressive myeloid cells and regulatory B (Breg) cells, hinders the effectiveness of immunotherapy. Although STING agonists activate myeloid cells to overcome immune suppression, it expands Breg cells, conferring STING resistance in PDAC. We discovered that blocking PI3K{gamma} during STING activation abolished IRF3 phosphorylation to eliminate Breg cells, while PI3K{gamma} inhibition sustained STING-induced IRF3 phosphorylation to preserve STING function in myeloid cells. Therefore, we developed a dual functional compound SH-273 and its albumin nanoformulation Nano-273, which stimulates STING to activate myeloid cells and inhibits PI3K{gamma} to eliminates Breg cells overcoming STING resistance. Nano-273 achieved systemic antitumor immunity through intravenous administration, which decreases Breg cells and remodels microenvironment in tumors and lymph nodes. Nano-273, combined with anti-PD-1, extended median survival to 200 days in transgenic KPC PDAC mice (KrasG12D-P53R172H-Cre), offering potential for PDAC treatment.

pharmacology and toxicology↗

bioRxiv2024

Peptide-based capture-and-release purification of extracellular vesicles and statistical algorithm enabled quality assessment

Circulating extracellular vesicles (EVs) have gained significant attention for discovering tumor biomarkers. However, isolating EVs with well-defined homogeneous populations from complex biological samples is challenging. Different isolation methods have been found to derive different EV populations carrying different molecular contents, which confounds current investigations and hinders subsequent clinical translation. Therefore, standardizing and building a rigorous assessment of isolated EV quality associated with downstream molecular analysis is essential. To address this need, we introduce a statistical algorithm (ExoQuality Index, EQI) by integrating multiple EV characterizations (size, particle concentration, zeta potential, total protein, and RNA), enabling direct EV quality assessment and comparisons between different isolation methods. We also introduced a novel capture-release isolation approach using a pH-responsive peptide conjugated with NanoPom magnetic beads (ExCy) for simple, fast, and homogeneous EV isolation from various biological fluids. Bioinformatic analysis of next-generation sequencing (NGS) data of EV total RNAs from pancreatic cancer patient plasma samples using our novel EV isolation approach and quality index strategy illuminates how this approach improves the identification of tumor associated molecular markers. Results showed higher human mRNA coverage compared to existing isolation approaches in terms of both pancreatic cancer pathways and EV cellular component pathways using gProfiler pathway analysis. This study provides a valuable resource for researchers, establishing a workflow to prepare and analyze EV samples carefully and contributing to the advancement of reliable and rigorous EV quality assessment and clinical translation.

bioengineering↗

bioRxiv2024

Embryonic origins of forebrain oligodendrocytes revisited by combinatorial genetic fate mapping

Multiple embryonic origins give rise to forebrain oligodendrocytes (OLs), yet controversies and uncertainty exist regarding their differential contributions. We established intersectional and subtractional strategies to genetically fate map OLs produced by medial ganglionic eminence/preoptic area (MGE/POA), lateral/caudal ganglionic eminences (LGE/CGE) and dorsal pallium. We found that, contrary to the canonical view, LGE/CGE-derived OLs make minimum contributions to the neocortex and corpus callosum, but dominate piriform cortex and anterior commissure. Additionally, MGE/POA-derived OLs, instead of being entirely eliminated, make small but sustained contribution to cortex with a distribution pattern distinctive from those derived from the dorsal origin. Our study provides a revised and more comprehensive view of cortical and white matter OL origins, and established valuable new tools and strategies for future OL studies.

neuroscience↗

bioRxiv2024

The role of m6A methyltransferase WTAP in inflammatory response of atherosclerosis through NF-κB/NLRP3 mediated pyroptosis

BackgroundPyroptosis is a new form of pro-inflammatory programmed cell death that has been linked to the development of atherosclerosis (AS). However, its exact mechanisms are not known. N6-methyladenosine (m6A) methylation is the commonest and most abundant epigenetic modification of eukaryotic mRNAs. m6A methylation modulates pathological and physiological processes involved in cardiovascular diseases. However, the exact mechanism by which it regulates inflammation in AS is unclear. MethodsIn this study, the level of m6A and WTAP in CHD was explored. To determine the effect of WTAP on the release of pyrolysis-related proteins and pro-inflammatory cytokines, the expression of WTAP in lipopolysaccharide (LPS)-treated endothelial cells was silenced. Pyroptosis-related proteins and pro-inflammatory cytokines were quantified in the presence of NLRP3 shRNA (shNLRP3) and NF-kB shRNA (shNF-kB(p50)). The interaction of NF-kB and NLRP3 was examined through immunoprecipitation (CO-IP), immunofluorescence (IF) and GST-pull down assays. ResultIt was observed that lipopolysaccharide (LPS) induced Nod-like receptor protein 3 (NLRP3)-mediated pyroptosis and inflammation, both of which were abolished through the knockdown of WTAP. Interestingly, our results indicated that WTAP enhanced the function of nuclear factor {kappa}B (NF-{kappa}B) p50 (an NF-{kappa}B subunit) and that p50 could interact with NLRP3 in endothelial cells. ConclusionIn conclusion, these results suggested that WTAP in the formation of pyroptosis and inflammation in endothelial cells exposed to LPS stress by activating the NF-{kappa}B/NLRP3 signaling pathway. These findings demonstrate the mechanism of WTAP regulation during the progression of AS.

immunology↗

bioRxiv2024

Reprogramming of 3D genome structure underlying HSPC development in zebrafish

Development of hematopoietic stem and progenitor cells (HSPC) is a multi-staged complex process that conserved between zebrafish and mammals; however, the mechanism underlying HSPC development is not fully understood. Chromatin conformation plays important roles in transcriptional regulation and cell fate decision, its dynamic and role in HSPC development is poorly investigated. Here, we performed chromatin structure and multi-omics dissection across different stages of HSPC developmental trajectory in zebrafish. Chromatin organization of zebrafish HSPC resemble mammalian cells with similar hierarchical structure and characteristics. We revealed the multi-scale reorganization of 3D genome and its influence on transcriptional regulation and transition of cell function during HSPC development. Nascent HSPC is featured by loose conformation with obscure structure at all layers. Notably, PU.1 was identified as a potential factor mediating formation of promoter-involved loops and regulating gene expression as well as HSPC function. Our results provided a global view of chromatin structure dynamics associated with development of zebrafish HSPC and discovered key transcription factor involved in HSPC chromatin interactions, which will provide new insights into the epigenetic regulatory mechanisms underlying vertebrate HSPC fate decision.

genomics↗

bioRxiv2023

Host-Pathogen Interactions in the Plasmodium-Infected Mouse Liver at Spatial and Single-Cell Resolution

Upon infecting its vertebrate host, the malaria parasite initially invades the liver where it undergoes massive replication, whilst remaining clinically silent. The spatial coordination of factors regulating immune responses and metabolic zonation during malaria infection, in the true tissue context, remains unexplored. Here, we perform spatial transcriptomics in combination with single-nuclei RNA-sequencing (snRNA-seq) over multiple time points during liver infection to delineate transcriptional programs of host-pathogen interactions across P. berghei-infected liver tissues. Our data suggest changes in gene expression related to lipid metabolism in response to Plasmodium infection in the proximity of infected hepatocytes, such as the modulation of the expression of genes involved in peroxisome proliferator-activated receptor pathway signaling. The data further indicate the presence of inflammatory hotspots with distinct cell type compositions and differential liver inflammation programs along the lobular axis in the malaria-infected tissues. Furthermore, a significant upregulation of genes involved in inflammation is observed in liver tissues of control mice injected with mosquito salivary gland components, which is considerably delayed compared to P. berghei infected mice. Our study establishes a benchmark for investigating transcriptome changes during host-parasite interactions in tissues, it provides informative insights regarding in vivo study design linked to infection, and provides a useful tool for the discovery and validation of de novo intervention strategies aimed at malaria liver stage infection.

molecular biology↗

bioRxiv2023

De novo design and optimization of aptamers with AptaDiff

Aptamers are single-stranded nucleic acid ligands, featuring high affinity and specificity to target molecules. Traditionally they are identified from large DNA/RNA libraries using in vitro methods, like Systematic Evolution of Ligands by Exponential Enrichment (SELEX). However, these libraries capture only a small fraction of theoretical sequence space, and various aptamer candidates are constrained by actual sequencing capabilities from the experiment. Addressing this, we proposed AptaDiff, the first in silico aptamer design and optimization method based on the diffusion model. Our Aptadiff can generate aptamers beyond the constraints of high-throughput sequencing data, leveraging motif-dependent latent embeddings from variational autoencoder, and can optimize aptamers by affinity-guided aptamer generation according to Bayesian optimization. Comparative evaluations revealed AptaDiffs superiority over existing aptamer generation methods in terms of quality and fidelity across four high-throughput screening data targeting distinct proteins. Moreover, Surface Plasmon Resonance (SPR) experiments were conducted to validate the binding affinity of aptamers generated through Bayesian optimization for two target proteins. The results unveiled a significant boost of 87.9% and 60.2% in RU values, along with a 3.6-fold and 2.4-fold decrease in KD values for the respective target proteins. Notably, the optimized aptamers demonstrated superior binding affinity compared to top experimental candidates selected through SELEX, underscoring the promising outcomes of our AptaDiff in accelerating the discovery of superior aptamers. Key PointsO_LIWe proposed AptaDiff, the first in silico aptamer design method based on the diffusion model. Aptadiff can generate aptamers beyond the constraints of high-throughput sequencing data. C_LIO_LIAptadiff can optimize aptamers through affinity-guided generation via Bayesian optimization within a motif-dependent latent space, and the affinity of the optimized aptamers to the target protein is better than the best experimental candidate from traditional SELEX screening. C_LIO_LIAptadiff consistently outperforms the current state-of-the-art method in terms of quality and fidelity across high-throughput screening data targeting distinct proteins. C_LI

bioinformatics↗

bioRxiv2023

Cell type-specific translational regulation by Human DUS enzymes

Dihydrouridine is an abundant and conserved modified nucleoside present on tRNA, but characterization and functional studies of modification sites and associated DUS writer enzymes in mammals is lacking. Here we use a chemical probing strategy, RNABPP-PS, to identify 5-chlorouridine as an activity-based probe for human DUS enzymes. We map D modifications using RNA-protein crosslinking and chemical transformation and mutational profiling to reveal D modification sites on human tRNAs. Further, we knock out individual DUS genes in two human cell lines to investigate regulation of tRNA expression levels and codon-specific translation. We show that whereas D modifications are present across most tRNA species, loss of D only perturbs the translational function of a subset of tRNAs in a cell type-specific manner. Our work provides powerful chemical strategies for investigating D and DUS enzymes in diverse biological systems and provides insight into the role of a ubiquitous tRNA modification in translational regulation.

biochemistry↗

bioRxiv2023

Voluntary wheel running mitigates disease in an Orai1 gain-of-function mouse model of tubular aggregate myopathy

Tubular aggregate myopathy (TAM) is an inherited skeletal muscle disease associated with progressive muscle weakness, cramps, and myalgia. Tubular aggregates (TAs) are regular arrays of highly ordered and densely packed SR straight-tubes in muscle biopsies; the extensive presence of TAs represent a key histopathological hallmark of this disease in TAM patients. TAM is caused by gain-of-function mutations in proteins that coordinate store-operated Ca2+ entry (SOCE): STIM1 Ca2+ sensor proteins in the sarcoplasmic reticulum (SR) and Ca2+-permeable ORAI1 channels in the surface membrane. We have previously shown that voluntary wheel running (VWR) prevents formation of TAs in aging mice. Here, we assessed the therapeutic potential of endurance exercise (in the form of VWR) in mitigating the functional and structural alterations in a knock-in mouse model of TAM (Orai1G100S/+ or GS mice) based on a gain-of-function mutation in the ORAI1 pore. WT and GS mice were singly-housed for six months (from two to eight months of age) with either free-spinning or locked low profile wheels. Six months of VWR exercise significantly increased soleus peak tetanic specific force production, normalized FDB fiber Ca2+ store content, and markedly reduced TAs in EDL muscle from GS mice. Six months of VWR exercise normalized the expression of mitochondrial proteins found to be altered in soleus muscle of sedentary GS mice in conjunction with a signature of increased protein translation and biosynthetic processes. Parallel proteomic analyses of EDL muscles from sedentary WT and GS mice revealed changes in a tight network of pathways involved in formation of supramolecular complexes, which were also normalized following six months of VWR. In summary, sustained voluntary endurance exercise improved slow twitch muscle function, reduced the presence of TAs in fast twitch muscle, and normalized the muscle proteome of GS mice consistent with protective adaptions in proteostasis, mitochondrial structure/function, and formation of supramolecular complexes.

physiology↗

bioRxiv2023

CRISPR-Cas9 Extracellular Vesicles for Treating Hearing Loss

Clinical translation of gene therapy has been challenging, due to limitations in current delivery vehicles such as traditional viral vectors. Herein, we report the use of gRNA:Cas9 ribonucleoprotein (RNP) complexes engineered extracellular vesicles (EVs) for in vivo gene therapy. By leveraging a novel high-throughput microfluidic droplet-based electroporation system (DES), we achieved 10-fold enhancement of loading efficiency and more than 1000-fold increase in processing throughput on loading RNP complexes into EVs (RNP-EVs), compared with conventional bulk electroporation. The flow-through droplets serve as enormous bioreactors for offering millisecond pulsed, low-voltage electroporation in a continuous-flow and scalable manner, which minimizes the Joule heating influence and surface alteration to retain natural EV stability and integrity. In the Shaker-1 mouse model of dominant progressive hearing loss, we demonstrated the effective delivery of RNP-EVs into inner ear hair cells, with a clear reduction of Myo7ash1 mRNA expression compared to RNP-loaded lipid-like nanoparticles (RNP-LNPs), leading to significant hearing recovery measured by auditory brainstem responses (ABR). One sentence summaryThe scalable microfluidic electroporation system enables the loading of gRNA:Cas9 ribonucleoprotein (RNP) complexes into extracellular vesicles, which leads to clinical translation potential employed in hearing disease gene therapy.

bioengineering↗

bioRxiv2023

Profiling plasma extracellular vesicle-derived microRNAs for noninvasive diagnosis of alpha-1 antitrypsin deficiency associated liver disease

Alpha-1 antitrypsin deficiency (AATD) is a rare genetic disease characterized by reduced circulating levels of alpha-1 antitrypsin (AAT) due to the retention of misfolded AAT in the hepatocytes. The toxic AAT aggregates in hepatocytes cause liver fibrosis, cirrhosis, and hepatocellular carcinoma. Most patients remain asymptomatic until the final stage in which liver transplantation becomes the only treatment. Timely diagnosis of AATD liver disease plays a critical role in intervention and finding curative solutions. Assessing the prevalence and severity of AATD liver disease remains challenging due to limitations in current methods. Liver biopsy, the gold standard for evaluating the hepatic AAT accumulation, the initiating stage for AATD liver disease, is hindered by invasiveness and sampling errors. To address these limitations, we conducted a study using unique and precious clinical samples. We analyzed plasma extracellular vesicle (EV) derived miRNAs and liver transcriptomes from AATD individuals to develop a sensitive and noninvasive diagnostic approach for AATD liver disease. In the testing stage of our study, we enrolled 17 AATD individuals with different stages of liver disease, as determined by liver biopsy, and 20 controls. We identified differential expression of 178 miRNAs within the AATD group compared to controls by miRNA sequencing. Among those miRNAs, we selected miR-223-3p, miR-23a-3p, miR-15b-5p, let-7a-5p, let-7f-5p, and miR-374a-5p for further validation in an independent cohort of 45 AATD individuals. Using a logistic model that combined three miRNAs, we achieved an AUC of 0.737 for detecting AATD liver disease. Adding a fourth miRNA into this model increased the AUC to 0.751. The changes in EV miRNAs are correlated to dysregulated expression of liver mRNAs in AATD individuals with different stages of liver disease. We propose that plasma-circulating EV exhibit distinct miRNAs in AATD individuals and could serve as clinically significant biomarkers for the early detection of AATD liver disease.

molecular biology↗

bioRxiv2023

A dynamic generative model can extract interpretable oscillatory components from multichannel neurophysiological recordings

Modern neurophysiological recordings are performed using multichannel sensor arrays that are able to record activity in an increasingly high number of channels numbering in the 100s to 1000s. Often, underlying lower-dimensional patterns of activity are responsible for the observed dynamics, but these representations are difficult to reliably identify using existing methods that attempt to summarize multivariate relationships in a post-hoc manner from univariate analyses, or using current blind source separation methods. While such methods can reveal appealing patterns of activity, determining the number of components to include, assessing their statistical significance, and interpreting them requires extensive manual intervention and subjective judgement in practice. These difficulties with component selection and interpretation occur in large part because these methods lack a generative model for the underlying spatio-temporal dynamics. Here we describe a novel component analysis method anchored by a generative model where each source is described by a bio-physically inspired state space representation. The parameters governing this representation readily capture the oscillatory temporal dynamics of the components, so we refer to it as Oscillation Component Analysis (OCA). These parameters - the oscillatory properties, the component mixing weights at the sensors, and the number of oscillations - all are inferred in a data-driven fashion within a Bayesian framework employing an instance of the expectation maximization algorithm. We analyze high-dimensional electroencephalography and magnetoencephalography recordings from human studies to illustrate the potential utility of this method for neuroscience data. Significance StatementNeuroscience studies often involve simultaneous recordings in a large number of sensors in which a smaller number of dynamic components generate the complex spatio-temporal patterns observed in the data. Current blind source separation techniques produce sub-optimal results and are difficult to interpret because these methods lack an appropriate generative model that can guide both statistical inference and interpretation. Here we describe a novel component analysis method employing a dynamic generative model that can decompose high-dimensional multivariate data into a smaller set of oscillatory components are learned in a data-driven way, with parameters that are immediately interpretable. We show how this method can be applied to neurophysiological recordings with millisecond precision that exhibit oscillatory activity such as electroencephalography and magnetoencephalography.

neuroscience↗

bioRxiv2023

MIDAS: a fast and simple simulator for realistic microbiome data

BackgroundAdvances in sequencing technology has led to the discovery of associations between the human microbiota and many diseases, conditions, and traits. With the increasing availability of microbiome data, many statistical methods have been developed for studying these associations. The growing number of newly developed methods highlights the need for simple, rapid, and reliable methods to simulate realistic microbiome data, which is essential for validating and evaluating the performance of these methods. However, generating realistic microbiome data is challenging due to the complex nature of microbiome data, which feature correlation between taxa, sparsity, overdispersion, and compositionality. Current methods for simulating microbiome data are deficient in their ability to capture these important features of microbiome data, or can require exorbitant computational time. MethodsWe develop MIDASim (MIcrobiome DAta Simulator), a fast and simple approach for simulating realistic microbiome data that reproduces the distributional and correlation structure of a template microbiome dataset. MIDASim is a two-step approach. The first step generates correlated binary indicators that represent the presence-absence status of all taxa, and the second step generates relative abundances and counts for the taxa that are considered to be present in step 1, utilizing a Gaussian copula to account for the taxon-taxon correlations. In the second step, MIDASim can operate in both a nonparametric and parametric mode. In the nonparametric mode, the Gaussian copula uses the empirical distribution of relative abundances for the marginal distributions. In the parametric mode, an inverse generalized gamma distribution is used in place of the empirical distribution. ResultsWe demonstrate improved performance of MIDASim relative to other existing methods using gut and vaginal data. MIDASim showed superior performance by PER-MANOVA and in terms of alpha diversity and beta dispersion in either parametric or nonparametric mode. We also show how MIDASim in parametric mode can be used to assess the performance of methods for finding differentially abundant taxa in a compositional model. ConclusionsMIDASim is easy to implement, flexible and suitable for most microbiome data simulation situations. MIDASim has three major advantages. First, MIDASim performs better in reproducing the distributional features of real data compared to other methods at both presence-absence level and relative-abundance level. MIDASim-simulated data are more similar to the template data than competing methods, as quantified using a variety of measures. Second, MIDASim makes few distributional assumptions for the relative abundances, and thus can easily accommodate complex distributional features in real data. Third, MIDASim is computationally efficient and can be used to simulate large microbiome datasets.

bioinformatics↗

bioRxiv2023

Neural Dynamic Underlying Coordination Process between Habitual and Goal-Directed Behavior

The coordination between habitual and goal-directed behaviors has significant evolutionary importance. However, the specific cognitive processes and neural mechanisms underlying this coordination process require further research. Since inducing natural habitual responses through repetitive stimuli-response training in a laboratory environment is extremely difficult in humans, well-trained sports experts with automatic perception-action features towards expertise-related stimuli serve as ideal natural samples to address this critical gap. We conducted scalp EEG recordings while sports experts performed an expertise Simon task that involved both automatic and goal-directed processes with moderate space of expertise-related stimuli congruent or incongruent with the response hand. In the congruent condition, sports experts showed larger response-locked LRP and beta band (15-25Hz) activity at the frontal-central region, indicating an enhanced automatic response tendency towards expertise-related stimuli. In the incongruent condition, a larger theta (3-8Hz) dynamic was observed in the superior frontal gyrus when sports experts needed to inhibit the automatic response tendency. The results indicated that sports experts exhibited an enhanced coordination process towards expertise-related stimuli, which was closely related to specific cognitive processes of response preparation and response inhibition in coordinating habitual and goal-directed behaviors

neuroscience↗

bioRxiv2023

Spatial transcriptomic analysis of virtual prostate biopsy reveals confounding effect of heterogeneity on genomic signature scoring

Genetic signatures have added a molecular dimension to prognostics and therapeutic decision-making. However, tumour heterogeneity in prostate cancer and current sampling methods could confound accurate assessment. Based on previously published spatial transcriptomic data from multifocal prostate cancer, we created virtual biopsy models that mimic conventional biopsy placement and core size. We then analysed the gene expression of different prognostic signatures (OncotypeDx(R), Decipher(R), Prostadiag(R)) using a step-wise approach increasing resolution from pseudo-bulk analysis of the whole biopsy, to differentiation by tissue subtype (benign, stroma, tumour), followed by distinct tumour grade and finally clonal resolution. The gene expression profile of virtual tumour biopsies revealed clear differences between grade groups and tumour clones, compared to a benign control, which were not reflected in bulk analyses. This suggests that bulk analyses of whole biopsies or tumour-only areas, as used in clinical practice, may provide an inaccurate assessment of gene profiles. The type of tissue, the grade of the tumour and the clonal composition all influence the gene expression in a biopsy. Clinical decision making based on biopsy genomics should be made with caution while we await more precise targeting and cost-effective spatial analyses. Patient summaryProstate cancers are very variable, including within a single tumour. Current genetic scoring systems, which are sometimes used to make decisions for how to treat patients with prostate cancer, are based on sampling methods which do not reflect these variations. We found, using state-of-the-art spatial genetic technology to simulate accurate assessment of variation in biopsies, that the current approaches miss important details which could negatively impact clinical decisions. Take home messageVirtual biopsies from spatial transcriptomic analysis of a whole prostate reveal that current genomic risk scores potentially deliver misleading results as they are based on bulk analysis of prostate biopsies and ignore tumour heterogeneity.

genomics↗

bioRxiv2023

Mitochondrial Pyruvate Carrier Inhibition in Hepatic Stellate Cells Attenuates Fibrosis in Nonalcoholic Steatohepatitis in Mice

Hepatic stellate cells (HSC) are non-parenchymal liver cells that produce extracellular matrix comprising fibrotic lesions in chronic liver diseases. Prior work demonstrated that mitochondrial pyruvate carrier (MPC) inhibitors suppress HSC activation and fibrosis in a mouse model of metabolic dysfunction-associated steatohepatitis (MASH). In the present study, pharmacologic or genetic inhibition of the MPC in HSC decreased expression of markers of activation in vitro. MPC knockdown also reduced the abundance of several intermediates of the TCA cycle, and diminished -ketoglutarate played a key role in attenuating HSC activation by suppressing hypoxia inducible factor-1 signaling. On high fat diets, mice with HSC-specific MPC deletion exhibited reduced circulating transaminases, numbers of HSC, and hepatic expression of markers of HSC activation and inflammation compared to wild-type mice. These data suggest that MPC inhibition modulates HSC metabolism to attenuate activation and illuminate mechanisms by which MPC inhibitors could prove therapeutically beneficial for treating MASH.

physiology↗