Biology subjects

Liu, C.-C.

Publications and source records attributed to Liu, C.-C..

16 recordsLinked to original sources

bioRxiv2026

A modular architecture of human cellular aging across organs and diseases

Aging is a heterogeneous biological process in which different cellular systems undergo molecular remodeling at distinct rates, yet whether human cellular aging follows an organized architecture across organs remains unclear. Here, we integrate a multi-organ human single-cell transcriptomic atlas with plasma proteomic profiles from approximately 50,000 participants to reconstruct cellular aging states at population scale. By projecting cell-type-enriched molecular signatures onto circulating proteins, we characterize aging patterns across 128 organ-cell type pairs and identify 14 cellular aging modules comprising conserved cross-organ programs and organ-specific aging states. These modules reveal cellular identity as a dominant organizing axis of human aging that transcends anatomical boundaries. Module-level aging states uncover substantial inter-individual heterogeneity, with 34% of individuals exhibiting extreme aging deviation in at least one cellular module. Cellular aging modules exhibit distinct temporal trajectories, with structural and tissue-resident modules showing earlier remodeling than immune lineages. The modular organization of cellular aging is reflected in disease susceptibility, with accelerated aging of specific modules, particularly epithelial aging, showing broad associations with disease burden and mortality. Longitudinal analyses further demonstrate the stability and clinical relevance of cellular aging states, whereas lifestyle, metabolic and pharmacological factors show selective relationships with individual aging programs. Together, our study establishes a modular framework for understanding human cellular aging and reveals an organization of biological aging that may help explain individual differences in healthspan.

cell biology↗

bioRxiv2026

Risk Assessment of Arterial Embolism from Neofilera(R) Filler in Rabbits

The incidence of vascular complications differs among dermal filler formulations. This study aimed to evaluate the embolic risk associated with Neofilera(R), a filler composed of carboxymethyl cellulose and polylactic acid microspheres, following intra-arterial injection. The central auricular arteries of rabbits were injected with Neofilera(R) at volumes of 0.1 mL or 0.2 mL under various conditions: normal saline (control) and Neofilera(R) diluted at ratios of 1:5 (Group 1), 1:10 (Group 2), and 1:15 (Group 3). The presence of transparent emboli was assessed immediately after injection, while tissue necrosis (percentage and area) and histopathological alterations were evaluated on days 1 and 7 post-injection. Relative to controls, Neofilera(R) administered at 0.1 mL dispersed within minutes and did not induce significant tissue necrosis at either observation time point. In contrast, administration of 0.2 mL, even in diluted form, was associated with an increased incidence of vascular occlusion. Overall, these findings indicate that Neofilera(R) presents a lower embolic risk when injected at a volume of 0.1 mL, whereas higher injection volumes may substantially increase the likelihood of embolic complications.

cell biology↗

bioRxiv2026

Phosphoglycerate mutase 5 regulates lipid metabolism and mitochondrial homeostasis in hepatocellular cancer cells

The mitochondrial membrane protein phosphoglycerate mutase 5 (PGAM5) is a protein of interest in the complex transition from hepatic steatosis to hepatocellular carcinoma. PGAM5 is a serine/threonine/histidine phosphatase that plays a role in mitochondrial biogenesis, mitophagy, and multiple cell death pathways. Increased expression of PGAM5 in hepatocellular carcinoma is correlated with reduced patient survival. In this study, we demonstrate that loss of PGAM5 alters the bioenergetic landscape of liver cancer by promoting mitochondrial oxidant injury and suppressing the glycerophospholipid and lysophospholipid pathways, leading to accumulation of the bioactive phospholipid lysophosphatidylcholine. Additionally, PGAM5 deletion downregulates fatty acid biosynthesis, resulting in reduced cellular diacylglycerol concentrations through two probable mechanisms: attenuated long chain fatty acid uptake and suppressed de novo synthesis. These findings underscore the broad impact of a single phosphatase on mitochondrial function and provide a rationale for therapeutically targeting PGAM5 to disrupt lipid metabolism in hepatocellular carcinoma.

cancer biology↗

bioRxiv2025

NK2R signaling governs intestinal lipid mobilization and mucosal inflammation

Neuropeptidergic control of lipid metabolism is conserved and increasingly implicated in metabolic diseases, but receptor-level mechanisms remain unclear. Here we identify the neurokinin-2 receptor (NK2R) as a central node linking tachykinin signals to intestinal lipid mobilization, epithelial composition, and mucosal inflammation. Across complementary genetic and pharmacological perturbations, modulation of NK2R drives bidirectional effects. Loss or blockade of NK2R increases postprandial triglyceridemia and expands intestinal lipid stores, whereas agonism suppresses chylomicron output, reduces adiposity, and improves glycemia in diet-induced obesity. Transcriptomic and cellular analyses indicate coordinated upregulation of lipid-metabolic programs with a concomitant dampening of immune pathways in the absence of NK2R, accompanied by sex-specific remodeling of secretory lineages and male-biased protection from colitis. NK2R signaling also shaped the fecal microbiota in a genotype- and diet-dependent manner, highlighting crosstalk among neuropeptide signaling, epithelial physiology, and host-microbe interactions. These findings position NK2R as a molecular switch for intestinal lipid handling and mucosal inflammation and suggest that NK2R-targeted agonists or antagonists could be deployed as context- and sex-dependent therapeutic strategies for metabolic disease and inflammatory bowel disease.

physiology↗

bioRxiv2025

RiboTRAP-seq identifies spatially distinct functions for the anterior and posterior intestine in immune and metabolic regulation in C. elegans

The intestine integrates food-derived cues to coordinate organismal physiology, yet the molecular specialization of discrete regions along the intestinal epithelium remains unclear. Here, we generate cell type-specific translatomes of the Caenorhabditis elegans intestine during fasting and refeeding using discrete promoters for the anterior quartet of intestinal cells (INT1) and the remaining 8 pairs of intestinal cells (INT2-9). We found that the anterior-most INT1 cells are a translationally distinct intestinal sub-compartment that is particularly enriched for immune-and stress-response genes. Functional assays using novel INT1-specific genes emerging from this study reveal that these specialized cells play a previously unappreciated role in pathogen avoidance and organismal survival. A second critical function of INT1 cells is their role in sensing and responding to the contents of the gut lumen. We show that luminal pyruvate is the key signal linking bacterial nutrients in the gut, to secretion of the gut insulin antagonist INS-7. These findings establish INT1 as sentinel enteroendocrine cells that integrate metabolic and immune cues to couple food status with immune and endocrine responses. Our studies also provide a rich resource for dissecting segment-specific intestinal biology, an overlooked and fertile area for future research.

physiology↗

bioRxiv2025

Integrative Epigenomic Landscape of Alzheimer's Disease Brains Reveals Oligodendrocyte Molecular Perturbations Associated with Tau

Alzheimers disease (AD) brains are characterized by neuropathologic and biochemical changes that are highly variable across individuals. Capturing epigenetic factors that associate with this variability can reveal novel biological insights into AD pathophysiology. We conducted an epigenome-wide association study of DNA methylation (DNAm) in 472 AD brains with neuropathologic measures (Braak stage, Thal phase, and cerebral amyloid angiopathy score) and brain biochemical levels of five proteins (APOE, amyloid-{beta} (A{beta})40, A{beta}42, tau, and p-tau) core to AD pathogenesis. Using a novel regional methylation (rCpGm) approach, we identified 5,478 significant associations, 99.7% of which were with brain tau biochemical measures. Of the tau-associated rCpGms, 93 had concordant associations in external datasets comprising 1,337 brain samples. Integrative transcriptome-methylome analyses uncovered 535 significant gene expression associations for these 93 rCpGms. Genes with concurrent transcriptome-methylome perturbations were enriched in oligodendrocyte marker genes, including known AD risk genes such as BIN1, myelination genes MYRF, MBP and MAG previously implicated in AD, as well as novel genes like LDB3. We further annotated the top oligodendrocyte genes in an additional 6 brain single cell and 2 bulk transcriptome datasets from AD and two other tauopathies, Picks disease and progressive supranuclear palsy (PSP). Our findings support consistent rCpGm and gene expression associations with these tauopathies and tau-related phenotypes in both bulk brain tissue and oligodendrocyte clusters. In summary, we uncover the integrative epigenomic landscape of AD and demonstrate tau-related oligodendrocyte gene perturbations as a common potential pathomechanism across different tauopathies.

genomics↗

bioRxiv2024

Breast tumor microbiome regulates anti-tumor immunity and T cell-associated metabolites

BackgroundBreast cancer, the most common cancer type among women, was recently found to contain a specific tumor microbiome, but its impact on host biology remains unclear. CD8+ tumor-infiltrating lymphocytes (TILs) are pivotal effectors of anti-tumor immunity that influence cancer prognosis and response to therapy. This study aims to elucidate interactions between CD8+ TILs and the breast tumor microbiome and metabolites, as well as how the breast tumor microbiome may affect the tumor metabolome. MethodsWe investigated the interplay among CD8+ TILs, the tumor microbiome, and the metabolome in a cohort of 46 breast cancer patients with mixed subtypes (Cohort A). We characterized the tumor metabolome by mass spectrometry and CD8+ TILs by immunohistochemistry. Microbiome composition and T cell gene transcript levels were obtained from data from our previous study, which utilized 16S rRNA gene sequencing and a targeted mRNA expression panel. To examine interactions between intratumoral Staphylococcus and specific breast cancer subtypes, we analyzed RNA sequencing data from an independent cohort of 370 breast cancer patients (Cohort B). We explored the functions of the tumor microbiome using mouse models of triple-negative breast cancer (TNBC). ResultsIn tumors from Cohort A, the relative abundance of Staphylococcus positively correlated with the expression of T cell activation genes. The abundances of multiple metabolites exhibited significant correlations with CD8+ TILs, of which NADH, {gamma}-glutamyltryptophan, and {gamma}-glutamylglutamate displayed differential abundance in Staphylococcus-positive versus Staphylococcus-negative breast tumors. In a larger breast cancer cohort (Cohort B), we observed positive correlations between tumoral Staphylococcus and CD8+ TIL activity exclusively in TNBC. Preclinical experiments demonstrated that intratumoral administration of S. aureus, the predominant species of Staphylococcus in human breast tumors, resulted in a depletion of total NAD metabolites, and reduced the growth of TNBC tumors by activating CD8+ TILs. ConclusionsWe identified specific metabolites and microbial taxa associated with CD8+ TILs, delineated interactions between the breast tumor microbiome and metabolome, and demonstrated that intratumoral Staphylococcus influences anti-tumor immunity and TIL-associated metabolites. These findings highlight the role of low-biomass microbes in tumor tissues and provide potential biomarkers and therapeutic agents for breast cancer immunotherapy that merit further investigation.

cancer biology↗

bioRxiv2024

The UFMylation pathway is impaired in Alzheimer's disease

BackgroundAlzheimers disease (AD) is characterized by the presence of neurofibrillary tangles made of hyperphosphorylated tau and senile plaques composed of beta-amyloid. These pathognomonic deposits have been implicated in the pathogenesis, although the molecular mechanisms and consequences remain undetermined. UFM1 is an important, but understudied ubiquitin-like protein that is covalently attached to substrates. This UFMylation has recently been identified as major modifier of tau aggregation upon seeding in experimental models. However, potential alterations of the UFM1 pathway in human AD brain have not been investigated yet. MethodsHere we used frontal and temporal cortex samples from individuals with or without AD to measure the protein levels of the UFMylation pathway in human brain. We used multivariable regression analyses followed by Bonferroni correction for multiple testing to analyze associations of the UFMylation pathway with neuropathological characteristics, primary biochemical measurements of tau and additional biochemical markers from the same cases. We further studied associations of the UFMylation cascade with cellular stress pathways using Spearman correlations with bulk RNAseq expression data and functionally validated these interactions using gene-edited neurons that were generated by CRISPR-Cas9. ResultsCompared to controls, human AD brain had increased protein levels of UFM1. Our data further indicates that this increase mainly reflects conjugated UFM1 indicating hyperUFMylation in AD. UFMylation was strongly correlated with pathological tau in both AD-affected brain regions. In addition, we found that the levels of conjugated UFM1 were negatively correlated with soluble levels of the deUFMylation enzyme UFSP2. Functional analysis of UFM1 and/or UFSP2 knockout neurons revealed that the DNA damage response as well as the unfolded protein response are perturbed by changes in neuronal UFM1 signaling. ConclusionsThere are marked changes in the UFMylation pathway in human AD brain. These changes are significantly associated with pathological tau, supporting the idea that the UFMylation cascade might indeed act as a modifier of tau pathology in human brain. Our study further nominates UFSP2 as an attractive target to reduce the hyperUFMylation observed in AD brain but also underscores the critical need to identify risks and benefits of manipulating the UFMylation pathway as potential therapeutic avenue for AD.

neuroscience↗

bioRxiv2023

A homeostatic gut-to-brain insulin antagonist restrains neuronally stimulated fat loss

In C. elegans mechanisms by which peripheral organs relay internal state information to the nervous system remain unknown, although strong evidence suggests that such signals do exist. Here we report the discovery of a peptide of the ancestral insulin superfamily called INS-7 that functions as an enteroendocrine peptide and is secreted from specialized cells of the intestine. INS-7 secretion increases during fasting, and acts as a bona fide gut-to-brain homeostatic signal that attenuates neuronally induced fat loss during food shortage. INS-7 functions as an antagonist at the canonical DAF-2 receptor in the nervous system, and phylogenetic analysis suggests that INS-7 bears greater resemblance to members of the broad insulin/relaxin superfamily than to conventional mammalian insulin and IGF peptides. The discovery of an endogenous insulin antagonist secreted by specialized intestinal cell with enteroendocrine functions suggests that much remains to be learned about the intestine and its role in directing neuronal functions.

physiology↗

bioRxiv2023

Hematopoietic Transfer of the Anti-Cancer and Lifespan-Extending Capabilities of A Genetically Engineered Blood System

A causal relationship exists among the aging process, organ decay and dis-function, and the occurrence of various diseases including cancer. A genetically engineered mouse model, termed Klf1K74R/K74R or Klf1(K74R), carrying mutation on the well-conserved sumoylation site of the hematopoietic transcription factor KLF1/ EKLF has been generated that possesses extended lifespan and healthy characteristics including cancer resistance. We show that the healthy longevity characteristics of the Klf1(K74R) mice, as exemplified by their higher anti- cancer capability, are likely gender-, age- and genetic background-independent. Significantly, the anti-cancer capability, in particular that against melanoma as well as hepatocellular carcinoma, and lifespan-extending property of Klf1(K74R) mice could be transferred to wild-type mice via transplantation of their bone marrow mononuclear cells at young age of the latter. Furthermore, NK(K74R) cells carry higher in vitro cancer cell-killing ability than wild type NK cells. Targeted/global gene expression profiling analysis has identified changes of the expression of specific proteins, including the immune checkpoint factors PDCD and CD274, and cellular pathways in the leukocytes of the Klf1(K74R) that are in the directions of anti-cancer and/or anti-aging. This study demonstrates the feasibility of developing a transferable hematopoietic/ blood system for long-term anti-cancer and, potentially, for anti-aging.

cancer biology↗

bioRxiv2022

Genome-wide association study of brain biochemical phenotypes reveals distinct genetic architecture of Alzheimer's Disease related proteins

Alzheimers disease (AD) is neuropathologically characterized by amyloid-beta (A{beta}) plaques and neurofibrillary tangles. Main protein components of these hallmarks include A{beta}40, A{beta}42, tau, phospho-tau and APOE. With the exception of the APOE-{varepsilon}4 variant, genetic risk factors associated with brain biochemical measures of these proteins have yet to be characterized. We performed a genome-wide association study in brains of 441 AD patients for quantitative levels of these proteins collected from three distinct fractions reflecting soluble, membrane-bound and insoluble biochemical states. We identified 123 genome-wide significant associations at seven novel loci and the APOE locus. Genes and variants at these loci also associate with multiple AD- related measures, regulate gene expression, have cell-type specific enrichment, and roles in brain health and other neuropsychiatric diseases. Pathway analysis identified significant enrichment of shared and distinct biological pathways. Although all biochemical measures tested reflect proteins core to AD pathology, our results strongly suggest that each have unique genetic architecture and biological pathways that influence their specific biochemical states in the brain. Our novel approach of deep brain biochemical endophenotype GWAS has implications for pathophysiology of proteostasis in AD that can guide therapeutic discovery efforts focused on these proteins.

genetics↗

bioRxiv2021

TREM2 interacts with TDP-43 and mediates microglial neuroprotection against TDP-43-related neurodegeneration

Triggering receptor expressed on myeloid cell 2 (TREM2) is a surface receptor that, in the central nervous system, is exclusively expressed on microglia. TREM2 variants have been linked to increased risk for neurodegenerative diseases, but the functional effects of microglial TREM2 remain largely unknown. To this end, we investigated TAR-DNA binding protein 43 kDa (TDP-43)-related neurodegenerative disease via viral-mediated expression of human TDP-43 protein (hTDP-43) in neonatal and adult mice or inducible expression of hTDP43 with defective nuclear localization signals in transgenic mice. We found that TREM2 deficiency impaired microglia phagocytic clearance of pathological TDP-43, and enhanced neuronal damage and motor function impairments. Mass cytometry analysis revealed that hTDP-43 induced a TREM2-dependent subpopulation of microglia with high CD11c expression and higher phagocytic ability. Using mass spectrometry and surface plasmon resonance analysis, we further demonstrated an interaction between TDP-43 and TREM2, in vitro and in vivo, in hTDP-43-expressing transgenic mouse brains. We computationally identified the region within hTDP-43 that interacts with TREM2 and observed the potential interaction in ALS patient tissues. Our data reveal the novel interaction between TREM2 and TDP-43, highlighting that TDP-43 is a possible ligand for microglial TREM2 and the interaction mediates neuroprotection of microglial TREM2 in TDP-43-related neurodegeneration.

neuroscience↗

bioRxiv2020

Dihydroceramide desaturase regulates the compartmentalization of Rac1 for neuronal oxidative stress

Disruption of sphingolipid homeostasis has been shown to cause neurological disorders. How specific sphingolipid species modulate the pathogenesis remains unknown. The last step of sphingolipid de novo synthesis is the conversion of dihydroceramide to ceramide catalyzed by dihydroceramide desaturase (human DEGS1; Drosophila Ifc). Loss of ifc leads to dihydroceramide accumulation and oxidative stress, resulting in photoreceptors degeneration, while DEGS1 variants were associated with leukodystrophy and neuropathy. Here, we demonstrated that ifc regulates Rac1 compartmentalization in fly photoreceptors and further showed that dihydroceramide alters the association of active Rac1 to membranes mimicking specific organelles. We also revealed that the major source of ROS originated from Rac1 and NADPH oxidase (NOX) in the cytoplasm, as the NOX inhibitor apocynin ameliorated the oxidative stress and functional defects in both fly ifc-KO photoreceptors and human neuronal cells with disease-associated variant DEGS1H132R. Therefore, DEGS1/ifc deficiency causes dihydroceramide accumulation, resulting in Rac1 translocation and NOX-dependent neurodegeneration. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=101 HEIGHT=200 SRC="FIGDIR/small/128579v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@174c3b0org.highwire.dtl.DTLVardef@db65e5org.highwire.dtl.DTLVardef@1fea501org.highwire.dtl.DTLVardef@10318f7_HPS_FORMAT_FIGEXP M_FIG A DEGS1/ifc converts dihydroceramide to ceramide in neuronal cells, and the endolysosomal NOX complex is not activated. B Dihydroceramide accumulates without functional DEGS1/ifc and causes alterations in membrane microdomains and recruits active Rac1 to endolysosomes. The activation of endolysosomal Rac1-NOX complex elevates cytosolic ROS levels, causing neurodegeneration. C_FIG In Brief (eTOC blurb)Deficiency in dihydroceramide desaturase causes oxidative stress-mediated neurological disorders. Tzou and Su et al. show that increased dihydroceramide causes the relocalization of active Rac1, whilst inhibition of the Rac1-NOX ameliorates the oxidative stress and neuronal defects. NOX inhibitor apocynin may provide new direction of treatments for patients with DEGS1 variants. HighlightsO_LIDeficiency in dihydroceramide (dhCer) desaturase induces cytoplasmic ROS elevation C_LIO_LIdhCer alters the binding of active Rac1 to reconstituted organelle membranes C_LIO_LIActive Rac1 is enriched in endolysosomes in ifc-KO neurons for ROS genesis C_LIO_LIRac1-NADPH oxidase elicits ROS, degenerating leukodystrophy-related neuronal cells C_LI

neuroscience↗

bioRxiv2020

Unmasking Anxiety in Autism: Explicit and Implicit Threatening Face Stimuli Dissociate Amygdala-centered Functional Connectivity

BackgroundAnxiety is the most prevalent comorbidity in individuals diagnosed with autism spectrum disorder (ASD). Amygdala reactivity to explicit and implicit threat processing is predictive of anxiety-related symptomatology. The neural mechanisms underlying the link between anxiety and ASD remains elusive. MethodsIn this fMRI study, we recruited young adults with ASD (N = 31) and matched them with controls, then proceeded to assess their autistic and anxiety traits by the use of the Autism-Spectrum Quotient (AQ) and the State-Trait Anxiety Inventory (STAI-S), respectively; and scanned their hemodynamic responses, including amygdala, in response to explicit and implicit (backwardly masked) perception of threatening faces. ResultsAs compared to controls, the amygdala reactivity in ASD subjects was significantly lower to explicit threat, but comparable for implicit threat. The correlations of the amygdala reactivity with the AQ and STAI-S were dissociated depending on threat processing (explicit or implicit). Furthermore, the amygdala in ASD relative to controls had a more negative functional connectivity with the superior parietal cortex, fusiform gyrus, and hippocampus for explicit threat, whereas a more positive connectivity with the medial prefrontal cortex, temporal pole, and hippocampus for implicit threat. ConclusionIn ASD, the transmission of socially relevant information along dorsal and ventral neural pathways centered on the amygdala is dissociated depending on explicit and implicit threat processing. This dissociation, ascribed to their failure to compromise pre-existing hyperarousal, might contribute to anxiety in ASD.

neuroscience↗

bioRxiv2019

Dissecting molecular regulatory mechanisms underlying noncoding susceptibility SNPs associated with 19 autoimmune diseases using multi-omics integrative analysis

The genome-wide association studies (GWAS) have identified hundreds of susceptibility loci associated with autoimmune diseases. However, over 90% of risk variants are located in the noncoding regions, leading to great challenges in deciphering the underlying causal functional variants/genes and biological mechanisms. Previous studies focused on developing new scoring method to prioritize functional/disease-relevant variants. However, they principally incorporated annotation data across all cells/tissues while omitted the cell-specific or context-specific regulation. Moreover, limited analyses were performed to dissect the detailed molecular regulatory circuits linking functional GWAS variants to disease etiology. Here we devised a new analysis frame that incorporate hundreds of immune cell-specific multi-omics data to prioritize functional noncoding susceptibility SNPs with gene targets and further dissect their downstream molecular mechanisms and clinical applications for 19 autoimmune diseases. Most prioritized SNPs have genetic associations with transcription factors (TFs) binding, histone modification or chromatin accessibility, indicating their allelic regulatory roles on target genes. Their target genes were significantly enriched in immunologically related pathways and other immunologically related functions. We also detected long-range regulation on 90.7% of target genes including 132 ones exclusively regulated by distal SNPs (eg, CD28, IL2RA), which involves several potential key TFs (eg, CTCF), suggesting the important roles of long-range chromatin interaction in autoimmune diseases. Moreover, we identified hundreds of known or predicted druggable genes, and predicted some new potential drug targets for several autoimmune diseases, including two genes (NFKB1, SH2B3) with known drug indications on other diseases, highlighting their potential drug repurposing opportunities. In summary, our analyses may provide unique resource for future functional follow-up and drug application on autoimmune diseases, which are freely available at http://fngwas.online/. Author SummaryAutoimmune diseases are groups of complex immune system disorders with high prevalence rates and high heritabilities. Previous studies have unraveled thousands of SNPs associated with different autoimmune diseases. However, it remains largely unknown on the molecular mechanisms underlying these genetic associations. Striking, over 90% of risk SNPs are located in the noncoding region. By leveraging multiple immune cell-specific multi-omics data across genomic, epigenetic, transcriptomic and 3D chromatin interaction information, we systematically analyzed the functional variants/genes and biological mechanisms underlying genetic association on 19 autoimmune diseases. We found that most functional SNPs may affect target gene expression through altering transcription factors (TFs) binding, histone modification or chromatin accessibility. Most target genes had known immunological functions. We detected prevailing long-range chromatin interaction linking distal functional SNPs to target genes. We also identified many known drug targets and predicted some new drug target genes for several autoimmune diseases, suggesting their potential clinical applications. All analysis results and tools are available online, which may provide unique resource for future functional follow-up and drug application. Our study may help reduce the gap between traditional genetic findings and biological mechanistically exploration of disease etiologies as well as clinical drug development.

immunology↗

bioRxiv2019

Treatment with β3 adrenergic agonists reverses impaired cardiac myocyte Na+ export and improves severely decompensated heart failure; a clinical application of an experimental finding

BackgroundReported one- and two-year mortality for patients with advanced heart failure (HF) treated medically are ~75% and nearly 100%. In such patients, reversible cellular abnormalities are potential treatment targets and a raised cytosolic Na+ concentration that impairs their myocardial contractility is one potential target. {beta}3 adrenoceptor ({beta}3 AR) agonists stimulate the myocyte Na+-K+ pump. MethodsWe induced severe HF in rabbits by coronary ligation and measured indices of organ congestion after treatment with {beta}3 AR agonists. Na+-K+ pump current was measured in voltage-clamped myocytes isolated from non-infarct myocardium. To assess if {beta}3 ARs might add benefit to optimised guideline-directed medical treatment we report outcomes of giving the {beta}3 AR agonist mirabegron to patients hospitalized with advanced, treatment-refractory stage D HF. ResultsTreatment of rabbits after coronary ligation with {beta}3 AR agonist reversed a decreased myocyte Na+-K+ pump current and significantly reduced organ congestion and prevalence of ascites. Oral treatment with mirabegron rapidly improved signs and symptoms of 9 patients with advanced HF and improvement of [≥]1 NYHA Class was maintained early post-discharge with continued treatment. One patient died from HF at 16 months, 4 died from other causes at 2 - 30 months and 4 remain alive at 38 {+/-} 4 months with NYHA Class II symptoms. ConclusionsParallel {beta}3 AR agonist-induced reversal of Na+-K+ pump inhibition and severe HF in rabbits identify pump inhibition as a treatment target, and changed in-hospital clinical trajectory and post-discharge course more favorable than expected suggest efficacy of mirabegron in advanced human HF.

physiology↗