Biology subjects

Zhao, X.

Publications and source records attributed to Zhao, X..

At least 271 records · Page 15Linked to original sources

bioRxiv2023

NeoHeadHunter: an algorithm for the detection, ranking and probabilistic classification of neoepitope candidates

BackgroundThe manufacturing of personalized cancer vaccine requires the accurate identification of neoepitopes, abnormal peptides presented by cancer cells and recognized by the host immune system of the cancer patient. ResultsWe designed and developed NeoHeadHunter, a computational algorithm and pipeline to detect and rank neoepitope candidates. Unlike other algorithms, NeoHeadHunter can estimate the probability that each predicted neoepitope candidate is true positive. To evaluate NeoHeadHunter, we used the Tumor neoantigEn SeLection Alliance (TESLA) data-set derived from the sequencing of nine patients and characterized by 44 experimentally validated positive neoepitopes, a data-set derived from the sequencing of three cancer patients and characterized by eight experimentally validated positive neoepitopes and a manually curated data-set consisting of 64 experimentally validated positive neoepitopes. Our evaluation shows that NeoHeadHunter performs the best compared with other algorithms for both detecting and ranking neoepitope candidates and that NeoHeadHunter can accurately predict such probabilities. ConclusionsNeoHeadHunter can increase the effectiveness of personalized cancer vaccine by sensitively detect, accurately rank and probabilistically classify neoepitope candidates. NeoHeadHunter is released under the APACHE-II license at https://github.com/XuegongLab/neoheadhunter for academic use.

bioinformatics↗

bioRxiv2023

Molecular mechanism of NAD+ binding to the Nudix homology domains of DBC1

DBC1 (deleted in breast cancer 1) is a human nuclear protein that modulates the activities of various proteins. NAD+ (oxidized form of nicotinamide adenine dinucleotide) is thought to potentially bind to the Nudix homology domains (NHDs) of DBC1, thereby regulating DBC1-PARP1 [poly (adenosine diphosphate-ribose) polymerase] interactions, the modulation of which may restore DNA repair to protect against cancer, radiation, and aging. Therefore, our study comprehensively employed methods including NMR (Nuclear Magnetic Resonance), ITC (isothermal titration calorimetry), genetic mutation, and computer biology to thoroughly investigate the molecular mechanism of the binding interaction between NAD+ and its precursor NMN with the NHD domain of DBC1 (DBC1354-396). The results from NMR and ITC indicate that NAD+ likely interacts with DBC1354-396 through hydrogen bonding, with a binding affinity nearly twice that of NMN. The key binding sites are primarily E363 and D372. Molecular Docking further revealed the importance of conventional hydrogen bonds and carbon-hydrogen bonds in the binding process. These findings may lead to a better understanding of how NAD+ regulates the physiological functions of DBC1, thereby offering guiding principles for the development of targeted therapies and drug research focused on tumor diseases associated with DBC1.

biochemistry↗

bioRxiv2023

Functional specialization of cytochrome b5 prior to the invention of syringyl lignin biosynthesis

The production of lignin represents a hallmark of vascular plant evolution. But syringyl-lignin production is lineage specific. Its emergence in angiosperms has been regarded as a recent evolution event, as is the appearance of syringyl monomer biosynthetic F5H (CYP84A1). Angiosperm F5H uniquely requires cytochrome b5 protein CB5D as an obligatory redox partner. However, it remains unclear how CB5D functionally evolved and specialized and whether it co-evolved with F5H. Here we show that plant CB5 family expanded and functionally specialized at the early stage of plant terrestrialization. CB5D was absent in green algae but emerged in bryophytes and conserved in most embryophytes, particularly proliferating in angiosperms. The innovation of CB5D is attributed to the evolution and maintenance of acidic amino residues in the helix 5 of CB5 protein. Interestingly, the syringyl-lignin producing lycophyte Selaginella lacks the functionally specialized CB5D. The Selaginella F5H (CYP788A1) solely relies on cytochrome P450 reductase as a redox partner. These results suggest that CB5 functionally diversified and specialized prior to the divergence of land plant lineages but lost in Selaginella; and the recently evolved angiosperm F5H has co-opted the anciently invented CB5D to form a modern cytochrome P450 monooxygenase system enabling the re-emergence of syringyl-lignin biosynthesis in higher plants. One Sentence SummaryCytochrome b5 D, an indispensable electron donor for F5H-catalyzed S-lignin biosynthesis, was invented prior to the divergence of land plant lineages, earlier than the emergence of vascular plant F5Hs.

plant biology↗

bioRxiv2023

Establishing an AI-based evaluation system that quantifies social/pathophysiological behaviors of common marmosets

Nonhuman primates (NHPs) are indispensable animal models by virtue of the continuity of behavioral repertoires across primates, including humans. However, behavioral assessment at the laboratory level has so far been limited. By applying multiple deep neural networks trained with large-scale datasets, we established an evaluation system that could reconstruct and estimate three-dimensional (3D) poses of common marmosets, a small NHP that is suitable for analyzing complex natural behaviors in laboratory setups. We further developed downstream analytic methodologies to quantify a variety of behavioral parameters beyond simple motion kinematics, such as social interactions and the internal state behind actions, obtained solely from 3D pose data. Moreover, a fully unsupervised approach enabled us to detect progressively-appearing symptomatic behaviors over a year in a Parkinsons disease model. The high-throughput and versatile nature of our analytic pipeline will open a new avenue for neuroscience research dealing with big-data analyses of social/pathophysiological behaviors in NHPs.

neuroscience↗

bioRxiv2023

Mechanisms of the FTO locus association with obesity: Irx3 controls a sumoylation-dependent switch between adipogenesis and osteogenesis

BackgroundIRX3 is implicated in genetic predisposition to obesity via the FTO variant locus. IRX3 shows FTO risk allele-dependent upregulation specifically during early adipogenesis, leading to a shift from energy-dissipation to fat storage in mature adipocytes. However, how changes in IRX3 expression at one developmental stage affect cellular phenotype at a later stage remains unclear. We here hypothesize that IRX3 regulates adipocyte development via transcriptional modulation of epigenetic reprogramming factors. MethodsWe combined ChIP-, ATAC- and RNA-sequencing to map direct Irx3 target genes in regions of open chromatin during early adipogenesis of wild-type and Irx3-KO preadipocytes. Gene ontology analyses was performed to identify significantly enriched biological pathways. Denaturing western blotting was used to assess sumoylation levels, and the inhibitor ML-792 was used to specifically block sumoylation. Luciferase assays were performed to estimate effects of ML-792 on Ppar{gamma} activity. Bodipy lipid staining, immunofluorescence and qPCR were employed to assess adipogenic differentiation in 3D culture. Alkaline phosphatase and Alizarine Red S staining, as well as immunofluorescence and qPCR were used to assess osteogenic differentiation in 3D culture. ResultsWe identified more than 300 Irx3 binding sites in preadipocytes, and these were almost exclusively restricted to promoter regions, with a strong enrichment of genes related to sumoylation, histone modifications and chromatin remodeling. Genes from every step of the sumoylation cycle were bound by Irx3 and differentially expressed in response to Irx3-KO, leading to increased global sumoylation levels in the KO cells. Irx3 ablation and elevated sumoylation inhibited Ppar{gamma} activity and adipogenic differentiation in preadipocytes, both of which could be restored by pharmacological inhibition of sumoylation. The Irx3-KO cells demonstrated reduced epigenetic suppression against osteogenesis, resulting in increased osteogenesis in 3D culture. Finally, osteogenesis induced by Irx3 ablation could partially be reversed by inhibition of sumoylation. ConclusionsOur study has uncovered IRX3 as a novel upstream regulator of sumoylation, and a potent controller of epigenetic regulators, both directly and indirectly via suppressing global sumoylation levels. This study indicates that the FTO locus promotes obesity via IRX3-mediated suppression of sumoylation, which promotes adipogenic commitment and differentiation through epigenetic programming. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=61 SRC="FIGDIR/small/562662v1_figu1.gif" ALT="Figure 1"> View larger version (16K): org.highwire.dtl.DTLVardef@115feaborg.highwire.dtl.DTLVardef@102a6c0org.highwire.dtl.DTLVardef@111bd1corg.highwire.dtl.DTLVardef@1969061_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2023

Nitric Oxide controls shoot meristem activity via regulation of DNA methylation

Despite the importance of Nitric Oxide (NO) as signaling molecule in both plant and animal development1-7, the regulatory mechanisms downstream of NO remain largely unclear. Here, we show that NO is involved in Arabidopsis shoot stem cell control via modifying expression and activity of ARGONAUTE 4 (AGO4), a core component of the RNA directed DNA Methylation (RdDM) pathway. Mutations in components of the RdDM pathway cause meristematic defects, and reduce responses of the stem cell system to NO signaling. Importantly, we found that the stem cell inducing WUSCHEL transcription factor directly interacts with AGO4 in an NO dependent manner, explaining how these two signaling systems may converge to modify DNA methylation patterns. Taken together, our results reveal that NO signaling plays an important role in controlling plant stem cell homeostasis via the regulation of de novo DNA methylation.

plant biology↗

bioRxiv2023

mTORC1/S6K1 signaling promotes sustained oncogenic translation through modulating CRL3IBTK-mediated non-degradative ubiquitination of eIF4A1

Enhanced protein synthesis is a crucial molecular mechanism that allows cancer cells to survive, proliferate, metastasize, and develop resistance to anti-cancer treatments, and often arises as a consequence of increased signaling flux channeled to mRNA-bearing eukaryotic initiation factor 4F (eIF4F). However, the post-translational regulation of eIF4A1, an ATP-dependent RNA helicase and subunit of the eIF4F complex, is still poorly understood. Here, we demonstrate that IBTK, a substrate-binding adaptor of Cullin 3-RING ubiquitin ligase (CRL3) complex, interacts with eIF4A1. The non-degradative ubiquitination of eIF4A1 catalyzed by CRL3IBTK complex promotes cap-dependent translational initiation, nascent protein synthesis, oncogene expression, and tumor cell growth both in vivo and in vitro. Moreover, we show that mTORC1 and S6K1, two key regulators of protein synthesis, directly phosphorylate IBTK to augment eIF4A1 ubiquitination and sustained oncogenic translation. This link between the CRL3IBTK complex and the mTORC1/S6K1 signaling pathway, which is frequently dysregulated in cancer, represents a promising target for anti-cancer therapies. Statement of Significance: Overexpression of IBTK contributes to the process of tumorigenesis by amplifying translation, and represents a promising target for anti-cancer therapies.

cancer biology↗

bioRxiv2023

A flexible, modular and versatile functional part assembly toolkit for gene cluster engineering in Streptomyces

Streptomyces has enormous potential to produce novel natural products (NPs) as it harbors a huge reservoir of uncharacterized and silent natural product biosynthetic gene clusters (BGCs). However, the lack of efficient gene cluster engineering strategies has hampered the pace of new drug discovery. Here, we developed an easy-to-use, highly flexible DNA assembly toolkit for gene cluster engineering. The DNA assembly toolkit are compatible with various DNA assembling approaches including Biobrick, Golden Gate, CATCH, yeast homologous recombination-based DNA assembly and homing endonuclease-mediated assembly. This compatibility offers great flexibility in handling multiple genetic parts or refactoring large gene clusters. To demonstrate the utility of this toolkit, we quantified a library of modular regulatory parts, and engineered a gene cluster (act) using characterized promoters that led to increased production. Overall, this work provides a powerful part assembly toolkit that can be used for natural product discovery and optimization in Streptomyces.

synthetic biology↗

bioRxiv2023

Enhanced neutralization of SARS-CoV-2 XBB sub-lineages and BA.2.86 by a tetravalent COVID-19 vaccine booster

As the SARS-CoV-2 virus continues to evolve, novel XBB sub-lineages such as XBB.1.5, XBB.1.16, EG.5, HK.3 (FLip), and XBB.2.3, as well as the most recent BA.2.86, have been identified and aroused global concern. Understanding the efficacy of current vaccines and the immune systems response to these emerging variants is critical for global public health. In this study, we evaluated the neutralization activities of sera from participants who received COVID-19 inactivated vaccines, or a booster vaccination of the recently approved tetravalent protein vaccine in China (SCTV01E), or had contracted a breakthrough infection with BA.5/BF.7/XBB virus. Comparative analysis of their neutralization profiles against a broad panel of 30 SARS-CoV-2 sub-lineage viruses revealed that strains such as BQ.1.1, CH.1.1, and all the XBB sub-lineages exhibited heightened resistance to neutralization than previous variants, however, despite the extra mutations carried by emerging XBB sub-lineages and BA.2.86, they did not demonstrate significantly increased resistance to neutralization compared to XBB.1.5. Encouragingly, the SCTV01E booster vaccination consistently induced robust and considerably higher neutralizing titers against all these variants than breakthrough infection did. Cellular immunity assays also showed that the SCTV01E booster vaccination elicited a higher frequency of virus-specific memory B cells but not IFN-{gamma} secreting T cells. Our findings underline the importance of developing novel multivalent vaccines to more effectively combat future viral variants.

immunology↗

bioRxiv2023

KaryoTap Enables Aneuploidy Detection in Thousands of Single Human Cells

Aneuploidy--the presence of chromosome gains and losses--is highly prevalent in human tumors, yet the contribution of chromosome missegregation rates and selection to shape these patterns remains poorly understood. To address this challenge at scale, we developed KaryoTap, a cost-effective single-cell DNA sequencing method combining custom targeted panels for the Tapestri platform with a Bayesian gaussian mixture model to detect chromosome- and chromosome arm-scale aneuploidy as well as integrated gRNAs and barcodes. KaryoTap achieves an average accuracy of >85% for arm events and >90% for chromosome events at <$1 per cell, allowing scalable analysis of tens of thousands of cells per experiment. Through KaryoTap-based analysis of 11,555 cells, we performed in vitro evolution screens on immortalized human cells from mammary gland, pancreas and melanocytes. By comparing aneuploidy frequencies immediately after reversine-induced missegregation versus after extended proliferation, we quantified positive and negative selection for specific aneuploidies. Most aneuploidies--both gains and losses--are under negative selection, yet some chromosomal gains are under positive selection (such as 8q and 7q). We found that proliferative selective pressures can explain tissue-specific patterns of chromosomal gains observed in human cancers. Critically, when positively selected events were excluded from analysis, correlations between in vitro and cancer gain frequencies strongly decreased or disappeared, whereas excluding negatively selected events largely preserved these correlations. These findings demonstrate that proliferative selection shapes the landscape of chromosomal gains in cancer, with a more prominent role for positive selection.

genomics↗

bioRxiv2023

Hippo-deficient cardiac fibroblasts differentiate into osteochondroprogenitors

Cardiac fibrosis, a common pathophysiology associated with various heart diseases, occurs from the excess deposition of extracellular matrix (ECM)1. Cardiac fibroblasts (CFs) are the primary cells that produce, degrade, and remodel ECM during homeostasis and tissue repair2. Upon injury, CFs gain plasticity to differentiate into myofibroblasts3 and adipocyte-like4,5 and osteoblast-like6 cells, promoting fibrosis and impairing heart function7. How CFs maintain their cell state during homeostasis and adapt plasticity upon injury are not well defined. Recent studies have shown that Hippo signalling in CFs regulates cardiac fibrosis and inflammation8-11. Here, we used single-nucleus RNA sequencing (snRNA-seq) and spatially resolved transcriptomic profiling (ST) to investigate how the cell state was altered in the absence of Hippo signaling and how Hippo-deficient CFs interact with macrophages during cardiac fibrosis. We found that Hippo-deficient CFs differentiate into osteochondroprogenitors (OCPs), suggesting that Hippo restricts CF plasticity. Furthermore, Hippo-deficient CFs colocalized with macrophages, suggesting their intercellular communications. Indeed, we identified several ligand-receptor pairs between the Hippo-deficient CFs and macrophages. Blocking the Hippo-deficient CF-induced CSF1 signaling abolished macrophage expansion. Interestingly, blocking macrophage expansion also reduced OCP differentiation of Hippo-deficient CFs, indicating that macrophages promote CF plasticity.

developmental biology↗

bioRxiv2023

Dietary Pyruvate Targets Cytosolic Phospholipase A2 to Mitigate Inflammation and Obesity in Mice

Obesity has a multifactorial etiology and is known to be a state of chronic low-grade inflammation, known as meta-inflammation. This state is associated with the development of metabolic disorders such as glucose intolerance and nonalcoholic fatty liver disease. Pyruvate is a glycolytic metabolite and a crucial node in various metabolic pathways. However, its role and molecular mechanism in obesity and associated complications are obscure. In this study, we reported that pyruvate substantially inhibited adipogenic differentiation in vitro and its administration significantly prevented HFD-induced weight gain, white adipose tissue inflammation, and metabolic dysregulation. To identify the target proteins of pyruvate, drug affinity responsive target stability was employed with proteomics, cellular thermal shift assay, and isothermal drug response to detect the interactions between pyruvate and its molecular targets. Consequently, we identified cytosolic phospholipase A2 (cPLA2) as a novel molecular target of pyruvate and demonstrated that pyruvate restrained diet-induced obesity, white adipose tissue inflammation, and hepatic steatosis in a cPLA2-dependent manner. Studies with global ablation of cPLA2 in mice showed that the protective effects of pyruvate were largely abrogated, confirming the importance of pyruvate/cPLA2 interaction in pyruvate attenuation of inflammation and obesity. Overall, our study not only establishes pyruvate as an antagonist of cPLA2 signaling and a potential therapeutic option for obesity, but it also sheds light on the mechanism of its action. Pyruvates prior clinical use indicates that it can be considered a safe and viable alternative for obesity, whether consumed as a dietary supplement or as part of a regular diet.

cell biology↗

bioRxiv2023

HIF-1α-mediated mitochondrial-glycolytic reprogramming controls the transition of precursor to terminally exhausted T cells

Functional exhaustion of T cells in cancer and persistent infections is characterized by the upregulation of inhibitory receptors, the progressive decline in cytokine secretion and impaired cytolytic activity. Terminally exhausted T cells are steadily replenished by a precursor population (Tpex) with phenotypic features of memory T cells and a stem-like capacity to self-renew. However, the metabolic principles of Tpex maintenance and the regulatory circuits that control the exhaustion of their progeny remain incompletely understood. Using a combination of gene-deficient mice, single-cell transcriptomics and metabolomic analyses, we here show that mitochondrial insufficiency is a cell-intrinsic trigger that initiates the T cell exhaustion program. At the molecular level, we found that diminished mitochondrial respiration and metabolic remodeling cause oxidative stress, which inhibits the proteasomal degradation of hypoxia inducible factor 1 alpha (HIF-1) in Tpex cells. HIF-1 mediates the transcriptional-glycolytic reprogramming of Tpex cells as an initial step towards terminal differentiation and functional exhaustion. Finally, we show that enhancing respiration by limiting the glycolytic activity of CAR T cells is a feasible metabolic intervention strategy to preserve the stemness of Tpex cells during chronic viral infection and cancer immunotherapy.

immunology↗

bioRxiv2023

ZC3H11A mutations cause high myopia by triggering PI3K-AKT and NF-κB mediated inflammatory reactions in humans and mice

High myopia (HM) is a severe form of refractive error that results in irreversible visual impairment and even blindness. However, the genetic and pathological mechanisms underlying this condition are not yet fully understood. From a cohort of 1015 patients with high myopia in adolescents, likely pathogenic missense mutations were identified in the ZC3H11A gene in four patients by whole exome sequencing. This gene is a zinc finger and stress-induced protein that plays a significant role in regulating nuclear mRNA export. To better understand the function and molecular pathogenesis of myopia in relation to gene mutations, a Zc3h11a knock-out (KO) mouse model was created. The heterozygous KO (Het-KO) mice exhibited significant shifts in refraction towards myopia. Myopia-related factors, including TGF-{beta}1, MMP-2 and IL-6 were found to be upregulated in the retina or sclera, and electroretinography and immunofluorescence staining results showed dysfunction and reduced number of bipolar cells in the retina. Transmission electron microscopy findings suggesting ultrastructural abnormalities of the retina and sclera. Retinal transcriptome sequencing showed that 769 genes were differentially expressed, and Zc3h11a was found to have a negative impact on the PI3K-AKT and NF-{kappa}B signaling pathways by quantitative PCR and western blotting. In summary, this study characterized a new candidate pathogenic gene associated with high myopia, and indicated that the ZC3H11A protein may serve as a stress-induced nuclear response trigger, and its abnormality causes disturbances in a series of inflammatory and myopic factors. These findings offer potential therapeutic intervention targets for controlling the development of HM.

genetics↗

bioRxiv2023

Rationally designed multimeric nanovaccines using icosahedral DNA origami for molecularly controlled display of SARS-CoV-2 receptor binding domain

Multivalent antigen display on nanoparticles can enhance the immunogenicity of nanovaccines targeting viral moieties, such as the receptor binding domain (RBD) of SARS-CoV-2. However, particle morphology and size of current nanovaccines are significantly different from those of SARS-CoV-2. Additionally, surface antigen patterns are not controllable to enable the optimization of B cell activation. Herein, we employed an icosahedral DNA origami (ICO) as a display particle for SARS-CoV-2 RBD nanovaccines. The morphology and diameter of the particles were close to those of the virus (91 {+/-} 11 nm). The surface addressability of the DNA origami permitted facile modification of the ICO surface with numerous RBD antigen clusters (ICO-RBD) to form various antigen patterns. Using an in vitro screening system, we demonstrate that the antigen spacing, antigen copies within clusters and cluster number parameters of the surface antigen pattern all impact the ability of the nanovaccines to activate B cells. Importantly, the optimized ICO-RBD nanovaccines evoked stronger and more enduring humoral and T cell immune responses in mouse models compared to soluble RBD antigens. Our vaccines activated similar humoral immunity and slightly stronger cellular immunity compared to mRNA vaccines. These results provide reference principles for the rational design of nanovaccines and exemplify the utility of DNA origami as a display platform for vaccines against infectious disease.

bioengineering↗

bioRxiv2023

Promotion of tumor angiogenesis and growth induced by low-dose antineoplastic agents via bone-marrow-derived cells

More research is needed to solidify the basis for reasonable metronomic chemotherapy regimens due to the inconsistent clinical outcomes from studies on metronomic chemotherapy with antineoplastic agents, along with signs of a nonlinear dose-response relationship at low doses. The present study therefore explored the dose-response relationships of representative antineoplastic agents in low dose ranges and their underlying mechanisms. Cyclophosphamide (CPA) and 5-fluorouracil (5-Fu) were employed to observe the effects of the frequent administration of low-dose antineoplastic agents on tumor growth, tumor angiogenesis, and bone-marrow-derived cell (BMDC) mobilization in mouse models. The effects of antineoplastic agents on tumor and endothelial cell functions with or without BMDCs were analyzed in vitro. Tumor growth and metastasis were significantly promoted after the administration of CPA or 5-Fu at certain low dose ranges, and were accompanied by enhanced tumor angiogenesis and proangiogenic factor expression in tumor tissues, increased proangiogenic BMDC release in the circulating blood, and augmented proangiogenic BMDC retention in tumor tissues. Low concentrations of CPA or 5-Fu were found to significantly promote tumor cell migration and invasion, and enhance BMDC adhesion to endothelial cells in vitro. These results suggest that there are risks in empirical metronomic chemotherapy using low-dose antineoplastic agents.

pharmacology and toxicology↗

bioRxiv2023

Percutaneous Intramyocardial Septal Cryoablation: A Canine Model with 6 months Follow-up

BACKGROUNDEchocardiography-guided percutaneous intramyocardial septal radiofrequency ablation (PIMSRA, Liwen procedure) is a novel treatment option for hypertrophic obstructive cardiomyopathy (HOCM). The safety and feasibility of using this procedure for cryoablation are unknown. OBJECTIVETo establish a canine model for echocardiography-guided percutaneous intramyocardial septal cryoablation (PIMSCA). METHODSEight canines underwent PIMSCA and had electrocardiography, echocardiography, myocardial contrast echocardiography (MCE), (ECG), serological and pathological examinations during the preoperative, immediate postoperative, and in 6-month follow-up. RESULTSAll eight canines underwent successful cryoablation and continued to be in sinus rhythm during ablation and without malignant arrhythmias. MCE showed that ablation area had decreased myocardial perfusion after procedure. Troponin I levels were significantly elevated [0.010 (0.005, 0.297) ng/mL vs. 3.122 (1.152,7.990) ng/mL, p < 0.05)]. At follow-up 6-months after procedure, all animals were alive, with thinning of the interventricular septum (7.26 {+/-} 0.52 mm vs. 3.86 {+/-} 0.29 mm, p < 0.05). Echocardiography showed no significant decrease in left ventricular ejection fractions (LVEF) (54.32 {+/-} 2.93 %vs. 54.70 {+/-} 2.47 %, p > 0.05) or changes by pulse-wave Doppler E/A (1.17 {+/-} 0.43 vs. 1.07 {+/-} 0.43, p > 0.05), E/e(8.09 {+/-} 1.49 vs. 10.05 {+/-}2.68, p > 0.05). Pathological findings proved effective cryoablation in myocardial tissues. We observed pericardial effusions and premature ventricular complexes (PVCs) associated with the procedure. CONCLUSIONOur findings provide preliminary evidence of the safety and feasibility of PIMSACA in interventricular septum reduction, which provides a potentially new treatment option for HOCM.

zoology↗

bioRxiv2023

Targeting adipocyte ESRRA promotes osteogenesis and vascular formation in adipocyte-rich bone marrow

Ectopic bone marrow adipocytes (BMAds) accumulation occurring under diverse pathophysiological conditions leads to bone deterioration. Estrogen-related receptor (ESRRA) is a key regulator responding to metabolic stress. Here, we show that adipocyte-specific ESRRA deficiency rescues osteogenesis and vascular formation in adipocyte-rich bone marrow due to estrogen deficiency or obesity. Mechanistically, adipocyte ESRRA interferes with E2/ESR1 signaling resulting in transcriptional repression of secreted phosphoprotein 1 (Spp1); and positively modulates Leptin expression by binding to its promoter. ESRRA abrogation results in enhanced SPP1 and decreased LEPTIN secretion from both visceral adipocytes and BMAds, concertedly dictating bone marrow stromal stem cell fate commitment and restoring type H vessel formation, constituting a feed-forward loop for bone formation. Pharmacological inhibition of ESRRA protects obese mice against bone loss and high marrow adiposity. Thus, our findings highlight a therapeutic approach via targeting adipocyte ESRRA to preserve bone formation especially in detrimental adipocyte-rich bone milieu. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/552932v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1132da3org.highwire.dtl.DTLVardef@19342aorg.highwire.dtl.DTLVardef@afe8d7org.highwire.dtl.DTLVardef@dfb1f9_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗