Biology subjects

li, r.

Publications and source records attributed to li, r..

4 recordsLinked to original sources

bioRxiv2022

IDOL deficiency inhibits cholesterol-rich diet-induced atherosclerosis in rabbits

BACKGROUNDThe E3 ubiquitin ligase IDOL (Inducible Degrader of the LDL-Receptor) contributes to regulation of cholesterol metabolism through degradation of LDLR, VLDLR and ApoER2. Human genetic studies support the hypothesis that IDOL could serve as a target for the treatment of dyslipidemia. However, species-specific differences in overall lipid metabolism and IDOL regulation require new preclinical models to realize its therapeutic potential. We leveraged the advantages afforded by the rabbit model to address those limitations and generated a novel rabbit IDOL knockout, which we characterized in the context of atherosclerosis. METHODSIDOL-/- rabbits were generated by CRISPR/Cas9 technology. IDOL-/- and wildtype littermates, on standard (SD) and atherogenic high-cholesterol diets (HCDs) were compared through assessment of lipid and lipoprotein profiles, triglyceride clearance, lipoprotein lipase (LPL) activity, liver pathology, atherosclerosis development, and fecal cholesterol, with bile acid contents assessed by mass spectrometry. ResultsHepatic IDOL expression was increased in response to hypercholesterolemia and hypertriglyceridemia induced by HCD. On SD, loss of IDOL increased LDLR stability with reduced total cholesterol in plasma. On HCD, IDOL-/- rabbits showed simultaneous and remarkable reduction in hypercholesterolemia and hypertriglyceridemia associated with enhanced lipid clearance and LPL activity as well as increased bile acid excretion in feces. IDOL-/- rabbits presented markedly reduced HCD-induced atherosclerosis in the aorta and left coronary artery, without enhanced liver steatosis. CONCLUSIONSLoss of IDOL in rabbits recapitulates human genetic findings, thus setting the stage to accelerate preclinical studies towards development of strategies targeting IDOL for the treatment of atherosclerotic cardiovascular disease.

physiology↗

bioRxiv2019

Compensatory replacement of the BigH1 variant histone by canonical H1 supports normal embryonic development in Drosophila

Histone variants carry specific functions in addition to those fulfilled by their canonical counterparts. Variants of the linker Histone H1 are prevalent in vertebrates and based on the pattern of their expression, many are presumed to function during germline and the earliest zygotic stages of development. While the existence of multiple H1 variants has hampered their study in vertebrates, a single variant, BigH1, was identified in Drosophila, promising to accelerate our understanding of the biological functions of H1 and H1 variants. Here we uncovered evidence for a compensatory activity that loads maternal H1 onto BigH1-devoid chromatin. Remarkably, this H1-based chromatin state is fully functional in supporting normal embryonic development, suggesting that H1 carries the essential function of the BigH1 molecule under the same developmental context. In addition, we discovered that this compensatory replacement of BigH1 with H1 might be limited to rapidly cycling cells in early embryos.

developmental biology↗

bioRxiv2019

Group Similarity Constraint Functional Brain Network Estimation for Mild Congititive Impairment Classification

Functional brain network (FBN) provides an effective biomarker for understanding brain activation patterns, which also improve the diagnostic criteria for neurodegenerative diseases or the information transmission of brain. Unfortunately, despite its efficiency, FBN still suffers several challenges for accurately estimate the biological meaningful or discriminative FBNs, under the poor quality of functional magnetic resonance imaging (fMRI) data as well as the limited understanding of human brain. Hence, there still a motivation to alleviate those issues above, it is currently still an open field to discover. In this paper, a novel FBN estimation model based on group similarity constraints is proposed. In particular, we extend the FBN estimation model to the tensor form and incorporate the trace-norm regularizer for formulating the group similarity constraint. In order to verify the proposed method, we conduct experiments on identifying Mild Cognitive Impairments (MCIs) from normal controls (NCs) based on the estimated FBNs. The experimental results illustrated that the proposed method can construct a more discriminative brain network. Consequently, we achieved an 91.97% classification accuracy which outperforms the baseline methods. The post hoc analysis further shown more biologically meaningful functional brain connections obtained by our proposed method.

bioinformatics↗

bioRxiv2019

Hypertriglyceridemia and obesity exacerbate the course of SIRS induced by SAP in Rats

The aim of the present study was to explore the mechanism underlying how HTG (hypertriglyceridaemia) and obesity exacerbate the course of the systemic inflammatory response syndrome (SIRS) induced by severe acute pancreatitis (SAP) in rats. Seventy-two rats were fed a normal or high-fat diet to induce HTG and obesity, and SAP was induced by retrograde injection of 5% sodium taurocholate solution at a volume of 1 ml/kg into the biliopancreatic duct. The injury to the pancreas was assessed by macroscopic observation, pancreatic histological evaluation and serum levels of amylase and lipase. SIRS was estimated by measuring SIRS scores and interleukin-6 (IL-6), tumour necrosis factor alpha (TNF-) and interleukin-10 (IL-10) expression. The results showed that the SIRS scores and pancreatic histological scores increased significantly and the blood calcium level decreased significantly in the hypertriglyceridaemia SAP (HSAP) group compared with those of the SAP group. In addition, HTG and obesity significantly increased plasma levels of the proinflammatory cytokines IL-6 and TNF- and significantly downregulated the proinflammatory cytokine IL-10. Our findings showed that HSAP rats exhibited more severe pancreatic injury and more serious SIRS scores than the SAP rats did. The underlying mechanism may be that HTG and obesity intensify early-stage SIRS by regulating the levels of inflammatory and anti-inflammatory cytokines.

pathology↗