Genomic structural variation contributes to evolved changes in gene expression in high-altitude Tibetan sheep.

Tibetan sheep were introduced to the Qinghai Tibet plateau roughly 3,000 B.P., making this species a good model for investigating genetic mechanisms of high-altitude adaptation over a relatively short timescale. Here, we characterize genomic structural variants (SVs) that distinguish Tibetan sheep from closely related, low-altitude Hu sheep, and we examine associated changes in tissue-specific gene expression. We document differentiation between the two sheep breeds in frequencies of SVs associated with genes involved in cardiac function and circulation. In Tibetan sheep, we identified high-frequency SVs in a total of 462 genes, including EPAS1, PAPSS2, and PTPRD. Single-cell RNA-Seq data and luciferase reporter assays revealed that the SVs had cis-acting effects on the expression levels of these three genes in specific tissues and cell types. In Tibetan sheep, we identified a high-frequency chromosomal inversion that exhibited modified chromatin architectures relative to the noninverted allele that predominates in Hu sheep. The inversion harbors several genes with altered expression patterns related to heart protection, brown adipocyte proliferation, angiogenesis, and DNA repair. These findings indicate that SVs represent an important source of genetic variation in gene expression and may have contributed to high-altitude adaptation in Tibetan sheep.

A Quantitative and Radiomics approach to monitoring ARDS in COVID-19 patients based on chest CT: a retrospective cohort study.

Rationale: Acute respiratory distress syndrome (ARDS) is one of the major reasons for ventilation and intubation management of COVID-19 patients but there is no noninvasive imaging monitoring protocol for ARDS. In this study, we aimed to develop a noninvasive ARDS monitoring protocol based on traditional quantitative and radiomics approaches from chest CT. Methods: Patients diagnosed with COVID-19 from Jan 20, 2020 to Mar 31, 2020 were enrolled in this study. Quantitative and radiomics data were extracted from automatically segmented regions of interest (ROIs) of infection regions in the lungs. ARDS existence was measured by Pa02/Fi02 <300 in artery blood samples. Three different models were constructed by using the traditional quantitative imaging metrics, radiomics features and their combinations, respectively. Receiver operating characteristic (ROC) curve analysis was used to assess the effectiveness of the models. Decision curve analysis (DCA) was used to test the clinical value of the proposed model. Results: The proposed models were constructed using 352 CT images from 86 patients. The median age was 49, and the male proportion was 61.9%. The training dataset and the validation dataset were generated by randomly sampling the patients with a 2:1 ratio. Chi-squared test showed that there was no significant difference in baseline of the enrolled patients between the training and validation datasets. The areas under the ROC curve (AUCs) of the traditional quantitative model, radiomics model and combined model in the validation dataset was 0.91, 0.91 and 0.94, respectively. Accordingly, the sensitivities were 0.55, 0.82 and 0.58, while the specificities were 0.97, 0.86 and 0.98. The DCA curve showed that when threshold probability for a doctor or patients is within a range of 0 to 0.83, the combined model adds more net benefit than "treat all" or "treat none" strategies, while the traditional quantitative model and radiomics model could add benefit in all threshold probability. Conclusions: It is feasible to monitor ARDS from CT images using radiomics or traditional quantitative analysis in COVID-19. The radiomics model seems to be the most practical one for possible clinical use. Multi-center validation with a larger number of samples is recommended in the future.

Genomic structural variation is associated with hypoxia adaptation in high-altitude zokors.

Zokors, an Asiatic group of subterranean rodents, originated in lowlands and colonized high-elevational zones following the uplift of the Qinghai-Tibet plateau about 3.6 million years ago. Zokors live at high elevation in subterranean burrows and experience hypobaric hypoxia, including both hypoxia (low oxygen concentration) and hypercapnia (elevated partial pressure of CO2). Here we report a genomic analysis of six zokor species (genus Eospalax) with different elevational ranges to identify structural variants (deletions and inversions) that may have contributed to high-elevation adaptation. Based on an assembly of a chromosome-level genome of the high-elevation species, Eospalax baileyi, we identified 18 large inversions that distinguished this species from congeners native to lower elevations. Small-scale structural variants in the introns of EGLN1, HIF1A, HSF1 and SFTPD of E. baileyi were associated with the upregulated expression of those genes. A rearrangement on chromosome 1 was associated with altered chromatin accessibility, leading to modified gene expression profiles of key genes involved in the physiological response to hypoxia. Multigene families that underwent copy-number expansions in E. baileyi were enriched for autophagy, HIF1 signalling and immune response. E. baileyi show a significantly larger lung mass than those of other Eospalax species. These findings highlight the key role of structural variants underlying hypoxia adaptation of high-elevation species in Eospalax.

Pan-cancer Analysis Combined with Experiments Deciphers PHB Regulation for Breast Cancer Cell Survival and Predicts Biomarker Function.

BACKGROUND: Breast carcinoma has become the leading fatal disease among women. The location of prohibitin in the chromosome is close to the breast cancer susceptibility gene 1 (BRCA1). Accumulated research reported that prohibitin could interact with a variety of transcription factors and cell cycle-regulating proteins. OBJECTIVE: This present study aims to comprehensively explore and reveal the biological functions of prohibitin on breast cancer via The Cancer Genome Atlas (TCGA) and validation experiment in vitro. METHODS: Exploring the expression level of prohibitin across 27 tumors based on the TGGA database by bioinformatic methods and its relationship with tumor immune infiltration. Furthermore, we thus analyzed the biological roles of prohibitin on human breast cancer cell line MCF- 7 with pEGFP-prohibitin overexpression plasmid by western blotting and transwell-assay. RESULTS: Firstly, we found prohibitin is overexpressed in most tumors based on The Cancer Genome Atlas database, and the negative relationships between prohibitin and tumors infiltrating lymphocytes including B lymphocyte, CD4 T lymphocyte, CD8 T lymphocyte, Neutrophil, Macrophage and Dendritic, and its significant correlation with the prognosis of human cancer. In vitro, expression not only inhibited cell viability and invasive abilities but also increased the apoptosis percentage of cells with a decreased percentage of the S phase and an increased G2 phase. The reduction of Bcl-2 was observed when prohibitin was upregulated, although the expression of E2F-1 did not change. CONCLUSION: Although prohibitin is over-expressed in various cancer types, it functions as an important tumor suppressor that may suppress breast cancer cell proliferation and the invasive ability of MCF-7 by influencing its DNA synthesis and promoting cell apoptosis. All these may be likely associated with P53, erbB-2, and Bcl-2.

Preoperative Prediction of Microvascular Invasion Risk Grades in Hepatocellular Carcinoma Based on Tumor and Peritumor Dual-Region Radiomics Signatures.

Objective: To predict preoperative microvascular invasion (MVI) risk grade by analyzing the radiomics signatures of tumors and peritumors on enhanced magnetic resonance imaging (MRI) images of hepatocellular carcinoma (HCC). Methods: A total of 501 HCC patients (training cohort n = 402, testing cohort n = 99) who underwent preoperative Gd-EOB-DTPA-enhanced MRI and curative liver resection within a month were studied retrospectively. Radiomics signatures were selected using the least absolute shrinkage and selection operator (Lasso) algorithm. Unimodal radiomics models based on tumors and peritumors (10mm or 20mm) were established using the Logistic algorithm, using plain T1WI, arterial phase (AP), portal venous phase (PVP), and hepatobiliary phase (HBP) images. Multimodal radiomics models based on different regions of interest (ROIs) were established using a combinatorial modeling approach. Moreover, we merged radiomics signatures and clinico-radiological features to build unimodal and multimodal clinical radiomics models. Results: In the testing cohort, the AUC of the dual-region (tumor & peritumor 20 mm)radiomics model and single-region (tumor) radiomics model were 0.741 vs 0.694, 0.733 vs 0.725, 0.667 vs 0.710, and 0.559 vs 0.677, respectively, according to AP, PVP, T1WI, and HBP images. The AUC of the final clinical radiomics model based on tumor and peritumoral 20mm incorporating radiomics features in AP&PVP&T1WI images for predicting MVI classification in the training and testing cohorts were 0.962 and 0.852, respectively. Conclusion: The radiomics signatures of the dual regions for tumor and peritumor on AP and PVP images are of significance to predict MVI.

CaMKIV limits metabolic damage through induction of hepatic autophagy by CREB in obese mice.

High-fat diet (HFD) not only induces insulin resistance in liver, but also causes autophagic imbalance and metabolic disorders, increases chronic inflammatory response and induces mitochondrial dysfunction. Calcium/calmodulin-dependent protein kinase IV (CaMKIV) has recently emerged as an important regulator of glucose metabolism and skeletal muscle insulin action. Its activation has been involved in the improvement of hepatic and adipose insulin action. But the underlying mechanism is not fully understood. In the present study, we aimed to address the direct effects of CaMKIV in vivo and to evaluate the potential interaction of impaired insulin sensitivity and autophagic disorders in hepatic insulin resistance. Our results indicated obese mice receiving CaMKIV showed decreased blood glucose and serum insulin and improved insulin sensitivity as well as increased glucose tolerance compared with vehicle injection. Meanwhile, defective hepatic autophagy activity, impaired insulin signaling, increased inflammatory response and mitochondrial dysfunction in liver tissues which are induced by high-fat diet were also effectively alleviated by injection of CaMKIV. Consistent with these results, the addition of CaMKIV to the culture medium of BNL cl.2 hepatocytes markedly restored palmitate-induced hepatic insulin resistance and autophagic imbalance. These effects were nullified by blockade of cyclic AMP response element-binding protein (CREB), indicating the causative role of CREB in action of CaMKIV. Our findings suggested that CaMKIV restores hepatic autophagic imbalance and improves impaired insulin sensitivity via phosphorylated CREB signaling pathway, which may offer novel opportunities for treatment of obesity and diabetes.