Genetic variation and relationships of eighteen Chinese indigenous pig breeds

Chinese indigenous pig breeds are recognized as an invaluable component of the world's pig genetic resources and are divided traditionally into six types. Twenty-six microsatellite markers recommended by the FAO (Food and Agriculture Organization) and ISAG (International Society of Animal Genetics) were employed to analyze the genetic diversity of 18 Chinese indigenous pig breeds with 1001 individuals representing five types, and three commercial breeds with 184 individuals. The observed heterozygosity, unbiased expected heterozygosity and the observed and effective number of alleles were used to estimate the genetic variation of each indigenous breed. The unbiased expected heterozygosity ranged between 0.700 (Mashen) and 0.876 (Guanling), which implies that there is an abundant genetic variation stored in Chinese indigenous pig breeds. Breed differentiation was shown by fixation indices (FIT, FIS, and FST). The FST per locus varied from 0.019 (S0090) to 0.170 (SW951), and the average FST of all loci was 0.077, which means that most of the genetic variation was kept within breeds and only a little of the genetic variation exists between populations. The Neighbor-Joining tree was constructed based on the Nei DA (1978) distances and one large cluster with all local breeds but the Mashen breed, was obtained. Four smaller sub-clusters were also found, which included two to four breeds each. These results, however, did not completely agree with the traditional type of classification. A Neighbor-Joining dendrogram of individuals was established from the distance of – ln(proportions of shared alleles); 92.14% of the individuals were clustered with their own breeds, which implies that this method is useful for breed demarcation. This extensive research on pig genetic diversity in China indicates that these 18 Chinese indigenous breeds may have one common ancestor, helps us to better understand the relative distinctiveness of pig genetic resources, and will assist in developing a national plan for the conservation and utilization of Chinese indigenous pig breeds

Platinum-based chemotherapy plus cetuximab first-line for Asian patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck: Results of an open-label, single-arm, multicenter trial

Background The purpose of this study was to assess the efficacy, safety, and pharmacokinetics of cisplatin-based chemotherapy plus cetuximab as first-line treatment in Chinese and Korean patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). Methods Patients (n = 68) received cetuximab weekly plus 3-week cycles of cisplatin/5-fluorouracil (5-FU) chemotherapy for up to 6 cycles. The primary endpoint was overall response rate. Results The overall response rate was 55.9%, including 2 complete responses (CRs). Median overall survival (OS) was 12.6 months and median progression-free survival (PFS) was 6.6 months. Grade 3/4 adverse events (AEs) were reported in 41 (60.3%) patients. The safety profile was in line with previous clinical experience. The pharmacokinetic profile was in line with that observed with cetuximab in white and Japanese patients. Conclusion The efficacy, safety, and pharmacokinetic findings from this study support the use of first-line platinum-based chemotherapy plus cetuximab in Chinese and Korean patients with recurrent and/or metastatic SCCHN (ClinicalTrials.gov NCT01177956). © 2014 The Authors Head & Neck Published by Wiley Periodicals, Inc. Head Neck 37: 1081–1087, 201

Inhibition of WEE1 Suppresses the Tumor Growth in Laryngeal Squamous Cell Carcinoma

WEE1 is a tyrosine kinase that regulates G2/M cell cycle checkpoint and frequently overexpressed in various tumors. However, the expression and clinical significance of WEE1 in human laryngeal squamous cell carcinoma (LSCC) are still unknown. In this study, we found that WEE1 was highly expressed in LSCC tissues compared with adjacent normal tissues. Importantly, overexpression of WEE1 was correlated with T stages, lymph node metastasis, clinical stages and poor prognosis of LSCC patients. Furthermore, inhibition of WEE1 by MK-1775 induced cell growth inhibition, cell cycle arrest and apoptosis with the increased intracellular reactive oxygen species (ROS) levels in LSCC cells. Pretreatment with ROS scavenger N-acetyl-L-cysteine could reverse MK-1775-induced ROS accumulation and cell apoptosis in LSCC cells. MK-1775 also inhibited the growth of LSCC xenografts in nude mice. Altogether, these findings suggest that WEE1 is a potential therapeutic target in LSCC, and inhibition of WEE1 is the prospective strategy for LSCC therapy

SAR-RARP50: Segmentation of surgical instrumentation and Action Recognition on Robot-Assisted Radical Prostatectomy Challenge

Surgical tool segmentation and action recognition are fundamental building blocks in many computer-assisted intervention applications, ranging from surgical skills assessment to decision support systems. Nowadays, learning-based action recognition and segmentation approaches outperform classical methods, relying, however, on large, annotated datasets. Furthermore, action recognition and tool segmentation algorithms are often trained and make predictions in isolation from each other, without exploiting potential cross-task relationships. With the EndoVis 2022 SAR-RARP50 challenge, we release the first multimodal, publicly available, in-vivo, dataset for surgical action recognition and semantic instrumentation segmentation, containing 50 suturing video segments of Robotic Assisted Radical Prostatectomy (RARP). The aim of the challenge is twofold. First, to enable researchers to leverage the scale of the provided dataset and develop robust and highly accurate single-task action recognition and tool segmentation approaches in the surgical domain. Second, to further explore the potential of multitask-based learning approaches and determine their comparative advantage against their single-task counterparts. A total of 12 teams participated in the challenge, contributing 7 action recognition methods, 9 instrument segmentation techniques, and 4 multitask approaches that integrated both action recognition and instrument segmentation. The complete SAR-RARP50 dataset is available at: https://rdr.ucl.ac.uk/projects/SARRARP50_Segmentation_of_surgical_instrumentation_and_Action_Recognition_on_Robot-Assisted_Radical_Prostatectomy_Challenge/19109

MAP kinase pathways and calcitonin influence CD44 alternate isoform expression in prostate cancer cells

<p>Abstract</p> <p>Background</p> <p>Dysregulated expression and splicing of cell adhesion marker CD44 is found in many types of cancer. In prostate cancer (PC) specifically, the standard isoform (CD44s) has been found to be downregulated compared with benign tissue whereas predominant variant isoform CD44v7-10 is upregulated. Mitogen-activated protein kinase pathways and paracrine calcitonin are two common factors linked to dysregulated expression and splicing of CD44 in cancer. Calcitonin has been found to increase proliferation and invasion in PC acting through the protein kinase A pathway.</p> <p>Methods</p> <p>In androgen-independent PC with known high CD44v7-10 expression, CD44 total and CD44v7-10 RNA or protein were assessed in response to exogenous and endogenous calcitonin and to inhibitors of protein kinase A, MEK, JNK, or p38 kinase. Benign cells and calcitonin receptor-negative PC cells were also tested.</p> <p>Results</p> <p>MEK or p38 but not JNK reduced CD44 total RNA by 40%–65% in cancer and benign cells. Inhibition of protein kinase A reduced CD44 total and v7-10 protein expression. In calcitonin receptor-positive cells only, calcitonin increased CD44 variant RNA and protein by 3 h and persisting to 48 h, apparently dependent on an uninhibited p38 pathway. Cells with constitutive CT expression showed an increase in CD44v7-10 mRNA but a decrease in CD44 total RNA.</p> <p>Conclusion</p> <p>The MEK pathway increases CD44 RNA, while calcitonin, acting through the protein kinase A and p38 pathway, facilitates variant splicing. These findings could be used in the formulation of therapeutic methods for PC targeting CD44 alternate splicing.</p

Frequent alterations in cytoskeleton remodelling genes in primary and metastatic lung adenocarcinomas

The landscape of genetic alterations in lung adenocarcinoma derived from Asian patients is largely uncharacterized. Here we present an integrated genomic and transcriptomic analysis of 335 primary lung adenocarcinomas and 35 corresponding lymph node metastases from Chinese patients. Altogether 13 significantly mutated genes are identified, including the most commonly mutated gene TP53 and novel mutation targets such as RHPN2, GLI3 and MRC2. TP53 mutations are furthermore significantly enriched in tumours from patients harbouring metastases. Genes regulating cytoskeleton remodelling processes are also frequently altered, especially in metastatic samples, of which the high expression level of IQGAP3 is identified as a marker for poor prognosis. Our study represents the first large-scale sequencing effort on lung adenocarcinoma in Asian patients and provides a comprehensive mutational landscape for both primary and metastatic tumours. This may thus form a basis for personalized medical care and shed light on the molecular pathogenesis of metastatic lung adenocarcinoma

The Minimum Variation Timescales of X-ray bursts from SGR J1935+2154

The minimum variation timescale (MVT) of soft gamma-ray repeaters can be an important probe to estimate the emission region in pulsar-like models, as well as the Lorentz factor and radius of the possible relativistic jet in gamma-ray burst (GRB)-like models, thus revealing their progenitors and physical mechanisms. In this work, we systematically study the MVTs of hundreds of X-ray bursts (XRBs) from SGR J1935+2154 observed by {\it Insight}-HXMT, GECAM and Fermi/GBM from July 2014 to Jan 2022 through the Bayesian Block algorithm. We find that the MVTs peak at $\sim$ 2 ms, corresponding to a light travel time size of about 600 km, which supports the magnetospheric origin in pulsar-like models. The shock radius and the Lorentz factor of the jet are also constrained in GRB-like models. Interestingly, the MVT of the XRB associated with FRB 200428 is $\sim$ 70 ms, which is longer than that of most bursts and implies its special radiation mechanism. Besides, the median of MVTs is 7 ms, shorter than the median MVTs of 40 ms and 480 ms for short GRBs or long GRBs, respectively. However, the MVT is independent of duration, similar to GRBs. Finally, we investigate the energy dependence of MVT and suggest that there is a marginal evidence for a power-law relationship like GRBs but the rate of variation is at least about an order of magnitude smaller. These features may provide an approach to identify bursts with a magnetar origin.Comment: accepted for publication in ApJ

Genomewide association study of leprosy.

BACKGROUND: The narrow host range of Mycobacterium leprae and the fact that it is refractory to growth in culture has limited research on and the biologic understanding of leprosy. Host genetic factors are thought to influence susceptibility to infection as well as disease progression. METHODS: We performed a two-stage genomewide association study by genotyping 706 patients and 1225 controls using the Human610-Quad BeadChip (Illumina). We then tested three independent replication sets for an association between the presence of leprosy and 93 single-nucleotide polymorphisms (SNPs) that were most strongly associated with the disease in the genomewide association study. Together, these replication sets comprised 3254 patients and 5955 controls. We also carried out tests of heterogeneity of the associations (or lack thereof) between these 93 SNPs and disease, stratified according to clinical subtype (multibacillary vs. paucibacillary). RESULTS: We observed a significant association (P<1.00x10(-10)) between SNPs in the genes CCDC122, C13orf31, NOD2, TNFSF15, HLA-DR, and RIPK2 and a trend toward an association (P=5.10x10(-5)) with a SNP in LRRK2. The associations between the SNPs in C13orf31, LRRK2, NOD2, and RIPK2 and multibacillary leprosy were stronger than the associations between these SNPs and paucibacillary leprosy. CONCLUSIONS: Variants of genes in the NOD2-mediated signaling pathway (which regulates the innate immune response) are associated with susceptibility to infection with M. leprae

Impeding the interaction between ​Nur77 and p38 reduces LPS-induced inflammation

该成果阐明了一条孤儿核受体Nur77通过p38-NF-κB信号通路参与炎症反应调控的新途径，为新的抗炎药物的筛选提供了新的靶标和理论基础。 吴乔课题组长期以来一直致力于孤儿核受体Nur77作用机理和生物学功能研究。该成果是吴乔课题组近年来在NatureChemicalBiology发表的第四篇系列研究论文，也是与不同学科领域相关课题组（包括结构生物学、化学生物学、天然产物药物研究等）合作的原创性成果。这些研究成果充分体现了学科交叉的优势，代表了相关研究的发展趋势。他们从分子机制、信号调控网络、共晶结构、小分子探针、药物靶点和疾病治疗等角度全面系统地阐明了Nur77作为临床重要的靶标，调控不同疾病的重要生物学功能，丰富和发展了孤儿核受体的理论知识，并且找到了能够降低血糖、抑制黑色素瘤生长和抗炎反应的小分子化合物，为治疗相关疾病提供了重要的先导化合物。该系列研究先后得到了多个国家自然科学基金重点项目和科技部“973”项目的长期支持。Sepsis, a hyperinflammatory response that can result in multiple organ dysfunctions, is a leading cause of mortality from infection. Here, we show that orphan nuclear receptor ​Nur77 (also known as ​TR3) can enhance resistance to lipopolysaccharide (LPS)-induced sepsis in mice by inhibiting NF-κB activity and suppressing aberrant cytokine production. ​Nur77 directly associates with ​p65 to block its binding to the κB element. However, this function of ​Nur77 is countered by the LPS-activated ​p38α phosphorylation of ​Nur77. Dampening the interaction between ​Nur77 and ​p38α would favor ​Nur77 suppression of the hyperinflammatory response. A compound, ​n-pentyl 2-[3,5-dihydroxy-2-(1-nonanoyl) phenyl]acetate, screened from a ​Nur77-biased library, blocked the ​Nur77-​p38α interaction by targeting the ligand-binding domain of ​Nur77 and restored the suppression of the hyperinflammatory response through ​Nur77 inhibition of NF-κB. This study associates the nuclear receptor with immune homeostasis and implicates a new therapeutic strategy to treat hyperinflammatory responses by targeting a ​p38α substrate to modulate ​p38α-regulated functions.This work was supported by grants from the National Natural Science Fund of China, the '973' Project of the Ministry of Science and Technology (91413113, 2014CB910602, 31370724, 31221065) and the Program of Introducing Talents of Discipline to Universities (B12001). The crystallographic data collection at Beamline BL17U1 at Shanghai Synchrotron Radiation Facility is gratefully acknowledged