Histone deacetylase 10, a potential epigenetic target for therapy

Histone deacetylase (HDAC) 10, a class II family, has been implicated in various tumors and non-tumor diseases, which makes the discovery of biological functions and novel inhibitors a fundamental endeavor. In cancers, HDAC10 plays crucial roles in regulating various cellular processes through its epigenetic functions or targeting some decisive molecular or signaling pathways. It also has potential clinical utility for targeting tumors and non-tumor diseases, such as renal cell carcinoma, prostate cancer, immunoglobulin A nephropathy (IgAN), intracerebral hemorrhage, human immunodeficiency virus (HIV) infection and schizophrenia. To date, relatively few studies have investigated HDAC10-specific inhibitors. Therefore, it is important to study the biological functions of HDAC10 for the future development of specific HDAC10 inhibitors. In this review, we analyzed the biological functions, mechanisms and inhibitors of HDAC10, which makes HDAC10 an appealing therapeutic target.     

LncRNA UCA1 elevates the resistance of human leukemia cells to daunorubicin by the PI3K/AKT pathway via sponging miR-613

Acute leukemia is a hematological malignant tumor. Long non-coding RNA urothelial cancer-associated 1 (UCA1) is involved in the chemo-resistance of diverse cancers, but it is unclear whether UCA1 is associated with the sensitivity of acute leukemia cells to daunorubicin (DNR). DNR (100 nM) was selected for functional analysis. The viability, cell cycle progression, apoptosis, and invasion of treated acute leukemia cells (HL-60 and U-937) were evaluated by cell counting kit-8 (CCK-8) assay, flow cytometry assay, or transwell assay. Protein levels were detected with Western blot analysis. Expression patterns of UCA1 and miR-613 were assessed by quantitative real-time polymerase chain reaction (qRT-PCR). The relationship between UCA1 and microRNA-613 (miR-613) was verified by dual-luciferase reporter assay. We observed that UCA1 expression was elevated in HL-60 and U-937cells. DNR constrained viability, cell cycle progression, invasion, and facilitated apoptosis of HL-60 and U-937 cells in a dose-dependent manner, but these impacts mediated by DNR were reverted after UCA1 overexpression. MiR-613 was down-regulated in HL-60 and U-937 cells, and UCA1 was verified as a miR-613 sponge. MiR-613 inhibitor reversed DNR treatment-mediated effects on viability, cell cycle progression, apoptosis, and invasion of HL-60 and U-937 cells, but these impacts mediated by miR-613 inhibitor were counteracted after UCA1 inhibition. Notably, the inactivation of the PI3K/AKT pathway caused by DNR treatment was reversed after miR-613 inhibitor introduction, but this influence mediated by miR-613 inhibitor was offset after UCA1 knockdown. In conclusion, UCA1 up-regulation facilitated the resistance of acute leukemia cells to DNR via the PI3K/AKT pathway by sponging miR-613.     

Genetic diversity of mitochondrial D-LOOP sequences in the spotted scat (Scatophagus argus) from different geographical populations along the northern coast of the South China Sea

The genetic diversity of 289 spotted scat (Scatophagus argus) from seven populations along the northern coast of the South China Sea was studied by analyzing the full-length sequences of the mitochondrial control region (D-LOOP). The S. argus D-LOOP sequence was 1,004–1,010 bp long and contained 156 variant sites. The seven studied S. argus populations had a high degree of genetic diversity (haplotype diversity [Hd] = 0.99135; nucleotide diversity (π) = 0.01313). There was no obvious genetic differentiation among the seven geographical populations and gene exchange was frequent (Fst = −0.01867–0.01117, p > .05). Four distinct mitochondrial lineages were identified in the phylogenetic tree and the haplotype network. The between-lineage Fst was 0.71690–0.84940 (p < .001), but these lineages showed no obvious phylogeographic pattern. Based on D-LOOP mutation rates, we estimated that the four lineages diverged approximately 513,800–93,600 years ago, during the Eocene ice age, at which time falling sea levels may have led to population segregation. We estimated that S. argus population expansion occurred approximately 2.29–0.68 million years ago, during the late Pleistocene. During this period, sea levels rose again, allowing previously separated lineages to come into sympatry, which eventually gave rise to a highly genetically diverse population without pyhlogeographic structure. Here, we characterized the genetic structure and differentiation of seven S. argus populations from the northern coast of the South China Sea. Our results suggested that the seven S. argus populations from the northern coast of the South China Sea have a relatively low level of genetic variation and can be considered a single unit for the purposes of fishery development, utilization, and management.     

成年雄性林麝消化道寄生虫群落 对不同扰动策略的响应

人工繁育是当前我国保护野生林麝（Moschus berezovskii）资源的主要手段之一,但在林麝种群复壮的过程中,消化道寄生虫病始终威胁着林麝的健康。为探究林麝消化道寄生虫群落对不同扰动策略的响应,本研究分别使用复合药阿苯达唑伊维菌素粉和单一成分药阿维菌素粉去除林麝体内线虫和绦虫,监测林麝其他寄生虫和群落动态变化。选取60只雄性林麝,随机分为三组,分别为阿苯达唑伊维菌素用药组（20只）、阿维菌素用药组（20只）和未做任何处理的对照组（20只）,并连续采集8周用药组和对照组林麝的新鲜粪便。基于改良的Wisconsin粪便虫卵漂浮计数法检测粪便中的虫卵和卵囊,对实验结果进行Kruskal-Wallis检验、Wilcoxon秩检验、Mann Whitney检验和双因素方差分析。研究结果显示,对照组和阿苯达唑伊维菌素用药组林麝的寄生虫感染均为混合感染,球虫为优势物种,其负载量显著高于线虫和绦虫（P < 0.05),阿维菌素用药组林麝仅感染球虫。药物扰动后,两组用药组的林麝球虫的流行率、平均感染强度均高于对照组,但线虫流行率均低于对照组（27.15%,42.15%）。此外,用药后,阿苯达唑伊维菌素用药组林麝先于阿维菌素用药组再次感染线虫和绦虫。通过比较用药组和对照组林麝寄生虫的群落动态变化,表明林麝消化道寄生虫感染现象较为普遍,多重感染中球虫和蠕虫存在竞争关系,复合药物阿苯达唑伊维菌素粉对林麝寄生虫群落的扰动程度更大,林麝寄生虫群落恢复能力与扰动程度成正比。建议林麝人工繁育基地加强科学性和计划性驱虫,并持续性开展林麝寄生虫感染的监测工作。     

Entropy subspace separation-based clustering for noise reduction (ENCORE) of scRNA-seq data

Single-cell RNA sequencing enables us to characterize the cellular heterogeneity in single cell resolution with the help of cell type identification algorithms. However, the noise inherent in single-cell RNA-sequencing data severely disturbs the accuracy of cell clustering, marker identification and visualization. We propose that clustering based on feature density profiles can distinguish informative features from noise. We named such strategy as ‘entropy subspace’ separation and designed a cell clustering algorithm called ENtropy subspace separation-based Clustering for nOise REduction (ENCORE) by integrating the ‘entropy subspace’ separation strategy with a consensus clustering method. We demonstrate that ENCORE performs superiorly on cell clustering and generates high-resolution visualization across 12 standard datasets. More importantly, ENCORE enables identification of group markers with biological significance from a hard-to-separate dataset. With the advantages of effective feature selection, improved clustering, accurate marker identification and high-resolution visualization, we present ENCORE to the community as an important tool for scRNA-seq data analysis to study cellular heterogeneity and discover group markers.     

荻草谷网蚜唾液蛋白基因Sm13498的克隆及功能分析

【目的】荻草谷网蚜Sitobion miscanthi为我国小麦Triticum aestivum主产区麦蚜优势种;Sm13498蛋白是在荻草谷网蚜唾液腺中特异表达的唾液蛋白。本研究旨在探析荻草谷网蚜功能未知的Sm13498在调节植物防御反应中的潜在作用。【方法】基于荻草谷网蚜唾液腺转录组测序数据,PCR克隆Sm13498的cDNA全长序列,并进行生物信息学分析;采用RT-qPCR测定Sm13498在取食小麦叶片不同时间的荻草谷网蚜无翅成蚜中的表达动态;通过酵母分泌系统验证Sm13498蛋白信号肽的分泌功能;利用根癌农杆菌Agrobacterium tumefaciens介导在本氏烟Nicotiana benthamiana中瞬时表达技术鉴定Sm13498蛋白功能及亚细胞定位。【结果】克隆获得了荻草谷网蚜Sm13498 cDNA全长序列(GenBank登录号：MW346655),开放阅读框(ORF)全长783 bp,编码260个氨基酸,预测蛋白分子量28.01 kD,第1-22位氨基酸为N端信号肽。系统进化树显示,Sm13498与豌豆蚜Acyrthosiphon pisum的功能未知蛋白LOC100159087precursor(GenBank登录号: NP_001313548.1)亲缘关系最近(氨基酸序列一致性为71.7%)。RT-qPCR结果表明,Sm13498在荻草谷网蚜无翅成蚜取食小麦叶片12 h时表达水平达到最高。含有Sm13498信号肽片段的酿酒酵母Saccharomyces cerevisiae YTK12可在YPRAA培养基正常生长,并可将无色2,3,5-氯化三苯基四氮唑(TTC)还原为不可溶的暗红色的氯化三苯基四氮唑(TTF),证实其信号肽具有分泌活性。经根癌农杆菌介导在本氏烟瞬时表达Sm13498蛋白可抑制Bcl-2相关X蛋白(Bcl-2-associated X protein, BAX)及病原菌激发子INF1诱导的程序性细胞死亡。亚细胞定位结果表明,Sm13498-GFP融合蛋白定位于本氏烟叶片细胞膜。【结论】结果说明荻草谷网蚜唾液蛋白Sm13498可抑制植物防御反应。本研究为发掘荻草谷网蚜唾液中效应子, 深入解析麦蚜对小麦品种强适应性奠定了基础。     

Mice with dysfunctional TGF-β signaling develop altered intestinal microbiome and colorectal cancer resistant to 5FU

Emerging data show a rise in colorectal cancer (CRC) incidence in young men and women that is often chemoresistant. One potential risk factor is an alteration in the microbiome. Here, we investigated the role of TGF-β signaling on the intestinal microbiome and the efficacy of chemotherapy for CRC induced by azoxymethane and dextran sodium sulfate in mice. We used two genotypes of TGF-β-signaling-deficient mice (Smad4^+/? and Smad4^+/?Sptbn1^+/?), which developed CRC with similar phenotypes and had similar alterations in the intestinal microbiome. Using these mice, we evaluated the intestinal microbiome and determined the effect of dysfunctional TGF-β signaling on the response to the chemotherapeutic agent 5-Fluoro-uracil (5FU) after induction of CRC. Using shotgun metagenomic sequencing, we determined gut microbiota composition in mice with CRC and found reduced amounts of beneficial species of Bacteroides and Parabacteroides in the mutants compared to the wild-type (WT) mice. Furthermore, the mutant mice with CRC were resistant to 5FU. Whereas the abundances of E. boltae, B.dorei, Lachnoclostridium sp., and Mordavella sp. were significantly reduced in mice with CRC, these species only recovered to basal amounts after 5FU treatment in WT mice, suggesting that the alterations in the intestinal microbiome resulting from compromised TGF-β signaling impaired the response to 5FU. These findings could have implications for inhibiting the TGF-β pathway in the treatment of CRC or other cancers.     

The Bio3D packages for structural bioinformatics

Bio3D is a family of R packages for the analysis of biomolecular sequence, structure, and dynamics. Major functionality includes biomolecular database searching and retrieval, sequence and structure conservation analysis, ensemble normal mode analysis, protein structure and correlation network analysis, principal component, and related multivariate analysis methods. Here, we review recent package developments, including a new underlying segregation into separate packages for distinct analysis, and introduce a new method for structure analysis named ensemble difference distance matrix analysis (eDDM). The eDDM approach calculates and compares atomic distance matrices across large sets of homologous atomic structures to help identify the residue wise determinants underlying specific functional processes. An eDDM workflow is detailed along with an example application to a large protein family. As a new member of the Bio3D family, the Bio3D‐eddm package supports both experimental and theoretical simulation‐generated structures, is integrated with other methods for dissecting sequence‐structure–function relationships, and can be used in a highly automated and reproducible manner. Bio3D is distributed as an integrated set of platform independent open source R packages available from: http://thegrantlab.org/bio3d/ .