pigenetic reprogramming in small cell lung cancer

Small cell lung cancer(SCLC),a highly lethal lung cancer sub-type with distinct neuroendocrine-like features,accounts for 10%–15%of all lung cancers.The overall 5-year survival rate remains less than 10%.SCLC is characterized by early metastasis,thus minimizing the potential patient benefits of surgery.In recent decades,the first-line treatment for SCLC has remained chemotherapy combining etoposide and cisplatin(E/P).Despite high rates of response to E/P treatment,SCLC eventually relapses and is almost universally resistant to treatment at recurrence,thus making SCLC a recalcitrant malignancy.Moreover,the limited knowledge regarding the molecular mechanisms underlying SCLC metastasis and resistance greatly hinders improvements in overall SCLC survival.To better understand the molecular mechanisms of SCLC and discover potential therapeutic targets,extensive efforts have continued for decades.

Urdnet:A Cryo-EM Particle Automatic Picking Method

Cryo-Electron Microscopy(Cryo-EM)images are characterized by the low signal-to-noise ratio,low contrast,serious background noise,more impurities,less data,difficult data labeling,simpler image semantics,and relatively fixed structure,while U-Net obtains low resolution when downsampling rate information to complete object category recognition,obtains highresolution information during upsampling to complete precise segmentation and positioning,fills in the underlying information through skip connection to improve the accuracy of image segmentation,and has advantages in biological image processing like Cryo-EM image.This article proposes A U-Net based residual intensive neural network(Urdnet),which combines point-level and pixel-level tags,used to accurately and automatically locate particles from cryo-electron microscopy images,and solve the bottleneck that cryo-EM Single-particle biologicalmacromolecule reconstruction requires tens of thousands of automatically picked particles.The 80S ribosome,HCN1 channel and TcdA1 toxin subunits,and other public protein datasets have been trained and tested on Urdnet.The experimental results show that Urdnet could reach the same excellent particle picking performances as the mainstream methods of RELION,DeepPicker,and acquire the 3Dstructure of picked particleswith higher resolution.

CNEReg Interprets Ruminant-specific Conserved Non-coding Elements by Developmental Gene Regulatory Network

The genetic information coded in DNA leads to trait innovation via a gene regulatory network(GRN)in development.Here,we developed a conserved non-coding element interpretation method to integrate multi-omics data into gene regulatory network(CNEReg)to investigate the ruminant multi-chambered stomach innovation.We generated paired expression and chromatin accessibility data during rumen and esophagus development in sheep,and revealed 1601 active ruminantspecific conserved non-coding elements(active-RSCNEs).To interpret the function of these activeRSCNEs,we defined toolkit transcription factors(TTFs)and modeled their regulation on rumenspecific genes via batteries of active-RSCNEs during development.Our developmental GRN revealed 18 TTFs and 313 active-RSCNEs regulating 7 rumen functional modules.Notably,6 TTFs(OTX1,SOX21,HOXC8,SOX2,TP63,and PPARG),as well as 16 active-RSCNEs,functionally distinguished the rumen from the esophagus.Our study provides a systematic approach to understanding how gene regulation evolves and shapes complex traits by putting evo-devo concepts into practice with developmental multi-omics data.

Modes of genetic adaptations underlying functional innovations in the rumen

The rumen is the hallmark organ of ruminants and hosts a diverse ecosystem of microorganisms that facilitates efficient digestion of plant fibers.We analyzed 897 transcriptomes from three Cetartiodactyla lineages:ruminants,camels and cetaceans,as well as data from ruminant comparative genomics and functional assays to explore the genetic basis of rumen functional innovations.We identified genes with relatively high expression in the rumen,of which many appeared to be recruited from other tissues.These genes show functional enrichment in ketone body metabolism,regulation of microbial community,and epithelium absorption,which are the most prominent biological processes involved in rumen innovations.Several modes of genetic change underlying rumen functional innovations were uncovered,including coding mutations,genes newly evolved,and changes of regulatory elements.We validated that the key ketogenesis rate-limiting gene(HMGCS2)with five ruminant-specific mutations was under positive selection and exhibits higher synthesis activity than those of other mammals.Two newly evolved genes(LYZ1 and DEFB1)are resistant to Gram-positive bacteria and thereby may regulate microbial community equilibrium.Furthermore,we confirmed that the changes of regulatory elements accounted for the majority of rumen gene recruitment.These results greatly improve our understanding of rumen evolution and organ evo-devo in general.

Spontaneous apoptosis of cells in therapeutic stem cell preparation exert immunomodulatory effects through release of phosphatidylserine

Mesenchymal stem cell(MSC)-mediated immunomodulation has been harnessed for the treatment of human diseases,but its underlying mechanism has not been fully understood.Dead cells,including apoptotic cells have immunomodulatory properties.It has been repeatedly reported that the proportion of nonviable MSCs in a MSC therapeutic preparation varied from 5-50%in the ongoing clinical trials.It is conceivable that the nonviable cells in a MSC therapeutic preparation may play a role in the therapeutic effects of MSCs.We found that the MSC therapeutic preparation in the present study had about 5%dead MSCs(DMSCs),characterized by apoptotic cells.Namely,1×10^(6) MSCs in the preparation contained about 5×10^(4) DMSCs.We found that the treatment with even 5×10^(4) DMSCs alone had the equal therapeutic effects as with 1×10^(6) MSCs.This protective effect of the dead MSCs alone was confirmed in four mouse models,including concanavalin A(ConA)-and carbon tetrachloride(CCI4)-induced acute liver injury,LPS-induced lung injury and spinal cord injury.We also found that the infused MSCs died by apoptosis in vivo.Furthermore,the therapeutic effect was attributed to the elevated level of phosphatidylserine(PS)upon the injection of MSCs or DMSCs.The direct administration of PS liposomes(PSLs)mimic apoptotic cell fragments also exerted the protective effects as MSCs and DMSCs.The Mer tyrosine kinase(MerTK)deficiency or the knockout of chemokine receptor C-C motif chemokine receptor 2(CCR2)reversed these protective effects of MSCs or DMSCs.These results revealed that DMSCs alone in the therapeutic stem cell preparation or the apoptotic cells induced in vivo may exert the same immunomodulatory property as the'living MSCs preparation"through releasing PS,which was further recognized by MerTK and participated in modulating immune cells.

Nanophase precipitation and strengthening in a dual-phase Al_(0.5)CoCrFeNi high-entropy alloy

Precipitation-hardening in fcc-based high-entro py alloys(HEAs)have usually been realized by introducing complex intermetallic compounds.In this study,enhanced strength is ascribed to the existence of L1_(2) precipitates and B2/bcc conjoint phases in the fcc matrix.The nano-size particles in the Al_(0.5)CoCrFeNi HEA are produced by cold-rolling,followed by intermediate-temperature-annealing at 650℃.For L1_(2) ordering,the initial granular structure has transformed into lamella structure and then kept stable when the holding time prolonged to 200 h.The formation of this conjoint B2/bcc driven by the concentration profiles takes place when the diffusion process of elements is sufficient after long-time aging.Based on the microstructure analysis,changes in mechanical properties are associated with the shape,size scale and volume fraction of the precipitates.The peak ultimate tensile stress reaches 1221.5 MPa,1.97 times compared with the as-cast alloy,remaining plasticity of 21.3%.

Epigenetic drug library screening identified an LSD1 inhibitor to target UTX-deficient cells for differentiation therapy

UTX(also known as KDM6A),a histone 3 lysine 27 demethylase,is among the most frequently mutated epigenetic regulators in myelodysplastic syndrome(MDS)and acute myeloid leukemia(AML).Recent studies have suggested that UTX mutations promote MDS and AML by blocking the differentiation of hematopoietic stem and progenitor cells(HSPCs).Here,we performed an epigenetic drug library screening for small molecules able to release the differentiation block on HSPCs induced by UTX deficiency.We found that SP2509,a selective inhibitor of LSD1,specifically promoted the differentiation of Utx-null HSPCs while sparing wild-type HSPCs.Transcriptome profiling showed that Utx loss reduced the expression of differentiation-related and tumor suppressor genes,correlating with their potential roles in HSPC self-renewal and leukemogenesis.In contrast,SP2509 treatment reversed these changes in gene expression in Utx-null HSPCs.Accordingly,Utx loss decreased H3K4 methylation level probably through the COMPASS-like complex,while LSD1 inhibition by SP2509 partially reversed the reduction of H3K4 methylation in Utx-deficient HSPCs.Further,SP2509 promoted the differentiation of Utx-null AML cells in vitro and in vivo and,therefore,extended the survival of these leukemic mice.Thus,our study identified a novel strategy to specifically target both premalignant and malignant cells with Utx deficiency for differentiation therapy and provided insights into the molecular mechanisms underlying the role of Utx in regulating HSPCs and related diseases.

基于高质量系统发育基因组学数据鉴定的反刍动物特异性基因及其在瘤胃演化中的作用

反刍动物是世界上最成功的哺乳动物类群之一,具有显著的形态特征比如瘤胃.新基因在物种的表型演化中有重要的作用.为研究新基因在反刍动物新器官演化中的作用,结合新组装的鼷鹿和林麝的高质量基因组,以及以前发表的其他反刍动物科的高质量基因组,以牛科的绵羊基因注释为主,本工作鉴定了1064个反刍动物特异的新基因.结果显示,反刍动物新基因和其他哺乳动物中的新基因具有相似的演化和表达模式.有一部分新基因在瘤胃的演化中有作用.但大部分瘤胃表达的新基因招募自原先在其他组织表达的基因.如,在瘤胃不同发育时期有表达波动的反刍特异性PRD-SPRRⅡ基因家族成员受到正选择作用,可能在瘤胃的表皮发育中有重要功能.该工作的研究结果为理解反刍动物新基因的起源进化模式和哺乳动物新器官的演化提供了新的见解.

Identifying a confused cell identity for esophageal squamous cell carcinoma

The cell identity of malignant cells and how they acquire it are fundamental for our understanding of cancer.Here,we report that esophageal squamous cell carcinoma(ESCC)cells display molecular features equally similar but distinct to all three types of normal esophageal epithelial cells,which we term as confused cell identity(CCI).CCI is an independent prognostic marker associated with poor prognosis in ESCC.Further,we identify tropomyosin 4(TPM4)as a critical CCI gene that promotes the aggressiveness of ESCC in vitro and in vivo.And TPM4 creates CCI through activating the Jak/STAT-SOX2 pathway.Thus,our study suggests an unrecognized feature of ESCC cells,which might be of value for clinic prognosis and potential interference.

Allele-specific expression and splicing provide insight into the phenotypic differences between thin- and fat-tailed sheep breeds

The sheep(Ovis aries) was one of the first grazing animals to be domesticated approximately 11,000 years ago in the Fertile Crescent(Chessa et al., 2009). Since domestication, a wide variety of sheep breeds with different production traitsand morphological characteristics have been shaped under the influence of natural and artificial selection. According to the fat content in tail, sheep can be mainly classified into two groups: thin-and fat-tailed breeds.

Correction: Spontaneous apoptosis of cells in therapeutic stemcell preparation exert immunomodulatory effects throughrelease of phosphatidylserine

After online publication of the article1,the authors noticed one inadvertent mistake in Fig.5a that needs to be corrected.In detail,the pathological picture of PBS group in Fig.5a is inadvertently duplicated as the image of PBS group in Fig.7b in the main text.This duplication is a result of errors in figure assembly,and the correct Fig.5 is provided as follows.The key findings of the article are not affected by these corrections.