Alpha5 nicotine acetylcholine receptor subunit promotes intrahepatic cholangiocarcinoma metastasis

Neurotransmitter-initiated signaling pathway were reported to play an important role in regulating the malignant phenotype of tumor cells.Cancer cells could exhibit a"neural addiction"property and build up local nerve networks to achieve an enhanced neurotransmitter-initiated signaling through nerve growth factor-mediated axonogenesis.Targeting the dysregulated nervous systems might represent a novel strategy for cancer treatment.However,whether intrahepatic cholangiocarcinoma(ICC)could build its own nerve networks and the role of neurotransmitters in the progression ICC remains largely unknown.Immunofluorescence staining and Enzyme-linked immunosorbent assay suggested that IcC cells and the infiltrated nerves could generate a tumor microenvironment rich in acetylcholine that promotes IcC metastasis by inducing epithelial-mesenchymal transition(EMT).Acetylcholine promoted iCC metastasis through interacting with its receptor,alpha 5 nicotine acetylcholine receptor subunits(CHRNA5).Furthermore,acetylcholine/CHRNA5 axis activated GSK3β/β-catenin signaling pathway partially through the influx of Ca^(2+)-mediated activation of Ca/calmodulin-dependent protein kinases(CAMKll).In addition,acetylcholine signaling activation also expanded nerve infiltration through increasing the expression of Brain-Derived Neurotrophic Factor(BDNF),which formed a feedforward acetylcholine-BDNF axis to promote ICC progression.KN93,a small-molecule inhibitor of CAMKIll,significantly inhibited the migration and enhanced the sensitivity to gemcitabine of ICC cells.Above all,Acetylcholine/CHRNA5 axis increased the expression ofβ-catenin to promote the metastasis and resistance to gemcitabine of ICC via CAMKIl/GSK3βsignaling,and the CAMKIl inhibitor KN93 may be an effective therapeutic strategy for combating ICC metastasis.

Whole-Genome Resequencing of a Worldwide Collection of Rapeseed Accessions Reveals the Genetic Basis of Ecotype Divergence

Rapeseed (Brassica napus),an important oilseed crop,has adapted to diverse climate zones and latitudes by forming three main ecotype groups,namely winter,semiwinter,and spring types. However,genetic variations underlying the divergence of these ecotypes are largely unknown. Here,we report the global pattern of genetic polymorphisms in rapeseed determined by resequencing a worldwide collection of 991 germplasm accessions.A total of 5.56 and 5.53 million singlenucleotide polymorphisms (SNPs)as Well as 1.86 and 1.92 million InDels were identified by mapping reads to the reference genomes of "Darmor-bzh"and "Tapidor,"respectively.We generated a map of allelic drift paths that shows splits and mixtures of the main populations,and revealed an asymmetric evolution of the two subgenomes of B.napus by calculating the genetic diversity and linkage disequilibrium parameters.Selective-sweep analysis revealed genetic changes in genes orthologous to those regulating various aspects of plant development and response to stresses.A genome-wide association study identified SNPs in the promoter regions of FLOWERING LOCUS T and FLOWERING LOCUS C orthologs that corresponded to the different rapeseed ecotype groups. Our study provides important insights into the genomic footprints of rapeseed evolution and flowering-time divergence among three ecotype groups,and will facilitate screening of molecular markers for accelerating rapeseed breeding.

The molecular biology of pancreatic adenocarcinoma:translational challenges and clinical perspectives

Pancreatic cancer is an increasingly common cause of cancer mortality with a tight correspondence between disease mortality and incidence.Furthermore,it is usually diagnosed at an advanced stage with a very dismal prognosis.Due to the high heterogeneity,metabolic reprogramming,and dense stromal environment associated with pancreatic cancer,patients benefit little from current conventional therapy.Recent insight into the biology and genetics of pancreatic cancer has supported its molecular classification,thus expanding clinical therapeutic options.In this review,we summarize how the biological features of pancreatic cancer and its metabolic reprogramming as well as the tumor microenvironment regulate its development and progression.We further discuss potential biomarkers for pancreatic cancer diagnosis,prediction,and surveillance based on novel liquid biopsies.We also outline recent advances in defining pancreatic cancer subtypes and subtype-specific therapeutic responses and current preclinical therapeutic models.Finally,we discuss prospects and challenges in the clinical development of pancreatic cancer therapeutics.

Review of Technologies for High-Voltage Integrated Circuits

High-Voltage power Integrated Circuits(HVICs) are widely used to realize high-efficiency power conversions(e.g., AC/DC conversion), gate drivers for power devices and LED lighting, and so on. The Bipolar-CMOS-DMOS(BCD) process is proposed to fabricate devices with bipolar, CMOS, and DMOS modes, and thereby realize the single-chip integration of HVICs. The basic integrated technologies of HVICs include High-Voltage(HV) integrated device technology, HV interconnection technology, and isolation technology. The HV integrated device is the core of HVICs. The basic requirements of the HV integrated device are high breakdown voltage, low specific on-resistance,and process compatibility with low-voltage circuits. The REduced SURFace field(RESURF) technology and junction termination technology are developed to optimize the surface field of integration power devices and breakdown voltage. Furthermore, the ENhanced DIelectric layer Field(ENDIF) and REduced BULk Field(REBULF) technologies are proposed to optimize bulk fields. The double/triple RESURF technologies are further developed, and the superjunction concept is introduced to integrated power devices and to reduce the specific on-resistance. This work presents a comprehensive review of these technologies, including the innovation technologies of the authors’ group,such as ENDIF and REBULF, substrate termination technology prospective integrated technologies and HVICs in wide band gap semiconductor materials are also discussed.