Chemokine Ligand 13 Expression is Abundant in the Tumor Microenvironment and Indicates Poor Prognosis of Kidney Clear Cell Carcinoma

The chemokine ligand 13-chemokine receptor 5(CXCL13-CXCR5)axis has been characterized as a critical tumor-promoting signaling pathway in the tumor microenvironment(TME)in multiple types of solid tumors.In this study,we analyzed the expression profile of CXCL13 in kidney clear cell carcinoma(KIRC)and its correlation with tumor-infiltrating immune cells(TIICs).A monoclonal antibody against CXCL13 with high affinity and purity was generated in our lab for western blot and immunohistochemistry(IHC).Bioinformatic analysis was performed based on bulk-seq data from the Cancer Genome Atlas(TCGA)-KIRC and single-cell RNA-seq data from scRNASeqDB and PanglaoDB.Results showed that high CXCL13 expression in TME was associated with shorter progression-free survival(PFS),disease-specific survival(DSS),and overall survival(OS).KIRC cell lines,as well as several other cancer cell lines,had negative CXCL13 expression.IHC staining from the Human Protein Atlas(HPA)and our tissue array indicated that CXCL13 might be mainly expressed by TIICs,but not KIRC tumor cells.CXCL13 expression was strongly and positively correlated withγδT cell abundance in TME.Besides,γδT cell infiltration was associated with poor survival of KIRC.Methylation 450k array data showed that CXCL13 promoter hypomethylation was common in TIICs.The methylation level of cg16361705 within the CXCL13 promoter might play an important role in modulating CXCL13 transcription.In conclusion,our study revealed that CXCL13 expression andγδT cell infiltration in TME is associated with unfavorable survival of KIRC.TIICs,most possiblyγδT cells,are the dominant source of CXCL13 in KIRC TME.

Time series canopy phenotyping enables the identification of genetic variants controlling dynamic phenotypes in soybean

Advances in plant phenotyping technologies are dramatically reducing the marginal costs of collecting multiple phenotypic measurements across several time points.Yet,most current approaches and best statistical practices implemented to link genetic and phenotypic variation in plants have been developed in an era of single-time-point data.Here,we used time-series phenotypic data collected with an unmanned aircraft system for a large panel of soybean(Glycine max(L.)Merr.)varieties to identify previously uncharacterized loci.Specifically,we focused on the dissection of canopy coverage(CC)variation from this rich data set.We also inferred the speed of canopy closure,an additional dimension of CC,from the time-series data,as it may represent an important trait for weed control.Genome-wide association studies(GWASs)identified 35 loci exhibiting dynamic associations with CC across developmental stages.The time-series data enabled the identification of 10 known flowering time and plant height quantitative trait loci(QTLs)detected in previous studies of adult plants and the identification of novel QTLs influencing CC.These novel QTLs were disproportionately likely to act earlier in development,which may explain why they were missed in previous single-time-point studies.Moreover,this time-series data set contributed to the high accuracy of the GWASs,which we evaluated by permutation tests,as evidenced by the repeated identification of loci across multiple time points.Two novel loci showed evidence of adaptive selection during domestication,with different genotypes/haplotypes favored in different geographic regions.In summary,the time-series data,with soybean CC as an example,improved the accuracy and statistical power to dissect the genetic basis of traits and offered a promising opportunity for crop breeding with quantitative growth curves.

Targeting fibrosis: mechanisms and clinical trials

Fibrosis is characterized by the excessive extracellular matrix deposition due to dysregulated wound and connective tissue repair response.Multiple organs can develop fibrosis,including the liver,kidney,heart,and lung.Fibrosis such as liver cirrhosis,idiopathic pulmonary fibrosis,and cystic fibrosis caused substantial disease burden.Persistent abnormal activation of myofibroblasts mediated by various signals,such as transforming growth factor,platelet-derived growth factor,and fibroblast growh factor,has been recongized as a major event in the occurrence and progression of fibrosis.Although the mechanisms driving organ-specific fibrosis have not been fully elucidated,drugs targeting these identified aberrant signals have achieved potent anti-fibrotic efficacy in clinical trials.In this review,we briefly introduce the aetiology and epidemiology of several fibrosis diseases,including liver fibrosis,kidney fibrosis,cardiac fibrosis,and pulmonary fibrosis.Then,we summarise the abnormal cells(epithelial cells,endothelial cells,immune cells,and fibroblasts)and their interactions in fibrosis.In addition,we also focus on the aberrant signaling pathways and therapeutic targets that regulate myofibroblast activation,extracellular matrix cross-linking,metabolism,and inflammation in fibrosis.Finally,we discuss the anti-fibrotic drugs based on their targets and clinical trials.This review provides reference for further research on fibrosis mechanism,drug development,and clinical trials.

Design, synthesis and pharmacological evaluation of 4-(3-chloro-4-(3-cyclopropylthioureido)-2-fluorophenoxy)-7-methoxyquinoline-6-carboxamide (WXFL-152):a novel triple angiokinase inhibitor for cancer therapy

Angiokinases, such as vascular endothelial-, fibroblast-and platelet-derived growth factor receptors(VEGFRs, FGFRs and PDGFRs) play crucial roles in tumor angiogenesis. Anti-angiogenesis therapy using multi-angiokinase inhibitor has achieved great success in recent years. In this study, we presented the design, synthesis, target identification, molecular mechanism, pharmacodynamics(PD)and pharmacokinetics(PK) research of a novel triple-angiokinase inhibitor WXFL-152. WXFL-152,identified from a series of 4-oxyquinoline derivatives based on a structureeactivity relationship study,inhibited the proliferation of vascular endothelial cells(ECs) and pericytes by blocking the angiokinase signals VEGF/VEGFR2, FGF/FGFRs and PDGF/PDGFRβ simultaneously in vitro. Significant anticancer effects of WXFL-152 were confirmed in multiple preclinical tumor xenograft models, including a patientderived tumor xenograft(PDX) model. Pharmacokinetic studies of WXFL-152 demonstrated high favourable bioavailability with single-dose and continuous multi-dose by oral administration in rats and beagles.In conclusion, WXFL-152, which is currently in phase Ib clinical trials, is a novel and effective tripleangiokinase inhibitor with clear PD and PK in tumor therapy.

Histones released by NETosis enhance the infectivity of SARS-CoV-2 by bridging the spike protein subunit 2 and sialic acid on host cells

Neutrophil extracellular traps(NETs)can capture and kill viruses,such as influenza viruses,human immunodeficiency virus(HIV),and respiratory syncytial virus(RSV),thus contributing to host defense.Contrary to our expectation,we show here that the histones released by NETosis enhance the infectivity of SARS-CoV-2,as found by using live SARS-CoV-2 and two pseudovirus systems as well as a mouse model.The histone H3 or H4 selectively binds to subunit 2 of the spike(S)protein,as shown by a biochemical binding assay,surface plasmon resonance and binding energy calculation as well as the construction of a mutant S protein by replacing four acidic amino acids.Sialic acid on the host cell surface is the key molecule to which histones bridge subunit 2 of the S protein.Moreover,histones enhance cell-cell fusion.Finally,treatment with an inhibitor of NETosis,histone H3 or H4,or sialic acid notably affected the levels of sgRNA copies and the number of apoptotic cells in a mouse model.These findings suggest that SARS-CoV-2 could hijack histones from neutrophil NETosis to promote its host cell attachment and entry process and may be important in exploring pathogenesis and possible strategies to develop new effective therapies for COVID-19.

The genomic and bulked segregant analysis of Curcuma alismatifolia revealed its diverse bract pigmentation

Compared with most flowers where the showy part comprises specialized leaves(petals)directly subtending the reproductive structures,most Zingiberaceae species produce showy“flowers”through modifications of leaves(bracts)subtending the true flowers throughout an inflorescence.Curcuma alismatifolia,belonging to the Zingiberaceae family,a plant species originating from Southeast Asia,has become increasingly popular in the flower market worldwide because of its varied and esthetically pleasing bracts produced in different cultivars.Here,we present the chromosome-scale genome assembly of C.alismatifolia“Chiang Mai Pink”and explore the underlying mechanisms of bract pigmentation.Comparative genomic analysis revealed C.alismatifolia contains a residual signal of whole-genome duplication.Duplicated genes,including pigment-related genes,exhibit functional and structural differentiation resulting in diverse bract colors among C.alismatifolia cultivars.In addition,we identified the key genes that produce different colored bracts in C.alismatifolia,such as F3′5'H,DFR,ANS and several transcription factors for anthocyanin synthesis,as well as chlH and CAO in the chlorophyll synthesis pathway by conducting transcriptomic analysis,bulked segregant analysis using both DNA and RNA data,and population genomic analysis.This work provides data for understanding the mechanism of bract pigmentation and will accelerate breeding in developing novel cultivars with richly colored bracts in C.alismatifolia and related species.It is also important to understand the variation in the evolution of the Zingiberaceae family.

Antimicrobial peptide DP7 with potential activity against SARS coronavirus infections

Dear Editor,The outbreak of the SARS-CoV-2 epidemic once again demonstrates that RNA viruses,through mutations,genetic recombination and cross-species transmission,can pose a serious threat to the health of people worldwide.Even after the severe acute respiratory syndrome(SARS)and middle east respiratory syndrome(MERS)outbreaks,the world still initially lacked effective means to control the current coronavirus disease 2019(COVID-19)outbreak.We must work together to develop effective drugs to treat existing and future potential coronavirus infections to reduce their impact on the global health system and human life.Due to time constraints,the'conventional drug in new use#method has become the main method of treating SARS-CoV-2 infections.However,long-term drug development goals should include treatments that can produce broad-spectrum effects on different coronaviruses,and provide the means to alleviate disease symptoms and prevent death.

Therapeutic potential of an anti-HER2 single chain antibody-DM1 conjugates for the treatment of HER2-positive cancer

Antibody–drug conjugates(ADCs)take the advantage of monoclonal antibodies to selectively deliver highly potent cytotoxic drugs to tumor cells,which have become a powerful measure for cancer treatment in recent years.To develop a more effective therapy for human epidermal growth factor receptor 2(HER2)-positive cancer,we explored a novel ADCs composed of anti-HER2 scFv–HSA fusion antibodies conjugates with a potent cytotoxic drug DM1.The resulting ADCs,T-SA1–DM1 and T-SA2–DM1(drug-to-antibody ratio in the range of 3.2–3.5)displayed efficient inhibition in the growth of HER2-positive tumor cell lines and the half-maximal inhibitory concentration on SKBR-3 and SKOV3 cells were both at the nanomolar levels in vitro.In HER2-positive human ovarian cancer xenograft models,T-SA1–DM1 and T-SA2–DM1 also showed remarkable antitumor activity.Importantly,three out of six mice exhibited complete remission without regrowth in the high-dose group of T-SA1–DM1.On the basis of the analysis of luminescence imaging,anti-HER2 scFv–HSA fusion antibodies,especially T-SA1,showed strong and rapid tumor tissue penetrability and distribution compared with trastuzumab.Collectively,the novel type of ADCs is effective and selective targeting to HER2-positive cancer,and may be a promising antitumor drug candidate for further studies.

Semantic Segmentation of Sorghum Using Hyperspectral Data Identifies Genetic Associations

This study describes the evaluation of a range of approaches to semantic segmentation of hyperspectral images of sorghum plants,classifying each pixel as either nonplant or belonging to one of the three organ types(leaf,stalk,panicle).While many current methods for segmentation focus on separating plant pixels from background,organ-specific segmentation makes it feasible to measure a wider range of plant properties.Manually scored training data for a set of hyperspectral images collected from a sorghum association population was used to train and evaluate a set of supervised classification models.Many algorithms show acceptable accuracy for this classification task.Algorithms trained on sorghum data are able to accurately classify maize leaves and stalks,but fail to accurately classify maize reproductive organs which are not directly equivalent to sorghum panicles.Trait measurements extracted from semantic segmentation of sorghum organs can be used to identify both genes known to be controlling variation in a previously measured phenotypes(e.g.,panicle size and plant height)as well as identify signals for genes controlling traits not previously quantified in this population(e.g.,stalk/leaf ratio).Organ level semantic segmentation provides opportunities to identify genes controlling variation in a wide range of morphological phenotypes in sorghum,maize,and other related grain crops.