Telomere-to-telomere and gap-free reference genome assembly of the kiwifruit Actinidia chinensis

Kiwifruit is an economically and nutritionally important fruit crop with extremely high contents of vitamin C.However,the previously released versions of kiwifruit genomes all have a mass of unanchored or missing regions.Here,we report a highly continuous and completely gap-free reference genome of Actinidia chinensis cv.‘Hongyang’,named Hongyang v4.0,which is the first to achieve two de novo haploid-resolved haplotypes,HY4P and HY4A.HY4P and HY4A have a total length of 606.1 and 599.6 Mb,respectively,with almost the entire telomeres and centromeres assembled in each haplotype.In comparison with Hongyang v3.0,the integrity and contiguity of Hongyang v4.0 is markedly improved by filling all unclosed gaps and correcting some misoriented regions,resulting in∼38.6–39.5 Mb extra sequences,which might affect 4263 and 4244 protein-coding genes in HY4P and HY4A,respectively.Furthermore,our gap-free genome assembly provides the first clue for inspecting the structure and function of centromeres.Globally,centromeric regions are characterized by higher-order repeats that mainly consist of a 153-bp conserved centromere-specific monomer(Ach-CEN153)with different copy numbers among chromosomes.Functional enrichment analysis of the genes located within centromeric regions demonstrates that chromosome centromeres may not only play physical roles for linking a pair of sister chromatids,but also have genetic features for participation in the regulation of cell division.The availability of the telomere-to-telomere and gap-free Hongyang v4.0 reference genome lays a solid foundation not only for illustrating genome structure and functional genomics studies but also for facilitating kiwifruit breeding and improvement.

Applying DNA Barcoding to Identify Actinidia in the Northeast of China

Identification of kiwifruit germplasm materials is the basis of protecting and utilizing these resources. However,identifying Actinidia arguta varieties based on morphology is difficult,especially for non-specialists. In this study,we collected 180 specimens comprising 60 varieties of three species（ A. arguta,A. kolomikta,and A. polygama） from the Northeast of China. The emphasis of our study was on the feasibility of identifying A. arguta varieties. Here,we used common analysis methods（ genetic distance,phylogenetic analysis and the DNA barcoding gap） and SNPs analysis to evaluate the discriminatory power of different DNA barcoding markers. The results revealed that common methods were insufficient to identify A. arguta varieties but SNPs analysis based on DNA barcoden was the potential method for identifying A. arguta varieties. Besides,Our study agree that DNA barcoding could be used to analysis the evaluation genetic relationship of the Actinidia plants.

A multicenter study of the clinicopathological characteristics and a risk prediction model of early-stage breast cancer with hormone receptor-positive/human epidermal growth factor receptor 2-low expression

Background:In light of the significant clinical benefits of antibody-drug conjugates in clinical trials,the human epidermal growth factor receptor 2(HER2)-low category in breast cancers has gained increasing attention.Therefore,we studied the clinicopathological characteristics of Chinese patients with hormone receptor(HR)-positive/HER2-low early-stage breast cancer and developed a recurrence risk prediction model.Methods:Female patients with HR-positive/HER2-low early-stage breast cancer treated in 29 hospitals of the Chinese Society of Breast Surgery(CSBrS)from Jan 2015 to Dec 2016 were enrolled.Their clinicopathological data and prognostic information were collected,and machine learning methods were used to analyze the prognostic factors.Results:In total,25,096 patients were diagnosed with breast cancer in 29 hospitals of CSBrS from Jan 2015 to Dec 2016,and clinicopathological data for 6486 patients with HER2-low early-stage breast cancer were collected.Among them,5629 patients(86.79%)were HR-positive.The median follow-up time was 57 months(4,76 months);the 5-year disease-free survival(DFS)rate was 92.7%,and the 5-year overall survival(OS)rate was 97.7%.In total,412 cases(7.31%)of metastasis were observed,and 124(2.20%)patients died.Multivariate Cox regression analysis revealed that T stage,N stage,lymphovascular thrombosis,Ki-67 index,and prognostic stage were associated with recurrence and metastasis(P<0.05).A recurrence risk prediction model was established using the random forest method and exhibited a sensitivity of 81.1%,specificity of 71.7%,positive predictive value of 74.1%,and negative predictive value of 79.2%.Conclusion:Most of patients with HER2-low early-stage breast cancer were HR-positive,and patients had favorable outcome;tumor N stage,lymphovascular thrombosis,Ki-67 index,and tumor prognostic stage were prognostic factors.The HR-positive/HER2-low early-stage breast cancer recurrence prediction model established based on the random forest method has a good reference value for predicting 5-year recurrence events.Registritation:ChiCTR.org.cn,ChiCTR2100046766.

Myeloid-specific targeting of Notch ameliorates murine renal fibrosis via reduced infiltration and activation of bone marrowderived macrophage

Macrophages play critical roles in renal fibrosis.However,macrophages exhibit ontogenic and functional heterogeneities,and which population of macrophages contributes to renal fibrosis and the underlying mechanisms remain unclear.In this study,we genetically targeted Notch signaling by disrupting the transcription factor recombination signal binding protein-JK(RBP-J),to reveal its role in regulation of macrophages during the unilateral ureteral obstruction(UUO)-induced murine renal fibrosis.Myeloid-specific disruption of RBP-J attenuated renal fibrosis with reduced extracellular matrix deposition and myofibroblast activation,as well as attenuated epithelial-mesenchymal transition,likely owing to the reduced expression of TGF-β.Mean while,RBP-J deletion significantly hampered macrophage infiltration and activation in fibrotic kidney,although their proliferation appeared unaltered.By using macrophage clearance experiment,we found that kidney resident macrophages made negligible contribution,but bone marrow(BM)-derived macrophages played a major role in renal fibrogenesis.Further mechanistic analyses showed that Notch blockade reduced monocyte emigration from BM by down-regulating CCR2 expression.Finally,we found that myeloid-specific Notch activation aggravated renal fibrosis,which was mediated by CCR2^+macrophages infiltration.In summary,our data have unveiled that myeloid-specific targeting of Notch could ameliorate renal fibrosis by regulating BM-derived macrophages recruitment and activation,providing a novel strategy for intervention of this disease.

Multicenter study of the clinicopathological features and recurrence risk prediction model of early-stage breast cancer with low-positive human epidermal growth factor receptor 2 expression in China (Chinese Society of Breast Surgery 021)

Background:Breast cancer with low-positive human epidermal growth factor receptor 2(HER2)expression has triggered further refinement of evaluation criteria for HER2 expression.We studied the clinicopathological features of early-stage breast cancer with low-positive HER2 expression in China and analyzed prognostic factors.Methods:Clinical and pathological data and prognostic information of patients with early-stage breast cancer with low-positive HER2 expression treated by the member units of the Chinese Society of Breast Surgery and Chinese Society of Surgery of Chinese Medical Association,from January 2015 to December 2016 were collected.The prognostic factors of these patients were analyzed.Results:Twenty-nine hospitals provided valid cases.From 2015 to 2016,a total of 25,096 cases of early-stage breast cancer were treated,7642(30.5%)of which had low-positive HER2 expression and were included in the study.After ineligible cases were excluded,6486 patients were included in the study.The median follow-up time was 57 months(4-76 months).The disease-free survival rate was 92.1%at 5 years,and the overall survival rate was 97.4%at 5 years.At the follow-up,506(7.8%)cases of metastasis and 167(2.6%)deaths were noted.Multivariate Cox regression analysis showed that tumor stage,lymphvascular invasion,and the Ki67 index were related to recurrence and metastasis(P<0.05).The recurrence risk prediction model was established using a machine learning model and showed that the area under the receiving operator characteristic curve was 0.815(95%confidence interval:0.750-0.880).Conclusions:Early-stage breast cancer patients with low-positive HER2 expression account for 30.5%of all patients.Tumor stage,lymphvascular invasion,and the Ki67 index are factors affecting prognosis.The recurrence prediction model for breast cancer with low-positive HER2 expression based on a machine learning model had a good clinical reference value for predicting the recurrence risk at 5 years.Trial registration:ChiCTR.org.cn,ChiCTR2100046766.

Augmented renal clearance in Chinese intensive care unit patients after traumatic brain injury: a cross-sectional study

To the Editor:Augmented renal clearance(ARC)refers to an enhanced elimination of circulating solutes,including drugs,by the kidneys at a rate statistically higher than normal.On the first day of intensive care unit(ICU)admission,ARC occurrence may predict continued creatinine clearance(CrCl)elevation for 1 day to several weeks.[1]ARC has a substantial adverse effect on renally cleared antibiotics'pharmacokinetics/pharmacodynamics.Treatment failure or worse outcomes are more frequent in ARC patients.Thus,a"one size fits all"approach to drug dosing in ARC patients is inappropriate;dosing requires adjustment for some variables.

Developing new drugs from annals of Chinese medicine

Developing new pharmaceuticals requires massive amounts of time,money and efforts.The key step is how to find a safe and effective entity for a disease condition and how to develop it as new drug effectively.Unfortunately,the FDA’s rate of approving new entities has declined dramatically in the last three decades.There is a strong need to review the current strategy and to optimize process in developing new drugs,both to shorten the process and increase the success rate.Chinese medicine has used natural products to treat patients for thousands of years,and Chinese medicine practitioners have chronicled the patients and treatment methods for thousands of years.There is much information that has not yet been used.The success stories of artimisinin and arsentic trioxide are wonderful examples of how the annals of Chinese medicine can provide leads for discovering new drugs.This paper argues that the annals of Chinese medicine are valuable and describes how they can be used in modern drug discovery.The major topics addressed are:(i)why Chinese medicine is a rich resource for finding new drugs;(ii)how to identify a potential valuable record from Chinese medicine annals;(iii)when a potential valuable record is identified from annals,how to proceed;and(iv)both why and how the approach used for chemical drugs should be revised for drugs based on the historical documents related to herbal medicine.In conclusion,we argue here that the annals of Chinese medicine offer not only a rich resource for new drugs,but also several centuries of patient data with regard to safety and efficacy,that in effect represent pilot studies.Acknowledging and using these data can shorten new drug discovery time and improve efficiency of the drug development process,bringing more effective,safe drugs to market much more quickly and cheaply.