Stabilization of MYC G-quadruplex DNA by ruthenium(II)complex overcomes imatinib resistance in chronic myeloid leukemia cells harboring T315I mutation

The key pathogenesis of chronic myeloid leukemia(CML)is the formation of BCR-ABL fusion gene,encoding a 210 kDa Bcr-Abl tyrosine kinase,which is crucial for the occurrence and development of CML.Imatinib(IM)is the first targeted anticancer drug approved by FDA for the treatment of CML;however,some patients,especially those in accelerated phase and blastic phase,develop primary or secondary drug resistance to IM.Particularly,the most challenging resistance is caused by T315I mutation of Bcr-Abl,which represents approximately 15%–20%of all acquired mutations and renders cell resistant to a variety of tyrosine kinase inhibitors.1,2 Thus,there is an urgent need to develop novel strategies to overcome Bcr-Abl T315I-meidated IM resistance.

Suppression or knockout of SaF/SaM overcomes the Sa-mediated hybrid male sterility in rice

Hybrids between the indica and japonica subspecies of rice （Oryza sativa） are usually sterile, which hinders utilization of heterosis in the inter-subspecific hybrid breeding. The complex locus Sa comprises two adjacently located genes, SaF and SaM, which interact to cause abortion of pollen grains carrying the japonica allele in japonica-indica hybrids. Here we showed that silencing of SaF or SaM by RNA interference restored male fertility in indica-japonica hybrids with heterozygous Sa. We further used clustered regularly interspaced short palindromic repeats （CRISPR）/Cas9-based genome editing to knockout the SaF and SaM alleles, respectively, of an indica rice line to create hybrid-compatible lines. The resultant artificial neutral alleles did not affect pollen viability and other agricultural traits, but did break down the reproductive barrier in the hybrids. We found that some rice lines have natural neutral allele Sa-n, which was compatible with the typical japonica or indica Sa alleles in hybrids. Our results demonstrate that SaF and SaM are required for hybrid male sterility, but are not essential for pollen development. This study provides effective approaches for the generation of hybrid-compatible lines by knocking out the Sa locus or using the natural Sa-n allele to overcome hybrid male sterility in rice breeding.

Editorial for the Special Issue on Safety for Intelligent and Connected Vehicles

Intelligent and connected vehicles(ICVs)are confronted with critically complex traffic scenarios and safety challenges that have attracted increasing attention from academia and industry.The intelligent safety of ICVs involves several technologies and requires the common efforts of researchers and engineers,including the safety of the intended functionality(SOTIF),the safety of artificial intelligence,the intricacies of cybersecurity,and ethical dilemmas.Ensuring the intelligent safety of ICVs presents substantial chal-lenges in both research and commercialization,particularly SOTIF,which refers to the absence of unreasonable risk owing to hazards resulting from functional insufficiencies of the intended functiona-lity or reasonably foreseeable misuse by person.Because of the limited scene coverage ability of training samples and the practical application conditions without boundary restrictions,it is very dif-ficult to find the functional insufficiency of the intended function-ality and overcome it under dynamic unknown scenarios,which is also the source of SOTIF.

Mission of the National Cancer Center Hospital in Japan to promote clinical trials for precision medicine

Precision medicine is a growing field worldwide.Despite its potential benefit to many patients,several major obstacles must be overcome before precision medicine can be more widely used in clinical practice.The main obstacles are associated with the quality of samples used for genomic analysis。

Insights and implications of sexual dimorphism in osteoporosis

Osteoporosis,a metabolic bone disease characterized by low bone mineral density and deterioration of bone microarchitecture,has led to a high risk of fatal osteoporotic fractures worldwide.Accumulating evidence has revealed that sexual dimorphism is a notable feature of osteoporosis,with sex-specific differences in epidemiology and pathogenesis.Specifically,females are more susceptible than males to osteoporosis,while males are more prone to disability or death from the disease.To date,sex chromosome abnormalities and steroid hormones have been proven to contribute greatly to sexual dimorphism in osteoporosis by regulating the functions of bone cells.Understanding the sex-specific differences in osteoporosis and its related complications is essential for improving treatment strategies tailored to women and men.This literature review focuses on the mechanisms underlying sexual dimorphism in osteoporosis,mainly in a population of aging patients,chronic glucocorticoid administration,and diabetes.Moreover,we highlight the implications of sexual dimorphism for developing therapeutics and preventive strategies and screening approaches tailored to women and men.Additionally,the challenges in translating bench research to bedside treatments and future directions to overcome these obstacles will be discussed.

An Information-Based Elite-Guided Evolutionary Algorithm for Multi-Objective Feature Selection

Dear Editor, This letter is concerned with the evolution strategy for addressing multi-objective feature selection problems in classification. Previous methods suffer from limitations such as being trapped in local optima and lacking stability. To overcome them, we propose a novel eliteguided mechanism based on information theory. Firstly, an elite solution is generated through a dimension reduction strategy and incorporated to the initialization population.

Chinese Documentaries

Leprosy Annihilator Director:Lin Haiyan Length:Two Episodes Producer:Documentary Center of Shandong Radio and Television Broadcasting Platform:bilibili The film series narrate the story of a 70-year-long national initiative to prevent and control leprosy.Several generations of Chinese medical professionals worked tirelessly to overcome the infectious disease that has plagued humanity for thousands of years.The film shares the little-known history with an impressive production to increase awareness of the endeavor in modern times.

Young Chinese Baker Rocks “Bread Olympics”

A young Chinese baker became a world champion by pursuing his passion and working hard to overcome challenges.Adancing lion,giant panda,roller coaster,and a merry-go-round in eye-popping shapes-when these elements are grouped together,what kind of magic can happen?Winning magic if you are Gong Xin,a Gen Z baker from China who made a one-meter-high artistic creation using all of these elements.He won the ninth World Bread Competition(Mondial du Pain)as a result.Many Chinese found it hard to believe what he had done after seeing pictures.“This is virtually a work of art,”and“it is equivalent to a foreigner taking first place in a dumpling-making contest in China,”were some of the many online comments.As the host of the competition,France,famous for its bread-making techniques,was beaten into second place,leaving the French media shocked that a Chinese baker had won the famous world bread contest.

Sculpting The Intangible

China strives to overcome challenges to maximising the value of data.Data plays a crucial role in our daily lives,enabling personalised services based on consumer habits,granting loans based on credit histories,and facilitating telemedicine through the use of medical data.These applications are made possible by the processing and exchange of large volumes of data.

创造世界高原冻土铁路养护奇迹

Over decades,he faithfully adhered to the"life forbidden zone,"where he always fought on the front line of maintaining the Qinghai-Xizang Railway at an area with an average altitude of 4,700 meters and above.It is at this place where he led his team to face the hardest"obstacles"and overcome all sorts of problems and difficulties,thanks to the harsh freezing temperature environment.It is the place where he and his team have worked together to achieve a miraculous maintenance of the frozen-soil-featured railway line on top of the world.He is Gao Qiansheng.

Jinwang Bismuth Industrial Overcomes Resource Bottlenecks and Accelerates Transformation

Recent information about Jinwang Bismuth Industrial reveals that the company has developed the world’s first oxygen-rich sideblown redox duplex furnace technology,solving the long-standing problems of environmental protection and resource recycling in bismuth smelting.It’s learned that the company recovers up to100,000 tons of bismuth-containing lead-

Tunable spatial-frequency-shift 3D nanoscopy with chip compatibility overcomes the diffraction limit of the linear optical imaging system

The superresolution microscopy that broadens the detection range in the spatial frequency domain through the spatialfrequency-shift(SFS)effect[1-5]shows intriguing advantages including a large field of view,high speed,and good modularity.Significantly,it captures pictures in the wide-field mode and allows a universal implementation without using special fluorophores labeling.To enable the sub-diffraction resolution in the SFS microscopy,it is essential to use the evanescent wave illumination with a large wave vector,which can be built on the integrated photonic configuration,paving the way for a compact nanoscopy on a thin chip[6-8].However,the lack of an approach to actively tune the SFS value in a large range hampers the progress to achieve deep-subwavelength resolution through evanescent illumination with ultra-large wave vectors.When the wave vector of the illumination surpasses twice the cutoff frequency of the objective,a missing band exists between the shifted components and the zeroth component in the spatial frequency domain,which causes severe artifacts and a distortion in the image.As a result,the resolution of current linear SFS microscopy has been restricted less than thrice the Abbe diffraction limit of the detection system.

Corrigendum to“A novel inhibitor of MDM2 oncogene blocks metastasis of hepatocellular carcinoma and overcomes chemoresistance”[Genes Dis 694(2019)419e430]

We regret that an error was made in“A novel inhibitor of MDM2 oncogene blocks metastasis of hepatocellular carcinoma and overcomes chemoresistance”(Genes Dis 2019 Dec;694:419e430).In Fig.1C of the original manuscript,the right panel(showing the migration ability of the MHCCLM3 cells)was erroneously duplicated with the left panel(showing the migration ability of the Huh7 cells)when the figures were assembled.We have now checked the original data and request to replace the right panel with the correct data for MHCCLM3 cells.The corrected Fig.

Machine Learning With Data Assimilation and Uncertainty Quantification for Dynamical Systems:A Review

Data assimilation(DA)and uncertainty quantification(UQ)are extensively used in analysing and reducing error propagation in high-dimensional spatial-temporal dynamics.Typical applications span from computational fluid dynamics(CFD)to geoscience and climate systems.Recently,much effort has been given in combining DA,UQ and machine learning(ML)techniques.These research efforts seek to address some critical challenges in high-dimensional dynamical systems,including but not limited to dynamical system identification,reduced order surrogate modelling,error covariance specification and model error correction.A large number of developed techniques and methodologies exhibit a broad applicability across numerous domains,resulting in the necessity for a comprehensive guide.This paper provides the first overview of state-of-the-art researches in this interdisciplinary field,covering a wide range of applications.This review is aimed at ML scientists who attempt to apply DA and UQ techniques to improve the accuracy and the interpretability of their models,but also at DA and UQ experts who intend to integrate cutting-edge ML approaches to their systems.Therefore,this article has a special focus on how ML methods can overcome the existing limits of DA and UQ,and vice versa.Some exciting perspectives of this rapidly developing research field are also discussed.Index Terms-Data assimilation(DA),deep learning,machine learning(ML),reduced-order-modelling,uncertainty quantification(UQ).

Wood Crack Detection Based on Data-Driven Semantic Segmentation Network

Dear Editor, This letter is concerned with wood crack detection which is important to guarantee the quality of wooden products. In the wood industry, the crack detection is one of the most challenging tasks in the wood defects detection, since the detection accuracy may be reduced due to the stains on the boards, the tiny cracks, and some cracks that are similar to the sound region. To overcome these challenges.

Current and novel modalities for management of chronic hepatitis B infection

Over 296 million people are estimated to have chronic hepatitis B viral infection(CHB),and it poses unique challenges for elimination.CHB is the result of hepatitis B virus(HBV)-specific immune tolerance and the presence of covalently closed circular DNA as mini chromosome inside the nucleus and the integrated HBV.Serum hepatitis B core-related antigen is the best surrogate marker for intrahepatic covalently closed circular DNA.Functional HBV“cure”is the durable loss of hepatitis B surface antigen(HBsAg),with or without HBsAg seroconversion and undetectable serum HBV DNA after completing a course of treatment.The currently approved therapies are nucleos(t)ide analogues,interferon-alpha,and pegylated-interferon.With these therapies,functional cure can be achieved in<10%of CHB patients.Any variation to HBV or the host immune system that disrupts the interaction between them can lead to reactivation of HBV.Novel therapies may allow efficient control of CHB.They include direct acting antivirals and immunomodulators.Reduction of the viral antigen load is a crucial factor for success of immune-based therapies.Immunomodulatory therapy may lead to modulation of the host immune system.It may enhance/restore innate immunity against HBV(as toll-like-receptors and cytosolic retinoic acid inducible geneⅠagonist).Others may induce adaptive immunity as checkpoint inhibitors,therapeutic HBV vaccines including protein(HBsAg/pre S and hepatitis B core antigen),monoclonal or bispecific antibodies and genetically engineered T cells to generate chimeric antigen receptor-T or T-cell receptor-T cells and HBV-specific T cells to restore T cell function to efficiently clear HBV.Combined therapy may successfully overcome immune tolerance and lead to HBV control and cure.Immunotherapeutic approaches carry the risk of overshooting immune responses causing uncontrolled liver damage.The safety of any new curative therapies should be measured in relation to the excellent safety of currently approved nucleos(t)ide analogues.Development of novel antiviral and immune modulatory therapies should be associated with new diagnostic assays used to evaluate the effectiveness or to predict response.

Intermittent Control for Fixed-Time Synchronization of Coupled Networks

Dear Editor, This letter deals with fixed-time synchronization(Fd-TS) of complex networks(CNs) under aperiodically intermittent control(AIC)for the first time. The average control rate and a new Lyapunov function are proposed to overcome the difficulty of dealing with fixedtime stability/synchronization of CNs for AIC.

Bacterial droplet-based single-cell RNA-seq reveals antibiotic-associated heterogeneous cellular states

We introduce BacDrop, a highly scalable technology for bacterial single-cell RNA sequencing that has overcome manychallenges hindering the development of scRNA-seq in bacteria. BacDrop can be applied to thousands to millions of cells fromboth gram-negative and gram-positive species. It features universal ribosomal RNA depletion and combinatorial barcodes thatenable multiplexing and massively parallel sequencing. We applied BacDrop to study Klebsiella pneumoniae clinical isolates andto elucidate their heterogeneous responses to antibiotic stress. In an unperturbed population presumed to be homogeneous, wefound within-population heterogeneity largely driven by the expression of mobile genetic elements that promote the evolution ofantibiotic resistance. Under antibiotic perturbation, BacDrop revealed transcriptionally distinct subpopulations associated withdifferent phenotypic outcomes including antibiotic persistence. BacDrop thus can capture cellular states that cannot be detectedby bulk RNA-seq, which will unlock new microbiological insights into bacterial responses to perturbations and larger bacterialcommunities such as the microbiome.

Quite amusing stem cells:Muse cells

Stem cells may be the future of therapeutics for stroke due to their regenerative and immunomodulatory capabilities.Major barriers faced when employing stem cells,however,include faulty migration,low cell survival,and diminished proliferation.M ultilineage-differentiating stress ensuring (Muse) cells,a subset of mesenchymal stem cells,overcome these barriers.Muse cells aid in neuroregeneration,have immense regenerative potential,and are pluripotent,non-tumorigenic,and immunomodulatory.In stroke specifically,these cells may restore an a nti-inflammatory environment,regenerate damaged neurons,and integrate into the neuronal architecture.In fact,Muse cells may be aptly designed to ameliorate neurovascular unit damage following stroke and observed in other neuroinflammatory disorders.

Evidence of bisphosphonate-conjugated sitafloxacin eradication of established methicillin-resistant S.aureus infection with osseointegration in murine models of implant-associated osteomyelitis

Eradication of MRSA osteomyelitis requires elimination of distinct biofilms.To overcome this,we developed bisphosphonateconjugated sitafloxacin(BCS,BV600072)and hydroxybisphosphonate-conjugate sitafloxacin(HBCS,BV63072),which achieve“target-and-release”drug delivery proximal to the bone infection and have prophylactic efficacy against MRSA static biofilm in vitro and in vivo.Here we evaluated their therapeutic efficacy in a murine 1-stage exchange femoral plate model with bioluminescent MRSA(USA300LAC::lux).Osteomyelitis was confirmed by CFU on the explants and longitudinal bioluminescent imaging(BLI)after debridement and implant exchange surgery on day 7,and mice were randomized into seven groups:1)Baseline(harvested at day7,no treatment);2)HPBP(bisphosphonate control for BCS)+vancomycin;3)HPHBP(hydroxybisphosphonate control for HBCS)+vancomycin;4)vancomycin;5)sitafloxacin;6)BCS+vancomycin;and 7)HBCS+vancomycin.BLI confirmed infection persisted in all groups except for mice treated with BCS or HBCS+vancomycin.Radiology revealed catastrophic femur fractures in all groups except mice treated with BCS or HBCS+vancomycin,which also displayed decreases in peri-implant bone loss,osteoclast numbers,and biofilm.To confirm this,we assessed the efficacy of vancomycin,sitafloxacin,and HBCS monotherapy in a transtibial implant model.The results showed complete lack of vancomycin efficacy while all mice treated with HBCS had evidence of infection control,and some had evidence of osseous integrated septic implants,suggestive of biofilm eradication.Taken together these studies demonstrate that HBCS adjuvant with standard of care debridement and vancomycin therapy has the potential to eradicate MRSA osteomyelitis.