Decoding the complexity of metastasis

Cancer metastasis remains one of the most confounding questions in oncology1,2.Although current cutting-edge techniques enable very early detection of tumors,profiling whether a tumor has already begun to spread and where it has attempted to colonize remains a major hurdle.Indeed,metastatic seeding events exhibit remarkable temporal and spatial heterogeneity,wherein the origin(primary site)and destination(metastatic site)are highly dynamic.For example,liver metastasis is particularly common and remains a leading cause of mortality3.

Prediction of gastric cancer risk by a polygenic risk score of Helicobacter pylori

BACKGROUND Genetic variants of Helicobacter pylori(H. pylori) are involved in gastric cancer occurrence. Single nucleotide polymorphisms(SNPs) of H. pylori that are associated with gastric cancer have been reported. The combined effect of H. pylori SNPs on the risk of gastric cancer remains unclear.AIM To assess the performance of a polygenic risk score(PRS) based on H. pylori SNPs in predicting the risk of gastric cancer.METHODS A total of 15 gastric cancer-associated H. pylori SNPs were selected. The associations between these SNPs and gastric cancer were further validated in 1022 global strains with publicly available genome sequences. The PRS model was established based on the validated SNPs. The performance of the PRS for predicting the risk of gastric cancer was assessed in global strains using quintiles and random forest(RF) methods. The variation in the performance of the PRS among different populations of H. pylori was further examined.RESULTS Analyses of the association between selected SNPs and gastric cancer in the global dataset revealed that the risk allele frequencies of six SNPs were significantly higher in gastric cancer cases than non-gastric cancer cases. The PRS model constructed subsequently with these validated SNPs produced significantly higher scores in gastric cancer. The odds ratio(OR) value for gastric cancer gradually increased from the first to the fifth quintile of PRS, with the fifth quintile having an OR value as high as 9.76(95% confidence interval: 5.84-16.29). The results of RF analyses indicated that the area under the curve(AUC) value for classifying gastric cancer and non-gastric cancer was 0.75, suggesting that the PRS based on H. pylori SNPs was capable of predicting the risk of gastric cancer. Assessing the performance of the PRS among different H. pylori populations demonstrated that it had good predictive power for cancer risk for hp Europe strains, with an AUC value of 0.78.CONCLUSION The PRS model based on H. pylori SNPs had a good performance for assessment of gastric cancer risk. It would be useful in the prediction of final consequences of the H. pylori infection and beneficial for the management of the infection in clinical settings.

RIPK1 plays a crucial role in maintaining regulatory T-Cell homeostasis by inhibiting both RIPK3-and FADD-mediated cell death

Regulatory T(T_(reg))cells play an essential role in maintaining immune balance across various physiological and pathological conditions.However,the mechanisms underlying T_(reg)homeostasis remain incompletely understood.Here,we report that RIPK1 is crucial for T_(reg) cell survival and homeostasis.We generated mice with T_(reg) cell-specific ablation of Ripk1 and found that these mice developed fatal systemic autoimmunity due to a dramatic reduction in the Treg cell compartment caused by excessive cell death.Unlike conventional T cells,Treg cells with Ripk1 deficiency were only partially rescued from cell death by blocking FADD-dependent apoptosis.However,simultaneous removal of both Fadd and Ripk3 completely restored the homeostasis of Ripk1-deficient Treg cells by blocking two cell death pathways.Thus,our study highlights the critical role of RIPK1 in regulating Treg cell homeostasis by controlling both apoptosis and necroptosis,thereby providing novel insights into the mechanisms of Treg cell homeostasis.

Discovery of Trametinib as an orchestrator for cytoskeletal vimentin remodeling

The dynamic remodeling of the cytoskeletal network of vimentin intermediate filaments supports various cellular functions,including cell morphology,elasticity,migration,organelle localization,and resistance against mechanical or pathological stress.Currently available chemicals targeting vimentin predominantly induce network reorganization and shrinkage around the nucleus.Effective tools for long-term manipulation of vimentin network dispersion in living cells are still lacking,limiting in-depth studies on vimentin function and potential therapeutic applications.Here,we verified that a commercially available small molecule,trametinib,is capable of inducing spatial spreading of the cellular vimentin network without affecting its transcriptional or Translational regulation.Further evidence confirmed its low cytotoxicity and similar effects on different cell types.Importantly,Trametinib has no impact on the other two cytoskeletal systems,actin filaments and the microtubule network.Moreover,Trametinib regulates vimentin network dispersion rapidly and efficiently,with effects persisting for up to 48 h after drug withdrawal.We also ruled out the possibility that Trametinib directly affects the phosphorylation level of vimentin.In summary,we identified an unprecedented regulator Trametinib,which is capable of spreading the vimentin network toward the cell periphery,and thus complemented the existing repertoire of vimentin remodeling drugs in the field of cytoskeletal research.

mRNA vaccine technology for infectious diseases and beyond

The rise of mRNA vaccine technology Vaccines stand as one of the most significant medical advancements,playing a crucial role in the prevention of infectious diseases and the improvement of global health.The triumph of smallpox vaccination stands as a towering achievement in the annals of healthcare,leading to the complete elimination of a oncedevastating disease and showcasing the efficacy of vaccination methods.

Assessing risk of Bombali virus spillover to humans by mutagenesis analysis of viral glycoprotein

Ebolaviruses,such as the highly pathogenic Ebola virus(EBOV),belong to the family Filoviridae and have caused out-breaks of severe and fatal hemorrhagic fever over the past years.Bombali virus(BOMV)is a newly discovered ebolavirus from bats with unknown potential to infect humans.For most ebolaviruses,the interaction between viral glycoprotein(GP)and host receptor Niemann-Pick C1(NPC1)is crucial for viral entry and determines host tropism.Here,we analyzed the BOMV GP-mediated virus entry into human cells using our recently developed EBOV transcription-and replication-competent virus-like particle(trVLP)system.We demonstrated that while BOMV GP can be efficiently incorporated into trVLPs,it is inefficient in mediating trVLP entry into human cells.However,BOMV GP-mediated virus entry into human cells can be significantly enhanced by a few mutations in the NPC1-binding domain of GP.Furthermore,we showed that these mutations increase the binding of BOMV-GP to human NPC1.In summary,our results suggested that although wild-type BOMV does not efficiently infect human cells,the emergence of mutations in viral GP may boost its ability to spill over to humans,highlighting the importance of monitoring BOMV GP evolution in preventing potential BOMV spillover events.

National Epidemiology and Evolutionary History of Four Hand, Foot and Mouth Disease-Related Enteroviruses in China from 2008 to 2016

Hand, foot and mouth disease(HFMD) is a major public health concern in China. The most predominant enteroviruses that cause HFMD have traditionally been attributed to enterovirus A71(EVA71) and coxsackievirus A16(CVA16). Since its first large outbreak in 2008, the dominant HFMD pathogens are constantly changing. In 2013 and 2015, CVA6 exceeded both EVA71 and CVA16 to become the leading cause of HFMD in some provinces. However, there still lacks a comprehensive overview on the molecular epidemiology and evolution of HFMD-related enteroviruses at the national level. In this study, we performed systematic epidemiological analyses of HFMD-related enteroviruses using the data of 64 published papers that met the inclusion criteria, and conducted phylogenetic analyses based on 12,080 partial VP1 sequences identified in China before 31 st June 2018. We found that EVA71 prevalence has decreased sharply but other enteroviruses have increased rapidly from 2008 to 2016 and that one subtype of each enterovirus is represented during the epidemic. In addition, four genotypes EVA71_C4, CVA16_B1, CVA6_D and CVA10_C are the most predominant enterovirus strains and collectively they cause over 90% of all HFMD cases in China according to the phylogenetic trees using representative partial VP1 sequences. These four major enterovirus genotypes have different geographical distributions, and they may cocirculate with other genotypes and serotypes. These results suggest that more molecular epidemiological studies should be performed on several enteroviruses simultaneously, and such information should have implications for virological surveillance, disease management, vaccine development and policy-making on the prevention and control of HFMD.

Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission

Dear Editor,The occurrence of concentrated pneumonia cases in Wuhan city,Hubei province of China was first reported on December 30,2019 by the Wuhan Municipal Health Commission(WHO,2020).The pneumonia cases were found to be linked to a large seafood and animal market in Wuhan,and measures for sanitation and disinfection were taken swiftly by the local government agency.The Centers for Disease Control and Prevention(CDC)and Chinese health authorities later determined and announced that a novel coronavirus(CoV),denoted as 2019-nCoV,had caused the pneumonia outbreak in Wuhan city(CDC,2020).Scientists from multiple groups had obtained the virus samples from hospitalized patients(Normile,2020).The isolated viruses were morphologically identical when observed under electron microscopy.

Combined effects of p53 and MDM2 polymorphisms on susceptibility and surgical prognosis in hepatitis B virus-related hepatocellular carcinoma

The p53 signaling pathway works as a potent barrier to tumor progression.Two single nucleotide polymor-phisms(SNPs)in the gene loci of p53 pathway,p53 codon 72 Arg72Pro and MDM2 SNP309(T>G),have been shown to cause perturbation of p53 function,but the effect of the two SNPs on the risk of hepatocellular carcinoma(HCC)remains inconsistent.This study in-vestigated the influence of combined p53 Arg72Pro and MDM2 SNP309 on the risk of developing HCC in pa-tients with chronic hepatitis B virus infection,and evaluated the significance of the two combined SNPs on patient prognosis.In total,350 HCC patients,230 non-HCC patients,and 96 healthy controls were geno-typed for the p53 Arg72Pro and MDM2 SNP309.The combined p53 Pro/Pro and MDM2 G/G genotype was significantly associated with HCC risk(P=0.047).Mul-tivariate analysis indicated that combined p53 Pro/Pro and MDM2 G/G genotype was an independent factor affecting recurrence and survival(P<0.05).Patients with combined p53 Pro/Pro and MDM2 G/G genotypes had a poorer prognosis than other genotypes,P<0.01 for both disease-free survival(DFS)and overall survival(OS).DFS and OS rates also differed significantly be-tween Barcelona Clinic Liver Cancer(BCLC)stage A patients with combined p53 Pro/Pro and MDM2 G/G and other genotypes(P<0.05).Thus,the combined p53 Pro/Pro and MDM2 G/G genotype is associated with increased risk of developing HCC and is an independ-ent adverse prognostic indicator in early stage HCC.

Genetic Variation of Multiple Serotypes of Enteroviruses Associated with Hand, Foot and Mouth Disease in Southern China

Enteroviruses(EVs)species A are a major public health issue in the Asia–Pacific region and cause frequent epidemics of hand,foot and mouth disease(HFMD)in China.Mild infections are common in children;however,HFMD can also cause severe illness that affects the central nervous system.To molecularly characterize EVs,a prospective HFMD virological surveillance program was performed in China between 2013 and 2016.Throat swabs,rectal swabs and stool samples were collected from suspected HFMD patients at participating hospitals.EVs were detected using generic real-time and nested reverse transcription-polymerase chain reactions(RT-PCRs).Then,the complete VP1 regions of enterovirus A71(EV-A71),coxsackievirus A16(CVA16)and CVA6 were sequenced to analyze amino acid changes and construct a viral molecular phylogeny.Of the 2836 enrolled HFMD patients,2,517(89%)were EV positive.The most frequently detected EVs were CVA16(32.5%,819),CVA6(31.2%,785),and EV-A71(20.4%,514).The subgenogroups CVA16B1 b,CVA6D3 a and EV-A71C4 a were predominant in China and recombination was not observed in the VP1 region.Sequence analysis revealed amino acid variations at the 30,29 and 44 positions in the VP1 region of EV-A71,CVA16 and CVA6(compared to the respective prototype strains Br Cr,G10 and Gdula),respectively.Furthermore,in 21 of 24(87.5%)identified EV-A71 samples,a known amino acid substitution(D31 N)that may enhance neurovirulence was detected.Our study provides insights about the genetic characteristics of common HFMD-associated EVs.However,the emergence and virulence of the described mutations require further investigation.

BL19U2:Small-angle X-ray scattering beamline for biological macromolecules in solution at SSRF

The BL19U2 at the Shanghai Synchrotron Radiation Facility is a small-angle X-ray scattering beamline dedicated to structural studies pertaining to biological macromolecules in solution.The beamline has been officially opened to users in March 2015,and since then,a series of technological innovations has been developed to optimize beamline performance,thereby significantly improving the data collection efficiency and broadening the application scope of biological small-angle X-ray scattering.BL19U2 is ideal for the high-throughput screening of weakly scattered proteins,protein assemblies,nucleic acids,inorganic nanomaterials,and organic drug molecules.This paper describes the design and overview of the BL19U2 beamline.Versatile sample environments at the experimental station and some recent scientific highlights are presented.

Achievements, challenges and prospects for the development of broadly protective multivalent vaccines and therapeutic antibodies against hand, foot and mouth disease

Hand, foot and mouth disease(HFMD) is a significant health concern in the Asia–Pacific regions for infants and young children in recent years. However, no vaccines or therapeutics are available at present. The causative agents for HFMD include human enterovirus 71(EV71), coxsackievirus A16(CVA16) and some other viruses. Recently, tremendous progress has been made in the development of monovalent and bivalent vaccines against HFMD. A few neutralizing monoclonal antibodies against EV71 or CVA16 have been identified and characterized. Here, we reviewed some achievements for the development of broadly protective vaccines and neutralizing antibodies against HFMD, and discussed challenges and prospects toward broadly protective multivalent vaccines and therapeutic antibodies against HFMD.

Both structure and function of human monoclonal antibodies contribute to enhancement of Zika virus infectivity in vitro

Dear Editor,Antibody-dependent enhancement（ADE）has long been recognized for dengue virus（DENV）in vitro and in vivo.It is now clear that antibodies to DENV can also enhance Zika virus（ZIKV）infection in vitro,and vice versa（Dejnirattisai et al.,2016;Stettler et al.,2016）.The characteristics of enhancing antibodies,however,remain elusive.

Design,synthesis,and biological evaluation of multiple targeting antimalarials

Malaria still threatens global health seriously today.While the current discoveries of antimalarials are almost totally focused on single mode-of-action inhibitors,multi-targeting inhibitors are highly desired to overcome the increasingly serious drug resistance.Here,we performed a structure-based drug design on mitochondrial respiratory chain of Plasmodium falciparum and identified an extremely potent molecule,RYL-581,which binds to multiple protein binding sites of P.falciparum simultaneously(allosteric site of type Ⅱ NADH dehydrogenase,Q_(o) and Q_(i) sites of cytochrome bc_(1)).Antimalarials with such multiple targeting mechanism of action have never been reported before.RYL-581 kills various drug-resistant strains in vitro and shows good solubility as well as in vivo activity.This structurebased strategy for designing RYL-581 from starting compound may be helpful for other medicinal chemistry projects in the future,especially for drug discovery on membrane-associated targets.

Ancient origin and complex evolution of porcine endogenous retroviruses

Porcine endogenous retroviruses(PERVs)are proviruses that have medical value in xenotransplantation.However,the evolutionary process leading to the generation of modern PERVs is not well understood.In this study,we in silico mined 14 pig genomes and other available 304 mammalian genomes,which led to the documentation of 185 full-length PERVs or PERV-like sequences.Notably,we found that lesser Egyptian jerboa(Jaculus jaculus),rock hyrax(Procavia capensis)and eight Muridae species all harbored ancestral PERV-like sequences,indicative of ancient cross-species transmission events from none-porcine species to pigs.We also revealed that 11 genomic rearrangement events were mediated via PERVs,during the process of porcine evolution.In conclusion,these new findings help us to understand the complex evolution of the modern PERVs.

Multi-valent mRNA vaccines against monkeypox enveloped or mature viron surface antigens demonstrate robust immune response and neutralizing activity

Monkeypox was declared a global health emergency by the World Health Organization,and as of March 2023,86,000 confirmed cases and 111 deaths across 110 countries have been reported.Its causal agent,monkeypox virus(MPV)belongs to a large family of double-stranded DNA viruses,Orthopoxviridae,that also includes vaccinia virus(VACV)and others.MPV produces two distinct forms of viral particles during its replication cycles:the enveloped viron(EV)that is released via exocytosis,and the mature viron(MV)that is discharged through lysis of host cells.This study was designed to develop multi-valent m RNA vaccines against monkeypox EV and MV surface proteins,and examine their efficacy and mechanism of action.Four m RNA vaccines were produced with different combinations of surface proteins from EV(A35R and B6R),MV(A29L,E8L,H3L and M1R),or EV and MV,and were administered in Balb/c mice to assess their immunogenicity potentials.A dynamic immune response was observed as soon as seven days after initial immunization,while a strong Ig G response to all immunogens was detected with ELISA after two vaccinations.The higher number of immunogens contributed to a more robust total Ig G response and correlating neutralizing activity against VACV,indicating the additive potential of each immunogen in generating immune response and nullifying VACV infection.Further,the m RNA vaccines elicited an antigen-specific CD4^(+)T cell response that is biased towards Th1.The m RNA vaccines with different combinations of EVand MV surface antigens protected a mouse model from a lethal dose VACV challenge,with the EV and MV antigens-combined vaccine offering the strongest protection.These findings provide insight into the protective mechanism of multi-valent m RNAvaccines against MPV,and also the foundation for further development of effective and safe m RNA vaccines for enhanced protection against monkeypox virus outbreak.

TRP (transient receptor potential) ion channel family:structures, biological functions and therapeutic interventions for diseases

Transient receptor potential(TRP)channels are sensors for a variety of cellular and environmental signals.Mammals express a total of 28 different TRP channel proteins,which can be divided into seven subfamilies based on amino acid sequence homology:TRPA(Ankyrin),TRPC(Canonical),TRPM(Melastatin),TRPML(Mucolipin),TRPN(NO-mechano-potential,NOMP),TRPP(Polycystin),TRPV(Vanilloid).They are a class of ion channels found in numerous tissues and cell types and are permeable to a wide range of cations such as Ca^(2+),Mg^(2+),Na^(+),K^(+),and others.TRP channels are responsible for various sensory responses including heat,cold,pain,stress,vision and taste and can be activated by a number of stimuli.Their predominantly location on the cell surface,their interaction with numerous physiological signaling pathways,and the unique crystal structure of TRP channels make TRPs attractive drug targets and implicate them in the treatment of a wide range of diseases.Here,we review the history of TRP channel discovery,summarize the structures and functions of the TRP ion channel family,and highlight the current understanding of the role of TRP channels in the pathogenesis of human disease.Most importantly,we describe TRP channel-related drug discovery,therapeutic interventions for diseases and the limitations of targeting TRP channels in potential clinical applications.

Quantitatively mapping local quality of super-resolution microscopy by rolling Fourier ring correlation

In fluorescence microscopy,computational algorithms have been developed to suppress noise,enhance contrast,and even enable super-resolution(SR).However,the local quality of the images may vary on multiple scales,and these differences can lead to misconceptions.Current mapping methods fail to finely estimate the local quality,challenging to associate the SR scale content.Here,we develop a rolling Fourier ring correlation(rFRC)method to evaluate the reconstruction uncertainties down to SR scale.To visually pinpoint regions with low reliability,a filtered rFRC is combined with a modified resolution-scaled error map(RSM),offering a comprehensive and concise map for further examination.We demonstrate their performances on various SR imaging modalities,and the resulting quantitative maps enable better SR images integrated from different reconstructions.Overall,we expect that our framework can become a routinely used tool for biologists in assessing their image datasets in general and inspire further advances in the rapidly developing field of computational imaging.

Advances in treatment strategies for COVID-19:Insights from other coronavirus diseases and prospects

The coronavirus disease 2019(COVID‐19)pandemic is the third human disease outbreak caused by an emerging coronavirus in the 21st century.Caused by severe acute respiratory syndrome coronavirus 2(SARS‐CoV‐2),the COVID‐19 pandemic has been the most devastating,with millions of deaths.Medical countermeasures are needed to limit the number of infections and fatalities.Here,we discuss advances in clinical and research‐based treatment methods for SARS‐CoV‐2 that were initially derived from treatments for other coronaviruses.Recent advances in SARS‐CoV‐2 treatments,from traditional drugs and immunotherapies to artificial intelligence to predict potential future treatment methods,are summarized and discussed.

Histone Deacetylase Inhibitor SAHA Induces Expression of Fatty Acid-Binding Protein 4 and Inhibits Replication of Human Cytomegalovirus

Suberoylanilide hydroxamic acid(SAHA) is a histone deacetylase inhibitor that shows marked efficacy against many types of cancers and is approved to treat severe metastatic cutaneous T-cell lymphomas. In addition to its anticancer activity,SAHA has significant effects on the growth of many viruses. The effect of SAHA on replication of human cytomegalovirus(HCMV) has not, however, been investigated. Here, we showed that the replication of HCMV was significantly suppressed by treatment with SAHA at concentrations that did not show appreciable cytotoxicity. SAHA reduced transcription and protein levels of HCMV immediate early genes, showing that SAHA acts at an early stage in the viral life-cycle. RNAsequencing data mining showed that numerous pathways and molecules were affected by SAHA. Interferon-mediated immunity was one of the most relevant pathways in the RNA-sequencing data, and we confirmed that SAHA inhibits HCMV-induced IFN-mediated immune responses using quantitative Real-time PCR(qRT-PCR). Fatty acid-binding protein 4(FABP4), which plays a role in lipid metabolism, was identified by RNA-sequencing. We found that FABP4 expression was reduced by HCMV infection but increased by treatment with SAHA. We then showed that knockdown of FABP4 partially rescued the effect of SAHA on HCMV replication. Our data suggest that FABP4 contributes to the inhibitory effect of SAHA on HCMV replication.