Small-molecule agents for cancer immunotherapy

Cancer immunotherapy,exemplified by the remarkable clinical benefits of the immune checkpoint blockade and chimeric antigen receptor T-cell therapy,is revolutionizing cancer therapy.They induce long-term tumor regression and overall survival benefit in many types of cancer.With the advances in our knowledge about the tumor immune microenvironment,remarkable progress has been made in the development of small-molecule drugs for immunotherapy.Small molecules targeting PRR-associated pathways,immune checkpoints,oncogenic signaling,metabolic pathways,cytokine/chemokine signaling,and immune-related kinases have been extensively investigated.Monotherapy of smallmolecule immunotherapeutic drugs and their combinations with other antitumor modalities are under active clinical investigations to overcome immune tolerance and circumvent immune checkpoint inhibitor resistance.Here,we review the latest development of small-molecule agents for cancer immunotherapy by targeting defined pathways and highlighting their progress in recent clinical investigations.

Chiral metal nanostructures:synthesis,properties and applications

Chirality,the property that an object cannot coincide with its mirror image arising from lack of mirror symmetry,is ubiquitous in nature at various length scales.The physical and chemical properties are strongly related to the nature of chiral complexes,playing a significant role in various fields such as photonics,biochemistry,medicine and catalysis.In particular,the recent flexible design of chiral metal nanostructures offers one platform for deeply understanding the origin of chirality and one roadmap for the precise construction of chiral nanomaterials directed by the applications.Herein,we summarize the different geometries and classical synthetic approaches to chiral noble metal nanomaterials.Moreover,chiroptical properties and potential applications of chiral metal nanostructures are discussed as well.Finally,the opportunities and challenges toward the synthesis and application of chiral metal nanostructures are proposed.

Metabolomics in drug research and development: The recent advances in technologies and applications

Emerging evidence has demonstrated the vital role of metabolism in various diseases or disorders.Metabolomics provides a comprehensive understanding of metabolism in biological systems.With advanced analytical techniques,metabolomics exhibits unprecedented significant value in basic drug research,including understanding disease mechanisms,identifying drug targets,and elucidating the mode of action of drugs.More importantly,metabolomics greatly accelerates the drug development process by predicting pharmacokinetics,pharmacodynamics,and drug response.In addition,metabolomics facilitates the exploration of drug repurposing and drug-drug interactions,as well as the development of personalized treatment strategies.Here,we briefly review the recent advances in technologies in metabolomics and update our knowledge of the applications of metabolomics in drug research and development.

Albumosomes formed by cytoplasmic pre-folding albumin maintain mitochondrial homeostasis and inhibit nonalcoholic fatty liver disease

Hepatic mitochondrial dysfunction contributes to the progression of nonalcoholic fatty liver disease(NAFLD).However,the factors that maintain mitochondrial homeostasis,especially in hepatocytes,are largely unknown.Hepatocytes synthesize various high-level plasma proteins,among which albumin is most abundant.In this study,we found that pre-folding albumin in the cytoplasm is completely different from folded albumin in the serum.

RNA structure determination:From 2D to 3D

RNA molecules serve a wide range of functions that are closely linked to their structures.The basic structural units of RNA consist of single-and double-stranded regions.In order to carry out advanced functions such as catalysis and ligand binding,certain types of RNAs can adopt higher-order structures.The analysis of RNA structures has progressed alongside advancements in structural biology techniques,but it comes with its own set of challenges and corresponding solutions.In this review,we will discuss recent advances in RNA structure analysis techniques,including structural probing methods,X-ray crystallography,nuclear magnetic resonance,cryo-electron microscopy,and small-angle X-ray scattering.Often,a combination of multiple techniques is employed for the integrated analysis of RNA structures.We also survey important RNA structures that have been recently determined using various techniques.

An orally-available monovalent SMAC mimetic compound as a broad-spectrum antiviral

DearEditor,The coronavirus disease 2019(COVID-19)pandemic caused great global morbidity and mortality concurrent with astronomical socioeconomic damages and losses.Until now,the culpable pathogen,SARS-CoV-2,has infected over 6 hundred million people resulting in more than 6 million deaths worldwide(WHO SARSCoV-2 cases).There is an urgent need for rapid development of effective and affordable therapeutics for COVID-19 patients.

High-voltage LiCoO_(2) cathodes for high-energy-density lithiumion battery

As the earliest commercial cathode material for lithium-ion batteries,lithium cobalt oxide(LiCoO_(2)) shows various advantages,including high theoretical capacity,excellent rate capability,compressed electrode density,etc.Until now,it still plays an important role in the lithium-ion battery market.Due to these advantages,further increasing the charging cutoff voltage of LiCoO_(2)to guarantee higher energy density is an irresistible development trend of LiCoO_(2)cathode materials in the future.However,using high charging cutoff voltage may induce a lot of negative effects,especially the rapid decay of cycle capacity.These are mainly caused by rapid destruction of crystal structure and aggravation of interface side reaction at high voltage during the cycle.Therefore,how to maintain a stable crystal structure of LiCoO_(2)to ensure the excellent long cycle performance at high voltage is a hot research issue in the further application of LiCoO_(2).In this review,we summarized the failure causes and extensive solutions of LiCoO_(2)at high voltage and promoted some new modification strategies.Moreover,the development trend of solving the failure problem of high-voltage LiCoO_(2)in the future such as defect engineering and high-temperature shock technique is also discussed.

Mirror-enhanced scanning light-field microscopy for long-term high-speed 3D imaging with isotropic resolution

Various biological behaviors can only be observed in 3D at high speed over the long term with low phototoxicity.Light-field microscopy(LFM)provides an elegant compact solution to record 3D information in a tomographic manner simultaneously,which can facilitate high photon efficiency.However,LFM still suffers from the missing-cone problem,leading to degraded axial resolution and ringing effects after deconvolution.Here,we propose a mirrorenhanced scanning LFM(MiSLFM)to achieve long-term high-speed 3D imaging at super-resolved axial resolution with a single objective,by fully exploiting the extended depth of field of LFM with a tilted mirror placed below samples.To establish the unique capabilities of MiSLFM,we performed extensive experiments,we observed various organelle interactions and intercellular interactions in different types of photosensitive cells under extremely low light conditions.Moreover,we demonstrated that superior axial resolution facilitates more robust blood cell tracking in zebrafish larvae at high speed.

Structural engineering of graphene for high-resolution cryo-electron microscopy

The revolutionary improvement of hardware and algorithm in cryogenic electron microscopy(cryo-EM)has made it a routine method to obtain structures of macromolecules at near-atomic resolution.Nevertheless,this technique still faces many challenges.The structure-solving efficiency of cryo-EM can be significantly reduced by the biomolecules'denaturation on the air–water interfaces,the preferred orientation,strong background noise from supporting films and particle motion,and so forth.To overcome these problems,nanomaterials with ultrahigh electronic conductivity and ultrathin thickness are explored as promising cryo-EM specimen supporting films.Herein,we summarize the structural engineering of graphene,for example,surface and interface modification,as supporting films for grids and the application on high-resolution cryo-EM and discuss potential future perspectives.

The mechanodonor-acceptor coupling (MDAC) approach for unidirectional multi-state fluorochromism

Uni-directional multi-state fluorochromic scaffolds are valuable photofunctional molecules and yet scarce. We report a general approach for their design, i.e., mechanodonor-acceptor coupling(MDAC). A photochromic molecule is a mechanodonor, due to its capability to convert photonic energy into mechanical force. Upon proper coupling, it can be used to drive a mechanochromic molecule for uni-directional multi-state fluorochromism. The embodiment of this approach is a rhodamine-dithienylethylene hydride(RDH), which has been successfully employed in super-resolution localization microscopy.

Recent progress and challenges in the treatment of spinal cord injury

Spinal cord injury(SCI)disrupts the structural and functional connectivity between the higher center and the spinal cord,resulting in severe motor,sensory,and autonomic dysfunction with a variety of complications.The pathophysiology of sci is complicated and multifaceted,and thus individual treatments acting on a specific aspect or process are inadequate to elicit neuronal regeneration and functional recovery after ScI.Combinatory strategies targeting multiple aspects of scI pathology have achieved greater beneficial effects than individuai therapy alone.Although many problems and challenges remain,the encouraging outcomes that have been achieved in preclinical models offer a promising foothold for the development of novel clinical strategies to treat scl.In this review,we characterize the mechanisms underlying axon regeneration of adult neurons and summarize recent advances in facilitating functional recovery following scI at both the acute and chronic stages.In addition,we analyze the current status,remaining problems,and realistic challenges towards clinical translation.Finally,we consider the future of scI treatment and provide insights into how to narrow the translational gap that currently exists between preclinical studies and clinical practice.Going forward,clinical trials should emphasize multidisciplinary conversation and cooperation to identify optimal combinatorial approaches to maximize therapeuticbenefitinhumanswithscl.

A paternal protein facilitates sperm RNA delivery to regulate zygotic development

Sperm contributes essential paternal factors,including the paternal genome,centrosome,and oocyte-activation signals,to sexual reproduction.However,it remains unresolved how sperm contributes its RNA molecules to regulate early embryonic development.Here,we show that the Caenorhabditis elegans paternal protein SPE-11 assembles into granules during meiotic divisions of spermatogenesis and later matures into a perinuclear structure where sperm RNAs localize.We reconstitute an SPE-11 liquid-phase scaffold in vitro and find that SPE-11 condensates incorporate the nematode RNA,which,in turn,promotes SPE-11 phase separation.Loss of SPE-11 does not affect sperm motility or fertilization but causes pleiotropic development defects in early embryos,and spe-11 mutant males reduce m RNA levels of genes crucial for an oocyte-to-embryo transition or embryonic development.These results reveal that SPE-11 undergoes phase separation and associates with sperm RNAs that are delivered to oocytes during fertilization,providing insights into how a paternal protein regulates early embryonic development.

Regulatory dynamics of the higher-plant PSI-LHCI supercomplex during state transitions

State transition is a fundamental light acclimation mechanism of photosynthetic organisms in response to the environmental light conditions.This process rebalances the excitation energy between photosystemI(PSl)and photosystem Il through regulated reversible binding of the light-harvesting complex Il(LHCll)to PSl.However,the structural reorganization of PSI-LHCI,the dynamic binding of LHCll,and the regulatory mechanisms underlying state transitions are less understood in higher plants.In this study,using cryoelectron microscopy we resolved the structures of PSI-LHCI in both state 1(PSI-LHCI-ST1)and state 2(PSILHCI-LHCll-ST2)from Arabidopsis thaliana.Combined genetic and functional analyses revealed novel contacts between Lhcb1 and PsaK that further enhanced the binding of the LHCll trimer to the PSI core with the known interactions between phosphorylated Lhcb2 and the PsaL/PsaH/PsaO subunits.Specifically,PsaO was absent in the PSI-LHCI-ST1 supercomplex but present in the PSI-LHCI-LHCIl-ST2 supercomplex,in which the PsaL/PsaK/PsaA subunits undergo several conformational changes to strengthen the binding of PsaO in ST2.Furthermore,the PSI-LHCI module adopts a more compact configuration with shorter Mg-to-Mg distances between the chlorophylls,which may enhance the energy transfer efficiency from the peripheral antenna to the PSl core in ST2.Collectively,our work provides novel structural and functional insights into the mechanisms of light acclimation during state transitions in higher plants.

ASFV transcription reporter screening system identifies ailanthone as a broad antiviral compound

African swine fever(ASF)is an acute,highly contagious and deadly viral disease in swine that jeopardizes the worldwide pig industry.Unfortunately,there are no authoritative vaccine and antiviral drug available for ASF control.African swine fever virus(ASFV)is the etiological agent of ASF.Among the ASFV proteins,p72 is the most abundant component in the virions and thus a potential target for anti-ASFV drug design.Here,we con-structed a luciferase reporter system driven by the promoter of p72,which is transcribed by the co-transfected ASFV RNA polymerase complex.Using this system,we screened over 3200 natural product compounds and obtained three potent candidates against ASFV.We further evaluated the anti-ASFV effects and proved that among the three candidates,ailanthone(AIL)inhibits the replication of ASFV at the nanomolar concentration(IC_(50)=15 nmol/L).Our in vitro experiments indicated that the antiviral effect of AIL is associated with its inhibition of the HSP90-p23 cochaperone.Finally,we showed the antiviral activity of AIL on Zika virus and hepatitis B virus(HBV),which supports that AIL is a potential broad-spectrum antiviral agent.

Diffuse midline glioma treated with epigenetic agent-based immunotherapy

Dear Editor,Diffuse midline glioma,H3K27-altered(DMG),is a pediatric-type high-grade diffuse glioma that preferentially localizes to the brainstem or pons,thalamus,and spinal cord.Surgical resection is challenging and biopsy is often performed in most cases.To date,no conventional,targeted or immune therapy has been convincingly shown to improve patients’overall survival(OS).

Cross-species binding spectrum of ACE2 to SARS-CoV-2 RBD

Dear Editor,Severe acute respiratory syndrome coronavirus 2(SARSCo V-2)is the cause of COVID-19,which has posed a massive threat to human health,economy,and security worldwide(Bai et al.,2022).Genomic analysis of SARS-Co V-2 and related coronaviruses revealed that SARS-Co V and SARS-Co V-2likely had ancestors(Xu et al.,2020),which might originate in bats,followed by subsequent spread within intermediate hosts(spillover hosts)and then transmission to humans(Wang et al.,2021).

Genome-wide evolution analysis reveals low CpG contents of fast-evolving genes and identifies antiviral microRNAs

Noncoding RNAs(ncRNAs) play important roles in many biological processes and provide materials for evolutionary adaptations beyond protein-coding genes, such as in the arms race between the host and pathogen. However, currently, a comprehensive high-resolution analysis of primate genomes that includes the latest annotated ncRNAs is not available. Here, we developed a computational pipeline to estimate the selections that act on noncoding regions based on comparisons with a large number of reference sequences in introns adjacent to the interested regions. Our method yields result comparable with those of the established codon-based method and phyloP method for coding genes;thus, it provides a holistic framework for estimating the selection on the entire genome. We further showed that fastevolving protein-coding genes and their corresponding 50 UTRs have a significantly lower frequency of the CpG dinucleotides than those evolving at an average pace, and these fast-evolving genes are enriched in the process of immunity and host defense. We also identified fast-evolving miRNAs with antiviral functions in cells. Our results provide a resource for high-resolution evolution analysis of the primate genomes.

冷冻电镜在纳米材料研究中的应用:进展与展望

自2013年“分辨率革命”以来,冷冻电子显微镜(cryo-EM)广泛推动了结构生物学研究的发展,并很快在2017年荣获诺贝尔化学奖.相机技术和软件算法的进步使cryo-EM得以实现对生物分子三维结构的近原子分辨率表征.生物分子通常对电子辐照损伤较为敏感,而低温可以将辐照损伤最小化.这一原理启发了材料科学家利用cryo-EM表征电子束或空气敏感型材料,例如锂离子电池中的电极、金属有机框架(MOFs)、共价有机框架(COFs)和沸石.此外,在cryo-EM中,反应体系可在玻璃冰状态快速冻结,从而保存材料的近初始状态.在此,我们回顾了cryo-EM和其他新兴冷冻技术的发展及其在材料科学、能源存储与转换等领域的应用.Cryo-EM技术能够直观地观察敏感材料和电催化反应过程,将极大地革新学界对材料科学及其相关机制的理解.

Understanding the phase separation characteristics of nucleocapsid protein provides a new therapeutic opportunity against SARS-CoV-2

Dear Editor To date,tens of millions of people have been infected with severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),causing the outbreak of the respiratory disease named the coronavirus disease 2019(COVID-19).As a newly emerged member of the coronavirus family,SARS-CoV-2 is an enveloped positive-strand RNA virus,which has probably the largest genome(approximately 30 kb)among all RNA viruses.The nucleocapsid(N)protein of SARS-CoV-2 is mainly responsible for recognizing and wrapping viral RNA into helically symmetric structures(Malik,2020).

Erratum to:Migrasomes:the knowns,the known unknowns and the unknown unknowns:a personal perspective

The article“Migrasomes:the knowns,the known unknowns and the unknown unknowns:a personal perspective”written by Li Yu,was originally published Online First without Open Access.After publication online first,the author decided to opt for Open Choice and to make the article an Open Access publication.Therefore,the copyright of the article has been changed to©The Author(s)2020 and the article is forthwith distributed under the terms of the Creative Commons Attribution 4.0 International License(http://creativecommons.org/licenses/by/4.0/),which permits use,duplication,adaptation,distribution and reproduction in any medium or format,as long as you give appropriate credit to the original author(s)and the source,provide a link to the Creative Commons license,and indicate if changes were made.