Three-dimensional cell-based strategies for liver regeneration

Liver regeneration and the development of effective therapies for liver failure remain formidable challenges in modern medicine.In recent years,the utilization of 3D cell-based strategies has emerged as a promising approach for addressing these urgent clinical requirements.This review provides a thorough analysis of the application of 3D cell-based approaches to liver regeneration and their potential impact on patients with end-stage liver failure.Here,we discuss various 3D culture models that incorporate hepatocytes and stem cells to restore liver function and ameliorate the consequences of liver failure.Furthermore,we explored the challenges in transitioning these innovative strategies from preclinical studies to clinical applications.The collective insights presented herein highlight the significance of 3D cell-based strategies as a transformative paradigm for liver regeneration and improved patient care.

Bispecific antibody drug conjugates:Making 1+1>2

Bispecific antibody‒drug conjugates(BsADCs)represent an innovative therapeutic category amalgamating the merits of antibody‒drug conjugates(ADCs)and bispecific antibodies(BsAbs).Positioned as the next-generation ADC approach,BsADCs hold promise for ameliorating extant clinical challenges associated with ADCs,particularly pertaining to issues such as poor internalization,off-target toxicity,and drug resistance.Presently,ten BsADCs are undergoing clinical trials,and initial findings underscore the imperative for ongoing refinement.This review initially delves into specific design considerations for BsADCs,encompassing target selection,antibody formats,and the linker–payload complex.Subsequent sections delineate the extant progress and challenges encountered by BsADCs,illustrated through pertinent case studies.The amalgamation of BsAbs with ADCs offers a prospective solution to prevailing clinical limitations of ADCs.Nevertheless,the symbiotic interplay among BsAb,linker,and payload necessitates further optimizations and coordination beyond a simplistic“1+1”to effectively surmount the extant challenges facing the BsADC domain.

Structural basis of negative regulation of CRISPR-Cas7-11 by TPR-CHAT

CRISPR‒Cas7-11 is a Type Ⅲ-E CRISPR-associated nuclease that functions as a potent RNA editing tool.Tetratrico-peptide repeat fused with Cas/HEF1-associated signal transducer(TPR-CHAT)acts as a regulatory protein that interacts with CRISPR RNA(crRNA)-bound Cas7-11 to form a CRISPR-guided caspase complex(Craspase).However,the precise modulation of Cas7-11’s nuclease activity by TPR-CHAT to enhance its utility requires further study.Here,we report cryo-electron microscopy(cryo-EM)structures of Desulfonema ishimotonii(Di)Cas7-11-crRNA,complexed with or without the full length or the N-terminus of TPR-CHAT.These structures unveil the molecular features of the Craspase complex.Structural analysis,combined with in vitro nuclease assay and electrophoretic mobility shift assay,reveals that DiTPR-CHAT negatively regulates the activity of DiCas7-11 by preventing target RNA from binding through the N-terminal 65 amino acids of DiTPR-CHAT(DiTPR-CHAT_(NTD)).Our work demonstrates that DiTPRCHAT_(NTD) can function as a small unit of DiCas7-11 regulator,potentially enabling safe applications to prevent overcutting and offtarget effects of the CRISPR‒Cas7-11 system.

Hydrogel-exosome system in tissue engineering:A promising therapeutic strategy

Characterized by their pivotal roles in cell-to-cell communication,cell proliferation,and immune regulation during tissue repair,exosomes have emerged as a promising avenue for“cell-free therapy”in clinical applications.Hydrogels,possessing commendable biocompatibility,degradability,adjustability,and physical properties akin to biological tissues,have also found extensive utility in tissue engineering and regenerative repair.The synergistic combination of exosomes and hydrogels holds the potential not only to enhance the efficiency of exosomes but also to collaboratively advance the tissue repair process.This review has summarized the advancements made over the past decade in the research of hydrogel-exosome systems for regenerating various tissues including skin,bone,cartilage,nerves and tendons,with a focus on the methods for encapsulating and releasing exosomes within the hydrogels.It has also critically examined the gaps and limitations in current research,whilst proposed future directions and potential applications of this innovative approach.

Antibody-drug conjugates:Recent advances in payloads

Antibody-drug conjugates(ADCs),which combine the advantages of monoclonal antibodies with precise targeting and payloads with efficient killing,show great clinical therapeutic value.The ADCs’payloads play a key role in determining the efficacy of ADC drugs and thus have attracted great attention in the field.An ideal ADC payload should possess sufficient toxicity,low immunogenicity,high stability,and modifiable functional groups.Common ADC payloads include tubulin inhibitors and DNA damaging agents,with tubulin inhibitors accounting for more than half of the ADC drugs in clinical development.However,due to clinical limitations of traditional ADC payloads,such as inadequate efficacy and the development of acquired drug resistance,novel highly efficient payloads with diverse targets and reduced side effects are being developed.This perspective summarizes the recent research advances of traditional and novel ADC payloads with main focuses on the structure-activity relationship studies,co-crystal structures,and designing strategies,and further discusses the future research directions of ADC payloads.This review also aims to provide valuable references and future directions for the development of novel ADC payloads that will have high efficacy,low toxicity,adequate stability,and abilities to overcome drug resistance.

Orthosteric ligand selectivity and allosteric probe dependence at Hydroxycarboxylic acid receptor HCAR2

Hydroxycarboxylic acid receptor 2(HCAR2),a member of Class A G-protein-coupled receptor(GPCR)family,plays a pivotal role in anti-lipolytic and anti-inflammatory effects,establishing it as a significant therapeutic target for treating dyslipidemia and inflammatory diseases.

Cryo-EM structure of the nucleocapsid-like assembly of respiratory syncytial virus

Respiratory syncytial virus(RSV)is a nonsegmented,negative strand RNA virus that has caused severe lower respiratory tract infections of high mortality rates in infants and the elderly,yet no effective vaccine or antiviral therapy is available.The RSV genome encodes the nucleoprotein(N)that forms helical assembly to encapsulate and protect the RNA genome from degradation,and to serve as a template for transcription and replication.Previous crystal structure revealed a decameric ring architecture of N in complex with the cellular RNA(N-RNA)of 70 nucleotides(70-nt),whereas cryo-ET reconstruction revealed a low-resolution left-handed filament,in which the crystal monomer structure was docked with the helical symmetry applied to simulate a nucleocapsid-like assembly of RSV.However,the molecular details of RSV nucleocapsid assembly remain unknown,which continue to limit our complete understanding of the critical interactions involved in the nucleocapsid and antiviral development that may target this essential process during the viral life cycle.Here we resolve the near-atomic cryo-EM structure of RSV N-RNA that represents roughly one turn of the helical assembly that unveils critical interaction interfaces of RSV nucleocapsid and may facilitate development of RSV antiviral therapy.

Oncolytic adenoviruses expressing checkpoint inhibitors for cancer therapy

Despite the remarkable success of immune checkpoint inhibitors(ICIs),primary resistance to ICIs causes only subsets of patients to achieve durable responses due to the complex tumor microenvironment(TME).Oncolytic viruses(OVs)can overcome the immunosuppressive TME and promote systemic antitumor immunity in hosts.Engineered OVs armed with ICIs would likely have improved effectiveness as a cancer therapy.According to the diverse immune cell landscapes among different types of tumors,we rationally and precisely generated three recombinant oncolytic adenoviruses(OAds):OAd-SIRPα-Fc,OAd-Siglec10-Fc and OAd-TIGIT-Fc.These viruses were designed to locally deliver SIRPα-Fc,Siglec10-Fc or TIGIT-Fc fusion proteins recognizing CD47,CD24 or CD155,respectively,in the TME to achieve enhanced antitumor effects.Our results suggested that OAd-SIRPα-Fc and OAd-Siglec10-Fc both showed outstanding efficacy in tumor suppression of macrophage-dominated tumors,while OAd-TIGIT-Fc showed the best antitumor immunity in CD8+T-cell-dominated tumors.Importantly,the recombinant OAds activated an inflammatory immune response and generated long-term antitumor memory.In addition,the combination of OAd-Siglec10-Fc with anti-PD-1 significantly enhanced the antitumor effect in a 4T1 tumor model by remodeling the TME.In summary,rationally designed OAds expressing ICIs tailored to the immune cell landscape in the TME can precisely achieve tumor-specific immunotherapy of cancer.

A multimodal integration pipeline for accurate diagnosis, pathogen identification, and prognosis prediction of pulmonary infections

Pulmonary infections pose formidable challenges in clinical settings with high mortality rates across all age groups worldwide.Accurate diagnosis and early intervention are crucial to improve patient outcomes.Artificial intelligence(AI)has the capability to mine imaging features specific to different pathogens and fuse multimodal features to reach a synergistic diagnosis,enabling more precise investigation and individualized clinical management.In this study,we successfully developed a multimodal integration(MMI)pipeline to differentiate among bacterial,fungal,and viral pneumonia and pulmonary tuberculosis based on a real-world dataset of 24,107 patients.The area under the curve(AUC)of the MMI system comprising clinical text and computed tomography(CT)image scans yielded 0.910(95%confidence interval[CI]:0.904–0.916)and 0.887(95%CI:0.867–0.909)in the internal and external testing datasets respectively,which were comparable to those of experienced physicians.Furthermore,the MMI system was utilized to rapidly differentiate between viral subtypes with a mean AUC of 0.822(95%CI:0.805–0.837)and bacterial subtypes with a mean AUC of 0.803(95%CI:0.775–0.830).Here,the MMI system harbors the potential to guide tailored medication recommendations,thus mitigating the risk of antibiotic misuse.Additionally,the integration of multimodal factors in the AI-driven system also provided an evident advantage in predicting risks of developing critical illness,contributing to more informed clinical decision-making.To revolutionize medical care,embracing multimodal AI tools in pulmonary infections will pave the way to further facilitate early intervention and precise management in the foreseeable future.