Blockade of CD300A enhances the ability of human NK cells to lyse hematologic malignancies

Objective: The human cluster of differentiation(CD)300A, a type-I transmembrane protein with immunoreceptor tyrosine-based inhibitory motifs, was investigated as a potential immune checkpoint for human natural killer(NK) cells targeting hematologic malignancies(HMs).Methods: We implemented a stimulation system involving the CD300A ligand, phosphatidylserine(PS), exposed to the outer surface of malignant cells. Additionally, we utilized CD300A overexpression, a CD300A blocking system, and a xenotransplantation model to evaluate the impact of CD300A on NK cell efficacy against HMs in in vitro and in vivo settings. Furthermore, we explored the association between CD300A and HM progression in patients.Results: Our findings indicated that PS hampers the function of NK cells. Increased CD300A expression inhibited HM lysis by NK cells. CD300A overexpression shortened the survival of HM-xenografted mice by impairing transplanted NK cells. Blocking PS–CD300A signals with antibodies significantly amplified the expression of lysis function-related proteins and effector cytokines in NK cells, thereby augmenting the ability to lyse HMs. Clinically, heightened CD300A expression correlated with shorter survival and an “exhausted” phenotype of intratumoral NK cells in patients with HMs or solid tumors.Conclusions: These results propose CD300A as a potential target for invigorating NK cell-based treatments against HMs.

Assessing the inhibition efficacy of clinical drugs against the main proteases of SARS-CoV-2 variants and other coronaviruses

The rapid evolution of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)mainly due to its high mutation rate and rapid viral replication,has led to new variants resistant to the available vaccines and monoclonal antibodies.In contrast,oral clinical drugs targeting viral protease and RNA polymerase remain effective against Omicron variants[1].Main protease(Mpro)plays a crucial role in the maturation and replication of viral strains,making it an attractive target for developing antiviral drugs.Nirmatrelvir(NTV)is the first-in-class Mpro peptidomimetic covalent inhibitor known as“Paxlovid”approved in 2021 by the Food and Drug Administration[2].Nevertheless,NTV-resistant Mpro mutants particularly the E166V mutation,have been characterized in the Global Initiative on Sharing Avian Influenza Data(GISAID)database[3]and reported in COVID-19 patients[4,5].

A flexible,modular and versatile functional part assembly toolkit for gene cluster engineering in Streptomyces

Streptomyces has enormous potential to produce novel natural products(NPs)as it harbors a huge reservoir of uncharacterized and silent natural product biosynthetic gene clusters(BGCs).However,the lack of efficient gene cluster engineering strategies has hampered the pace of new drug discovery.Here,we developed an easy-to-use,highly flexible DNA assembly toolkit for gene cluster engineering.The DNA assembly toolkit is compatible with various DNA assembling approaches including Biobrick,Golden Gate,CATCH,yeast homologous recombination-based DNA assembly and homing endonuclease-mediated assembly.This compatibility offers great flexibility in handling multiple genetic parts or refactoring large gene clusters.To demonstrate the utility of this toolkit,we quantified a library of modular regulatory parts,and engineered a gene cluster(act)using characterized promoters that led to increased production.Overall,this work provides a powerful part assembly toolkit that can be used for natural product discovery and optimization in Streptomyces.

T cell receptor signaling and cell immunotherapy

As the major sensor of adaptive immune system,T cell receptor(TCR)can recognize diverse antigens and initiate specific immune responses against invading pathogens and cancer cells.Understanding the mechanisms of TCR signaling has led to the development of engineered T cell therapies,which have extensive applications in the treatment of diseases such as cancer,infection and autoimmunity.Here,we review the current understanding of antigen-induced TCR signaling and discuss its applications in T cell therapies.

Genome-scale metabolic models applied for human health and biopharmaceutical engineering

Over the last 15 years,genome-scale metabolic models(GEMs)have been reconstructed for human and model animals,such as mouse and rat,to systematically understand metabolism,simulate multicellular or multi-tissue interplay,understand human diseases,and guide cell factory design for biopharmaceutical protein production.Here,we describe how metabolic networks can be represented using stoichiometric matrices and well-defined constraints for flux simulation.Then,we review the history of GEM development for quantitative understanding of Homo sapiens and other relevant animals,together with their applications.We describe how model develops from H.sapiens to other animals and from generic purpose to precise context-specific simulation.The progress of GEMs for animals greatly expand our systematic understanding of metabolism in human and related animals.We discuss the difficulties and present perspectives on the GEM development and the quest to integrate more biological processes and omics data for future research and translation.We truly hope that this review can inspire new models developed for other mammalian organisms and generate new algorithms for integrating big data to conduct more in-depth analysis to further make progress on human health and biopharmaceutical engineering.