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Abstract Tumor-infiltrating lymphocyte (TIL) therapy in adoptive T-cell therapy (ACT) has already caused durable regression in a variety of cancer types due to T-cell persistence, clinical activity, and duration of objective response and safety. TILs are composed of polyclonal effector T-cells specific to heterogenetic tumor antigens, reasonably providing a promising means for tumor therapy. In addition, their expansion in vitro can release them from the suppressive tumor microenvironment. Even though significant advances have been made in the procedure of TIL therapy, from TIL isolation, modification, expansion, and infusion back to the patient to target the tumor, strategy optimization is always ongoing to overcome drawbacks such as a complex process, options for the lineage differentiation status of TILs, and sufficient trafficking of TILs to the tumor. In this review, we summarize the current advances of TIL therapy, raise problem-based optimization strategies, and provide future perspectives on next-generation TIL therapy as a potential avenue for enhancing cell-based immunotherapy.

Abstract Skeletal editing of single-atom insertion to basic chemicals has been demonstrated as an efficient strategy for the discovery of structurally diversified compounds. Previous endeavors in skeletal editing have successfully facilitated the insertion of boron, nitrogen, and carbon atoms. Given the prevalence of oxygen atoms in biologically active molecules, the direct oxygenation of C-C bonds through single-oxygen-atom insertion like Baeyer-Villiger reaction is of particular significance. Herein, we present an approach for the skeletal modification of styrenes using O2 via oxygen insertion, resulting in the formation of aryl ether frameworks under mild reaction conditions. The broad functional-group tolerance and the excellent chemo- and regioselectivity are demonstrated in this protocol. A preliminary mechanistic study indicates the potential involvement of 1,2-aryl radical migration in this reaction.

Elucidation of the adaptation mechanisms and survival strategies of deep-sea microorganisms to extreme environments could provide a theoretical basis for the industrial development of extreme enzymes. There is currently a lack of understanding of the metabolic adaptation mechanisms of deep-sea microorganisms to high-pressure environments. The objective of this study was to investigate the metabolic regulatory mechanisms enabling a strain of the deep-sea bacterium Shewanella eurypsychrophilus to thrive under high-pressure conditions. To achieve this, we used nuclear magnetic resonance-based metabolomic and RNA sequencing-based transcriptomic analyses of S. eurypsychrophilus strain YLB-09, which was previously isolated by our research group and shown to be capable of tolerating high pressure levels and low temperatures. We found that high-pressure conditions had pronounced impacts on the metabolic pattern of YLB-09, as evidenced by alterations in energy, amino acid, and glycerolipid metabolism, among other processes. YLB-09 adapted to the high-pressure conditions of the deep sea by switching from aerobic intracellular energy metabolism to trimethylamine N-oxide respiration, altering the amino acid profile, and regulating the composition and the fluidity of cell membrane. The findings of our study demonstrate the capacity of microorganisms to alter their metabolism in response to elevated pressure, thereby establishing a foundation for a more profound understanding of the survival mechanisms of life in high-pressure environments.

Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor characterized by poor prognosis and lack of effective treatments. In recent years, peptide vaccines that use sequences based on tumor-specific or tumor-associated antigens to activate immune responses against tumor cells have emerged as a new therapeutic strategy. In this study, we developed a novel therapeutic polypeptide vaccine targeting the tumor-associated antigen Fibrinogen-Like Protein 2 (FGL2), whose dominant epitope peptide was tandemly linked to the C-terminus of HCMV-IE1mut via a linker. We used this vaccine to compare the therapeutic efficacy of HCMV-IE1mut alone versus HCMV-IE1mut-FGL2172-220 and investigate the potential mechanism of action of HCMV-IE1mut-FGL2172-220 in glioma treatment. An in situ GBM model (GL261-IE1-luc cells) was used to determine the efficacy of the vaccine. Treatment with HCMV-IE1mut-FGL2172-220 exerted antitumor effects and extended the survival of the GL261 animal model. We observed reduced proportions of microglia, regulatory T cells (Treg), and myeloid-derived suppressor cells (MDSC) in the tumor microenvironment (TME) by immunofluorescence. Flow cytometry showed that compared to HCMV-IE1mut alone, treatment with HCMV-IE1mut-FGL2172-220 increased the proportion of CD8+ T cells and tissue-resident memory T cells (TRM). ELISA analysis showed that it improved the secretion of tumor-specific IFN-γ and TNF-α by these cells and downregulated the expression of IL-6 and IL-10. Our study demonstrates that the long-peptide FGL2172-220 improves the antitumor efficacy of HCMV-IE1mut, possibly by reshaping immune cells in the glioma microenvironment. These findings lay the groundwork for the development of therapeutic antigenic peptide vaccines to improve antitumor effects for cancer.

In recent decades, with the advancement of micro-electro-mechanical systems technology, traditional materials have become insufficient to meet the demands of cutting-edge technology for various material properties. Composites have attracted widespread attention as an effective and viable solution. Silicon carbide whiskers (SiCw) have emerged as excellent reinforcements due to their high thermal conductivity, low thermal expansion coefficient, high melting point, superior mechanical properties, and high chemical stability. This article provides a comprehensive review of the reinforcement mechanisms and current research state of SiCw-reinforced composites. The reinforcement mechanisms include mainly grain refinement, load transfer, and crack bridging. The composites are categorized based on the type of the matrix: ceramic-based, metal-based, and polymer-based composites. The influence and parameter performance of the reinforcement mechanism on SiCw-reinforced composite materials with different matrices vary. However, the key to improving SiCw-reinforced composites lies in understanding the interplay of properties between the matrix and the reinforcement, as well as the ordered and regular distribution and binding at the interface. Finally, the current state and limitations of SiCw-reinforced composites are summarized, and future development trends are discussed. This article represents a great contribution to the future applications of SiCw-reinforced composite materials.

BackgroundKeratoconus is a diseased corneal dilation of unknown etiology. Studies have shown that inflammation may play a role in keratoconus. Inflammatory enteritis (IBD), including ulcerative colitis (UC), is a chronic, systemic inflammatory disease. We used Mendelian randomization to assess the causal relationship among IBD, UC and keratoconus.MethodsThe instrumental variable of IBD and UC was selected, the information of the instrumental variable in keratoconus outcome was extracted, and the causal relationship was assessed by the inverse variance weighted method by primary analysis, and its relevant sensitivity analysis.ResultsA causal relationship between IBD and keratoconus was observed significantly (P = 0.017, OR = 1.21, 95% CI = 1.03–1.41), and same as to UC and keratoconus (P = 0.038, OR = 1.25, 95% CI = 1.01–1.54).ConclusionIBD may play a causal role in the development of keratoconus, but the mechanism needs to be further elucidated.

Clustered Regularly Interspaced Short Palindromic Repeats (CRISPRs) and CRISPR-associated (Cas) proteins serve as an adaptive immune system that safeguards prokaryotes and some of the viruses that infect prokaryotes from foreign nucleic acids (such as viruses and plasmids). The genomes of the majority of archaea and about half of all bacteria contain various CRISPR-Cas systems. CRISPR-Cas systems depend on CRISPR RNAs (crRNAs). They act as a navigation system to specifically cut and destroy foreign nucleic acids by recognizing invading foreign nucleic acids and binding Cas proteins. In this review, we provide a brief overview of the evolution and classification of the CRISPR-Cas system, focusing on the functions and applications of the CRISPR-Cas13a system. We describe the CRISPR-Cas13a system and discuss its RNA-directed ribonuclease function. Meanwhile, we briefly introduce the mechanism of action of the CRISPR-Cas13a system and summarize the applications of the CRISPR-Cas13a system in pathogen detection, eukaryotes, agriculture, biosensors, and human gene therapy. We are right understanding of CRISPR-Cas13a has been broadened, and the CRISPR-Cas13a system will be useful for developing new RNA targeting tools. Therefore, understanding the basic details of the structure, function, and biological characterization of CRISPR-Cas13a effector proteins is critical for optimizing RNA targeting tools.

Background: Neurodegenerative retinal diseases such as retinitis pigmentosa are serious disorders that may cause irreversible visual impairment. Ferroptosis is a novel type of programmed cell death, and the involvement of ferroptosis in retinal degeneration is still unclear. This study aimed to investigate the related ferroptosis genes in a mice model of retinal degeneration induced by light damage. Methods: A public dataset of GSE10528 deriving from the Gene Expression Omnibus database was analyzed to identify the differentially expressed genes (DEGs). Gene set enrichment analysis between light damage and control group was conducted. The differentially expressed ferroptosis-related genes (DE-FRGs) were subsequently identified by intersecting the DEGs with a ferroptosis genes dataset retrieved from the FerrDb database. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were further performed using the DE-FRGs. A protein-protein interaction (PPI) network was constructed to identify hub ferroptosis-related genes (HFRGs). The microRNAs (miRNAs)-HFRGs, transcription factors (TFs)-HFRGs networks as well as target drugs potentially interacting with HFRGs were analyzed utilizing bioinformatics algorithms. Results: A total of 932 DEGs were identified between the light damage and control group. Among these, 25 genes were associated with ferroptosis. GO and KEGG analyses revealed that these DE-FRGs were mainly enriched in apoptotic signaling pathway, response to oxidative stress and autophagy, ferroptosis, necroptosis and cytosolic DNA-sensing pathway. Through PPI network analysis, six hub ferroptosis-related genes (Jun, Stat3, Hmox1, Atf3, Hspa5 and Ripk1) were ultimately identified. All of them were upregulated in light damage retinas, as verified by the GSE146176 dataset. Bioinformatics analyses predicated that 116 miRNAs, 23 TFs and several potential therapeutic compounds might interact with the identified HFRGs. Conclusion: Our study may provide novel potential biomarkers, therapeutic targets and new insights into the ferroptosis landscape in retinal neurodegenerative diseases.