Protein Family Research Articles

Molecular cross-talk among human intestinal bifidobacteria as explored by a human gut model

Bifidobacteria are well known as common and abundant colonizers of the human gut and are able to exert multiple beneficial effects on their host, although the cooperative and competitive relationships that may occur among bifidobacterial strains are still poorly investigated. Therefore, to dissect possible molecular interactions among bifidobacterial species that typically colonize the human gut, three previously identified bifidobacterial prototypes, i.e., B. bifidum PRL2010, B. breve PRL2012, and B. longum PRL2022 were cultivated individually as well as in bi- and tri-association in a human gut-simulating medium. Transcriptomic analyses of these co-associations revealed up-regulation of genes predicted to be involved in the production of extracellular structures including pili (i.e., flp pilus assembly TadE protein gene), exopolysaccharides (i.e., GtrA family protein gene) and teichoic acids (i.e., ABC transporter permease), along with carbohydrate, amino acid and vitamin metabolism-related genes (i.e., exo-alpha-sialidase; beta-galactosidase and pyridoxamine kinase), suggesting that co-cultivation of bifidobacteria induces a response, in individual bifidobacterial strains, aimed at enhancing their proliferation and survival, as well as their ability to cooperate with their host to promote their persistence. Furthermore, exposure of the selected prototypes to human cell line monolayers unveiled the ability of the bifidobacterial tri-association to communicate with their host by increasing the expression of genes involved in adherence to/interaction with intestinal human cells. Lastly, bifidobacterial tri-association promoted the transcriptional upregulation of genes responsible for maintaining the integrity and homeostasis of the intestinal epithelial barrier.

Approaches to anticancer therapy based on modulation of DNA methylation

Background. DNA methylation is a crucial mechanism of epigenetic regulation of transcription. Disturbances in DNA methylation mechanism are associated with various malignancies such as acute myeloid leukaemia, breast cancer, prostate cancer, etc. Influencing the functional status of DNA methyltransferases (DNMTs) enzymes and TET family proteins (TETs), which regulate DNA methylation and demethylation, is the basis of epigenetic anticancer therapy approach. In this review, we have considered the challenges and prospects of nucleoside and non-nucleoside inhibitors of DNMTs as well as TETs inhibitors. The results of clinical trials on the efficacy of DNMTs inhibitors used individually and as part of combination chemotherapy conducted over the last 15 years are also evaluated. Material and Methods. Sources were searched in PubMed, ScienceDirect, Web of Science, eLibrary, CyberLeninka. More than 700 publications were used in the analysis, but the review included mainly works of the last 10 years. A number of articles published earlier than 2015 were used for historical reference. Results. The review provides information on current advances in the development and study of epigenetically active compounds whose action is aimed at the regulation of DNA methylation. Data on the in vitro and in vivo effects of agents considered for use in the therapy of various malignancies are presented. In addition, the data of clinical trials of the most promising epigenetic modulators are presented.

Epitranscriptomic regulation of lipid oxidation and liver fibrosis via ENPP1 mRNA m6A modification

BackgroundDysregulated lipid oxidation occurs in several pathological processes characterized by cell proliferation and migration. Nonetheless, the molecular mechanism of lipid oxidation is not well appreciated in liver fibrosis, which is accompanied by enhanced fibroblast proliferation and migration.MethodsWe investigated the causes and consequences of lipid oxidation in liver fibrosis using cultured cells, animal models, and clinical samples.ResultsIncreased ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP1) expression caused increased lipid oxidation, resulting in the proliferation and migration of hepatic stellate cells (HSCs) that lead to liver fibrosis, whereas fibroblast-specific ENPP1 knockout reversing these results. Elevated ENPP1 and N6-methyladenosine (m6A) levels were associated with high expression of Wilms tumor 1 associated protein (WTAP). Mechanistically, WTAP-mediated m6A methylation of the 3'UTR of ENPP1 mRNA and induces its translation dependent of YTH domain family proteins 1 (YTHDF1). Additionally, ENPP1 could interact with hypoxia inducible lipid droplet associated (HILPDA) directly; overexpression of ENPP1 further recruits HILPDA-mediated lipid oxidation, thereby promotes HSCs proliferation and migration, while inhibition of ENPP1 expression produced the opposite effect. Clinically, increased expression of WTAP, YTHDF1, ENPP1, and HILPDA, and increased m6A mRNA content, enhanced lipid oxidation, and increased collagen deposition in human liver fibrosis tissues.ConclusionsWe describe a novel mechanism in which WTAP catalyzes m6A methylation of ENPP1 in a YTHDF1-dependent manner to enhance lipid oxidation, promoting HSCs proliferation and migration and liver fibrosis.Graphical abstract

Immunohistochemical parameters of serous ovarian carcinomas and possible mechanism of development of resistance to platinum-based drugs

The aim of the study was to evaluate a prognostic significance of immunohistochemical parameters in serous ovarian carcinomas and their statistical relationships after neoadjuvant treatment to assess the development of tumor resistance to platinum-containing adjuvant polychemotherapy regimens. Material and Methods. An immunohistochemical study of tumor tissue was carried out in patients with high-grade serous ovarian cancer (stage IIIC–IV). The age of the patients ranged from 49–72 years. There were 59 patients who were sensitive and 22 patients who were resistant to platinum-containing adjuvant polychemotherapy. In the tissue of ovarian tumors obtained during surgery after noadjuvant polychemotherapy, we studied immunohistochemical indicators of proliferative activity (Ki67), expression of the DNA excision repair protein ERCC1 and proteins of the ABC transporter family – Pgp and BCRP, as well as statistical relationships between these indicators (Spearman’s rank correlation coefficient). Results. After effective neoadjuvant polychemotherapy, more pronounced signs of activity in the processes of proliferation, DNA repair and xenobiotic efflux were noted in serous ovarian carcinomas, which subsequently demonstrated resistance to platinum-containing polychemotherapy regimens compared to tumors that retained platinum sensitivity. Moreover, in 40 % of cases or more, there was a coincidence in the ranges of values of the studied parameters in tumors with different sensitivity to platinum drugs. The expression of transporter proteins greater than 60 % for BCRP and 65 % for Pgp was shown to precede the development of resistance to adjuvant treatment with carboplatin. In the studied groups, differences in the number and significance of statistical relationships between the variables were observed. The most significant differences were noted for the Ki67 – BCRP correlation, which had the opposite direction in groups with different sensitivity to adjuvant treatment with carboplatin. Conclusion. A comprehensive immunohistochemical analysis of highgrade serous ovarian carcinomas after neoadjuvant polychemotherapy, which further demonstrated different sensitivity to platinum-containing adjuvant regimens, was carried out, and the prognostic value of the studied parameters was assessed. The revealed critical levels of Pgp and BCRP expression in tumor tissue may have a prognostic value regarding the effect of adjuvant polychemotherapy. The results of the correlation analysis suggest a relationship between the development of platinum resistance and changes in the nature of the regulatory relationships between proliferative activity and transport processes in tumor tissue.

Component-resolved diagnosis: enhancing precision diagnosis and clinical management of shellfish allergies

Shellfish, being one of the eight major food allergens, affects approximately 3% of the global population. The occurrence of shellfish allergy is not only related to the individual's immune system sensitivity but is also influenced by geographical environment, food availability, and dietary habits. Although crustaceans (such as shrimp, crab, and lobster) and mollusks (such as oysters, mussels, and squid) are collectively referred to as shellfish, they exhibit significant differences in biological evolution and the spectrum of allergenic molecules they contain, leading to various allergic reactions. Accurate identification of allergenic proteins is crucial for the diagnosis and management of shellfish allergies, with key allergenic protein families including tropomyosin, arginine kinase, and hemocyanin. Furthermore, due to the diversity of shellfish allergens and their cross-reactivity with dust mite and insect allergens, diagnosing and managing shellfish allergies is complex, especially concerning tropomyosin and arginine kinase protein families. Currently, there are no specific immunotherapy treatments for shellfish allergies, and clinical management primarily relies on avoiding allergens and using anti-allergy medications. This article thoroughly interprets the " Molecular Allergology User's Guide 2.0 (MAUG 2.0)" published by the European Academy of Allergy and Clinical Immunology (EAACI) and the latest research on shellfish allergies both domestically and internationally. It highlights the significant role of allergen component diagnostics in optimizing the diagnostic and treatment processes for shellfish allergies, effectively assisting clinicians in accurately identifying common allergens and cross-reactions, thereby providing patients with more personalized diagnosis and treatment plans.

Research progress of follistatin-related proteins in digestive system tumors

Tumors of the digestive system are one of the most important factors affecting people's quality of life and have become a serious public health problem globally.Early screening and intervention of tumor markers in high-risk groups for tumors is the key to tumor prevention. Follistatin-related proteins (FRP) are important members of the follistatin family and such proteins are involved in the pathological process of tumors of the reproductive system and respiratory system, among others. In recent years, FRP has attracted extensive attention in the study of digestive system tumors, suggesting that FRP may play a significant role in the development of digestive system tumors, and is a potential marker for clinical diagnosis and treatment. The article reviews the biological function, expression and potential mechanism of action of FRP associated with digestive system tumors, with a view to providing reference for the diagnosis and prevention of digestive system tumors, prognosis assessment and drug development.

Evidence that extracellular HSPB1 contributes to inflammation in alcohol-associated hepatitis.

Alcohol-associated hepatitis (AH) is the most life-threatening form of alcohol-associated liver disease (ALD). AH is characterized by severe inflammation attributed to increased levels of ethanol, microbes or microbial components, and damage-associated molecular pattern (DAMP) molecules in the liver. HSPB1 (Heat Shock Protein Family B (Small) Member 1; also known as Hsp25/27) is a DAMP that is rapidly increased in and released from cells experiencing stress, including hepatocytes. The goal of this study was to define the role of HSPB1 in AH pathophysiology. Serum HSPB1 was measured in a retrospective study of 184 heathy controls (HC), heavy alcohol consumers (HA), patients with alcohol-associated cirrhosis (AC), and patients with AH recruited from major hospital centers. HSPB1 was also retrospectively evaluated in liver tissue from 10 HC and AH patients and an existing liver RNA-seq dataset. Finally, HSPB1 was investigated in a murine Lieber-DeCarli diet model of early ALD as well as cellular models of ethanol stress in hepatocytes and hepatocyte-macrophage communication during ethanol stress. Circulating HSPB1 was significantly increased in AH patients and levels positively correlated with disease-severity scores. Likewise, HSPB1 was increased in the liver of patients with severe AH and in the liver of ethanol-fed mice. In vitro , ethanol-stressed hepatocytes released HSPB1, which then triggered TNFα-mediated inflammation in macrophages. Anti-HSPB1 antibody prevented TNFα release from macrophages exposed to media conditioned by ethanol-stressed hepatocytes. Our findings support investigation of HSPB1 as both a biomarker and therapeutic target in ALD. Furthermore, this work demonstrates that anti-HSPB1 antibody is a rational approach to targeting HSPB1 with the potential to block inflammation and protect hepatocytes, without inactivating host defense. HSPB1 is significantly increased in serum and liver of patients with alcohol-associated hepatitis.Ethanol consumption leads to early increases in HSPB1 in the mouse liver.Hepatocytes subjected to ethanol stress release HSPB1 into the extracellular environment where it activates TNFα-mediated inflammation in macrophages.Anti-HSPB1 antibody blocks hepatocyte-triggered TNFα in a model of hepatocyte-macrophage communication during ethanol stress.

EP4 receptor agonist CAY10598 upregulates ROS-dependent Hsp90 cleavage in colorectal cancer cells

Prostaglandin E2 (PGE2) interacts with four specific G protein-coupled receptors, namely EP1, EP2, EP3, and EP4, playing a pivotal role in determining the fate of cells. Our previous findings highlighted that stimulating the EP4 receptor with its agonist, CAY10598, triggers apoptosis in colon cancer HCT116 cells via the production of reactive oxygen species (ROS). This process also reduces the phosphorylation of the oncogenic protein JAK2 and leads to its degradation in these cells. In this study, our goal was to explore the pathways through which CAY10598 leads to JAK2 degradation. We focused on Hsp90, a heat shock protein family member known for its role as a molecular chaperone maintaining the stability of several key proteins including EGFR, MET, Akt, and JAK2. Our results show that CAY10598 decreases the levels of client proteins of Hsp90 in HCT116 cells, an effect reversible by pretreatment with the ROS scavenger N-acetyl cysteine (NAC) or the proteasome inhibitor MG132, indicating that the degradation is likely driven by ROS. Furthermore, we observed that CAY10598 cleaves both α and β isoforms of Hsp90, the process inhibited by NAC. Inhibition of EP4 with the antagonist GW627368x not only prevented the degradation of Hsp90 client proteins but also the cleavage of Hsp90 itself in CAY10598-treated HCT116 cells. Additionally, CAY10598 suppressed the growth of HCT116 cells implanted in mice. Our findings reveal that CAY10598 induces apoptosis in cancer cells by a novel mechanism involving the ROS-dependent cleavage of Hsp90, thereby inhibiting the function of crucial Hsp90 client proteins.

Exploring the structural landscape of DNA maintenance proteins

Evolutionary annotation of genome maintenance (GM) proteins has conventionally been established by remote relationships within protein sequence databases. However, often no significant relationship can be established. Highly sensitive approaches to attain remote homologies based on iterative profile-to-profile methods have been developed. Still, these methods have not been systematically applied in the evolutionary annotation of GM proteins. Here, by applying profile-to-profile models, we systematically survey the repertoire of GM proteins from bacteria to man. We identify multiple GM protein candidates and annotate domains in numerous established GM proteins, among other PARP, OB-fold, Macro, TUDOR, SAP, BRCT, KU, MYB (SANT), and nuclease domains. We experimentally validate OB-fold and MIS18 (Yippee) domains in SPIDR and FAM72 protein families, respectively. Our results indicate that, surprisingly, despite the immense interest and long-term research efforts, the repertoire of genome stability caretakers is still not fully appreciated.

Multiplexed Spatial Imaging at the Single-Cell Level Reveals Mutually Exclusive Expression of B7 Family Proteins

Targeting novel inhibitory ligands beyond anti-PD-1 and PD-L1 and CTLA-4 therapies is essential for the next decade of the immunotherapy era. Agents for the B7 family molecules B7-H3, B7-H4, and B7-H5 are emerging in clinical trial phases; therefore, further accumulation of evidence from both clinical and basic aspects is vital. Here, we applied a 7-color multiplexed imaging technique to analyze the profile of B7 family B7-H3/B7-H4/B7-H5 expression, in addition to PD-L1, and the spatial characteristics of immune cell infiltrates in urothelial carcinoma (UC). The results revealed that B7-H3 and B7-H4 were mainly expressed on tumor cells and B7-H5 on immune cells in UC, and most of the B7-H3/B7-H4/B7-H5-positive cells were mutually exclusive with PD-L1-positive cells. Also, the expression of B7-H4 was elevated in patients with advanced pathologic stages, and high B7-H4 expression was a significant factor affecting overall mortality following surgery in UC. Furthermore, spatial analysis revealed that the distance from the B7-H4+ cells to the nearest CD8+ cells was markedly far compared with other B7 family-positive tumor cells. Interestingly, the distance from B7-H4+ cells to the nearest CD8+ cells was significantly farther in patients dying from cancer after surgery or immune checkpoint inhibitors compared with cancer survivors; thus, high B7-H4 expression in tumor cells may inhibit CD8 infiltration into the tumor space and that B7-H4-positive cells form a specific spatial niche. In summary, we performed a comprehensive evaluation of B7 family member expression and found that the spatial distribution of B7-H4 suggests the potentially useful role of combination blockade with both B7-H4 and the current anti-PD-1/PD-L1 axis in the treatment of UC.

Versatile whey acidic protein four-disulfide core domain proteins: biology and role in diseases.

The Whey acidic protein four-disulfide core (WFDC) protein family consists of proteins with one or more WFDC domains which are ubiquitously expressed throughout the body of human and perform a wide range of functions, including antiprotease, antibacterial, and immunomodulatory functions. Aberrant expression of WFDC proteins is associated with human diseases. However, review on the WFDC protein family is limited and insufficient. Furthermore, a systematic summary of the underlying mechanisms of WFDC protein activity is lacking. In this review, we give a summary of the structural basis and molecular function of these proteins and review the immune regulatory mechanisms and signaling pathways of WFDC proteins in the development of certain diseases. Furthermore, we discuss the diagnostic and prognostic potential of multiple WFDC proteins in the aforementioned conditions, as well as their prospective use. At last, we also discuss the progress of WFDC protein in clinical trials and put forward some research difficulties and the directions of follow-up research. Our review highlights the functional diversity and clinical significance of WFDC proteins family, while providing potential targets for drug development and innovative therapeutic strategies, this review lays the foundation and direction for future research on WFDC proteins.

Therapeutic Advances in Advanced Basal Cell Carcinoma.

Basal cell carcinoma (BCC) is the most common type of cancer with an estimated 3.6 million cases diagnosed annually in the US alone. While most cases are treatable with low recurrence rates, 1-10% progress to an advanced stage which can behave aggressively, leading to local destruction and posing substantial challenges in management. The pathogenesis often involves dysregulation of the patched/hedgehog protein family, a pivotal pathway targeted by recently approved therapies. Furthermore, the role of immunotherapy is evolving in this type of tumor as we learn more about tumor microenvironment dynamics. In recent years, there have been advancements in the therapeutic landscape of advanced BCC, offering patients new hope and options for managing this complex and potentially life-threatening condition. In this review, we aim to provide a comprehensive overview of this disease, including the risk factors, underlying pathogenesis, current treatment options of advanced disease, and the ongoing exploration and development of novel therapies.

A conserved protein family in mirid bug Riptortus pedestris plays dual roles in regulating plant immunity.

The mirid bug (Riptortus pedestris), a major soybean pest, migrates into soybean fields during the pod filling stage and causes staygreen syndrome, which leads to substantial yield losses. The mechanism by which R. pedestris elicits soybean (Glycine max) defenses and counter-defenses remains largely unexplored. In this study, we characterized a protein family from R. pedestris, designated Riptortus pedestris HAMP 1 (RPH1) and its putative paralogs (RPH1L1, 2, 3, 4, and 5), whose members exhibit dual roles in triggering and inhibiting plant immunity. RPH1 and RPH1L1 function as herbivore-associated molecular patterns (HAMPs), activating pattern-triggered immunity (PTI) in tobacco (Nicotiana benthamiana) and G. max. Furthermore, RPH1 stimulates jasmonic acid and ethylene biosynthesis in G. max, thereby enhancing its resistance to R. pedestris feeding. Additionally, RPH1 homologs are universally conserved across various herbivorous species, with many homologs also acting as HAMPs that trigger plant immunity. Interestingly, the remaining RPH1 putative paralogs (RPH1L2-5) serve as effectors that counteract RPH1-induced PTI, likely by disrupting the extracellular perception of RPH1. This research uncovers a HAMP whose homologs are conserved in both chewing and piercing-sucking insects. Moreover, it unveils an extracellular evasion mechanism utilized by herbivores to circumvent plant immunity using functionally differentiated paralogs.

Identification and functional analysis of C-type lectin from mosquito Aedes albopictus in response to dengue virus infection

BackgroundC-type lectins (CTLs) are a large family of proteins with sugar-binding activity. CTLs contain an evolutionarily conserved C-type lectin domain (CTLD) that binds microbial carbohydrates in a calcium-dependent manner, thereby playing a key role in both microbial pathogenesis and innate immune responses. Aedes albopictus is an important vector for transmitting dengue virus (DENV) worldwide. Currently, the molecular characteristics and functions of CTLs in Ae. albopictus are largely unknown.MethodsTranscripts encoding CTL proteins in the Ae. albopictus genome assembly were analyzed via sequence blast. Phylogenetic analysis and molecular characterization were performed to identify the functional domains of the CTLs. Quantitative analysis was performed to determine the gene expression features of CTLs during mosquito development and in different tissues of female adults after blood feeding. In addition, the functional role of CTLs in response to DENV infection was investigated in Ae. albopictus mosquito cells.ResultsWe identified 39 transcripts encoding CTL proteins in the Ae. albopictus transcriptome. Aedes albopictus CTLs are classified into three groups based on the number of CTLDs and the domain architecture. These included 29 CTL-Ss (single-CTLDs), 1 immulectins (dual-CTLD) and 9 CTL-Xs (CTLDs with other domains). Phylogenetic analysis and structural modeling indicated that CTLs in Ae. albopictus are highly conserved with the homologous CTLs in Aedes aegypti. The expression profile assay revealed differential expression patterns of CTLs in both developmental stages and in adult female tissues. Knockdown and overexpression of three CTLs (CTL-S12, S17 and S19) confirmed that they can promote dengue virus infection in Ae. albopictus cells.ConclusionsThe CTL genes in Ae. albopictus mosquito and other mosquito species are evolutionarily conserved and exhibit different developmental and tissue expression features. The functional assay indicated that three CTLs in Ae. albopictus mosquitoes are involved in promoting dengue virus infection. Our study revealed that CTLs play important roles in both the physiological processes and viral infection in mosquito vectors.Graphical

SOX7 inhibits the malignant progression of bladder cancer via the DNMT3B/CYGB axis

Bladder cancer (BCa) stands out as a highly prevalent malignant tumor affecting the urinary system. The Sex determining region Y-box protein family is recognized for its crucial role in BCa progression. However, the effect of Sex determining region Y-box 7 (SOX7) on BCa progression has not been fully elucidated. Herein, RNA-sequencing, western blot (WB), immunohistochemistry (IHC), immunofluorescence (IF) and tissue microarray were utilized to assess SOX7 expression in vitro and in vivo. Additionally, SOX7 expression, prognosis, and SOX7 + cytoglobin (CYGB) score were analyzed using R software. In vitro and vivo experiments were performed with BCa cell lines to validate the effect of SOX7 knockdown and overexpression on the malignant progression of BCa. The results showed that SOX7 exhibits low expression in BCa. It functions in diverse capacities, inhibiting the proliferative, migratory, and invasive capabilities of BCa. In addition, the experimental database demonstrated that SOX7 binds to the promoter of DNA methyltransferase 3 beta (DNMT3B), leading to the transcriptional inhibition of DNMT3B. This subsequently results in a reduced methylation of CYGB promoter, ultimately inhibiting the tumor progression of BCa. SOX7 + CYGB scores were significantly linked to patient prognosis. In conclusion, SOX7 inhibits the malignant progression of BCa via the DNMT3B/CYGB axis. Additionally, the SOX7 + CYGB score is capable of predicting the prognostic outcomes of BCa patients. Therefore, SOX7 and CYGB may play an important role in the progression of bladder cancer, and they can be used as prognostic markers of bladder cancer patients.

Chemerin in immunity.

Chemerin is a distant member of the cystatin protein family, initially discovered as a chemotactic factor and subsequently also reported to act as adipokine and angiogenetic factor. The biological activity of chemerin is regulated at different levels, such as gene expression, protein processing and interaction with both signaling and nonsignaling receptors. Chemerin is mostly produced by stromal cells, such as adipocytes, fibroblasts, epithelial and endothelial cells and circulates in almost all human tissues as a zymogen that needs to be proteolytically activated to exert its biological functions. At the receptor level, chemerin binds a G protein-coupled seven transmembrane domain receptor Chemerin1 (also named ChemR23 and CMKLR1), mostly expressed by innate immune cells, such as macrophages, dendritic cells and NK cells and by border cells. In addition, chemerin may bind GPR1, a weak signaling receptor, and CCRL2, a nonsignaling receptor expressed by barrier cells, such as endothelial and epithelial cells, able to regulate leukocytes migration by multiple mechanisms. The aim of this review is to summarize the contribution of chemerin in the regulation of immune responses.

Exploring multigene families of odorant binding proteins and cytochrome P450 monooxygenases in the stink bug pest complex through comparative transcriptomics

Exploring multigene families of odorant binding proteins and cytochrome P450 monooxygenases in the stink bug pest complex through comparative transcriptomics

Brief Communication on MAGE-A4 and Coexpression of Cancer Testis Antigens in Metastatic Synovial Sarcomas: Considerations for Development of Immunotherapeutics.

Therapeutic options for synovial sarcoma (SyS) have not evolved for several decades and the efficacy of second-line treatments is very limited. The expression of a large family of proteins known as cancer testis antigens (CTAs) in SyS has spurred the development of targeted T-cell therapies currently in clinical trials, such as those aimed at melanoma-associated antigen (MAGE)-A4 and New York esophageal squamous cell carcinoma 1 (NY-ESO-1), which have shown promising clinical efficacy. Extensive knowledge of the prevalence of expression and coexpression of CTAs is critical to design T-cell therapies with optimal coverage of the patient population. We analyzed the expression of CTAs of the MAGE-A family as well as NY-ESO-1 and preferentially expressed antigen in melanoma (PRAME) by RNA sequencing in a large cohort of 133 SyS samples from patients registered in the French sarcoma database (NETSARC+). Among MAGE-As, MAGE-A4 had the highest prevalence (65%), followed by MAGE-A10 (15%) and MAGE-A9 (13%). Almost all samples (92%) expressing any of the MAGE-As also expressed MAGE-A4. NY-ESO-1 was expressed in 65% of samples, with a large but incomplete overlap with MAGE-A4, whereas PRAME was present in 121 (91%) samples. Complementary immunohistochemical analyses were used to establish the positive correlation between RNA and protein expression for MAGE-A4 and NY-ESO-1. These data inform the strategy for optimal coverage of the SyS patient population with T-cell therapies, offering patients with SyS new options for single or combined second lines of treatment.

Function of ZmBT2a gene in resistance to pathogen infection in maize

The BTB-TAZ protein is a subfamily of the BTB protein family and plays a crucial regulatory role in plant resistance to pathogen infection. However, the function of the maize BTB-TAZ protein ZmBT2a in maize resistance to pathogens has not been reported. Here, we investigate the role of ZmBT2a in maize resistance to pathogen infection by examining its expression characteristics. The results showed that the expression level of ZmBT2a changed significantly in response to biotic and abiotic stresses in maize. Moreover, ZmBT2a-OE exhibited enhanced resistance to Botrytis cinerea and Pseudomonas syringae pv. tomato DC3000, while the maize ZmBT2a mutants Zmbt2a-1 and Zmbt2a-2 showed increased sensitivity to Fusarium graminearum and Cochliobolus carbonum infections. Notably, the expression of the key synthetic genes ZmLOXs and pathogenesis-related genes ZmPRs in the JA synthesis pathway was significantly down-regulated during F. graminearum infection. Additionally, yeast two-hybrid assays confirmed the direct interaction between ZmBT2a and E3 ubiquitinated proteins ZmCUL3a and ZmCUL3b. These findings suggest that the ZmBT2a gene is crucial in maize resistance to pathogen infection. It is hypothesized that ZmBT2a binds to ZmCUL3 and, through ubiquitination, affects the transcriptional regulation of ZmLOXs and ZmPRs by downstream transcription factors, thus participating in the disease resistance process of maize.

Positive Selection Drives the Evolution of the Structural Maintenance of Chromosomes (SMC) Complexes

Structural Maintenance of Chromosomes (SMC) complexes are an evolutionary conserved protein family. In most eukaryotes, three SMC complexes have been characterized, as follows: cohesin, condensin, and SMC5/6 complexes. These complexes are involved in a plethora of functions, and defects in SMC genes can lead to an increased risk of chromosomal abnormalities, infertility, and cancer. To investigate the evolution of SMC complex genes in mammals, we analyzed their selective patterns in an extended phylogeny. Signals of positive selection were identified for condensin NCAPG, for two SMC5/6 complex genes (SMC5 and NSMCE4A), and for all cohesin genes with almost exclusive meiotic expression (RAD21L1, REC8, SMC1B, and STAG3). For the latter, evolutionary rates correlate with expression during female meiosis, and most positively selected sites fall in intrinsically disordered regions (IDRs). Our results support growing evidence that IDRs are fast evolving, and that they most likely contribute to adaptation through modulation of phase separation. We suggest that the natural selection signals identified in SMC complexes may be the result of different selective pressures: a host-pathogen arms race in the condensin and SMC5/6 complexes, and an intragenomic conflict for meiotic cohesin genes that is similar to that described for centromeres and telomeres.