Oxidative stress is involved in immunosuppression and macrophage regulation in glioblastoma.

Oxidative stress dually affected cancer progression, while its effect on glioblastomas remained unclear. Herein, we clustered the multicenter glioblastoma cohorts based on the oxidative-stress-responsive genes (OSS) expression. We found that cluster 2 with high OSS levels suffered a worse prognosis. Functional analyses and immune-related analyses results exhibited that M2-like pro-tumoral macrophages and neutrophils were enriched in cluster 2, while Natural killer cells' infiltration was decreased. The increased M2-like pro-tumoral macrophages in cluster 2 was confirmed by immunofluorescence. An integrated single-cell analysis validated the malignant features of cluster 2 neoplastic cells and discovered their crosstalk with M2-like pro-tumoral macrophages. Moreover, we observed that SOD3 knockdown might decrease the M2-like pro-tumoral transformation of macrophage in vitro and in vivo. Comprehensively, we revealed oxidative stress' prognostic and immunosuppressive potential in glioblastoma and discovered SOD3's potential role in regulating macrophage M2-like pro-tumoral transformation.

Machine learning-based tumor-infiltrating immune cell-associated lncRNAs for predicting prognosis and immunotherapy response in patients with glioblastoma.

Long noncoding ribonucleic acids (RNAs; lncRNAs) have been associated with cancer immunity regulation. However, the roles of immune cell-specific lncRNAs in glioblastoma (GBM) remain largely unknown. In this study, a novel computational framework was constructed to screen the tumor-infiltrating immune cell-associated lncRNAs (TIIClnc) for developing TIIClnc signature by integratively analyzing the transcriptome data of purified immune cells, GBM cell lines and bulk GBM tissues using six machine learning algorithms. As a result, TIIClnc signature could distinguish survival outcomes of GBM patients across four independent datasets, including the Xiangya in-house dataset, and more importantly, showed superior performance than 95 previously established signatures in gliomas. TIIClnc signature was revealed to be an indicator of the infiltration level of immune cells and predicted the response outcomes of immunotherapy. The positive correlation between TIIClnc signature and CD8, PD-1 and PD-L1 was verified in the Xiangya in-house dataset. As a newly demonstrated predictive biomarker, the TIIClnc signature enabled a more precise selection of the GBM population who would benefit from immunotherapy and should be validated and applied in the near future.

Causal association between circulating blood cell traits and pulmonary embolism: a mendelian randomization study.

BACKGROUND: Pulmonary embolism (PE) is a life-threatening thromboembolic disease for which there is limited evidence for effective prevention and treatment. Our goal was to determine whether genetically predicted circulating blood cell traits could influence the incidence of PE. METHODS: Using single variable Mendelian randomization (SVMR) and multivariate Mendelian randomization (MVMR) analyses, we identified genetic associations between circulating blood cell counts and lymphocyte subsets and PE. GWAS blood cell characterization summary statistics were compiled from the Blood Cell Consortium. The lymphocyte subpopulation counts were extracted from summary GWAS statistics for samples from 3757 individuals that had been analyzed by flow cytometry. GWAS data related to PE were obtained from the FinnGen study. RESULTS: According to the SVMR and reverse MR, increased levels of circulating white blood cells (odds ratio [OR]: 0.88, 95% confidence interval [CI]: 0.81-0.95, p = 0.0079), lymphocytes (OR: 0.90, 95% CI: 0.84-0.97, p = 0.0115), and neutrophils (OR: 0.88, 95% CI: 0.81-0.96, p = 0.0108) were causally associated with PE susceptibility. MVMR analysis revealed that lower circulating lymphocyte counts (OR: 0.84, 95% CI: 0.75-0.94, p = 0.0139) were an independent predictor of PE. According to further MR results, this association may be primarily related to HLA-DR+ natural killer (NK) cells. CONCLUSIONS: Among European populations, there is a causal association between genetically predicted low circulating lymphocyte counts, particularly low HLA-DR+ NK cells, and an increased risk of PE. This finding supports observational studies that link peripheral blood cells to PE and provides recommendations for predicting and preventing this condition.

Identification of a single cell-based signature for predicting prognosis risk and immunotherapy response in patients with glioblastoma.

This study constructed a novel gene pair signature based on bulk and single-cell sequencing samples in relative expression order within the samples. The subsequent analysis included glioma samples from Xiangya Hospital. Gene pair signatures possessed a solid ability to predict the prognosis of glioblastoma and pan-cancer. Samples having different malignant biological hallmarks were distinguished by the algorithm, with the high gene pair score group featuring classic copy number variations, oncogenic mutations, and extensive hypomethylation, mediating poor prognosis. The increased gene pair score group with a poorer prognosis demonstrated significant enrichment in tumor and immune-related signaling pathways while presenting immunological diversity. The remarkable infiltration of M2 macrophages in the high gene pair score group was validated by multiplex immunofluorescence, suggesting that combination therapies targeting adaptive and innate immunity may serve as a therapeutic option. Overall, a gene pair signature applicable to predict prognosis hopefully provides a reference to guide clinical practice.

Engineering Rhodosporidium toruloides for production of 3-hydroxypropionic acid from lignocellulosic hydrolysate.

Microbial production of valuable bioproducts is a promising route towards green and sustainable manufacturing. The oleaginous yeast, Rhodosporidium toruloides, has emerged as an attractive host for the production of biofuels and bioproducts from lignocellulosic hydrolysates. 3-hydroxypropionic acid (3HP) is an attractive platform molecule that can be used to produce a wide range of commodity chemicals. This study focuses on establishing and optimizing the production of 3HP in R. toruloides. As R. toruloides naturally has a high metabolic flux towards malonyl-CoA, we exploited this pathway to produce 3HP. Upon finding the yeast capable of catabolizing 3HP, we then implemented functional genomics and metabolomic analysis to identify the catabolic pathways. Deletion of a putative malonate semialdehyde dehydrogenase gene encoding an oxidative 3HP pathway was found to significantly reduce 3HP degradation. We further explored monocarboxylate transporters to promote 3HP transport and identified a novel 3HP transporter in Aspergillus pseudoterreus by RNA-seq and proteomics. Combining these engineering efforts with media optimization in a fed-batch fermentation resulted in 45.4 g/L 3HP production. This represents one of the highest 3HP titers reported in yeast from lignocellulosic feedstocks. This work establishes R. toruloides as a host for 3HP production from lignocellulosic hydrolysate at high titers, and paves the way for further strain and process optimization towards enabling industrial production of 3HP in the future.

Identification of a specific exporter that enables high production of aconitic acid in Aspergillus pseudoterreus.

Aconitic acid is an unsaturated tricarboxylic acid that is attractive for its potential use in manufacturing biodegradable and biocompatible polymers, plasticizers, and surfactants. Previously Aspergillus pseudoterreus was engineered as a platform to produce aconitic acid by deleting the cadA (cis-aconitic acid decarboxylase) gene in the itaconic acid biosynthetic pathway. In this study, the aconitic acid transporter gene (aexA) was identified using comparative global discovery proteomics analysis between the wild-type and cadA deletion strains. The protein AexA belongs to the Major Facilitator Superfamily (MFS). Deletion of aexA almost abolished aconitic acid secretion, while its overexpression led to a significant increase in aconitic acid production. Transportation of aconitic acid across the plasma membrane is a key limiting step in its production. In vitro, proteoliposome transport assay further validated AexA's function and substrate specificity. This research provides new approaches to efficiently pinpoint and characterize exporters of fungal organic acids and accelerate metabolic engineering to improve secretion capability and lower the cost of bioproduction.

Global Burden and Its Association with Socioeconomic Development Status of Meningitis Caused by Specific Pathogens over the Past 30 years: A Population-Based Study.

BACKGROUND: Meningitis is a severe and fatal neurological disease and causes lots of disease burden. The purpose of this study was to assess the global, regional, and national burdens and trends of meningitis by age, sex, and etiology. METHODS: Data on the burden of meningitis were collected from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019. R and Joinpoint were used for statistical analysis and charting. RESULTS: In 2019, meningitis caused 236,222 deaths and 15,649,865 years of life lost (YLL) worldwide. The age-standardized death rate and age-standardized YLL rate of meningitis were 3.29 and 225, which decreased steadily. Burden change was mainly driven by epidemiological changes. Regionally, meningitis burden was the highest in Sub-Saharan Africa. Burden of disease increasingly concentrated in low sociodemographic index countries, and this was most pronounced in meningitis caused by N. meningitidis. Countries such as Mali, Nigeria, Sierra Leone, etc., especially need to enhance the rational allocation of public health resources to reduce the disease burden. Children and men were more likely to be affected by meningitis. PM2.5 was found to be an important risk factor. CONCLUSIONS: This study provides the first comprehensive understanding of the global disease burden of meningitis caused by specific pathogens and highlights policy priorities to protect human health worldwide, with particular attention to vulnerable regions, susceptible populations, environmental factors, and specific pathogens.

Glioma targeted therapy: insight into future of molecular approaches.

Gliomas are the common type of brain tumors originating from glial cells. Epidemiologically, gliomas occur among all ages, more often seen in adults, which males are more susceptible than females. According to the fifth edition of the WHO Classification of Tumors of the Central Nervous System (WHO CNS5), standard of care and prognosis of gliomas can be dramatically different. Generally, circumscribed gliomas are usually benign and recommended to early complete resection, with chemotherapy if necessary. Diffuse gliomas and other high-grade gliomas according to their molecule subtype are slightly intractable, with necessity of chemotherapy. However, for glioblastoma, feasible resection followed by radiotherapy plus temozolomide chemotherapy define the current standard of care. Here, we discuss novel feasible or potential targets for treatment of gliomas, especially IDH-wild type glioblastoma. Classic targets such as the p53 and retinoblastoma (RB) pathway and epidermal growth factor receptor (EGFR) gene alteration have met failure due to complex regulatory network. There is ever-increasing interest in immunotherapy (immune checkpoint molecule, tumor associated macrophage, dendritic cell vaccine, CAR-T), tumor microenvironment, and combination of several efficacious methods. With many targeted therapy options emerging, biomarkers guiding the prescription of a particular targeted therapy are also attractive. More pre-clinical and clinical trials are urgently needed to explore and evaluate the feasibility of targeted therapy with the corresponding biomarkers for effective personalized treatment options.

Membrane progesterone receptor α (mPRα) enhances hypoxia-induced vascular endothelial growth factor secretion and angiogenesis in lung adenocarcinoma through STAT3 signaling.

Lung cancer remains a huge challenge to public health because of its high incidence and mortality, and lung adenocarcinoma (LUAD) is the main subtype of lung cancer. Hypoxia-induced vascular endothelial growth factor (VEGF) release and angiogenesis have been regarded as critical events in LUAD carcinogenesis. In the present study, membrane progesterone receptor α (mPRα) is deregulated within LUAD tissue samples; increased mPRα contributes to a higher microvessel density (MVD) in LUAD tissues. mPRα knockdown in A549 and PC-9 cells significantly inhibited STAT3 phosphorylation, as well as HIF1α and VEGF protein levels, decreasing cancer cell migration and invasion. The in vivo xenograft model further confirmed that mPRα enhanced the aggressiveness of LUAD cells. Furthermore, mPRα knockdown significantly inhibited hypoxia-induced upregulation in HIF1α and VEGF levels, as well as LUAD cell migration and invasion. Under the hypoxic condition, conditioned medium (CM) derived from mPRα knockdown A549 cells, namely si-mPRα-CM, significantly inhibited HUVEC migration and tube formation and decreased VEGF level in the culture medium. In contrast, CM derived from mPRα-overexpressing A549 cells, namely mPRα-CM, further enhanced HUVEC migration and tube formation and increased VEGF level under hypoxia, which was partially reversed by STAT3 inhibitor Stattic. In conclusion, in LUAD cells, highly expressed mPRα enhances the activation of cAMP/JAK/STAT3 signaling and increases HIF1α-induced VEGF secretion into the tumor microenvironment, promoting HUVEC migration and tube formation under hypoxia.

Neutrophil extracellular traps induced by cigarette smoke contribute to airway inflammation in mice.

Neutrophil extracellular traps (NETs) were initially identified as an important antimicrobial barrier to capture and kill microorganisms. Emerging evidence suggests that NETs play a crucial role in chronic airway inflammation induced by cigarette smoke (CS). However, how NETs form and the mechanisms by which NETs function in CS-related airway diseases are still unclear. To explore NET formation and its potential role in CS-related airway diseases, we first established a CS-induced subacute airway inflammation model in mice and verified NET formation in the airways. Moreover, NETs degradation by aerosolized DNase I treatment significantly inhibited the airway inflammation induced by CS in mice. More importantly, by in vitro experiments, we found that cigarette smoke extract (CSE) induces NET formation in an NADPH oxidase-dependent manner, and that macrophages and human bronchial epithelial cells (HBEs) are important targets for the NETs-induced secretion of inflammatory cytokines. Therefore, NETs may represent a critical link among neutrophils, macrophages and HBEs under chronic inflammation conditions induced by CS.

Correction to: Clinical characterization, genetic profiling, and immune infiltration of TOX in diffuse gliomas.

An amendment to this paper has been published and can be accessed via the original article.

Clinical characterization, genetic profiling, and immune infiltration of TOX in diffuse gliomas.

BACKGROUND: Immunotherapies targeting glioblastoma (GBM) have led to significant improvements in patient outcomes. TOX is closely associated with the immune environment surrounding tumors, but its role in gliomas is not fully understood. METHODS: Using data from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA), we analyzed the transcriptomes of 1691 WHO grade I-IV human glioma samples. The R language was used to perform most of the statistical analyses. Somatic mutations and somatic copy number variation (CNV) were analyzed using GISTIC 2.0. RESULTS: TOX was down-regulated in malignant gliomas compared to low grade gliomas, and upregulated in the proneural and IDH mutant subtypes of GBM. TOXlow tumours are associated with the loss of PTEN and amplification of EGFR, while TOXhigh tumours harbor frequent mutations in IDH1 (91%). TOX was highly expressed in leading edge regions of tumours. Gene ontology and pathway analyses demonstrated that TOX was enriched in multiple immune related processes including lymphocyte migration in GBM. Finally, TOX had a negative association with the infiltration of several immune cell types in the tumour microenvironment. CONCLUSION: TOX has the potential to be a new prognostic marker for GBM.

Deletion analysis of the itaconic acid biosynthesis gene cluster components in Aspergillus pseudoterreus ATCC32359.

The filamentous fungus Aspergillus terreus has been successfully used for industrial production of itaconic acid (IA) for many years. The IA biosynthesis pathway has recently been characterized at a molecular genetic level as an IA gene cluster by a clone-based transcriptomic approach. The cluster consists of four genes, including genes for cis-aconitic acid decarboxylase (cadA), a predicted transcription factor (tf), a mitochondrial organic acid transporter (mttA) and an MFS (major facilitator superfamily) type transporter (mfsA). In this research, we performed expressed sequence tag (EST) analysis and systematic gene deletions to further investigate the role of those genes during IA biosynthesis in A. pseudoterreus ATCC32359. EST analysis showed a similar expression pattern among those four genes that were distinct from neighboring genes and further confirmed that they belong to the same biosynthesis cluster. Systematic gene deletion analysis demonstrated that tf, cadA, mttA and mfsA genes in the cluster are essential for IA production; deletion of any of them will either completely abolish the IA production or dramatically decrease the amount of IA produced. The tf gene plays a regulatory role in this cluster. Deletion of tf led to decreased expression levels of cadA, mttA and mfsA. More importantly, a significant amount of aconitic acid was detected in the cadA deletion strain but not in the other deletion strains. Therefore, by deleting only one gene, the cadA, we established a novel microbial host for the production of aconitic acid and other value-added chemicals from sugars in lignocellulosic biomass.

Deletion of the KU70 homologue facilitates gene targeting in Lipomyces starkeyi strain NRRL Y-11558.

The objective of this study was to disrupt the non-homologous end-joining (NHEJ) pathway gene (Lsku70Δ) and evaluate the effects of selected gene deletions related to glycogen synthesis (LsGSY1) and lipid degradation (LsMFE1, LsPEX10, and LsTGL4) on lipid production in the oleaginous yeast Lipomyces starkeyi. Disruption of the NHEJ pathway to reduce the rate of non-homologous recombination is a common approach used to overcome low-efficiency targeted deletion or insertion in various organisms. Here, the homologue of the LsKU70 gene was identified and disrupted in L. starkeyi NRRL Y-11558. The LsGSY1, LsMFE1, LsPEX10, LsTGL4, and LsURA3 genes were then replaced with a resistance marker in the Lsku70Δ strain and several site-specific insertions were assessed for targeted over-expression of selected genes. The targeted disruption efficiency of five selected genes (LsGSY1, LsMFE1, LsPEX10, LsTGL4, and LsURA3) was increased from 0 to 10% in the parent to 50-100% of transformants screened in the Lsku70Δ strain with 0.8-1.4 kb homologous flanking sequences, while the efficiency of site-specific gene insertion with the ß-glucuronidase reporter gene was 100% in the locus near the 3'-end coding (LsKU70) and non-coding (LsGSY1, LsMFE1, and LsPEX10) regions. Disruption of LsKU70 in isolation and in conjunction with LsGSY1, LsMFE1, LsPEX10, or LsTGL4 did not affect lipid production in L. starkeyi. Furthermore, ß-glucuronidase reporter gene activity was similar in strains containing site-specific targeted insertions. Therefore, over-expression of genes related to lipid synthesis at targeted loci can be further examined for improvement of total lipid production in L. starkeyi.

Agrobacterium tumefaciens-mediated transformation of oleaginous yeast Lipomyces species.

Interest in using renewable sources of carbon, especially lignocellulosic biomass, for the production of hydrocarbon fuels and chemicals has fueled interest in exploring various organisms capable of producing hydrocarbon biofuels and chemicals or their precursors. The oleaginous (oil-producing) yeast Lipomyces starkeyi is the subject of active research regarding the production of triacylglycerides as hydrocarbon fuel precursors using a variety of carbohydrate and nutrient sources. The genome of L. starkeyi has been published, which opens the door to production strain improvements through the development and use of the tools of synthetic biology for this oleaginous species. The first step in establishment of synthetic biology tools for an organism is the development of effective and reliable transformation methods with suitable selectable marker genes and demonstration of the utility of the genetic elements needed for expression of introduced genes or deletion of endogenous genes. Chemical-based methods of transformation have been published but suffer from low efficiency. To address these problems, Agrobacterium-mediated transformation was investigated as an alternative method for L. starkeyi and other Lipomyces species. In this study, Agrobacterium-mediated transformation was demonstrated to be effective in the transformation of both L. starkeyi and other Lipomyces species. The deletion of the peroxisomal biogenesis factor 10 gene was also demonstrated in L. starkeyi. In addition to the bacterial antibiotic selection marker gene hygromycin B phosphotransferase, the bacterial ß-glucuronidase reporter gene under the control of L. starkeyi translation elongation factor 1α promoter was also stably expressed in six different Lipomyces species. The results from this study demonstrate that Agrobacterium-mediated transformation is a reliable and effective genetic tool for homologous recombination and expression of heterologous genes in L. starkeyi and other Lipomyces species.

Lipid Metabolism in Vascular Smooth Muscle Cells Infuenced by HCMV Infection.

BACKGROUND: The present study was designed to observe the infection of human cytomegalovirus (HCMV) to human vascular smooth muscle cells (VSMCs), and the effect of viral infection on lipid metabolism in VSMCs. METHODS: The cytopathic effects were observed by inverted microscopy and viral infection were examined by electron microscopy and RT-PCR. The lipid metabolism related gene profiling of VSMCs after HCMV infection was assayed by cDNA assay and the abnormal expression of genes were validated by quantitative RT-PCR. The content of cholesterol in VSMCs after HCMV infection was assayed by cholesterol detection kit. RESULTS: VSMCs showed obvious cytopathic effects after HCMV infection. Intact viral particles could be detected in VSMCs using electron microscope. By use of RT-PCR technology, IE gene of HCMV could be amplified from VSMCs. The expression of cell lipid metabolism related gene profiling showed obvious disorders. The expression levels of HMG-CoA synthase and HMG-CoA reductase after infection increased significantly. The cellular cholesterol content (µmol/106 cells) was significantly higher than that of mock infected group at 72h post infection. CONCLUSION: HCMV can infect VSMCs and the infection can affect cellular lipid metabolism related gene expression, which get involved in the occurrence and development of atherosclerosis (AS).

Production and Characterization of Desmalonichrome Relative Binding Affinity for Uranyl Ions in Relation to Other Siderophores.

Siderophores are iron (Fe)-binding secondary metabolites that have been investigated for their uranium-binding properties. Previous work has focused on characterizing hydroxamate types of siderophores, such as desferrioxamine B, for their uranyl (UO2)-binding affinity. Carboxylate forms of these metabolites hold potential to be more efficient chelators of UO2, yet they have not been widely studied. Desmalonichrome is a carboxylate siderophore that is not commercially available and so was obtained from the fungus Fusarium oxysporum cultivated under Fe-depleted conditions. The relative affinity for UO2 binding of desmalonichrome was investigated using a competitive analysis of binding affinities between UO2 acetate and different concentrations of Fe(III) chloride using electrospray ionization mass spectrometry. In addition to desmalonichrome, three other siderophores, including two hydroxamates (desferrioxamine B and desferrichrome) and one carboxylate (desferrichrome A), were studied to understand their relative affinities for the UO2(2+) ion at two pH values. The binding affinities of hydroxamate siderophores to UO2(2+) ions were observed to decrease with increasing Fe(III)Cl3 concentration at the lower pH. On the other hand, decreasing the pH has a smaller impact on the binding affinities between carboxylate siderophores and the UO2(2+) ion. Desmalonichrome in particular was shown to have the greatest relative affinity for UO2 at all pH and Fe(III) concentrations examined. These results suggest that acidic functional groups in the ligands are important for strong chelation with UO2 at lower pH.

Proteome-wide light/dark modulation of thiol oxidation in cyanobacteria revealed by quantitative site-specific redox proteomics.

Reversible protein thiol oxidation is an essential regulatory mechanism of photosynthesis, metabolism, and gene expression in photosynthetic organisms. Herein, we present proteome-wide quantitative and site-specific profiling of in vivo thiol oxidation modulated by light/dark in the cyanobacterium Synechocystis sp. PCC 6803, an oxygenic photosynthetic prokaryote, using a resin-assisted thiol enrichment approach. Our proteomic approach integrates resin-assisted enrichment with isobaric tandem mass tag labeling to enable site-specific and quantitative measurements of reversibly oxidized thiols. The redox dynamics of ∼2,100 Cys-sites from 1,060 proteins under light, dark, and 3-(3,4-dichlorophenyl)-1,1-dimethylurea (a photosystem II inhibitor) conditions were quantified. In addition to relative quantification, the stoichiometry or percentage of oxidation (reversibly oxidized/total thiols) for ∼1,350 Cys-sites was also quantified. The overall results revealed broad changes in thiol oxidation in many key biological processes, including photosynthetic electron transport, carbon fixation, and glycolysis. Moreover, the redox sensitivity along with the stoichiometric data enabled prediction of potential functional Cys-sites for proteins of interest. The functional significance of redox-sensitive Cys-sites in NADP-dependent glyceraldehyde-3-phosphate dehydrogenase, peroxiredoxin (AhpC/TSA family protein Sll1621), and glucose 6-phosphate dehydrogenase was further confirmed with site-specific mutagenesis and biochemical studies. Together, our findings provide significant insights into the broad redox regulation of photosynthetic organisms.

Comparative genomics of citric-acid-producing Aspergillus niger ATCC 1015 versus enzyme-producing CBS 513.88.

The filamentous fungus Aspergillus niger exhibits great diversity in its phenotype. It is found globally, both as marine and terrestrial strains, produces both organic acids and hydrolytic enzymes in high amounts, and some isolates exhibit pathogenicity. Although the genome of an industrial enzyme-producing A. niger strain (CBS 513.88) has already been sequenced, the versatility and diversity of this species compel additional exploration. We therefore undertook whole-genome sequencing of the acidogenic A. niger wild-type strain (ATCC 1015) and produced a genome sequence of very high quality. Only 15 gaps are present in the sequence, and half the telomeric regions have been elucidated. Moreover, sequence information from ATCC 1015 was used to improve the genome sequence of CBS 513.88. Chromosome-level comparisons uncovered several genome rearrangements, deletions, a clear case of strain-specific horizontal gene transfer, and identification of 0.8 Mb of novel sequence. Single nucleotide polymorphisms per kilobase (SNPs/kb) between the two strains were found to be exceptionally high (average: 7.8, maximum: 160 SNPs/kb). High variation within the species was confirmed with exo-metabolite profiling and phylogenetics. Detailed lists of alleles were generated, and genotypic differences were observed to accumulate in metabolic pathways essential to acid production and protein synthesis. A transcriptome analysis supported up-regulation of genes associated with biosynthesis of amino acids that are abundant in glucoamylase A, tRNA-synthases, and protein transporters in the protein producing CBS 513.88 strain. Our results and data sets from this integrative systems biology analysis resulted in a snapshot of fungal evolution and will support further optimization of cell factories based on filamentous fungi.

ZC3H13 promotes ITGA6 m6A modification for chronic obstructive pulmonary disease progression.

Chronic obstructive pulmonary disease (COPD) is potentially fatal, and as society ages, its effects on human health are predicted to deteriorate. The potential function of m6A modifications within COPD has become a hot topic recently. This study was conducted to clarify the function and related mechanisms of the m6A methylation transferase ZC3H13 in COPD. The expression of m6A-associated protease and ITGA6 in COPD tissues was assessed using GEO data, qRT-PCR, and western blot. COPD models in cells and mice were established through cigarette smoke extract (CSE) and smoke exposure. Inflammatory marker levels were measured by ELISA, apoptosis by flow cytometry, and mRNA stability with Actinomycin D assay. m6A modification levels were checked by MeRIP-PCR. HE and Masson staining evaluated lung pathology, and alveolar lavage fluid analysis included total cell count and Giemsa staining. ZC3H13 and METTL3 were differentially expressed m6A regulators in COPD, with ZC3H13 being more significantly upregulated. Further analysis revealed the ZC3H13 expression-related differentially expressed genes (DEGs) functions were enriched in the immunoinflammatory pathway, indicating ZC3H13's involvement in COPD pathogenesis through inflammation, and immune responses. Knockdown studies in cellular and mouse models demonstrated ZC3H13's role in exacerbating COPD symptoms, including inflammation, apoptosis, and EMT, and its suppression led to significant improvements. The identification of ITGA6 as a target gene further elucidated the mechanism, showing that ZC3H13 enhances ITGA6 expression and mRNA stability through m6A modification, influencing bronchial epithelial cell inflammation and fibrosis. In conclusion, targeting ZC3H13/ITGA6 could be an underlying therapeutic approach for treating COPD.