Functional Pathways Research Articles

Comparative review of transcortical and trans-Sylvian approaches for surgical resection of giant insular gliomas: outcomes and challenges

Abstract The giant insular glioma is defined as occupying all zone of the insula according to the Berger-Sanai classification. It is often encountered with a large volume, extending to the surrounding areas, functional pathway, and vascular structure, making its surgical resection very challenging for a neurosurgeon. In the literature, some studies revealed that it is more likely not to achieve a great extent of resection and is associated with a high postoperative morbidity rate. However, those studies included different insular gliomas regarding the location, extension, and surgical approach addressed. The giant insular gliomas subtype has been reported in the literature combined with all the insular gliomas and different surgical methods, which may bias the outcomes. The main approaches for insular glioma surgery are transcortical (TC) and trans-Sylvian (TS) approaches. This review aims to evaluate the evidence supporting the use of TS and TC surgical approaches for the management of giant insular gliomas. It will also analyze the associated postoperative outcomes to provide insights into their effectiveness and safety.

Multiple machine learning-based integrations of multi-omics data to identify molecular subtypes and construct a prognostic model for HNSCC

BackgroundImmunotherapy has introduced new breakthroughs in improving the survival of head and neck squamous cell carcinoma (HNSCC) patients, yet drug resistance remains a critical challenge. Developing personalized treatment strategies based on the molecular heterogeneity of HNSCC is essential to enhance therapeutic efficacy and prognosis.MethodsWe integrated four HNSCC datasets (TCGA-HNSCC, GSE27020, GSE41613, and GSE65858) from TCGA and GEO databases. Using 10 multi-omics consensus clustering algorithms via the MOVICS package, we identified two molecular subtypes (CS1 and CS2) and validated their stability. A machine learning-driven prognostic signature was constructed by combining 101 algorithms, ultimately selecting 30 prognosis-related genes (PRGs) with the Elastic Net model. This signature was further linked to immune infiltration, functional pathways, and therapeutic sensitivity.ResultsCS1 exhibited superior survival outcomes in both TCGA and META-HNSCC cohorts. The PRG-based signature stratified patients into low- and high-risk groups, with the low-risk group showing prolonged survival, enhanced immune cell infiltration (B cells, T cells, monocytes), and activated immune functions (cytolytic activity, T cell co-stimulation). High-risk patients were more sensitive to radiotherapy and chemotherapy (e.g., Cisplatin, 5-Fluorouracil), while low-risk patients responded better to immunotherapy and targeted therapies.ConclusionOur study delineates two molecular subtypes of HNSCC and establishes a robust prognostic model using multi-omics data and machine learning. These findings provide a framework for personalized treatment selection, offering clinical insights to optimize therapeutic strategies for HNSCC patients.

Silica Nanoparticles Induce SH-SY5Y Cells Death Via PARP and Caspase Signaling Pathways.

A growing stream of research indicates that exposure to Silica nanoparticles (SiNPs) can cause nervous system damage, leading to the occurrence of neurodegenerative diseases such as Alzheimer's disease. However, the specific mechanism by which SiNPs cause neuroblast injury remains unclear and requires further research. This study established an in vitro experimental model of SH-SY5Y cells exposed to SiNPs and observed cell growth through an inverted fluorescence microscope. Cell viability was measured using an MTT assay. The intracellular ROS and Ca2+ levels were detected by flow cytometry. Cell apoptosis was observed using both Hoechst33342 staining and TUNEL staining. The activities of SOD and ATPase and the content of ATP in the cells were tested by biochemical methods. The genes including parp-1, aif, par, ucp2, vdac and prdx3 were explored using quantitative real-time PCR. The expressions of PARP, AIF, PAR, Caspase-3, Caspase-9 and Cyt C proteins were evaluated by Western Blot. The immunofluorescence technique was used to observe the distribution of Parthanatos-related proteins induced by SiNPs. The results showed that SiNPs reduced cell survival rate, induced excessive ROS and Ca2+ overload, decreased SOD activity, ATPase activity, intracellular and mitochondrial ATP content, increased the expression of mitochondrial function and PARP pathway related genes, as well as PARP and Caspase pathway protein expression, ultimately inducing cell apoptosis. As a further test of the roles of PARP and Caspase pathways in SiNPs induced SH-SY5Y cells death, we selected the PARP inhibitor Olaparib and Caspase inhibitor Z-VAD, and the above effects were significantly improved after treatment with the inhibitors. Conclusively, this study confirmed that SiNPs can generate excessive ROS production in SH-SY5Y cells, alter mitochondrial function, and induce cell death through Parthanatos and caspase dependent apoptotic pathways, which can coexist and interact with each other.

Children who develop celiac disease are predicted to exhibit distinct metabolic pathways among their gut microbiota years before diagnosis.

We analyzed gut microbiome data from children who later developed celiac disease (CD progressors) compared to healthy children in the first 5 years of life. Using fecal samples corresponding to the three phases of gut microbiome development, we uncovered enriched functional microbial pathways in CD progressors at age 1. Some of these pathways, implicated in bacterial pathogenesis, microbiota modulation, and inflammation, have been correlated with CD. We also identified taxa in CD progressors at age 1 including Lachnospiraceae, Alistipes, and Bifidobacterium dentium that were previously associated with CD. These findings suggest a potential role for these taxa and enriched pathways in pediatric CD onset years before diagnosis, highlighting potential for early interventions. While the findings of this exploratory study should be validated with larger sample sizes, our study suggests microbial metabolic pathways related to CD onset, enhancing our understanding of CD pathogenesis and the role of gut microbiome-mediated early alterations.

CD19.CAR-T cell-derived extracellular vesicles express CAR and kill leukemic cells, contributing to antineoplastic therapy.

Chimeric Antigen Receptor (CAR) T cell-derived Extracellular Vesicles (EVs) might represent a new therapeutic tool for boosting CAR-T cell antileukemic effects. Here, a cohort of 22 patients infused with CD19.CAR-T cells was monitored for the presence of circulating CD19.CAR+-T cell-derived EVs (CD19.CAR+EVs), which were then separated and functionally characterized for their killing abilities. A GMP-compliant separation method was also developed. Results demonstrated that CD19.CAR+EVs were detectable in peripheral blood up to 2 years after infusion indicating long-lasting persistence of their parental cells. Notably, early decreases of circulating CD19.CAR+EVs concentrations correlated with failure of CAR-T therapy. Circulating CD19.CAR+EVs displayed a median size (SD) of 133.1±65.5 nm and carried a pro-apoptotic protein cargo. These EVs expressed higher CAR levels than their parental cells. Furthermore, CD19.CAR+EVs did not activate heterologous T cells and produced significant, specific and dose-dependent cytotoxic effects on CD19+ cell lines and on primary cells. The new GMP-compliant EV isolation method allowed a recovery of 63±5.7 % of CD19.CAR+EVs. A deeper analysis of the different protein cargoes carried by EVs derived from different CAR-T cell subpopulations identified a pro-apoptotic functional pathway linked to CD8+LAG-3+ EVs. Overall, our data indicate that CD19.CAR+EVs may be proposed as promising dynamic new biomarkers of CAR-T cell activity and, contributing to the direct killing of the leukemic target, represent a new product with a strong therapeutic potential that could be infused independently from CAR-T cells.

The Effects of miR-22-3p on Differentiation of Human Dental Pulp Stem Cells into Neural Progenitor-Like Cells.

Stem cell treatment shows promise in treating conditions such as neurodegenerative disorders and spinal injuries, but its effectiveness is hampered by cell death and apoptosis. Improving the differentiation of MSCs into neural cells could enhance their therapeutic potential. The role of miR-22-3p in human dental pulp stem cells (HDPSCs), a superior alternative to treat neurodegenerative disorders, and its molecular mechanisms during neural differentiation remain elusive. Therefore, we investigated the miR-22-3p transfections during HDPSC differentiation into neural progenitor-like cells (NPCs) and elucidated the molecular processes through transcriptomic analysis. HDPSCs were differentiated into NPCs after transfection with a miR-22-3p mimic and inhibitor; the differentiation process was assessed by cell viability and expression of Nestin protein. mRNA sequencing on days 1, 3, and 7 of the differentiation process identified several differentially expressed genes (DEGs). Cytoscape and functional enrichment analysis pinpointed central hub genes among the DEGs and uniquely expressed genes. miR-22-3p mimic hindered HDPSC differentiation by reducing proliferation and increasing apoptosis. It downregulated genes linked to extracellular matrix, synaptic and vesicle functions, lipid metabolism, JAK-STAT, and cell cycle pathways across all days while activating proteasome and digestion pathways. In contrast, miR-22-3p inhibition boosts NPC proliferation and elevates Nestin neural marker protein expression. Altogether, miR-22-3p disrupts synapse functioning and lipid metabolism pathways, resulting in apoptosis and death. Conversely, inhibiting miR-22-3p enhances neural differentiation and proliferation of HDPSCs, suggesting its potential application in generating a greater quantity of NPCs and neurons.

Gut microbiome features associate with immune checkpoint inhibitor response in individuals with non-melanoma skin cancers: an exploratory study.

Immune checkpoint inhibitor (ICI) therapy has yielded revolutionary outcomes among some individuals with skin cancer, but a large percentage of individuals do not benefit from these treatments. The gut microbiota is hypothesized to impact ICI therapy outcomes. However, data on ICI therapy, gut microbiota, and non-melanoma skin cancers are limited. To examine the association of gut microbiota structure and function with non-melanoma skin cancer ICI outcomes, we performed 16S rRNA V1-V2 gene amplicon sequencing of 68 fecal samples collected longitudinally from individuals with basal cell carcinoma (n = 5), Merkel cell carcinoma (n = 5), or cutaneous squamous cell carcinoma (CSCC, n = 11), followed by tumor-dependent differential analyses of bacterial composition and fecal sample analysis by untargeted metabolomics. Across all tumor types, we identified 10 differential bacterial genera between responders (R) or non-responders (NR) to ICI therapy. Among individuals with CSCC, we identified 10 genera and 20 species that differentiated between R and NR and yielded 8 pathways enriched in NR and 12 pathways enriched in R by predicted functional pathway analyses. Untargeted fecal metabolomics to examine putative gut microbiota metabolites associated with CSCC ICI R/NR identified nine KEGG pathways associated with ICI efficacy. In summary, this exploratory study suggests gut microbiota features that are associated with ICI efficacy in individuals with non-melanoma skin cancers and highlights the need for larger studies to validate the results.IMPORTANCEPrior studies examining associations between ICI efficacy and the gut microbiome have focused primarily on individuals with melanoma, for whom ICI therapy was first approved. Meanwhile, data regarding microbiome features associated with ICI responses in individuals with non-melanoma skin cancers (NMSCs) have remained limited. This initial fecal microbiota examination of individuals with NMSCs suggests that larger-scale studies to extend and validate our findings may yield predictive or prognostic biomarkers for individuals with NMSC receiving ICI with potential to provide insight to complementary, effective therapeutic interventions through microbiota modification.

Neuroimaging as a Tool for Advancing Pediatric Psychopharmacology.

Neuroimaging, specifically magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and positron emission tomography (PET), plays an important role in improving the therapeutic landscape of pediatric neuropsychopharmacology by detecting target engagement, pathway modulation, and disease-related changes in the brain. This review provides a comprehensive update on the application of neuroimaging to detect neural effects of psychotropic medication in pediatrics. Additionally, we discuss opportunities and challenges for expanding the use of neuroimaging to advance pediatric neuropsychopharmacology. PubMed and Embase were searched for studies published between 2012 and 2024 reporting neural effects of attention deficit hyperactivity disorder (ADHD) medications (e.g., methylphenidate, amphetamine, atomoxetine, guanfacine), selective serotonin reuptake inhibitors (e.g., fluoxetine, escitalopram, sertraline), serotonin/norepinephrine reuptake inhibitors (e.g., duloxetine, venlafaxine), second-generation antipsychotics (e.g., aripiprazole, olanzapine, risperidone, quetiapine, ziprasidone), and others (e.g., lithium, carbamazepine, lamotrigine, ketamine, naltrexone) used to treat pediatric psychiatric conditions. Of the studies identified (N = 57 in 3314 pediatric participants), most (86%, total participants n = 3045) used MRI to detect functional pathway modulation or anatomical changes. Fewer studies (14%, total participants n = 269) used MRS to understand neurochemical modulation. No studies used PET. Studies that included healthy controls detected normalization of disease-altered pathways following treatment. Studies that focused on affected youth detected neuromodulation following single-dose and ongoing treatment. Neuroimaging is positioned to serve as a biomarker capable of demonstrating acute brain modulation, predicting clinical response, and monitoring disease, yet biomarker validation requires further work. Neuroimaging is also well suited to fill the notable knowledge gap of long-term neuromodulatory effects of psychotropic medications in the context of ongoing brain development in children and adolescents. Future studies can leverage advancements in neuroimaging technology, acquisition, and analysis to fill these gaps and accelerate the discovery of novel therapeutics, leading to more effective prescribing and ensuring faster recovery.

WEIGHTED GENE CO-EXPRESSION NETWORK ANALYSIS IDENTIFIES BIOLOGICAL PATHWAYS AND BIOMARKER GENES ASSOCIATED WITH CHICKENS' ADAPTATION TO BOTH LOW AND HIGH ALTITUDES

The main aim of the study was to identify modules, hub genes, and possible pathways linked with hypoxia adaptation in six types of tissues and organs (heart, kidney, liver, lung, muscle, and spleen) at altitudes ranging from 2,300 to 3,500 metersOn a transcription dataset from hypoxia-sensitive tissues, we performed weighted gene co-expression network analysis on 13,940 selected genes, and 10 transcriptional modules in total were detected (Turquoise 196 genes, Purple 27 genes, Blue 196, Brown 182, Yellow 108, Green 79 genes, Red 69 genes, Black 50 genes, Pink 44 genes, and Magenta 37 genes). Furthermore, we discovered that the majority of variable genes were screened by sub-setting 1000 genes; samples belonging to the same tissue clearly clustered together, and the expression in the liver and lung was more associated than in the heart and spleen. Functional enrichment analysis of all genes in 12 selected modules revealed that 9 KEGG pathways were considerably enriched, 13 Gene ontology terms were significantly enriched in the biological process and cellular component pathways, and 15 gene ontology terms were significantly enriched in the molecular function pathway. Through weighted gene co-expression network analysis, the results of this study expand our knowledge of the molecular pathway of catalytic and metabolic activity as a biomarker pathway

A case-control genome-wide association study of estimated breeding values for resistance to gastrointestinal nematodes in two local dairy sheep breeds.

In sheep, gastrointestinal nematodes (GINs) can cause disease, reduced feed intake, and nutritional deficiencies. To counteract GINs, anthelmintics are widely used although it is well known they may enter the environment impacting ecosystems. In addition, anthelmintics resistance has rapidly developed and consequently, alternative approaches are crucial for profitable and sustainable sheep production. The occurrence of resistant individuals is mainly due to their intrinsic genetic diversity; therefore, the implementation of breeding plans for resistant animals may provide a promising strategy to reduce the use of anthelmintics. This study is aimed at identifying genomic regions involved in sheep resistance to GINs. To do this, faecal samples were collected from 642 Comisana and 323 Massese sheep over 3years to assess Faecal Egg Counts, and Estimated Breeding Values (EBVs) for GIN resistance were estimated by a repeatability animal model. Then, EBVs in the 99.95th and 0.05th percentiles were used to identify the most and least "genetically resistant" individuals to GINs, using genotyped individuals with the Illumina OvineSNP50 beadchip. A genome-wide case-control analysis was performed retaining the most significant single nucleotide polymorphisms (SNPs) with a threshold of 0.005% for the false discovery rate. Genes and Quantitative Trait Loci overlapping significant SNPs were annotated and enriched respectively while genes have been also enriched for functional pathways. As a result, 13 genes on 12 chromosomes and 10 genes on 11 different chromosomes were identified in the Comisana and Massese breed, respectively. Among these, genes involved in the physiology or pathology of the gastrointestinal tract, in adaptive processes and in production traits, were detected. The enrichment analysis highlighted 36 significant pathways in the Comisana breed and 21 in the Massese breed. Many of these pathways were involved in the regulation of the immune response, drug metabolism and detoxification, and vitamin metabolism. Interestingly, pathways involved in vitamin and drug metabolism were also identified in previous research and have shown to play an active role in GIN resistance. In this study, we took advantage of the use of EBVs as a metric for GIN resistance in a case-control genome-wide framework and successfully identified several genomic regions that might be involved in the trait. The presence of overlapping functional pathways related to different genes in the two breeds seems to reinforce the idea of the polygenicity of this trait, and further studies are needed in order to make selection schemes an effective tool to contrast GINs.

Alterations in gut microbiome in age- and diet-induced colorectal cancer (CRC) progression in a preclinical model.

223 Background: CRC is the third leading cause of cancer related deaths worldwide with age and diet among the strongest risk factors. Emerging evidence suggests gut microbiome plays important role in CRC and is highly impacted by the exposome primarily the food intake. Since diet and age plays an important role in gut microbiome diversity, the present study aimed to investigate the alterations in the gut microbiome in young versus old mice harboring CRC allografts and fed with different diets. Methods: Two cohorts of C57BL/6 including young (n = 9, age = 6 weeks) and old (n = 9, age = 20-24 months) mice were implanted with 1x10 6 MSI (microsatellite instable) CRC MC38 tumor cells. Mice in both cohorts were randomized into three different diet groups: normal diet (ND; standard chow), high-fat (HF) and calorie-restricted (CR: 30% reduction in total calories). Mice were housed individually under standard laboratory conditions. Mice fecal samples were collected and subjected to DNA isolation (ZymoBIOMICS-96 MagBead DNA Kit), followed by metagenomic shotgun and whole genome sequencing (ZymoBIOMICSe and Illumina NovaSeq, respectively). P ≤ 0.05 were considered as statistically significant. Results: Fecal microbiome analysis showed that old microbiome has higher alpha diversity compared to the young mice. No statistically significant differences in were found in microbiome diversities between the diet groups. Pairwise permanova results showed statistically significant differences between microbiomes of old vs. young groups ( P : 0.001), CR vs. HF groups ( P : 0.012) and HF vs. ND groups ( P : 0.021). ANCOM-BC analysis determined the differentiating features and microbial functional pathways in the young mice compared to the old mice group and in different diet groups with relative abundance differences of larger than log 10 2. Bacteroides thetaiotaomicron ( P : 1.43E-39) and Parabacteroides goldsteinii ( P : 2.20E-23) were enriched in young and old groups, respectively. Akkermansia muciniphila ( P : 0.008) was significantly enriched in ND compared to CR group. Lactococcus lactis ( P : 9.94E-160) and Lachnospiraceae bacterium A4 ( P : 4.95E-10) were significantly enriched in HF compared to ND diet groups and vice-versa, respectively. Among the functional pathways, CMP-legionaminate biosynthesis I ( P : 2.38E-13) and L-arginine biosynthesis IV (archaebacteria) ( P : 4.77E-11) were the most significantly enriched in young and old groups, respectively. Conclusions: Our findings highlight the differential diversity and microbial features of gut microbiome in age- and diet-induced CRC progression. Collectively, alteration in diet and age of the host lead to changes in gut microbiota which has a direct impact on activation of specific signaling pathways, metabolism and local and systemic immune responses, which may in turn affect chemosensitivity and outcome in CRC

Current intensity and hydraulic retention time play differential roles in functional gene expression or electron transfer pathways in a pyrite-filled three-dimensional biofilm electrode reactor (P3DBER).

This study developed a pyrite-filled three-dimensional biofilm electrode reactor (P3DBER) to treat nitrate wastewater with a low carbon/nitrogen ratio. Meanwhile, the joint effect of current intensity (CI) and hydraulic retention time (HRT) on the performance of the P3DBER was investigated. Results indicated that under the optimal conditions (CI = 30 mA, HRT = 4.9 h), the total inorganic nitrogen removal efficiency (TINRE) reached a maximum of 93.5 ± 1.4%, with a low electrical consumption of 0.075 kW·h/g TIN. Increasing CI under different HRTs significantly enhanced the nitrogen removal capacity of the P3DBER. However, at high CI (30 mA), prolonging HRT did not further improve the nitrogen removal efficiency. The introduction of pyrite not only increased the types of electron donors but also could effectively maintain the stability of pH in the P3DBER. Variation partitioning analysis (VPA) showed that CI had a greater impact on the microbial community/functional genes than HRT. In addition, network analysis demonstrated a strong interconnection among microorganisms/functional genes within the P3DBER. This study offers valuable information for optimizing the operating parameters of the P3DBER.

Exercise and exerkines: Mechanisms and roles in anti-aging and disease prevention.

Aging is a complex biological process characterized by increased inflammation and susceptibility to various age-related diseases, including cognitive decline, osteoporosis, and type 2 diabetes. Exercise has been shown to modulate mitochondrial function, immune responses, and inflammatory pathways, thereby attenuating aging through the regulation of exerkines secreted by diverse tissues and organs. These bioactive molecules, which include hepatokines, myokines, adipokines, osteokines, and neurokines, act both locally and systemically to exert protective effects against the detrimental aspects of aging. This review provides a comprehensive summary of different forms of exercise for older adults and the multifaceted role of exercise in anti-aging, focusing on the biological functions and sources of these exerkines. We further explore how exerkines combat aging-related diseases, such as type 2 diabetes and osteoporosis. By stimulating the secretion of these exerkines, exercise supports healthy longevity by promoting tissue homeostasis and metabolic balance. Additionally, the integration of exercise-induced exerkines into therapeutic strategies represents a promising approach to mitigating age-related pathologies at the molecular level. As our understanding deepens, it may pave the way for personalized interventions leveraging physical activity to enhance healthspan and improve quality of life.

Alterations in the Tongue Coating Microbiome in Patients With Diarrhea-Predominant Irritable Bowel Syndrome: A Cross-Sectional Study.

The gut microbiota plays a critical role in the occurrence and development of IBS-D, however, IBS-D-associated tongue coating microbiome dysbiosis has not yet been clearly defined. To address this, we analyzed the structure and composition of the tongue coating microbiome in 23 IBS-D patients and 12 healthy controls using 16S rRNA high-throughput sequencing analysis. The 16S rRNA sequencing results revealed that the overall observed OTUs of tongue coating microbiome in IBS-D patients exhibited a significant decrease compared with the healthy controls. Alpha diversity analysis showed that the diversity and community richness were significantly reduced in IBS-D patients, and PCoA revealed a distinct clustering of tongue coating microbiome between the IBS-D patients and healthy controls. Microbial comparisons at the genus level showed that the abundance of Veillonella, Prevotella in IBS-D patients was higher than those in healthy controls, while Streptococcus, Haemophilus, Granulicatella, and Rothia were significantly reduced compared with the healthy volunteers. Functional analysis results showed significant differences in 88 functional metabolic pathways between the IBS-D patients and the healthy controls, including fatty acid biosynthesis. These findings identified the structure, composition, functionality of tongue coating microbiome in IBS-D patients, and hold promise the potential for therapeutic targets during IBS-D management.

Knockdown of GSDMD inhibits pyroptosis in psoriasis by blocking the NOD-like receptor signaling pathway.

Psoriasis is a chronic inflammatory skin disease regulated by autoimmunity, and pyroptosis plays an important role in this condition. This research sought to examine the function and potential molecular pathway of Gasdermin D (GSDMD) in psoriasis. GSDMD expression was examined by immunohistochemistry in biopsied skin tissues from patients with psoriasis. Pyroptosis-related genes and inflammatory factors were quantified using qRT-PCR and ELISA, respectively. HaCaT cells were treated with M5 cytokines to develop an in vitro psoriasis model, while imiquimod (IMQ) was administered to construct an in vivo psoriasis model. To counteract the inhibition of the NOD-like receptor (NLR) pathway caused by GSDMD knockdown, the pathway activator M-TriDAP was employed. In the lesional skin tissues of patients with psoriasis, GSDMD expression was highly expressed. The levels of pro-pyroptosis mediators were increased, whereas the level of anti-inflammatory factor was lowered. GSDMD knockdown and disulfiram treatment inhibited pyroptosis and promoted apoptosis in M5-induced HaCaT cells. In the IMQ-induced psoriasis-like mouse model, GSDMD knockdown suppressed pyroptosis and improved skin lesion severity, alleviating erythema, epidermal thickness, and inflammatory cell infiltration. Mechanistically, GSDMD knockdown inhibited the NLR pathway, accompanied by reduced protein levels of NLRP3, NOD1, NOD2, and PYCARD. NLR pathway activator, M-TriDAP treatment significantly reversed the effects of GSDMD knockdown on psoriasis progression. Knockdown of GSDMD inhibits pyroptosis in psoriasis by blocking the NLR signaling pathway, presenting a novel potential strategy for psoriasis treatment.

Metagenomic insights into nitrite accumulation in sulfur-based denitrification systems utilizing different electron donors: functional microbial communities and metabolic mechanisms

Sulfur-based autotrophic denitrification (SADN) offers new pathway for nitrite supply. However, sequential transformation of nitrogen and sulfur forms, and the functional microorganisms driving nitrite accumulation in SADN with different reduced inorganic sulfur compounds (RISCs), remain unclear. Desirable nitrite accumulation was achieved using elemental sulfur (S0-group), sulfide (S2--group) and thiosulfate (S2O32--group) as electron donors. Under equivalent electron supply conditions, S2O32--group exhibited a superior nitrate conversion rate (NCR) of 0.285 kg N/(m³·d) compared to S2--group (0.103 kg N/(m³·d)). Lower NCR in S2--group was attributed to sulfide strongly inhibiting energy metabolism process of TCA cycle, resulting in reduced reaction rates. Moreover, the NCR of S0-group (0.035 kg N/(m³·d)) was poor due to the chemical inertness of S0. Specific microbial communities were selectively enriched in phylum level, with Proteobacteria increasing to an astonished 96.27-98.49%. Comprehensive analyses of functional genus, genes, and metabolic pathways revealed significant variability in the active functional genus, with even the same genus showed significant metabolic differences in response to different RISCs. In S0-group, Thiomonas (10.0%) and Acidithiobacillus (5.1%) were the primary contributor to nitrite accumulation. Thiobacillus was the most abundant sulfur-oxidizing bacteria in S2--group (43.84%) and S2O32--group (18.92%). In S2--group, it contributed to nitrite accumulation, while in S2O32--group, it acted as a complete denitrifier (NO3--N→N2). Notably, heterotrophic denitrifying bacteria, Comamonas (12.52%), were crucial for nitrite accumulation in S2O32--group, predominating NarG while lacking NirK/S. Overall, this work advances our understanding of SADN systems with different RISCs, offering insights for optimizing nitrogen and sulfur removal.

Identification and validation of a prognostic risk model based on radiosensitivity-related genes in nasopharyngeal carcinoma.

Despite advancements with intensity-modulated radiation therapy (IMRT), about 10 % of nasopharyngeal carcinoma (NPC) patients remain resistant to radiotherapy, leading to recurrence and poor prognosis. This study aims to identify radiosensitivity-related genes in NPC and develop a prognostic model to predict patient outcomes. We analyzed 179 NPC samples from Fujian Cancer Hospital using RNA sequencing. Differentially expressed genes (DEGs) were identified between radiotherapy-sensitive and resistant samples. Machine learning algorithms and Cox regression were used to construct a prognostic risk model, validated in the GSE102349 dataset. Additional analyses included functional pathway, immune infiltration, and drug sensitivity. A risk model based on six genes (LCN8, IGSF1, RIMS2, RBP4, TBX10, ETV4) was developed. Kaplan-Meier analysis showed significantly shorter progression-free survival (PFS) in the high-risk group. The model's AUC values were 0.872, 0.807, and 0.802 for 1-year, 3-year, and 5-year predictions. A nomogram including clinical factors was created, and enrichment analysis linked the high-risk group to radiotherapy resistance mechanisms. This study established a novel radiosensitivity-related prognostic model, offering insights into NPC prognosis and radiotherapy resistance mechanisms.

Exosomal insights into ovarian cancer stem cells: revealing the molecular hubs

Ovarian cancer is a deadly disease, often diagnosed at advanced stages due to a lack of reliable biomarkers. Exosomes, which carry a variety of molecules such as proteins, lipids, DNA, and non-coding RNAs, have recently emerged as promising tools for early cancer detection. While exosomes have been studied in various cancer types, comprehensive network analyses of exosome proteins in ovarian cancer remain limited. In this study, we used a protein-protein interaction (PPI) network. Using the Clustermaker2 app and the MCODE algorithm, we identified six significant clusters within the network, highlighting regions involved in functional pathways. A four-fold algorithmic approach, including MCC, DMNC, Degree, and EPC, identified 12 common hub genes. STRING analysis and visualization techniques provided a detailed understanding of the biological processes associated with these hub genes. Notably, 91.7% of the identified hub genes were involved in translational processes, showing an important role in protein synthesis regulation in ovarian cancer. In addition, we identified the miRNAs and LncRNAs carried by ovarian cancer exosomes. These findings highlight potential biomarkers for early detection and therapeutic targets.

Single-cell RNA sequencing and functional analysis reveal the role of altered glycosylation levels of hepatic macrophages in liver cirrhosis.

Liver cirrhosis represents a critical stage of chronic liver disease, characterized by progressive liver damage, cellular dysfunction, and disrupted cell-to-cell interactions. Glycosylation, an essential post-translational modification, significantly influences cellular behavior and disease progression. Its role in cirrhosis at the single-cell level remains unclear, despite its importance. This study, based on single-cell glycosylation and transcriptome data, compared the expression of differentially expressed genes in liver tissues from cirrhotic and healthy control samples, identifying changes in glycosylation-related genes and their functional pathway enrichment characteristics. Additionally, it analyzed the composition of immune cells and intercellular interaction features, with a focus on the interaction between macrophages and other immune cells and their potential role in immune regulation. The analysis revealed significant changes in immune cell composition and glycosylation patterns in cirrhotic livers. Specifically, the number of macrophages increased substantially, while overall glycosylation levels decreased. Enhanced interactions between macrophages and other cell types were observed, highlighting the central role of macrophages in reshaping the immune microenvironment during cirrhosis progression. Gene expression analysis showed a marked upregulation of FUCA1, a gene encoding a glycosylation-related hydrolase. This change was strongly associated with the observed reduction in glycosylation levels. Functional enrichment analysis further revealed that glycosylation-related genes were primarily involved in immune pathways, including antigen processing and presentation, cytokine signaling, and immune activation. Single-cell glycosylation analysis provides crucial insights into immune cell interactions in cirrhosis. Targeting glycosylation pathways in macrophages may offer new treatment strategies for cirrhosis.

Tolerance mechanisms in polysaccharide biosynthesis: Implications for undecaprenol phosphate recycling in Escherichia coli and Shigella flexneri.

Bacterial polysaccharide synthesis is catalysed on the universal lipid carrier, undecaprenol phosphate (UndP). The cellular UndP pool is shared by different polysaccharide synthesis pathways including peptidoglycan biogenesis. Disruptions in cytosolic polysaccharide synthesis steps are detrimental to bacterial survival due to effects on UndP recycling. In contrast, bacteria can survive disruptions in the periplasmic steps, suggesting a tolerance mechanism to mitigate UndP sequestration. Here we investigated tolerance mechanisms to disruptions of polymerases that are involved in UndP-releasing steps in two related polysaccharide synthesis pathways: that for enterobacterial common antigen (ECA) and that for O antigen (OAg), in Escherichia coli and Shigella flexneri. Our study reveals that polysaccharide polymerisation is crucial for efficient UndP recycling. In E. coli K-12, cell survival upon disruptions in OAg polymerase is dependent on a functional ECA synthesis pathway and vice versa. This is because disruptions in OAg synthesis lead to the redirection of the shared lipid-linked sugar substrate UndPP-GlcNAc towards increased ECA production. Conversely, in S. flexneri, the OAg polymerase is essential due to its limited ECA production, which inadequately redirects UndP flow to support cell survival. We propose a model whereby sharing the initial sugar intermediate UndPP-GlcNAc between the ECA and OAg synthesis pathways allows UndP to be redirected towards ECA production, mitigating sequestration issues caused by disruptions in the OAg pathway. These findings suggest an evolutionary buffering mechanism that enhances bacterial survival when UndP sequestration occurs due to stalled polysaccharide biosynthesis, which may allow polysaccharide diversity in the species to increase over time.