Colorectal cancer subtyping and immune landscape analysis based on natural killer cell-related genes.

BACKGROUND AND STUDY AIMS: The prognosis of colorectal cancer (CRC) is related to natural killer (NK) cells, but the molecular subtype features of CRC based on NK cells are still unknown. This study aimed to identify NK cell-related molecular subtypes of CRC and analyze the survival status and immune landscape of patients with different subtypes. PATIENTS/MATERIAL AND METHODS: mRNA expression data, single nucleotide variant (SNV) data, and clinical information of CRC patients were obtained from The Cancer Genome Atlas. Differentially expressed genes (DEGs) were obtained through differential analysis, and the intersection was taken with NK cell-associated genes to obtain 103 NK cell-associated CRC DEGs (NCDEGs). Based on NCDEGs, CRC samples were divided into three clusters through unsupervised clustering analysis. Survival analysis, immune analysis, Gene Set Enrichment Analysis (GSEA), and tumor mutation burden (TMB) analysis were performed. Finally, NCDEG-related small-molecule drugs were screened using the CMap database. RESULTS: Survival analysis revealed that cluster2 had a lower survival rate than cluster1 and cluster3 (p < 0.05). Immune infiltration analysis found that the immune infiltration levels and immune checkpoint expression levels of cluster1_3 were substantially higher than those of cluster2, and the tumor purity was the opposite (p < 0.05). GSEA presented that cluster1_3 was significantly enriched in the chemokine signaling pathway, ECM receptor interaction, and antigen processing and presentation pathways (p < 0.05). The TMB of cluster1_3 was significantly higher than that of cluster2 (p < 0.05). Genes with the highest mutation rate in CRC were APC, TP53, TTN, and KRAS. Drug prediction results showed that small-molecule drugs that reverse the upregulation of NCDEGs, deoxycholic acid, dipivefrine, phenformin, and other drugs may improve the prognosis of CRC. CONCLUSION: NK cell-associated CRC subtypes can be used to evaluate the tumor characteristics of CRC patients and provide an important reference for CRC patients.

Speciation and distribution of arsenic in cold seep sediments of the South China Sea.

Arsenic (As) is an abundant metalloid in marine environments, while the biogeochemical cycling of As in cold seeps remains poorly understood. We characterized the speciation of As and investigated controls of As distribution in cold seeps of South China Sea. High methane concentrations (0.2-5.5 mmol/L) and rapid sulfate depletion were observed in the seepage. Dissolved inorganic arsenic (DIAs) was enriched in the porewater ranging from 7.5 to 23.5 µg/L. As in the solid phase ranged from 2.9 to 22.6 µg/g, and sulfide mineral-bound As dominated the total arsenic (TAs) pool, followed by iron (manganese, aluminum) oxide-bound As. The significant correlations between porewater Fe2+ and DIAs reflect the controls of iron on DIAs release. Incubation experiments showed that adsorption to the solid phase and sulfate reduction activity affected the bioavailability and removal of DIAs, suggesting that multiple processes regulate the speciation and transformation of As in seep sediments.

Assessing cognitive biases induced by acute formalin or hotplate treatment: an animal study using affective bias test.

Pain, a universal and burdensome condition, influences numerous individuals worldwide. It encompasses sensory, emotional, and cognitive facets, with recent research placing a heightened emphasis on comprehending pain's impact on emotion and cognition. Cognitive bias, which encompasses attentional bias, interpretation bias, and memory bias, signifies the presence of cognitive distortions influenced by emotional factors. It has gained significant prominence in pain-related research. Human studies have shown that individuals experiencing pain exhibit cognitive bias. Similarly, animal studies have demonstrated cognitive bias in pain-induced states across various species and disease models. In this study, we aimed to investigate the memory bias displayed by rats experiencing acute pain, using the affective bias test (ABT) as a tool and administering either hotplate or formalin to induce acute pain. Our data showed that rats demonstrated a significant preference for the control treatment-related substrate over the substrate associated with formalin treatment (p < 0.001), an indication of the prominent memory bias stimulated by acute formalin injections. However, when exposed to substrates related to hotplate treatment and control treatment, the acute pain induced by the hotplate treatment failed to generate a statistically significant choice bias in rats (p = 0.674). Our study demonstrates that the negative emotions associated with acute pain can be reflected by memory bias in ABT, at least for formalin-induced acute pain. This finding will augment our comprehension of the emotional and cognitive aspects of acute pain.

Transcriptomic data of BT549 triple negative breast cancer cells treated with 20 µM NU7441, a DNA-dependent kinase inhibitor.

DNA-dependent protein kinase catalytic subunit (DNA-PK) is a multifunctional serine­threonine protein kinase that plays roles in non-homologous end joining of DNA repair in cells. NU7441 is a specific DNA-PKcs inhibitor. We investigated the effects of NU7441 on the transcriptome of BT549 triple negative breast cancer cells. Total RNA extracted from NU7441-treated or control BT549 cells was processed for preparation of sequencing libraries. Assessment of read quality was performed using fastqc tool. Trimming and filtering low-quality reads were performed using fastp. Reads were aligned by hisat2. SAM files were converted to BAM files using Samtools. The gene differential expression analysis, Gene Ontology (GO) analysis and KEGG pathway analysis were performed. After NU7441 treatment, total number of 2045 differential genes were selected according to |log2(FoldChange)| >= 1 & padj<= 0.05, among which 1365 genes were down-regulated and 680 genes were up-regulated. The differential expression genes in pattern recognition receptors (PRRs) immune responses signals, including NOD-like receptor signaling, Toll-like receptor signaling, RIG-I-like receptor signaling and cytosolic DNA-sensing pathways were noted in this paper.

A multicenter, randomized, double-blinded, placebo-controlled, phase â ¢ study evaluating the efficacy and safety of Xeligekimab (GR1501) in patients with moderate-to-severe plaque psoriasis.

BACKGROUND: Xeligekimab is a fully human monoclonal antibody that selectively neutralizes IL-17A and had shown potential efficacy in preliminary trials. OBJECTIVE: To evaluate the efficacy and safety of Xeligekimab in Chinese patients with moderate-to-severe psoriasis. METHODS: A total of 420 Chinese patients were randomized to 200 mg Xeligekimab every 2 weeks (n = 281) or placebo (n = 139) for the first 12 weeks, followed by extending the treatment schedule to GR1501 every 4 weeks for further 40 weeks. Efficacy was assessed by evaluating the Physician's Global Assessment (PGA) 0/1 and Psoriasis Area and Severity Index (PASI) 75/90/100 improvement. The safety profile was also evaluated. RESULTS: At week 12, The PASI 75/90/100 were achieved in 90.7%/74.4%/30.2%% patients in GR1501 group compared with 8.6%/1.4%/0% patients in placebo group, respectively. The PGA 0/1 were achieved in 74.4% patients of GR1501 group and 3.6% patients in placebo group, respectively. The PASI 75 and PGA 0/1 maintained until week 52. No unexpected adverse events were observed. CONCLUSION: Xeligekimab showed high efficacy and is well tolerated in Chinese patients with moderate-to-severe plaque psoriasis.

Structure characterization of an agavin-type fructan isolated from Polygonatum cyrtonema and its effect on the modulation of the gut microbiota in vitro.

The herbal medicine Polygonatum cyrtonema is highly regarded in China for its medicinal and dietary properties. However, further research is needed to elucidate the structure of its polysaccharide and understand how it promotes human health by modulating the gut microbiota. This study aims to investigate a homogeneous polysaccharide (PCP95-1-1) from Polygonatum cyrtonema and assess its susceptibility to digestion as well as its utilization by intestinal microbiota. The results confirmed that PCP95-1-1 is an agavin-type fructan, which possesses two fructose chains, namely ß-(2 â†’ 6) and ß-(2 â†’ 1) fructosyl-fructose, attached to the sucrose core, and has branches of ß-D-Fruf residues. Moreover, PCP95-1-1 demonstrated resistance to digestion and maintained its reducing sugar content throughout the digestive system, indicating it could reach the gut without being digested. In vitro fermentation of PCP95-1-1 significantly decreased the pH value (p < 0.05) while notably increasing the production of short-chain fatty acids (SCFAs), confirming its utilization by human gut microbiota. Additionally, PCP95-1-1 exhibited a significant ability (p < 0.05) to beneficial bacteria such as Megamonas and Bifidobacterium, while reducing the presence of facultative or conditional pathogens such as Escherichia-Shigella and Klebsiella at the genus level. Consequently, PCP95-1-1 has the potential to positively influence physical well-being by modulating the gut microbiota environment and can be developed as a functional food.

Triptolide induces apoptosis and cytoprotective autophagy by ROS accumulation via directly targeting peroxiredoxin 2 in gastric cancer cells.

Triptolide, a natural bioactive compound derived from herbal medicine Tripterygium wilfordii, has multiple biological activities including anti-cancer effect, which is being tested in clinical trials for treating cancers. However, the exact mechanism by which Triptolide exerts its cytotoxic effects, particularly its specific protein targets, remains unclear. Here, we show that Triptolide effectively induces cytotoxicity in gastric cancer cells by increasing reactive oxygen species (ROS) levels. Further investigations reveal that ROS accumulation contributes to the induction of Endoplasmic Reticulum (ER) stress, and subsequently autophagy induction in response to Triptolide. Meanwhile, this autophagy is cytoprotective. Interestingly, through activity-based protein profiling (ABPP) approach, we identify peroxiredoxins-2 (PRDX2), a component of the key enzyme systems that act in the defense against oxidative stress and protect cells against hydroperoxides, as direct binding target of Triptolide. By covalently binding to PRDX2 to inhibit its antioxidant activity, Triptolide increases ROS levels. Moreover, overexpression of PRDX2 inhibits and knockdown of the expression of PRDX2 increases Triptolide-induced apoptosis. Collectively, these results indicate PRDX2 as a direct target of Triptolides for inducing apoptosis. Our results not only provide novel insight into the underlying mechanisms of Triptolide-induced cytotoxic effects, but also indicate PRDX2 as a promising potential therapeutic target for developing anti-gastric cancer agents.

Translatome and Transcriptome Analyses Reveal the Mechanism that Underlies the Enhancement of Salt Stress by the Small Peptide Ospep5 in Plants.

Salt stress significantly impedes plant growth and the crop yield. This study utilized de novo transcriptome assembly and ribosome profiling to explore mRNA translation's role in rice salt tolerance. We identified unrecognized translated open reading frames (ORFs), including 42 upstream transcripts and 86 unannotated transcripts. A noteworthy discovery was the role of a small ORF, Ospep5, in conferring salt tolerance. Overexpression of Ospep5 in plants increased salt tolerance, while its absence led to heightened sensitivity. This hypothesis was corroborated by the findings that exogenous application of the synthetic small peptide Ospep5 bolstered salt tolerance in both rice and Arabidopsis. We found that the mechanism underpinning the Ospep5-mediated salt tolerance involves the maintenance of intracellular Na+/K+ homeostasis, facilitated by upregulation of high-affinity potassium transporters (HKT) and Na+/H+ exchangers (SOS1). Furthermore, a comprehensive multiomics approach, particularly ribosome profiling, is instrumental in uncovering unannotated ORFs and elucidating their functions in plant stress responses.

Contrastive learning of graphs under label noise.

In the domain of graph-structured data learning, semi-supervised node classification serves as a critical task, relying mainly on the information from unlabeled nodes and a minor fraction of labeled nodes for training. However, real-world graph-structured data often suffer from label noise, which significantly undermines the performance of Graph Neural Networks (GNNs). This problem becomes increasingly severe in situations where labels are scarce. To tackle this issue of sparse and noisy labels, we propose a novel approach Contrastive Robust Graph Neural Network (CR-GNN), Firstly, considering label sparsity and noise, we employ unsupervised contrastive loss and further incorporate homophily in the graph structure, thus introducing neighbor contrastive loss. Moreover, data augmentation is typically used to construct positive and negative samples in contrastive learning, which may result in inconsistent prediction outcomes. Based on this, we propose a dynamic cross-entropy loss, which selects the nodes with consistent predictions as reliable nodes for cross-entropy loss and benefits to mitigate the overfitting to labeling noise. Finally, we propose cross-space consistency to narrow the semantic gap between the contrast and classification spaces. Extensive experiments on multiple publicly available datasets demonstrate that CR-GNN notably outperforms existing methods in resisting label noise.

Perioperative complication incidence and risk factors for retroperitoneal neuroblastoma in children: analysis of 571 patients.

BACKGROUND: Surgery plays an important role in the treatment of neuroblastoma. Perioperative complications may impact the course of neuroblastoma treatment. To date, comprehensive analyses of complications and risk factors have been lacking. METHODS: Patients with retroperitoneal neuroblastoma undergoing tumor resection were retrospectively analyzed between 2014 and 2021. The data collected included clinical characteristics, operative details, operative complications and postoperative outcomes. Risk factors for perioperative complications of retroperitoneal neuroblastoma were analyzed. RESULTS: A total of 571 patients were enrolled in this study. Perioperative complications were observed in 255 (44.7%) patients. Lymphatic leakage (28.4%), diarrhea (13.5%), and injury (vascular, nerve and organ; 7.5%) were the most frequent complications. There were three operation-related deaths (0.53%): massive hemorrhage (n = 1), biliary tract perforation (n = 1) and intestinal necrosis (n = 1). The presence of image-defined risk factors (IDRFs) [odds ratio (OR) = 2.09, P < 0.01], high stage of the International Neuroblastoma Risk Group staging system (INRGSS) (OR = 0.454, P = 0.04), retroperitoneal lymph node metastasis (OR = 2.433, P = 0.026), superior mesenteric artery encasement (OR = 3.346, P = 0.003), and inferior mesenteric artery encasement (OR = 2.218, P = 0.019) were identified as independent risk factors for perioperative complications. CONCLUSIONS: Despite the high incidence of perioperative complications, the associated mortality rate was quite low. Perioperative complications of retroperitoneal neuroblastoma were associated with IDRFs, INRGSS, retroperitoneal lymph node metastasis and vascular encasement. Patients with high-risk factors should receive more serious attention during surgery but should not discourage the determination to pursue total resection of neuroblastoma. Video Abstract (MP4 94289 KB).

Efficacy and safety of CM310 in moderate-to-severe atopic dermatitis: A multicenter, randomized, double-blind, placebo-controlled phase 2b trial.

BACKGROUND: Atopic dermatitis (AD) affects approximately 10% of adults worldwide. CM310 is a humanized monoclonal antibody targeting interleukin-4 receptor alpha that blocks interleukin-4 and interleukin-13 signaling. This trial aimed to evaluate the efficacy and safety of CM310 in Chinese adults with moderate-to-severe AD. METHODS: This multicenter, randomized, double-blind, placebo-controlled, phase 2b trial was conducted in 21 medical institutions in China from February to November 2021. Totally 120 eligible patients were enrolled and randomized (1:1:1) to receive subcutaneous injections of 300 mg CM310, 150 mg CM310, or placebo every 2 weeks for 16 weeks, followed by an 8-week follow-up period. The primary endpoint was the proportion of patients achieving ≥75% improvement in the Eczema Area and Severity Index (EASI-75) score from baseline at week 16. Safety and pharmacodynamics were also studied. RESULTS: At week 16, the proportion of EASI-75 responders from baseline was significantly higher in the CM310 groups (70% [28/40] for high-dose and 65% [26/40] for low-dose) than that in the placebo group (20%[8/40]). The differences in EASI-75 response rate were 50% (high vs . placebo, 95% CI 31%-69%) and 45% (low vs . placebo, 95% CI 26%-64%), with both P values <0.0001. CM310 at both doses also significantly improved the EASI score, Investigator's Global Assessment score, daily peak pruritus Numerical Rating Scale, AD-affected body surface area, and Dermatology Life Quality Index compared with placebo. CM310 treatment reduced levels of thymus and activation-regulated chemokine, total immunoglobulin E, lactate dehydrogenase, and blood eosinophils. The incidence of treatment-emergent adverse events (TEAEs) was similar among all three groups, with the most common TEAEs reported being upper respiratory tract infection, atopic dermatitis, hyperlipidemia, and hyperuricemia. No severe adverse events were deemed to be attributed to CM310. CONCLUSION: CM310 at 150 mg and 300 mg every 2 weeks demonstrated significant efficacy and was well-tolerated in adults with moderate-to-severe AD.

Soreness Reminds Me of Grief: Patients With Chronic Pain Show Less Differentiated Representations of Emotional Feelings and Bodily States.

People experience similarities between emotional feelings and bodily states on a daily basis, but both the magnitude and pervasiveness of this experiential similarity vary across individuals. Inspired by previous findings that chronic pain (CP) is characterized by strengthened pain-affect coupling and reduced interoceptive accuracy, we conducted 2 cross-sectional studies to examine whether patients with CP would exhibit less differentiated perception and mental representation of emotional feelings and bodily states. In study 1 (N = 500), patients with CP and healthy controls (HCs) completed a self-report questionnaire that asked explicitly about the perceived similarity between 5 basic emotion categories and a series of bodily states. In study 2 (N = 73), a specially designed false memory test was administered to examine whether patients with CP would have reduced differentiation of concepts of negative emotion and somatic distress. We found that patients with CP perceived greater and more pervasive similarities between emotional feelings and bodily states, as indicated by higher questionnaire scores and denser, less specialized bipartite emotion-body networks, both associated with lower subjective interoceptive accuracy. Furthermore, patients with CP formed false memories of negative emotion words (eg, grief) more readily than HCs after memorizing somatic distress words (eg, soreness), as if they represented negative emotion and somatic distress as a single, enmeshed semantic category. Our findings extend previous literature by demonstrating reduced discrimination between emotional and bodily experiences in CP that is not restricted to pain-related emotional and sensory experiences and may be related to a fundamentally less differentiated interoception. PERSPECTIVES: This study shows that patients with chronic pain have a profoundly less differentiated perception and implicit conceptualization of emotional feelings and bodily states, which appears to be associated with altered interoception. These findings may provide new perspectives on why they often experience a stronger pain-affect coupling.

Burnout, moral injury, and suicidal/self-harm ideation among healthcare professionals in Mainland China: Insights from an online survey during the COVID-19 pandemic.

OBJECTIVE: This survey aimed to explore the relationships between burnout, moral injury, and suicidal/self-harm ideation among Chinese health professionals to provide a reference for protecting their mental health. METHOD: Health professionals were surveyed online using the Maslach Burnout Inventory-Human Services Survey for Medical Personnel, Patient Health Questionnaire-9, and the Moral Injury Symptoms Scale-Health Professional. RESULTS: In the analysis, 6146 eligible respondents were included in the study. The average participant age was 34.9 ± 8.5 years, and suicidal/self-harm ideation was detected in 2338 participants (38.0%). The prevalence of suicidal/self-harm ideation among those with severe burnout in the dimensions of emotional exhaustion, depersonalisation, and decreased personal accomplishment was significantly higher than those with mild burnout. The prevalence of suicidal/self-harm ideation among those with significant moral injury symptoms was higher than those without moral injury. Unconditional logistic regression analysis showed that those with moderate or severe emotional exhaustion, moderate or severe reduced sense of professional accomplishment and moderate or severe depersonalisation had increased risks of suicidal/self-harm ideation. CONCLUSIONS: Structural equation modelling demonstrated that burnout significantly mediated the relationship between moral injury and suicidal/self-harm ideation. The proportion of mediation (PM) by burnout was 43.0%. Burnout and moral injury were potential predictors of suicidal/self-harm ideation among health professionals. Both moral injury and burnout had positive and direct effects on suicidal/self-harm ideation, and burnout was a mediator in this relationship among Chinese health professionals. Therefore, to alleviate the moral injury and subsequent burnout of healthcare workers and enhance their mental qualities, active interventions should be developed in the future.

DMSOP-cleaving enzymes are diverse and widely distributed in marine microorganisms.

Dimethylsulfoxonium propionate (DMSOP) is a recently identified and abundant marine organosulfur compound with roles in oxidative stress protection, global carbon and sulfur cycling and, as shown here, potentially in osmotolerance. Microbial DMSOP cleavage yields dimethyl sulfoxide, a ubiquitous marine metabolite, and acrylate, but the enzymes responsible, and their environmental importance, were unknown. Here we report DMSOP cleavage mechanisms in diverse heterotrophic bacteria, fungi and phototrophic algae not previously known to have this activity, and highlight the unappreciated importance of this process in marine sediment environments. These diverse organisms, including Roseobacter, SAR11 bacteria and Emiliania huxleyi, utilized their dimethylsulfoniopropionate lyase 'Ddd' or 'Alma' enzymes to cleave DMSOP via similar catalytic mechanisms to those for dimethylsulfoniopropionate. Given the annual teragram predictions for DMSOP production and its prevalence in marine sediments, our results highlight that DMSOP cleavage is likely a globally significant process influencing carbon and sulfur fluxes and ecological interactions.

The Immune Regulatory Role of Adenosine in the Tumor Microenvironment.

Adenosine, an immunosuppressive metabolite, is produced by adenosine triphosphate (ATP) released from dying or stressed cells and is found at high levels in the tumor microenvironment of most solid tumors. It mediates pro-tumor activities by inducing tumor cell proliferation, migration or invasion, tumor tissue angiogenesis, and chemoresistance. In addition, adenosine plays an important role in regulating anti-tumor immune responses and facilitating tumor immune escape. Adenosine receptors are broadly expressed by tumor-infiltrated immune cells, including suppressive tumor-associated macrophages and CD4+ regulatory T cells, as well as effector CD4+ T cells and CD8+ cytotoxic T lymphocytes. Therefore, adenosine is indispensable in down-regulating anti-tumor immune responses in the tumor microenvironment and contributes to tumor progression. This review describes the current progress on the role of adenosine/adenosine receptor pathway in regulating the tumor-infiltrating immune cells that contribute to tumor immune evasion and aims to provide insights into adenosine-targeted tumor immunotherapy.

MIR31HG, a potential lncRNA in human cancers and non-cancers.

Long non-coding RNAs have recently attracted considerable attention due to their aberrant expression in human diseases. LncMIR31HG is a novel lncRNA that is abnormally expressed in multiple diseases and implicated in various stages of disease progression. A large proportion of recent studies have indicated that MIR31HG has biological functions by triggering various signalling pathways in the pathogenesis of human diseases, especially cancers. More importantly, the abnormal expression of MIR31HG makes it a potential biomarker in diagnosis and prognosis, as well as a promising target for treatments. This review aims to systematically summarize the gene polymorphism, expression profiles, biological roles, underlying mechanisms, and clinical applications of MIR31HG in human diseases.

Constructing single atom sites on bipyridine covalent organic frameworks for selective electrochemical production of H2O2.

We developed a series of single atom catalysts (SACs) anchored on bipyridine-rich COFs. By tuning the active metal center, the optimal Py-Bpy-COF-Zn shows the highest selectivity of 99.1% and excellent stability toward H2O2 production via oxygen reduction, which can be attributed to the high *OOH dissociation barrier indicated by the theoretical calculations. As a proof of concept, it acts as a cathodic catalyst in a homemade Zn-air battery, together with efficient wastewater treatment.

PDA-BPs integrated mussel-inspired multifunctional hydrogel coating on PPENK implants for anti-tumor therapy, antibacterial infection and bone regeneration.

Currently, many cancer patients with bone defects are still threatened by tumor recurrence, postoperative bacterial infection, and massive bone loss. Many methods have been studied to endow bone implants with biocompatibility, but it is difficult to find an implant material that can simultaneously solve the problems of anticancer, antibacterial and bone promotion. Here, a multifunctional gelatin methacrylate/dopamine methacrylate adhesive hydrogel coating containing 2D black phosphorus (BP) nanoparticle protected by polydopamine (pBP) is prepared by photocrosslinking to modify the surface of poly (aryl ether nitrile ketone) containing phthalazinone (PPENK) implant. The multifunctional hydrogel coating works in conjunction with pBP, which can deliver drug through photothermal mediation and kill bacteria through photodynamic therapy at the initial phase followed by promotion of osteointegration. In this design, photothermal effect of pBP control the release of doxorubicin hydrochloride loaded via electrostatic attraction. Meanwhile, pBP can generate reactive oxygen species (ROS) to eliminate bacterial infection under 808 nm laser. In the slow degradation process, pBP not only effectively consumes excess ROS and avoid apoptosis induced by ROS in normal cells, but also degrade into PO43- to promote osteogenesis. In summary, nanocomposite hydrogel coatings provide a promising strategy for treatment of cancer patients with bone defects.

Molecular discoveries in microbial DMSP synthesis.

Dimethylsulfoniopropionate (DMSP) is one of the Earth's most abundant organosulfur compounds because many marine algae, bacteria, corals and some plants produce it to high mM intracellular concentrations. In these organisms, DMSP acts an anti-stress molecule with purported roles to protect against salinity, temperature, oxidative stress and hydrostatic pressure, amongst many other reported functions. However, DMSP is best known for being a major precursor of the climate-active gases and signalling molecules dimethylsulfide (DMS), methanethiol (MeSH) and, potentially, methane, through microbial DMSP catabolism. DMSP catabolism has been extensively studied and the microbes, pathways and enzymes involved have largely been elucidated through the application of molecular research over the last 17 years. In contrast, the molecular biology of DMSP synthesis is a much newer field, with the first DMSP synthesis enzymes only being identified in the last 5 years. In this review, we discuss how the elucidation of key DMSP synthesis enzymes has greatly expanded our knowledge of the diversity of DMSP-producing organisms, the pathways used, and what environmental factors regulate production, as well as to inform on the physiological roles of DMSP. Importantly, the identification of key DMSP synthesis enzymes in the major groups of DMSP producers has allowed scientists to study the distribution and predict the importance of different DMSP-producing organisms to global DMSP production in diverse marine and sediment environments. Finally, we highlight key challenges for future molecular research into DMSP synthesis that need addressing to better understand the cycling of this important marine organosulfur compound, and its magnitude in the environment.

Cuproptosis-related risk score predicts prognosis and characterizes the tumor microenvironment in colon adenocarcinoma.

Introduction: Cuproptosis is a novel copper-dependent regulatory cell death (RCD), which is closely related to the occurrence and development of multiple cancers. However, the potential role of cuproptosis-related genes (CRGs) in the tumor microenvironment (TME) of colon adenocarcinoma (COAD) remains unclear. Methods: Transcriptome, somatic mutation, somatic copy number alteration and the corresponding clinicopathological data of COAD were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus database (GEO). Difference, survival and correlation analyses were conducted to evaluate the characteristics of CRGs in COAD patients. Consensus unsupervised clustering analysis of CRGs expression profile was used to classify patients into different cuproptosis molecular and gene subtypes. TME characteristics of different molecular subtypes were investigated by using Gene set variation analysis (GSVA) and single sample gene set enrichment analysis (ssGSEA). Next, CRG Risk scoring system was constructed by applying logistic least absolute shrinkage and selection operator (LASSO) cox regression analysis and multivariate cox analysis. Real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC) were used to exam the expression of key Risk scoring genes. Results: Our study indicated that CRGs had relatively common genetic and transcriptional variations in COAD tissues. We identified three cuproptosis molecular subtypes and three gene subtypes based on CRGs expression profile and prognostic differentially expressed genes (DEGs) expression profile, and found that changes in multilayer CRGs were closely related to the clinical characteristics, overall survival (OS), different signaling pathways, and immune cell infiltration of TME. CRG Risk scoring system was constructed according to the expression of 7 key cuproptosis-related risk genes (GLS, NOX1, HOXC6, TNNT1, GLS, HOXC6 and PLA2G12B). RT-qPCR and IHC indicated that the expression of GLS, NOX1, HOXC6, TNNT1 and PLA2G12B were up-regulated in tumor tissues, compared with those in normal tissues, and all of GLS, HOXC6, NOX1 and PLA2G12B were closely related with patient survival. In addition, high CRG risk scores were significantly associated with high microsatellite instability (MSI-H), tumor mutation burden (TMB), cancer stem cell (CSC) indices, stromal and immune scores in TME, drug susceptibility, as well as patient survival. Finally, a highly accurate nomogram was constructed to promote the clinical application of the CRG Risk scoring system. Discussion: Our comprehensive analysis showed that CRGs were greatly associated with TME, clinicopathological characteristics, and prognosis of patient with COAD. These findings may promote our understanding of CRGs in COAD, providing new insights for physicians to predict prognosis and develop more precise and individualized therapy strategies.