Fusobacterium nucleatum extracellular vesicles are enriched in colorectal cancer and facilitate bacterial adhesion.

Fusobacterium nucleatum in colorectal cancer (CRC) tissue is implicated at multiple stages of the disease, while the mechanisms underlying bacterial translocation and colonization remain incompletely understood. Herein, we investigated whether extracellular vesicles derived from F. nucleatum (FnEVs) have impacts on bacterial colonization. In mice with colitis-related CRC, a notable enrichment of FnEVs was observed, leading to a significant increase in intratumor colonization by F. nucleatum and accelerated progression of CRC. The enrichment of FnEVs in clinical CRC tissues was demonstrated. Subsequently, we revealed that FnEVs undergo membrane fusion with CRC cells, leading to the transfer and retention of FomA on recipient cell surfaces. Given its ability to facilitate F. nucleatum autoaggregation through interaction with FN1441, the presence of FomA on CRC cell surfaces presents a target for bacterial adhesion. Collectively, the findings unveil a mechanism used by EVs to prepare a niche conducive for bacterial colonization in distal organs.

Experts consensus on management of tooth luxation and avulsion.

Traumatic dental injuries (TDIs) of teeth occur frequently in children and adolescents. TDIs that impact the periodontal tissues and alveolar tissue can be classified into concussion, subluxation, extrusive luxation, intrusive luxation, lateral luxation, and avulsion. In these TDIs, management of injured soft tissue, mainly periodontal ligament, and dental pulp, is crucial in maintaining the function and longevity of the injured teeth. Factors that need to be considered for management in laxation injuries include the maturation stage of the traumatic teeth, mobility, direction of displacement, distance of displacement, and whether there are alveolar fractures. In avulsion, the maturation stage of the permanent tooth, the out-socket time, storage media/condition of the avulsed tooth, and management of the PDL should also be considered. Especially, in this review, we have subdivided the immature tooth into the adolescent tooth (Nolla stage 9) and the very young tooth (Nolla stage 8 and below). This consensus paper aimed to discuss the impacts of those factors on the trauma management and prognosis of TDI to provide a streamlined guide for clinicians from clinical evaluation, diagnostic process, management plan decision, follow-up, and orthodontic treatment for tooth luxation and avulsion injuries.

Metabolic rewiring during bone development underlies tRNA m7G-associated primordial dwarfism.

Translation of mRNA to protein is tightly regulated by tRNAs, which are subject to various chemical modifications that maintain the structure, stability and function. Deficiency of tRNA N7-methylguanosine (m7G) modification in patients causes a type of primordial dwarfism, but the underlying mechanism remains unknown. Here we report the loss of m7G rewires cellular metabolism, leading to the pathogenesis of primordial dwarfism. Conditional deletion of the catalytic enzyme Mettl1 or missense mutation of the scaffold protein Wdr4 severely impaired endochondral bone formation and bone mass accrual. Mechanistically, Mettl1 knockout decreased abundance of m7G-modified tRNAs and inhibited translation of mRNAs relating to cytoskeleton and Rho GTPase signaling. Meanwhile, Mettl1 knockout enhanced cellular energy metabolism despite of incompetent proliferation and osteogenic commitment. Further exploration revealed that impaired Rho GTPase signaling upregulated branched-chain amino acid transaminase 1 (BCAT1) level that rewired cell metabolism and restricted intracellular α-ketoglutarate (αKG). Supplementation of αKG ameliorated the skeletal defect of Mettl1-deficient mice. In addition to the selective translation of metabolism-related mRNAs, we further revealed that Mettl1 knockout globally regulated translation via integrated stress response (ISR) and mammalian target of rapamycin complex 1 (mTORC1) signaling. Restoring translation either by targeting ISR or mTORC1 aggravated bone defects of Mettl1-deficient mice. Overall, our study unveils a critical role of m7G tRNA modification in bone development by regulating cellular metabolism, and indicates that suspension of translation initiation as quality control mechanism in response to tRNA dysregulation.

Predicting the Risk of In-Hospital Mortality in Traumatic Brain Injury Patients on Invasive Mechanical Ventilation in the Intensive Care Unit: Construction and Validation of an Online Nomogram.

OBJECTIVE: To explore mortality risk factors and to construct an online nomogram for predicting in-hospital mortality in traumatic brain injury (TBI) patients receiving invasive mechanical ventilation (IMV) in intensive care unit (ICU). METHODS: We retrospectively analyzed TBI patients on IMV in ICU from Medical Information Mart for Intensive Care IV database and 2 hospitals. Least absolute shrinkage and selection operation regression and multiple logistic regression were used to detect predictors of in-hospital mortality and to construct an online nomogram. The predictive performance of nomogram was evaluated using area under the receiver operating characteristic curves (AUC), calibration curves, decision curve analysis, and clinical impact curves. RESULTS: Five hundred ten from Medical Information Mart for Intensive Care IV database were enrolled for nomogram construction (80%, n = 408) and internal validation (20%, n = 102). One hundred eighty-five from 2 hospitals were enrolled for external validation. Least absolute shrinkage and selection operation-logistic regression revealed predictors of in-hospital mortality among TBI patients on IMV in ICU included Glasgow Coma Scale (GCS) after ICU admission, Acute Physiology Score III (APS III) after ICU admission, neutrophil and lymphocyte ratio after IMV, blood urea nitrogen after IMV, arterial serum lactate after IMV, and in-hospital tracheotomy. The AUC, calibration curves, decision curve analysis, and clinical impact curves indicated the nomogram had good discrimination, calibration, clinical benefit, and applicability. The multimodel comparisons revealed the nomogram had higher AUC than GCS, APS III, and Simplified Acute Physiology Score II. CONCLUSIONS: We constructed and validated an online nomogram based on routinely recorded factors at admission to ICU and at the beginning of IMV to target prediction of in-hospital mortality among TBI patients on IMV in ICU.

Risk Factors and Predictive Nomogram for Survival in Elderly Patients with Brain Glioma.

OBJECTIVE: To determine the factors that contribute to the survival of elderly individuals diagnosed with brain glioma and develop a prognostic nomogram. METHODS: Data from elderly individuals (age ≥65 years) histologically diagnosed with brain glioma were sourced from the Surveillance, Epidemiology, and End Results (SEER) database. The dataset was randomly divided into a training cohort and an internal validation cohort at a 6:4 ratio. Additionally, data obtained from Tangdu Hospital constituted an external validation cohort for the study. The identification of independent prognostic factors was achieved through the least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analysis, enabling the construction of a nomogram. Model performance was evaluated using C-index, ROC curves, calibration plot and decision curve analysis (DCA). RESULTS: A cohort of 20 483 elderly glioma patients was selected from the SEER database. Five prognostic factors (age, marital status, histological type, stage, and treatment) were found to significantly impact overall survival (OS) and cancer-specific survival (CSS), with tumor location emerging as a sixth variable independently linked to CSS. Subsequently, nomogram models were developed to predict the probabilities of survival at 6, 12, and 24 months. The assessment findings from the validation queue indicate a that the model exhibited strong performance. CONCLUSION: Our nomograms serve as valuable prognostic tools for assessing the survival probability of elderly glioma patients. They can potentially assist in risk stratification and clinical decision-making.

The association between proactive personality and interprofessional learning readiness in nursing students: The chain medication effects of perceived social support and professional identity.

BACKGROUND: Interprofessional education (IPE) has been advocated for all healthcare students, and readiness for interprofessional learning significantly influences its effectiveness. It is essential to explore the antecedent factors of readiness for interprofessional learning among nursing students to promote IPE. While a proactive personality might impact readiness for interprofessional learning, its specific role has remained unspecified. OBJECTIVE: To examine the mediation effects of perceived social support and professional identity on the association between proactive personality and readiness for interprofessional learning among nursing students. DESIGN: The study utilised a cross-sectional design. SETTINGS: Research was conducted at two universities and two vocational schools in Hainan Province, China. PARTICIPANTS: On-campus nursing students were invited to participate between March and May 2023. METHODS: A flyer was distributed to the participants with a QR code to scan to voluntarily complete the online survey, including the Readiness for Interprofessional Learning Scale (RIPLS), Proactive Personality Scale, Perceived Social Support Scale and Professional Identity Status Questionnaire Scale 5d. Descriptive analysis, Pearson associations and mediation analysis were conducted using SPSS software version 26.0 and PROCESS version 4.2 for SPSS. RESULTS: The participants' average RIPLS score was 66.93 ± 9.28. Proactive personality (r = 0.633, p < 0.01), perceived social support (r = 0.605, p < 0.01) and professional identity (r = 0.549, p < 0.01) were all positively related to readiness for interprofessional learning. Meanwhile, the relationship between proactive personality and readiness for interprofessional learning was partly mediated by perceived social support (25.15 %), professional identity (13.35 %) and the chain effects (9.48 %) of perceived social support and professional identity. CONCLUSIONS: The nursing students in Hainan, China demonstrated a medium level of readiness for interprofessional learning. Compound strategies that foster proactive personality, provide social support and boost positive professional identity are warranted to improve nursing students' readiness for interprofessional learning.

Controlled Synthesis of Large-Area Oriented ZnO Nanoarrays.

Large-area oriented ZnO nanoarrays (including nanowire, nanorod, and nanotube) on ITO glass substrates are synthesized via the simple hydrothermal, electrodeposition, and electrochemical etching approach. The morphology of ZnO nanoarrays is controlled by adjusting the reaction temperature, reaction time, and current density. The scanning and transmission electron microscopy (SEM and TEM) results indicate the successful preparation of large-area oriented ZnO nanoarrays with different types, and the energy-dispersive X-microanalysis spectrum (EDS) and X-ray diffraction (XRD) results confirm that the composition of the obtained nanoarrays is ZnO. More importantly, the as-prepared ZnO nanotube arrays are observed with about a 40% increase in ultraviolet absorption intensity compared to the ZnO nanowire/nanorod arrays, due to having larger specific surface areas. The as-prepared different types of ZnO nanoarrays have great potential for applications in low-cost and high-performance optoelectronic devices.

Exosomes isolated from TNF-α-treated bone marrow mesenchymal stem cells ameliorate pelvic floor dysfunction in rats.

Exosomes derived from bone marrow-derived mesenchymal stem cells (BMSCs) can alleviate the symptoms of pelvic floor dysfunction (PFD) in rats. However, the potential therapeutical effects of exosomes derived from BMSCs treated with tumour necrosis factor (TNF)-α on the symptoms of PFD in rats are unknown. Exosomes extracted from BMSCs treated with or without TNF-α were applied to treat PFD rats. Our findings revealed a significant elevation in interleukin (IL)-6 and TNF-α, and matrix metalloproteinase-2 (MMP2) levels in the vaginal wall tissues of patients with pelvic organ prolapse (POP) compared with the control group. Daily administration of exosomes derived from BMSCs, treated either with or without TNF-α (referred to as Exo and TNF-Exo), resulted in increased void volume and bladder void pressure, along with reduced peak bladder pressure and leak point pressure in PFD rats. Notably, TNF-Exo treatment demonstrated superior efficacy in restoring void volume, bladder void pressure and the mentioned parameters compared with Exo treatment. Importantly, TNF-Exo exhibited greater potency than Exo in restoring the levels of multiple proteins (Elastin, Collagen I, Collagen III, IL-6, TNF-α and MMP2) in the anterior vaginal walls of PFD rats. The application of exosomes derived from TNF-α-treated BMSCs holds promise as a novel therapeutic approach for treating PFD.

Early infiltrating NKT lymphocytes attenuate bone regeneration through secretion of CXCL2.

Trauma rapidly mobilizes the immune response of surrounding tissues and activates regeneration program. Manipulating immune response to promote tissue regeneration shows a broad application prospect. However, the understanding of bone healing dynamics at cellular level remains limited. Here, we characterize the landscape of immune cells after alveolar bone injury and reveal a pivotal role of infiltrating natural killer T (NKT) cells. We observe a rapid increase in NKT cells after injury, which inhibit osteogenic differentiation of mesenchymal stem cells (MSCs) and impair alveolar bone healing. Cxcl2 is up-regulated in NKT cells after injury. Systemic administration of CXCL2-neutralizing antibody or genetic deletion of Cxcl2 improves the bone healing process. In addition, we fabricate a gelatin-based porous hydrogel to deliver NK1.1 depletion antibody, which successfully promotes alveolar bone healing. In summary, our study highlights the importance of NKT cells in the early stage of bone healing and provides a potential therapeutic strategy for accelerating bone regeneration.

SGLT2 inhibition, circulating proteins, and insomnia: A mendelian randomization study.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) initially emerged as oral antidiabetic medication but were subsequently discovered to exhibit pleiotropic actions. Insomnia is a prevalent and debilitating sleep disorder. To date, the causality between SGLT2 inhibitors and insomnia remains unclear. This study aims to evaluate the causality between SGLT2 inhibitors and insomnia and identify potential plasma protein mediators. METHODS: Using a two-sample Mendelian Randomization (MR) analysis, we estimated the causality of SGLT2 inhibition on insomnia and sleep duration. Additionally, employing a two-step and proteome-wide MR analysis, we evaluated the causal link of SGLT2 inhibition on 4907 circulating proteins and the causality of SGLT2 inhibition-driven plasma proteins on insomnia. We applied a false discovery rate (FDR) correction for multiple comparisons. Furthermore, mediation analyses were used to identify plasma proteins that mediate the effects of SGLT2 inhibition on insomnia. RESULTS: SGLT2 inhibition was negatively correlated with insomnia (odds ratio [OR] = 0.791, 95 % confidence interval [CI] [0.715, 0.876], P = 5.579*10^-6) and positively correlated with sleep duration (ß = 0.186, 95 % CI [0.059, 0.314], P = 0.004). Among the 4907 circulating proteins, diadenosine tetraphosphatase (Ap4A) was identified as being linked to both SGLT2 inhibition and insomnia. Mediation analysis indicated that the effect of SGLT2 inhibition on insomnia partially operates through Ap4A (ß = -0.018, 95 % CI [-0.036, -0.005], P = 0.023), with a mediation proportion of 7.7 %. CONCLUSION: The study indicated a causality between SGLT2 inhibition and insomnia, with plasma Ap4A potentially serving as a mediator.

Glutathione S-Transferase α4 Alleviates Hyperlipidemia-Induced Vascular Neointimal Hyperplasia in Arteriovenous Grafts via Inhibiting Endoplasmic Reticulum Stress.

ABSTRACT: Neointimal hyperplasia causes the failure of coronary artery bypass grafting. Our previous studies have found that endothelial dysfunction is 1 candidate for triggering neointimal hyperplasia, but which factors are involved in this process is unclear. Glutathione S-transferase α4 (GSTA4) plays an important role in metabolizing 4-hydroxynonenal (4-HNE), a highly reactive lipid peroxidation product, which causes endothelial dysfunction or death. Here, we investigated the role of GSTA4 in neointima formation after arteriovenous grafts (AVGs) with or without high-fat diet (HFD). Compared with normal diet, HFD caused endothelial dysfunction and increased neointima formation, concomitantly accompanied by downregulated expression of GSTA4 at the mRNA and protein levels. In vitro, overexpression of GSTA4 attenuated 4-HNE-induced endothelial dysfunction and knockdown of GSTA4 aggravated endothelial dysfunction. Furthermore, silencing GSTA4 expression facilitated the activation of 4-HNE-induced endoplasmic reticulum stress and inhibition of endoplasmic reticulum stress pathway alleviated 4-HNE-induced endothelial dysfunction. In addition, compared with wild-type mice, mice with knockout of endothelial-specific GSTA4 (GSTA4 endothelial cell KO) exhibited exacerbated vascular endothelial dysfunction and increased neointima formation caused by HFD. Together, these results demonstrate the critical role of GSTA4 in protecting the function of endothelial cells and in alleviating hyperlipidemia-induced vascular neointimal hyperplasia in arteriovenous grafts.

Multifunctional Material Building Blocks from Plant Pollen.

With its multifaceted nature, plant pollen serves not only as a key element in the reproductive cycle of seed plants but also as an influential contributor to environmental, human health, safety, and climate-related concerns. Pollen functions as a carrier of nutrients and organisms and holds a pivotal role in sustaining pollinator populations. Moreover, it is vital in ensuring the safety and quality of our food supply while presenting potential therapeutic applications. Pollen, often referred to as the diamond of the organic world due to its distinctive physical structures and properties, has been underappreciated from a material science and engineering standpoint. We propose adopting a more interdisciplinary and comprehensive approach to its study. Recent groundbreaking research has focused on the development of pollen-based building blocks that transform practically indestructible plant pollen into microgel, paper, and sponge, thereby unveiling numerous potential applications. In this review, we highlight the transformative potential of plant pollen as it is converted into a variety of building blocks, thereby unlocking myriad prospective applications through eco-friendly processing.

N-Acetylcysteine Attenuates Sepsis-Induced Muscle Atrophy by Downregulating Endoplasmic Reticulum Stress.

(1) Background: Sepsis-induced muscle atrophy is characterized by a loss of muscle mass and function which leads to decreased quality of life and worsens the long-term prognosis of patients. N-acetylcysteine (NAC) has powerful antioxidant and anti-inflammatory properties, and it relieves muscle wasting caused by several diseases, whereas its effect on sepsis-induced muscle atrophy has not been reported. The present study investigated the effect of NAC on sepsis-induced muscle atrophy and its possible mechanisms. (2) Methods: The effect of NAC on sepsis-induced muscle atrophy was assessed in vivo and in vitro using cecal ligation and puncture-operated (CLP) C57BL/6 mice and LPS-treated C2C12 myotubes. We used immunofluorescence staining to analyze changes in the cross-sectional area (CSA) of myofibers in mice and the myotube diameter of C2C12. Protein expressions were analyzed by Western blotting. (3) Results: In the septic mice, the atrophic response manifested as a reduction in skeletal muscle weight and myofiber cross-sectional area, which is mediated by muscle-specific ubiquitin ligases-muscle atrophy F-box (MAFbx)/Atrogin-1 and muscle ring finger 1 (MuRF1). NAC alleviated sepsis-induced skeletal muscle wasting and LPS-induced C2C12 myotube atrophy. Meanwhile, NAC inhibited the sepsis-induced activation of the endoplasmic reticulum (ER) stress signaling pathway. Furthermore, using 4-Phenylbutyric acid (4-PBA) to inhibit ER stress in LPS-treated C2C12 myotubes could partly abrogate the anti-muscle-atrophy effect of NAC. Finally, NAC alleviated myotube atrophy induced by the ER stress agonist Thapsigargin (Thap). (4) Conclusions: NAC can attenuate sepsis-induced muscle atrophy, which may be related to downregulating ER stress.

Expert consensus on pediatric orthodontic therapies of malocclusions in children.

Malocclusion, identified by the World Health Organization (WHO) as one of three major oral diseases, profoundly impacts the dental-maxillofacial functions, facial esthetics, and long-term development of ~260 million children in China. Beyond its physical manifestations, malocclusion also significantly influences the psycho-social well-being of these children. Timely intervention in malocclusion can foster an environment conducive to dental-maxillofacial development and substantially decrease the incidence of malocclusion or reduce the severity and complexity of malocclusion in the permanent dentition, by mitigating the negative impact of abnormal environmental influences on the growth. Early orthodontic treatment encompasses accurate identification and treatment of dental and maxillofacial morphological and functional abnormalities during various stages of dental-maxillofacial development, ranging from fetal stages to the early permanent dentition phase. From an economic and societal standpoint, the urgency for effective early orthodontic treatments for malocclusions in childhood cannot be overstated, underlining its profound practical and social importance. This consensus paper discusses the characteristics and the detrimental effects of malocclusion in children, emphasizing critical need for early treatment. It elaborates on corresponding core principles and fundamental approaches in early orthodontics, proposing comprehensive guidance for preventive and interceptive orthodontic treatment, serving as a reference for clinicians engaged in early orthodontic treatment.

Protective role of pretreatment with Anisodamine against sepsis-induced diaphragm atrophy via inhibiting JAK2/STAT3 pathway.

There is an increasing tendency for sepsis patients to suffer from diaphragm atrophy as well as mortality. Therefore, reducing diaphragm atrophy could benefit sepsis patients' prognoses. Studies have shown that Anisodamine (Anis) can exert antioxidant effects when blows occur. However, the role of Anisodamine in diaphragm atrophy in sepsis patients has not been reported. Therefore, this study investigated the antioxidant effect of Anisodamine in sepsis-induced diaphragm atrophy and its mechanism. We used cecal ligation aspiration (CLP) to establish a mouse septic mode and stimulated the C2C12 myotube model with lipopolysaccharide (LPS). After treatment with Anisodamine, we measured the mice's bodyweight, diaphragm weight, fiber cross-sectional area and the diameter of C2C12 myotubes. The malondialdehyde (MDA) levels in the diaphragm were detected using the oxidative stress kit. The expression of MuRF1, Atrogin1 and JAK2/STAT3 signaling pathway components in the diaphragm and C2C12 myotubes was measured by RT-qPCR and Western blot. The mean fluorescence intensity of ROS in C2C12 myotubes was measured by flow cytometry. Meanwhile, we also measured the levels of Drp1 and Cytochrome C (Cyt-C) in vivo and in vitro by Western blot. Our study revealed that Anisodamine alleviated the reduction in diaphragmatic mass and the loss of diaphragmatic fiber cross-sectional area and attenuated the atrophy of the C2C12 myotubes by inhibiting the expression of E3 ubiquitin ligases. In addition, we observed that Anisodamine inhibited the JAK2/STAT3 signaling pathway and protects mitochondrial function. In conclusion, Anisodamine alleviates sepsis-induced diaphragm atrophy, and the mechanism may be related to inhibiting the JAK2/STAT3 signaling pathway.

Transcription factor DIVARICATA1 positively modulates seed germination in response to salinity stress.

Seed germination is a critical checkpoint for plant growth under unfavorable environmental conditions. In Arabidopsis (Arabidopsis thaliana), the abscisic acid (ABA) and gibberellic acid (GA) signaling pathways play important roles in modulating seed germination. However, the molecular links between salinity stress and ABA/GA signaling are not well understood. Herein, we showed that the expression of DIVARICATA1 (DIV1), which encodes a MYB-like transcription factor, was induced by GA and repressed by ABA, salinity, and osmotic stress in germinating seeds. DIV1 positively regulated seed germination in response to salinity stress by directly regulating the expression of DELAY OF GERMINATION 1-LIKE 3 (DOGL3) and GA-STIMULATED ARABIDOPSIS 4 (GASA4) and indirectly regulating the expression of several germination-associated genes. Moreover, NUCLEAR FACTOR-YC9 (NF-YC9) directly repressed the expression of DIV1 in germinating seeds in response to salinity stress. These results help reveal the function of the NF-YC9-DIV1 module and provide insights into the regulation of ABA and GA signaling in response to salinity stress during seed germination in Arabidopsis.

Significance of Aneuploidy in Predicting Prognosis and Treatment Response of Uveal Melanoma.

AIMS: This study aimed to improve personalized treatment strategies and predict survival outcomes for patients with uveal melanoma (UM). BACKGROUND: Copy number aberrations (CNAs) have been considered as a main feature of metastatic UM. OBJECTIVE: This study was designed to explore the feasibility of using copy number variation (CNV) in UM classification, prognosis stratification and treatment response. METHODS: The CNV data in the TCGA-UVM cohort were used to classify the samples. The differentially expressed genes (DEGs) between subtypes were screened by the "Limma" package. The module and hub genes related to aneuploidy score were identified by performing weighted gene co-expression network analysis (WGCNA) on the DEGs. Univariate Cox and least absolute shrinkage and selection operator (LASSO) regression analysis were employed to train the hub genes for developing a prognosis model for UM. Finally, the expression levels of the screened prognostic key genes were verified in UM cells, and the cell migration and invasion abilities were detected using real-time quantitative PCR (qRT-PCR) and transwell assay. RESULTS: The UM samples were divided into 3 CNV subtypes, which differed significantly in overall survival (OS) and disease-specific survival (DSS). C1 had the shortest OS and DSS and the highest level of immune infiltration. A total of 2036 DEGs were obtained from the three subtypes. Eighty hub genes with the closest correlation with aneuploidy scores were selected by WGCNA. Univariate Cox and LASSO regression-based analyses finally determined eight genes as the key prognostic genes, including HES6, RNASEH2C, NQO1, NUDT14, TTYH3, GJC1, FKBP10, and MRPL24. A prognostic model was developed using the eight genes, demonstrating a strong prediction power. Differences in the response to immunotherapy among patients in different risk groups were significant. We found that high-risk patients were more sensitive to two drugs (Palbociclib_ 1054 and Ribociclib_1632), while low-risk patients were more sensitive to AZD1208_1449, ERK_2440_1713, Mirin_1048, and Selumetinib_1736. CONCLUSION: UM in this study was divided into three CNV subtypes, and a model based on eight aneuploidy score-related genes was established to evaluate the prognosis and drug treatment efficacy of UM patients. The current results may have the potential to help the clinical decision-making process for UM management.

Exosomes secreted by Fusobacterium nucleatum-infected colon cancer cells transmit resistance to oxaliplatin and 5-FU by delivering hsa_circ_0004085.

BACKGROUND: A large number of Fusobacterium nucleatum (Fn) are present in colorectal cancer (CRC) tissues of patients who relapse after chemotherapy, and Fn has been reported to promote oxaliplatin and 5-FU chemoresistance in CRC. Pathogens such as bacteria and parasites stimulate exosome production in tumor cells, and the regulatory mechanism of exosomal circRNA in the transmission of oxaliplatin and 5-FU chemotherapy resistance in Fn-infected CRC remains unclear. METHODS: Hsa_circ_0004085 was screened by second-generation sequencing of CRC tissues. The correlation between hsa_circ_0004085 and patient clinical response to oxaliplatin/5-FU was analyzed. Exosome tracing experiments and live imaging systems were used to test the effect of Fn infection in CRC on the distribution of hsa_circ_0004085. Colony formation, ER tracking analysis and immunofluorescence were carried out to verify the regulatory effect of exosomes produced by Fn-infected CRC cells on chemotherapeutic resistance and ER stress. RNA pulldown, LC-MS/MS analysis and RIP were used to explore the regulatory mechanism of downstream target genes by hsa_circ_0004085. RESULTS: First, we screened out hsa_circ_0004085 with abnormally high expression in CRC clinical samples infected with Fn and found that patients with high expression of hsa_circ_0004085 in plasma had a poor clinical response to oxaliplatin/5-FU. Subsequently, the circular structure of hsa_circ_0004085 was identified. Fn infection promoted hsa_circ_0004085 formation by hnRNP L and packaged hsa_circ_0004085 into exosomes by hnRNP A1. Exosomes produced by Fn-infected CRC cells transferred hsa_circ_0004085 between cells and delivered oxaliplatin/5-FU resistance to recipient cells by relieving ER stress. Hsa_circ_0004085 enhanced the stability of GRP78 mRNA by binding to RRBP1 and promoted the nuclear translocation of ATF6p50 to relieve ER stress. CONCLUSIONS: Plasma levels of hsa_circ_0004085 are increased in colon cancer patients with intracellular Fn and are associated with a poor response to oxaliplatin/5-FU. Fn infection promoted hsa_circ_0004085 formation by hnRNP L and packaged hsa_circ_0004085 into exosomes by hnRNP A1. Exosomes secreted by Fn-infected CRC cells deliver hsa_circ_0004085 between cells. Hsa_circ_0004085 relieves ER stress in recipient cells by regulating GRP78 and ATF6p50, thereby delivering resistance to oxaliplatin and 5-FU.

[Latest Findings on Phase Separation of Cytomechanical Proteins]. / ç»†èƒžåŠ›å­¦è›‹ç™½ç›¸åˆ†ç¦»çš„ç ”ç©¶è¿›å±•.

The cellular response to mechanical stimuli depends largely on the structure of the cell itself and the abundance of intracellular cytomechanical proteins also plays a key role in the response to the stimulation of external mechanical signals. Liquid-liquid phase separation (LLPS) is the process by which proteins or protein-RNA complexes spontaneously separate and form two distinct "phases", ie, a low-concentration phase coexisting with a high-concentration phase. According to published findings, membrane-free organelles form and maintain their structures and regulate their internal biochemical activities through LLPS. LLPS, a novel mechanism for intracellular regulation of the biochemical reactions of biomacromolecules, plays a crucial role in modulating the responses of cytomechanical proteins. LLPS leads to the formation of highly concentrated liquid-phase condensates through multivalent interactions between biomacromolecules, thereby regulating a series of intracellular life activities. It has been reported that a variety of cytomechanical proteins respond to external mechanical signals through LLPS, which in turn affects biological behaviors such as cell growth, proliferation, spreading, migration, and apoptosis. Herein, we introduced the mechanisms of cytomechanics and LLPS. In addition, we presented the latest findings on cytomechanical protein phase separation, covering such issues as the regulation of focal adhesion maturation and mechanical signal transduction by LIM domain-containing protein 1 (LIMD1) phase separation, the regulation of intercellular tight junctions by zonula occludens (ZO) phase separation, and the regulation of cell proliferation and apoptosis by cytomechanical protein phase separation of the Hippo signaling pathway. The proposition of LLPS provides an explanation for the formation mechanism of intracellular membraneless organelles and supplies new approaches to understanding the biological functions of intracellular physiology or pathology. However, the molecular mechanisms by which LLPS drives focal adhesions and cell-edge dynamics are still not fully understood. It is not clear whether LLPS under in vitro conditions can occur under physiological conditions of organisms. There are still difficulties to be overcome in using LLPS to explain the interactions of multiple intracellular molecules. Researchers should pursue answers to these questions in the future.