PTPN23[Thr] variant reduces susceptibility and tumorigenesis in esophageal squamous cell carcinoma through dephosphorylation of EGFR.

Post-translational modifications (PTMs) have emerged as pivotal regulators of the development of cancers, including esophageal squamous cell carcinoma (ESCC). Here, we conducted a comprehensive analysis of PTM-related genetic variants associated with ESCC risk using large-scale genome-wide and exome-wide association datasets. We observed significant enrichment of PTM-related variants in the ESCC risk loci and identified five variants that were significantly associated with ESCC risk. Among them, rs6780013 in PTPN23 exhibited the highest level of significance in ESCC susceptibility in 9,728 ESCC cases and 10,977 controls (odds ratio [OR] = 0.85, 95 % confidence interval [CI] = 0.81- 0.89, P = 9.77 × 10-14). Further functional investigations revealed that PTPN23[Thr] variant binds to EGFR and modulates its phosphorylation at Thr699. PTPN23[Thr] variant substantially inhibited ESCC cell proliferation both in vitro and in vivo. Our findings underscore the critical role of PTPN23[Thr]-EGFR interaction in ESCC development, providing more insights into the pathogenesis of this cancer.

Uncertainty quantification in multivariable regression for material property prediction with Bayesian neural networks.

With the increased use of data-driven approaches and machine learning-based methods in material science, the importance of reliable uncertainty quantification (UQ) of the predicted variables for informed decision-making cannot be overstated. UQ in material property prediction poses unique challenges, including multi-scale and multi-physics nature of materials, intricate interactions between numerous factors, limited availability of large curated datasets, etc. In this work, we introduce a physics-informed Bayesian Neural Networks (BNNs) approach for UQ, which integrates knowledge from governing laws in materials to guide the models toward physically consistent predictions. To evaluate the approach, we present case studies for predicting the creep rupture life of steel alloys. Experimental validation with three datasets of creep tests demonstrates that this method produces point predictions and uncertainty estimations that are competitive or exceed the performance of conventional UQ methods such as Gaussian Process Regression. Additionally, we evaluate the suitability of employing UQ in an active learning scenario and report competitive performance. The most promising framework for creep life prediction is BNNs based on Markov Chain Monte Carlo approximation of the posterior distribution of network parameters, as it provided more reliable results in comparison to BNNs based on variational inference approximation or related NNs with probabilistic outputs.

Lactobacillus paracasei Jlus66 relieves DSS-induced ulcerative colitis in a murine model by maintaining intestinal barrier integrity, inhibiting inflammation, and improving intestinal microbiota structure.

PURPOSE: Ulcerative colitis (UC) is a serious health problem with increasing morbidity and prevalence worldwide. The pathogenesis of UC is complex, currently believed to be influenced by genetic factors, dysregulation of the host immune system, imbalance in the intestinal microbiota, and environmental factors. Currently, UC is typically managed using aminosalicylates, immunosuppressants, and biologics as adjunctive therapies, with the risk of relapse and development of drug resistance upon discontinuation. Therefore, further research into the pathogenesis of UC and exploration of potential treatment strategies are necessary to improve the quality of life for affected patients. According to previous studies, Lactobacillus paracasei Jlus66 (Jlus66) reduced inflammation and may help prevent or treat UC. METHODS: We used dextran sulfate sodium (DSS) to induce a mouse model of UC to assess the effect of Jlus66 on the progression of colitis. During the experiment, we monitored mouse body weight, food and water consumption, as well as rectal bleeding. Hematoxylin-eosin staining was performed to assess intestinal pathological damage. Protein imprinting and immunohistochemical methods were used to evaluate the protein levels of nuclear factor-kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and tight junction (TJ) proteins in intestinal tissues. Fecal microbiota was analyzed based on partial 16S rRNA gene sequencing. RESULTS: Jlus66 supplementation reduced the degree of colon tissue damage, such as colon shortening, fecal occult blood, colon epithelial damage, and weight loss. Supplementation with Jlus66 reduced DSS-induced upregulation of cytokine levels such as TNF-α, IL-1ß, and IL-6 (p < 0.05). The NF-κB pathway and MAPK pathway were inhibited, and the expression of TJ proteins (ZO-1, Occludin, and Claudin-3) was upregulated. 16S rRNA sequencing of mouse cecal contents showed that Jlus66 effectively regulated the structure of the intestinal biota. CONCLUSION: In conclusion, these data indicate that Jlus66 can alter the intestinal biota and slow the progression of UC, providing new insights into potential therapeutic strategies for UC.

Unveiling Organic Electrode Materials in Aqueous Zinc-Ion Batteries: From Structural Design to Electrochemical Performance.

Aqueous zinc-ion batteries (AZIBs) are one of the most compelling alternatives of lithium-ion batteries due to their inherent safety and economics viability. In response to the growing demand for green and sustainable energy storage solutions, organic electrodes with the scalability from inexpensive starting materials and potential for biodegradation after use have become a prominent choice for AZIBs. Despite gratifying progresses of organic molecules with electrochemical performance in AZIBs, the research is still in infancy and hampered by certain issues due to the underlying complex electrochemistry. Strategies for designing organic electrode materials for AZIBs with high specific capacity and long cycling life are discussed in detail in this review. Specifically, we put emphasis on the unique electrochemistry of different redox-active structures to provide in-depth understanding of their working mechanisms. In addition, we highlight the importance of molecular size/dimension regarding their profound impact on electrochemical performances. Finally, challenges and perspectives are discussed from the developing point of view for future AZIBs. We hope to provide a valuable evaluation on organic electrode materials for AZIBs in our context and give inspiration for the rational design of high-performance AZIBs.

Influence of land use change on habitat quality: a case study of coal mining subsidence areas.

Revealing the spatiotemporal evolution characteristics and key driving processes behind the habitat quality is of great significance for the scientific management of production, living, and ecological spaces in resource-based cities, as well as for the efficient allocation of resources. Focusing on the largest coal-mining subsidence area in Jiangsu Province of China, this study examines the spatiotemporal evolution of land use intensity, morphology, and functionality across different time periods. It evaluates the habitat quality characteristics of the Pan'an Lake area by utilizing the InVEST model, spatial autocorrelation, and hotspot analysis techniques. Subsequently, by employing the GTWR model, it quantifies the influence of key factors, unveiling the spatially varying characteristics of their impact on habitat quality. The findings reveal a notable surge in construction activity within the Pan'an Lake area, indicative of pronounced human intervention. Concurrently, habitat degradation intensifies, alongside an expanding spatial heterogeneity in degradation levels. The worst habitat quality occurs during the periods of coal mining and large-scale urban construction. The escalation in land use intensity emerges as the primary catalyst for habitat quality decline in the Pan'an Lake area, with other factors exhibiting spatial variability in their effects and intensities across different stages.

Terf2ip deficiency accelerates non-alcoholic steatohepatitis through regulating lipophagy and fatty acid oxidation via Sirt1/AMPK pathway.

BACKGROUND & AIMS: Our previous study has demonstrated that Telomeric repeat-binding factor 2-interacting protein 1(Terf2ip), played an important role in hepatic ischemia reperfusion injury. This study is aimed to explore the function and mechanism of Terf2ip in non-alcoholic steatohepatitis (NASH). METHODS: The expression of Terf2ip was detected in liver tissue samples obtained from patients diagnosed with NASH. Mice NASH models were constructed by fed with high-fat diet (HFD) or methionine/choline deficient diet (MCD) in Terf2ip knockout and wild type (WT) mice. To further investigate the role of Terf2ip in NASH, adeno-associated viruses (AAV)-Terf2ip was administrated to mice. RESULTS: We observed a significant down-regulation of Terf2ip levels in the livers of NASH patients and mice NASH models. Terf2ip deficiency was associated with an exacerbation of hepatic steatosis in mice under HFD or MCD. Additionally, Terf2ip deficiency impaired lipophagy and fatty acid oxidation (FAO) in NASH models. Mechanically, we discovered that Terf2ip bound to the promoter region of Sirt1 to regulate Sirt1/AMPK pathway activation. As a result, Terf2ip deficiency was shown to inhibit lipophagy through the AMPK pathway, while the activation of Sirt1 alleviated steatohepatitis in the livers of mice. Finally, re-expression of Terf2ip in hepatocyes alleviated liver steatosis, inflammation, and restored lipophagy. CONCLUSIONS: These results revealed that Terf2ip played a protective role in the progression of NASH through regulating lipophagy and FAO by binding to Sirt1 promoter. Our findings provided a potential therapeutic target for the treatment of NASH.

CuCS/Cur composite wound dressings promote neuralized skin regeneration by rebuilding the nerve cell "factory" in deep skin burns.

Regenerating skin nerves in deep burn wounds poses a significant clinical challenge. In this study, we designed an electrospun wound dressing called CuCS/Cur, which incorporates copper-doped calcium silicate (CuCS) and curcumin (Cur). The unique wound dressing releases a bioactive Cu2+-Cur chelate that plays a crucial role in addressing this challenge. By rebuilding the "factory" (hair follicle) responsible for producing nerve cells, CuCS/Cur induces a high expression of nerve-related factors within the hair follicle cells and promotes an abundant source of nerves for burn wounds. Moreover, the Cu2+-Cur chelate activates the differentiation of nerve cells into a mature nerve cell network, thereby efficiently promoting the reconstruction of the neural network in burn wounds. Additionally, the Cu2+-Cur chelate significantly stimulates angiogenesis in the burn area, ensuring ample nutrients for burn wound repair, hair follicle regeneration, and nerve regeneration. This study confirms the crucial role of chelation synergy between bioactive ions and flavonoids in promoting the regeneration of neuralized skin through wound dressings, providing valuable insights for the development of new biomaterials aimed at enhancing neural repair.

A New Species of Diploderma (Squamata, Agamidae) from the Valley of Dadu River in Sichuan Province, with a Redescription of Topotypes of D. splendidum from Hubei Province, China.

This study describes a novel species of Diploderma (Squamata, Agamidae) from the lower valley of the Dadu River of the Sichuan Province of Western China based on its distinct morphological features and molecular evidence. D. daduense sp. nov. can be distinguished from its congeners by its tympanum concealed; head mainly green-yellow, supplemented by black; skin folds under the nuchal and dorsal crest obviously present in adult males only, its vertebral crest discontinuous between nuchal and dorsal sections with a distinct gap; transverse gular fold present but not obvious in some individuals; gular spot absent in both sexes; dorsolateral stripes green-yellow anteriorly, cyan in the center and blurry off-white posteriorly in adult males, the upper edge of dorsolateral stripes strongly jagged in adult males; no radial stripes around the eyes; inner-lip coloration smoky-white, and the coloration of the tongue and oral cavity as a light-flesh color in life; bright green-yellow transverse stripes on dorsal body in males; black patches are evenly distributed along the vertebral line between the dorsolateral stripes from the neck to the base of the tail in males; beech-brown or gray-brown line along the vertebral line with heart-shaped or diamond-shaped black patches on the dorsal body in females; and supratemporals fewer than four on at least one side. The phylogenetic tree based on mitochondrial ND2 sequences indicates that D. daduense sp. nov. forms an independent clade with strong support 1/100 in ML bootstrap/Bayesian posterior probability and is the sister group to D. splendidum. At the inter-species level, the p-distance is at least 6.95%, further confirming that an independent species had been identified. Our work raises the number of species within the genus Diploderma to 47.

Cuprorivaite/hardystonite/alginate composite hydrogel with thermionic effect for the treatment of peri-implant lesion.

Peri-implant lesion is a grave condition afflicting numerous indi-viduals with dental implants. It results from persistent periodontal bacteria accumulation causing inflammation around the implant site, which can primarily lead to implant loosening and ultimately the implant loss. Early-stage peri-implant lesions exhibit symptoms akin to gum disease, including swelling, redness and bleeding of the gums surrounding the implant. These signs indicate infection and inflammation of the peri-implant tissues, which may result in bone loss and implant failure. To address this problem, a thermionic strategy was applied by designing a cuprorivaite-hardystonite bioceramic/alginate composite hydrogel with photothermal and Cu/Zn/Si multiple ions releasing property. This innovative approach creates a thermionic effect by the release of bioactive ions (Cu2+ and Zn2+ and SiO32-) from the composite hydrogel and the mild heat environment though the photothermal effect of the composite hydrogel induced by near-infrared light irradiation. The most distinctive advantage of this thermionic effect is to substantially eliminate periodontal pathogenic bacteria and inhibit inflammation, while simultaneously enhance peri-implant osseointegration. This unique attribute renders the use of this composite hydrogel highly effective in significantly improving the survival rate of implants after intervention in peri-implant lesions, which is a clinical challenge in periodontics. This study reveals application potential of a new biomaterial-based approach for peri-implant lesion, as it not only eliminates the infection and inflammation, but also enhances the osteointegration of the dental implant, which provides theoretical insights and practical guidance to prevent and manage early-stage peri-implant lesion using bioactive functional materials.

Effects of silencing hsa_circ_0015326 on proliferation, migration, invasion, and apoptosis of epithelial ovarian cancer cells.

Although the treatment of ovarian cancer has made great progress, there are still many patients who are not timely detected and given targeted therapy due to unknown pathogenesis. Recent studies have found that hsa_circ_0015326 is upregulated in ovarian cancer and is involved in the proliferation, invasion, and migration of ovarian cancer cells. However, whether hsa_circ_0015326 can be used as a new target of ovarian cancer needs further investigation. Therefore, the effect of hsa_circ_0015326 on epithelial ovarian cancer was investigated in this study. At first, si-hsa_circ_0015326 lentivirus was transfected into epithelial ovarian cancer cells. Then real-time fluorescence quantitative PCR (qRT-PCR) was used to detect hsa_circ_0015326 level. The proliferation of ovarian cancer cells was detected by CCK-8 assay. The horizontal and vertical migration abilities of the cells were detected by wound-healing assay and Transwell assay, respectively. Transwell assay was also used to determine the invasion rate. As for the apoptosis rate, it was assessed by flow cytometry. As a result, the expression level of hsa_circ_0015326 in A2780 and SKOV3 was found to be higher than that in IOSE-80. However, after transfecting si-hsa_circ_0015326 and si-NC into the cells, the proliferation, migration, and invasion abilities of A2780 and SKOV3 cells in the si-hsa_circ_0015326 group were significantly reduced in comparison to those in the si-NC and mock groups, while their apoptosis rates were elevated. Collectively, silencing hsa_circ_0015326 bears the capability of inhibiting the proliferation, migration, and invasion of ovarian cancer cells while increasing apoptosis rate. It can be concluded that hsa_circ_0015326 promotes the malignant biological activities of epithelial ovarian cancer cells.

Electropolymerization of Donor-Acceptor Conjugated Polymer for Efficient Dual-Ion Storage.

Rationally designed organic redox-active materials have attracted numerous interests due to their excellent electrochemical performance and reasonable sustainability. However, they often suffer from poor cycling stability, intrinsic low operating potential, and poor rate performance. Herein, a novel Donor-Acceptor (D-A) bipolar polymer with n-type pyrene-4,5,9,10-tetraone unit storing Li cations and p-type carbazole unit which attracts anions and provides polymerization sites is employed as a cathode for lithium-ion batteries through in situ electropolymerization. The multiple redox reactions and boosted kinetics by the D-A structure lead to excellent electrochemical performance of a high discharge capacity of 202 mA h g-1 at 200 mA g-1, impressive working potential (2.87 and 4.15 V), an outstanding rate capability of 119 mA h g-1 at 10 A g-1 and a noteworthy energy density up to 554 Wh kg-1. This strategy has significant implications for the molecule design of bipolar organic cathode for high cycling stability and high energy density.

Lipopolysaccharide promotes cancer cell migration and invasion through METTL3/PI3K/AKT signaling in human cholangiocarcinoma.

Purpose: As a major structural component of the outer membrane of Gram-negative bacteria, lipopolysaccharide (LPS) has been detected in the blood circulation and tissues in patients with chronic diseases and cancers, which plays a critical role in the tumor formation and progression. However, the biological role of LPS in human intrahepatic cholangiocarcinoma remains unclear. The aims of this study were to investigate the role of LPS in the malignant progression of intrahepatic cholangiocarcinoma. Methods: The cell migration and invasion capacities of cholangiocarcinoma cell lines were evaluated by Boyden chamber assays. Expression levels of the key molecules involved in the PI3K/AKT signaling and METTL3 were detected by qPCR and western blot. The molecular mechanism by which LPS promotes the malignant behaviors was investigated by using siRNAs, plasmids and small molecule inhibitors. Results: In vitro experiments showed that exogenous LPS treatment promoted cell migration and invasion capacities in both QBC939 and HUCCT1 cell lines, while did not affect cell proliferation and apoptosis. Mechanistically, exogenous LPS treatment had been proved to induce the increased expression of METTL3 and activate the downstream PI3K/AKTsignaling pathway. In addition, suppression of METTL3 expression reduced cell proliferation, migration and invasion capacities in both cell lines. Furthermore, inhibition of METTL3 expression or inhibition of PI3K/AKT signaling decreased LPS-induced cell migration and invasion capacities. Moreover, knockdown of METTL3 or inhibition of METTL3 significantly inhibited LPS-induced activation of the PI3K/AKT signaling. Conclusion: In general, these results suggest that the LPS-METTL3-PI3K/AKT signal axis promotes cell migration and invasion in ICC, which contributes to a reduced overall survival in patients with ICC. It may broaden the horizon of cancer therapy with potential therapeutic targets.

Global patterns of human-wildlife spatial associations and implications for differentiating conservation strategies.

Understanding the global patterns of human and wildlife spatial associations is essential for pragmatic conservation implementation, yet analytical foundations and indicator-based assessments that would further this understanding are lacking. We integrated the global distributions of 30,664 terrestrial vertebrates and human pressures to map human-nature index (HNI) categories that indicate the extent and intensity of human-wildlife interactions. Along the 2 dimensions of biodiversity and human activity, the HNI allowed placement of terrestrial areas worldwide in one of 4 HNI categories: anthropic (human-dominated areas), wildlife-dominated (little human influence and rich in wildlife), co-occurring (substantial presence of humans and wildlife), and harsh-environment (limited presence of humans and wildlife) areas. The HNI varied considerably among taxonomic groups, and the leading driver of HNI was global climate patterns. Co-occurring regions were the most prevalent (35.9%), and wildlife-dominated and anthropic regions encompassed 26.45% and 6.50% of land area, respectively. Our results highlight the necessity for customizing conservation strategies to regions based on human-wildlife spatial associations and the distribution of existing protected area networks. Human activity and biodiversity should be integrated for complementary strategies to support conservation toward ambitious and pragmatic 30×30 goals.

Patrones globales de las asociaciones espaciales entre humanos y fauna y las implicaciones para la diferenciación de las estrategias de conservación Resumen Es esencial entender los patrones globales de asociaciones entre humanos y fauna para la implementación pragmática de la conservación. Aun así, son muy pocos los fundamentos analíticos y las evaluaciones basadas en indicadores que incrementarían este conocimiento. Integramos la distribución global de 30,664 vertebrados terrestres y presiones humanas para mapear las categorías del índice de naturaleza humana (INH) que indican la extensión e intensidad de las interacciones humano­fauna. El INH permitió la colocación de áreas terrestres en todo el mundo en las dos dimensiones de la biodiversidad y las actividades humanas dentro de una de las cuatro categorías del INH: áreas antrópicas (dominadas por humanos), dominadas por fauna (poca influencia humana y rica en fauna), co­ocurrentes (presencia sustancial de humanos y fauna) y de ambiente severo (presencia limitada de humanos y fauna). El INH varió considerablemente entre los taxones, y el factor principal fueron los patrones climáticos mundiales. Las regiones co­ocurrentes fueron las más frecuentes (35.9%) las regiones antrópicas y dominadas por fauna englobaron el 26.45% y 6.50% del área terrestre respectivamente. Nuestros resultados enfatizan la necesidad de personalizar las estrategias de conservación acorde a la región con base en las asociaciones espaciales entre humanos y fauna y la distribución de las redes existentes de áreas protegidas. La actividad humana y la biodiversidad deberían estar integradas para las estrategias complementarias para respaldar a la conservación hacia los objetivos ambiciosos y pragmáticos de 30 para el 30.

RBM10 C761Y mutation induced oncogenic ASPM isoforms and regulated ß-catenin signaling in cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma (CCA) comprises a heterogeneous group of biliary tract cancer. Our previous CCA mutation pattern study focused on genes in the post-transcription modification process, among which the alternative splicing factor RBM10 captured our attention. However, the roles of RBM10 wild type and mutations in CCA remain unclear. METHODS: RBM10 mutation spectrum in CCA was clarified using our initial data and other CCA genomic datasets from domestic and international sources. Real-time PCR and tissue microarray were used to detect RBM10 clinical association. Function assays were conducted to investigate the effects of RBM10 wild type and mutations on CCA. RNA sequencing was to investigate the changes in alternative splicing events in the mutation group compared to the wild-type group. Minigene splicing reporter and interaction assays were performed to elucidate the mechanism of mutation influence on alternative splicing events. RESULTS: RBM10 mutations were more common in Chinese CCA populations and exhibited more protein truncation variants. RBM10 exerted a tumor suppressive effect in CCA and correlated with favorable prognosis of CCA patients. The overexpression of wild-type RBM10 enhanced the ASPM exon18 exon skipping event interacting with SRSF2. The C761Y mutation in the C2H2-type zinc finger domain impaired its interaction with SRSF2, resulting in a loss-of-function mutation. Elevated ASPM203 stabilized DVL2 and enhanced ß-catenin signaling, which promoted CCA progression. CONCLUSIONS: Our results showed that RBM10C761Y-modulated ASPM203 promoted CCA progression in a Wnt/ß-catenin signaling-dependent manner. This study may enhance the understanding of the regulatory mechanisms that link mutation-altering splicing variants to CCA.

Smoking and outcomes following personalized antiplatelet therapy in chronic coronary syndrome patients: A substudy from the randomized PATH-PCI trial.

BACKGROUND: This is a sub-analysis of the Personalized Antithrombotic Therapy for Coronary Heart Disease after PCI (PATH-PCI) trial in China to explore the relationship between smoking and outcomes following personalized antiplatelet therapy (PAT) in chronic coronary syndrome (CCS) patients undergoing percutaneous coronary intervention (PCI). METHODS: As a single-center, prospective, randomized controlled and open-label trial, the PATH-PCI trial randomized CCS patients undergoing PCI into standard group or personalized group guided by a novel platelet function test (PFT), from December 2016 to February 2018. All patients were divided into smokers and nonsmokers according to their smoking status. Subsequently, we underwent a 180-day follow-up evaluation. The primary endpoint was the net adverse clinical events (NACE). RESULTS: Regardless of smoking status, in the incidence of NACE, there was a reduction with PAT but that the reductions are not statistically significant. In the incidence of bleeding events, we found no statistically significant difference between two groups (smokers: 2.0% vs. 1.4%, HR = 1.455, 95% confidence interval [CI]: 0.595-3.559, p = .412; nonsmokers: 2.2% vs. 1.8%, HR = 1.228, 95% CI: 0.530-2.842, p = .632). In smokers, PAT reduced major adverse cardiac and cerebrovascular events (MACCE) by 48.7% (3.0% vs. 5.9%, HR = 0.513, 95% CI: 0.290-0.908, p = .022), compared with standard antiplatelet therapy (SAT). PAT also reduced the major adverse cardiovascular events (MACE) but there was no statistically difference in the reductions (p > .05). In nonsmokers, PAT reduced MACCE and MACE by 51.5% (3.3% vs. 6.7%, HR = 0.485, 95% CI: 0.277-0.849, p = .011) and 63.5% (1.8% vs. 4.9%, HR = 0.365, 95% CI: 0.178-0.752, p = .006), respectively. When testing p-values for interaction, we found there was no significant interaction of smoking status with treatment effects of PAT (pint-NACE = .184, pint-bleeding = .660). CONCLUSION: Regardless of smoking, PAT reduced the MACE and MACCE, with no significant difference in bleeding. This suggests that PAT was an recommendable regimen to CCS patients after PCI, taking into consideration both ischemic and bleeding risk.

Siglec9 + tumor-associated macrophages predict prognosis and therapeutic vulnerability in patients with colon cancer.

BACKGROUND: Siglec9 has been identified as an immune checkpoint molecule on tumor-associated macrophages (TAMs). Nevertheless, the expression profile and clinical significance of Siglec9 + TAMs in colon cancer (CC) are still not fully understood. METHODS: Two clinical cohorts from distinct medical centers were retrospectively enrolled. Immunohistochemistry and immunofluorescence were conducted to evaluate the infiltration of immune cells. Single-cell RNA sequencing and flow cytometry were utilized to identify the impact of Siglec9 + TAMs on the tumor immune environment, which was subsequently validated through bioinformatics analysis of the TCGA database. Prognosis and the benefit of adjuvant chemotherapy (ACT) were also evaluated using Cox regression analysis and the Kaplan-Meier method. RESULTS: High infiltration of Siglec9 + TAMs was associated with worse prognosis and better benefit from 6-month ACT. Siglec9 + TAMs contributed to immunoevasion by promoting the infiltration of immunosuppressive cells and the dysfunction process of CD8 + T cells. Additionally, high infiltration of Siglec9 + TAMs was associated with the mesenchymal-featured subtype and overexpression of the VEGF signaling pathway, which was validated by the strongest communication between Siglec9 + TAMs and vascular endothelial cells. CONCLUSIONS: Siglec9 + TAMs may serve as a biomarker for prognosis and response to ACT in CC. Furthermore, the immunoevasive contexture and angiogenesis stimulated by Siglec9 + TAMs suggest potential treatment combinations for CC patients.

Protective effect of synbiotic combination of Lactobacillus plantarum SC-5 and olive oil extract tyrosol in a murine model of ulcerative colitis.

BACKGROUND: Ulcerative colitisis (UC) classified as a form of inflammatory bowel diseases (IBD) characterized by chronic, nonspecific, and recurrent symptoms with a poor prognosis. Common clinical manifestations of UC include diarrhea, fecal bleeding, and abdominal pain. Even though anti-inflammatory drugs can help alleviate symptoms of IBD, their long-term use is limited due to potential side effects. Therefore, alternative approaches for the treatment and prevention of inflammation in UC are crucial. METHODS: This study investigated the synergistic mechanism of Lactobacillus plantarum SC-5 (SC-5) and tyrosol (TY) combination (TS) in murine colitis, specifically exploring their regulatory activity on the dextran sulfate sodium (DSS)-induced inflammatory pathways (NF-κB and MAPK) and key molecular targets (tight junction protein). The effectiveness of 1 week of treatment with SC-5, TY, or TS was evaluated in a DSS-induced colitis mice model by assessing colitis morbidity and colonic mucosal injury (n = 9). To validate these findings, fecal microbiota transplantation (FMT) was performed by inoculating DSS-treated mice with the microbiota of TS-administered mice (n = 9). RESULTS: The results demonstrated that all three treatments effectively reduced colitis morbidity and protected against DSS-induced UC. The combination treatment, TS, exhibited inhibitory effects on the DSS-induced activation of mitogen-activated protein kinase (MAPK) and negatively regulated NF-κB. Furthermore, TS maintained the integrity of the tight junction (TJ) structure by regulating the expression of zona-occludin-1 (ZO-1), Occludin, and Claudin-3 (p < 0.05). Analysis of the intestinal microbiota revealed significant differences, including a decrease in Proteus and an increase in Lactobacillus, Bifidobacterium, and Akkermansia, which supported the protective effect of TS (p < 0.05). An increase in the number of Aspergillus bacteria can cause inflammation in the intestines and lead to the formation of ulcers. Bifidobacterium and Lactobacillus can regulate the micro-ecological balance of the intestinal tract, replenish normal physiological bacteria and inhibit harmful intestinal bacteria, which can alleviate the symptoms of UC. The relative abundance of Akkermansia has been shown to be negatively associated with IBD. The FMT group exhibited alleviated colitis, excellent anti-inflammatory effects, improved colonic barrier integrity, and enrichment of bacteria such as Akkermansia (p < 0.05). These results further supported the gut microbiota-dependent mechanism of TS in ameliorating colonic inflammation. CONCLUSION: In conclusion, the TS demonstrated a remission of colitis and amelioration of colonic inflammation in a gut microbiota-dependent manner. The findings suggest that TS could be a potential natural medicine for the protection of UC health. The above results suggest that TS can be used as a potential therapeutic agent for the clinical regulation of UC.

Spatiotemporal formation of glands in plants is modulated by MYB-like transcription factors.

About one third of vascular plants develop glandular trichomes, which produce defensive compounds that repel herbivores and act as a natural biofactory for important pharmaceuticals such as artemisinin and cannabinoids. However, only a few regulators of glandular structures have been characterized so far. Here we have identified two closely-related MYB-like genes that redundantly inhibit the formation of glandular cells in tomatoes, and they are named as GLAND CELL REPRESSOR (GCR) 1 and 2. The GCR genes highly express in the apical cells of tomato trichomes, with expression gradually diminishing as the cells transition into glands. The spatiotemporal expression of GCR genes is coordinated by a two-step inhibition process mediated by SlTOE1B and GCRs. Furthermore, we demonstrate that the GCR genes act by suppressing Leafless (LFS), a gene that promotes gland formation. Intriguingly, homologous GCR genes from tobacco and petunia also inhibit gland formation, suggesting that the GCR-mediated repression mechanism likely represents a conserved regulatory pathway for glands across different plant species.

Loss of UBE2S causes meiosis I arrest with normal spindle assembly checkpoint dynamics in mouse oocytes.

The timely degradation of proteins that regulate the cell cycle is essential for oocyte maturation. Oocytes are equipped to degrade proteins via the ubiquitin-proteasome system. In meiosis, anaphase promoting complex/cyclosome (APC/C), an E3 ubiquitin-ligase, is responsible for the degradation of proteins. Ubiquitin-conjugating enzyme E2 S (UBE2S), an E2 ubiquitin-conjugating enzyme, delivers ubiquitin to APC/C. APC/C has been extensively studied, but the functions of UBE2S in oocyte maturation and mouse fertility are not clear. In this study, we used Ube2s knockout mice to explore the role of UBE2S in mouse oocytes. Ube2s-deleted oocytes were characterized by meiosis I arrest with normal spindle assembly and spindle assembly checkpoint dynamics. However, the absence of UBE2S affected the activity of APC/C. Cyclin B1 and securin are two substrates of APC/C, and their levels were consistently high, resulting in the failure of homologous chromosome separation. Unexpectedly, the oocytes arrested in meiosis I could be fertilized and the embryos could become implanted normally, but died before embryonic day 10.5. In conclusion, our findings reveal an indispensable regulatory role of UBE2S in mouse oocyte meiosis and female fertility.

Identification of New Markers of Angiogenic Sprouting Using Transcriptomics: New Role for RND3.

BACKGROUND: New blood vessel formation requires endothelial cells to transition from a quiescent to an invasive phenotype. Transcriptional changes are vital for this switch, but a comprehensive genome-wide approach focused exclusively on endothelial cell sprout initiation has not been reported. METHODS: Using a model of human endothelial cell sprout initiation, we developed a protocol to physically separate cells that initiate the process of new blood vessel formation (invading cells) from noninvading cells. We used this model to perform multiple transcriptomics analyses from independent donors to monitor endothelial gene expression changes. RESULTS: Single-cell population analyses, single-cell cluster analyses, and bulk RNA sequencing revealed common transcriptomic changes associated with invading cells. We also found that collagenase digestion used to isolate single cells upregulated the Fos proto-oncogene transcription factor. Exclusion of Fos proto-oncogene expressing cells revealed a gene signature consistent with activation of signal transduction, morphogenesis, and immune responses. Many of the genes were previously shown to regulate angiogenesis and included multiple tip cell markers. Upregulation of SNAI1 (snail family transcriptional repressor 1), PTGS2 (prostaglandin synthase 2), and JUNB (JunB proto-oncogene) protein expression was confirmed in invading cells, and silencing JunB and SNAI1 significantly reduced invasion responses. Separate studies investigated rounding 3, also known as RhoE, which has not yet been implicated in angiogenesis. Silencing rounding 3 reduced endothelial invasion distance as well as filopodia length, fitting with a pathfinding role for rounding 3 via regulation of filopodial extensions. Analysis of in vivo retinal angiogenesis in Rnd3 heterozygous mice confirmed a decrease in filopodial length compared with wild-type littermates. CONCLUSIONS: Validation of multiple genes, including rounding 3, revealed a functional role for this gene signature early in the angiogenic process. This study expands the list of genes associated with the acquisition of a tip cell phenotype during endothelial cell sprout initiation.