A Dielectric MXene-Induced Self-Built Electric Field in Polymer Electrolyte Triggering Fast Lithium-Ion Transport and High-Voltage Cycling Stability.

Quasi-solid polymer electrolyte (QPE) lithium (Li)-metal battery holds significant promise in the application of high-energy-density batteries, yet it suffers from low ionic conductivity and poor oxidation stability. Herein, a novel self-built electric field (SBEF) strategy is proposed to enhance Li+ transportation and accelerate the degradation dynamics of carbon-fluorine bond cleavage in LiTFSI by optimizing the termination of MXene. Among them, the SBEF induced by dielectric Nb4C3F2 MXene effectively constructs highly conductive LiF-enriched SEI and CEI stable interfaces, moreover, enhances the electrochemical performance of the QPE. The related Li-ion transfer mechanism and dual-reinforced stable interface are thoroughly investigated using ab initio molecular dynamics, COMSOL, XPS depth profiling, and ToF-SIMS. This comprehensive approach results in a high conductivity of 1.34 mS cm-1, leading to a small polarization of approximately 25 mV for Li//Li symmetric cell after 6000 h. Furthermore, it enables a prolonged cycle life at a high voltage of up to 4.6 V. Overall, this work not only broadens the application of MXene for QPE but also inspires the great potential of the self-built electric field in QPE-based high-voltage batteries.

Pleiotropic role of GAS6 in cardioprotection against ischemia-reperfusion injury.

INTRODUCTION: Myocardial ischemia-reperfusion (IR) injury is a common medical issue contributing to the onset and progression of ischemic heart diseases (IHD). Growth arrest-specific gene 6 (GAS6), a vitamin K-dependent secretory protein, promotes cell proliferation and inhibits inflammation and apoptosis through binding with Tyro3, Axl, and Mertk (TAM) receptors. OBJECTIVES: Our study aimed to examine the effect of GAS6 pathways activation as a potential new treatment in myocardial IR injury. METHODS: Gain- and loss-of-function experiments were utilized to determine the roles of GAS6 in the pathological processes of myocardial IR injury. RESULTS: Our results revealed down-regulated levels of GAS6, Axl, and SIRT1 in murine hearts subjected to IR injury, and cardiomyocytes challenged with hypoxia reoxygenation (HR) injury. GAS6 overexpression significantly improved cardiac dysfunction in mice subjected to myocardial IR injury, accompanied by reconciled mitochondrial dysfunction, oxidative stress, and apoptosis. In vitro experiments also observed a protective effect of GAS6 in cardiomyocytes. SIRT1 was found to function as a downstream regulator for GAS6/Axl signaling axis. Through screening a natural product library, a polyphenol natural compound catechin was identified to exhibit a protective effect by turning on GAS6/Axl-SIRT1 cascade. CONCLUSIONS: Together, our findings indicate that GAS6 emerges as a potential novel target in the management of myocardial IR injury and other related anomalies.

High KRT17 expression in tumour budding indicates immunologically 'hot' tumour budding and predicts good survival in patients with colorectal cancer.

Objectives: Emerging evidence has demonstrated that tumour budding (TB) is negatively associated with T-lymphocyte infiltration in CRC. Despite extensive research, the molecular characteristics of immunologically 'hot' TB remain poorly understood. Methods: We quantified the number of TB by haematoxylin-eosin (H&E) sections and the densities of CD3+ and CD8+ T-lymphocytes by immunohistochemistry in a CRC cohort of 351 cases who underwent curative resection. We analysed the differential expression and T-lymphocyte infiltration score of 37 human epithelial keratins in CRC using RNA sequencing from the TCGA dataset. In 278 TB-positive cases, KRT17 expression was evaluated in tumour centre (TC) and TB with a staining score. Patient demographic, clinicopathological features and survival rates were analysed. Results: In a CRC cohort of 351 cases, low-grade TB was associated with high CD3+ and CD8+ T-cell densities in the invasive margin (IM) but not in the TC. Of 37 human epithelial keratins, only KRT17 expression in TB had an apparent association with TB-grade and T-lymphocyte infiltration. In 278 TB-positive cases, high KRT17 expression in TB (KRT17TB) was negatively associated with low-grade TB and positively associated with high CD3+ and CD8+ T-cell densities in IM. High KRT17TB predicted early tumour grade, absence of lymph node metastasis and absence of tumour deposits. Additionally, patients with high KRT17TB had good overall survival and disease-free survival. Notably, low KRT17TB can specifically identify those patients with a poor prognosis among colorectal cancer patients with low TB and high T-lymphocyte infiltration. Conclusions: KRT17 can be employed as a new indicator for distinguishing different immunological TBs.

Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family in physiological and pathophysiological process and diseases.

Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family (PGC-1s), consisting of three members encompassing PGC-1α, PGC-1ß, and PGC-1-related coactivator (PRC), was discovered more than a quarter-century ago. PGC-1s are essential coordinators of many vital cellular events, including mitochondrial functions, oxidative stress, endoplasmic reticulum homeostasis, and inflammation. Accumulating evidence has shown that PGC-1s are implicated in many diseases, such as cancers, cardiac diseases and cardiovascular diseases, neurological disorders, kidney diseases, motor system diseases, and metabolic disorders. Examining the upstream modulators and co-activated partners of PGC-1s and identifying critical biological events modulated by downstream effectors of PGC-1s contribute to the presentation of the elaborate network of PGC-1s. Furthermore, discussing the correlation between PGC-1s and diseases as well as summarizing the therapy targeting PGC-1s helps make individualized and precise intervention methods. In this review, we summarize basic knowledge regarding the PGC-1s family as well as the molecular regulatory network, discuss the physio-pathological roles of PGC-1s in human diseases, review the application of PGC-1s, including the diagnostic and prognostic value of PGC-1s and several therapies in pre-clinical studies, and suggest several directions for future investigations. This review presents the immense potential of targeting PGC-1s in the treatment of diseases and hopefully facilitates the promotion of PGC-1s as new therapeutic targets.

Li ions traffic controller on thin lithium metal anode: Regulating deposition, optimizing and protecting solid electrolyte interphase.

The performance of thin lithium metal anodes is affected due to issues that weaken the electrode-electrolyte interphase. In this work, a coating layer serving as a Li+ traffic controller based on hexadecyl trimethyl ammonium bis(trifluoromethanesulphonyl)imide ([CTA][TFSI]) and poly (vinylidene difluoride co-hexafluoropropylene) (P(VDF-HFP)) is used to stabilize the thin lithium metal interface. The CTA+ ions in the coating layer can effectively regulate the distribution of Li+ concentration to promote uniform deposition of lithium. The anion of [CTA][TFSI] can optimize solid electrolyte interphase (SEI) with inorganic-rich components, which improve the ionic conductivity and reaction kinetics. Furthermore, the flexible polymer skeleton can fortify the fragile SEI, facilitating the consistent operation of the battery. Due to these improvements, a thin Li metal anode (4 mAh cm-2) with a coating layer in a Li||Li symmetric cell demonstrates a lifespan of 600 h at 1 mA cm-2 and 1 mAh cm-2. Notably, full cells with an ultra-low negative electrode/positive electrode = 1 (N/P = 1) demonstrate a stable performance over 200 cycles and 90 cycles at 0.5C and 1C (1C = 170 mA g-1), respectively.

Mitochondrial DNA copy number plays opposing roles in T-lymphocyte infiltration of colorectal cancer based on mismatch repair status: new directions for immunotherapy?

BACKGROUND: Researchers have previously reported that mitochondrial DNA copy number (mtDNA-CN) can play different roles in microsatellite instable/mismatch repair-deficient (MSI/dMMR) and microsatellite stable/mismatch repair-proficient (MSS/pMMR) colorectal cancer (CRC). To support malignancy, dMMR CRC relies on glycolysis, while pMMR CRC favors oxidative phosphorylation. However, it is unclear whether mtDNA-CN changes are related to T cell infiltration in CRC. METHODS: The mtDNA-CN was detected by qRT-PCR in 532 patients, and the expression of CD3 and CD8 in 485 patients was detected by immunohistochemistry. The correlation between mtDNA-CN and the prognosis of CRC patients was further analyzed, and the correlation between mtDNA-CN and T lymphocyte infiltration was also analyzed. Biopsy specimens from the immune checkpoint inhibitors (ICIs) treatment cohort were obtained to verify the correlation between mtDNA-CN and the efficacy of ICIs. The effects of mtDNA-CN and MMR status on gene expression were analyzed by RNA-seq. RESULTS: Our results show that mtDNA-CN has inverse relationships to CRC prognosis in cases with different MMR statuses, potentially inducing the U-shaped association in CRC. The opposing correlations between mtDNA-CN and T lymphocyte infiltration in cases of dMMR CRC and pMMR CRC further suggest that mtDNA-CN might play an important role in CRC development. More importantly, cases of pMMR CRC with lower mtDNA-CN and of dMMR CRC with higher mtDNA-CN can benefit more dramatically from ICIs. Furthermore, RNA-seq revealed a link between the level of mtDNA-CN and T lymphocyte infiltration in CRC cases with different MMR statuses. CONCLUSION: Our study found a potential relationship between mtDNA-CN and CRC development that differs by MMR status, potentially providing a rationale for the use of mtDNA-CN as both a predictive biomarker and a therapeutic target for ICIs.

MRI-defined T3, clear mesorectal fascia mid-low rectal cancer: is neoadjuvant treatment necessary?

AIM: Neoadjuvant treatments (nCRT) are becoming the standard treatment for patients with stage II or III mid-low rectal cancer. Recently, some studies have shown that surgery alone may be sufficient for patients with T3 rectal cancer. This raises the question of whether nCRT is necessary for all patients with T3 rectal cancer. Therefore, this study compared the clinical outcomes of patients with MRI-defined T3, clear MRF mid-low rectal cancer treated with surgery alone (TME group) or nCRT followed by surgery (nCRT + TME group). METHODS: A total of 1509 patients were enrolled in this study. After a 1:1 propensity score matching analysis, 480 patients were included in each group. The primary endpoint was 3-year disease-free survival (DFS). The secondary endpoints included the perioperative outcomes, histopathologic outcomes, and other follow-up outcomes. RESULTS: nCRT had advantages in rates of sphincter-preserving surgery and tumor downstaging, but it was accompanied by a higher rate of enterostomies. At 3 years after surgery, local recurrence occurred in 3.3% of patients in the TME group and in 3.5% of patients in the nCRT + TME group (P = 0.914), the DFS rates were 78.3% in the TME group and 75.3% in the nCRT + TME group (P = 0.188), and the overall survival rates were 90.3% in the TME group and 89.9% in the nCRT + TME group (P = 0.776). CONCLUSIONS: Surgery alone versus nCRT followed by surgery may provide similar long-term oncological outcomes for patients with MRI-defined T3, clear MRF, and mid-low rectal cancer. nCRT may cause overtreatment in some patients.

Effects of tumour budding on adjuvant chemotherapy in colorectal cancer.

BACKGROUND: High tumour budding has been indicated as a risk factor of poor survival in colorectal cancer. This study aimed to investigate the impact of tumour budding grades and the use of adjuvant chemotherapy on prognosis in patients with colorectal cancer. METHODS: This study included consecutive colorectal cancer patients who underwent radical surgery for primary colorectal adenocarcinoma at The Sixth Hospital of Sun Yat-sen University between 2009 and 2019. Tumour budding was assessed based on the recommendations of the International Tumor Budding Consensus Conference using haematoxylin and eosin (H&E)-stained slides with tumour samples. The primary outcome of interest was to correlate tumour budding with disease-free survival and overall survival; the secondary outcome was investigation of the impact of adjuvant therapy on different tumour budding grades. In addition, a subgroup analysis was performed for the effects of lymphocytic infiltration on adjuvant chemotherapy in patients with Bd3. RESULTS: Of 709 eligible patients, 412 with colorectal cancer were included. According to the International Tumor Budding Consensus Conference, 210 (50.9 per cent), 127 (30.8 per cent) and 75 (18.2 per cent) were classified as low budding (Bd1), intermediate budding (Bd2) and high budding (Bd3) respectively. Patients with Bd1, Bd2 and Bd3 had 5-year disease-free survival rates of 82.9 per cent, 70.1 per cent and 49.3 per cent respectively, and 5-year overall survival rates of 90 per cent, 79.5 per cent and 62.7 per cent respectively (P <0.001). Adjuvant chemotherapy yielded a significant survival benefit in patients with Bd3 (5-year disease-free survival, 65 per cent versus 31.4 per cent, P <0.001; 5-year overall survival, 84.4 per cent versus 63.1 per cent, P <0.001), but not in those with Bd1 or Bd2. In patients with Bd3, the benefit of adjuvant chemotherapy was maintained in those with low, but not high lymphocytic infiltration. CONCLUSION: High grade of tumour budding was strongly correlated with poorer survival outcomes in colorectal cancer. Patients with Bd3 benefited from adjuvant chemotherapy, with the exclusion of patients with high lymphocytic infiltration.

circGlis3 promotes ß-cell dysfunction by binding to heterogeneous nuclear ribonucleoprotein F and encoding Glis3-348aa protein.

Circular RNAs (circRNAs) are crucial regulators of ß-cell function and are involved in lipotoxicity-induced ß-cell damage in type 2 diabetes mellitus (T2DM). We previously identified that circGlis3, a circRNA derived from exon 4 of the diabetes susceptibility gene Glis3, was upregulated in lipotoxic ß cells. However, the functional role and molecular mechanism of circGlis3 in ß cells remain largely unknown. Here, we revealed that the splicing factor CUGBP Elav-Like Family Member 1 (CELF1) facilitated the biogenesis of circGlis3. Moreover, we established a transgenic mouse model and confirmed that the overexpression of circGlis3 impaired ß-cell function. Mechanistically, circGlis3 bound to heterogeneous nuclear ribonucleoprotein F (hnRNPF) and blocked its nuclear translocation, thereby reducing Sirt1 levels. Additionally, circGlis3 encoded a 348aa protein that interacted with GLIS3 and inhibited its transcriptional activity. Our data uncover a critical role of circGlis3 in ß-cell dysfunction, suggesting that circGlis3 may be a potential therapeutic target for T2DM.

Mutant KRAS-activated circATXN7 fosters tumor immunoescape by sensitizing tumor-specific T cells to activation-induced cell death.

Mutant KRAS (KRASMUT) is often exploited by cancers to shape tumor immunity, but the underlying mechanisms are not fully understood. Here we report that tumor-specific cytotoxic T lymphocytes (CTLs) from KRASMUT cancers are sensitive to activation-induced cell death (AICD). circATXN7, an NF-κB-interacting circular RNA, governs T cell sensitivity to AICD by inactivating NF-κB. Mechanistically, histone lactylation derived from KRASMUT tumor cell-produced lactic acid directly activates transcription of circATXN7, which binds to NF-κB p65 subunit and masks the p65 nuclear localization signal motif, thereby sequestering it in the cytoplasm. Clinically, circATXN7 upregulation in tumor-specific CTLs correlates with adverse clinical outcomes and immunotherapeutic resistance. Genetic ablation of circAtxn7 in CD8+ T cells leads to mutant-selective tumor inhibition, while also increases anti-PD1 efficacy in multiple tumor models in female mice. Furthermore, targeting circATXN7 in adoptively transferred tumor-reactive CTLs improves their antitumor activities. These findings provide insight into how lymphocyte-expressed circRNAs contribute to T-cell fate decisions and anticancer immunotherapies.

Glycolytic Activation of CD14+ Intestinal Macrophages Contributes to the Inflammatory Responses via Exosomal Membrane Tumor Necrosis Factor in Crohn's Disease.

BACKGROUND: Macrophage (Mφ) activation plays a critical role in the inflammatory response. Activated Mφ go through profound reprogramming of cellular metabolism. However, changes in their intracellular energy metabolism and its effect on inflammatory responses in Crohn's disease (CD) remain currently unclear. The aim of this study is to explore metabolic signatures of CD14+ Mφ and their potential role in CD pathogenesis as well as the underlying mechanisms. METHODS: CD14+ Mφ were isolated from peripheral blood or intestinal tissues of CD patients and control subjects. Real-time flux measurements and enzyme-linked immunosorbent assay were used to determine the inflammatory states of Mφ and metabolic signatures. Multiple metabolic routes were suppressed to determine their relevance to cytokine production. RESULTS: Intestinal CD14+ Mφ in CD patients exhibited activated glycolysis compared with those in control patients. Specifically, macrophagic glycolysis in CD largely induced inflammatory cytokine release. The intestinal inflammatory microenvironment in CD elicited abnormal glycolysis in Mφ. Mechanistically, CD14+ Mφ derived exosomes expressed membrane tumor necrosis factor (TNF), which engaged TNFR2 and triggered glycolytic activation via TNF/nuclear factor κB autocrine and paracrine signaling. Importantly, clinically applicable anti-TNF antibodies effectively prevented exosomal membrane TNF-induced glycolytic activation in CD14+ Mφ. CONCLUSIONS: CD14+ Mφ take part in CD pathogenesis by inducing glycolytic activation via membrane TNF-mediated exosomal autocrine and paracrine signaling. These results provide novel insights into pathogenesis of CD and enhance understanding of the mechanisms of anti-TNF agents.

Inflammatory stress response after transanal vs laparoscopic total mesorectal excision: a cohort study based on the TaLaR trial.

BACKGROUND: Transanal total mesorectal excision (taTME) is a novel approach to radical surgery for low rectal cancer; however, it is not clear whether taTME causes a more severe inflammatory stress response than laparoscopic total mesorectal excision (laTME). Therefore, the authors conducted this study to address this question, with the secondary objective of analyzing the predictive effect of inflammatory indexes on postoperative infective complications between laTME and taTME. METHODS: A total of 545 cases of laTME and 544 cases of taTME from the TaLaR randomized controlled trial were included. Inflammatory stress response was assessed via C-reactive protein (CRP), white blood cell count, neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, lymphocyte-monocyte ratio, and prognostic nutritional index. Inflammatory indexes were measured and calculated preoperatively (t1) and on postoperative days one (t2) and seven (t3). The accuracy of inflammatory indexes as predictor of infective complications was evaluated by areas under the receiver operating characteristic curve. RESULTS: Preoperative blood parameters were comparable between the two surgical methods. There were no significant differences in CRP, white blood cell count, neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, lymphocyte-monocyte ratio, or prognostic nutritional index between the two surgical methods at any time point ( P >0.05). Among the inflammatory indexes at three time points, CRP on the first postoperative day was the most accurate predictor of infective complications, which is suitable for two surgical methods. The AUC was 0.7671 ( P <0.0001) with a cutoff of 39.84 mg/l, yielding 94% sensitivity and 47% specificity. CONCLUSIONS: Compared with laTME, taTME surgery has no obvious disadvantage with respect to the postoperative inflammatory stress response. In addition, inflammatory indexes were favorable in predicting infective complications, with the best results for CRP on the first postoperative day. Defining the specific predictors for laTME and taTME is unnecessary.

GAS6 attenuates sepsis-induced cardiac dysfunction through NLRP3 inflammasome-dependent mechanism.

Sepsis is a major health threat and often results in heart failure. Growth arrest-specific gene 6 (GAS6), a 75-kDa vitamin K-dependent protein, participates in immune regulation and inflammation through binding to AXL (the TAM receptor family). This study was designed to examine the myocardial regulatory role of GAS6 in sepsis. Serum GAS6 levels were increased in septic patients and mice while myocardial GAS6 levels were decreased in septic mice. Single-cell RNA sequencing further revealed a decline in GAS6 levels of nearly all cell clusters including cardiomyocytes. GAS6 overexpression via adeno-associated virus 9 (AAV9) overtly improved cardiac dysfunction in cecum ligation and puncture (CLP)-challenged mice, along with alleviated mitochondrial injury, endoplasmic reticulum stress, oxidative stress, and apoptosis. However, GAS6-elicited beneficial effects were removed by GAS6 knockout. The in vitro study was similar to these findings. Our data also noted a downstream effector role for NLRP3 in GAS6-initiated myocardial response. GAS6 knockout led to elevated levels of NLRP3, the effect of which was reconciled by GAS6 overexpression. Taken together, these results revealed the therapeutical potential of targeting GAS6/AXL-NLRP3 signaling in the management of heart anomalies in sepsis.

KRT17 Promotes T-lymphocyte Infiltration Through the YTHDF2-CXCL10 Axis in Colorectal Cancer.

Poor infiltration of T lymphocytes has been regarded as a crucial mechanism of tumor immune escape. Here, we demonstrate a protective role of KRT17 in colorectal cancer, where KRT17 reversed the tumor immunosuppressive microenvironment by increasing T-lymphocyte infiltration. High-throughput RNA sequencing suggested that KRT17 was significantly upregulated in deficient mismatch repair (dMMR) tumors compared with proficient mismatch repair (pMMR) tumors. In a colorectal cancer cohort of 446 cases, KRT17 expression positively correlated with better clinical outcomes. Krt17 overexpression decreased xenograft tumor growth in immune-competent mice. T-cell depletion in a murine model showed that the presence of T lymphocytes was necessary for Krt17-mediated disruption of tumorigenesis. Mass spectrometry and coimmunoprecipitation assays suggested KRT17 caused YTHDF2 degradation through the ubiquitin-proteasome system. Through high-throughput RNA immunoprecipitation sequencing, we found that CXCL10 was the target gene of the N6-methyladenosine (m6A) "reader" YTHDF2. KRT17 synergized with anti-PD-1 for better tumor control in an immunotherapy-resistant murine model. In a cohort of patients with colorectal cancer receiving pembrolizumab, high KRT17 expression was found within the tumors of responders. Collectively, we elucidated a critical role of KRT17 in colorectal cancer to prevent immune escape. These findings present new insights into potential therapeutic strategies and effective markers of immunotherapy reactivity against pMMR tumors.

A Nitrogen Battery Electrode involving Eight-Electron Transfer per Nitrogen for Energy Storage.

Redox flow batteries have been discussed as scalable and simple stationary energy storage devices. However, currently developed systems encounter less competitive energy density and high costs, restricting their wider application. There is a lack of appropriate redox chemistry, preferably based on active materials that are abundant in nature and show high solubility in aqueous electrolytes. A nitrogen-centered redox cycle operating between the limiting species ammonia and nitrate via an eight-electron redox reaction stayed practically unnoticed, albeit its ubiquity in biological processes. Ammonia or nitrate are world-scale chemicals with high aqueous solubility, and are then comparably safe. We demonstrate here the successful implementation of such a nitrogen-based redox cycle between ammonia and nitrate with eight-electron transfer as a catholyte for Zn-based flow batteries, which continuously worked for 12.9 days with 930 charging-discharging cycles. A very competitive energy density of 577 Wh L-1 can be reached, which is well above most reported flow batteries (e.g. 8 times the standard Zn-bromide battery), demonstrating that the nitrogen cycle with eight-electron transfer can offer promising cathodic redox chemistry for safe, affordable, and scalable high-energy-density storage devices.

The Deepest Extent of Acellular Mucin Pools in Resected Locally Advanced Rectal Cancer With Pathological Complete Response After Preoperative Chemoradiotherapy: A Hidden Killer?

For patients with locally advanced rectal cancer (LARC) with pathological complete response (pCR), the clinical significance of the distribution extent of acellular mucin pools (AMP) distribution remains unclear, so this study was conducted to address key unanswered questions. We performed a retrospective analysis of 317 patients with LARC with pCR after preoperative chemoradiotherapy and total mesorectal resection from January 2011 to June 2020. Based on AMP existence and the deepest tissue layer of distribution, patients were assigned new stages. The patient information was recorded, and the main outcome measures included 5-year disease-free survival (DFS) and 5-year overall survival (OS). A total of 83/317 (26.2%) patients exhibited AMP, and disease recurrence occurred in 46/317 (14.5%) patients. Over the 5-year median follow-up period, the patients with AMP showed 5-year DFS rates (75.9% vs. 88.9%, P =0.004) and 5-year OS rates (85.5% vs. 95.7%, P =0.002) statistically lower than those of patients without AMP. Disease recurrence was seen in 15/54 (27.8%) patients with AMP within the subserosa and/or the serosa, or adipose tissue. Univariate and multivariate analysis showed that the existence of AMP within the subserosa and/or the serosa, or adipose tissue was an independent risk factor for DFS [hazard ratio (HR): 2.344; 95% confidence interval (CI): 1.256-4.376; P =0.007] and OS [HR: 3.374; 95% CI: 1.438-7.917; P =0.005]. The new stages based on the deepest extent of AMP were related to worse DFS ( P =0.004) and OS ( P =0.003) rates among patients with pCR. In conclusion, the presence of AMP might reduce the prognosis of LARC patients with pCR after chemoradiotherapy, especially in patients with AMP in deeper tissue layers. Therefore, the influence of the deepest AMP extent might be worth considering in staging. Moreover, the revised staging of patients with pCR according to the deepest extent of AMP, which is unrelated to the clinical T stage, might facilitate postoperative management.

Activation of NR1H3 attenuates the severity of septic myocardial injury by inhibiting NLRP3 inflammasome.

Most sepsis deaths are due to the development of multiple organ failure, in which heart failure is a recognized manifestation of sepsis. To date, the role of liver X receptors α (NR1H3) in sepsis is still uncertain. Here, we hypothesized that NR1H3 mediates multiple essential sepsis-related signalings to attenuate septic heart failure. Adult male C57BL/6 or Balbc mice and HL-1 myocardial cell line were performed for in vivo and in vitro experiments, respectively. NR1H3 knockout mice or NR1H3 agonist T0901317 was applied to evaluate the impact of NR1H3 on septic heart failure. We found decreased myocardial expression levels of NR1H3-related molecules while increased NLRP3 level in septic mice. NR1H3 knockout worsensed cardiac dysfunction and injury in mice subjected to cecal ligation and puncture (CLP), in association with exacerbated NLRP3-mediated inflammation, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, and apoptosis-related markers. The administration of T0901317 reduced systemic infection and improve cardiac dysfunction in septic mice. Moreover, Co-IP assays, luciferase reporter assays, and chromatin immunoprecipitation analysis, confirmed that NR1H3 directly repressed NLRP3 activity. Finally, RNA-seq detection further clarified an overview of the roles of NR1H3 in sepsis. In general, our findings indicate that NR1H3 had a significant protective effect against sepsis and sepsis-induced heart failure.

A novel protein encoded by circINSIG1 reprograms cholesterol metabolism by promoting the ubiquitin-dependent degradation of INSIG1 in colorectal cancer.

BACKGROUND: Hypoxia is a hallmark of solid tumors and leads to the metabolic reprogramming of cancer cells. The role of epigenetic regulation between hypoxia and aberrant cholesterol metabolism in colorectal cancer (CRC) remains elusive. METHODS: Hypoxia-responsive circular RNAs (circRNAs) were identified by high throughput RNA sequencing between CRC cells cultured under normoxia or hypoxia. The protein-coding potential of circINSIG1 was identified by polysome profiling and LC-MS. The function of circINSIG1 was validated in vitro and in vivo by gain or loss of function assays. Mechanistic results were concluded by immunoprecipitation analyses. RESULTS: A novel hypoxia-responsive circRNA named circINSIG1 was identified, which was upregulated in CRC tissues and correlated with advanced clinical stages and poor survival. Mechanistically, circINSIG1 encoded a 121 amino acid protein circINSIG1-121 to promote K48-linked ubiquitination of the critical cholesterol metabolism regulator INSIG1 at lysine 156 and 158 by recruiting CUL5-ASB6 complex, a ubiquitin E3 ligase complex, thereby inducing cholesterol biosynthesis to promote CRC proliferation and metastasis. The orthotopic xenograft tumor models and patient-derived xenograft models further identified the role of circINSIG1 in CRC progression and potential therapeutic target of CRC. CONCLUSIONS: circINSIG1 presents an epigenetic mechanism which provides insights into the crosstalk between hypoxia and cholesterol metabolism, and provides a promising therapeutic target for the treatment of CRC.

A non-Newtonian fluid quasi-solid electrolyte designed for long life and high safety Li-O2 batteries.

The Li dendrite growth and the liquid electrolyte volatilization under semi-open architecture are intrinsic issues for Li-O2 battery. In this work, we propose a non-Newtonian fluid quasi-solid electrolyte (NNFQSE) SiO2-SO3Li/PVDF-HFP, which has both shear-thinning and shear-thickening properties. The component interactions among the sulfonated silica nanoparticles, liquid electrolyte, and polymer network are beneficial for decent Li+ conductivity and high liquid electrolyte retention without volatilization. Furthermore, NNFQSE exhibits shear-thinning property to eliminate the stress of dendrite growth during repeated cycling. Meanwhile, when the force suddenly increases, such as a high current rate, the NNFQSE may dynamically turn shear-thickening to respond and mechanically stiffen to inhibit the lithium dendrite penetration. By coupling with the NNFQSE, the lithium symmetrical battery can run over 2000 h under 1 mA cm-2 at room temperature, and the quasi-solid Li-O2 battery actualizes long life above 5000 h at 100 mA g-1.