Fusobacterium nucleatum facilitates anti-PD-1 therapy in microsatellite stable colorectal cancer.

Microsatellite stable (MSS) colorectal cancers (CRCs) are often resistant to anti-programmed death-1 (PD-1) therapy. Here, we show that a CRC pathogen, Fusobacterium nucleatum (Fn), paradoxically sensitizes MSS CRC to anti-PD-1. Fecal microbiota transplantation (FMT) from patients with Fn-high MSS CRC to germ-free mice bearing MSS CRC confers sensitivity to anti-PD-1 compared to FMT from Fn-low counterparts. Single Fn administration also potentiates anti-PD-1 efficacy in murine allografts and CD34+-humanized mice bearing MSS CRC. Mechanistically, we demonstrate that intratumoral Fn generates abundant butyric acid, which inhibits histone deacetylase (HDAC) 3/8 in CD8+ T cells, inducing Tbx21 promoter H3K27 acetylation and expression. TBX21 transcriptionally represses PD-1, alleviating CD8+ T cell exhaustion and promoting effector function. Supporting this notion, knockout of a butyric acid-producing gene in Fn abolishes its anti-PD-1 boosting effect. In patients with MSS CRC, high intratumoral Fn predicts favorable response to anti-PD-1 therapy, indicating Fn as a potential biomarker of immunotherapy response in MSS CRC.

4-Phenylbutyric acid suppresses psoralen-induced hepatotoxicity by inhibiting ERS and reestablishing mitochondrial fusion-fission balance in mice.

Psoralen is a main active molecule of the traditional Chinese herb medicine Fructus Psoraleae. Our previous studies have shown that psoralen induced liver injury through the endoplasmic reticulum stress (ERS) signaling pathways. In this article, we studied whether the ERS inhibitor, 4-phenylbutyrate acid (4-PBA) could inhibit the liver toxicity caused by psoralen, and explored the underlying mechanisms. Mice were given the solvent, 20mg/kg, 40mg/kg, 80mg/kg of psoralen, or 80mg/kg of psoralen plus 4-PBA for 14 days. We found that 4-PBA significantly reduced the serum LDH and liver tissue MDA level, increased the activities of SOD and CAT, reduced liver weight and coefficient, repaired histopathological damage, and inhibited hepatocytes apoptosis induced by psoralen. RNA-seq transcriptomics found that except for the endoplasmic reticulum, the mitochondria was severely affected by psoralen. And genes involved in mitochondrial fusion, apoptosis, protein folding, and autophagy were found differently expressed in the psoralen group. Further studies found that 4-PBA inhibited the overexpression of GRP78 and CHOP, increased the Bcl-2/Bax ratio, and reduced the expression of Caspase-3. Moreover, 4-PBA reduced the overexpression of mitochondrial fission protein DRP1, increased the expression of fusion proteins Mfn-2 and OPA1, but has no inhibitory effects on autophagy proteins Atg5 or LC3A/B. In conclusion, 4-PBA inhibited ERS and reestablished mitochondrial fusion-fission balance, thereby blocking cell apoptosis, oxidative stress, and mitochondrial dysfunction, thus prevented against psoralen-induced hepatotoxicity.

The role of residual inflammatory risk and LDL cholesterol in patients with in-stent restenosis undergoing percutaneous coronary intervention.

BACKGROUND: To evaluate the relationships between residual inflammatory risk [assessed by high-sensitivity C-reactive protein (hsCRP)], residual cholesterol risk [assessed by low-density lipoprotein cholesterol (LDL-C)] and clinical outcomes among patients who underwent percutaneous coronary intervention (PCI) for in-stent restenosis (ISR) lesions. METHODS: Between January 2017 and December 2018, a total of 2079 patients who underwent PCI for ISR were consecutively enrolled. The primary outcome was the rate of major adverse cardiac events (MACE), defined as a composite endpoint of all-cause death, spontaneous myocardial infarction (MI), or repeat revascularization. RESULTS: During a median follow-up of 36 months, 436 MACEs occurred. Baseline hsCRP was significantly associated with MACE (highest versus lowest quartile, adjusted hazard ratio [aHR] 1.90 [95 % CI, 1.39-2.59]; P < 0.001). By contrast, the baseline LDL-C quartile was not associated with MACE (highest versus lowest quartile, aHR 0.93 [95 % CI, 0.71- 1.22]; P = 0.59). Compared with patients without residual risk (hsCRP <2 mg/L and LDL-C < 70 mg/dL), participants with both residual inflammatory and LDL-C risk (hsCRP ≥2 mg/L and LDL-C ≥ 70 mg/dL) (aHR, 1.39 [95 % CI, 1.06-1.83]; P = 0.02) and those with residual inflammatory risk only (hsCRP ≥2 mg/L and LDL-C < 70 mg/dL) (aHR, 1.34 [95 % CI, 1.01-1.72]; P = 0.04) had significantly higher risks of MACE. CONCLUSIONS: In the current cohort of patients after ISR PCI, inflammation assessed by hsCRP predicted higher risk of adverse clinical outcomes, whereas the level of LDL-C was not associated with adverse prognosis.

Inhibition of cGAS attenuates neonatal hypoxic-ischemic encephalopathy via regulating microglia polarization and pyroptosis.

Background: Neonatal hypoxic-ischemic encephalopathy (HIE) is a condition causing brain injury in newborns with unclear pathogenesis. Cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) signaling pathway and NOD-like receptor protein 3 (NLRP3) mediated pyroptosis are thought to be involved in the pathological process of HIE, but whether these two mechanisms act independently is still unknown. Therefore, we aim to clarify whether there is any interaction between these two pathways and thus synergistically affects the progression of HIE. Methods: The HIE model of neonatal rats was established using the Rice-Vannucci method. The potential therapeutic effect of RU.521 targeting cGAS on HIE was explored through rescue experiment. Twenty-four hours after modeling was selected as observation point, sham + vehicle group, HIE + vehicle group and HIE + RU.521 group were established. A complete medium of BV2 cells was adjusted to a glucose-free medium, and the oxygen-glucose deprivation model was established after continuous hypoxia for 4 hours and reoxygenation for 12 to 24 hours. 2,3,5-triphenyl tetrazolium chloride staining was employed to detect ischemic cerebral infarction in rat brain tissue, and hematoxylin and eosin staining was used to observe tissue injury. Immunofluorescence was applied to monitor the expression of cGAS. Real-time quantitative polymerase chain reaction and western blot were utilized to detect the expression of messenger RNA and protein. Results: cGAS expression was increased in brain tissues of neonatal rats with HIE, and mainly localized in microglia. RU.521 administration reduced infarct size and pathological damage in rat HIE. Moreover, blocking cGAS with RU.521 significantly reduced inflammatory conditions in the brain by down-regulating STING expression, decreasing NLRP3 inflammasome activation and reducing microglial pyroptosis both in vivo and in vitro. Besides, RU.521 promoted the switching of BV2 cells towards the M2 phenotype. Conclusions: This study revealed a link between the cGAS/STING pathway and the NLRP3/GSDMD/pyroptosis pathway in neonatal HIE. Furthermore, the small molecule compound RU.521 can negatively regulate cGAS/STING/NLRP3/pyroptosis axis and promote M2 polarization in microglia, which provides a potential therapeutic strategy for the treatment of neuroinflammation in HIE.

Impact of nitroglycerin on machine-learning fractional flow reserve in coronary computed tomography (CT)-angiography.

Background: Nitroglycerin administration prior to examination improves stenosis assessment of coronary computed tomography (CT) angiography (CCTA). However, whether nitroglycerin influences CT-derived fractional flow reserve (FFR, CT-FFR) evaluation remains unclear. This study aimed to investigate the effect of nitroglycerin on diagnostic performance of CT-FFR. Methods: In this single-center retrospective study, 107 consecutive patients suspected of coronary artery disease (CAD) with nitroglycerin administration prior to CCTA in 2019 were matched to 107 patients without nitroglycerin in 2016 from Fuwai Hospital. All patients underwent CCTA and invasive FFR in a month. Vessel-based and patient-based accuracy and diagnostic performance of CT-FFR were compared between the two groups, as well as image quality, coronary artery diameter and evaluability. Quantitative variables were compared by Kruskal-Wallis H test. Categorical variables and rates were compared by χ2 test or Fisher exact test. Results: A total of 214 patients (56.1±8.9 years, 155 male) with 237 target lesion vessels were analyzed, including 120 vessels in nitroglycerin and 117 vessels in non-nitroglycerin group. Per-vessel based accuracy of CT-FFR was higher in nitroglycerin group {80.0% [95% confidence interval (CI): 71.7-86.7%] vs. 68.4% (59.1-76.7%), P=0.041}. On a per-patient basis, nitroglycerin administration improved the accuracy [83.2% (74.7-89.7%) vs. 68.2% (58.5-76.9%), P=0.01], specificity [82.7% (69.7-91.8%) vs. 61.9% (48.8-73.9%), P=0.01], positive predictive value (PPV) [83.6% (73.6-90.4%) vs. 58.6% (50.0-66.9%), P=0.004], and area under the curve (AUC) [0.83 (0.75-0.89) vs. 0.71 (0.61-0.79), P=0.03] of CT-FFR. Vessel diameters (left main arteries: 4.3 vs. 3.8 mm, P<0.001; left anterior descending arteries: 3.1 vs. 2.9 mm, P=0.001; left circumflex arteries: 2.9 vs. 2.7 mm, P=0.01; right coronary arteries: 3.7 vs. 3.4 mm, P=0.001) and number of evaluable coronary arteries (11.0 vs. 8.0, P<0.001) were larger in nitroglycerin group. Conclusions: Nitroglycerin administration prior to CCTA has positive effects on diagnostic performance of CT-FFR.

The street space planning and design of artificial intelligence-assisted deep learning neural network in the Internet of Things.

This study begins by discussing Internet of Things (IoT) technology and analyzing the classification of street space into four types, along with the Green Looking Ratio (GLR). Following this, the Fully Convolutional Network (FCN)-8s framework is employed to construct a street view image semantic segmentation model based on FCN principles. Subsequently, IoT technology is utilized to analyze the proportion of GLR and satisfaction in the street space within the historical urban area of T City. The findings reveal a significant positive correlation (significance level p < 0.05, R2 = 0.919) between the GLR satisfaction score of street view images and the average GLR of the area. Among the four types of street space-life leisure, historical streets, traffic areas, and landscape-style streets-the dissatisfaction rates with GLR are 35 %, 33 %, 20 %, and 18 %, respectively, correlating with varying GLR satisfaction levels. To enhance street space greening, planting ponds and boxes are proposed for "blind spots" and "dead corners," thereby completing greenery in these areas. These initiatives aim to improve street greening policies, integrate street function zones, and advance the scientific greening of urban streets. The analysis of GLR and satisfaction in street spaces provides valuable insights for refining urban street space greening efforts.

Photocatalytic deuterocarboxylation of alkynes with oxalate.

Herein, a catalytic photoredox-neutral strategy for alkyne deuterocarboxylation with tetrabutylammonium oxalate as the carbonyl source and D2O as the deuteration agent was described. For the first time, the oxalic salt acted as both the reductant and carbonyl source through single electron transfer and subsequential homolysis of the C-C bond. The strongly reductive CO2 radical anion species in situ generated from oxalate played significant roles in realizing the global deuterocarboxylation of terminal and internal alkynes to access various tetra- and tri-deuterated aryl propionic acids with high yields and deuteration ratios.

Comparative study on the transcriptional activities of grass carp (Ctenopharyngodon idellus) peroxisome proliferator-activated receptors induced by different fatty acids.

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that are part of the nuclear hormone receptor family, playing a crucial role in gene expression regulation. They serve as a connection between lipid metabolism disorders and innate immunity by being activated by fatty acids and their derivatives, facilitating signal transduction between the cell surface and nucleus. However, the specific transcriptional effects of different fatty acids (FAs) in fish are not yet fully understood. In our research, we identified and characterized PPARs in grass carp (Ctenopharyngodon idellus). The complete coding sequences of pparαa, pparαb, pparγ, pparδa, and pparδb were 1443 bp, 1404 bp, 1569 bp, 1551 bp, and 1560 bp in length, respectively. Pparα showed the highest expression in the liver, pparγ was mainly expressed in abdominal adipose tissue, and pparδ exhibited increased expression in the heart compared to other tissues. Gene localization analysis revealed that only pparδa was present in both the nucleus and cytoplasm, while the other four genes were exclusively located in the nucleus. Furthermore, our study explored the influence of various fatty acids (docosahexaenoic acid, palmitic acid, lauric acid and oleic acid at concentrations of 0, 50, 100, and 200 µM) on the transcriptional activities of different PPARs, demonstrating the diverse effects of fatty acid ligands on PPAR transcriptional activity. These results have significant implications for understanding the regulation of PPARs transcriptional activity.

Recent Progress in Synthesis of Alkyl Fluorinated Compounds with Multiple Contiguous Stereogenic Centers.

Organic fluorides are widely used in pharmaceuticals, agrochemicals, material sciences, and other fields due to the special physical and chemical properties of fluorine atoms. The synthesis of alkyl fluorinated compounds bearing multiple contiguous stereogenic centers is the most challenging research area in synthetic chemistry and has received extensive attention from chemists. This review summarized the important research progress in the field over the past decade, including asymmetric electrophilic fluorination and the asymmetric elaboration of fluorinated substrates (such as allylic alkylation reactions, hydrofunctionalization reactions, Mannich addition reactions, Michael addition reactions, aldol addition reactions, and miscellaneous reactions), with an emphasis on synthetic methodologies, substrate scopes, and reaction mechanisms.

Prognostic value of the triglyceride-glucose index for adverse cardiovascular outcomes in young adult hypertension.

BACKGROUND: The triglyceride-glucose (TyG) index is a reliable marker of insulin resistance that is involved in the progression of hypertension. This study aimed to evaluate the association of the TyG index with the risk for major cardiovascular events (MACE) in young adult hypertension. METHODS: A total of 2,651 hypertensive patients aged 18-40 years were consecutively enrolled in this study. The TyG index was calculated as Ln [triglycerides × fasting plasma glucose/2]. The cutoff value for an elevated TyG index was determined to be 8.43 by receiver-operating characteristic curve analysis. The primary endpoint was MACE, which was a composite of all-cause death, non-fatal myocardial infarction, coronary revascularization, non-fatal stroke, and end-stage renal dysfunction. The secondary endpoints were individual MACE components. RESULTS: During the median follow-up time of 2.6 years, an elevated TyG index was associated with markedly increased risk of MACE (adjusted hazard ratio [HR] 3.440, P < 0.001) in young hypertensive adults. In subgroup analysis, the elevated TyG index predicted an even higher risk of MACE in women than men (adjusted HR 6.329 in women vs. adjusted HR 2.762 in men, P for interaction, 0.001); and in patients with grade 2 (adjusted HR 3.385) or grade 3 (adjusted HR 4.168) of hypertension than those with grade 1 (P for interaction, 0.024). Moreover, adding the elevated TyG index into a recalibrated Systematic COronary Risk Evaluation 2 model improved its ability to predict MACE. CONCLUSIONS: An elevated TyG index is associated with a higher risk of MACE in young adult hypertension, particularly in women and those with advanced hypertension. Regular evaluation of the TyG index facilitates the identification of high-risk patients.

DMXL2 Is Required for Endocytosis and Recycling of Synaptic Vesicles in Auditory Hair Cells.

Ribbon synapses of inner hair cells (IHCs) are uniquely designed for ultrafast and indefatigable neurotransmission of the sound. The molecular machinery ensuring the efficient, compensatory recycling of the synaptic vesicles (SVs), however, remains elusive. This study showed that hair cell knock-out of murine Dmxl2, whose human homolog is responsible for nonsyndromic sensorineural hearing loss DFNA71, resulted in auditory synaptopathy by impairing synaptic endocytosis and recycling. The mutant mice in the C57BL/6J background of either sex had mild hearing loss with severely diminished wave I amplitude of the auditory brainstem response. Membrane capacitance measurements of the IHCs revealed deficiency in sustained synaptic exocytosis and endocytic membrane retrieval. Consistent with the electrophysiological findings, 3D electron microscopy reconstruction showed reduced reserve pool of SVs and endocytic compartments, while the membrane-proximal and ribbon-associated vesicles remain intact. Our results propose an important role of DMXL2 in hair cell endocytosis and recycling of the SVs.

Characteristic changes in blood routine and peripheral blood lymphocyte subpopulations in recipients of different types of rejection. / ä¸åŒç±»åž‹æŽ’æ–¥ååº”å—è€ è¡€å¸¸è§„åŠå¤–å‘¨è¡€æ·‹å·´ç»†èƒžäºšç¾¤ç‰¹å¾æ€§å˜åŒ–.

OBJECTIVES: Rejection remains the most important factor limiting the survival of transplanted kidneys. Although a pathological biopsy of the transplanted kidney is the gold standard for diagnosing rejection, its limitations prevent it from being used as a routine monitoring method. Recently, peripheral blood lymphocyte subpopulation testing has become an important means of assessing the body's immune system, however, its application value and strategy in the field of kidney transplantation need further exploration. Additionally, the development and utilization of routine test parameters are also important methods for exploring diagnostic strategies and predictive models for kidney transplant diseases. This study aims to explore the correlation between peripheral blood lymphocyte subpopulations and T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR), as well as their diagnostic value, in conjunction with routine blood tests. METHODS: A total of 154 kidney transplant recipients, who met the inclusion and exclusion criteria and were treated at the Second Xiangya Hospital of Central South University from January to December, 2021, were selected as the study subjects. They were assigned into a stable group, a TCMR group, and an ABMR group, based on the occurrence and type of rejection. The basic and clinical data of these recipients were retrospectively analyzed and compared among the 3 groups. The transplant kidney function, routine blood tests, and peripheral blood lymphocyte subpopulation data of the TCMR group and the ABMR group before rejection treatment were compared with those of the stable group. RESULTS: The stable, TCMR group, and ABMR group showed no statistically significant differences in immunosuppressive maintenance regimens or sources of transplanted kidneys (all P>0.05). However, the post-transplant duration was significantly longer in the ABMR group compared with the stable group (P<0.001) and the TCMR group (P<0.05). Regarding kidney function, serum creatinine levels in the ABMR group were higher than in the stable group and the TCMR group (both P<0.01), with the TCMR group also showing higher levels than the stable group (P<0.01). Both TCMR and ABMR groups had significantly higher blood urea nitrogen levels than the stable group (P<0.01), with no statistically significant difference between TCMR and ABMR groups (P>0.05). The estimated glomerular filtration rate (eGFR) was lower in both TCMR and ABMR groups compared with the stable group (both P<0.01). In routine blood tests, the ABMR group had lower hemoglobin, red blood cell count, and platelet count than the stable group (all P<0.05). The TCMR group had higher neutrophil percentage (P<0.05) and count (P<0.05) than the stable group, and the ABMR group had a higher neutrophil percentage than the stable group (P<0.05). The eosinophil percentage and count in the TCMR group were lower than in the stable and ABMR groups (all P<0.05). Both TCMR and ABMR groups had lower basophil percentage and count, as well as lower lymphocyte percentage and count, compared with the stable group (all P<0.05). There were no significant differences in monocyte percentage and count among the 3 groups (all P>0.05). In lymphocyte subpopulations, the TCMR and ABMR groups had lower counts of CD45+ cells and T cells compared with the stable group (all P<0.05). The TCMR group also had lower counts of CD4+ T cells, NK cells, and B cells than the stable group (all P<0.05). There were no significant differences in the T cell percentage, CD4+ T cell percentage, CD8+ T cell percentage and their counts, CD4+/CD8+ T cell ratio, NK cell percentage, and B cell percentage among the stable, TCMR, and ABMR groups (all P>0.05). CONCLUSIONS: The occurrence of rejection leads to impaired transplant kidney function, accompanied by characteristic changes in some parameters of routine blood tests and peripheral blood lymphocyte subpopulations in kidney transplant recipients. The different characteristics of changes in some parameters of routine blood tests and peripheral blood lymphocyte subpopulations during TCMR and ABMR may help predict and diagnose rejection and differentiate between TCMR and ABMR.

Spectrum and genotype-phenotype relationship of ALPK3 variants in Chinese patients with hypertrophic cardiomyopathy.

Background: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease, and it has obvious genetic and clinical heterogeneity. Recently, heterozygous ALPK3 truncating variants (ALPK3tv) have been shown to cause HCM. However, the spectrum of ALPK3 variants and their relationships with the clinical characteristics of Chinese patients with HCM remain to be elucidated. Methods and results: Whole-exome sequencing data from 986 patients with HCM and 761 controls without HCM were utilized to analyze ALPK3 variants. Eleven ALPK3tv were detected in 18 patients with HCM (1.8 %), while no such variants were identified in controls. We also detected 21 rare ALPK3 missense variants in 16 patients with HCM (1.6 %) and 8 controls (1.1 %), respectively. ALPK3tv were significantly enriched in patients with HCM (P < 0.001), whereas the prevalence of missense variants was comparable between the HCM and control groups (P = 0.309). Patients with ALPK3tv exhibited a significantly lower left ventricular outflow tract gradient (P = 0.011) and a higher prevalence of apical HCM (27.8 %; P = 0.008). Conclusions: Our study supports that heterozygous ALPK3tv, but not APLK3 missense variants, are a genetic cause of HCM. Patients with HCM carrying ALPK3tv have a greater likelihood of developing apical HCM.

Analyzing risk factors for second malignancies in early gastric carcinoma from the SEER database.

This retrospective study analyzed a large population of gastric cancer (GC) patients treated between 2010 and 2015 to investigate the clinical features and predictive risk factors for developing secondary primary malignancies (SPMs). The cumulative incidence of SPM was assessed using Kaplan-Meier analysis. Competing risk analyses adjusted for mortality were conducted using stratified Cox proportional hazard regression models and multivariate analyses to identify independent predictors of SPM. A total of 3289 out of 167,747 GC patients were included in the analytic cohort, with 155 patients diagnosed with SPM. Patients whose histologic type other than adenocarcinomas (AC) and signet ring cell carcinoma (SRCC) emerged as an independent risk factor for developing SPM (hazard ratio [HR] 2.262, 95% confidence interval [CI] 1.146-4.465, P = 0.019) in multivariate Cox regression analysis. The surgical method, including biopsy/local excision (HR 2.3, [CI] 1.291-4.095, P = 0.005) and subtotal/total resection ([HR] 1.947, [CI] 1.028-3.687, P = 0.041), chemotherapy ([HR] 1.527, [CI] 1.006-2.316, P = 0.047), and histologic type ([HR] 2.318, [CI] 1.193-4.504, P = 0.013)), were identified as independent risk factors in the competitive risk model. Subgroup analyses, stratified by chemotherapy, revealed an increased risk of SPM among older patients. Furthermore, a nomogram was developed and internally validated to predict the cumulative incidence of SPM in GC patients (C-index = 0.73 for 72 months). These findings suggested that in specific histologic types of GC, the lymph node infiltration region missed after local surgical resection, and concomitant chemotherapy would have an increased risk of SPM for cancer survivors.

Tibetan Plateau Runoff and Evapotranspiration Dataset by an observation-constrained cryosphere-hydrology model.

Runoff and evapotranspiration (ET) are pivotal constituents of the water, energy, and carbon cycles. This research presents a 5-km monthly gridded runoff and ET dataset for 1998-2017, encompassing seven headwaters of Tibetan Plateau rivers (Yellow, Yangtze, Mekong, Salween, Brahmaputra, Ganges, and Indus) (hereinafter TPRED). The dataset was generated using the advanced cryosphere-hydrology model WEB-DHM, yielding a Nash coefficient ranging from 0.77 to 0.93 when compared to the observed discharges. The findings indicate that TPRED's monthly runoff notably outperforms existing datasets in capturing hydrological patterns, as evidenced by robust metrics such as the correlation coefficient (CC) (0.944-0.995), Bias (-0.68-0.53), and Root Mean Square Error (5.50-15.59 mm). Additionally, TPRED's monthly ET estimates closely align with expected seasonal fluctuations, as reflected by a CC ranging from 0.94 to 0.98 when contrasted with alternative ET products. Furthermore, TPRED's annual values exhibit commendable concordance with operational products across multiple dimensions. Ultimately, the TPRED will have great application on hydrometeorology, carbon transport, water management, hydrological modeling, and sustainable development of water resources.