AdipoRon ameliorates the progression of heart failure with preserved ejection fraction via mitigating lipid accumulation and fibrosis.

INTRODUCTION: Obesity and imbalance in lipid homeostasis contribute greatly to heart failure with preserved ejection fraction (HFpEF), the dominant form of heart failure. Few effective therapies exist to control metabolic alterations and lipid homeostasis. OBJECTIVES: We aimed to investigate the cardioprotective roles of AdipoRon, the adiponectin receptor agonist, in regulating lipid accumulation in the two-hit HFpEF model. METHODS: HFpEF mouse model was induced using 60 % high-fat diet plus L-NAME drinking water. Then, AdipoRon (50 mg/kg) or vehicle were administered by gavage to the two-hit HFpEF mouse model once daily for 4 weeks. Cardiac function was evaluated using echocardiography, and Postmortem analysis included RNA-sequencing, untargeted metabolomics, transmission electron microscopy and molecular biology methods. RESULTS: Our study presents the pioneering evidence that AdipoR was downregulated and impaired fatty acid oxidation in the myocardia of HFpEF mice, which was associated with lipid metabolism as indicated by untargeted metabolomics. AdipoRon, orally active synthetic adiponectin receptor agonist, could upregulate AdipoR1/2 (independently of adiponectin) and reduce lipid droplet accumulation, and alleviate fibrosis to restore HFpEF phenotypes. Finally, AdipoRon primarily exerted its effects through restoring the balance of myocardial fatty acid intake, transport, and oxidation via the downstream AMPKα or PPARα signaling pathways. The protective effects of AdipoRon in HFpEF mice were reversed by compound C and GW6471, inhibitors of AMPKα and PPARα, respectively. CONCLUSIONS: AdipoRon ameliorated the HFpEF phenotype by promoting myocardial fatty acid oxidation, decreasing fatty acid transport, and inhibiting fibrosis via the upregulation of AdipoR and the activation of AdipoR1/AMPKα and AdipoR2/PPARα-related downstream pathways. These findings underscore the therapeutic potential of AdipoRon in HFpEF. Importantly, all these parameters get restored in the context of continued mechanical and metabolic stressors associated with HFpEF.

Hazards and influence factors of arsenic in the upper pleistocene aquifer, Hetao region, using machine learning modeling.

The Hetao region is one of the regions with the most serious problem of the greatest measured arsenic concentrations in China. The enrichment of arsenic in groundwater may poses a great risk to the health of local residents. A comprehensive understanding of the groundwater quality, spatial distribution characteristics and hazard of the high arsenic in groundwater is indispensable for the sustainable utilization of groundwater resources and resident health. This study selected six environmental factors, climate, human activity, sedimentary environment, hydrogeology, soil, and others, as the independent input variables to the model, compared three machine learning algorithms (support vector machine, extreme gradient boosting, and random forest), and mapped unsafe arsenic to estimate the population that may be exposed to unhealthy conditions in the Hetao region. The results show that nearly half the number of the 605 sampling wells for arsenic exceeded the WHO provisional guide value for drinking water, the water chemistry of groundwater are mainly Na-HCO3-Cl or Na-Mg-HCO3-Cl type water, and the groundwater with excessive arsenic concentration is mainly concentrated in the ancient stream channel influence zone and the Yellow River crevasse splay. The results of factor importance explanation revealed that the sedimentary environment was the key factor affecting the primary high arsenic groundwater concentration, followed by climate and human activities. The random forest algorithm produced the probability distribution of high arsenic groundwater that is consistent with the observed results. The estimated area of groundwater with excessive arsenic reached 38.81 %. An estimated 940,000 people could be exposed to high arsenic in groundwater.

Ce doped V-W/Ti as selective catalytic reduction catalysts for cement kiln flue gas denitration.

In cement industry, the selection of catalyst temperature window and the inhibition effect of dust composition in flue gas on catalyst are the key issues of flue gas denitrification. In this article, a pilot study with Ce doped V-W/Ti catalyst on the removal of NOx by selective catalytic reduction with ammonia (NH3-SCR) from the cement kiln flue gas was presented. Cement kiln dust loading on catalysts obviously decreased the NO conversion in the absence of SO2 and H2O, while the denitration efficiency restored from 75 to 98% at 280 ℃ after SO2 and H2O introduced into the reaction system, which mainly because the SO2 may enhance the acidic site on the catalyst surface, and prefer to be bonded with the coordinated Ca species, releasing the active sites poisoned by dust. The NH3-temperature programmed desorption (NH3-TPD), X-ray photoelectron spectroscopy (XPS), and H2-temperature programmed reduction (H2-TPR) detections were performed to reveal that the appropriate Ce and W ratios catalyst contributed better denitrification activity. The optimum ratio of Ce doped catalyst was amplified to form the standard honeycomb monomer catalyst, and then, the activity of catalyst was verified on the side line of cement kiln. The effect of temperature and space velocity on denitrification efficiency was investigated, and the denitration efficiency reached to 92.5% at 300℃ and 3000 h-1 space velocity. Moreover, the life of catalyst was verified and predicted by GM (1,1) grey model. The study realized the innovation from the laboratory data rules to the industrial pilot application, providing positive promoting value for the industrial large-scale demonstration application of the catalyst.

Efficacy of a WeChat-Based Multimodal Digital Transformation Management Model in New-Onset Mild to Moderate Hypertension: Randomized Clinical Trial.

BACKGROUND: The advantages of multimodal digitally transformed mobile health management for patients diagnosed with mild to moderate hypertension are not yet established. OBJECTIVE: We aim to evaluate the therapeutic benefits of a novel WeChat-based multimodal digital transforming management model in mobile health blood pressure (BP) management. METHODS: This randomized controlled clinical trial included 175 individuals with new-onset mild to moderate hypertension who were admitted to our center between September and October 2022. The patients were randomly assigned to either the multimodal intervention group (n=88) or the usual care group (n=87). The primary composite outcome was home and office BP differences after 6 months. The major secondary outcomes were 6-month quality-of-life scores, including the self-rating anxiety scale, self-rating depression scale, and Pittsburgh Sleep Quality Index. RESULTS: The mean home BP decreased from 151.74 (SD 8.02)/94.22 (SD 9.32) to 126.19 (SD 8.45)/82.28 (SD 9.26) mm Hg in the multimodal intervention group and from 150.78 (SD 7.87)/91.53 (SD 9.78) to 133.48 (SD 10.86)/84.45 (SD 9.19) mm Hg in the usual care group, with a mean difference in systolic blood pressure and diastolic blood pressure of -8.25 mm Hg (95% CI -11.71 to -4.78 mm Hg; P<.001) and -4.85 mm Hg (95% CI -8.41 to -1.30 mm Hg; P=.008), respectively. The mean office BP decreased from 153.64 (SD 8.39)/93.56 (SD 8.45) to 127.81 (SD 8.04)/ 82.16 (SD 8.06) mm Hg in the multimodal intervention group and from 151.48 (SD 7.14)/(91.31 (SD 9.61) to 134.92 (SD 10.11)/85.09 (SD 8.26) mm Hg in the usual care group, with a mean difference in systolic blood pressure and diastolic blood pressure of -9.27 mm Hg (95% CI -12.62 to -5.91 mm Hg; P<.001) and -5.18 mm Hg (95% CI -8.47 to -1.89 mm Hg; P=.002), respectively. From baseline to 6 months, home BP control <140/90 mm Hg was achieved in 64 (72.7%) patients in the multimodal intervention group and 46 (52.9%) patients in the usual care group (P=.007). Meanwhile, home BP control <130/80 mm Hg was achieved in 32 (36.4%) patients in the multimodal intervention group and 16 (18.4%) patients in the usual care group (P=.008). After 6 months, there were significant differences in the quality-of-life total and graded scores, including self-rating anxiety scale scores (P=.04), self-rating depression scale scores (P=.03), and Pittsburgh Sleep Quality Index scores (P<.001), in the multimodal intervention group compared with the usual care group. CONCLUSIONS: The WeChat-based multimodal intervention model improved the BP control rates and lowered the BP levels more than the usual care approach. The multimodal digital transforming management model for hypertension represents an emerging medical practice that utilizes the individual's various risk factor profiles for primary care and personalized therapy decision-making in patients with hypertension. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2200063550; https://www.chictr.org.cn/showproj.html?proj=175816.

Role of ventrolateral part of ventromedial hypothalamus in post-myocardial infarction cardiac dysfunction induced by sympathetic nervous system.

Psychological stress has been recognized as a contributing factor to worsened prognosis in patients with cardiac failure following myocardial infarction (MI). Although the ventrolateral part of the ventromedial hypothalamus (VMHVL) has been implicated in emotional distress, its involvement in post-MI cardiac dysfunction remains largely unexplored. This study was designed to investigate the effect of the VMHVL activation in the MI rat model and its underlying mechanisms. Our findings demonstrate that activation of VMHVL neurons enhances the activity of the cardiac sympathetic nervous system through the paraventricular nucleus (PVN) and superior cervical ganglion (SCG). This activation leads to an elevation in catecholamine levels, which subsequently modulates myosin function and triggers the release of anti-inflammatory factors, to exacerbate the post-MI cardiac prognosis. The denervation of the superior cervical ganglion (SGN) effectively blocked the cardiac sympathetic effects induced by the VMHVL activation, and ameliorated the cardia fibrosis and dysfunction. Therefore, our study identified the role of the "VMHVL-PVN-SCG" sympathetic pathway in the post-MI heart, and proposed SGN as a promising strategy in mitigating cardiac prognosis in stressful rats.

A computational study of fluid transport characteristics in the brain parenchyma of dementia subtypes.

The cerebral environment is a complex system consisting of parenchymal tissue and multiple fluids. Dementia is a common class of neurodegenerative diseases, caused by structural damages and functional deficits in the cerebral environment. In order to better understand the pathology of dementia from a cerebral fluid transport angle and provide clearer evidence that could help differentiate between dementia subtypes, such as Alzheimer's disease and vascular dementia, we conducted fluid-structure interaction modelling of the brain using a multiple-network poroelasticity model, which considers both neuropathological and cerebrovascular factors. The parenchyma was further subdivided and labelled into parcellations to obtain more localised and detailed data. The numerical results were converted to computed functional images by an in-house workflow. Different cerebral blood flow (CBF) and cerebrospinal fluid (CSF) clearance abnormalities were identified in the modelling results, when comparing Alzheimer's disease and vascular dementia. This paper presents our preliminary results as a proof of concept for a novel clinical diagnostic tool, and paves the way for a larger clinical study.

Identification of DDIT4 as a potential prognostic marker associated with chemotherapeutic and immunotherapeutic response in triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is the most heterogenous and aggressive subtype of breast cancer. Chemotherapy remains the standard treatment option for patients with TNBC owing to the unavailability of acceptable targets and biomarkers in clinical practice. Novel biomarkers and targets for patient stratification and treatment of TNBC are urgently needed. It has been reported that the overexpression of DNA damage-inducible transcript 4 gene (DDIT4) is associated with resistance to neoadjuvant chemotherapy and poor prognosis in patients with TNBC. In this study, we aimed to identify novel biomarkers and therapeutic targets using RNA sequencing (RNA-seq) and data mining using data from public databases. METHODS: RNA sequencing (RNA-Seq) was performed to detect the different gene expression patterns in the human TNBC cell line HS578T treated with docetaxel or doxorubicin. Sequencing data were further analyzed by the R package "edgeR" and "clusterProfiler" to identify the profile of differentially expressed genes (DEGs) and annotate gene functions. The prognostic and predictive value of DDIT4 expression in patients with TNBC was further validated by published online data resources, including TIMER, UALCAN, Kaplan-Meier plotter, and LinkedOmics, and GeneMANIA and GSCALite were used to investigate the functional networks and hub genes related to DDIT4, respectively. RESULTS: Through the integrative analyses of RNA-Seq data and public datasets, we observed the overexpression of DDIT4 in TNBC tissues and found that patients with DDIT4 overexpression showed poor survival outcomes. Notably, immune infiltration analysis showed that the levels of DDIT4 expression correlated negatively with the abundance of tumor-infiltrating immune cells and immune biomarker expression, but correlated positively with immune checkpoint molecules. Furthermore, DDIT4 and its hub genes (ADM, ENO1, PLOD1, and CEBPB) involved in the activation of apoptosis, cell cycle, and EMT pathways. Eventually, we found ADM, ENO1, PLOD1, and CEBPB showed poor overall survival in BC patients. CONCLUSION: In this study, we found that DDIT4 expression is associated with the progression, therapeutic efficacy, and immune microenvironment of patients with TNBC, and DDIT4 would be as a potential prognostic biomarker and therapeutic target. These findings will help to identify potential molecular targets and improve therapeutic strategies against TNBC.

Association of bevacizumab and stroke in ovarian cancer: a systematic review and meta-analysis.

Background: The prognosis for patients with ovarian cancer is bleak. Clinical trials have shown the efficacy of bevacizumab in ovarian cancer treatment. However, life-threatening strokes may limit the usage of bevacizumab and require specific follow-up strategies. This study aims to systematically evaluate the risk of stroke of bevacizumab treatment in ovarian cancer. Methods: We retrieved all relevant articles published up to December 4th, 2022, from Embase, PubMed, Web of Science, and the Cochrane Library. The risk of stroke in patients with ovarian cancer treated with bevacizumab combined with chemotherapy was analyzed. Meta-analysis was performed using the Stata 17 software and R 4.2.1 program. Results: Six randomized controlled trials (RCTs) of bevacizumab combined with chemotherapy or chemotherapy for ovarian cancer and six single-experimental-arm trials were included in this study. The meta-analysis showed a pooled risk ratio (RR) of 2.14 [95% confidence interval (CI): 0.88-7.99] for patients with ovarian cancer treated with bevacizumab combined with chemotherapy. Subgroup analyses showed that the incidence of stroke-related adverse events in the carboplatin + paclitaxel + bevacizumab group was 0.01% (95% CI: 0.00-0.01, p < 0.01). The incidence of stroke-related adverse events was 0.01% (95% CI: 0.00-0.01, p < 0.01) in patients aged ≥60. The incidence of stroke caused by cerebral ischemia and cerebral hemorrhage was 0.01% (95% CI: 0.01-0.02, p = 0.27) and 0.01% (95% CI: 0.00-0.01, p < 0.01), respectively. Conclusions: This meta-analysis indicates that chemotherapy combined with bevacizumab may not increase the incidence of stroke in patients with ovarian cancer. However, stroke-related adverse events may be higher in older patients. Cerebral hemorrhage might cause the incidence of stroke more than cerebral ischemia. Systematic review registration: PROSPERO (CRD42022381003).

TRIM29 (Tripartite Motif Containing 29) Alleviates NLRC4 (NLR Family CARD Domain Containing Protein 4) Inflammasome Related Cerebral Injury via Promoting Proteasomal Degradation of NLRC4 in Ischemic Stroke.

BACKGROUND: Neuroinflammation plays extremely crucial roles in the neurological damage mediated by ischemic stroke. TRIM29 (tripartite motif containing 29) has previously been proposed to contribute to the regulation of innate immunity, however, the effect of TRIM29 on ischemic stroke induced neurodegenerative processes and neuroinflammation still largely unexplored. In the current article, we aimed to investigate the function and the precise mechanisms of TRIM29 in ischemic stroke. METHODS: Middle cerebral artery occlusion mice model and oxygen-glucose deprivation cell model were established as in vivo and in vitro models of ischemic stroke. Quantitative real-time polymerase chain reaction (PCR), Western blot, and ELSIA were used to detect the expression levels of TRIM29, cytokines, and marker proteins. Immunofluorescence assay was performed to examine the extent of cell death. Different truncations were generated, and coimmunoprecipitation assays were used to confirm the protein interaction. Ubiquitination assay was performed to detect the ubiquitination levels. RESULTS: We found that the cerebral ischemia-reperfusion induced injury was aggravated in TRIM29 knockout mice after middle cerebral artery occlusion operation as well as the increased neurological deficits score. TRIM29 expression was also found to be up-regulated upon middle cerebral artery occlusion or OGD administration, and loss of TRIM29 promoted the apoptosis and pyroptosis of neurons and microglial cells induced by middle cerebral artery occlusion or OGD, consistent with the enhanced proinflammatory mediators production and activation of NLRC4 (NLR [NOD-like receptor] family CARD [caspase recruitment domain] domain containing protein 4) inflammasome. Furthermore, we observed that TRIM29 interacted with NLRC4 directly and promoted the K48-linked polyubiquitination of NLRC4, lead to the proteasomal degradation of NLRC4. CONCLUSIONS: In conclusion, for the first time, we revealed the role of TRIM29 in ischemic stroke and illustrated the direct relationship between TRIM29 and NLRC4.

Increased sympathetic outflow induced by emotional stress aggravates myocardial ischemia-reperfusion injury via activation of TLR7/MyD88/IRF5 signaling pathway.

BACKGROUND AND OBJECTIVE: Emotional stress substantially increases the risk of ischemic cardiovascular diseases. Previous study indicates that sympathetic outflow is increased under emotional stress. We aim to investigate the role of increased sympathetic outflow induced by emotional stress in myocardial ischemia-reperfusion (I/R) injury, and explore the underlying mechanisms. METHODS AND RESULTS: We used Designer Receptors Exclusively Activated by Designer Drugs technique to activate the ventromedial hypothalamus (VMH), a critical emotion-related nucleus. The results revealed that emotional stress stimulated by VMH activation increased sympathetic outflow, enhanced blood pressure, aggravated myocardial I/R injury, and exacerbated infarct size. The RNA-seq and molecular detection demonstrated that toll-like receptor 7 (TLR7), myeloid differentiation factor 88 (MyD88), interferon regulatory factor 5 (IRF5), and downstream inflammatory markers in cardiomyocytes were significantly upregulated. Emotional stress-induced sympathetic outflow further exacerbated the disorder of the TLR7/MyD88/IRF5 inflammatory signaling pathway. While inhibition of the signaling pathway partially alleviated myocardial I/R injury aggravated by emotional stress-induced sympathetic outflow. CONCLUSION: Increased sympathetic outflow induced by emotional stress activates TLR7/MyD88/IRF5 signaling pathway, ultimately aggravating I/R injury.

Identification of arsenic spatial distribution by hydrogeochemical processes represented by different ion ratios in the Hohhot Basin, China.

The Hohhot Basin, a typical inland basin of the Yellow River Basin in China, has high concentrations of arsenic (As) in its shallow groundwater, while the factors dominating the distribution of high arsenic levels remain to be further identified. An analysis of the ratio of hydrogeochemical compositions can help to reveal the spatial characteristics of the shallow groundwater environmental conditions and the distribution of high-arsenic water (As >10 µg/L). In this study, a total of 170 samples of shallow groundwater in the Hohhot Basin were collected and water samples with As >10 µg/L accounted for 29.4% of the total. Based on the slope changes of the cumulative frequency curves of (HCO3- + CO32-)/SO42-, Ca2+/(HCO3- + CO32-), Ca2+/Mg2+, and Na+/Ca2+, the groundwater in the study area can be categorized into six different zones according to the environmental characteristics including redox condition, water recharge intensity, and cation exchange level. The result shows that the groundwater in the front of the piedmont alluvial plain and platform is in a weak reducing condition with high lateral recharge intensity, fast runoff, and weak cation exchange. In the Dahei River alluvial plain, which serves as the groundwater discharge zone, the groundwater runoff is sluggish with poor lateral recharge, sufficient exchange between cations in the groundwater and the aquifer matrix, and enhanced reducibility. The degree of oxidation increased in the groundwater near the Hasuhai Lake and the drainage canal, which adverse to the arsenic enrichment. High-arsenic groundwater is mainly distributed in aquifers of (HCO3- + CO32-)/SO42 > 10, Na+/Ca2+ > 13, and Ca2+/(HCO3- + CO32-) < 0.1, which represent the strong reducing condition, low surface water recharge intensity, and strong cation exchange condition. Reductive dissolution of iron oxide, strong evaporation and concentration process, and competition from phosphate in aquifers jointly lead to the release of arsenic into groundwater.

Bmal1 knockdown in the left stellate ganglion inhibits neural activity and prevents ventricular arrhythmias after myocardial ischemia.

Objectives: The neural activity of the left stellate ganglion (LSG) is closely related to the occurrence of ventricular arrhythmias (VAs). Bmal1 modulates genes associated with neural activity in the central nervous system. However, few studies indicated the role of Bmal1 in the LSG and the subsequent effect on the heart. Therefore, we aimed to investigate the influence of Bmal1 knockdown in the LSG on its neural activity and cardiac electrophysiology and to explore the mechanisms. Materials and methods: We used adeno-associated virus (AAV) to knock down Bmal1 in the LSG. Male beagles were randomized into the Bmal1 knockdown group and the control group. After 4 weeks of injection, the LSG function, neural activity, left ventricular effective refractory period (ERP), and action potential duration (APD) were measured. Electrocardiography for 1 h was recorded for VAs analysis after myocardial ischemia. Nerve growth factor (NGF) and c-fos in the LSG were quantified by immunofluorescence. Transcriptomic analysis was performed to assess the gene expression in the LSG. Results: Bmal1 was sufficiently knocked down by AAV. Compared with the control group, heart rate variability (HRV) in the knockdown group was altered. Bmal1 knockdown inhibited neural activity and function of LSG. It also prolonged ERP as well as APD90. Ischemia-induced VAs were significantly reduced. Nerve growth factor (NGF) and c-fos in the LSG were reduced. Bmal1 knockdown led to the expression changes of genes associated with neural activity in the LSG. Conclusion: Bmal1 knockdown in the LSG suppresses neural activity and prevents ventricular arrhythmias after myocardial ischemia.

Enrichment of High Arsenic Groundwater Controlled by Hydrogeochemical and Physical Processes in the Hetao Basin, China.

Based on 447 samples collected from a shallow aquifer (depths from 0 to 150 m) in the Hetao Basin, Northern China, an integrated hydrogeochemical approach was used in this study to conceptualize the enrichment of high arsenic groundwater in the Hetao Basin. An unconventional method of distinguishing hydrogeochemical and physical processes from a dataset was tested by investigating the cumulative frequency distribution of ionic ratios expressed on a probability scale. By applying cumulative frequency distribution curves to characterize the distribution of ionic ratios throughout the Hetao Basin, hydrogeochemical indicators were obtained that distinguish the series of hydrogeochemical processes that govern groundwater composition. All hydrogeochemical processes can basically be classified as recharge intensity of groundwater, evaporation concentration intensity, and reductive degree controlling the spatial distribution of arsenic. By considering the three processes, we found that the concentration of arsenic was more than 10 µg/L when the (HCO3-+CO32-)/SO42- ratio was over 4.1 (strong reductive area). As the evaporation concentration intensity increased, the median value of arsenic increased from 10.74 to 382.7 µg/L in the median reductive area and rapidly increased from 89.11 to 461.45 µg/L in the strong reductive area. As the river recharge intensity increased (with the intensity index increasing from 0 to 5), the median value of arsenic dropped from 40.2 to 6.8 µg/L in the median reductive area and decreased more markedly from 219.85 to 23.73 µg/L in the strong reductive area. The results provide a new insight into the mechanism of As enrichment in groundwater.

Risk factors for hemodynamic instability during laparoscopic resection of pheochromocytoma.

BACKGROUND: Laparoscopic adrenalectomy for pheochromocytoma is associated with high risk of intraoperative hemodynamic instability. Our study aimed to identify predictive factors for hemodynamic instability during laparoscopic resection of pheochromocytoma. METHODS: Between January 2011 and December 2021, 136 patients underwent unilateral laparoscopic adrenalectomy for pheochromocytoma. The patients were divided into 2 groups depending on the presence or absence of hemodynamic instability during surgery. Intraoperative hemodynamic parameters were compared between the 2 groups. Patient demographic characteristics and preoperative evaluations were assessed for their prognostic relevance with respect to intraoperative hemodynamic instability via both univariate analysis and multivariate logistic regression analysis. RESULTS: There was greater blood pressure fluctuations and higher maximum blood pressure and heart rate in the hemodynamic instability group. More patients need intraoperative administration of vasoactive drugs in the hemodynamic instability group. In the univariate analysis, presence of coronary artery disease, tumour size, and previous hypertension history were significantly associated with intraoperative hemodynamic instability. The multivariate logistic regression analysis showed that tumour size and previous hypertension history were independent risk factors for intraoperative hemodynamic instability. CONCLUSION: Tumour size and previous hypertension history were associated with hemodynamic instability during laparoscopic resection of pheochromocytoma.

Sarcomatoid-associated gene risk index for clear cell renal cell carcinoma.

Sarcomatoid renal cell carcinoma is a de-differentiated form of kidney cancer with an extremely poor prognosis. Genes associated with sarcomatoid differentiation may be closely related to the prognosis of renal cell carcinoma. The prognosis of renal cell carcinoma itself is extremely variable, and a new prognostic model is needed to stratify patients and guide treatment. Data on clear cell renal cell carcinoma with or without sarcomatoid differentiation were obtained from TCGA database, and a sarcomatoid-associated gene risk index (SAGRI) and column line graphs were constructed using sarcomatoid-associated genes. The predictive power of the SAGRI and column line graphs was validated using an internal validation set and an independent validation set (E-MTAB-1980). The SAGRI was constructed using four sarcoma-like differentiation-related genes, COL7A1, LCTL, NPR3, ZFHX4, and had a 1-year AUC value of 0.725 in the training set, 0.712 in the internal validation set, and 0.770 in the independent validation set for TCGA training cohort, with high model reliability. The molecular characteristics among the SAGRI subgroups were analyzed by multiple methods, and results suggested that the SAGRI-HIGH subgroup may benefit more from immunotherapy to improve prognosis. SAGRI satisfactorily predicted the prognosis of patients with clear cell renal cell carcinoma with or without sarcomatoid differentiation.

Melatonin improves cardiac remodeling and brain-heart sympathetic hyperactivation aggravated by light disruption after myocardial infarction.

Light in the external environment might affect cardiovascular function. The light disruption seems to be related to changes in cardiovascular physiological functions, and disturbing light may be a risk factor for cardiovascular diseases. Prior studies have found that light disruption after myocardial infarction (MI) exacerbates cardiac remodeling, and the brain-heart sympathetic nervous system may be one of the key mechanisms. However, how to improve light-disrupted cardiac remodeling remains unclear. Melatonin is an indoleamine secreted by the pineal gland and controlled by endogenous circadian oscillators within the suprachiasmatic nucleus, which is closely associated with light/dark cycle. This study aimed to explore whether melatonin could improve light-disrupted cardiac remodeling and modulate the brain-heart sympathetic nervous system. Our study revealed that light disruption reduced serum melatonin levels, aggravated cardiac sympathetic remodeling, caused overactivation of the brain-heart sympathetic nervous system, exacerbated cardiac dysfunction, and increased cardiac fibrosis after MI, while melatonin treatment improved light disruption-exacerbated cardiac remodeling and brain-heart sympathetic hyperactivation after MI. Furthermore, RNA-Seq results revealed the significant changes at the cardiac transcription level. In conclusion, melatonin may be a potential therapy for light-disrupted cardiac remodeling.

Contrasting behaviors of groundwater arsenic and fluoride in the lower reaches of the Yellow River basin, China: Geochemical and modeling evidences.

Genesis of the contrasting distributions of high arsenic (>10 µg/L) and fluoride (>1 mg/L) groundwater and their negative correlations remain poorly understood. We investigated spatial distributions of groundwater arsenic and fluoride concentrations in the lower reaches of the Yellow River basin, Henan Province, China, using bivariate statistical analyses and geochemical simulations. Results suggest that high arsenic and fluoride groundwater showed contrasting distributions with few overlapped area. Groundwater arsenic concentrations were significantly negatively correlated with oxidation-reduction potential (ORP) values and positively with NH4+ and Fe(II) concentrations, while the opposites were true for groundwater fluoride concentrations. These may suggest that high arsenic groundwater is related to stronger organic matter degradation and Fe(III) oxide reduction, while groundwater fluoride enrichment occurs with less extent of organic matter degradation. Geochemical calculations supported that groundwater fluoride enrichment was governed by extent of fluorite dissolution, which was constrained by varied saturation indices of fluorite in groundwater. However, groundwater arsenic mobility may be explained by different solubility of Fe(III) oxides. Higher Fe(III) oxide solubility corresponding to goethite and lepidocrocite was related to higher arsenic concentrations, while hematite was too low in solubility to produce high arsenic groundwater. The study presented both geochemical and modeling evidences for the contrasting behaviors of groundwater arsenic and fluoride concentrations in anoxic aquifers.

Ultrasound-guided injection of botulinum toxin type A blocks cardiac sympathetic ganglion to improve cardiac remodeling in a large animal model of chronic myocardial infarction.

BACKGROUND: Strategies to improve various cardiovascular diseases by blocking cardiac sympathetic ganglion have been increasingly available currently. Botulinum toxin type A (BTA), a typical neurotoxin, has been shown to block neural transmission in a safe and long-lasting manner. OBJECTIVE: The aim of the present preclinical study was to assess the efficacy of BTA microinjection to alleviate cardiac remodeling after chronic myocardial infarction (MI) by blocking cardiac sympathetic ganglion in a canine model. METHODS: Beagles were randomly divided into a control group (saline microinjection with sham surgery), an MI group (saline microinjection with MI), and an MI + BTA group (BTA microinjection with MI). Ultrasound-guided percutaneous BTA or saline injection into the left stellate ganglion (LSG) was performed followed by MI induction via left anterior descending artery occlusion (LADO) or sham surgery. After 30 days, electrocardiography, Doppler echocardiography, LSG function, neural activity, and ventricular electrophysiological detection were performed in all experimental dogs. At the end, LSG and ventricular tissues were collected for further detection. RESULTS: BTA treatment significantly inhibited LSG function and neural activity and improved heart rate variability. Additionally, BTA application alleviated ventricular remodeling, ameliorated cardiac function, and prevented ventricular arrhythmias after 30-day chronic LADO-induced MI. CONCLUSION: Ultrasound-guided percutaneous microinjection of BTA can block cardiac sympathetic ganglion to improve cardiac remodeling in a large animal model of chronic LADO-induced MI. Ultrasound-guided BTA microinjection has potential for clinical application as a novel cardiac sympathetic ganglion blockade strategy for MI.

First-Trimester Serum Cytokine Profile in Pregnancies Conceived After Assisted Reproductive Technology (ART) With Subsequent Pregnancy-Induced Hypertension.

Pregnancy-induced hypertension (PIH) is one of the most common pregnancy complications that seriously affects the mother and fetus. The incidence of PIH is higher in pregnancies conceived after assisted reproductive technology (ART) than in spontaneous pregnancies; thus, exploring potential serum biomarkers before PIH onset is of great significance for effective early prediction and prevention of PIH in the ART population. Cytokines are involved in the inflammatory response and immune regulation, which play an essential role in the pathogenesis of PIH. A description of the cytokine profile in the first trimester of pregnancy could help identify new diagnostic tools and develop targeted therapies for PIH in the ART population. The concentrations of classical predictive markers for PIH and another 48 cytokines were measured in the first-trimester pregnancy serum samples from 33 PIH patients and 33 matched normotensive controls (NC), both of whom conceived after ART treatment. The measured values were compared and analyzed between NC and PIH, followed by comprehensive bioinformatic analysis and logistic regression analysis. There was no significant difference in classical predictive markers, including Activin A, PlGF, sFLT1 (VEGFR), and sFLT1/PlGF, between the PIH and NC groups (P > 0.05), while 29 cytokines were significantly lower in the PIH group than in the NC group (P < 0.05). Logistic regression analysis revealed that 17 cytokines (IL-2Rα, M-CSF, IL-6, IL-2, ß-NGF, IL-7, IL-12 (p70), SCF, IL-10, IL-9, MIG, GM-CSF, LIF, IL-1α, MCP-3, IL-4, and HGF) in the first-trimester pregnancy serum were significantly negatively correlated with the subsequent onset of PIH. With the top 3 cytokines (IL-7, MIG, and SCF) of receiver operating characteristic (ROC) analysis, we constructed an efficient multifactor combined detection and prediction model for PIH in ART pregnancy. Classical early predictors for hypertensive disorder complicating pregnancy cannot distinguish PIH from their normal peers in ART pregnancy. In comparison, the description of the cytokine profile in the first trimester of pregnancy enables us to distinguish high-risk ART pregnancy for PIH, permitting enough time for PIH prevention therapy. The cytokine profile we described also provides immunological insight into the further mechanistic exploration of PIH.

Autonomic Neural Circuit and Intervention for Comorbidity Anxiety and Cardiovascular Disease.

Anxiety disorder is a prevalent psychiatric disease and imposes a significant influence on cardiovascular disease (CVD). Numerous evidence support that anxiety contributes to the onset and progression of various CVDs through different physiological and behavioral mechanisms. However, the exact role of nuclei and the association between the neural circuit and anxiety disorder in CVD remains unknown. Several anxiety-related nuclei, including that of the amygdala, hippocampus, bed nucleus of stria terminalis, and medial prefrontal cortex, along with the relevant neural circuit are crucial in CVD. A strong connection between these nuclei and the autonomic nervous system has been proven. Therefore, anxiety may influence CVD through these autonomic neural circuits consisting of anxiety-related nuclei and the autonomic nervous system. Neuromodulation, which can offer targeted intervention on these nuclei, may promote the development of treatment for comorbidities of CVD and anxiety disorders. The present review focuses on the association between anxiety-relevant nuclei and CVD, as well as discusses several non-invasive neuromodulations which may treat anxiety and CVD.