Integrated metagenomic and metabolomic analysis reveals distinctive stage-specific gut-microbiome-derived metabolites in intracranial aneurysms.

OBJECTIVE: Our study aimed to explore the influence of gut microbiota and their metabolites on intracranial aneurysms (IA) progression and pinpoint-related metabolic biomarkers derived from the gut microbiome. DESIGN: We recruited 358 patients with unruptured IA (UIA) and 161 with ruptured IA (RIA) from two distinct geographical regions for conducting an integrated analysis of plasma metabolomics and faecal metagenomics. Machine learning algorithms were employed to develop a classifier model, subsequently validated in an independent cohort. Mouse models of IA were established to verify the potential role of the specific metabolite identified. RESULTS: Distinct shifts in taxonomic and functional profiles of gut microbiota and their related metabolites were observed in different IA stages. Notably, tryptophan metabolites, particularly indoxyl sulfate (IS), were significantly higher in plasma of RIA. Meanwhile, upregulated tryptophanase expression and indole-producing microbiota were observed in gut microbiome of RIA. A model harnessing gut-microbiome-derived tryptophan metabolites demonstrated remarkable efficacy in distinguishing RIA from UIA patients in the validation cohort (AUC=0.97). Gut microbiota depletion by antibiotics decreased plasma IS concentration, reduced IA formation and rupture in mice, and downregulated matrix metalloproteinase-9 expression in aneurysmal walls with elastin degradation reduction. Supplement of IS reversed the effect of gut microbiota depletion. CONCLUSION: Our investigation highlights the potential of gut-microbiome-derived tryptophan metabolites as biomarkers for distinguishing RIA from UIA patients. The findings suggest a novel pathogenic role for gut-microbiome-derived IS in elastin degradation in the IA wall leading to the rupture of IA.

Cerebrospinal fluid metabolomic and proteomic characterization of neurologic post-acute sequelae of SARS-CoV-2 infection.

The mechanism by which SARS-CoV-2 causes neurological post-acute sequelae of SARS-CoV-2 (neuro-PASC) remains unclear. Herein, we conducted proteomic and metabolomic analyses of cerebrospinal fluid (CSF) samples from 21 neuro-PASC patients, 45 healthy volunteers, and 26 inflammatory neurological diseases patients. Our data showed 69 differentially expressed metabolites and six differentially expressed proteins between neuro-PASC patients and healthy individuals. Elevated sphinganine and ST1A1, sphingolipid metabolism disorder, and attenuated inflammatory responses may contribute to the occurrence of neuro-PASC, whereas decreased levels of 7,8-dihydropterin and activation of steroid hormone biosynthesis may play a role in the repair process. Additionally, a biomarker cohort consisting of sphinganine, 7,8-dihydroneopterin, and ST1A1 was preliminarily demonstrated to have high value in diagnosing neuro-PASC. In summary, our study represents the first attempt to integrate the diagnostic benefits of CSF with the methodological advantages of multi-omics, thereby offering valuable insights into the pathogenesis of neuro-PASC and facilitating the work of neuroscientists in disclosing different neurological dimensions associated with COVID-19.

Associations of long-term mortality with serum uric acid at admission in acute decompensated heart failure with different phenotypes.

BACKGROUND AND AIMS: It remains unclear whether the long-term prognostic value of serum uric acid (SUA) at admission differs in acute decompensated heart failure (HF) patients across the spectrum of left ventricular ejection fraction (EF). METHODS AND RESULTS: In 2375 patients (38.9% women; mean age, 68.8 years), we assessed the risk of long-term (>1 year) all-cause mortality associated with per 1-SD increase in SUA at admission, using multivariable Cox regression in HF with preserved (HFpEF), mildly reduced (HFmrEF) and reduced (HFrEF) EF. During a median follow-up of 4.1 years, the long-term mortality rate was 39.9%. In all patients, the multivariable-adjusted hazard ratio (HR) expressing the risk of long-term mortality associated with SUA was 1.18 (95% CI, 1.11-1.26; P < 0.001). Compared with the low tertile of the SUA distribution, the sex- and age-adjusted cumulative incidence of long-term mortality was higher in the top tertile. In patients with HFpEF and HFrEF, SUA predicted the risk of long-term mortality with HRs amounting to 1.12 (95% CI, 1.02-1.21; P = 0.012) and 1.28 (95% CI, 1.12-1.47; P < 0.001), respectively. However, there were no associations between the risk of mortality and SUA in HFmrEF. Furthermore, age, sex, NYHA class, and the prevalence of coronary heart disease interacted significantly with SUA for predicting long-term mortality. CONCLUSION: Higher levels of SUA at admission were associated with higher risk of long-term mortality in patients with different HF subtypes. The risk conferred by SUA was age and sex dependent. Our observations highlight that measuring SUA at admission may help to improve risk stratification.

Comparative Effectiveness and Safety of Non-Vitamin K Antagonist Oral Anticoagulants in Atrial Fibrillation Patients.

BACKGROUND AND PURPOSE: Several observational studies have compared the effect of the non-vitamin K antagonist oral anticoagulants to each other in patients with atrial fibrillation. However, confounding by indication is a major problem when comparing non-vitamin K antagonist oral anticoagulant treatments in some of these studies. This meta-analysis was conducted to compare the effectiveness and safety between non-vitamin K antagonist oral anticoagulant and non-vitamin K antagonist oral anticoagulant by only including the propensity score matching studies. METHODS: We systematically searched the PubMed and Ovid databases until May 2020 to identify relevant observational studies. Hazard ratios (HRs) and 95% CIs of the reported outcomes were collected and then pooled by a random-effects model complemented with an inverse variance heterogeneity or quality effects model. RESULTS: A total of 17 retrospective cohort studies were included in this meta-analysis. Compared with dabigatran use, the use of rivaroxaban was significantly associated with increased risks of stroke or systemic embolism (HR, 1.16 [95% CI, 1.05-1.29]) and major bleeding (HR, 1.32 [95% CI, 1.24-1.41]), whereas the use of apixaban was associated with a reduced risk of major bleeding (HR, 0.78 [95% CI, 0.67-0.90]) but not stroke or systemic embolism (HR, 0.84 [95% CI, 0.56-1.28]). Compared with rivaroxaban use, the use of apixaban was associated with a decreased risk of major bleeding (HR, 0.63 [95% CI, 0.54-0.73]) but not stroke or systemic embolism (HR, 0.83 [95% CI, 0.67-1.04]). Reanalyses with the inverse variance heterogeneity or quality effects model produced similar results as the random-effects model. CONCLUSIONS: Current observational comparisons with propensity score matching methods suggest that apixaban might be a better choice compared with dabigatran or rivaroxaban for stroke prevention in atrial fibrillation patients.

An electrographic AV optimization for the maximum integrative atrioventricular and ventricular resynchronization in CRT.

BACKGROUND: Atrioventricular (AV) delay could affect AV and ventricular synchrony in cardiac resynchronization therapy (CRT). Strategies to optimize AV delay according to optimal AV synchrony (AVopt-AV) or ventricular synchrony (AVopt-V) would potentially be discordant. This study aimed to explore a new AV delay optimization algorithm guided by electrograms to obtain the maximum integrative effects of AV and ventricular resynchronization (opt-AV). METHODS: Forty-nine patients with CRT were enrolled. AVopt-AV was measured through the Ritter method. AVopt-V was obtained by yielding the narrowest QRS. The opt-AV was considered to be AVopt-AV or AVopt-V when their difference was < 20 ms, and to be the AV delay with the maximal aortic velocity-time integral between AVopt-AV and AVopt-V when their difference was > 20 ms. RESULTS: The results showed that sensing/pacing AVopt-AV (SAVopt-AV/PAVopt-AV) were correlated with atrial activation time (Pend-As/Pend-Ap) (P < 0.05). Sensing/pacing AVopt-V (SAVopt-V/PAVopt-V) was correlated with the intrinsic AV conduction time (As-Vs/Ap-Vs) (P < 0.01). The percentages of patients with more than 20 ms differences between SAVopt-AV/PAVopt-AV and SAVopt-V/PAVopt-V were 62.9% and 57.1%, respectively. Among them, opt-AV was linearly correlated with SAVopt-AV/PAVopt-AV and SAVopt-V/PAVopt-V. The sensing opt-AV (opt-SAV) = 0.1 × SAVopt-AV + 0.4 × SAVopt-V + 70 ms (R2 = 0.665, P < 0.01) and the pacing opt-AV (opt-PAV) = 0.25 × PAVopt-AV + 0.5 × PAVopt-V + 30 ms (R2 = 0.560, P < 0.01). CONCLUSION: The SAVopt-AV/PAVopt-AV and SAVopt-V/PAVopt-V were correlated with the atrial activation time and the intrinsic AV conduction interval respectively. Almost half of the patients had a > 20 ms difference between SAVopt-AV/PAVopt-AV and SAVopt-V/PAVopt-V. The opt-AV could be estimated based on electrogram parameters.

Brain-Gut-Microbiota Axis in Amyotrophic Lateral Sclerosis: A Historical Overview and Future Directions.

Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease which is strongly associated with age. The incidence of ALS increases from the age of 40 and peaks between the ages of 65 and 70. Most patients die of respiratory muscle paralysis or lung infections within three to five years of the appearance of symptoms, dealing a huge blow to patients and their families. With aging populations, improved diagnostic methods and changes in reporting criteria, the incidence of ALS is likely to show an upward trend in the coming decades. Despite extensive researches have been done, the cause and pathogenesis of ALS remains unclear. In recent decades, large quantities of studies focusing on gut microbiota have shown that gut microbiota and its metabolites seem to change the evolvement of ALS through the brain-gut-microbiota axis, and in turn, the progression of ALS will exacerbate the imbalance of gut microbiota, thereby forming a vicious cycle. This suggests that further exploration and identification of the function of gut microbiota in ALS may be crucial to break the bottleneck in the diagnosis and treatment of this disease. Hence, the current review summarizes and discusses the latest research advancement and future directions of ALS and brain-gut-microbiota axis, so as to help relevant researchers gain correlative information instantly.

Satellite cloud image segmentation based on lightweight convolutional neural network.

More than 50% of the images captured by optical satellites are covered by clouds, which reduces the available information in the images and seriously affects the subsequent applications of satellite images. Therefore, the identification and segmentation of cloud regions come to be one of the most important problems in current satellite image processing. Due to the complexity and variability of satellite images, especially when the ground is covered with snow, the boundary information of cloud regions is difficult to be accurately identified. The fast and accurate segmentation of cloud regions is a difficult point in the current research. We propose a lightweight convolutional neural network. Firstly, channel attention is used to optimize the effective information in the feature maps as a way to improve the network's ability to extract semantic information at each scale. Then, we fuse high and low-dimensional feature maps to enhance the network's ability to obtain small-scale semantic information. In addition, the feature aggregation module automatically adjusts the input multi-level feature weights to highlight the details of different features. Finally, we design the fully connected conditional random field to solve the problem that some noise in the input image and local minima during training is passed to the output layer resulting in the loss of edge features. Experimental results show that the proposed method achieves 0.9695 and 0.8218 for overall accuracy and recall, respectively, which has higher segmentation accuracy with the shortest time consumption compared with other state-of-the-art methods.

Prognostic Implication of Admission Mean and Pulse Pressure in Acute Decompensated Heart Failure With Different Phenotypes.

BACKGROUND: It remains unknown whether admission mean (MAP) and pulse pressure (PP) pressure are associated with short- and long-term mortality in Chinese patients with heart failure with preserved (HFpEF), mid-range (HFmrEF), and reduced (HFrEF) ejection fraction. METHODS: In 2,706 acute decompensated heart failure (HF) patients, we assessed the risk of 30-day, 1-year, and long-term (>1 year) mortality with 1-SD increment in MAP and PP, using multivariable logistic and Cox regression, respectively. RESULTS: During a median follow-up of 4.1 years, 1,341 patients died. The 30-day, 1-year, and long-term mortality were 3.5%, 16.7%, and 39.4%, respectively. A lower MAP was associated with a higher risk of 30-day mortality in women (P = 0.023) and a higher risk of 30-day and 1-year mortality in men (P ≤ 0.006), while higher PP predicted long-term mortality in men (P ≤ 0.014) with no relationship observed in women. In adjusted analyses additionally accounted for PP, 1-SD increment in MAP was associated with 30-day mortality in HFpEF (odds ratio [OR], 0.63; 95% CI, 0.43 to 0.92; P = 0.018), with 1-year mortality in HFmrEF (OR, 0.46; 95% CI, 0.32 to 0.66; P < 0.001) and HFrEF (OR, 0.54; 95% CI, 0.40 to 0.72; P < 0.001). In the adjusted model additionally accounted for MAP, 1-SD increment in PP was associated with long-term mortality in HFpEF (hazard ratio, 1.16; 95% CI, 1.05 to 1.28; P = 0.003). CONCLUSIONS: A lower MAP was associated with a higher risk of short-term mortality in all HF subtypes, while a higher PP predicted a higher risk of long-term mortality in men and in HFpEF. Our observations highlight the clinical importance of admission blood pressure for risk stratification in HF subtypes.

Protective effect of electroacupuncture at ST36 against damage of intestinal mucosa, oxidative stress and apoptosis induced by 5-FU chemotherapy in mice with colon cancer. / 电针"足三里"å‡è½»å¤§è‚ ç™Œå°é¼ åŒ–ç–—åŽè‚ é»è†œæŸä¼¤åŠå ¶å¯¹æ°§åŒ–åº”æ¿€å’Œç»†èƒžå‡‹äº¡çš„å½±å“.

OBJECTIVES: To observe the effect of electroacupuncture (EA) at "Zusanli"(ST36) on intestinal mucosal damage, intestinal mucosal oxidative stress injury and apoptosis induced by 5-fluorouraeil (5-FU) chemotherapy in colorectal cancer-bearing mice. METHODS: Thirty male BALB/c mice were randomly divided into normal control, colorectal cancer (CT26), 5-FU, non-acupoint and ST36 groups, with 6 mice in each group. Except for those of the normal control group, mice of the remaining 4 groups received subcutaneous implantation of colorectal CT26 cell suspension (0.1 mL) in the right armpit for establishing colorectal cancer model. Rats of the 5-FU group, non-acupoint group and ST36 group were given with 5 mg/mL 5-FU solution once every 3 days for a total of 21 days. For mice of the non-acupoint group and ST36 group, EA (2 Hz, 1-2 mA) was applied to bilateral ST36 or non-acupoints (the bilateral sunken spots about 3 mm to the midpoint between the tail root and the anus) for 5 min after each intraperitoneal infusion of 5-FU, once every 3 days, for a total of 21 days. After the intervention, the diarrhea index was assessed. The length of colon (from the endpoint of cecum to the anal orifice) was measured. Histopathological changes of colonic mucosa were observed by H.E. staining, and the length of colonic villi was measured. The content of malondialdehyde (MDA), and activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) of colonic tissue were detected by thibabituric acid, xanthine oxidase and colorimetric method, respectively. The rate of cell apoptosis in the colonic tissue was measured by TUNEL assay. The positive expressions of Bax and Bcl-2 in colonic tissue were determined by immunohistochemistry. RESULTS: The CT26 model group didn't show any significant changes in the diarrhea index, colon length, colon villus length, MDA content, SOD and GSH-Px activities, colonic cell apoptosis rate, and Bax and Bcl-2 expression levels when compared with the normal group. Compared with the CT26 group, the 5-FU group had a remarkable increase in the diarrhea index, MDA content, colonic cell apoptosis rate and Bax expression level (P<0.01, P<0.05), and a marked decrease in the colon length, colon villus length, SOD and GSH-Px activities and Bcl-2 expression level (P<0.01), suggesting the side effects of administration of 5-FU. Compared with the 5-FU group, the diarrhea index, MDA content, colonic cell apoptosis rate and Bax expression level were markedly decreased (P<0.05, P<0.01) and those of the colon length, colon villus length, SOD and GSH-Px activities and Bcl-2 expression level were obviously increased (P<0.01) in the ST36 group. Compared with the 5-FU group, the non-acupoint group also had an increase in the colon villus length, SOD and GSH-Px activities (P<0.01, P<0.05) and a decrease in the cell apoptosis rate (P<0.01). CONCLUSIONS: EA at ST36 has a positive effect in reducing intestinal mucosal damage induced by 5-FU chemotherapy in cancer-bearing mice, which may be related to its function in relieving oxidative stress injury and inhibiting apoptosis of colonic tissue.

LINC01088 promotes the growth and invasion of glioma cells through regulating small nuclear ribonucleoprotein polypeptide A transcription.

Altered long non-coding RNAs (LncRNAs) exert pivotal parts in pathogenic processes in glioma. Here, we uncovered a differentially expressed long intergenic non-coding RNA 1088 (LINC01088) in glioma and elucidated the molecular mechanism by which LINC01088 affected the malignant phenotypes of glioma cells. Functionally, LINC01088 silencing degraded cell proliferation, invasion in glioma, while LINC01088 overexpression elicited opposite results. Mechanistically, we verified LINC01088 physically interacted with small nuclear ribonucleoprotein polypeptide A (SNRPA) and regulated the expression of SNRPA at the transcription level. Phenotypic analysis ascertained that LINC01088 substantively aggravated glioma cell progression in an SNRPA-dependent manner, and SNRPA played a pivotal part in the tumor-promoting properties of LINC01088. Our findings revealed a novel mechanism by which LINC01088 exerted pro-oncogenic functions through binding with SNRPA and transcriptionally regulating SNRPA mRNA in glioma.

Associations of short- and long-term mortality with admission blood pressure in Chinese patients with different heart failure subtypes.

It remains unknown whether systolic (SBP) and diastolic (DBP) pressure on admission are associated with short- and long-term mortality in Chinese patients with heart failure with preserved (HFpEF), mildly reduced (HFmrEF), and reduced (HFrEF) ejection fraction. In 2706 HF patients (39.1% women; mean age, 68.8 years), we assessed the risk of 30-day, 1-year, and long-term (> 1 year) mortality with 1-SD increment in SBP and DBP, using multivariable logistic and Cox regression, respectively. During a median follow-up of 4.1 years, 1341 patients died. The 30-day, 1-year, and long-term mortality were 3.5%, 16.7%, and 39.4%, respectively. In multivariable-adjusted analyses additionally accounted for DBP or SBP, a higher SBP conferred a higher risk of long-term mortality (hazard ratio, 1.11; 95% CI, 1.02-1.22; p = .017) and a lower DBP was associated with a higher risk of all types of mortality (p ≤ .011) in all HF patients. Independent of potential confounders including DBP or SBP, in patients with HFpEF, higher SBP and lower DBP levels predicted a higher risk of long-term mortality with hazard ratios amounting to 1.16 (95% CI, 1.04-1.29; p = .007) and .89 (95% CI, .80-.99; p = .028), respectively. In patients with HFmrEF and HFrEF, irrespective of adjustments of potential confounders, DBP was associated with 1-year mortality with odds ratios ranging from .49 to .62 (p ≤ .006). In conclusion, lower DBP and higher SBP levels on admission were associated with a higher risk of different types of all-cause mortality in Chinese patients with different HF subtypes. Our observations highlight that admission BP may help to improve risk stratification.

Preparation of ionic-crosslinked chitosan-based gel beads and effect of reaction conditions on drug release behaviors.

Drug-loaded chitosan (CS) beads were prepared under simple and mild condition using trisodium citrate as ionic crosslinker. The beads were further coated with poly(methacrylic acid) (PMAA) by dipping the beads in PMAA aqueous solution. The surface and cross-section morphology of these beads were observed by scanning electron microscopy and the observation showed that the coating beads had core-shell structure. In vitro release of model drug from these beads obtained under different reaction conditions was investigated in buffer medium (pH 1.8). The results showed that the rapid drug release was restrained by PMAA coating and the optimum conditions for preparing CS-based drug-loaded beads were decided through the effect of reaction conditions on the drug release behaviors. In addition, the drug release mechanism of CS-based drug-loaded beads was analyzed by Peppa's potential equation. According to this study, the ionic-crosslinked CS beads coated by PMAA could serve as suitable candidate for drug site-specific carrier in stomach.

Preparation, characterization and controlled release investigation of interpenetrating polymer networks of poly(acrylic acid)/triazole modified poly(vinyl alcohol).

A series of interpenetrating polymer networks of poly(acrylic acid) (PAA)/triazole modified poly(vinyl alcohol) (TMIPNs) were synthesized by radical polymerization in methanol at room temperature with l-ascorbic acid (Vc) and peroxide hydrogen (H2O2) as initiators and trihydroxymethyl propane glycidol ether (6360) as a crosslinker. The structures of the gels were characterized by Fourier transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC). The swelling/deswelling behavior of hydrogels was studied in different pH and different concentrations of NaCl aqueous solutions. The results showed that the TMIPNs hydrogels had excellent pH- and salt-sensitivity in the range of the investigation. The mechanism of the swelling and the deswelling was discussed and the results were confirmed further by scanning electron microscope (SEM). In addition, the controlled release behavior of TMIPNs in vitro was also studied. The effects of physical stimulus (ultraviolet ray and ultrasonic wave), salt concentration, pH value and the swelling/deswelling on the controlled released behavior were also explored.

Preparation of oxidized sodium alginate-graft-poly((2-dimethylamino) ethyl methacrylate) gel beads and in vitro controlled release behavior of BSA.

Graft copolymerization of amino group-terminated poly((2-dimethylamino) ethyl methacrylate) (PDMAEMA-NH2) onto oxidized sodium alginate (OSA) was reacted without using a catalyst. The structure of the graft was investigated by Fourier transform infrared (FT-IR) spectroscopy. The OSA-g-PDMAEMA gel beads were prepared by dropping the aqueous solution of the graft copolymer into CaCl2 aqueous solution. The effects of pH and ionic strength on the swelling behaviors of the gel beads were studied. The results indicate that the gel beads have pH and ionic strength sensitivity. Bovine serum albumin (BSA) was entrapped in the beads and the in vitro drug release profiles were established in buffer solution with pH 1.8 (HCl), pH 7.4 (KH2PO4-NaOH), and 0.9% (w/v) NaCl at 37 degrees C. The results showed that the oral delivery of proteins can be controlled by adjusting the graft percentage (G, %), pH and ionic strength. According to this study, the OSA-g-PDMAEMA gel beads could be suitable for the oral delivery of proteins.

MMTCA recognition by molecular imprinting in interpenetrating polymer network hydrogels based on poly(acrylic acid) and poly(vinyl alcohol).

A novel IPN hydrogel designed to recognize MMTCA is prepared by applying the molecular-imprinting method. The IPN is characterized by FT-IR, DSC, and SEM. Langmuir analysis shows that an equal class of adsorption is formed in the hydrogel. The adsorption equilibrium constant and the maximum adsorption capacity are evaluated, and the effect of the pH on MMTCA adsorption is discussed. The selectivity of the imprinted polymer for MMTCA is studied in aqueous solutions of MMTCA/aspirin/riboflavin. The results suggest that the MMTCA-imprinted polymer shows superior selectivity for MMTCA as compared to riboflavin and aspirin. The reproducibility of the imprinted polymer to MMTCA is also studied.