Single-cell RNA sequencing reveals the heterogeneity of epithelial cell and fibroblast cells from non- to metastatic lymph node OTSCC.

Lymph node metastasis (LNM) is one of the common features of oral tongue squamous cell carcinoma (OTSCC). LNM is also taken as a sign of advanced OTSCC and poor survival rate. Recently, single-cell RNA sequencing has been applied in investigating the heterogeneity of tumor microenvironment and discovering the potential biomarkers for helping the diagnosis and prognosticating. Pathogenesis of LNM in OTSCC remains unknown. Specifically, cancer-associated fibroblasts (CAFs) and epithelial tumor cells could foster the progression of tumors. Thus, in this study, we aimed to comprehensively analyze the roles of subpopulations of CAFs and epithelial tumor cells in lymph node metastatic OTSCC using the integration of OTSCC single-cell RNA sequencing datasets. Four distinct subtypes of CAFs, namely vascular CAFs, myofibroblast CAFs, inflammatory CAFs, and growth arrest CAFs were successfully discovered in LNM tumor and confirmed the roles of GAS and PTN pathways in the progression of tumor metastasis. In addition, NKAIN2+ epithelial cells and FN1+ epithelial cells specifically exhibited an upregulation of PTN, NRG, MIF, and SPP1 signaling pathways in the metastatic OTSCC. In doing so, we put forth some potential biomarkers that could be utilized for the purpose of diagnosing and prognosticating OTSCC during its metastatic phase and tried to confirm by immunofluorescence assays.

Three-Step Depletion Strategy of Glutathione: Tunable Metal-Organic-Framework-Engineered Nanozymes for Driving Oxidative/Nitrative Stress to Maximize Ferroptosis Therapy.

Ferroptosis is a novel type of nonapoptotic programmed cell death involving the accumulation of lipid peroxidation (LPO) to a lethal threshold. Herein, we propose tunable zeolitic imidazolate framework (ZIFs)-engineered biodegradable nanozymes for ferroptosis mediated by both reactive oxygen species (ROS) and nitrogen species (RNS). l-Arginine is utilized as an exogenous nitric oxide donor and loaded into hollow ZIFs@MnO2 artificial nanozymes, which are formed by etching ZIFs with potassium permanganate and simultaneously generating a MnO2 shell in situ. The constructed nanozymes with multienzyme-like activities including peroxidase, oxidase, and catalase can release satisfactory ROS and RNS through a cascade reaction, consequently promoting the accumulation of LPO. Furthermore, it can improve the efficiency of ferroptosis through a three-step strategy of glutathione (GSH) depletion; that is, the outer MnO2 layer consumes GSH under slightly acidic conditions and RNS downregulates SLC7A11 and glutathione reductase, thus directly inhibiting GSH biosynthesis and indirectly preventing GSH regeneration.

Neural Representations in Visual and Parietal Cortex Differentiate between Imagined, Perceived, and Illusory Experiences.

Humans constantly receive massive amounts of information, both perceived from the external environment and imagined from the internal world. To function properly, the brain needs to correctly identify the origin of information being processed. Recent work has suggested common neural substrates for perception and imagery. However, it has remained unclear how the brain differentiates between external and internal experiences with shared neural codes. Here we tested this question in human participants (male and female) by systematically investigating the neural processes underlying the generation and maintenance of visual information from voluntary imagery, veridical perception, and illusion. The inclusion of illusion allowed us to differentiate between objective and subjective internality: while illusion has an objectively internal origin and can be viewed as involuntary imagery, it is also subjectively perceived as having an external origin like perception. Combining fMRI, eye-tracking, multivariate decoding, and encoding approaches, we observed superior orientation representations in parietal cortex during imagery compared with perception, and conversely in early visual cortex. This imagery dominance gradually developed along a posterior-to-anterior cortical hierarchy from early visual to parietal cortex, emerged in the early epoch of imagery and sustained into the delay epoch, and persisted across varied imagined contents. Moreover, representational strength of illusion was more comparable to imagery in early visual cortex, but more comparable to perception in parietal cortex, suggesting content-specific representations in parietal cortex differentiate between subjectively internal and external experiences, as opposed to early visual cortex. These findings together support a domain-general engagement of parietal cortex in internally generated experience.SIGNIFICANCE STATEMENT How does the brain differentiate between imagined and perceived experiences? Combining fMRI, eye-tracking, multivariate decoding, and encoding approaches, the current study revealed enhanced stimulus-specific representations in visual imagery originating from parietal cortex, supporting the subjective experience of imagery. This neural principle was further validated by evidence from visual illusion, wherein illusion resembled perception and imagery at different levels of cortical hierarchy. Our findings provide direct evidence for the critical role of parietal cortex as a domain-general region for content-specific imagery, and offer new insights into the neural mechanisms underlying the differentiation between subjectively internal and external experiences.

Lysine-372-dependent SUMOylation inhibits the enzymatic activity of glutamine synthases.

Glutamine synthetase (GS) is a crucial enzyme involved in de novo synthesis of glutamine and participates in several biological processes, including nitrogen metabolism, nucleotide synthesis, and amino acid synthesis. Post-translational modification makes GS more adaptable to the needs of cells, and acetylation modification of GS at double sites has attracted considerable attention. Despite very intensive research, how SUMOylation affects GS activity at a molecular level remains unclear. Here, we report that previously undiscovered GS SUMOylation which is deficient mutant K372R of GS exhibits more bluntness under glutamine starvation. Mechanistically, glutamine deprivation triggers the GS SUMOylation, and this SUMOylation impaired the protein stability of GS, within a concomitant decrease in enzymatic activity. In addition, we identified SAE1, Ubc9, and PIAS1 as the assembly enzymes of GS SUMOylation respectively. Furthermore, Senp1/2 functions as a SUMO-specific protease to reverse the SUMOylation of GS. This study provides the first evidence that SUMOylation serves as a regulatory mechanism for determining the GS enzymatic activity, contributing to understanding the GS regulation roles in various cellular and pathophysiological processes.

The mediating effect of perceived social support between family resilience and meaning in life in breast cancer patients.

PURPOSE: The beneficial effects of family resilience and meaning in life on patients are established, but limited is known for the effect of perceived social support. We aim to investigate the impact of family resilience on the meaning of life among Chinese patients with breast cancer (BC) and to further detect whether perceived social support mediated this association. METHODS: From February to June 2022, we conducted this cross-sectional study with 276 women who were diagnosed with BC in a tertial hospital in Guangdong province, China. The Chinese version of Meaning in Life Scale (C-MiLS) was used to measure the meaning in life. The Chinese version of the family resilience assessment scale (C-FRAS) and the perceived social support scale (PSSS) were adopted to obtain the family resilience and perceived social support, respectively. The mediating effect of perceived spousal support was estimated using the bootstrapped confidence interval (CI) via IBM SPSS AMOS 22.0. RESULTS: The mean scores were 60.79 ± 11.63 for meaning in life, 82.08 ± 11.48 for family resilience, and 62.72 ± 12.19 for perceived social support, respectively. Our results indicated the positive correlations of meaning in life with family resilience (ß = 0.822, P < 0.05) and perceived social support (ß = 0.886, P < 0.05). The perceived social support exerted the mediating effect in the relationship between family resilience and meaning in life (ß = 0.368 [95%CI, 0.274, 0.450], P < 0.001), accounting for 54.6% of the variance in meaning in life. CONCLUSIONS: Our findings highlight that family resilience and perceived social support should be enhanced for BC patients to improve their meaning in life. In particular, the association between family resilience and meaning in life was positively mediated by perceived social support. Thus, interventions for improving family resilience and perceived social support might be useful in easing psychological distress and improving meaning in life in individuals with BC.

Altered controllability of white matter networks and related brain function changes in first-episode drug-naive schizophrenia.

Understanding how structural connectivity alterations affect aberrant dynamic function using network control theory will provide new mechanistic insights into the pathophysiology of schizophrenia. The study included 140 drug-naive schizophrenia patients and 119 healthy controls (HCs). The average controllability (AC) quantifying capacity of brain regions/networks to shift the system into easy-to-reach states was calculated based on white matter connectivity and was compared between patients and HCs as well as functional network topological and dynamic properties. The correlation analysis between AC and duration of untreated psychosis (DUP) were conducted to characterize the controllability progression pattern without treatment effects. Relative to HCs, patients exhibited reduced AC in multiple nodes, mainly distributed in default mode network (DMN), visual network (VN), and subcortical regions, and increased AC in somatomotor network. These networks also had impaired functional topology and increased temporal variability in dynamic functional connectivity analysis. Longer DUP was related to greater reductions of AC in VN and DMN. The current study highlighted potential structural substrates underlying altered functional dynamics in schizophrenia, providing a novel understanding of the relationship of anatomic and functional network alterations.

The Efficacy of Tiaoshen Acupuncture in Traditional Chinese Medicine for Insomnia Treatment: A Systematic Review and Meta-analysis.

Background: In recent years, Tiaoshen acupuncture in Traditional Chinese Medicine (TCM) has been employed for treating patients with insomnia, but the clinical efficacy remains to be substantiated. Objective: To assess the efficacy and safety of acupuncture in treating insomnia using the Tiaoshen method in TCM. Design: A systematic review and meta-analysis was conducted. Setting: The research was conducted in Shenzhen. Methods: Electronic databases, including Chinese National Knowledge Infrastructure (CNKI), Wanfang, SinoMed, Weipu, PubMed, Web of Science, EMBASE, and Cochrane databases, were retrieved up to September 15, 2023. Randomized controlled trials (RCTs) meeting inclusion criteria were screened. Quality assessment of included articles was performed using the Cochrane Risk of Bias tool. Valid data were then extracted and analyzed via meta-analysis using Review Manager 5.3. The study was registered in the International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY), 2023100051. Results: A total of 13 articles were included, comprising 849 patients with insomnia (diagnosed as chronic insomnia or primary insomnia). Meta-analysis results indicated that acupuncture with the Tiaoshen method could decrease the Pittsburgh Sleep Quality Index (PSQI) score [RR=-3.03, 95% CI (-3.73, -2.33), P < .00001], hyperarousal (HAS) scale score [RR=-7.75, 95% CI (-12.29, -3.22), P < .0008], and fatigue scale-14 (FS-14) score [RR=-2.11, 95% CI (-2.83, -1.38), P < .00001] compared with superficial acupuncture on non-effective acupoints or conventional acupuncture manipulation. Additionally, acupuncture with the Tiaoshen method demonstrated safety. However, the funnel plot suggested the presence of publication bias. Conclusions: Acupuncture with the Tiaoshen method could enhance sleep quality and efficiency. Due to the low quality of some literature, further high-quality RCTs are needed to improve the level of evidence.

Global warming potential assessment under reclaimed water and livestock wastewater irrigation coupled with co-application of inhibitors and biochar.

The application of nitrification inhibitors (nitrapyrin) and urease inhibitors (N-(N-butyl) thiophosphoric triamide) under conventional water resources has been considered as an effective means to improve nitrogen utilization efficiency and mitigate soil greenhouse gas emissions. However, it is not known whether the inhibitors still have an inhibitory effect under unconventional water resources (reclaimed water and livestock wastewater) irrigation and whether their use in combination with biochar improves the mitigation effect. Therefore, unconventional water resources were used for irrigation, with groundwater (GW) control. Nitrapyrin and N-(N-butyl) thiophosphoric triamide were used alone or in combination with biochar in a pot experiment, and CO2, N2O, and CH4 emissions were measured. The results showed that irrigation of unconventional water resources exacerbated global warming potential (GWP). All exogenous substance treatments increased CO2 and CH4 emissions and suppressed N2O emissions, independent of the type of water, compared to no substances (NS). The inhibitors were ineffective in reducing the GWP whether or not in combination with biochar, and the combined application of inhibitors with biochar further increased the GWP. This study suggests that using inhibitors and biochar in combination to regulate the greenhouse effect under unconventional water resources irrigation should be done with caution.

The stress response of tetracycline resistance genes and bacterial communities under the existence of microplastics in typical leachate biological treatment system.

Landfill leachate is an important source of microplastics (MPs) and antibiotic-resistance genes (ARGs). Here, in the presence of polystyrene MPs (PS-MPs) and polyethylene MPs (PE-MPs), the nitrogen and phosphorus removal effect and sludge structure performance were affected in an anaerobic-anoxic-aerobic system, a typical biological leachate treatment process. The abundance of tetracycline-resistance genes (tet genes) in biofilms on the two types of MP was significantly higher than that in the leachate and sludge, and the load on PE-MPs was higher than that on PS-MPs because of the porous structure of PE-MPs. Aging of the MPs increased their surface roughness and abundance of oxygen-containing functional groups and shaped the profile of ARGs in the MP biofilms. The biofilm biomass and growth rate on the two types of MP increased with the incubation time in the first 30 days, and was affected by environmental factors. Structural equation models and co-occurrence network analysis demonstrated that the MPs indirectly affected the spectrum of ARGs by affecting biofilm formation, and, to a lesser extent, had a direct impact on the selective enrichment of ARGs. We discuss the mechanisms of the relationships between MPs and ARGs in the leachate treatment system, which will have guiding significance for future research. Our data on the colonization of microorganisms and tet genes in MPs biofilms provide new evidence concerning the accumulation and transmission of these ARGs, and are important for understanding the mechanisms of MPs in spreading pollution.

Identification of a distal enhancer that determines the expression pattern of acute phase marker C-reactive protein.

C-reactive protein (CRP) is a major acute phase protein and inflammatory marker, the expression of which is largely liver specific and highly inducible. Enhancers are regulatory elements critical for the precise activation of gene expression, yet the contributions of enhancers to the expression pattern of CRP have not been well defined. Here, we identify a constitutively active enhancer (E1) located 37.7 kb upstream of the promoter of human CRP in hepatocytes. By using chromatin immunoprecipitation, luciferase reporter assay, in situ genetic manipulation, CRISPRi, and CRISPRa, we show that E1 is enriched in binding sites for transcription factors STAT3 and C/EBP-ß and is essential for the full induction of human CRP during the acute phase. Moreover, we demonstrate that E1 orchestrates with the promoter of CRP to determine its varied expression across tissues and species through surveying activities of E1-promoter hybrids and the associated epigenetic modifications. These results thus suggest an intriguing mode of molecular evolution wherein expression-changing mutations in distal regulatory elements initiate subsequent functional selection involving coupling among distal/proximal regulatory mutations and activity-changing coding mutations.

Vestibular rehabilitation therapy on balance and gait in patients after stroke: a systematic review and meta-analysis.

BACKGROUND: There is limited evidence to support the use of vestibular rehabilitation therapy (VRT) on improving balance and gait in patients after stroke. This systematic review aimed to evaluate the effects of VRT in addition to usual rehabilitation compared with usual rehabilitation on improving balance and gait for patients after stroke. METHODS: This review followed the Preferred Reporting Items for Systematic reviews and Meta-Analysis statement guidelines. Ten electronic databases were searched up to 1 June 2023 without restrictions in language and publication status. The PEDro scale and the Grading of Recommendations Assessment Development, and Evaluation were used to evaluate the risk of bias and the certainty of evidence. The meta-analysis was conducted with Review Manager 5.3. RESULTS: Fifteen randomised controlled trials with 769 participants were included. PEDro scale was used to assess the risk of bias with a mean score of 5.9 (0.7). VRT was effective in improving balance for patients after stroke (SMD = 0.59, 95% CI (0.40, 0.78), p < 0.00001), particularly for patients after stroke that occurred within 6 months (SMD = 0.56, 95% CI (0.33, 0.79), p < 0.00001) with moderate certainty of evidence. Subgroup analysis showed that VRT provided as gaze stability exercises combined with swivel chair training (SMD = 0.85, 95% CI (0.48, 1.22), p < 0.00001) and head movements (SMD = 0.75, 95% CI (0.43, 1.07), p < 0.00001) could significantly improve balance. Four-week VRT had better effect on balance improvement (SMD = 0.64, 95% CI (0.40, 0.89), p < 0.00001) than the less than 4-week VRT. The pooled mean difference of values of Timed Up-and-Go test showed that VRT could significantly improve gait function for patients after stroke (MD = -4.32, 95% CI (-6.65, -1.99), p = 0.0003), particularly for patients after stroke that occurred within 6 months (MD = -3.92, 95% CI (-6.83, -1.00), p = 0.008) with moderate certainty of evidence. CONCLUSIONS: There is moderate certainty of evidence supporting the positive effect of VRT in improving balance and gait of patients after stroke. TRIAL REGISTRATION: PROSPERO CRD42023434304.

A c-MET-Targeted Topical Fluorescent Probe cMBP-ICG Improves Oral Squamous Cell Carcinoma Detection in Humans.

INTRODUCTION: The postoperative survival of oral squamous cell carcinoma (SCC) relies on precise detection and complete resection of original tumors. The mucosal extension of the tumor is evaluated visually during surgery, but small and flat foci are difficult to detect. Real-time fluorescence imaging may improve detection of tumor margins. MATERIALS AND METHODS: In the current study, a peptide-based near-infrared (NIR) fluorescence dye, c-MET-binding peptide-indocyanine green (cMBP-ICG), which specifically targets tumor via c-MET binding, was synthetized. A prospective pilot clinical trial then was conducted with oral SCC patients and intraoperatively to assess the feasibility of cMBP-ICG used to detect tumors margins. Fluorescence was histologically correlated to determine sensitivity and specificity. RESULTS: The immunohistochemistry (IHC) results demonstrated increased c-Met expression in oral SCC compared with normal mucosa. Tumor-to-background ratios ranged from 2.71 ± 0.7 to 3.11 ± 1.2 in different concentration groups. From 10 patients with oral SCC, 60 specimens were collected from tumor margins. The sensitivity and specificity of discriminative value derived from cMBP-ICG application in humans were respectively 100% and 75%. CONCLUSIONS: Topical application of cMBP-ICG is feasible and safe for optimizing intraoperative visualization and tumor margin detection in oral SCC patients, which could clinically increase the probability of complete resections and improve oncologic outcomes.

Prognostic implications of obstructive sleep apnea in patients with acute coronary syndrome stratified by homocysteine level: a prospective cohort study.

BACKGROUND: Sporadic studies have examined the impact of OSA on ACS patients by homocysteine (Hcy) level. This study attempted to comprehensively evaluate the effects of the interaction between Hcy and OSA on long-term cardiovascular outcomes in ACS patients. METHODS: In this prospective, large-scale cohort study, 2160 patients admitted for ACS were recruited to undergo overnight sleep monitoring. OSA was diagnosed when apnea-hypopnea index ≥ 15 events/h. Patients with normohomocysteinemia (NHcy) were defined as having serum Hcy ≤ 15 µmol/L, and the others had hyperhomocysteinemia (HHcy). The primary endpoint was major adverse cerebrocardiovascular event (MACCE), a composite of cardiovascular death, myocardial infarction, stroke, ischemia-driven revascularization and hospitalization for unstable angina and heart failure. RESULTS: A total of 1553 eligible ACS patients (average age: 56.3 ± 10.5 years) were enrolled, among which 819 (52.7%) had OSA, and 988 (63.6%) were with NHcy. OSA did not significantly affect the level of Hcy. During a median follow-up of 2.9 (1.6, 3.5) years, after adjustment for clinical confounders, OSA was associated with increased risk for MACCE occurrence versus non-OSA ones in ACS patients with NHcy (adjusted hazard ratio [HR] = 1.36, 95% confidence interval [CI] 1.02-1.83, P = 0.039), but not in those with HHcy (adjusted HR = 0.92, 95%CI 0.62-1.36, P = 0.668). There was an absence of interaction between homocysteine level and OSA in relation to MACCE (interaction P = 0.106). CONCLUSIONS: OSA was independently associated with worse prognosis in ACS patients with NHcy. Our study emphasized the necessity to identify potential presence of OSA in such a population. TRIAL REGISTRATION: ClinicalTrials.gov; Number: NCT03362385; URL: www. CLINICALTRIALS: gov .

Integrin signaling in cancer: bidirectional mechanisms and therapeutic opportunities.

Integrins are transmembrane receptors that possess distinct ligand-binding specificities in the extracellular domain and signaling properties in the cytoplasmic domain. While most integrins have a short cytoplasmic tail, integrin ß4 has a long cytoplasmic tail that can indirectly interact with the actin cytoskeleton. Additionally, 'inside-out' signals can induce integrins to adopt a high-affinity extended conformation for their appropriate ligands. These properties enable integrins to transmit bidirectional cellular signals, making it a critical regulator of various biological processes.Integrin expression and function are tightly linked to various aspects of tumor progression, including initiation, angiogenesis, cell motility, invasion, and metastasis. Certain integrins have been shown to drive tumorigenesis or amplify oncogenic signals by interacting with corresponding receptors, while others have marginal or even suppressive effects. Additionally, different α/ß subtypes of integrins can exhibit opposite effects. Integrin-mediated signaling pathways including Ras- and Rho-GTPase, TGFß, Hippo, Wnt, Notch, and sonic hedgehog (Shh) are involved in various stages of tumorigenesis. Therefore, understanding the complex regulatory mechanisms and molecular specificities of integrins are crucial to delaying cancer progression and suppressing tumorigenesis. Furthermore, the development of integrin-based therapeutics for cancer are of great importance.This review provides an overview of integrin-dependent bidirectional signaling mechanisms in cancer that can either support or oppose tumorigenesis by interacting with various signaling pathways. Finally, we focus on the future opportunities for emergent therapeutics based on integrin agonists. Video Abstract.

Clinical outcomes of obstructive sleep apnea in patients with acute coronary syndrome in relation to hyperuricemia status.

The clinical outcome of obstructive sleep apnea in patients with acute coronary syndrome in relation to hyperuricemia is still unclear. We aimed to explore the clinical prognosis of obstructive sleep apnea in patients with acute coronary syndrome in relation to hyperuricemia status. This was a prospective cohort study. We included consecutively eligible patients with acute coronary syndrome who underwent cardiorespiratory polygraphy between June 2015 and January 2020. According to apnea-hypopnea index ≥ 15 events per hr and serum uric acid level, the population was divided into four groups: hyperuricemia with obstructive sleep apnea; hyperuricemia with non-obstructive sleep apnea; no hyperuricemia with obstructive sleep apnea; and no hyperuricemia with non-obstructive sleep apnea. The primary endpoint was major adverse cardiovascular and cerebrovascular events, including cardiovascular death, myocardial infarction, stroke, ischaemia-driven revascularization, and readmission for unstable angina or heart failure. Spearman correlation analysis and Cox regression model were mainly used to estimate the data. The median follow-up was 2.9 years. Among 1925 patients with acute coronary syndrome, 29.6% had hyperuricemia and 52.6% had obstructive sleep apnea. Uric acid was negatively correlated with minimum arterial oxygen saturation and mean arterial oxygen saturation, and positively correlated with apnea-hypopnea index, oxygen desaturation index and the duration of time with arterial oxygen saturation < 90% (p < 0.001). During 2.9 (1.5, 3.6) years of follow-up, obstructive sleep apnea was associated with an increased risk of major adverse cardiovascular and cerebrovascular events in patients with hyperuricemia (23.5% versus 13.4%; adjusted hazard ratio: 1.834; 95% confidence interval: 1.192-2.821, p = 0.006), but not in patients without hyperuricemia (21.9% versus 19.2%; adjusted hazard ratio: 1.131; 95% confidence interval: 0.880-1.453, p = 0.336). There was a correlation between uric acid levels and sleep respiratory indicators. Obstructive sleep apnea was associated with increased risk of major adverse cardiovascular and cerebrovascular events in patients with acute coronary syndrome with hyperuricemia, but not in patients without hyperuricemia.

Pde5 Inhibition Reduced Blood Pressure and Alleviated Target Organ Damage in Chronic Intermittent Hypoxia.

ABSTRACT: The role of phosphodiesterase 5 (Pde5) in obstructive sleep apnea (OSA) induced damage remains unclear. Our study aimed to investigate the role of Pde5 in chronic intermittent hypoxia (CIH) model. C57BL/6J wild-type (WT) mice (n=48) and Pde5 knockout (Pde5-/-) mice (n=24) were randomly assigned to CIH group and room air (RA) group. After 6 weeks, some WT mice (n=24) in CIH group were given sildenafil or saline gavage for another 4 weeks. Blood pressure was regularly measured during the experiment. Echocardiography was used to estimate cardiac function. We collected organs from each group of mice and measured their physical indicators. Histochemical staining was used to explore the size of cardiomyocyte and fibrosis area of various organs. Cyclic guanosine monophosphate (cGMP) and Malondialdehyde (MDA) concentrations in serum were measured by ELISA assay. Compared to the RA-treated group, the 6-week CIH resulted in a significant increase in blood pressure, altered heart structure and reduced serum cGMP in WT mice. Pde5-/- mice and sildenafil intragastric administration significantly reduced systolic blood pressure in CIH condition and attenuated the damage of target organs. In CIH model, we found that the cardiomyocyte size and fibrosis area of heart and kidney significantly reduced in Pde5-/- groups. Besides, endogenous and exogenous inhibition of Pde5 reduced MDA level and inflammatory and oxidative stress markers expression in CIH condition. In the present study, we found that Pde5 inhibition could reduce blood pressure and alleviate target organ damage in the CIH model, which may be mediated through the oxidative stress pathway.

The impact of obstructive sleep apnea and comorbidity status on cardiovascular outcomes in patients with acute coronary syndrome.

BACKGROUND AND AIMS: The association of comorbidities on the prognosis of patients with acute coronary syndrome (ACS) was well documented. However, the impact of obstructive sleep apnea (OSA) on this association has been less studied. METHODS AND RESULTS: Between June 2015 to Jan 2020, we included consecutively eligible patients with ACS who underwent cardiorespiratory polygraphy. The definition of OSA was apnea-hypopnea index (AHI) ≥15 events/hour. Charlson Comorbidity Index (CCI) was used to evaluate the comorbidities. The primary endpoint was major adverse cardiovascular and cerebrovascular events (MACCE), including cardiovascular death, myocardial infarction, stroke, ischemia-driven revascularization, and hospitalization for unstable angina or heart failure. In the 1927 ACS patients, 1014 (52.6%) had OSA. The prevalence of the mild (CCI = 0), moderate (CCI = 1-2), and severe (CCI≥3) comorbidity were 23.6%, 65.9%, and 10.5%, respectively. During a median follow-up of 2.9 (1.5, 3.6) years, compared with patients without OSA, the presence of OSA increased the risk of MACCE in the moderate comorbidity group (22.6% vs. 17.5%; adjusted HR: 1.327; 95% CI: 1.019-1.728, p = 0.036) and severe comorbidity group (36.2% vs. 18.6%; adjusted HR: 2.194; 95% CI: 1.170-4.117, p = 0.014). There was no significant difference between OSA and non-OSA patients in the mild comorbidity group. CONCLUSION: Among ACS patients, OSA was associated with an increased risk of subsequent events in the moderate and severe comorbidity groups but not in the mild comorbidity group. ACS patients with comorbidities should not be overlooked for OSA screening.

Emerging Strategies for Enhancing Propionate Conversion in Anaerobic Digestion: A Review.

Anaerobic digestion (AD) is a triple-benefit biotechnology for organic waste treatment, renewable production, and carbon emission reduction. In the process of anaerobic digestion, pH, temperature, organic load, ammonia nitrogen, VFAs, and other factors affect fermentation efficiency and stability. The balance between the generation and consumption of volatile fatty acids (VFAs) in the anaerobic digestion process is the key to stable AD operation. However, the accumulation of VFAs frequently occurs, especially propionate, because its oxidation has the highest Gibbs free energy when compared to other VFAs. In order to solve this problem, some strategies, including buffering addition, suspension of feeding, decreased organic loading rate, and so on, have been proposed. Emerging methods, such as bioaugmentation, supplementary trace elements, the addition of electronic receptors, conductive materials, and the degasification of dissolved hydrogen, have been recently researched, presenting promising results. But the efficacy of these methods still requires further studies and tests regarding full-scale application. The main objective of this paper is to provide a comprehensive review of the mechanisms of propionate generation, the metabolic pathways and the influencing factors during the AD process, and the recent literature regarding the experimental research related to the efficacy of various strategies for enhancing propionate biodegradation. In addition, the issues that must be addressed in the future and the focus of future research are identified, and the potential directions for future development are predicted.

A multimodal meta-analysis of regional structural and functional brain alterations in type 2 diabetes.

Neuroimaging studies have identified brain structural and functional alterations of type 2 diabetes mellitus (T2DM) patients; however, there is no systematic information on the relations between abnormalities in these two domains. We conducted a multimodal meta-analysis of voxel-based morphometry and regional resting-state functional MRI studies in T2DM, including fifteen structural datasets (693 patients and 684 controls) and sixteen functional datasets (378 patients and 358 controls). We found, in patients with T2DM compared to controls, conjoint decreased regional gray matter volume (GMV) and altered intrinsic activity mainly in the default mode network including bilateral superior temporal gyrus/Rolandic operculum, left middle and inferior temporal gyrus, and left supramarginal gyrus; decreased GMV alone in the limbic system; and functional abnormalities alone in the cerebellum, insula, and visual cortex. This meta-analysis identified complicated patterns of conjoint and dissociated brain alterations in T2DM patients, which may help provide new insight into the neuropathology of T2DM.

Subtypes of schizophrenia identified by multi-omic measures associated with dysregulated immune function.

Epigenetic modifications are plausible molecular sources of phenotypic heterogeneity across schizophrenia patients. The current study investigated biological heterogeneity in schizophrenia using peripheral epigenetic profiles to delineate illness subtypes independent of their phenomenological manifestations. We applied epigenome-wide profiling with a DNA methylation array from blood samples of 63 schizophrenia patients and 59 healthy controls. Non-negative matrix factorization (NMF) and k-means clustering were performed to identify DNA methylation-related patient subtypes. The validity of the partition was tested by assessing the profile of the T cell receptor (TCR) repertoires. The uniqueness of the identified subtypes in relation to brain structural and clinical measures were evaluated. Two distinct patterns of DNA methylation profiles were identified in patients. One subtype (60.3% of patients) showed relatively limited changes in methylation levels and cell composition compared to controls, while a second subtype (39.7% of patients) exhibited widespread methylation level alterations among genes enriched in immune cell activity, as well as a higher proportion of neutrophils and lower proportion of lymphocytes. Differentiation of the two patient subtypes was validated by TCR repertoires, which paralleled the partition based on DNA methylation profiles. The subtype with widespread methylation modifications had higher symptom severity, performed worse on cognitive measures, and displayed greater reductions in fractional anisotropy of white matter tracts and evidence of gray matter thickening compared to the other subtype. Identification of a distinct subtype of schizophrenia with unique molecular, cerebral, and clinical features provide a novel parcellation of the schizophrenia syndrome with potential to guide development of individualized therapeutics.