Propofol improves survival in a murine model of sepsis via inhibiting Rab5a-mediated intracellular trafficking of TLR4.

BACKGROUND: Propofol is a widely used anesthetic and sedative, which has been reported to exert an anti-inflammatory effect. TLR4 plays a critical role in coordinating the immuno-inflammatory response during sepsis. Whether propofol can act as an immunomodulator through regulating TLR4 is still unclear. Given its potential as a sepsis therapy, we investigated the mechanisms underlying the immunomodulatory activity of propofol. METHODS: The effects of propofol on TLR4 and Rab5a (a master regulator involved in intracellular trafficking of immune factors) were investigated in macrophage (from Rab5a-/- and WT mice) following treatment with lipopolysaccharide (LPS) or cecal ligation and puncture (CLP) in vitro and in vivo, and peripheral blood monocyte from sepsis patients and healthy volunteers. RESULTS: We showed that propofol reduced membrane TLR4 expression on macrophages in vitro and in vivo. Rab5a participated in TLR4 intracellular trafficking and both Rab5a expression and the interaction between Rab5a and TLR4 were inhibited by propofol. We also showed Rab5a upregulation in peripheral blood monocytes of septic patients, accompanied by increased TLR4 expression on the cell surface. Propofol downregulated the expression of Rab5a and TLR4 in these cells. CONCLUSIONS: We demonstrated that Rab5a regulates intracellular trafficking of TLR4 and that propofol reduces membrane TLR4 expression on macrophages by targeting Rab5a. Our study not only reveals a novel mechanism for the immunomodulatory effect of propofol but also indicates that Rab5a may be a potential therapeutic target against sepsis.

Bioinformatic Analysis of lncRNA Mediated CeRNA Network in Intestinal Ischemia/Reperfusion Injury.

INTRODUCTION: Recently, accumulating studies have reported the roles of competitive endogenous RNA (ceRNA) networks in ischemia/reperfusion (I/R) injury in several organs, including the liver, kidney, heart, brain, and intestine. However, the functions and mechanisms of long noncoding RNAs (lncRNAs)-which serve as ceRNA networks in intestinal I/R injury-remain elusive. METHODS: RNA expression data were retrieved from the National Center for Biotechnology Information-Gene Expression Omnibus database. Differentially expressed microRNAs (miRNAs) (miDEGs) were explored between the sham and intestinal I/R injury samples. Next, targeted lncRNAs and messenger RNAs in the database were matched based on miDEGs. Hub ceRNA networks were constructed and visualized via Cytoscape. Intersection analysis was performed to screen mDEGs between two datasets. Finally, the vital nodes of the ceRNA networks were validated by quantitative PCR. RESULTS: A total of 189 miDEGs were identified. Forty miRNAs were found to be associated with 240 predicted target genes from miRWalk 3.0. The ceRNA network was constructed with 10 miRNAs, including the 1700020114Rik/mmu-miR-7a-5p/Klf4 axis. Furthermore, the expression of lncRNA 1700020114Rik (P < 0.05) and messenger RNA Klf4 (P < 0.01) was markedly decreased in mouse models of intestinal I/R injury, whereas the expression level of mmu-miR-7a-5p was significantly increased (P < 0.05). CONCLUSIONS: The results provide novel insights into the molecular mechanism of ceRNA networks in intestinal I/R injury and highlight the potential of the 170002700020114Rik/mmu-miR-7a-5p/Klf4 axis in the prevention and treatment of intestinal I/R injury.

Sex-Specific Associations Between Preoperative Hemoglobin and Outcomes After Major Noncardiac Surgery: A Retrospective Cohort Study.

BACKGROUND: Preoperative anemia is an established risk factor for morbidity and mortality after surgery. Men and women have different hemoglobin concentrations and are at different risks of postoperative complications. However, sex-stratified analysis on the association between preoperative hemoglobin and outcomes after noncardiac surgery has been limited in previous studies. METHODS: This was a retrospective cohort study of adult patients undergoing elective major noncardiac surgery in a large academic hospital. The primary outcome was a collapsed composite of postoperative mortality or cardiovascular, renal, pulmonary, and infectious complications during hospitalization. Sex-specific univariable associations between preoperative hemoglobin and the composite outcome were visualized using moving-average and cubic-spline smoothing plots. Multivariable regression models adjusting for patient demographics, comorbidities, medication uses, laboratory tests, and anesthesia/surgery features were used to estimate confounder-adjusted associations. Restricted cubic spline and piecewise linear functions were used to assess the possible nonlinear relationships between preoperative hemoglobin and the outcomes. The interaction between patient sex and hemoglobin on outcomes was assessed using a likelihood-ratio test. RESULTS: We included 22,550 patients, with 6.7% (622 of 9268) of women and 9.7% (1293 of 13,282) of men developing the primary outcome. Lower preoperative hemoglobin was associated with a higher incidence of the primary composite outcome in both men and women. Nonlinearity for the association was not statistically significant in either women ( P = .539) or men ( P = .165). The multivariable-adjusted odds ratios per 1 g/dL increase in hemoglobin were 0.93 (95% confidence interval [CI], 0.87-0.98; P = .013) for women and 0.94 (95% CI, 0.90-0.97; P < .001) for men, with no interaction by sex ( Pinteraction = .923). No hemoglobin thresholds were confirmed at which the associations with the primary outcome changed significantly. CONCLUSIONS: Low preoperative hemoglobin was associated with a higher risk of complications or mortality after elective noncardiac surgery in both men and women. No differences in the strength of associations between sexes were found. Further studies are needed to assess whether these associations are linear or there are sex-specific thresholds of preoperative hemoglobin concentrations below which postoperative risks begin to increase.

Predictive and Preventive Potential of Preoperative Gut Microbiota in Chronic Postoperative Pain in Breast Cancer Survivors.

BACKGROUND: Evidence suggests a potential relationship between gut microbiota and chronic postoperative pain (CPP). This study aimed to explore the predictive and preventive potential of preoperative gut microbiota in CPP in breast cancer survivors. METHODS: In the clinical experiments, we designed a nested case-control study to compared preoperative gut microbiota of breast cancer survivors with and without CPP using 16s rRNA sequencing. The primary outcome was clinically meaningful pain in or around the operative area 3 months after surgery. Logistic prediction models based on previously identified risk factors for CPP in breast cancer survivors were tested with and without differential bacteria to evaluate the model's potential for improvement with the addition of gut microbiota information. In the animal experiments, preoperative fecal microbiota was transplanted from patients with and without CPP to mice, and a spared nerve injury (SNI) model was used to mimic neuropathic pain in CPP. Mechanical hyperalgesia and the expression of markers of spinal microglia and peroxisome proliferator-activated receptor-γ (PPAR-γ) were assessed. RESULTS: Sixty-six CPP patients and 66 matched controls were analyzed. Preoperative gut microbiota composition was significantly different in the 2 groups at phylus, family, and genera levels. The discrimination of the clinical prediction model (determined by area under the receiver operating characteristic curve) improved by 0.039 and 0.099 after the involvement of differential gut microbiota at the family and genus levels, respectively. After fecal microbiota transplantation (FMT), "CPP microbiota" recipient mice exhibited significantly increased mechanical hyperalgesia and decreased expression of Ppar-γ and arginase-1 (Arg-1) in the spinal cord. CONCLUSIONS: Preoperative gut microbiota has the potential to predict and prevent the development of CPP and plays a causal role in its development via the PPAR-γ-microglia pathway in the spinal cord. Thus, it could be targeted to develop a prevention strategy for CPP in breast cancer survivors.

TTP488 ameliorates NLRP3-associated inflammation, viability, apoptosis, and ROS production in an Alzheimer's disease cell model by mediating the JAK1/STAT3/NFκB/IRF3 pathway.

Alzheimer's disease (AD), the most prevalent dementia, is identified as a neurodegenerative disease arising from a degenerative disturbance in the central nervous system. A previous study reported that TTP488 could ameliorate symptoms in patients with mild AD, but the underlying mechanisms need to be studied further. Therefore, the objective of this study was to explore the role of TTP488 in the development of an AD cell model. Administration of TTP448 in an AD cell model reduced the expression of pro-inflammatory cytokines [interleukin (IL)-1ß, IL-6, and TNF-α], reversed the inhibitory role of Aß on cell proliferation and viability, and decreased Aß-triggered cell apoptosis and reactive oxygen species (ROS) production. Furthermore, Aß treatment induced activation of JAK1/STAT3/NFκB/IRF3 pathway as well as NLRP3 expression, and TTP488 administration partially reversed the activation of this pathway and NLRP3 expression. Use of WP1160, a STAT3 agonist, re-activated the downstream STAT3/NFκB/IRF3 pathway and NLRP3 expression. Moreover, we found that WP1160 counteracted the role of TTP488 in Aß-induced SH-SY5Y cells' viability, inflammation, apoptosis, and ROS production. SIGNIFICANCE OF THE STUDY: This study explores the role of TTP488 in the development of an Alzheimer's disease (AD) cell model and confirms that TTP488 administration notably promotes cell proliferation and reduces apoptosis, inflammatory factor expression, and reactive oxygen species generation. Further, this study suggests that the NLRP3-relevant JAK1/STAT3/P65/IRF3 signalling pathway is related to AD pathogenesis.

Relationships of sleep disturbance, intestinal microbiota, and postoperative pain in breast cancer patients: a prospective observational study.

PURPOSE: Our study was designed to examine the possible relationship between gut microbiota, sleep disturbances, and acute postoperative pain. METHODS: Using 16S rRNA sequencing, we analyzed preoperative fecal samples from women undergoing breast cancer surgery. Preoperative sleep disturbance was evaluated with the Pittsburgh Sleep Quality Index (PSQI) questionnaire. Peak and average pain at rest and movement were evaluated 24 h after surgery, using a numerical rating scale (NRS). Preoperative symptoms of depression and anxiety were assessed with the Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7), respectively. Inflammation was measured using white blood cell and neutrophil counts, together with platelet-lymphocyte ratio, and neutrophil-lymphocyte ratio. RESULTS: Preoperative sleep disturbance was associated with more severe acute postoperative pain. At the phylum level, women with poor sleep quality had higher relative abundance of Firmicutes (p = 0.021) and lower relative abundance of Bacteroidetes (p = 0.013). At the genus level, women with poor sleep quality harbored higher relative abundance of Acidaminococcus and lower relative abundance of several genera. The genus Alloprevotella was negatively associated with peak pain at movement during the first 24 h (r = - 0.592, p < 0.001). The genus Desulfovibrio was negatively associated with symptoms of anxiety (r = - 0.448, p = 0.006). However, partial correlations suggested that the relationship between Alloprevotella and peak pain at movement during the first 24 h was not statistically significant after controlling for sleep (r = - 0.134, p = 0.443). CONCLUSION: These findings suggest that the changed gut microbiota may be involved in sleep-pain interaction and could be applied as a potential preventive method for postoperative pain. TRIAL REGISTRATION: The present clinical study has been registered on Chinese Clinical Trial Registry ( www.chictr.org.cn ); the clinical trial registration number is ChiCTR1900021730; the date of registration is March 7, 2019.

An increase in neutrophil-to-lymphocyte ratio predicts poor functional outcomes in older patients with acute ischemic stroke: a retrospective study.

The neutrophil-to-lymphocyte ratio has emerged as a predictor of functional outcome in stroke patients. However, less is known about the value of neutrophil to lymphocyte ratio in older patients. This clinical study evaluated whether the neutrophil-to-lymphocyte ratio is associated with stroke severity and early clinical outcomes in older patients with acute ischemic stroke. This observational study included acute ischemic stroke patients aged 80 years or older. The patients were divided into three groups, and information was collected, including demographic, clinical and laboratory data. The neutrophil associations to lymphocyte ratio with stroke severity and early clinical outcomes were assessed with logistic regression. Overall, 356 older patients were enrolled in this study, with a median age of 85.0 (82.0-88.0). Split by tertiles of neutrophil-to-lymphocyte ratio, 118 patients were in the bottom tertile (<2.17), 118 patients were in the middle tertile (2.17-3.36), and 120 patients were in the top tertile (>3.36). After multivariable analysis, patients in the highest tertile were likely to have moderate to severe stroke on admission (OR 4.87, 95% CI, 1.93-12.30, P = 0.001), higher risks of primary unfavorable outcome (OR 2.70, 95% CI, 1.09-6.69, P = 0.032) and secondary unfavorable outcome (OR 2.00, 95% CI, 1.00-4.00, P = 0.050) compared to the lowest tertile. Our finding demonstrated that the neutrophil-to-lymphocyte ratio is an independent predictor of stroke severity and early clinical outcomes in older patients with acute ischemic stroke.

Deflazacort vs prednisone treatment for Duchenne muscular dystrophy: A meta-analysis of disease progression rates in recent multicenter clinical trials.

INTRODUCTION: In this study we characterized disease progression over 48 weeks among boys receiving deflazacort vs prednisone/prednisolone placebo arm treatment in two recent Duchenne muscular dystrophy (DMD) clinical trials. METHODS: Ambulatory boys with DMD receiving placebo in the phase 3 ataluren (N = 115) and tadalafil (N = 116) trials were included. The trials required at least 6 months of prior corticosteroid use and stable baseline dosing. Associations between corticosteroid use and 48-week changes in ambulatory function were estimated using mixed models. Adjusted differences between corticosteroid groups were pooled in a meta-analysis. RESULTS: In the meta-analysis, deflazacort-treated patients vs prednisone/prednisolone-treated patients experienced, on average, lower declines of 28.3 meters on 6-minute walk distance (95% confidence interval [CI], 5.7, 50.9; 2.9 seconds on rise from supine [95% CI, 0.9, 4.9 seconds]; 2.3 seconds on 4-stair climb [95% CI, 0.5, 4.1 seconds]; and 2.9 [95% CI, 0.1, 5.8] points on the North Star Ambulatory Assessment linearized score). DISCUSSION: Deflazacort-treated patients experienced significantly lower functional decline over 48 weeks.

Modulating NMDA receptors to treat MK-801-induced schizophrenic cognition deficit: effects of clozapine combining with PQQ treatment and possible mechanisms of action.

BACKGROUND: Clozapine has remarkable efficacy on both negative and cognitive symptoms of schizophrenia due to its slight activation of NMDA receptor. In fact, much evidence to the contrary. NMDAR is a complex containing specific binding sites, which are regulated to improve negative symptoms and cognitive deficits associated with individuals affected by schizophrenia. PQQ is a powerful neuroprotectant that specifically binds with NMDA receptors in the brain to produce beneficial physiological and cognitive outcomes. The aim of this study was to enhance NMDAR function and improve cognitive ability in schizophrenia by PQQ combined with clozapine. METHODS: Rats were divided into four groups (n = 5) including control (saline), model (MK-801, 0.5 mg·kg- 1·d- 1), atypical antipsychotic (MK-801 (0.5 mg·kg- 1·d- 1) + Clozapine (1.0 mg·kg- 1·d- 1), and co-agonist NMDA receptor (MK-801 (0.5 mg·kg- 1·d- 1) + Clozapine (0.5 mg·kg- 1·d- 1) + PQQ (1.0 µg·kg- 1·d- 1) group. Each group of rats was injected subcutaneously every day for 6 weeks. Behavior test, including stereotyped behavior, locomotor hyperactivity, learning and memory, was performed. The Western blot assay was performed to analyze the expression of GSK-3ß, Akt, NMDAR1, and MGLUR in rat hippocampus. RESULTS: Results indicated that clozapine and PQQ combination therapy can improve MK801-induced schizophrenia behavior including stereotyped behavior, locomotor hyperactivity and cognitive impairment. Furthermore, we found that modulating NMDA receptors could ameliorate the memory impairments in Mk-801 induced schizophrenia rats by reducing the expression of NMDAR1 and MGLUR3, decreasing hippocampal tau hyperphosphorylation and inhibiting apoptosis through Akt /GSK-3ß signaling pathway. CONCLUSIONS: These findings suggest that combination therapy for enhancing NMDA receptors may be able to rescue cognition deficit in schizophrenia. More studies are needed to better elucidate these mechanisms.

Effects of Winter Cover Crops on Rice Pests, Natural Enemies, and Grain Yield in a Rice Rotation System.

Rotations that include winter cover crops are widely used in agricultural systems and can provide numerous agroecological and economic benefits. However, the effects of winter cover crops on arthropod diversity, specifically rice pests and related natural enemies in rice rotation systems, are still largely unknown. We compared the effects of three winter cover crops, rapeseed, Brassica napus L. (Brassicales: Brassicaceae), Chinese milkvetch, Astragalus sinicus L. (Fabales: Fabaceae), and garlic, Allium sativum L. (Asparagales: Amaryllidaceae), on arthropods species diversity and evenness, densities of populations of major rice pests and major natural enemies, and grain yield in an experimental double cropping rotational rice field in Jiangxi Province, China. We did not observe any effects of cover crops on arthropod species diversity and evenness. The presence of prior cover crops also had no effect on the number of plants infested by the two major rice pests, Chilo suppressalis Walker (Lepidoptera: Pyralidae) and Cnaphalocrocis medinalis (Guenée) (Lepidoptera: Pyralidae). Our study did not show any effects of rapeseed and Chinese milkvetch on grain yield. However, grain yield was increased in the garlic treatment. Our results suggest that although the winter cover crops we tested in our study do not affect the number of rice plants infected by major rice pests, they do not negatively affect the arthropod community and grain yields in rice rotation systems. Therefore, planting of winter cover crops may increase agricultural land utilization and have an overall economic benefit in rice rotational systems.

Prediction of potential distributions of Morina kokonorica and Morina chinensis in China.

Changes in the habitats of species can provide insights into the impact of climate change on their habitats. Species in the genus Morina (Morinoideae) are perennial herbaceous plants that are mainly distributed in the South Asian Mountains and Eastern Mediterranean. In China, there are four species and two varieties of this genus distributed across the Yunnan, Sichuan, Qinghai, and Gansu provinces. This study used the optimal MaxEnt model to simulate past, current, and future potentially suitable habitats of Morina kokonorica and Morina chinensis. Seventy data of M. kokonorica occurrences and 3 of M. chinensis were used in the model to predict potentially suitable habitats. The model prediction results indicated that both M. kokonorica and M. chinensis exhibited trends of northward migration to higher latitudes and westward migration along the Himalayas to higher elevations, suggesting that the northern valleys of Hengduan Mountains and northern and eastern parts of the Himalayas were potential refugia for M. kokonorica, and the potential refugia for M. chinensis was located in the eastern part of Qinghai-Tibet Plateau. The results of this niche analysis showed that the two species had higher levels of interspecific competition and that the environmental adaptability of M. chinensis was stronger. This research could help further understand the response pattern of Morina to environmental change, to understand the adaptability of species to the environment, and promote the protection of species.

Meaningful changes in motor function in Duchenne muscular dystrophy (DMD): A multi-center study.

Evaluations of treatment efficacy in Duchenne muscular dystrophy (DMD), a rare genetic disease that results in progressive muscle wasting, require an understanding of the 'meaningfulness' of changes in functional measures. We estimated the minimal detectable change (MDC) for selected motor function measures in ambulatory DMD, i.e., the minimal degree of measured change needed to be confident that true underlying change has occurred rather than transient variation or measurement error. MDC estimates were compared across multiple data sources, representing >1000 DMD patients in clinical trials and real-world clinical practice settings. Included patients were ambulatory, aged ≥4 to <18 years and receiving steroids. Minimal clinically important differences (MCIDs) for worsening were also estimated. Estimated MDC thresholds for >80% confidence in true change were 2.8 units for the North Star Ambulatory Assessment (NSAA) total score, 1.3 seconds for the 4-stair climb (4SC) completion time, 0.36 stairs/second for 4SC velocity and 36.3 meters for the 6-minute walk distance (6MWD). MDC estimates were similar across clinical trial and real-world data sources, and tended to be slightly larger than MCIDs for these measures. The identified thresholds can be used to inform endpoint definitions, or as benchmarks for monitoring individual changes in motor function in ambulatory DMD.

Exosomal circEZH2_005, an intestinal injury biomarker, alleviates intestinal ischemia/reperfusion injury by mediating Gprc5a signaling.

Intestinal ischemia/reperfusion (I/R) injury is a severe clinical condition without optimal diagnostic markers nor clear molecular etiological insights. Plasma exosomal circular RNAs (circRNAs) are valuable biomarkers and therapeutic targets for various diseases, but their role in intestinal I/R injury remains unknown. Here we screen the expression profile of circRNAs in intestinal tissue exosomes collected from intestinal I/R mice and identify circEZH2_005 as a significantly downregulated exosomal circRNA. In parallel, circEZH2_005 is also reduced in the plasma of clinical cardiac surgery patients who developed postoperative intestinal I/R injury. Exosomal circEZH2_005 displays a significant diagnostic value for intestinal injury induced by I/R. Mechanistically, circEZH2_005 is highly expressed in intestinal crypt cells. CircEZH2_005 upregulation promotes the proliferation of Lgr5+ stem cells by direct interaction with hnRNPA1, and enhanced Gprc5a stability, thereby alleviating I/R-induced intestinal mucosal damage. Hence, exosomal circEZH2_005 may serve as a biomarker for intestinal I/R injury and targeting the circEZH2_005/hnRNPA1/Gprc5a axis may be a potential therapeutic strategy for intestinal I/R injury.

SPARC expression and prognostic value in non-small cell lung cancer.

Secreted protein, acidic and rich in cysteine (SPARC) is expressed in numerous types of tumors and is suggested to have prognostic value. Moreover, because of its strong affinity for albumin, and hence albumin-bound drugs, SPARC has increasingly become a focus for research. In this study, we aimed to determine SPARC expression in patients with non-small cell lung cancer (NSCLC) and investigate the association of SPARC with disease prognosis. Tissue microarrays were constructed with specimens from 105 patients with NSCLC treated at Sun Yat-sen University Cancer Center, and immunohistochemical analysis was performed on these tissue microarrays to assess SPARC expression. Our results showed that SPARC expression status did not significantly relate with age, gender, and tumor stage. However, SPARC was expressed more frequently in squamous cell carcinoma than in adenocarcinoma (75% vs. 43.5%, P = 0.004). Patients with smoking history had higher SPARC expression than non-smokers (68.2% vs. 33.3%, P = 0.002). In both univariate and multivariate analyses, SPARC was a prognostic factor of overall survival (HR = 0.32; 95% CI: 0.16-0.65) but not disease-free survival. Our study indicates that SPARC expression is higher in squamous cell carcinoma than in adenocarcinoma in NSCLC. Most notably, SPARC can be used as a prognostic factor for NSCLC.

Integrated Analysis of Ferroptosis and Immunity-Related Genes Associated with Intestinal Ischemia/Reperfusion Injury.

Purpose: Intestinal ischemia/reperfusion (I/R) injury is an unresolved clinical challenge due to its high prevalence, difficulty in diagnosis, and lack of clinically effective therapeutic agents. Ferroptosis is a novel form of cell-regulated death that has been shown to play a role in various I/R models and has been shown to be immune-related. Further unraveling the molecular mechanisms associated with ferroptosis and immunity in intestinal I/R injury may lead to the discovery of potentially effective drugs. Methods: We obtained differentially expressed mRNAs (DEGs) in mouse intestinal tissues following intestinal I/R injury or sham surgery. Then, we extracted ferroptosis-related DEGs (FRGs) and immune-related DEGs (IRGs) from the DEGs. In addition, we performed functional analysis of FRGs and IRGs. Next, we used transcriptome sequencing from patients with intestinal I/R injury to validate the results. Then, we constructed transcription factors (TFs)-gene networks and gene-drug networks using mouse and human co-expressed FRGs (coFRG) and mouse and human co-expressed IRGs (coIRG). We also analyzed the composition of immune cells to reveal correlations between FRGs signatures and immune cells in the mouse and human gut. Finally, we validated these results through animal experiments. Results: We extracted 61 FRGs and 294 IRGs from mouse samples and performed PPI and functional analyses. We extracted 45 FRGs and 200 IRGs from human samples for validation, and identified 24 coFRGs,100 coIRGs and 6 hub genes (HSPA5, GDF15, TNFAIP3, HMOX1, CXCL2 and IL6) in both. We also predicted potential TF-gene networks for coFRGs and coIRGs, as well as predicted gene-drug pairs for hub genes. In addition, we found that the immune cells were altered in the early stages of intestinal I/R injury and that FRGs were closely associated with immune cells in mice and humans. Finally, we validated the hub genes in mouse samples. Conclusion: In conclusion, we identified ferroptosis and immunity-related genes to predict their correlations in intestinal I/R injury. We also predicated potential TF-genes network and potential therapeutic targets (HSPA5, GDF15, TNFAIP3, HMOX1, CXCL2 and IL6) to provide clues for further investigation of intestinal I/R injury.

Effect of mixed primary and secondary sludge for two-stage anaerobic digestion (AD).

As an energy-efficient and eco-friendly sludge treatment process, two-stage anaerobic digestion (AD) is widely employed to recovery biomass energy from waste sludge. However, the effect of primary and secondary sludge for two-stage AD was not clear. In this study, two-stage AD of mixed sludge in different volume ratio was investigated. The maximum cumulative H2 yield (100.5 ml) and CH4 yield (2643.6 ml) were obtained in volume ratio of 1:3 (primary sludge: secondary sludge). In two-phase AD, mixed sludge could induce positive effect on both organics releasing in extracellular polymeric substances (EPS) and the utilization of volatile fatty acids (VFAs). By investigating the compositional characteristics of dissolved organic matters (DOM) through excitation-emission matrix (EEM) coupling with fluorescence regional integration (FRI), it revealed more degradable substances utilization in mixture of sludge. Results from this work suggest that two-phase AD with mixed sludge is efficient for renewable energy recovery.

Real-world and natural history data for drug evaluation in Duchenne muscular dystrophy: suitability of the North Star Ambulatory Assessment for comparisons with external controls.

Using external controls based on real-world or natural history data (RWD/NHD) for drug evaluations in Duchenne muscular dystrophy (DMD) is appealing given the challenges of enrolling placebo-controlled trials, especially for multi-year trials. Comparisons to external controls, however, face risks of bias due to differences in outcomes between trial and RWD/NHD settings. To assess this bias empirically, we conducted a multi-institution study comparing mean 48-week changes in North Star Ambulatory Assessment (NSAA) total score between trial placebo arms and RWD/NHD sources, with and without adjustment for baseline prognostic factors. Analyses used data from three placebo arms (235 48-week intervals, N = 235 patients) and three RWD/NHD sources (348 intervals, N = 202 patients). Differences in mean ΔNSAA between placebo arms and RWD/NHD sources were small before adjustment (-1.2 units, 95% CI: [-2.0 -0.5]) and were attenuated and no longer statistically significant after adjustment (0.1 units (95% CI: [-0.6, 0.8]). Results were similar whether adjusting using multivariable regression or propensity score matching. This consistency in ΔNSAA between trial placebo arms and RWD/NHD sources accords with prior findings for the six-minute walk distance, provides a well-validated framework for baseline adjustment of prognostic factors, and supports the suitability of RWD/NHD external controls for drug evaluations in ambulatory DMD.

Nmnat1 Modulates Mitochondrial Oxidative Stress by Inhibiting Caspase-3 Signaling in Alzheimer's Disease.

Nigrostriatal pathway disturbance is one of the major pathogenic factors in Alzheimer's disease (AD). Dopaminergic neuron dysfunction results in bradykinesia and akinesia (inability to initiate movement), indicating a significant risk factor for substantia nigra pars compacta lesions. Furthermore, the nicotinamide adenine dinucleotide (NAD+) is associated with Aß toxicity decline in AD therapy. Nicotinamide mononucleotide adenylyltransferase 1 (Nmnat1) is an essential enzyme that preserves normal neuronal function and protects neurons from insult. This study aimed to investigate the potential therapeutic effects of Nmnat1 and its underlying mechanisms in a triple-transgenic mouse model of AD (3xTgAD). Results showed that Nmnat1 improved the substantial behavioral measures of cognitive impairments compared with the 3xTgAD control. Additionally, Nmnat1 overexpression significantly increased tyrosine hydroxylase-positive neurons and anti-apoptotic protein Bcl2 and caspase-3 expression levels in 3xTgAD mice. Nmnat1 also effectively controlled SOD1 activation. In conclusion, Nmnat1 substantially decreases multiple AD-associated pathological characteristics at least partially by the increase of caspase-3 activation.

Screening and Identification of Key Genes, Pathways, and Drugs Associated with Neuropathic Pain in Dorsal Horn: Evidence from Bioinformatic Analysis.

PURPOSE: Neuropathic pain is a devastating complex condition occurring post-nervous system damage. Microglia in dorsal horn drives neuropathic pain as a kind of immune cell. We aimed to find potential differentially expressed genes (DEGs) and candidate pathways, which induced neuropathic pain, and to identify some new transcription factors and therapeutic drugs via bioinformatic analysis. METHODS: The microarray profile GSE60670 was downloaded and analyzed. DEGs were screened and analyzed through Gene Ontology (GO), pathway enrichment, and protein-to-protein interaction (PPI) network. Respectively, transcription factors (TFs) and potential therapeutic drugs for DEGs were predicted through NetworkAnalyst and DGIdb databases. At last, we chose top 10 DEGs for external validation. RESULTS: A total of 100 DEGs were identified. The results of pathway and GO analyses were closely related to malaria inflammatory pathway and inflammatory response. Three necessary PPI modules and 9 hub genes were identified in PPI analysis, and 277 DEG-TF pairs were found among 54 DEGs and 32 TF. Moreover, 22 candidate drugs were found to match 9 hub genes. External validation of 9 of the top 10 DEGs were consistent with bioinformatic analysis. CONCLUSION: This study provided comprehensive analyses for the functional gene sets and pathways related to neuropathic pain and promoted our understanding of the mechanism or therapy of neuropathic pain.