Stable Mg Single-Atom Solid Base Catalysts Anchored on Metal-Organic Framework-Derived Nitrogen-Doped Carbon.

Solid base catalysts are widely used in the chemical industry owing to their advantages of environmental friendliness and easy separation. However, their application is limited by basic site aggregation and poor stability. In this study, we report the preparation of magnesium (Mg) single-atom catalysts with high activity and stability by a sublimation-trapping strategy. The Mg net was sublimated as Mg vapor at 620 °C, subsequently transported through argon, and finally trapped on the defects of nitrogen-doped carbon derived from metal-organic framework ZIF-8, producing Mg1/NC. Because of the atomically dispersed Mg sites, the obtained Mg1/NC exhibits high catalytic activity and stability for Knoevenagel condensation of benzaldehyde with malononitrile, which is a typical base-catalyzed reaction. The Mg1/NC catalyst achieves a high efficiency with a turnover frequency of 49.6 h-1, which is much better than that of the traditional counterpart MgO/NC (7.7 h-1). In particular, the activity of Mg1/NC shows no decrease after five catalytic cycles, while that of MgO/NC declines due to the instability of basic sites.

Polyhydroxybutyrate Plastics Show Rapid Disintegration and More Straightforward Biogeochemical Impacts than Polyethylene under Marine Biofragmentation.

Although massive studies have investigated the spatiotemporally occurring marine plastisphere, a new microbial ecosystem colonizing the surfaces of plastics, the resulting biofragmentation process and impacts of plastics on biogeochemical cycles remain largely unknown. Here, we leverage synchrotron-based Fourier transform infrared spectromicroscopy (FTIR mapping) and metagenomic sequencing to explore independent marine microcosms amended with petroleum-based polyethylene (PE) and biobased polyhydroxybutyrate (PHB) plastic films. FTIR mapping results demonstrate unequal fragmentation scenarios by which the PE plastic rarely releases oxidized fragments while PHB disintegrates quickly, gradually forming fragments composed of extracellular polymeric substances resembling plastic films. Metagenomic analysis shows the critical role of hydrocarbonoclastic lineages in the biodegradation of the two plastics by the fatty acid degradation pathway, where the PE plastics host different microbial trajectories between the plastisphere (dominated by Alcanivorax) and surrounding seawater. In contrast, the PHB addition demonstrates decreased microbial richness and diversity, consistent community composition (dominated by Phaeobacter and Marinobacter), and apparently stimulated sulfur cycle and denitrification pathways in both the plastisphere and surrounding seawater. Our study gives scientific evidence on the marine biotic processes distinguishing petroleum- and biobased plastics, highlighting marine PHB input exerting straightforward impacts on the water phase and deserving critical management practices.

Avenues for Strengthening PCORnet's Capacity to Advance Patient-Centered Economic Outcomes in Patient-Centered Outcomes Research (PCOR).

PCORnet, the National Patient-Centered Clinical Research Network, provides the ability to conduct prospective and observational pragmatic research by leveraging standardized, curated electronic health records data together with patient and stakeholder engagement. PCORnet is funded by the Patient-Centered Outcomes Research Institute (PCORI) and is composed of 8 Clinical Research Networks that incorporate at total of 79 health system "sites." As the network developed, linkage to commercial health plans, federal insurance claims, disease registries, and other data resources demonstrated the value in extending the networks infrastructure to provide a more complete representation of patient's health and lived experiences. Initially, PCORnet studies avoided direct economic comparative effectiveness as a topic. However, PCORI's authorizing law was amended in 2019 to allow studies to incorporate patient-centered economic outcomes in primary research aims. With PCORI's expanded scope and PCORnet's phase 3 beginning in January 2022, there are opportunities to strengthen the network's ability to support economic patient-centered outcomes research. This commentary will discuss approaches that have been incorporated to date by the network and point to opportunities for the network to incorporate economic variables for analysis, informed by patient and stakeholder perspectives. Topics addressed include: (1) data linkage infrastructure; (2) commercial health plan partnerships; (3) Medicare and Medicaid linkage; (4) health system billing-based benchmarking; (5) area-level measures; (6) individual-level measures; (7) pharmacy benefits and retail pharmacy data; and (8) the importance of transparency and engagement while addressing the biases inherent in linking real-world data sources.

Implementing a home-based virtual hypertension programme-a pilot feasibility study.

INTRODUCTION: Implementing a health system-based hypertension programme may lower blood pressure (BP). METHODS: We performed a randomized, controlled pilot study to assess feasibility, acceptability, and safety of a home-based virtual hypertension programme integrating evidence-based strategies to overcome current barriers to BP control. Trained clinical pharmacists staffed the virtual collaborative care clinic (vCCC) to remotely manage hypertension using a BP dashboard and phone "visits" to monitor BP, adherence, side effects of medications, and prescribe anti-hypertensives. Patients with uncontrolled hypertension were identified via electronic health records. Enrolled patients were randomized to either vCCC or usual care for 3 months. We assessed patients' home BP monitoring behaviour, and patients', physicians', and pharmacists' perspectives on feasibility and acceptability of individual programme components. RESULTS: Thirty-one patients (vCCC = 17, usual care = 14) from six physician clinics completed the pilot study. After 3 months, average BP decreased in the vCCC arm (P = 0.01), but not in the control arm (P = 0.45). The vCCC participants measured BP more (9.9 vs. 1.2 per week, P < 0.001). There were no intervention-related adverse events. Participating physicians (n = 6), pharmacists (n = 5), and patients (n = 31) rated all programme components with average scores of >4.0, a pre-specified benchmark. Nine adaptations in vCCC design and delivery were made based on potential barriers to implementing the programme and suggestions. CONCLUSION: A home-based virtual hypertension programme using team-based care, technology, and a logical integration of evidence-based strategies is safe, acceptable, and feasible to intended users. These pilot data support studies to assess the effectiveness of this programme at a larger scale.

Mechanism and clinical value of exosomes and exosomal contents in regulating solid tumor radiosensitivity.

Radiotherapy is among the routine treatment options for malignant tumors. And it damages DNA and other cellular organelles in target cells by using ionizing radiation produced by various rays, killing the cells. In recent years, multiple studies have demonstrated that exosomes are mechanistically involved in regulating tumor formation, development, invasion and metastasis, and immune evasion. The latest research shows that radiation can affect the abundance and composition of exosomes as well as cell-to-cell communication. In the environment, exosome-carried miRNAs, circRNA, mRNA, and proteins are differentially expressed in cancer cells, while these molecules play a role in numerous biological processes, including the regulation of oncogene expression, mediation of signaling pathways in cancer cells, remodeling of tumor-related fibroblasts, regulation of cell radiosensitivity, and so forth. Therefore, elucidation of the mechanism underlying the role of exosomes in radiotherapy of malignant tumors is crucial for improving the efficacy of radiotherapy. This review will summarize the research advances in radiosensitivity of malignant tumors related to exosomes.

Metagenomic and Metatranscriptomic Responses of Chemical Dispersant Application during a Marine Dilbit Spill.

The global increase in marine transportation of dilbit (diluted bitumen) can increase the risk of spills, and the application of chemical dispersants remains a common response practice in spill events. To reliably evaluate dispersant effects on dilbit biodegradation over time, we set large-scale (1,500 mL) microcosms without nutrient addition using a low dilbit concentration (30 ppm). Shotgun metagenomics and metatranscriptomics were deployed to investigate microbial community responses to naturally and chemically dispersed dilbit. We found that the large-scale microcosms could produce more reproducible community trajectories than small-scale (250 mL) ones based on the 16S rRNA gene amplicon sequencing. In the early-stage large-scale microcosms, multiple genera were involved in the biodegradation of dilbit, while dispersant addition enriched primarily Alteromonas and competed for the utilization of dilbit, causing depressed degradation of aromatics. The metatranscriptomic-based metagenome-assembled genomes (MAG) further elucidated early-stage microbial antioxidation mechanism, which showed that dispersant addition triggered the increased expression of the antioxidation process genes of Alteromonas species. Differently, in the late stage, the microbial communities showed high diversity and richness and similar compositions and metabolic functions regardless of dispersant addition, indicating that the biotransformation of remaining compounds can occur within the post-oil communities. These findings can guide future microcosm studies and the application of chemical dispersants for responding to a marine dilbit spill. IMPORTANCE In this study, we employed microcosms to study the effects of marine dilbit spill and dispersant application on microbial community dynamics over time. We evaluated the impacts of microcosm scale and found that increasing the scale is beneficial for reducing community stochasticity, especially in the late stage of biodegradation. We observed that dispersant application suppressed aromatics biodegradation in the early stage (6 days), whereas exerting insignificant effects in the late stage (50 days), from both substance removal and metagenomic/metatranscriptomic perspectives. We further found that Alteromonas species are vital for the early-stage chemically dispersed oil biodegradation and clarified their degradation and antioxidation mechanisms. These findings help us to better understand microcosm studies and microbial roles for biodegrading dilbit and chemically dispersed dilbit and suggest that dispersant evaluation in large-scale systems and even through field trails would be more realistic after marine oil spill response.

Demographics, clinical characteristics, and prognostic factors of amyotrophic lateral sclerosis in Midwest.

INTRODUCTION/AIMS: The Midwest has the highest regional prevalence of self-reported amyotrophic lateral sclerosis (ALS) in the United States, but with limited epidemiological studies. We aimed to explore the characteristics of patients with ALS in the Midwest. METHODS: This was a retrospective cohort study of participants with ALS deceased between January, 2010, and September, 2020, registered with the ALS Association Mid-America Chapter. Demographics and clinical variables included gender, race/ethnicity, military status, site of onset, interventions (gastrostomy, non-invasive ventilation, tracheostomy), and visits to ALS Association-registered clinics. Disease characteristics were compared to the National ALS Registry, and survival analysis was performed followed by sample augmentation with historical data to estimate survival with hypothetical censoring. RESULTS: The database included 1447 participants with a mean age at diagnosis of 65.7 ± 11.9 y (>60 y at diagnosis: 72%). The median survival from symptom onset was 28.0 mo (95% confidence limit: 26.3, 29.7); sample augmentation increased this to 41.0 mo (38.5, 43.5). Bulbar onset disease and older age at diagnosis were associated with shorter survival. Participants not followed in ALS-Association registered clinics were more frequently male, had familial onset and tracheostomy. Veterans (N = 298) were older at diagnosis but had similar survival after adjustment for age. DISCUSSIONS: Our cohort had an older age at onset and more frequent bulbar onset than the National ALS Registry, perhaps reflecting ascertainment biases in each registry. Prospective cohort studies with more clinical and functional data are needed to better characterize ALS in Midwest, veterans, and non-clinic populations, and to optimize care.

Population Pharmacokinetics of Intranasal Dexmedetomidine in Infants and Young Children.

BACKGROUND: Intranasal dexmedetomidine provides noninvasive, effective procedural sedation for pediatric patients, and has been widely used in clinical practice. However, the dosage applied has varied fourfold in pediatric clinical studies. To validate an appropriate dosing regimen, this study investigated the pharmacokinetics of intranasal dexmedetomidine in Chinese children under 3 yr old. METHODS: Intranasal dexmedetomidine 2 µg · kg-1 was administered to children with simple vascular malformations undergoing interventional radiological procedures. A population pharmacokinetic analysis with data from an optimized sparse-sampling design was performed using nonlinear mixed-effects modeling. Clearance was modeled using allometric scaling and a sigmoid postmenstrual age maturation model. Monte Carlo simulations were performed to assess the different dosing regimens. RESULTS: A total of 586 samples from 137 children aged 3 to 36 months were included in the trial. The data were adequately described by a two-compartment model with first-order elimination. Body weight with allometric scaling and maturation function were significant covariates of dexmedetomidine clearance. The pharmacokinetic parameters for the median subjects (weight 10 kg and postmenstrual age 101 weeks) in the authors' study were apparent central volume of distribution 7.55 l, apparent clearance of central compartment 9.92 l · h-1, apparent peripheral volume of distribution 7.80 l, and apparent intercompartmental clearance 61.7 l · h-1. The simulation indicated that at the dose of 2 µg · kg-1, 95% of simulated individuals could achieve a target therapeutic concentration of 0.3 ng · ml-1 within 20 min, and the average peak concentration of 0.563 ng · ml-1 could be attained at 61 min. CONCLUSIONS: The pharmacokinetic characteristics of intranasal dexmedetomidine were evaluated in Chinese pediatric patients aged between 3 and 36 months. An evidence-based dosing regimen at 2 µg · kg-1 could achieve a preset therapeutic threshold of mild to moderate sedation that lasted for up to 2 h.

Impacts of Frazil Ice on the Effectiveness of Oil Dispersion and Migration of Dispersed Oil.

Oil spills in the Arctic have drawn dramatic attention in recent years. Frazil ice, as the essential formation of sea ice, may affect the effectiveness of dispersants during oil spill response and the associated behaviors of dispersed oil. However, these impacts remain poorly understood, limiting the appropriate usage of dispersants in ice-covered regions. Herein this work explored the effects of frazil ice on the dispersion effectiveness of two dispersants (Corexit 9500A and hydrolyzed shrimp waste) and the migration of dispersed oil within frazil ice. We discovered that frazil ice inhibited dispersion effectiveness by attenuating water velocity. Permeable frazil ice encapsulated 11-30% of dispersed oil, implying a lower oil bioavailability. We thus proposed and verified a microscopic mechanism to unravel the migration of dispersed oil toward permeable constrictions in frazil ice. We predicted the concentration of dispersed oil encapsulated in frazil ice using bed filtration theory and verified the prediction through experiments. Furthermore, the presence of frazil ice can lead to the breakup and coalescence of dispersed oil. Overall, our findings would facilitate the appropriate planning and decision-making of dispersant-based oil spill response and a better understanding of the fate of dispersed oil in the frazil ice-infested ocean.

Patients with type 2 diabetes and elevated fibrosis-4 are under-referred to hepatology and have unrecognized hepatic decompensation.

BACKGROUND AND AIM: The American Association for the Study of Liver Diseases recommends a high index of suspicion for nonalcoholic steatohepatitis and advanced fibrosis in patients with type 2 diabetes (T2D) and an elevated fibrosis-4 index (FIB-4). We investigated the referral pattern of patients with T2D and FIB4 > 3.25 to the hepatology clinic and evaluated the clinical benefits to the patient. METHODS: We included patients aged 18-80 years with T2D and a FIB4 score >3.25 who had visited the internal medicine, family medicine, endocrinology clinic from 01/01/2014-5/31/2019. The first time point of high-risk FIB-4 was identified as the baseline for time-to-event analysis. The patients were classified based on whether they had visited the hepatology clinic (referred vs not referred). RESULTS: Of the 2174 patients, 290 (13.3%) were referred to the hepatology clinic, and 1884 (86.7%) were not referred. In multivariate analyses, the referred patients had a lower overall mortality risk (Hazard Ratio: 0.57; 95% CI: 0.38-87). Notably, the referred patients had the same rate of biochemical decompensation, as measured by progression to MELD ≥ 14, but a substantially higher rate of diagnosis in cirrhosis (27, 19-38) and cirrhosis complications, including ascites (2.9, 2.0-4.1), hepatic encephalopathy (99, 13-742), and liver cancer (14, 5-38). CONCLUSIONS: We found that patients with T2D and high-risk FIB4 are associated with better overall survival after referral to a hepatology clinic. We speculate that the survival difference is due to the increased recognition of cirrhosis and cirrhosis complications in the referred populations.

Uncover diagnostic immunity/hypoxia/ferroptosis/epithelial mesenchymal transformation-related CCR5, CD86, CD8A, ITGAM, and PTPRC in kidney transplantation patients with allograft rejection.

The aim of this study was to identify predictive immunity/hypoxia/ferroptosis/epithelial mesenchymal transformation (EMT)-related biomarkers, pathways and new drugs in allograft rejection in kidney transplant patients. First, gene expression data were downloaded followed by identification of differentially expressed genes (DEGs), weighted gene co-expression network analysis (WGCNA) and protein-protein interaction (PPI) analysis. Second, diagnostic model was construction based on key genes, followed by correlation analysis between immune/hypoxia/ferroptosis/EMT and key diagnostic genes. Finally, drug prediction of diagnostic key genes was carried out. Five diagnostic genes were further identified, including CCR5, CD86, CD8A, ITGAM, and PTPRC, which were positively correlated with allograft rejection after the kidney transplant. Highly infiltrated immune cells, highly expression of hypoxia-related genes and activated status of EMT were significantly positively correlated with five diagnostic genes. Interestingly, suppressors of ferroptosis (SOFs) and drivers of ferroptosis (DOFs) showed a complex regulatory relationship between ferroptosis and five diagnostic genes. CD86, CCR5, and ITGAM were respectively drug target of ABATACEPT, MARAVIROC, and CLARITHROMYCIN. PTPRC was drug target of both PREDNISONE and EPOETIN BETA. In conclusion, the study could be useful in understanding changes in the microenvironment within transplantation, which may promote or sustain the development of allograft rejection after kidney transplantation.

Machine Learning-Aided Causal Inference Framework for Environmental Data Analysis: A COVID-19 Case Study.

Links between environmental conditions (e.g., meteorological factors and air quality) and COVID-19 severity have been reported worldwide. However, the existing frameworks of data analysis are insufficient or inefficient to investigate the potential causality behind the associations involving multidimensional factors and complicated interrelationships. Thus, a causal inference framework equipped with the structural causal model aided by machine learning methods was proposed and applied to examine the potential causal relationships between COVID-19 severity and 10 environmental factors (NO2, O3, PM2.5, PM10, SO2, CO, average air temperature, atmospheric pressure, relative humidity, and wind speed) in 166 Chinese cities. The cities were grouped into three clusters based on the socio-economic features. Time-series data from these cities in each cluster were analyzed in different pandemic phases. The robustness check refuted most potential causal relationships' estimations (89 out of 90). Only one potential relationship about air temperature passed the final test with a causal effect of 0.041 under a specific cluster-phase condition. The results indicate that the environmental factors are unlikely to cause noticeable aggravation of the COVID-19 pandemic. This study also demonstrated the high value and potential of the proposed method in investigating causal problems with observational data in environmental or other fields.

Laboratory indicators predict axillary nodal pathologic complete response after neoadjuvant therapy in breast cancer.

The purpose was to integrate clinicopathological and laboratory indicators to predict axillary nodal pathologic complete response (apCR) after neoadjuvant therapy (NAT). The pretreatment clinicopathological and laboratory indicators of 416 clinical nodal-positive breast cancer patients who underwent surgery after NAT were analyzed from April 2015 to 2020. Predictive factors of apCR were examined by logistic analysis. A nomogram was built according to logistic analysis. Among the 416 patients, 37.3% achieved apCR. Multivariate analysis showed that age, pathological grading, molecular subtype and neutrophil-to-lymphocyte ratio were independent predictors of apCR. A nomogram was established based on these four factors. The area under the curve (AUC) was 0.758 in the training set. The validation set showed good discrimination, with AUC of 0.732. In subtype analysis, apCR was 23.8, 47.1 and 50.8% in hormone receptor-positive/HER2-, HER2+ and triple-negative subgroups, respectively. According to the results of the multivariate analysis, pathological grade and fibrinogen level were independent predictors of apCR after NAT in HER2+ patients. Except for traditional clinicopathological factors, laboratory indicators could also be identified as predictive factors of apCR after NAT. The nomogram integrating pretreatment indicators demonstrated its distinguishing capability, with a high AUC, and could help to guide individualized treatment options.

Lay abstract The purpose of this study was to integrate more pretreatment indicators, including clinicopathological factors and simple laboratory indicators, to predict axillary nodal pathologic complete response (apCR) after neoadjuvant therapy for breast cancer. The authors collected the pretreatment clinicopathological factors and laboratory indexes of 416 nodal-positive patients with breast cancer. The authors then built a nomogram to predict the therapeutic effect in axillary lymph nodes. Among 416 patients, 37.3% (155 of 416) achieved apCR. The results showed that age, pathological grading, molecular subtype and neutrophil-to-lymphocyte ratio were independent predictors of apCR. Based on these four factors, a nomogram was then built. This nomogram helped to predict apCR. In addition to traditional clinicopathological factors, laboratory indicators were also identified as predictive factors of apCR after neoadjuvant therapy. Integrating pretreatment indicators might help to predict apCR and guide individualized treatment options.

A data-driven binary-classification framework for oil fingerprinting analysis.

A marine oil spill is one of the most challenging environmental issues, resulting in severe long-term impacts on ecosystems and human society. Oil dispersants are widely applied as a treating agent in oil spill response operations. The usage of dispersants significantly changes the behaviors of dispersed oil and consequently challenges the oil fingerprinting analysis. In this study, machine learning was first introduced to analyze oil fingerprinting by developing a data-driven binary classification framework. The modeling integrated dimensionality reduction algorithms (e.g., principal component analysis, PCA) to distinguish. Five groups of biomarkers, including terpanes, steranes, triaromatic steranes (TA-steranes), monoaromatic steranes (MA-steranes), and diamantanes, were selected. Different feature spaces were created from the diagnostic index of biomarkers, and six ML algorithms were applied for comparative analysis and optimizing the modeling process, including k-nearest neighbor (KNN), support vector classifier (SVC), random forest classifier (RFC), decision tree classifier (DTC), logistic regression classifier (LRC), and ensemble vote classifier (EVC). Hyperparameter optimization and cross-validation through GridSearchCV were applied to prevent overfitting and increase the model accuracy. Model performance was evaluated by model score and F-score through confusion matrices. The results indicated that the RFC algorithm from the diamantanes dataset performed the best. It delivered the highest F-score (0.871) versus the lowest F-score (0.792) from the EVC algorithm from the TA-steranes dataset by PCA with a variance of 95%. Therefore, diamantanes were recommended as the most suitable biomarker for distinguishing WCO and CDO to aid oil fingerprinting under the conditions in this study. The results proved the proposed method as a potential analysis tool for oil spill source identification through ML-aided oil fingerprinting. The study also showed the value of ML methods in oil spill response research and practice.

Time- and dose-dependent correlations between patient-controlled epidural analgesia and intrapartum maternal fever.

BACKGROUND: To investigate the relationship between intrapartum maternal fever and the duration and dosage of patient-controlled epidural analgesia (PCEA). METHODS: This observational study included 159 pregnant women who voluntarily accepted PCEA. During labor, patients with body temperature ≥ 38 °C were classified into the Fever group, (n = 42), and those with body temperature < 38 °C were classified into the No-fever group (n = 117). The outcome measures included the duration of PCEA, number of PCEA, and total PCEA amount. Body temperature and parturient variables, including interpartum fever status and the duration of any fever were monitored. RESULTS: The total PCEA duration and total PCEA amount in the Fever group were significantly higher than the corresponding values in the No-fever group (both, p < 0.05). The duration of fever was weakly correlated with the duration of PCEA (R2 = 0.08) and the total PCEA amount (R2 = 0.05) (both, p < 0.05). The total and effective PCEA were higher in the Fever group than in the No-fever group (both, p < 0.05). The total PCEA duration and total PCEA amount were positively correlated with the incidence of fever (both, p < 0.05). The diagnostic cutoff value for fever was 383 min, with a sensitivity of 78.6% and specificity of 57.3%. The mean temperature-time curves showed that parturients who developed fever had a steeper rise in temperature. CONCLUSIONS: This study showed that there were weak time- and dose-dependent correlations between PCEA and maternal fever during delivery. A total PCEA duration exceeding 6.3 h was associated with an increase in the duration of maternal intrapartum fever.

Selection of an ASIC1a-blocking combinatorial antibody that protects cells from ischemic death.

Acid-sensing ion channels (ASICs) have emerged as important, albeit challenging therapeutic targets for pain, stroke, etc. One approach to developing therapeutic agents could involve the generation of functional antibodies against these channels. To select such antibodies, we used channels assembled in nanodiscs, such that the target ASIC1a has a configuration as close as possible to its natural state in the plasma membrane. This methodology allowed selection of functional antibodies that inhibit acid-induced opening of the channel in a dose-dependent way. In addition to regulation of pH, these antibodies block the transport of cations, including calcium, thereby preventing acid-induced cell death in vitro and in vivo. As proof of concept for the use of these antibodies to modulate ion channels in vivo, we showed that they potently protect brain cells from death after an ischemic stroke. Thus, the methodology described here should be general, thereby allowing selection of antibodies to other important ASICs, such as those involved in pain, neurodegeneration, and other conditions.

Protein Kinase C Lambda Mediates Acid-Sensing Ion Channel 1a-Dependent Cortical Synaptic Plasticity and Pain Hypersensitivity.

Chronic pain is a serious debilitating disease for which effective treatment is still lacking. Acid-sensing ion channel 1a (ASIC1a) has been implicated in nociceptive processing at both peripheral and spinal neurons. However, whether ASIC1a also contributes to pain perception at the supraspinal level remains elusive. Here, we report that ASIC1a in ACC is required for thermal and mechanical hypersensitivity associated with chronic pain. ACC-specific genetic deletion or pharmacological blockade of ASIC1a reduced the probability of cortical LTP induction and attenuated inflammatory thermal hyperalgesia and mechanical allodynia in male mice. Using cell type-specific manipulations, we demonstrate that ASIC1a in excitatory neurons of ACC is a major player in cortical LTP and pain behavior. Mechanistically, we show that ASIC1a tuned pain-related cortical plasticity through protein kinase C λ-mediated increase of membrane trafficking of AMPAR subunit GluA1 in ACC. Importantly, postapplication of ASIC1a inhibitors in ACC reversed previously established nociceptive hypersensitivity in both chronic inflammatory pain and neuropathic pain models. These results suggest that ASIC1a critically contributes to a higher level of pain processing through synaptic potentiation in ACC, which may serve as a promising analgesic target for treatment of chronic pain.SIGNIFICANCE STATEMENT Chronic pain is a debilitating disease that still lacks effective therapy. Ion channels are good candidates for developing new analgesics. Here, we provide several lines of evidence to support an important role of cortically located ASIC1a channel in pain hypersensitivity through promoting long-term synaptic potentiation in the ACC. Our results indicate a promising translational potential of targeting ASIC1a to treat chronic pain.

Antibiofilm Activity of Lactobacillus plantarum 12 Exopolysaccharides against Shigella flexneri.

In developing countries, Shigella flexneri is the most common enteric pathogen causing bacillary dysentery. Biofilm formation by S. flexneri can cause the emergence of antibiotic-resistant strains, which poses serious threats to food safety and human health. In this study, the effects of Lactobacillus plantarum 12 exopolysaccharides (L-EPSs) and S. flexneri exopolysaccharides (S-EPSs) on S. flexneri CMCC51574 biofilm formation were investigated. The results showed that L-EPS could decrease polysaccharide production in the extracellular polymeric matrix of S. flexneri and inhibit biofilm formation by S. flexneri L-EPS could decrease the minimum biofilm elimination concentration (MBEC) of antibiotics against S. flexneri biofilm and inhibit S. flexneri adhesion to and invasion into HT-29 cell monolayers, which might be ascribed to S. flexneri biofilm disturbance by L-EPS. In contrast, S-EPS exhibited the opposite effects compared to L-EPS. The monosaccharide composition analysis showed that L-EPS was composed of mannose, glucuronic acid, galactosamine, glucose, galactose, and xylose, with the molar ratio of 32.26:0.99:1.79:5.63:0.05:4.07, while S-EPS was composed of mannose, glucuronic acid, galactosamine, glucose, and galactose, with the molar ratio of 25.43:2.28:7.13:5.35. L-EPS was separated into the neutral polysaccharide L-EPS 1-1 and the acidic polysaccharide L-EPS 2-1 by ion-exchange chromatography and gel chromatography. L-EPS 2-1 exerted higher antibiofilm activity than L-EPS 1-1. The antibiofilm activity of L-EPS might be associated with its structure.IMPORTANCES. flexneri is a widespread foodborne pathogen causing food contamination and responsible for food poisoning outbreaks related to various foods in developing countries. Not only has biofilm formation by S. flexneri been difficult to eliminate, but it has also increased the drug resistance of the strain. In the present study, it was demonstrated that L-EPSs secreted by Lactobacillus plantrum 12 could inhibit S. flexneri biofilm formation on, adhesion to, and invasion into HT-29 cells. Also, L-EPSs could decrease the minimum biofilm elimination concentration (MBEC) of the antibiotics used against S. flexneri biofilm. Therefore, L-EPSs were shown to be bioactive macromolecules with the potential ability to act against S. flexneri infections.

MicroRNA-621 Acts as a Tumor Radiosensitizer by Directly Targeting SETDB1 in Hepatocellular Carcinoma.

Radiotherapy is one of the most important treatment methods of tumors. However, the application of radiotherapy in hepatocellular carcinoma (HCC) is limited due to the low tolerance of normal liver cells for radiation and inherent radiation resistance in HCC. With the in-depth study of microRNAs (miRNAs) in tumor therapy, the regulation of tumor radiosensitivity by miRNAs has been a research hotspot in recent years. In the present study, the expression of miR-621 was lower in HCC tissues and cells, and such low expression of miR-621 was associated with poor prognosis in HCC patients. In addition, in vivo and in vitro assays confirmed that the high expression of miR-621 could significantly enhance the radiosensitivity of HCC. Moreover, the expressions of miR-621 and SETDB1 in HCC tissues were negatively correlated. Dual-luciferase reporter assays indicated that miR-621 could directly target the 3' UTR of SETDB1. In addition, miR-621 enhanced the radiosensitivity of HCC cells via directly inhibiting SETDB1. Besides, the miR-621 and/or SETDB1 axis improved the radiosensitivity of HCC cells via activating the p53-signaling pathway. Taken together, miR-621 and/or SETDB1 might be used as a novel therapeutic target for the treatment of HCC.

Effect of caudal ketamine on minimum local anesthetic concentration of ropivacaine in children: a prospective randomized trial.

BACKGROUND: Caudal ketamine has been shown to provide an effective and prolonged post-operative analgesia with few adverse effects. However, the effect of caudal ketamine on the minimum local anesthetic concentration (MLAC) of ropivacaine for intra-operative analgesia is unclear. METHODS: One hundred and sixty-nine children were randomized to five groups: Group C (caudal ropivacaine only), Group K0.25 (caudal ropivacaine plus 0.25 mg/kg ketamine), Group K0.5 (caudal ropivacaine plus 0.5 mg/kg ketamine), Group K0.75 (caudal ropivacaine plus 0.75 mg/kg ketamine), and Group K1.0 (caudal ropivacaine plus 1.0 mg/kg ketamine). The primary outcome was the MLAC values of ropivacaine with/without ketamine for caudal block. RESULTS: The MLAC values of ropivacaine were 0.128% (0.028%) in the control group, 0.112% (0.021%) in Group K0.25, 0.112% (0.018%) in Group K0.5, 0.110% (0.019%) in Group K0.75, and 0.110% (0.020%) in Group K1.0. There were no significant differences among the five groups for the MLAC values (p = 0.11). During the post-operative period the mean durations of analgesia were 270, 381, 430, 494, and 591 min in the control, K0.25, K0. 5, K0.75, and K1.0 groups respectively, which shown that control group is significantly different from all ketamine groups. Also there were significant differences between K0.25 and K0.75 groups, and between K1.0 groups and the other ketamine groups. CONCLUSIONS: Adding caudal ketamine to ropivacaine prolong the duration of post-operative analgesia; however, it does not decrease the MLAC of caudal ropivacaine for intra-operative analgesia in children. CLINICAL TRIAL REGISTRATION: ChiCTR-TRC-13003492. Registered on 13 August 2013.