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The content of Cu2+ in lubricants is an essential indicator for determining the quality of the lubricant and predicting mechanical failure. Finding an effective and sensitive method for detecting Cu2+ in lubricants is of great importance in oil monitoring. In this work, AgInS2 (AIS) and AgInS2-ZnS (ZAIS) nanoparticles (NPs) were synthesized by a simple one-step approach via in-situ surface modification by oleylamine. The as-synthesized AIS and ZAIS NPs exhibit good dispersion stability in various apolar media. The photoluminescence (PL) of AIS and ZAIS NPs as lubricating additives could reflect and monitor the lubrication state of steel-copper pairs due to the quenching effect of Cu2+ from the friction process. With an optimum concentration of 0.5 wt% in paraffin oil, the friction coefficient of the AIS and ZAIS NPs at 100 N was decreased by 56.8 and 52.1% for steel-steel contacts, respectively. ZAIS was observed to be more effective than AIS in improving anti-wear (AW) and extreme pressure (EP) properties, with a load-bearing capacity of up to 1100 N. Characterization of the wear tracks by SEM and XPS indicates that a tribofilm composed of metal sulfides and oxides was formed during the lubricating process. This work not only reveals AIS and ZAIS NPs as a new class of promising candidates for lubricating additives but also unveils their potential for monitoring lubricant conditions and exploring lubricant service life.

As one of the most induced genes in activated macrophages, immune-responsive gene 1 (IRG1) encodes a mitochondrial metabolic enzyme catalysing the production of itaconic acid (ITA). Although ITA has an anti-inflammatory property, the underlying mechanisms are not fully understood. Here we show that ITA is a potent inhibitor of the TET-family DNA dioxygenases. ITA binds to the same site on TET2 as the co-substrate α-ketoglutarate, inhibiting TET2 catalytic activity. Lipopolysaccharide treatment, which induces Irg1 expression and ITA accumulation, inhibits Tet activity in macrophages. Transcriptome analysis reveals that TET2 is a major target of ITA in suppressing lipopolysaccharide-induced genes, including those regulated by the NF-κB and STAT signalling pathways. In vivo, ITA decreases the levels of 5-hydroxymethylcytosine, reduces lipopolysaccharide-induced acute pulmonary oedema as well as lung and liver injury, and protects mice against lethal endotoxaemia, depending on the catalytic activity of Tet2. Our study thus identifies ITA as an immune modulatory metabolite that selectively inhibits TET enzymes to dampen the inflammatory responses.

Background It has been reported that metal exposure is associated with the risk of diabetes, but the results are inconsistent.The relationship between diabetes and a single metal might be attenuated or strengthened due to the complex interactions of metals and the chronic diseases comorbidity (especially in the elderly). However, the evidence of multiple metal exposure effect in participants with diabetes only is limited, particularly in the elderly. The present case-control study of 188 diabetic and 376 healthy participants aimed to evaluate the potential relationships between the concentrations of 9 metals in urine and the risk of diabetes and to access the interactive effects of metals in Chinese community-dwelling elderly. Methods The urine levels of 9 metals (cobalt, zinc, copper, arsenic, molybdenum, cadmium, tellurium, thallium, lead) were detected by inductively coupled plasma mass spectrometry (ICP-MS) in 564 adults recruited from Yinchuan Community Health Service Center (Yinchuan, China).Logistic regression and restricted cubic spline (RCS) analysis were used to explore the associations and dose-response relationships of urine metals with diabetes. To analysis of multi-metal exposures and diabetes risk, weighted quantile sum regression Models (WQS) and the Bayesian Kernel Machine Regression (BKMR) model were applied. Results The concentrations of cobalt, zinc, copper, arsenic, molybdenum, cadmium, tellurium, thallium and lead were higher in the diabetes group (p P-overall P-nonlinear

The impact of regional trade shocks on population health has been a topic of interest in health economics in recent years. Unfortunately, there are few studies directly discussing the impact of regional trade shocks caused by China’s WTO accession on the health of Chinese residents, which is essential to explore the connection between a country´s opening to international trade and the health of its residents. Taking China’s accession to the WTO as a quasi-natural experiment, based on the micro individual samples of the China Health and Nutrition Survey (CHNS) from 1993 to 2011, this paper, for the first time, studies the impact of regional tariff uncertainty caused by China’s accession to the WTO on the health of Chinese residents and its mechanisms by adopting the Difference-in-Difference (DID) model. The study finds that compared with the areas initially facing low tariff uncertainty, the areas with high initial tariff uncertainty have a greater negative impact on the health of residents after China acceded to WTO, which means that the trade shock caused damage to the health of residents. After a series of tests on the effectiveness and robustness of DID, this conclusion is still valid. The impact of the trade shock on residents’ health varies with the type of residence, gender, and geographical location, and there is a nonlinear relationship. Further mechanism tests show that the trade shock has worsened the health status of residents through rural migration channels, working hours channels, and pollution emission channels. This study provides micro evidence for objectively evaluating the health effects of trade shock and has important implication for considering the health loss of Chinese residents in the process of trade liberalization.

Jonathan Corren,1 Sarbjit S Saini,2 Remi Gagnon,3 Mark H Moss,4 Gordon Sussman,5 Joshua Jacobs,6 Elizabeth Laws,7 Elinore S Chung,8 Tatiana Constant,8 Yiping Sun,8 Jennifer Maloney,8 Jennifer D Hamilton,8 Marcella Ruddy,8 Claire Q Wang,8 Meagan P O’Brien8 1Departments of Medicine and Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; 2Department of Internal Medicine, Division of Allergy and Clinical Immunology, Johns Hopkins Asthma and Allergy Center, Baltimore, MD, USA; 3Clinique Spécialisée en Allergie de la Capitale, Québec, QC, Canada; 4Departments of Medicine and Pediatrics, Division of Allergy, Pulmonary and Critical Care, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; 5Department of Medicine, University of Toronto, Toronto, ON, Canada; 6Allergy and Asthma Clinical Research, Inc, Walnut Creek, CA, USA; 7Sanofi, Bridgewater, NJ, USA; 8Regeneron Pharmaceuticals, Inc, Tarrytown, NY, USACorrespondence: Meagan P O’BrienRegeneron Pharmaceuticals, Inc, 777 Old Saw Mill River Road, Tarrytown, NY, 10591, USATel +1 914 826-5271Email meagan.obrien@regeneron.comJonathan CorrenDepartments of Medicine and Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, 10833 Le Conte Ave, Los Angeles, CA, 90095, USATel +1 310 312-5050, ext 250Email jcorren@ucla.eduBackground: Subcutaneous immunotherapy (SCIT) has been proven as an effective therapy against some allergens for seasonal allergic rhinitis (SAR) patients unresponsive to intranasal corticosteroids and/or antihistamines but carries risk of systemic allergic reactions. Dupilumab blocks the shared receptor component for interleukin-4 and interleukin-13, key and central drivers of type 2 inflammation in multiple diseases.Objective: To evaluate the efficacy and safety of SCIT+dupilumab vs SCIT alone.Methods: This phase 2a, multicenter, double-blind, placebo-controlled parallel-group study conducted in 103 adults with grass pollen-induced SAR (NCT03558997) randomized patients 1:1:1:1 to SCIT, dupilumab (300 mg every 2 weeks), SCIT+dupilumab, or placebo. SCIT was administered using an 8-week cluster protocol followed by 8 weeks of maintenance injections. Primary endpoint was change from pre-treatment baseline in area under the curve (AUC) in total nasal symptom score (TNSS) 0– 1 h following nasal allergen challenge (NAC) with timothy grass extract at Week 17.Results: Although 16 weeks of treatment with SCIT+dupilumab did not significantly improve TNSS AUC (0– 1 h) following NAC at Week 17 vs SCIT (least squares mean − 56.76% vs − 52.03%), a higher proportion of SCIT+dupilumab-treated patients (61.5%) achieved SCIT maintenance dose vs SCIT (46.2%). A lower proportion of SCIT+dupilumab-treated patients (7.7%) required epinephrine rescue treatment vs SCIT (19.2%). There were significantly fewer withdrawals in the SCIT+dupilumab group than in the SCIT group (n = 2 [7.7%] vs n = 8 [30.8%]; P = 0.0216); the majority of SCIT group withdrawals were due to SCIT-related intolerability, compared with no discontinuations from the SCIT+dupilumab group.Conclusion: In SAR patients, 16 weeks of SCIT+dupilumab may improve SCIT tolerability but did not incrementally reduce post-allergen challenge nasal symptoms compared with SCIT alone.Clinical Study Number: NCT03558997.Keywords: dupilumab, seasonal allergic rhinitis, subcutaneous immunotherapy, nasal allergen responses

The impact of regional trade shocks on population health has been a topic of interest in health economics in recent years. Unfortunately, there are few studies directly discussing the impact of regional trade shocks caused by China’s WTO accession on the health of Chinese residents, which is essential to explore the connection between a country´s opening to international trade and the health of its residents. Taking China’s accession to the WTO as a quasi-natural experiment, based on the micro individual samples of the China Health and Nutrition Survey (CHNS) from 1993 to 2011, this paper, for the first time, studies the impact of regional tariff uncertainty caused by China’s accession to the WTO on the health of Chinese residents and its mechanisms by adopting the Difference-in-Difference (DID) model. The study finds that compared with the areas initially facing low tariff uncertainty, the areas with high initial tariff uncertainty have a greater negative impact on the health of residents after China acceded to WTO, which means that the trade shock caused damage to the health of residents. After a series of tests on the effectiveness and robustness of DID, this conclusion is still valid. The impact of the trade shock on residents’ health varies with the type of residence, gender, and geographical location, and there is a nonlinear relationship. Further mechanism tests show that the trade shock has worsened the health status of residents through rural migration channels, working hours channels, and pollution emission channels. This study provides micro evidence for objectively evaluating the health effects of trade shock and has important implication for considering the health loss of Chinese residents in the process of trade liberalization.

There is a need to investigate the role of nuclear factor kappa B in the regulation of cyclooxygenase-2 expression in the epileptic rat brain and cultured hippocampal neurons. Immunofluorescence and polymerase chain reaction was used to detect the expression of nuclear factor kappa B and cyclooxygenase-2. In cultured hippocampal neurons and rat brain: the control group compared with the normal group, nuclear factor kappa B expression in the hippocampal dentate gyrus, cerebral cortex, the piriform cortex brain regions were significantly increased (P < 0.01). This is accompanied by a significant increase in cyclooxygenase-2 protein and mRNA expressions in the hippocampus (P < 0.01). In the experimental group compared to the control group, the nuclear factor-kappa B expression in the hippocampal dentate gyrus, cerebral cortex, piriform cortex, and other brain regions was significantly lower (P < 0.01), with the accompanying decrease in cyclooxygenase-2 protein and mRNA expression (P < 0.01) in the hippocampus. In conclusion, κB-decoy can inhibit nuclear factor kappa B activation in epileptic rat brain and cyclooxygenase-2 overexpression.

DNA methyltransferases (DNMTs) catalyze DNA methylation, and their functions in mammalian embryonic development and diseases including cancer have been extensively studied. However, regulation of DNMTs remains under study. Here, we show that CCAAT/enhancer binding protein α (CEBPA) interacts with the long splice isoform DNMT3A, but not the short isoform DNMT3A2. CEBPA, by interacting with DNMT3A N-terminus, blocks DNMT3A from accessing DNA substrate and thereby inhibits its activity. Recurrent tumor-associated CEBPA mutations, such as preleukemic CEBPA N321D mutation, which is particularly potent in causing AML with high mortality, disrupt DNMT3A association and cause aberrant DNA methylation, notably hypermethylation of PRC2 target genes. Consequently, leukemia cells with the CEBPA N321D mutation are hypersensitive to hypomethylation agents. Our results provide insights into the functional difference between DNMT3A isoforms and the regulation of de novo DNA methylation at specific loci in the genome. Our study also suggests a therapeutic strategy for the treatment of CEBPA -mutated leukemia with DNA-hypomethylating agents.

Objective Patients with cardiac surgery–associated acute kidney injury are at risk of renal replacement therapy and in-hospital death. We aimed to develop and validate a novel predictive model for poor in-hospital outcomes among patients with cardiac surgery–associated acute kidney injury. Methods A total of 196 patients diagnosed with cardiac surgery–associated acute kidney injury were enrolled in this study as the training cohort, and 32 blood cytokines were measured. Least absolute shrinkage and selection operator regression and random forest quantile-classifier were performed to identify the key blood predictors for in-hospital composite outcomes (requiring renal replacement therapy or in-hospital death). The logistic regression model incorporating the selected predictors was validated internally using bootstrapping and externally in an independent cohort (n = 52). Results A change in serum creatinine (delta serum creatinine) and interleukin 16 and interleukin 8 were selected as key predictors for composite outcomes. The logistic regression model incorporating interleukin 16, interleukin 8, and delta serum creatinine yielded the optimal performance, with decent discrimination (area under the receiver operating characteristic curve: 0.947; area under the precision-recall curve: 0.809) and excellent calibration (Brier score: 0.056, Hosmer–Lemeshow test P = .651). Application of the model in the validation cohort yielded good discrimination. A nomogram was generated for clinical use, and decision curve analysis demonstrated that the new model adds more net benefit than delta serum creatinine. Conclusions We developed and validated a promising predictive model for in-hospital composite outcomes among patients with cardiac surgery–associated acute kidney injury and demonstrated interleukin-16 and interleukin-8 as useful predictors to improve risk stratification for poor in-hospital outcomes among those with cardiac surgery–associated acute kidney injury.

Although the relationship between trade and environment has been widely discussed in past studies, trade policy has been in a state of continuous change in recent years. Previous studies have focused on the impact of trade opening or liberalization on the environment, ignoring discussion of the dynamic changes of trade policy. Therefore, it is very important to explore the connection between trade policy changes and environmental pollution for future environmental protection. In order to realize the in-depth study of this mechanism, the paper will try to solve the following three problems: (1) What is the relationship between change in trade policy uncertainty and China’s environmental pollution? (2) What is the mechanism by which trade uncertainty changes environmental pollution? (3) Due to China’s vast territory and regional differences, will changes in trade policy uncertainty have heterogeneous effects due to regional differences? To solve these problems, based on China’s accession to the WTO at the end of 2001, this paper, for the first time, uses PM2.5 concentration data of 246 prefecture-level cities in China to explore the impact of trade policy uncertainty on China’s environmental pollution, then we make an in-depth analysis of the impact path and heterogeneity of urban spatial distribution and city size. We found that, after China’s accession to the WTO, the growth rate of PM2.5 concentration reduced in cities with lower trade policy uncertainty and the inhibition effect was different due to the spatial distribution of city size. A further mechanism test shows that reduction in trade policy uncertainty can improve environmental pollution through industrial, structural and technological effects.

With the development of human society, the shortage of traditional fossil fuels has intensified, and due to sustainable development and ecological environment, new green and pollution-free energy has entered the public’s field of vision. Thin-film solar cells have high photoelectric conversion efficiency, stable performance and low consumption of raw materials. However, some elements in raw materials are toxic and their reserves are small, which limits their large-scale popularization and use. Perovskite solar cells have attracted public attention because of their low cost and simple production process. The traditional energy content is limited, and the demand for energy is increasing with the development of the world economy, so the world is bound to face the dilemma that single fossil energy cannot meet the demand for energy for economic maintenance and development. As a clean energy, extensive use of solar energy is also an effective solution to the pollution caused by traditional energy utilization. This paper mainly analyzes the electrochemical preparation methods of perovskite solar cells, and studies its performance optimization.

MicroRNAs, a class of small and non-encoding RNAs that transcriptionally or post-transcriptionally modulate the expression of their target genes, have been implicated as critical regulatory molecules in ischemia-/reperfusion-induced cardiac injury. In the present study, we report on the role of miR-208a in myocardial I/R injury and the underlying cardio-protective mechanism. The gain-of-function and loss-of-function were used to explore the effects of miR-208a on cardiac injury induced by H2O2 in cardiomyocytes. As predicted, knockdown of endogenous miR-208a significantly decreased the level of cellular reactive oxygen species (ROS) and reduced cardiomyocyte apoptosis. In addition, miR-208a overexpression increased the ROS level and attenuated cell apoptosis in cardiomyocytes. Furthermore, protein tyrosine phosphatase receptor type G (PTPRG) and protein tyrosine phosphatase, non-receptor type 4 (PTPN4), which participate in regulating the level of cellular protein tyrosine phosphorylation balance, were predicted and verified as potential miR-208a targets using bioinformatics and luciferase assay. In summary, this study demonstrated that miR-208a plays a critical protective role in ROS-induced cardiac apoptosis.

EPR spectroscopy was used to monitor formation of free radicals in human hair upon UV irradiation. While the EPR spectra of brown hair were dominated by melanin signal, those of white hair were keratin-derived. The decay of UV induced keratin radicals was enhanced at increased ambient humidity. We argue that at higher humidity the swollen hair provides a more liquid-like environment, and higher molecular mobility in this environment leads to faster radical reactions. This interpretation is consistent with the increased UV-triggered protein damage in hair at high humidity as demonstrated by the protein loss, MALDI-TOF and FT-IR data.

There is a need to investigate the role of nuclear factor kappa B in the regulation of cyclooxygenase-2 expression in the epileptic rat brain and cultured hippocampal neurons. Immunofluorescence and polymerase chain reaction was used to detect the expression of nuclear factor kappa B and cyclooxygenase-2. In cultured hippocampal neurons and rat brain: the control group compared with the normal group, nuclear factor kappa B expression in the hippocampal dentate gyrus, cerebral cortex, the piriform cortex brain regions were significantly increased (P < 0.01). This is accompanied by a significant increase in cyclooxygenase-2 protein and mRNA expressions in the hippocampus (P < 0.01). In the experimental group compared to the control group, the nuclear factor-kappa B expression in the hippocampal dentate gyrus, cerebral cortex, piriform cortex, and other brain regions was significantly lower (P < 0.01), with the accompanying decrease in cyclooxygenase-2 protein and mRNA expression (P < 0.01) in the hippocampus. In conclusion, κB-decoy can inhibit nuclear factor kappa B activation in epileptic rat brain and cyclooxygenase-2 overexpression.

Chondroitin sulfate (CS) and dermatan sulfate (DS) proteoglycans (PGs) are major extracellular matrix (ECM) components of the central nervous system (CNS). A large body of evidence has shown that CSPGs/DSPGs play critical roles in neuronal growth, axon guidance, and plasticity in the developing and mature CNS. It has been proposed that these PGs exert their function through specific interaction of CS/DS chains with its binding partners in a manner that depends on the sulfation patterns of CS/DS. It has been reported that dermatan 4-O-sulfotransferase-1 (Chst14/D4st1) specific for DS, but not chondroitin 4-O-sulfotransferase-1 (Chst11/C4st1) specific for CS, regulates proliferation and neurogenesis of neural stem cells (NSCs), indicating that CS and DS play distinct roles in the self-renewal and differentiation of NSCs. However, it remains unknown whether specific sulfation profiles of DS has any effect on CNS plasticity. In the present study, Chst14/D4st1-deficient (Chst14−/−) mice was employed to investigate the involvement of DS in synaptic plasticity. First, behavior study using Morris Water Maze (MWM) showed that the spatial learning and memory of Chst14−/− mice was impaired when compared to their wild type (WT) littermates. Corroborating the behavior result, long-term potentiation (LTP) at the hippocampal CA3-CA1 connection was reduced in Chst14−/− mice compared to the WT mice. Finally, the protein levels of N-Methyl-D-aspartate (NMDA) receptor, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, postsynaptic density 95 (PSD95), growth associated protein 43 (GAP-43), synaptophysin (SYN) and N-ethylmaleimide sensitive factor (NSF) which are important in synaptic plasticity were examined and Chst14/D4st1 deficiency was shown to significantly reduce the expression of these proteins in the hippocampus. Further studies revealed that Akt/mammalian target rapamycin (mTOR) pathway proteins, including protein kinase B (p-Akt), p-mTOR and p-S6, were significantly lower in Chst14−/− mice, which might contribute to the decreased protein expression. Together, this study reveals that specific sulfation of DS is critical in synaptic plasticity of the hippocampus and learning and memory, which might be associated with the changes in the expression of glutamate receptors and other synaptic proteins though Akt/mTOR pathway.

The protective effects of dioscin, a natural steroidal saponin from some medicinal plants including Dioscorea nipponica Makino, against lipopolysaccharide (LPS)- induced acute liver and renal damages have been reported in our previous works. However, its effect on LPS-induced acute lung injury (ALI) remains unknown. In the present study, the effects and possible mechanisms of dioscin against LPS-induced ALI in vitro and in vivo were investigated. The results showed that dioscin effectively inhibited cell proliferation and markedly decreased reactive oxidative species (ROS) level in 16HBE cells treated by LPS. In addition, dioscin significantly attenuated LPS-induced histological alterations, suppressed the infiltration of inflammatory cells, as well as decreased the levels of MDA, SOD, NO and iNOS in mice and rats (p < 0.05). Mechanistically, dioscin significantly decreased the protein levels of TLR4, MyD88, TRAF6, TKB1, TRAF3, phosphorylation levels of PI3K, Akt, IκBα, NF-κB, and the mRNA levels of IL-1β, IL-6 and TNF-α against oxidative stress and inflammation (p < 0.05). TLR4 overexpression was also decreased by dioscin, leading to the markedly decreased the levels of MyD88, TRAF6, TKB1, TRAF3, p-PI3K, p-Akt, p-IκBα and p-NF-κB. These findings provide new insights that dioscin exhibited protective effect against LPS-induced ALI via adjusting TLR4/MyD88- mediated oxidative stress and inflammation, which should be developed as one potent candidate for the treatment of ALI in the future.

A lot of literature show that social isolation stress could be a key reason that leads to cognitive deficits for both humans and rodent models; however, the detailed mechanisms are still not clear completely. ADAR1 (Adenosine deaminase acting on RNA) is an enzyme involved in RNA editing that has a close relation to cognitive function. We hypothesize that social isolation stress may impact the expression of ADAR1, leading to cognitive deficits. To prove our hypothesis, we evaluated the cognition ability of the mice isolated for different durations (2, 4, and 8 weeks) using object recognition and object location tests; we also measured ADAR1 expressions in hippocampus and cortex using immunohistochemistry and western blot. Our study showed that social isolation stress significantly induced spatial and non-spatial cognition deficits. In addition, social isolation significantly increased both the immuno reactivity and protein expressions of ADAR1 in the hippocampus and frontal cortex. Furthermore, we found that adolescent re-socialization recovered not only the cognition deficits but also the increased ADAR1 protein expression in hippocampus and the increased number of ADAR1 positive cells in frontal cortex of the isolated mice. In conclusion, social isolation stress significantly increased ADAR1 expressions in the hippocampus and cortex, leading to cognitive deficits.

Adenosine deaminase acting on RNA (ADAR) activity increases in response to inflammation. Social isolation stress is related to neuroinflammation; however, it remains unclear whether ADAR1 is altered in response to social isolation stress-induced cognitive deficits. To investigate our hypothesis that ADAR1 displayed patterns of change in response to social isolation stress, we addressed this issue systemically by isolating Kunming mice for 2, 4 and 8 weeks individually since postnatal 21 days to set up isolation mouse model. Furthermore, we arranged re-socialization group to evaluate the alterations of ADAR1 in the cognitive deficits recovery. The results of behavior tests showed that social isolation stress resulted in cognitive dysfunction, which was recovered by re-socialization in re-gregarious rearing group. Furthermore, the immunohistochemistry and western blot results displayed that both the immunoreactivity and protein expression of ADAR1 in the hippocampus and frontal cortex increased obviously as compared to the same age mice without isolation. The above abnormal alterations of ADAR1 were recovered by re-socialization in re-gregarious rearing group. Our study supports the hypothesis that ADAR1 is altered in mice affected by social isolation stress-induced cognitive deficits.

Background Myocardial infarction (MI) remains the most common cause of heart failure (HF) worldwide. For almost 50 years, HF has been recognized as a determinant of adverse prognosis after MI, but efforts to promote myocardial repair have failed to be translated into clinical therapies. Aims In this study, we investigated the effects of BRD4 on cardiac function and the underlying mechanism. Material and methods The in vivo rat model of AMI and in vitro neonatal cardiomyocytes were established and cultured respectively, the BRD4 and NPPA/NPPB expression levels were detected by qPCR and Western blot, and interaction of BRD4 with acetylation RelA or NPPA/B promoters were examined by co-immunoprecipitation and chromatin immunoprecipitation assays, respectively. Results We found that BRD4 protein expression was significantly increased in cardiomyocytes of MI rat model and cardiomyocytes under hypoxia, accompanied by the expression of natriuretic peptide A (NPPA) and natriuretic peptide B (NPPB). Functionally, knockdown of BRD4 greatly downregulated the NPPA and NPPB in vivo and in vitro, improved the hemodynamic and biometric parameters in rat with heart failure, as well as decreased the apoptosis occurrence. In vitro studies further demonstrated that BRD4 bound with acetylated RelA to enhance the activation of NF-κb signaling, which resulted in activation of NPPA and NPPB transcriptions. Conclusions Taken together, our findings suggest that inhibition of BRD4 attenuated cardiomyocyte apoptosis via NF-κB pathway in myocardial infarction, and this study sheds light on developing new strategies to overcome myocardial damage.

Introduction Social isolation enhances the aggressive behavior of animals, but the detailed mechanism remains unclear. Epigenetic studies have suggested that Htr2c RNA editing is closely related to aggressive behavior. This study aims to obtain a fundamental understanding of how social isolation impacts adenosine deaminase acting on RNA 1 (ADAR1, RNA editing enzyme) and Htr2c RNA editing, leading to aggressive behavior, and explore the effective solutions for the recovery of this behavior. Methods We evaluated 21-day-old BALB/c mice with and without isolation for aggressive behavior using a resident-intruder test. Immune-reactivity and protein expression of ADAR1 (p110) were measured using immunohistochemistry and Western blotting. Htr2c RNA editing was evaluated using pyrosequencing. In addition, the 5-HT 2C R antagonist SB243213/5-HT 2C R inverse agonist SB206553 was used to treat the isolated mice, and the performance of both treatments on the behavior, ADAR1 (p110) expression, and Htr2c RNA editing in isolated mice was examined. Results Both the protein expression and immune-reactivity of ADAR1 (p110) in the amygdala decreased, but the percentage of Htr2c RNA editing at A and B sites of amygdala only showed a moderate increase in isolated BALB/c mice with enhanced aggressive behavior compared to the age-matched group-housed BALB/c mice. Additionally, treatment with the 5-HT 2C R antagonist SB243213/5-HT 2C R inverse agonist SB206553 recovered the enhanced aggressive behavior of isolated mice and returned the protein expression and immune-reactivity of ADAR1 (p110) back to the normal level. Moreover, compared to the age-matched isolated mice treated with physiological saline, isolated mice treated with 5-HT 2C R inverse agonist SB206553 showed a lower percentage of Htr2c RNA editing at both A and B sites, and the same result occurred in isolated mice treated with 5-HT 2C R antagonist SB243213 at B site of Htr2c RNA editing. Conclusions The 5-HT 2C R antagonist SB243213/5-HT 2C R inverse agonist SB206553 recovered increased aggressive behavior of isolated BALB/c mice mediated by ADAR1 (p110) expression and Htr2c RNA editing.

Delay in diagnosis of leprosy can increase the risk of nerve function impairments and promote the transmission of the infection in a community. In order to understand the factors associated with the delays in diagnosis of leprosy, a questionnaire-based interview was conducted to collect information on the delays among 88 newly diagnosed leprosy patients. The results showed that delay was common and associated with the high rate of disability in the study population. The total mean delay was 50.18 months (median 36 months). The mean patient delay was 24-4 months (median 9.5 months) and the mean health service delay was 257 months (median 12 months). Patients with leprosy reported a variety of symptoms/signs at an early stage of the disease, particularly numbness and tingling. Ignorance of the illness was reported to be the main reason for the patient's delay. Health seeking actions ranged from 1 to 50 with a mean of 7.2 after becoming aware of the first symptom/sign. The effectiveness of early diagnosis of leprosy through health promotion in the population needs to be validated and continuous training on leprosy among healthcare providers is needed.

Anticorrosive behaviors of 2-mercaptobenzothiazole (MBT) self-assembled monolayers (SAMs) on silver and zinc electrodes were comparatively studied by means of electrochemical impedance spectroscopy (EIS). The promising inhibition effect of the MBT for silver and zinc from corrosion had been confirmed. The adsorption geometries of MBT monolayers on zinc and silver electrodes were observed by surface enhanced Raman scattering (SERS) technique. The SERS spectra implied that monolayers of MBT could be self-assembled on Ag surface through S 10 and N 3 atoms and the molecular plane should be tilted with respect to the surface. On Zn surface, MBT molecules formed monolayers via both S atoms and the other moieties of the molecule away from the surface. From the in situ electrochemical SERS results it can be found that MBT monolayers on both Ag and Zn surfaces experienced the changes of adsorption fashions as the potential shifting to more negative direction.

Advanced renal cell carcinoma (RCC) is resistant to cytotoxic chemotherapy, and immunotherapy has modest activity. Proteasome inhibitors represent a novel class of anticancer agents that have activity across a wide spectrum of tumor types. We investigated the efficacy of the proteasome inhibitor bortezomib (VELCADE, formerly known as PS-341) in RCC and found that bortezomib potently induces apoptosis of RCC cell lines. Blockade of the nuclear factor-κB (NF-κB) pathway is considered a crucial effect in bortezomib-induced apoptosis, but the dependence on NF-κB inhibition for bortezomib-mediated death has not been formally demonstrated. Thus, we also studied the contribution of NF-κB inhibition as a mechanism of bortezomib-induced apoptosis in RCC cells, which display constitutive NF-κB activation. Ectopic expression of the NF-κB family members, p65 (Rel A) and p50 (NF-κB1), markedly reduced bortezomib-induced apoptosis. However, when we used selective genetic and chemical inhibitors of NF-κB, we found that NF-κB blockade was not sufficient to induce apoptosis of RCC cells. Thus, we conclude that maximal bortezomib-induced apoptosis is dependent on its NF-κB inhibitory effect, but NF-κB-independent effects also play a critical role in the induction of apoptosis by bortezomib. This represents the first report to formally demonstrate that bortezomib-induced NF-κB blockade is required to achieve the maximum degree of apoptosis by this drug.

Protein protease inhibitors could potentially be used to stabilize proteases in commercial products such as liquid laundry detergents. However, many protein protease inhibitors are susceptible to hydrolysis inflicted by the protease. We have engineered Streptomyces subtilisin inhibitor (SSI) to resist proteolysis by adding an interchain disulfide bond and removing a subtilisin cleavage site at leucine 63. When these stabilizing changes were combined with changes to optimize the affinity for subtilisin, the resulting inhibitor provided complete protease stability for at least 5 months at 31 degrees C in a subtilisin-containing liquid laundry detergent and allowed full recovery of the subtilisin activity upon the dilution that occurs in a North American washing machine.

The Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a FADD-like interferon converting enzyme or caspase 8 (FLICE) inhibitory protein (vFLIP) that prevents death receptor-mediated apoptosis by inhibiting the recruitment and activation of FLICE. Since vFLIP physically interacts with tumor necrosis factor receptor associated factor 2 (TRAF2) and TRAF2 mediates activation of the jun NH(2)-terminal kinase (JNK)/activation protein 1 (AP1) pathway, we hypothesized that vFLIP might also activate this pathway. To evaluate this hypothesis, we transiently and stably transfected a vFLIP expression construct and performed several complementary assays to document that vFLIP activates the JNK/AP1 pathway and does so in a TRAF-dependent fashion. As vFLIP also activates the nuclear factor kappaB (NF-kappaB) signaling pathway and the NF-kappaB and JNK/AP1 pathways both modulate cellular interleukin-6 (cIL-6) expression, we postulated that vFLIP induces expression of this cytokine. We show that vFLIP induces cIL-6 expression and activates the cIL-6 promoter, and maximal activation of the cIL-6 promoter by vFLIP requires NF-kappaB and AP1 activation. In addition, vFLIP and latency-associated nuclear antigen (LANA), another KSHV-encoded latent protein, potentiate each other's ability to activate the cIL-6 promoter. Gene silencing experiments by RNA interference demonstrate that vFLIP in BCBL-1 endogenously infected primary effusion lymphoma (PEL) cells mediates JNK/AP1 activation and cIL-6 expression. Thus, we conclude that vFLIP, in addition to its known effects on NF-kappaB activation, also modulates the JNK/AP1 pathway and induces gene expression from the cIL-6 promoter in a JNK/AP1-dependent fashion.

Kinetic interactions of β-lactam antibiotics such as penicillin-G and cefotaxime with normal, penicillin-susceptible PBP2x from Streptococcus pneumoniae and a penicillin-resistant PBP2x (PBP2xR) from a resistant clinical isolate (CS109) of the bacterium have been extensively characterized using electrospray mass spectrometry coupled with a fast reaction (quench flow) technique. Kinetic evidence for a two-step acylation of PBP2x by penicillin-G has been demonstrated, and the dissociation constant, K d of 0.9 mm, and the acylation rate constant, k 2 of 180 s−1, have been determined for the first time. The millimolar range K d implies that the β-lactam fits to the active site pocket of the penicillin-sensitive PBP rather poorly, whereas the extremely fast k 2 value indicates that this step contributes most of the binding affinity of the β-lactam. The values of K d (4 mm) and k 2 (0.56 s−1) were also determined for PBP2xR. The combined value ofk 2/K d, known as overall binding efficiency, for PBP2xR (137m −1 s−1) was over 1000-fold slower than that for PBP2x (200,000 m −1s−1), indicating that a major part is played by the acylation steps in penicillin resistance. Most of the decreased binding efficiency of PBP2xR comes from the decreased (∼300-fold)k 2. Kinetic studies of cefotaxime acylation of the two PBP2x proteins confirmed all of the above findings. Deacylation rate constants (k 3) for the third step of the interactions were determined to be 8 × 10−6s−1 for penicilloyl-PBP2x and 5.7 × 10−4 s−1 for penicilloyl-PBP2xR, corresponding to over 70-fold increase of the deacylation rate for the resistant PBP2xR. Similarly, over 80-fold enhancement of the deacylation rate was found for cefotaxime-PBP2xRcomplex (k 3 = 3 × 10−4s−1) as compared with that of cefotaxime-PBP2x complex (3.5 × 10−6 s−1). This is the first time that such a significant increase ofk 3 values was found for a β-lactam-resistant penicillin-binding protein. These data indicate that the deacylation step also plays a role, which is much more important than previously thought, in PBP2xR resistance to β-lactams.

It has been reported that social isolation stress could be a key factor that leads to cognitive deficit for both humans and rodent models. However, detailed mechanisms are not yet clear. ADAR1 (Adenosine deaminase acting on RNA) is an enzyme involved in RNA editing that has a close relation to cognitive function. We have hypothesized that social isolation stress may impact the expression of ADAR1 in the brain of mice with cognitive deficit. To test our hypothesis, we evaluated the cognition ability of mice isolated for different durations (2, 4, and 8 weeks) using object recognition and object location tests; we also measured ADAR1 expression in hippocampus and cortex using immunohistochemistry and western blot. Our study showed that social isolation stress induced spatial and non-spatial cognition deficits of the tested mice. In addition, social isolation significantly increased both the immunoreactivity and protein expression of ADAR1 (p110) in the hippocampus and frontal cortex. Furthermore, re-socialization could not only recover the cognition deficits, but also bring ADAR1 (p110) immunoreactivity of hippocampus and frontal cortex, as well as ADAR1 (p110) protein expression of hippocampus back to the normal level for the isolated mice in adolescence. In conclusion, social isolation stress significantly increases ADAR1 (p110) expression in the hippocampus and frontal cortex of the mice with cognitive deficit. This finding may open a window to better understand the reasons (e.g., epigenetic change) that are responsible for social isolation-induced cognitive deficit and help the development of novel therapies for the resulted diseases.

Crystallins, the structural proteins of the lens, have been isolated from human lenses using a combination of gel filtration and reversed phase high performance liquid chromatography (HPLC). The molecular weights of the isolated crystallins have been determined by electrospray ionization mass spectrometry. The isolated crystallins have also been proteolytically digested into peptides, the peptides fractionated by HPLC, and the masses of the peptides determined by fast atom bombardment mass spectrometry. With these techniques, it is possible to confirm and/or correct known protein sequences and identify and locate post translational modifications. I NTRODU CTl ON Cataract, which can be defined as an opacity of the eye lens, is the leading cause of blindness worldwide. In countries where surgery to remove a cataractous lens and replace it with a synthetic lens is readily available, cataract may not be a serious impairment; however, in much of the world this surgery is not available, and the development of cataract leads to blindness. The two types of cataract, cortical and nuclear, both involve changes in the lens proteins, called the crystallins. For the lens to be transparent, the crystallins must be tightly and uniformly packed producing a lens with a uniform refractive index. In cortical cataract, the density of the crystallins is altered, causing a non-uniform density with variations in the lens refractive index and consequent light scattering (ref. 1). Nuclear cataract is associated with the formation of insoluble protein aggregates. In both cases, there are modifications to the lens crystallins that either prevent their normal close packing in the cortex or cause their aggregation in the nucleus. The focus of our research is to determine which proteins are modified, where the modifications are located, and the identity of the modifications. Cataract is most commonly associated with old age. Most people over age 80 have at least early indications of cataract. Cataract occurs earlier in people with diabetes, renal failure, chronic diarrhea or who have experienced prolonged exposure to W radiation. The mechanisms that have been proposed for the development of cataract vary, depending on the disease with which it is associated. Cataract associated with old age, diabetes, renal failure and chronic diarrhea are all proposed to occur because of modifications to the lysyl residues of the crystallins. In old age, the concentration of glutathione in the lens is lower. This permits an increase in the concentration of dehydroascorbic acid, which is normally reduced by glutathione in younger lenses. Dehydroascorbic acid can react with the amino groups of the lysyl residues, forming a Schiff base which can then rearrange or possibly form cross-links (ref. 2). In diabetes, the elevated concentrations of glucose may lead to formation of a similar Schiff base between the lysyl residues and glucose (ref. 3). Both renal failure and chronic diarrhea are associated with elevated urea, which forms an equilibrium with isocyanate. Isocyanate can also react with lysyl residues forming a carbamylated protein (refs. 4, 5). A different mechanism, oxidation of the tryptophan residues to form kynurenine, has been proposed

Although the precise mechanisms of transient hypotension after intravenous infusion of hypertonic saline (HTS) are not yet clarified, a rapid infusion of HTS is widely used as the initial therapy of hypovolemia. We investigated the effect of the intravenous infusion of a small dose of 0.97-9.7% NaCl solutions in anesthetized rats. Intravenous infusion of HTS at a rate of 0.3 ml/kg/min for 1 min produced the transient hypotension lasting for several minutes. The depressor response to HTS was not abolished by bilateral cervical vagotomy. The HTS infusion into the femoral vein evoked the depressor response with a larger magnitude and a shorter latency than that into the aortic arch. While the arterial baroreceptor pressure was kept constant at the baseline level of systemic arterial pressure, HTS-induced hypotension was significantly augmented. The gain factor of the arterial baroreflex was reduced by intravenous HTS. Pretreatment with bretylium tosylate completely abolished the depressor response without affecting the baseline level of arterial pressure. These results suggest that the depressor response to the very small dose of intravenous HTS is the sympathosympathetic neural reflex with cardiopulmonary afferents and vasomotor efferents.

This paper described a facile method for preparation of gold nanoparticles with high efficient SERS activity within short reaction time in the presence of an environmentally benign and low-cost reagent named inositol hexaphosphate (IP(6)). IP(6) acted as a tunable cross-linker to obtain a suitable separation (about 2nm) between the neighboring particles for certain surface plasmons by adjusting the dosages of IP(6). When the molar ratio of Au to IP(6) was 10:1, gold particles presented in nano-pearl-necklace pattern, demonstrating the high enhancement factor (>10(7)) for 2-mercaptopyridine (2-Mpy) Raman scattering and high stability (>2months).

Prior studies suggest Staphylococcus aureus exotoxins are not produced when the organism is cultured in human blood. Human blood was fractionated into plasma and water-lysed red blood cells, and it was demonstrated that mixtures of alpha and beta globins of hemoglobin (as low as 1 mug/mL) inhibited S. aureus exotoxin production while increasing production of protein A and not affecting bacterial growth. Pepsin but not trypsin digestion destroyed the ability of alpha and beta globin to inhibit exotoxin production. Exotoxin production by both methicillin-resistant and methicillin-susceptible organisms was inhibited. Production of streptococcal pyrogenic exotoxin A by Streptococcus pyogenes was unaffected by alpha and beta globin chains but was inhibited when produced in S. aureus. Use of isogenic S. aureus strains suggested the targets of alpha and beta globin chains, leading to inhibition of staphylococcal exotoxins, included the two-component system SrrA-SrrB. delta hemolysin production was also inhibited, suggesting the two-component (and quorum sensing) system AgrA-AgrC was targeted. The alpha and beta globin chains represent promising molecules to interfere with the pathogenesis of serious staphylococcal diseases.

Fungi in the genus Malassezia are ubiquitous skin residents of humans and other warm-blooded animals. Malassezia are involved in disorders including dandruff and seborrheic dermatitis, which together affect >50% of humans. Despite the importance of Malassezia in common skin diseases, remarkably little is known at the molecular level. We describe the genome, secretory proteome, and expression of selected genes of Malassezia globosa . Further, we report a comparative survey of the genome and secretory proteome of Malassezia restricta , a close relative implicated in similar skin disorders. Adaptation to the skin environment and associated pathogenicity may be due to unique metabolic limitations and capabilities. For example, the lipid dependence of M. globosa can be explained by the apparent absence of a fatty acid synthase gene. The inability to synthesize fatty acids may be complemented by the presence of multiple secreted lipases to aid in harvesting host lipids. In addition, an abundance of genes encoding secreted hydrolases (e.g., lipases, phospholipases, aspartyl proteases, and acid sphingomyelinases) was found in the M. globosa genome. In contrast, the phylogenetically closely related plant pathogen Ustilago maydis encodes a different arsenal of extracellular hydrolases with more copies of glycosyl hydrolase genes. M. globosa shares a similar arsenal of extracellular hydrolases with the phylogenetically distant human pathogen, Candida albicans , which occupies a similar niche, indicating the importance of host-specific adaptation. The M. globosa genome sequence also revealed the presence of mating-type genes, providing an indication that Malassezia may be capable of sex.