•Longer-chain perfluoroalkyl substances strongly inhibited carboxylesterase.•The higher binding affinity caused more severe inhibition.•Inhibition kinetics was studied, and in vitro-in vivo ...extrapolation was performed.
Ion mobility spectrometry (IMS) is a rapid separation technique that has experienced exponential growth as a field of study. Interfacing IMS with mass spectrometry (IMS-MS) provides additional ...analytical power as complementary separations from each technique enable multidimensional characterization of detected analytes. IMS separations occur on a millisecond timescale, and therefore can be readily nested into traditional GC and LC/MS workflows. However, the continual development of novel IMS methods has generated some level of confusion regarding the advantages and disadvantages of each. In this critical insight, we aim to clarify some common misconceptions for new users in the community pertaining to the fundamental concepts of the various IMS instrumental platforms (i.e., DTIMS, TWIMS, TIMS, FAIMS, and DMA), while addressing the strengths and shortcomings associated with each. Common IMS-MS applications are also discussed in this review, such as separating isomeric species, performing signal filtering for MS, and incorporating collision cross-section (CCS) values into both targeted and untargeted omics-based workflows as additional ion descriptors for chemical annotation. Although many challenges must be addressed by the IMS community before mobility information is collected in a routine fashion, the future is bright with possibilities.
Medical-related professions are at high suicide risk. However, data are contradictory and comparisons were not made between gender, occupation and specialties, epochs of times. Thus, we conducted a ...systematic review and meta-analysis on suicide risk among health-care workers.
The PubMed, Cochrane Library, Science Direct and Embase databases were searched without language restriction on April 2019, with the following keywords: suicide* AND (« health care worker* » OR physician* OR nurse*). When possible, we stratified results by gender, countries, time, and specialties. Estimates were pooled using random-effect meta-analysis. Differences by study-level characteristics were estimated using stratified meta-analysis and meta-regression. Suicides, suicidal attempts, and suicidal ideation were retrieved from national or local specific registers or case records. In addition, suicide attempts and suicidal ideation were also retrieved from questionnaires (paper or internet).
The overall SMR for suicide in physicians was 1.44 (95CI 1.16, 1.72) with an important heterogeneity (I2 = 93.9%, p<0.001). Female were at higher risk (SMR = 1.9; 95CI 1.49, 2.58; and ES = 0.67; 95CI 0.19, 1.14; p<0.001 compared to male). US physicians were at higher risk (ES = 1.34; 95CI 1.28, 1.55; p <0.001 vs Rest of the world). Suicide decreased over time, especially in Europe (ES = -0.18; 95CI -0.37, -0.01; p = 0.044). Some specialties might be at higher risk such as anesthesiologists, psychiatrists, general practitioners and general surgeons. There were 1.0% (95CI 1.0, 2.0; p<0.001) of suicide attempts and 17% (95CI 12, 21; p<0.001) of suicidal ideation in physicians. Insufficient data precluded meta-analysis on other health-care workers.
Physicians are an at-risk profession of suicide, with women particularly at risk. The rate of suicide in physicians decreased over time, especially in Europe. The high prevalence of physicians who committed suicide attempt as well as those with suicidal ideation should benefits for preventive strategies at the workplace. Finally, the lack of data on other health-care workers suggest to implement studies investigating those occupations.
Nonalcoholic steatohepatitis (NASH) is a serious liver disease associated with obesity. Characterized by metabolic syndrome, hepatic steatosis, and liver inflammation, NASH is believed to be under ...the influence of the gut microflora. Here, the composition of gut bacterial communities of NASH, obese, and healthy children was determined by 16S ribosomal RNA pyrosequencing. In addition, peripheral blood ethanol was analyzed to monitor endogenous ethanol production of patients and healthy controls. UniFrac‐based principle coordinates analysis indicated that most of the microbiome samples clustered by disease status. Each group was associated with a unique pattern of enterotypes. Differences were abundant at phylum, family, and genus levels between healthy subjects and obese patients (with or without NASH), and relatively fewer differences were observed between obese and the NASH microbiomes. Among those taxa with greater than 1% representation in any of the disease groups, Proteobacteria, Enterobacteriaceae, and Escherichia were the only phylum, family and genus types exhibiting significant difference between obese and NASH microbiomes. Similar blood‐ethanol concentrations were observed between healthy subjects and obese non‐NASH patients, but NASH patients exhibited significantly elevated blood ethanol levels. Conclusions: The increased abundance of alcohol‐producing bacteria in NASH microbiomes, elevated blood‐ethanol concentration in NASH patients, and the well‐established role of alcohol metabolism in oxidative stress and, consequently, liver inflammation suggest a role for alcohol‐producing microbiota in the pathogenesis of NASH. We postulate that the distinct composition of the gut microbiome among NASH, obese, and healthy controls could offer a target for intervention or a marker for disease. (HEPATOLOGY 2013)
Two-dimensional (2D) crystalline materials possess unique structural, mechanical and electronic properties that make them highly attractive in many applications. Although there have been advances in ...preparing 2D materials that consist of one or a few atomic or molecular layers, bottom-up assembly of 2D crystalline materials remains a challenge and an active area of development. More challenging is the design of dynamic 2D lattices that can undergo large-scale motions without loss of crystallinity. Dynamic behaviour in porous three-dimensional (3D) crystalline solids has been exploited for stimuli-responsive functions and adaptive behaviour. As in such 3D materials, integrating flexibility and adaptiveness into crystalline 2D lattices would greatly broaden the functional scope of 2D materials. Here we report the self-assembly of unsupported, 2D protein lattices with precise spatial arrangements and patterns using a readily accessible design strategy. Three single- or double-point mutants of the C4-symmetric protein RhuA were designed to assemble via different modes of intermolecular interactions (single-disulfide, double-disulfide and metal-coordination) into crystalline 2D arrays. Owing to the flexibility of the single-disulfide interactions, the lattices of one of the variants ((C98)RhuA) are essentially defect-free and undergo substantial, but fully correlated, changes in molecular arrangement, yielding coherently dynamic 2D molecular lattices. (C98)RhuA lattices display a Poisson's ratio of -1-the lowest thermodynamically possible value for an isotropic material-making them auxetic.
Pathogenesis of nonalcoholic steatohepatitis Liu, Wensheng; Baker, Robert D.; Bhatia, Tavleen ...
Cellular and molecular life sciences : CMLS,
05/2016, Letnik:
73, Številka:
10
Journal Article
Recenzirano
Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease and a risk factor for cirrhosis and hepatocellular carcinoma. The pathological features of NASH include ...steatosis, hepatocyte injury, inflammation, and various degrees of fibrosis. Steatosis reflects disordered lipid metabolism. Insulin resistance and excessive fatty acid influx to the liver are two important contributing factors. Steatosis is also likely associated with lipotoxicity and cellular stresses such as oxidative stress and endoplasmic reticulum stress, which result in hepatocyte injury. Inflammation and fibrosis are frequently triggered by various signals such as proinflammatory cytokines and chemokines, released by injuried hepatocytes and activated Kupffer cells. Although much progress has been made, the pathogenesis of NASH is not fully elucidated. The purpose of this review is to discuss the current understanding of NASH pathogenesis, mainly focusing on factors contributing to steatosis, hepatocyte injury, inflammation, and fibrosis.
Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor that antagonizes the phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR pathway by functioning as a lipid phosphatase. ...This ubiquitous and evolutionarily conserved signaling cascade influences numerous functions including cell growth, survival, proliferation, migration and metabolism. Inherited mutations in PTEN cause pleiotropic effects including cancer predisposition as well as a range of neurological abnormalities revealing specialized roles for PTEN in nervous system development and maintenance. Somatic mutations in PTEN occur frequently as late events in sporadic brain tumors. Mouse models based on Pten deletion in the brain have provided insights into the normal functions of Pten in the nervous system as well as the initiation and progression of gliomas. Compromised PTEN function may contribute to gliomagenesis through disrupted regulation of proliferation, migration, invasion, angiogenesis, stem cell self-renewal and regulation of other tumor suppressor pathways such as p53. Clinical findings in high-grade glioma suggest that PTEN gene alterations are associated with poor prognosis and may influence response to specific therapies. Emerging research using specific pharmacological inhibitors of the PI3K pathway may provide novel therapeutic options for the treatment of PTEN-deficient tumors.
Wild-type D. melanogaster males innately possess the ability to perform a multistep courtship ritual to conspecific females. The potential for this behavior is specified by the male-specific products ...of the fruitless (fruM) gene; males without fruM do not court females when held in isolation. We show that such fruM null males acquire the potential for courtship when grouped with other flies; they apparently learn to court flies with which they were grouped, irrespective of sex or species and retain this behavior for at least a week. The male-specific product of the doublesex gene (dsxM) is necessary and sufficient for the acquisition of the potential for such experience-dependent courtship. These results reveal a process that builds, via dsxM and social experience, the potential for a more flexible sexual behavior, which could be evolutionarily conserved as dsx-related genes that function in sexual development are found throughout the animal kingdom.
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•Naive fruM null males do not court, but after group-housing they do court•dsxM is necessary and sufficient for such fruM-independent courtship•Socially experienced fruM null males retain the ability to court for a week or more•The mate preference of experienced fruM males is dependent on prior experiences
Male flies lacking the fruitless gene can still carry out courtship behavior, but they lose the innate preference for courting conspecific females, and instead show a courting preference for flies with which they have been housed—be they males or females or females from another species.
We review recent findings and hypotheses on the roles of gut microbiome in the pathogenesis of nonalcoholic fatty liver diseases (NAFLD). Microbial metabolites and cell components contribute to the ...development of hepatic steatosis and inflammation, key components of nonalcoholic steatohepatitis (NASH), the severe form of NAFLD. Altered gut microbiome can independently cause obesity, the most important risk factor for NAFLD. This capability is attributed to short-chain fatty acids (SCFAs), major gut microbial fermentation products. SCFAs account for a large portion of caloric intake of the host, and they enhance intestinal absorption by activating GLP-2 signaling. However, elevated SCFAs may be an adaptive measure to suppress colitis, which could be a higher priority than imbalanced calorie intake. The microbiome of NASH patients features an elevated capacity for alcohol production. The pathomechanisms for alcoholic steatohepatitis may apply to NASH. NAFLD/NASH is associated with elevated Gram-negative microbiome and endotoxemia. However, many NASH patients exhibited normal serum endotoxin indicating that endotoxemia is not required for the pathogenesis of NASH. These observations suggest that microbial intervention may benefit NAFLD/NASH patients. However, very limited effects were observed using traditional probiotic species. Novel probiotic therapy based on NAFLD/NASH specific microbial composition represents a promising future direction.
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