Type II secretion (T2S) is one means by which Gram-negative pathogens secrete proteins into the extracellular milieu and/or host organisms. Based upon recent genome sequencing, it is clear that T2S ...is largely restricted to the
, occurring in many, but not all, genera in the
,
,
, and
classes. Prominent human and/or animal pathogens that express a T2S system(s) include
,
,
,
,
,
,
,
,
, and
T2S-expressing plant pathogens include
,
,
,
,
,
, and
T2S also occurs in nonpathogenic bacteria, facilitating symbioses, among other things. The output of a T2S system can range from only one to dozens of secreted proteins, encompassing a diverse array of toxins, degradative enzymes, and other effectors, including novel proteins. Pathogenic processes mediated by T2S include the death of host cells, degradation of tissue, suppression of innate immunity, adherence to host surfaces, biofilm formation, invasion into and growth within host cells, nutrient assimilation, and alterations in host ion flux. The reach of T2S is perhaps best illustrated by those bacteria that clearly use it for both environmental survival and virulence; e.g.,
employs T2S for infection of amoebae, growth within lung cells, dampening of cytokines, and tissue destruction. This minireview provides an update on the types of bacteria that have T2S, the kinds of proteins that are secreted via T2S, and how T2S substrates promote infection.
Aptamers as Therapeutics Nimjee, Shahid M; White, Rebekah R; Becker, Richard C ...
Annual review of pharmacology and toxicology,
01/2017, Letnik:
57, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Aptamers are single-stranded nucleic acid molecules that bind to and inhibit proteins and are commonly produced by systematic evolution of ligands by exponential enrichment (SELEX). Aptamers undergo ...extensive pharmacological revision, which alters affinity, specificity, and therapeutic half-life, tailoring each drug for a specific clinical need. The first therapeutic aptamer was described 25 years ago. Thus far, one aptamer has been approved for clinical use, and numerous others are in preclinical or clinical development. This review presents a short history of aptamers and SELEX, describes their pharmacological development and optimization, and reviews potential treatment of diseases including visual disorders, thrombosis, and cancer.
Aberrant signaling through the class I phosphatidylinositol 3-kinase (PI3K)—Akt axis is frequent in human cancer. Here, we show that Beclin 1, an essential autophagy and tumor suppressor protein, is ...a target of the protein kinase Akt. Expression of a Beclin 1 mutant resistant to Akt-mediated phosphorylation increased autophagy, reduced anchorage-independent growth, and inhibited Akt-driven tumorigenesis. Akt-mediated phosphorylation of Beclin 1 enhanced its interactions with 14-3-3 and vimentin intermediate filament proteins, and vimentin depletion increased autophagy and inhibited Akt-driven transformation. Thus, Akt-mediated phosphorylation of Beclin 1 functions in autophagy inhibition, oncogenesis, and the formation of an autophagy-inhibitory Beclin 1/14-3-3/vimentin intermediate filament complex. These findings have broad implications for understanding the role of Akt signaling and intermediate filament proteins in autophagy and cancer.
Glucagon-like peptide 1 receptor (GLP-1R) agonists decrease body weight and improve glycemic control in obesity and diabetes. Patient compliance and maximal efficacy of GLP-1 therapeutics are limited ...by adverse side effects, including nausea and emesis. In three different species (i.e., mice, rats, and musk shrews), we show that glucose-dependent insulinotropic polypeptide receptor (GIPR) signaling blocks emesis and attenuates illness behaviors elicited by GLP-1R activation, while maintaining reduced food intake, body weight loss, and improved glucose tolerance. The area postrema and nucleus tractus solitarius (AP/NTS) of the hindbrain are required for food intake and body weight suppression by GLP-1R ligands and processing of emetic stimuli. Using single-nuclei RNA sequencing, we identified the cellular phenotypes of AP/NTS cells expressing GIPR and GLP-1R on distinct populations of inhibitory and excitatory neurons, with the greatest expression of GIPR in γ-aminobutyric acid-ergic neurons. This work suggests that combinatorial pharmaceutical targeting of GLP-1R and GIPR will increase efficacy in treating obesity and diabetes by reducing nausea and vomiting.
The stigma of mental illness in the labor market Hipes, Crosby; Lucas, Jeffrey; Phelan, Jo C. ...
Social science research,
March 2016, 2016-Mar, 2016-03-00, 20160301, Letnik:
56
Journal Article
Recenzirano
Odprti dostop
Mental illness labels are accompanied by devaluation and discrimination. We extend research on reactions to mental illness by utilizing a field experiment (N = 635) to test effects of mental illness ...labels on labor market discrimination. This study involved sending fictitious applications to job listings, some applications indicating a history of mental illness and some indicating a history of physical injury. In line with research indicating that mental illness leads to stigma, we predicted fewer callbacks to candidates with mental illness. We also predicted relatively fewer callbacks for applicants with mental illness when the jobs involved a greater likelihood for interpersonal contact with the employer. Results showed significant discrimination against applicants with mental illness, but did not indicate an effect of potential proximity to the employer. This contributes a valuable finding in a natural setting to research on labor market discrimination towards people with mental illness.
•Mental illness stigma is documented, but not recently tested in a natural setting.•We used an experiment to test discrimination against persons with mental illness.•We applied to jobs as an applicant with a history of injury or mental illness.•Our results demonstrate that mental illness stigma persists in the labor market.•Social distance between hirers and our applicant did not affect callback rates.
Chitinases are important enzymes that contribute to the generation of carbon and nitrogen from chitin, a long chain polymer of N-acetylglucosamine that is abundant in insects, fungi, invertebrates ...and fish. Although mammals do not produce chitin, chitinases have been identified in bacteria that are key virulence factors in severe respiratory, gastrointestinal and urinary diseases. However, it is unclear how these enzymes are able to carry out this dual function. Legionella pneumophila is the causative agent of Legionnaires' disease, an often-fatal pneumonia and its chitinase ChiA is essential for the survival of L. pneumophila in the lung. Here we report the first atomic resolution insight into the pathogenic mechanism of a bacterial chitinase. We derive an experimental model of intact ChiA and show how its N-terminal region targets ChiA to the bacterial surface after its secretion. We provide the first evidence that L. pneumophila can bind mucins on its surface, but this is not dependent on ChiA. This demonstrates that additional peripheral mucin binding proteins are also expressed in L. pneumophila. We also show that the ChiA C-terminal chitinase domain has novel Zn2+-dependent peptidase activity against mammalian mucin-like proteins, namely MUC5AC and the C1-esterase inhibitor, and that ChiA promotes bacterial penetration of mucin gels. Our findings suggest that ChiA can facilitate passage of L. pneumophila through the alveolar mucosa, can modulate the host complement system and that ChiA may be a promising target for vaccine development.
Chronic liver disease due to alcohol-use disorder contributes markedly to the global burden of disease and mortality
. Alcoholic hepatitis is a severe and life-threatening form of alcohol-associated ...liver disease. The gut microbiota promotes ethanol-induced liver disease in mice
, but little is known about the microbial factors that are responsible for this process. Here we identify cytolysin-a two-subunit exotoxin that is secreted by Enterococcus faecalis
-as a cause of hepatocyte death and liver injury. Compared with non-alcoholic individuals or patients with alcohol-use disorder, patients with alcoholic hepatitis have increased faecal numbers of E. faecalis. The presence of cytolysin-positive (cytolytic) E. faecalis correlated with the severity of liver disease and with mortality in patients with alcoholic hepatitis. Using humanized mice that were colonized with bacteria from the faeces of patients with alcoholic hepatitis, we investigated the therapeutic effects of bacteriophages that target cytolytic E. faecalis. We found that these bacteriophages decrease cytolysin in the liver and abolish ethanol-induced liver disease in humanized mice. Our findings link cytolytic E. faecalis with more severe clinical outcomes and increased mortality in patients with alcoholic hepatitis. We show that bacteriophages can specifically target cytolytic E. faecalis, which provides a method for precisely editing the intestinal microbiota. A clinical trial with a larger cohort is required to validate the relevance of our findings in humans, and to test whether this therapeutic approach is effective for patients with alcoholic hepatitis.
The aim of this study was to evaluate the incremental prognostic value of global coronary flow reserve (CFR) in patients with known or suspected coronary artery disease who were undergoing stress ...cardiac magnetic resonance (CMR) imaging.
Coronary microvascular dysfunction results in impaired global CFR and is implicated in the development of both atherosclerosis and heart failure. Although noninvasive assessment of CFR with positron emission tomography provides independent prognostic information, the incremental prognostic value of CMR-derived CFR remains unclear.
Consecutive patients undergoing stress perfusion CMR were prospectively enrolled (n = 507). Coronary sinus flow was measured using phase-contrast imaging at baseline (pre) and immediately after stress (peak) perfusion. CFR was calculated as the ratio of peak to pre-flow. Patients were followed for major adverse cardiac events (MACE): death, nonfatal myocardial infarction, heart failure hospitalization, sustained ventricular tachycardia, and late revascularization. Cox proportional hazards regression modeling was used to examine the association between CFR and MACE. The incremental prognostic value of CFR was assessed in nested models.
Over a median follow-up of 2.1 years, 80 patients experienced MACE. By Kaplan-Meier analysis, the risk of MACE was significantly higher in patients with CFR lower than the median (2.2) (log-rank p < 0.001); this remained significant after adjustment for the presence of ischemia and late gadolinium enhancement (LGE) (log-rank p < 0.001). CFR was significantly associated with the risk of MACE after adjustment for clinical and imaging risk factors, including ischemia extent, ejection fraction, and LGE size (hazard ratio: 1.238; p = 0.018). Addition of CFR in this model resulted in significant improvement in the C-index (from 0.70 to 0.75; p = 0.0087) and a continuous net reclassification improvement of 0.198 (95% confidence interval: 0.120 to 0.288).
CMR-derived CFR is an independent predictor of MACE in patients with known or suspected coronary artery disease, incremental to common clinical and CMR risk factors. These findings suggest a role for CMR-derived CFR in identifying patients at risk of adverse events following stress CMR, even in the absence of ischemia and LGE.
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The skeletal remains of a small bear (Protarctos abstrusus) were collected at the Beaver Pond fossil site in the High Arctic (Ellesmere I., Nunavut). This mid-Pliocene deposit has also yielded 12 ...other mammals and the remains of a boreal-forest community. Phylogenetic analysis reveals this bear to be basal to modern bears. It appears to represent an immigration event from Asia, leaving no living North American descendants. The dentition shows only modest specialization for herbivory, consistent with its basal position within Ursinae. However, the appearance of dental caries suggest a diet high in fermentable-carbohydrates. Fossil plants remains, including diverse berries, suggests that, like modern northern black bears, P. abstrusus may have exploited a high-sugar diet in the fall to promote fat accumulation and facilitate hibernation. A tendency toward a sugar-rich diet appears to have arisen early in Ursinae, and may have played a role in allowing ursine lineages to occupy cold habitats.
Excessive fibroproliferation is a central hallmark of idiopathic pulmonary fibrosis (IPF), a chronic, progressive disorder that results in impaired gas exchange and respiratory failure. Fibroblasts ...are the key effector cells in IPF, and aberrant expression of multiple genes contributes to their excessive fibroproliferative phenotype. DNA methylation changes are critical to the development of many diseases, but the DNA methylome of IPF fibroblasts has never been characterized. Here, we utilized the HumanMethylation 27 array, which assays the DNA methylation level of 27,568 CpG sites across the genome, to compare the DNA methylation patterns of IPF fibroblasts (n = 6) with those of nonfibrotic patient controls (n = 3) and commercially available normal lung fibroblast cell lines (n = 3). We found that multiple CpG sites across the genome are differentially methylated (as defined by P value less than 0.05 and fold change greater than 2) in IPF fibroblasts compared to fibroblasts from nonfibrotic controls. These methylation differences occurred both in genes recognized to be important in fibroproliferation and extracellular matrix generation, as well as in genes not previously recognized to participate in those processes (including organ morphogenesis and potassium ion channels). We used bisulfite sequencing to independently verify DNA methylation differences in 3 genes (CDKN2B, CARD10, and MGMT); these methylation changes corresponded with differences in gene expression at the mRNA and protein level. These differences in DNA methylation were stable throughout multiple cell passages. DNA methylation differences may thus help to explain a proportion of the differences in gene expression previously observed in studies of IPF fibroblasts. Moreover, significant variability in DNA methylation was observed among individual IPF cell lines, suggesting that differences in DNA methylation may contribute to fibroblast heterogeneity among patients with IPF. These results demonstrate that IPF fibroblasts exhibit global differences in DNA methylation that may contribute to the excessive fibroproliferation associated with this disease.
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