Lck and Zap70, two non-receptor tyrosine kinases, play a crucial role in the regulation of membrane proximal TCR signaling critical for thymic selection, CD4/CD8 lineage choice and mature T cell ...function. Signal initiation upon TCR/CD3 and peptide/MHC interaction induces Lck-mediated phosphorylation of CD3 ITAMs. This is necessary for Zap70 recruitment and its phosphorylation by Lck leading to full Zap70 activation. In its native state Zap70 maintains a closed conformation creating an auto-inhibitory loop, which is relieved by Lck-mediated phosphorylation of Y315/Y319. Zap70 is differentially expressed in thymic subsets and mature T cells with CD8 T cells expressing the highest amount compared to CD4 T cells. However, the mechanistic basis of differential Zap70 expression in thymic subsets and mature T cells is not well understood. Here, we show that Zap70 is degraded relatively faster in DP and mature CD4 T cells compared to CD8 T cells, and inversely correlated with relative level of activated Zap70. Importantly, we found that Zap70 expression is negatively regulated by Lck activity: augmented Lck activity resulting in severe diminution in total Zap70. Moreover, Lck-mediated phosphorylation of Y315/Y319 was essential for Zap70 degradation. Together, these data shed light on the underlying mechanism of Lck-mediated differential modulation of Zap70 expression in thymic subsets and mature T cells.
The three-spined stickleback is a widespread Holarctic species complex that radiated from the sea into freshwaters after the retreat of the Pleistocene ice sheets. In Switzerland, sticklebacks were ...absent with the exception of the far northwest, but different introduced populations have expanded to occupy a wide range of habitats since the late 19th century. A well-studied adaptive phenotypic trait in sticklebacks is the number of lateral plates. With few exceptions, freshwater and marine populations in Europe are fixed for either the low plated phenotype or the fully plated phenotype, respectively. Switzerland, in contrast, harbours in close proximity the full range of phenotypic variation known from across the continent. We addressed the phylogeographic origins of Swiss sticklebacks using mitochondrial partial cytochrome b and control region sequences. We found only five different haplotypes but these originated from three distinct European regions, fixed for different plate phenotypes. These lineages occur largely in isolation at opposite ends of Switzerland, but co-occur in a large central part. Across the country, we found a strong correlation between a microsatellite linked to the high plate ectodysplasin allele and the mitochondrial haplotype from a region where the fully plated phenotype is fixed. Phylogenomic and population genomic analysis of 481 polymorphic amplified fragment length polymorphism loci indicate genetic admixture in the central part of the country. The same part of the country also carries elevated within-population phenotypic variation. We conclude that during the recent invasive range expansion of sticklebacks in Switzerland, adaptive and neutral between-population genetic variation was converted into within-population variation, raising the possibility that hybridization between colonizing lineages contributed to the ecological success of sticklebacks in Switzerland.
Abstract Background Recent trials of fish oil for the prevention of atrial fibrillation (AF) recurrence have provided mixed results. Notable uncertainties in the existing evidence base include the ...roles of high-dose fish oil, inflammation, and oxidative stress in patients with paroxysmal or persistent AF not receiving conventional antiarrhythmic (AA) therapy. Objectives The aim of this study was to evaluate the influence of high-dose fish oil on AF recurrence, inflammation, and oxidative stress parameters. Methods We performed a double-blind, randomized, placebo-controlled, parallel-arm study in 337 patients with symptomatic paroxysmal or persistent AF within 6 months of enrollment. Patients were randomized to fish oil (4 g/day) or placebo and followed, on average, for 271 ± 129 days. Results The primary endpoint was time to first symptomatic or asymptomatic AF recurrence lasting >30 s. Secondary endpoints were high-sensitivity C-reactive protein (hs-CRP) and myeloperoxidase (MPO). The primary endpoint occurred in 64.1% of patients in the fish oil arm and 63.2% of patients in the placebo arm (hazard ratio: 1.10; 95% confidence interval: 0.84 to 1.45; p = 0.48). hs-CRP and MPO were within normal limits at baseline and decreased to a similar degree at 6 months (Δhs-CRP, 11% vs. −11%; ΔMPO, −5% vs. −9% for fish oil vs. placebo, respectively; p value for interaction = NS). Conclusions High-dose fish oil does not reduce AF recurrence in patients with a history of AF not receiving conventional AA therapy. Furthermore, fish oil does not reduce inflammation or oxidative stress markers in this population, which may explain its lack of efficacy. (Multi-center Study to Evaluate the Effect of N-3 Fatty Acids OMEGA-3 on Arrhythmia Recurrence in Atrial Fibrillation AFFORD; NCT01235130 ).
Summary Background Catheter ablation is increasingly used to manage atrial fibrillation, but arrhythmia recurrences are common. Adenosine might identify pulmonary veins at risk of reconnection by ...unmasking dormant conduction, and thereby guide additional ablation to improve arrhythmia-free survival. We assessed whether adenosine-guided pulmonary vein isolation could prevent arrhythmia recurrence in patients undergoing radiofrequency catheter ablation for paroxysmal atrial fibrillation. Methods We did this randomised trial at 18 hospitals in Australia, Europe, and North America. We enrolled patients aged older than 18 years who had had at least three symptomatic atrial fibrillation episodes in the past 6 months, and for whom treatment with an antiarrhythmic drug failed. After pulmonary vein isolation, intravenous adenosine was administered. If dormant conduction was present, patients were randomly assigned (1:1) to additional adenosine-guided ablation to abolish dormant conduction or to no further ablation. If no dormant conduction was revealed, randomly selected patients were included in a registry. Patients were masked to treatment allocation and outcomes were assessed by a masked adjudicating committee. Patients were followed up for 1 year. The primary outcome was time to symptomatic atrial tachyarrhythmia after a single procedure in the intention-to-treat population. The trial is registered with ClinicalTrials.gov , number NCT01058980. Findings Adenosine unmasked dormant pulmonary vein conduction in 284 (53%) of 534 patients. 102 (69·4%) of 147 patients with additional adenosine-guided ablation were free from symptomatic atrial tachyarrhythmia compared with 58 (42·3%) of 137 patients with no further ablation, corresponding to an absolute risk reduction of 27·1% (95% CI 15·9–38·2; p<0·0001) and a hazard ratio of 0·44 (95% CI 0·31–0·64; p<0·0001). Of 115 patients without dormant pulmonary vein conduction, 64 (55·7%) remained free from symptomatic atrial tachyarrhythmia (p=0·0191 vs dormant conduction with no further ablation). Occurrences of serious adverse events were similar in each group. One death (massive stroke) was deemed probably related to ablation in a patient included in the registry. Interpretation Adenosine testing to identify and target dormant pulmonary vein conduction during catheter ablation of atrial fibrillation is a safe and highly effective strategy to improve arrhythmia-free survival in patients with paroxysmal atrial fibrillation. This approach should be considered for incorporation into routine clinical practice. Funding Canadian Institutes of Health Research, St Jude Medical, Biosense-Webster, and M Lachapelle (Montreal Heart Institute Foundation).
Stress associated with caring for a mentally ill spouse can adversely affect the health status of caregivers and their children. Adding to the stress of caregiving is the stigma often placed against ...spouses and children of people with mental illness. Contrary to mental illness, many physical disorders such as cancer may be less stigmatized (expect pulmonary cancer). In this study, we measured externalized and internalized stigma, as well as psychological (depressive symptoms and stressful life events) and physiological (basal salivary cortisol levels) markers of stress in 115 spouses and 154 children of parents suffering from major depressive disorder, cancer, or no illness (control group). The results show that spouses and children from families with parental depression present significantly more externalized stigma than spouses and children from families with parental cancer or no illness, although we find no group differences on internalized stigma. The analysis did not show a significant group difference either for spouses or their children on depressive symptomatology, although spouses from the parental depression group reported greater work/family stress. Finally, we found that although for both spouses children the awakening cortisol response was greater on weekdays than on weekend days, salivary cortisol levels did not differ between groups. Bayes factor calculated on the null result for cortisol levels was greater than 100, providing strong evidence for the null hypothesis H0. Altogether, these results suggest an impact of stigma toward mental health disorder on psychological markers of stress but no impact of stigma on physiological markers of stress. We suggest that these results may be due to the characteristics of the families who participated in the present study.
There is accumulating evidence supporting the use of probiotics, which are defined as "live micro-organisms which, when administered in adequate amounts, confer a health benefit on the host", as a ...preventive measure against respiratory tract infections (RTI). Two recent meta-analyses showed probiotic consumption (daily intake of 107 to 1010 CFU in any form for up to 3 months) significantly reduced RTI duration, frequency, antibiotic use and work absenteeism.
The aim of this study was to assess the impact of probiotic use in terms of number of RTI episodes and days averted, and the number of antibiotic prescriptions and missed workdays averted, in the general population of Canada. In addition, the corresponding economic impact from both a healthcare payer and a productivity perspective was estimated.
A microsimulation model was developed to reproduce the Canadian population (sample rate of 1/1000 = 35 540 individuals) employing age and gender. RTI incidence was taken from FluWatch consultation rates for influenza-like illness (2013-14) and StatCan all-cause consultations statistics. The model was calibrated on a 2.1% RTI annual incidence in the general population (5.2 million RTI days) and included known risk factors (smoking status, shared living conditions and vaccination status). RTI-related antibiotic prescriptions and work absenteeism were obtained from the literature.
The results indicate that probiotic use saved 573 000-2.3 million RTI-days, according to the YHEC-Cochrane scenarios respectively. These reductions were associated with an avoidance of 52 000-84 000 antibiotic courses and 330 000-500 000 sick-leave days. A projection of corresponding costs reductions amounted to Can$1.3-8.9 million from the healthcare payer perspective and Can$61.2-99.7 million when adding productivity losses.
The analysis shows that the potential of probiotics to reduce RTI-related events may have a substantial clinical and economic impact in Canada.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Previous studies have reported that polyphenol-rich extracts from various sources can prevent obesity and associated gastro-hepatic and metabolic disorders in diet-induced obese (DIO) mice. However, ...whether such extracts can reverse obesity-linked metabolic alterations remains unknown. In the present study, we aimed to investigate the potential of a polyphenol-rich extract from cranberry (CE) to reverse obesity and associated metabolic disorders in DIO-mice.
Mice were pre-fed either a Chow or a High Fat-High Sucrose (HFHS) diet for 13 weeks to induce obesity and then treated either with CE (200 mg/kg, Chow + CE, HFHS + CE) or vehicle (Chow, HFHS) for 8 additional weeks.
CE did not reverse weight gain or fat mass accretion in Chow- or HFHS-fed mice. However, HFHS + CE fully reversed hepatic steatosis and this was linked to upregulation of genes involved in lipid catabolism (e.g., PPARα) and downregulation of several pro-inflammatory genes (eg, COX2, TNFα) in the liver. These findings were associated with improved glucose tolerance and normalization of insulin sensitivity in HFHS + CE mice. The gut microbiota of HFHS + CE mice was characterized by lower Firmicutes to Bacteroidetes ratio and a drastic expansion of Akkermansia muciniphila and, to a lesser extent, of Barnesiella spp, as compared to HFHS controls.
Taken together, our findings demonstrate that CE, without impacting body weight or adiposity, can fully reverse HFHS diet-induced insulin resistance and hepatic steatosis while triggering A. muciniphila blooming in the gut microbiota, thus underscoring the gut-liver axis as a primary target of cranberry polyphenols.
The eukaryotic translation initiation factor eIF4E is elevated in 30% of malignancies including M4/M5 subtypes of acute myeloid leukemia (AML). The oncogenic potential of eIF4E arises from its ...ability to bind the 7-methyl guanosine (m7G) cap on mRNAs, thereby selectively enhancing eIF4E-dependent nuclear mRNA export and translation. We tested the clinical efficacy of targeting eIF4E in M4/M5 AML patients with a physical mimic of the m7G cap, ribavirin. Among 11 evaluable patients there were 1 complete remission (CR), 2 partial remissions (PRs), 2 blast responses (BRs), 4 stable diseases (SDs), and 2 progressive diseases (PDs). Ribavirin-induced relocalization of nuclear eIF4E to the cytoplasm and reduction of eIF4E levels were associated with clinical response. Lack of response or relapse coincided with continued or renewed nuclear localization of eIF4E. This first clinical study to target eIF4E in human malignancy demonstrates clinical activity and associated molecular responses in leukemic blasts. This trial is registered at ClinicalTrials.gov (NCT00559091).
Blast crisis chronic myelogenous leukemia (CML-BC) and Philadelphia chromosome-positive (Ph1-positive) acute lymphocytic leukemia (ALL) are 2 fatal BCR/ABL-driven leukemias against which Abl kinase ...inhibitors fail to induce a long-term response. We recently reported that functional loss of protein phosphatase 2A (PP2A) activity is important for CML blastic transformation. We assessed the therapeutic potential of the PP2A activator FTY720 (2-amino-2-2-(4-octylphenyl)ethyl-1,3-propanediol hydrochloride), an immunomodulator in Phase III trials for patients with multiple sclerosis or undergoing organ transplantation, in CML-BC and Ph1 ALL patient cells and in in vitro and in vivo models of these BCR/ABL+ leukemias. Our data indicate that FTY720 induces apoptosis and impairs clonogenicity of imatinib/dasatinib-sensitive and -resistant p210/p190(BCR/ABL) myeloid and lymphoid cell lines and CML-BC(CD34+) and Ph1 ALL(CD34+/CD19+) progenitors but not of normal CD34+ and CD34+/CD19+ bone marrow cells. Furthermore, pharmacologic doses of FTY720 remarkably suppress in vivo p210/p190(BCR/ABL)-driven including p210/p190(BCR/ABL)(T315I) leukemogenesis without exerting any toxicity. Altogether, these results highlight the therapeutic relevance of rescuing PP2A tumor suppressor activity in Ph1 leukemias and strongly support the introduction of the PP2A activator FTY720 in the treatment of CML-BC and Ph1 ALL patients.
The oncogenic BCR/ABL kinase activity induces and maintains chronic myelogenous leukemia (CML). We show here that, in BCR/ABL-transformed cells and CML blast crisis (CML-BC) progenitors, the ...phosphatase activity of the tumor suppressor PP2A is inhibited by the BCR/ABL-induced expression of the PP2A inhibitor SET. In imatinib-sensitive and -resistant (T315I included) BCR/ABL
+ cell lines and CML-BC progenitors, molecular and/or pharmacological activation of PP2A promotes dephosphorylation of key regulators of cell proliferation and survival, suppresses BCR/ABL activity, and induces BCR/ABL degradation. Furthermore, PP2A activation results in growth suppression, enhanced apoptosis, restored differentiation, impaired clonogenic potential, and decreased in vivo leukemogenesis of imatinib-sensitive and -resistant BCR/ABL
+ cells. Thus, functional inactivation of PP2A is essential for BCR/ABL leukemogenesis and, perhaps, required for blastic transformation.
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