238 research outputs found
Recruitment of functionally distinct membrane proteins to chromatin mediates nuclear envelope formation in vivo
Formation of the nuclear envelope (NE) around segregated chromosomes occurs by the reshaping of the endoplasmic reticulum (ER), a reservoir for disassembled nuclear membrane components during mitosis. In this study, we show that inner nuclear membrane proteins such as lamin B receptor (LBR), MAN1, Lap2ÎČ, and the trans-membrane nucleoporins Ndc1 and POM121 drive the spreading of ER membranes into the emerging NE via their capacity to bind chromatin in a collaborative manner. Despite their redundant functions, decreasing the levels of any of these trans-membrane proteins by RNAi-mediated knockdown delayed NE formation, whereas increasing the levels of any of them had the opposite effect. Furthermore, acceleration of NE formation interferes with chromosome separation during mitosis, indicating that the time frame over which chromatin becomes membrane enclosed is physiologically relevant and regulated. These data suggest that functionally distinct classes of chromatin-interacting membrane proteins, which are present at nonsaturating levels, collaborate to rapidly reestablish the nuclear compartment at the end of mitosis
Induction of Macrophage Chemotaxis by Aortic Extracts from Patients with Marfan Syndrome Is Related to Elastin Binding Protein
Marfan syndrome is an autosomal dominantly inherited disorder of connective tissue with prominent skeletal, ocular, and cardiovascular manifestations. Aortic aneurysm and dissection are the major determinants of premature death in untreated patients. In previous work, we showed that extracts of aortic tissues from the mgR mouse model of Marfan syndrome showed increased chemotactic stimulatory activity related to the elastin-binding protein. Aortic samples were collected from 6 patients with Marfan syndrome and 8 with isolated aneurysms of the ascending aorta. Control samples were obtained from 11 organ donors without known vascular or connective tissue diseases. Soluble proteins extracted from the aortic samples of the two patient groups were compared against buffer controls and against the aortic samples from controls with respect to the ability to induce macrophage chemotaxis as measured using a modified Boyden chamber, as well as the reactivity to a monoclonal antibody BA4 against bioactive elastin peptides using ELISA. Samples from Marfan patients displayed a statistically significant increase in chemotactic inductive activity compared to control samples. Additionally, reactivity to BA4 was significantly increased. Similar statistically significant increases were identified for the samples from patients with idiopathic thoracic aortic aneurysm. There was a significant correlation between the chemotactic index and BA4 reactivity, and the increases in chemotactic activity of extracts from Marfan patients could be inhibited by pretreatment with lactose, VGVAPG peptides, or BA4, which indicates the involvement of EBP in mediating the effects. Our results demonstrate that aortic extracts of patients with Marfan syndrome can elicit macrophage chemotaxis, similar to our previous study on aortic extracts of the mgR mouse model of Marfan syndrome (Guo et al., Circulation 2006; 114:1855-62)
α2C-Adrenoceptor polymorphism is associated with improved event-free survival in patients with dilated cardiomyopathy
Aims The sympathetic nervous system plays a central role in cardiac growth but its overstimulation is associated with increased mortality in patients with chronic heart failure. Pre-synaptic α2-adrenoceptors are essential feedback regulators to control the release of norepinephrine from sympathetic nerves. In this study we tested whether a deletion polymorphism in the human α2C-adrenoceptor gene (α2CDel322-325) affects progression of heart failure in patients with dilated cardiomyopathy (DCM). Methods and results We genotyped and phenotyped 345 patients presenting with DCM in the heart transplant unit of the German Heart Institute, starting in 1994. Patients were treated according to guidelines (99% ACEI, 76% ÎČ-blockers) and were followed until December 2002 or until a first event [death, heart transplantation, or implantation of a left ventricular assist device (LVAD) for a life-threatening condition] occurred. Mean follow-up time was 249 weeks (4.9â
years) in event-free patients and 104 weeks (2â
years) in patients with events. During follow-up, 51% of the patients exhibited an event: death (18%), implantation of LVAD as bridging for transplantation (7%), or heart transplantation (25%). By Kaplan-Meier analysis, DCM patients with the deletion variant Del322-325 in the α2C-adrenoceptor showed significantly decreased event rates (P=0.0043). Cox regression analysis revealed that the presence of the deletion was associated with reduced death rate (relative risk: 0.129, 95% CI: 0.18-0.9441, P=0.044) and event rates (relative risk: 0.167, 95% CI: 0.041-0.685, P=0.012). Conclusion α2C-Adrenoceptor deletion may be a novel, strong, and independent predictor of reduced event rates in DCM patients treated according to guideline
Age Mosaicism across Multiple Scales in Adult Tissues
Most neurons are not replaced during an animalâs lifetime. This nondividing state is characterized by extreme longevity and age-dependent decline of key regulatory proteins. To study the lifespans of cells and proteins in adult tissues, we combined isotope labeling of mice with a hybrid imaging method (MIMS-EM). Using ^(15)N mapping, we show that liver and pancreas are composed of cells with vastly different ages, many as old as the animal. Strikingly, we also found that a subset of fibroblasts and endothelial cells, both known for their replicative potential, are characterized by the absence of cell division during adulthood. In addition, we show that the primary cilia of beta cells and neurons contains different structural regions with vastly different lifespans. Based on these results, we propose that age mosaicism across multiple scales is a fundamental principle of adult tissue, cell, and protein complex organization
Detection of Gender Differences in Incomplete Revascularization after Coronary Artery Bypass Surgery Varies with Classification Technique
Background. Incomplete revascularization negatively affects survival after coronary artery bypass surgery (CABG). Since gender and classification technique might impact outcome and reporting, we investigated their effect on revascularization patterns and mortality. Methods. A cohort of bypass patients ( = 1545, 23% women) was enrolled prospectively. The degree of revascularization was determined as mathematical difference between affected vessels upon diagnosis and number of grafts or the surgeon's rating on the case file. Results. Although men displayed more triple-vessel disease, they obtained complete revascularization more frequently than women (85% versus 77%, < 0.001). The two calculation methods identified analogous percentages of incompletely revascularized patients, yet there was only a 50% overlap between the two groups. Mathematically, more women, older patients, and patients with NYHA class III/IV appeared incompletely revascularized, while the surgeons identified more patients undergoing technically challenging procedures. Regardless of the definition, incompleteness was a significant risk factor for mortality in both genders (mathematical calculation: HR 2.62, 95% CI 1.76-3.89, < 0.001; surgeon: HR 2.04, 95% CI 1.35-3.89, = 0.001). Conclusions. Given the differences in identification patterns, we advise that the mathematical calculation be performed afterprocedure in all patients regardless of the surgeons' rating to uncover additional subjects at increased risk
Altered Coupling of Psychological Relaxation and Regional Volume of Brain Reward Areas in Multiple Sclerosis
Background:Psychological stress can influence the severity of multiple sclerosis (MS), but little is known about neurobiological factors potentially counteracting these effects. Objective:To identify gray matter (GM) brain regions related to relaxation after stress exposure in persons with MS (PwMS). Methods:36 PwMS and 21 healthy controls (HCs) reported their feeling of relaxation during a mild stress task. These markers were related to regional GM volumes, heart rate, and depressive symptoms. Results:Relaxation was differentially linked to heart rate in both groups (t= 2.20,p= 0.017), i.e., both markers were only related in HCs. Relaxation was positively linked to depressive symptoms across all participants (t= 1.99,p= 0.045) although this link differed weakly between groups (t= 1.62,p= 0.108). Primarily, the volume in medial temporal gyrus was negatively linked to relaxation in PwMS (t= -5.55, p(family-wise-error(FWE)corrected)= 0.018). A group-specific coupling of relaxation and GM volume was found in ventromedial prefrontal cortex (VMPFC) (t= -4.89, p(FWE)= 0.039). Conclusion:PwMS appear unable to integrate peripheral stress signals into their perception of relaxation. Together with the group-specific coupling of relaxation and VMPFC volume, a key area of the brain reward system for valuation of affectively relevant stimuli, this finding suggests a clinically relevant misinterpretation of stress-related affective stimuli in MS
The Conserved Nup107-160 Complex Is Critical for Nuclear Pore Complex Assembly
AbstractNuclear pore complexes (NPCs) are large multiprotein assemblies that allow traffic between the cytoplasm and the nucleus. During mitosis in higher eukaryotes, the Nuclear Envelope (NE) breaks down and NPCs disassemble. How NPCs reassemble and incorporate into the NE upon mitotic exit is poorly understood. We demonstrate a function for the conserved Nup107-160 complex in this process. Partial in vivo depletion of Nup133 or Nup107 via RNAi in HeLa cells resulted in reduced levels of multiple nucleoporins and decreased NPC density in the NE. Immunodepletion of the entire Nup107-160 complex from in vitro nuclear assembly reactions produced nuclei with a continuous NE but no NPCs. This phenotype was reversible only if Nup107-160 complex was readded before closed NE formation. Depletion also prevented association of FG-repeat nucleoporins with chromatin. We propose a stepwise model in which postmitotic NPC assembly initiates on chromatin via early recruitment of the Nup107-160 complex
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