Physical and Mental Health Aging can cause one’s physical mobility to be compromised in various degrees by any of a number of benign conditions, such as spinal-disc disorders, imbalance conditions, ...and so on, that do not involve a compromise of intellectual function. Heart Disease (1931) by Dr. Paul Dudley White, Clinical Heart Disease (1936) by Dr. Samuel A. Levine, Diseases of the Heart (1949) by Dr. Charles K. Friedberg, and Diseases of the Heart and Circulation (1950) by Dr. Paul Wood, to name a few of the more prominent earlier textbooks. Since 1970, cardiology clinical research has exploded with randomized drug, device, diagnostic, and interventional clinical trials, often with involvement of basic scientists, that dramatically improved management of patients with hypertension, hypercholesterolemia, coronary heart disease, cardiomyopathy, heart block, risk of sudden cardiac death, heart failure, congenital heart disease, and genetic cardiac channelopathies. During the past 50 years, leadership in cardiology has been dominated by editor-in-chiefs and the editorial board members of the major cardiology journals (including the JACC, Circulation, and European Heart Journal families), or by involvement in multiedited textbooks such as Braunwald’s Heart Diseases: A Textbook of Cardiovascular Medicine (1980) and Hurst’s The Heart (1966).
Long‐term changes in global mean sea level (MSL) rise have important practical implications for shoreline and beach erosion, coastal wetlands inundation, storm surge flooding, and coastal ...development. Altimetry since 1993 indicates that global MSL rise has increased about 50% above the 20th century rise rate, from 2 to 3 mm yr−1. At the same time, both tide gauge measurements and altimetry indicate virtually no increase along the Pacific coast of North America during the satellite epoch. Here we show that the dynamical steric response of North Pacific eastern boundary ocean circulation to a dramatic change in wind stress curl, τxy, which occurred after the mid‐1970s regime shift, can account for the suppression of regional sea level rise along this coast since 1980. Alarmingly, mean τxy over the North Pacific recently reached levels not observed since before the mid‐1970s regime shift. This change in wind stress patterns may be foreshadowing a Pacific Decadal Oscillation regime shift, causing an associated persistent change in basin‐scale τxy that may result in a concomitant resumption of sea level rise along the U.S. West Coast to global or even higher rates.
Key Points
Suppression of sea level rise along the eastern boundary of the North Pacific
Suppression is caused primarily by regional changes in wind stress curl
Recent changes in wind stress curl suggest coastal sea level rise may accelerate
As adenosine 5′‐triphosphate (ATP) released from astrocytes can modulate many neural signaling systems, the triggers and pathways for this ATP release are important. Here, the ability of mechanical ...strain to trigger ATP release through pannexin channels and the effects of sustained strain on pannexin expression were examined in rat optic nerve head astrocytes. Astrocytes released ATP when subjected to 5% of equibiaxial strain or to hypotonic swelling. Although astrocytes expressed mRNA for pannexins 1–3, connexin 43, and VNUT, pharmacological analysis suggested a predominant role for pannexins in mechanosensitive ATP release, with Rho kinase contribution. Astrocytes from panx1−/− mice had reduced baseline and stimulated levels of extracellular ATP, confirming the role for pannexins. Swelling astrocytes triggered a regulatory volume decrease that was inhibited by apyrase or probenecid. The swelling‐induced rise in calcium was inhibited by P2X7 receptor antagonists A438079 and AZ10606120, in addition to apyrase and carbenoxolone. Extended stretch of astrocytes in vitro upregulated expression of panx1 and panx2 mRNA. A similar upregulation was observed in vivo in optic nerve head tissue from the Tg‐MYOCY437H mouse model of chronic glaucoma; genes for panx1, panx2, and panx3 were increased, whereas immunohistochemistry confirmed increased expression of pannexin 1 protein. In summary, astrocytes released ATP in response to mechanical strain, with pannexin 1 the predominant efflux pathway. Sustained strain upregulated pannexins in vitro and in vivo. Together, these findings provide a mechanism by which extracellular ATP remains elevated under chronic mechanical strain, as found in the optic nerve head of patients with glaucoma. GLIA 2014;62:1486–1501
Main Points:
Mechanical strain triggers ATP release from astrocytes via pannexin 1.
Released ATP autostimulates P2X7 receptors.
Sustained stretch increased pannexin expression.
Mechanism for sustained elevation of extracellular ATP under chronic stretch.
Repair Schwann cells play a critical role in orchestrating nerve repair after injury, but the cellular and molecular processes that generate them are poorly understood. Here, we perform a combined ...whole-genome, coding and non-coding RNA and CpG methylation study following nerve injury. We show that genes involved in the epithelial-mesenchymal transition are enriched in repair cells, and we identify several long non-coding RNAs in Schwann cells. We demonstrate that the AP-1 transcription factor C-JUN regulates the expression of certain micro RNAs in repair Schwann cells, in particular miR-21 and miR-34. Surprisingly, unlike during development, changes in CpG methylation are limited in injury, restricted to specific locations, such as enhancer regions of Schwann cell-specific genes (e.g., Nedd4l), and close to local enrichment of AP-1 motifs. These genetic and epigenomic changes broaden our mechanistic understanding of the formation of repair Schwann cell during peripheral nervous system tissue repair.
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•Epithelial-mesenchymal genes are enriched in the injured nerve•Identification of differentially expressed lncRNAs following nerve injury•c-Jun regulates specific microRNA expression after nerve injury•Limited changes in CpG methylation following nerve injury
Arthur-Farraj et al. report a combined transcriptome and whole-genome CpG methylation study in repair Schwann cells after nerve injury. They identify Schwann cell-expressed lncRNAs and miRNAs under the control of c-Jun, as well differential methylation of enhancers of repair program genes.
Sorting of endocytic ligands and receptors is critical for diverse cellular processes. The physiological significance of endosomal sorting proteins in vertebrates, however, remains largely unknown. ...Here we report that sorting nexin 3 (Snx3) facilitates the recycling of transferrin receptor (Tfrc) and thus is required for the proper delivery of iron to erythroid progenitors. Snx3 is highly expressed in vertebrate hematopoietic tissues. Silencing of Snx3 results in anemia and hemoglobin defects in vertebrates due to impaired transferrin (Tf)-mediated iron uptake and its accumulation in early endosomes. This impaired iron assimilation can be complemented with non-Tf iron chelates. We show that Snx3 and Vps35, a component of the retromer, interact with Tfrc to sort it to the recycling endosomes. Our findings uncover a role of Snx3 in regulating Tfrc recycling, iron homeostasis, and erythropoiesis. Thus, the identification of Snx3 provides a genetic tool for exploring erythropoiesis and disorders of iron metabolism.
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► Snx3 is highly expressed in vertebrate hematopoietic tissues ► Silencing of Snx3 results in anemia and hemoglobin defects in vertebrates ► Snx3 and Vps35 physically interact with Tfrc ► Snx3 is required for endosomal recycling of Tf-Tfrc complex
The kinases MSK1 and MSK2 are activated 'downstream' of the p38 and Erk1/2 mitogen-activated protein kinases. Here we found that MSK1 and MSK2 were needed to limit the production of proinflammatory ...cytokines in response to stimulation of primary macrophages with lipopolysaccharide. By inducing transcription of the mitogen-activated protein kinase phosphatase DUSP1 and the anti-inflammatory cytokine interleukin 10, MSK1 and MSK2 exerted many negative feedback mechanisms. Deficiency in MSK1 and MSK2 prevented the binding of phosphorylated transcription factors CREB and ATF1 to the promoters of the genes encoding interleukin 10 and DUSP1. Mice doubly deficient in MSK1 and MSK2 were hypersensitive to lipopolysaccharide-induced endotoxic shock and showed prolonged inflammation in a model of toxic contact eczema induced by phorbol 12-myristate 13-acetate. Our results establish MSK1 and MSK2 as key components of negative feedback mechanisms needed to limit Toll-like receptor-driven inflammation.
The Risk for Type B Aortic Dissection in Marfan Syndrome den Hartog, Alexander W., MD; Franken, Romy, MD; Zwinderman, Aeilko H., PhD ...
Journal of the American College of Cardiology,
01/2015, Letnik:
65, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Abstract Background Aortic dissections involving the descending aorta are a major clinical problem in patients with Marfan syndrome. Objectives The purpose of this study was to identify clinical ...parameters associated with type B aortic dissection and to develop a risk model to predict type B aortic dissection in patients with Marfan syndrome. Methods Patients with the diagnosis of Marfan syndrome and magnetic resonance imaging or computed tomographic imaging of the aorta were followed for a median of 6 years for the occurrence of type B dissection or the combined end point of type B aortic dissection, distal aortic surgery, and death. A model using various clinical parameters as well as genotyping was developed to predict the risk for type B dissection in patients with Marfan syndrome. Results Between 1998 and 2013, 54 type B aortic dissections occurred in 600 patients with Marfan syndrome (mean age 36 ± 14 years, 52% male). Independent variables associated with type B aortic dissection were prior prophylactic aortic surgery (hazard ratio: 2.1; 95% confidence interval: 1.2 to 3.8; p = 0.010) and a proximal descending aorta diameter ≥27 mm (hazard ratio: 2.2; 95% confidence interval: 1.1 to 4.3; p = 0.020). In the risk model, the 10-year occurrence of type B aortic dissection in low-, moderate-, and high-risk patients was 6%, 19%, and 34%, respectively. Angiotensin II receptor blocker therapy was associated with fewer type B aortic dissections (hazard ratio: 0.3; 95% confidence interval: 0.1 to 0.9; p = 0.030). Conclusions Patients with Marfan syndrome with prior prophylactic aortic surgery are at substantial risk for type B aortic dissection, even when the descending aorta is only slightly dilated. Angiotensin II receptor blocker therapy may be protective in the prevention of type B aortic dissections.
We show that a simplified, single-photodiode per polarization heterodyne receiver is able to directly suppress signal-signal beat interference (SSBI), without the need for cancellation in the digital ...domain. We characterize performance degradation due to SSBI, and show that a strong LO in the receiver can mitigate SSBI. Transmission of 400 Gb/s-class signals is shown over single fiber spans of up to 160 km, and over field-deployed metropolitan area fiber. These results indicate that a single photodiode can be used to receive complex optical signals in high speed fiber systems without the need for SSBI cancellation in the digital domain.
PPARγ is a critical transcriptional regulator of adipogenesis and type 2 immune responses, however until recently its role in type 2 innate lymphoid cells had not been characterised. In two papers in ...this issue of Mucosal Immunology, PPARγ is shown to have a dominant role in ILC2 responses, mediating IL-33-responsiveness and activation.
Many cancers utilize l-glutamine as a major energy source. Often cited in the literature as “l-glutamine addiction”, this well-characterized pathway involves hydrolysis of l-glutamine by a ...glutaminase to l-glutamate, followed by oxidative deamination, or transamination, to α-ketoglutarate, which enters the tricarboxylic acid cycle. However, mammalian tissues/cancers possess a rarely mentioned, alternative pathway (the glutaminase II pathway): l-glutamine is transaminated to α-ketoglutaramate (KGM), followed by ω-amidase (ωA)-catalyzed hydrolysis of KGM to α-ketoglutarate. The name glutaminase II may be confused with the glutaminase 2 (GLS2) isozyme. Thus, we recently renamed the glutaminase II pathway the “glutamine transaminase—ω-amidase (GTωA)” pathway. Herein, we summarize the metabolic importance of the GTωA pathway, including its role in closing the methionine salvage pathway, and as a source of anaplerotic α-ketoglutarate. An advantage of the GTωA pathway is that there is no net change in redox status, permitting α-ketoglutarate production during hypoxia, diminishing cellular energy demands. We suggest that the ability to coordinate control of both pathways bestows a metabolic advantage to cancer cells. Finally, we discuss possible benefits of GTωA pathway inhibitors, not only as aids to studying the normal biological roles of the pathway but also as possible useful anticancer agents.
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