Ventricular‐Vascular Coupling in Marfan and Non‐Marfan Aortopathies

Background: Marfan syndrome (MFS) and familial non–syndromal thoracic aortic aneurysm and dissection (ns‐TAAD) are genetic aortopathies causing aortic dilatation with increased aortic stiffness. Left ventricular (LV) contractility and ventricular‐vascular coupling index (VVI) were compared between MFS and ns‐TAAD and determinants of VVI were investigated. Methods and Results: Patients with MFS (M 57, F 47) and ns‐TAAD (M 72, F 39) were studied by echocardiography and compared with controls (M 77, F 71). Aortic geometry, hemodynamics, LV work, LV contractility (end‐systolic elastance [Ees]), and VVI were documented. Aortic sinuses were equally dilated in MFS (19.7±2.4) and ns‐TAAD (19.8±1.8) compared to controls (16.2±1.4 mm·m−2, P<0.001). Aortic stiffness index was increased in MFS (9.7±5.1) and ns‐TAAD (10.8±4.7) versus controls (5.4±2.0, P<0.01); LV stroke work was unchanged in MFS (436±74) compared to controls (435±60) but increased in ns‐TAAD (492±109 mJ·m−2 P<0.01). The LV Ees was reduced in MFS (1.32±0.19) compared to controls (1.65±0.29 mm Hg·mL−1, P<0.01) but increased in ns‐TAAD (1.83±0.30, P<0.01) and VVI was abnormal in MFS (0.71±0.11) compared to controls (0.62±0.07, P<0.01) and ns‐TAAD (0.62±0.09). Treatment with β‐blockers was associated with partial normalization of VVI in MFS. A VVI ≥0.8 was associated with increased risk of death and heart failure in MFS. Conclusions: Left ventricular contractility and ventricular‐vascular coupling are abnormal in MFS but preserved in ns‐TAAD, and are independent of aortic stiffness, consistent with intrinsic impairment of myocardial contractility in MFS

Structural basis for phosphorylation and lysine acetylation cross-talk in a kinase motif associated with myocardial ischemia and cardioprotection

Myocardial ischemia and cardioprotection by ischemic pre-conditioning induce signal networks aimed at survival or cell death if the ischemic period is prolonged. These pathways are mediated by protein post-translational modifications that are hypothesized to cross-talk with and regulate each other. Phosphopeptides and lysine-acetylated peptides were quantified in isolated rat hearts subjected to ischemia or ischemic pre-conditioning, with and without splitomicin inhibition of lysine deacetylation. We show lysine acetylation (acetyl-Lys)-dependent activation of AMP-activated protein kinase, AKT, and PKA kinases during ischemia. Phosphorylation and acetyl-Lys sites mapped onto tertiary structures were proximal in >50% of proteins investigated, yet they were mutually exclusive in 50 ischemic pre-conditioning- and/or ischemia-associated peptides containing the KXXS basophilic protein kinase consensus motif. Modifications in this motif were modeled in the C terminus of muscle-type creatine kinase. Acetyl-Lys increased proximal dephosphorylation by 10-fold. Structural analysis of modified muscle-type creatine kinase peptide variants by two-dimensional NMR revealed stabilization via a lysine-phosphate salt bridge, which was disrupted by acetyl-Lys resulting in backbone flexibility and increased phosphatase accessibility

CD64 plays a key role in diabetic wound healing

IntroductionWound healing poses a clinical challenge in diabetes mellitus (DM) due to compromised host immunity. CD64, an IgG-binding Fcgr1 receptor, acts as a pro-inflammatory mediator. While its presence has been identified in various inflammatory diseases, its specific role in wound healing, especially in DM, remains unclear.ObjectivesWe aimed to investigate the involvement of CD64 in diabetic wound healing using a DM animal model with CD64 KO mice.MethodsFirst, we compared CD64 expression in chronic skin ulcers from human DM and non-DM skin. Then, we monitored wound healing in a DM mouse model over 10 days, with or without CD64 KO, using macroscopic and microscopic observations, as well as immunohistochemistry.ResultsCD64 expression was significantly upregulated (1.25-fold) in chronic ulcerative skin from DM patients compared to non-DM individuals. Clinical observations were consistent with animal model findings, showing a significant delay in wound healing, particularly by day 7, in CD64 KO mice compared to WT mice. Additionally, infiltrating CD163+ M2 macrophages in the wounds of DM mice decreased significantly compared to non-DM mice over time. Delayed wound healing in DM CD64 KO mice correlated with the presence of inflammatory mediators.ConclusionCD64 seems to play a crucial role in wound healing, especially in DM conditions, where it is associated with CD163+ M2 macrophage infiltration. These data suggest that CD64 relies on host immunity during the wound healing process. Such data may provide useful information for both basic scientists and clinicians to deal with diabetic chronic wound healing

A brown dwarf candidate in the Praesepe Open Cluster

We present optical and infrared observations of RPr1, a faint (I = 21.01) and very red object (I - K = 4.57) discovered in a deep CCD survey, covering an area of 800 square arcmin of the Praesepe open cluster. A low resolution spectrum shows that RPr1 is a very late object, the latest object in Praesepe for which a spectrum has been taken to date. Our estimates give a mass between 0.063 and 0.084 solar masses, and indicate that RPr1 may turn out to be the first brown dwarf in this cluster.Comment: 7 pages, 3 Postscript figures, to be published in The Astrophysical Journal Letter

What’s in a “research passport”? A collaborative autoethnography of institutional approvals in public involvement in research

© 2016 Laterza et al. Background In the growing literature on public involvement in research (PIR), very few works analyse PIR organizational and institutional dimensions in depth. We explore the complex interactions of PIR with institutions and bureaucratic procedures, with a focus on the process of securing institutional permissions for members of the public (we refer to them as “research partners”) and academics involved in health research. Methods We employ a collaborative autoethnographic approach to describe the process of validating “research passports” required by UK NHS trusts, and the individual experiences of the authors who went through this journey– research partners and academics involved in a qualitative study of PIR across eight health sciences projects in England and Wales. Results Our findings show that research partners encountered many challenges, as the overall bureaucratic procedures and the emotional work required to deal with them proved burdensome. The effects were felt by the academics too who had to manage the whole process at an early stage of team building in the project. Our thematic discussion focuses on two additional themes: the emerging tensions around professionalisation of research partners, and the reflexive effects on PIR processes. Conclusions In the concluding section, we make a number of practical recommendations. Project teams should allow enough time to go through all the hurdles and steps required for institutional permissions, and should plan in advance for the right amount of time and capacity needed from project leaders and administrators. Our findings are a reminder that the bureaucratic and organisational structures involved in PIR can sometimes produce unanticipated and unwanted negative effects on research partners, hence affecting the overall quality and effectiveness of PIR. Our final recommendation to policy makers is to focus their efforts on making PIR bureaucracy more inclusive and ultimately more democratic

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The Epidemiology of COVID-19 in the Gansu and Jinlin Provinces, China

The COVID-19 outbreak has become a pandemic. The outbreak was able to be controlled in China by mid-April through the implementation of critical measures; however, significant reverse transmission has resulted in hot spots perturbing prevention and control. To date, there have only been a total of 92 indigenous COVID-19 cases confirmed in the Gansu Province, which is considered to be a consequence of the strict screening approach applied during the outbreak. The emergency response level to COVID-19 were able to be decreased from high to low, despite some relatively minor reverse transmission cases from other countries in March 2020. The stringent preparative measures undertaken by the Gansu authorities, involving high-level, streamlined cooperation between the transportation, quarantine, and medical resource departments, have underpinned this success. There has been an emergence of clusters of freshly infected COVID-19 patients in the Jilin Province in northeast China. The single largest cluster has been in Shulan of the Jilin Province, involving 43 confirmed infections. A strict lockdown was implemented immediately. The source of the current outbreak of COVID-19 is suggested to be travelers returning from Russia. The current strategy from the Chinese authorities is aimed at preventing reverse transmission via international importation to avert a rebound of COVID-19 in China. These data highlight the need for an exceptionally high level of vigilance and for a pre-emptive response that is informative for the development of policy to prevent a second and further waves of infections in general

FTO associations with obesity and telomere length

Abstract This review examines the biology of the Fat mass- and obesity-associated gene (FTO), and the implications of genetic association of FTO SNPs with obesity and genetic aging. Notably, we focus on the role of FTO in the regulation of methylation status as possible regulators of weight gain and genetic aging. We present a theoretical review of the FTO gene with a particular emphasis on associations with UCP2, AMPK, RBL2, IRX3, CUX1, mTORC1 and hormones involved in hunger regulation. These associations are important for dietary behavior regulation and cellular nutrient sensing via amino acids. We suggest that these pathways may also influence telomere regulation. Telomere length (TL) attrition may be influenced by obesity-related inflammation and oxidative stress, and FTO gene-involved pathways. There is additional emerging evidence to suggest that telomere length and obesity are bi-directionally associated. However, the role of obesity risk-related genotypes and associations with TL are not well understood. The FTO gene may influence pathways implicated in regulation of TL, which could help to explain some of the non-consistent relationship between weight phenotype and telomere length that is observed in population studies investigating obesity

Diabetic retinopathy: reversibility of epigenetic modifications and new therapeutic targets

Abstract In recent years, considerable progress has been made in the molecular mechanisms of epigenetics in disease development and progression, the reversible characteristics of epigenetic modification provide new insights for the treatment of such diseases. The pathogenesis of diabetic retinopathy (DR) has not yet been fully understood, treatment of refractory and recurrent diabetic macular edema remains a big change in clinical practice. This review emphasizes that reversibility of epigenetic modification could provide a new strategy for the prevention and treatment of diseases

Molecular Mechanisms in Genetic Aortopathy–Signaling Pathways and Potential Interventions

Thoracic aortic disease affects people of all ages and the majority of those aged <60 years have an underlying genetic cause. There is presently no effective medical therapy for thoracic aneurysm and surgery remains the principal intervention. Unlike abdominal aortic aneurysm, for which the inflammatory/atherosclerotic pathogenesis is well established, the mechanism of thoracic aneurysm is less understood. This paper examines the key cell signaling systems responsible for the growth and development of the aorta, homeostasis of endothelial and vascular smooth muscle cells and interactions between pathways. The evidence supporting a role for individual signaling pathways in pathogenesis of thoracic aortic aneurysm is examined and potential novel therapeutic approaches are reviewed. Several key signaling pathways, notably TGF-β, WNT, NOTCH, PI3K/AKT and ANGII contribute to growth, proliferation, cell phenotype and survival for both vascular smooth muscle and endothelial cells. There is crosstalk between pathways, and between vascular smooth muscle and endothelial cells, with both synergistic and antagonistic interactions. A common feature of the activation of each is response to injury or abnormal cell stress. Considerable experimental evidence supports a contribution of each of these pathways to aneurysm formation. Although human information is less, there is sufficient data to implicate each pathway in the pathogenesis of human thoracic aneurysm. As some pathways i.e., WNT and NOTCH, play key roles in tissue growth and organogenesis in early life, it is possible that dysregulation of these pathways results in an abnormal aortic architecture even in infancy, thereby setting the stage for aneurysm development in later life. Given the fine tuning of these signaling systems, functional polymorphisms in key signaling elements may set up a future risk of thoracic aneurysm. Multiple novel therapeutic agents have been developed, targeting cell signaling pathways, predominantly in cancer medicine. Future investigations addressing cell specific targeting, reduced toxicity and also less intense treatment effects may hold promise for effective new medical treatments of thoracic aortic aneurysm