Previous studies have demonstrated that activation of calcineurin induces pathological cardiac hypertrophy (CH). In these studies, loss‐of‐function was mostly achieved by systemic administration of ...the calcineurin inhibitor cyclosporin A. The lack of conditional knockout models for calcineurin function has impeded progress toward defining the role of this protein during the onset and the development of CH in adults. Here, we exploited a mouse model of CH based on the infusion of a hypertensive dose of angiotensin II (AngII) to model the role of calcineurin in CH in adulthood. AngII‐induced CH in adult mice was reduced by treatment with cyclosporin A, without affecting the associated increase in blood pressure, and also by induction of calcineurin deletion in adult mouse cardiomyocytes, indicating that cardiomyocyte calcineurin is required for AngII‐induced CH. Surprisingly, cardiac‐specific deletion of calcineurin, but not treatment of mice with cyclosporin A, significantly reduced AngII‐induced cardiac fibrosis and apoptosis. Analysis of profibrotic genes revealed that AngII‐induced expression of Tgfβ family members and Lox was not inhibited by cyclosporin A but was markedly reduced by cardiac‐specific calcineurin deletion. These results show that AngII induces a direct, calcineurin‐dependent prohypertrophic effect in cardiomyocytes, as well as a systemic hypertensive effect that is independent of calcineurin activity.
Cardiac hypertrophy (CH) has evolved as a protective mechanism to cope with cardiac stress; however, in a pathological context it is a major risk factor for heart failure. Previous studies have shown that pathological CH can be induced by activation of calcineurin. Here, Juan Miguel Redondo and colleagues established a conditional knockout model for calcineurin function in adult mice, based on induction of calcineurin activation by angiotensin II and inhibition of its activity by cyclosporin A. They demonstrate that the pro‐hypertrophic effect of angiotensin II in cardiomyocytes is calcineurin‐dependent, while its effect on blood pressure is independent of calcineurin activity.
MHCII in antigen-presenting cells (APCs) is a key regulator of adaptive immune responses. Expression of MHCII genes is controlled by the transcription coactivator CIITA, itself regulated through cell ...type-specific promoters. Here we show that the transcription factor NFAT5 is needed for expression of
and MHCII in macrophages, but not in dendritic cells and other APCs. NFAT5-deficient macrophages showed defective activation of MHCII-dependent responses in CD4
T lymphocytes and attenuated capacity to elicit graft rejection in vivo. Ultrasequencing analysis of NFAT5-immunoprecipitated chromatin uncovered an NFAT5-regulated region distally upstream of
This region was required for CIITA and hence MHCII expression, exhibited NFAT5-dependent characteristics of active enhancers such as H3K27 acetylation marks, and required NFAT5 to interact with
myeloid promoter I. Our results uncover an NFAT5-regulated mechanism that maintains CIITA and MHCII expression in macrophages and thus modulates their T lymphocyte priming capacity.
This edited volume examines the performance of physicians, psychiatrists and other scientists as expert witnesses in modern European courts of law and police investigations. Its chapters discuss ...cases from criminal, civil and international law to parse the impact of forensic evidence and expertise in different European countries (Scotland, England, Germany, Spain, Italy, Russia, Portugal, Norway and the Netherlands) in the nineteenth and twentieth centuries. They show how modern forensic science and technology was inextricably entangled with political ideology, gender norms, changes in the law and legal systems. New scientific ideas and technology, such as blood tests and DNA, helped develop forensic science, but did not necessarily lead to a straightforward acceptance of expertise in the courtroom. Discussing fascinating case studies, the chapters in this book highlight how the ideology of authoritarian and liberal regimes affected the practical enactment of forensic expertise. They also emphasise the influence of images of masculinity and femininity on the performance of experts and their assessment of evidence, victims and perpetrators, for example in cases of rape, infanticide and crimes of passion. This book is an important contribution to our knowledge of modern European forensic practices, which, as several chapters underline, sometimes surprisingly diverge from institutional regulations.
Nature is an amazing source of inspiration for the design of thermal insulation strategies, which are key for saving energy. In nature, thermal insulation structures, such as penguin feather and ...polar bear hair, are well developed; enabling the animals’ survival in frigid waters. The detailed microscopy investigations conducted in this study, allowed us to perform microstructural analysis of these thermally insulating materials, including statistical measurements of keratin fiber and pore dimensions directly from high resolution Scanning Electron Microscope (SEM) images. The microscopy study revealed many similarities in both materials, and showed the importance of their hierarchically-organized porous structure. Finally, we propose the schematic configuration of a thermally-insulating structure, based on the penguin feather and polar bear hair. These optimized thermal-insulator systems indicate the road maps for future development, and new approaches in the design of material properties.
We present the first detailed comparison of microstructures of penguin feather and polar bear hair for designing optimum thermal insulation properties. This unique study involves the measurement of the sizes of pores and fibers of these two keratin-based materials, including the investigation of their 3D arrangements. We revealed porosity interconnection, especially in polar bear hair, which is one of the key designs exhibited by thermal insulation materials.
Thoracic aortic aneurysm, as occurs in Marfan syndrome, is generally asymptomatic until dissection or rupture, requiring surgical intervention as the only available treatment. Here, we show that ...nitric oxide (NO) signaling dysregulates actin cytoskeleton dynamics in Marfan Syndrome smooth muscle cells and that NO-donors induce Marfan-like aortopathy in wild-type mice, indicating that a marked increase in NO suffices to induce aortopathy. Levels of nitrated proteins are higher in plasma from Marfan patients and mice and in aortic tissue from Marfan mice than in control samples, indicating elevated circulating and tissue NO. Soluble guanylate cyclase and cGMP-dependent protein kinase are both activated in Marfan patients and mice and in wild-type mice treated with NO-donors, as shown by increased plasma cGMP and pVASP-S239 staining in aortic tissue. Marfan aortopathy in mice is reverted by pharmacological inhibition of soluble guanylate cyclase and cGMP-dependent protein kinase and lentiviral-mediated Prkg1 silencing. These findings identify potential biomarkers for monitoring Marfan Syndrome in patients and urge evaluation of cGMP-dependent protein kinase and soluble guanylate cyclase as therapeutic targets.
Disrupted organ growth leads to disease development. Hypertrophy underlies postnatal heart growth and is triggered after stress, but the molecular mechanisms involved in these processes are largely ...unknown. Here we show that cardiac activation of p38γ and p38δ increases during postnatal development and by hypertrophy-inducing stimuli. p38γ/δ promote cardiac hypertrophy by phosphorylating the mTORC1 and mTORC2 inhibitor DEPTOR, which leads to its degradation and mTOR activation. Hearts from mice lacking one or both kinases are below normal size, have high levels of DEPTOR, low activity of the mTOR pathway and reduced protein synthesis. The phenotype of p38γ/δ(-/-) mice is reverted by overactivation of mTOR with amino acids, shRNA-mediated knockdown of Deptor, or cardiomyocyte overexpression of active p38γ and p38δ. Moreover, in WT mice, heart weight is reduced by cardiac overexpression of DEPTOR. Our results demonstrate that p38γ/δ control heart growth by modulating mTOR pathway through DEPTOR phosphorylation and subsequent degradation.
Purpose
Coffee is rich in bioactive compounds with health beneficial properties, with green coffee presenting higher phenol content than roasted. We evaluated the effects of regularly consuming ...realistic amounts of a green/roasted coffee blend on cardiovascular health-related biomarkers.
Methods
A randomized, cross-over, controlled study was carried out in 25 normocholesterolemic total cholesterol (TC) < 200 mg/dL and 27 hypercholesterolemic (TC 200–240 mg/dL) subjects. During 8 weeks, volunteers consumed 6 g/day of soluble green/roasted (35:65) coffee or a control beverage (water or an isotonic drink). Blood pressure, heart rate and body weight were monitored at the end of each intervention, and serum lipids TC, HDL-C, LDL-C, VLDL-C, triglycerides and phospholipids, cytokines and chemokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12, IL-13, IL-17, G-CSF, GM-CSF, MCP-1, MIP-1β, TNF-α, INF-γ), adhesion molecules (ICAM-1, VCAM-1), and C-reactive protein were measured. Plasma antioxidant capacity (FRAP, ORAC and ABTS methods), and lipid (malondialdehyde, MDA) and protein (carbonyl groups, CG) oxidation were also determined.
Results
Attending to the general lineal model of variance for repeated measures, after the green/roasted coffee intervention significant reductions in TC, LDL-C, VLDL-C and triglycerides levels (
p
= 0.006, 0.001, 0.003 and 0.017, respectively), and a significant group effect were observed (0.001, < 0.001, 0.019 and 0.027, respectively). Only within the hypercholesterolemic group, attending to the Bonferroni test, the aforementioned lipid parameters were significantly lower after regular green/roasted coffee intake compared to baseline values. Moreover, after the coffee stage, plasma antioxidant capacity improved, according to the increase in ORAC and FRAP values (
p
< 0.001 and
p
< 0.001, respectively) and decrease of MDA (
p
= 0.015) and CG (
p
< 0.001) levels, without differences between groups. Systolic (
p
= 0.001) and diastolic (
p
< 0.001) blood pressure, heart rate (
p
= 0.035), and body weight (
p
= 0.017) were reduced in both normo- and hypercholesterolemic groups.
Conclusion
Regular consumption of moderate amounts of a soluble green/roasted (35:65) coffee blend may contribute to improve cardiovascular health in moderately hypercholesterolemic people, as reducing serum lipids, blood pressure and body weight effects, as well as increasing plasma antioxidant capacity, have been observed. Moreover, positive influences on blood pressure, body weight, and plasma antioxidant capacity were obtained in the healthy group. Therefore, incorporation of green coffee beans into the coffee brew can be recommended as part of a dietary strategy to protect from cardiovascular disease.
Municipalities are key actors in planning and enabling the transition in the built environment to sustainable heat systems. Literature on the municipal experiences in the early phases of the heat ...transition is scarce. This paper addresses this gap by depicting the approaches of twenty-eight municipalities in the Netherlands. It aims to assess the municipal approaches to data collection, technology choice, and area prioritisation during the planning and (early) implementation stages and the barriers municipalities face. Identifying and choosing the optimal solutions per area requires numerous data, in-house knowledge and societal support. The lack of municipal capacity and know-how has led to a strong dependency on external expertise. District heating networks and heat pumps are presently seen as the most promising alternative systems, while building improvements are planned in areas when the technological choice is uncertain. Two important lock-in effects have hampered the local efforts to execute projects: a lack of binding policies to terminate natural gas use and poor affordability of the alternative heating systems. An overarching lesson is that the timely establishment of these aspects is critical to support the starting phase of the transition and that effective local governance cannot be achieved without centrally-established supportive mechanisms.
•We examined the efforts to decarbonise heating systems in buildings by local governments in the Netherlands.•Local heat planning and implementation is complex and requires high municipal capacity and know-how.•Regulatory, economic and technical lock-in effects are present.•Cost-efficiency alone gives poor guidance in selecting technical systems.•District heating, heat pumps and building insulation will play a significant role.
This study poses a methodology in order to simultaneously quantify ACC deaminase and IAA levels in the same culture medium. Ten bacterial strains isolated from plant rhizosphere naturally settled in ...mining residues were chosen. These bacterial strains were characterized as PGPB, and all of them showed at least three characteristics (indole-3 acetic acid and siderophore production, ACC deaminase enzyme activity, and inorganic phosphate solubilization). Taxonomic identification showed that the strains belong to Enterobacter, Serratia, Klebsiella, and Escherichia genera. Similarly, both the ACC deaminase enzyme activity and the IAA synthesis in the presence of Cu, As, Pb, Ni, Cd, and Mn were measured. The results showed that both the ACC deaminase enzyme activity and the IAA synthesis were higher with the Pb, As, and Cu treatments than with the Escherichia N16, Enterobacter K131, Enterobacter N9, and Serratia K120 control treatments. On the other hand, Ni, Cd, and Mn negatively affected both the ACC deaminase enzyme activity and the IAA production on every bacterium except on the Klebsiella Mc173 strain. Serratia K120 bacterium got a positive correlation between ACC deaminase and IAA in the presence of every heavy metal, and it also promoted Helianthus annuus plant growth, showing a potential use in phytoremediation systems.
Macrophages contribute to tissue homeostasis and influence inflammatory responses by modulating their phenotype in response to the local environment. Understanding the molecular mechanisms governing ...this plasticity would open new avenues for the treatment for inflammatory disorders. We show that deletion of calcineurin (CN) or its inhibition with LxVP peptide in macrophages induces an anti‐inflammatory population that confers resistance to arthritis and contact hypersensitivity. Transfer of CN‐targeted macrophages or direct injection of LxVP‐encoding lentivirus has anti‐inflammatory effects in these models. Specific CN targeting in macrophages induces p38 MAPK activity by downregulating MKP‐1 expression. However, pharmacological CN inhibition with cyclosporin A (CsA) or FK506 did not reproduce these effects and failed to induce p38 activity. The CN‐inhibitory peptide VIVIT also failed to reproduce the effects of LxVP. p38 inhibition prevented the anti‐inflammatory phenotype of CN‐targeted macrophages, and mice with defective p38‐activation were resistant to the anti‐inflammatory effect of LxVP. Our results identify a key role for CN and p38 in the modulation of macrophage phenotype and suggest an alternative treatment for inflammation based on redirecting macrophages toward an anti‐inflammatory status.
Synopsis
Targeting of calcineurin in macrophages unveils their anti‐inflammatory activity, which bears significant potential for therapeutic exploitation.
Calcineurin deletion or inhibition with LxVP peptide, but not the immunosuppressive drugs CsA or FK506, induces anti‐inflammatory macrophages.
p38 activity mediates the anti‐inflammatory activation induced by specific calcineurin targeting in macrophages.
Calcineurin targeting releases p38 from MKP‐1‐mediated repression.
In gene or cell therapy approaches, specific calcineurin targeting in macrophages confers resistance to inflammation associated with arthritis and contact hypersensitivity.
Targeting of calcineurin in macrophages unveils their anti‐inflammatory activity, which bears significant potential for therapeutic exploitation.
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