Search

Background: Stem cell antigen-1 (Sca-1)-expressing progenitor cells contribute to vessel remodeling by differentiating into vascular smooth muscle cells and related myofibroblast-like progeny. However, the functional role for Sca-1 expression in vessel remodeling has not been examined. Here, we assessed the requirement for vascular Sca-1 using a mouse model of Sca-1 deficiency. Methods & Results: Male and female Sca-1-deficient mice (Sca1KO) and C57BL/6N wild-type mice (WT) controls, aged 12-14-wk, were subjected to wire denudation injury of the left common carotid artery. Sca1KO displayed larger neointima at 14d post-injury [35±3mm 2 vs. 25±3mm 2 , p2 vs. 58±4mm 2 , p2 vs. 51±11mm 2 , pvs. 435±30, pvs. 485±47, p- Ki67 + staining was increased 1.8-fold in neointima [pvs. WT. Cell-type analyses of Sca1KO vs. WT revealed increased pro-fibrotic vimentin + cell proportions at 8d [1.4-fold in neointima, p+ leukocyte proportions were increased 1.5-fold in neointima [p Conclusion: Taken together, our findings suggest that the loss of Sca-1 worsens remodeling by disinhibiting proliferative, pro-fibrotic, and immune responses to injury, demonstrating a critical role for vascular Sca-1 expression, which may inform novel strategies for the prevention and treatment of vessel remodeling.

Background: B-cells have been shown to serve pathogenic roles in heart failure through cardiac-specific monocyte mobilization and autoantibody deposition. Beyond this, we recently showed that mice with hypomorphic c-Myb activity ( c-myb h/h ) have reduced B-cells and that B-cell deficiency is associated with increased sodium- and water-excretion and reduced blood pressure. Here, we determine the relevance of these responses in an experimental model of heart failure. Methods & Results: C57BL/6J wild-type (WT) and B-cell deficient c-myb h/h mice (male and female; aged 10-12 weeks) underwent either: (i) permanent LAD ligation to induce myocardial infarction (MI); or (ii) sham surgery. Echocardiography showed that B-cell deficiency preserved ejection fraction (53±2 vs. 44±2 %; N=6-7/group; P c-myb h/h mice. Indeed, mice with B-cell deficiency manifest reduced right lung weight/tibia length ratio (0.005±0.000 vs. 0.009±0.001 g/mm; N=5-6/group; P Conclusion: Together, these data show that B-cells play a role in sodium- and water-retention, and consequently, extracellular fluid volume expansion and congestion post-MI, and suggest that B-cells may represent a therapeutic target in heart failure.

The proto-oncogene c-myb (and corresponding nuclear transcription factor, c-Myb) regulates the proliferation and differentiation of hematologic and vascular smooth muscle cells; however, the role of c-Myb in blood pressure regulation is unknown. Here, we show that mice homozygous for a hypomorphic c-myb allele ( c-myb h/h ) conferring reduced c-Myb activity manifest reduced peripheral blood and kidney B220 + B-cells and have decreased systolic (104±2 versus 120±1 mm Hg; P P WT (wild type) mice. Additionally, c-myb h/h mice had lower susceptibility to deoxycorticosterone acetate-salt experimental hypertension. Although cardiac (echocardiography) and resistance artery (perfusion myography) functions were normal, metabolic cage studies revealed that c-myb h/h mice had increased 24-hour urine output and sodium excretion versus WT . Reconstitution of WT mice with c-myb h/h bone marrow transplant and chimeric bone marrow transplant using mice lacking B-cells ( J H T ; h/h>WT and h/h:J H T>WT , respectively) decreased blood pressure and increased 24-hour urine output compared with controls ( WT>WT ; WT:J H T>WT ). J H T mice also had decreased systolic (103±2 versus 115±1 mm Hg; P P WT . Real-time quantitative reverse transcription polymerase chain reaction of kidney medulla revealed reduced V 2 R (vasopressin receptor 2) expression in c-myb h/h and J H T mice. These data implicate B-cells in the regulation of V 2 R and its associated effects on salt and water handling and blood pressure homeostasis.

Macrophage colony stimulating factor-1 (CSF-1) plays a critical role in maintaining myeloid lineage cells. However, congenital global deficiency of CSF-1 (Csf1

Hematopoietic stem and progenitor cells reside within specialized niches. Colony stimulating factor 1 (CSF1) might serve as a monocyte niche factor given its critical role in regulating survival, proliferation, and differentiation of myeloid lineage cells. However, the role of CSF1 in adult monopoiesis and its functionally important cellular sources remain uncertain. Here, we show that conditional deletion of Csf1 in adulthood regulated monocyte abundance independent of its effects on bone development. Bone histology revealed monocytes reside near sinusoidal endothelial cells (ECs) and leptin receptor (Lepr)-expressing perivascular stromal cells. Concomitantly, targeted in vivo deletion of Csf1 from sinusoidal but not arteriolar ECs selectively reduced Ly6Cnegative monocytes in the bone marrow and blood. Combined depletion of Csf1 from both Lepr-expressing perivascular stromal cells and ECs had additive effects, further decreasing classical Ly6Chigh cells. Thus, different monocyte subsets are supported by distinct cellular sources of CSF1 within a perivascular bone marrow niche.%%%%M.Sc.

Summary: Mechanisms that govern transcriptional regulation of inflammation in atherosclerosis remain largely unknown. Here, we identify the nuclear transcription factor c-Myb as an important mediator of atherosclerotic disease in mice. Atherosclerosis-prone animals fed a diet high in cholesterol exhibit increased levels of c-Myb in the bone marrow. Use of mice that either harbor a c-Myb hypomorphic allele or where c-Myb has been preferentially deleted in B cell lineages revealed that c-Myb potentiates atherosclerosis directly through its effects on B lymphocytes. Reduced c-Myb activity prevents the expansion of atherogenic B2 cells yet associates with increased numbers of IgM-producing antibody-secreting cells (IgM-ASCs) and elevated levels of atheroprotective oxidized low-density lipoprotein (OxLDL)-specific IgM antibodies. Transcriptional profiling revealed that c-Myb has a limited effect on B cell function but is integral in maintaining B cell progenitor populations in the bone marrow. Thus, targeted disruption of c-Myb beneficially modulates the complex biology of B cells in cardiovascular disease. : Shikatani et al. demonstrate that the nuclear transcription factor c-Myb exacerbates experimental atherosclerosis directly through its effects on B lymphocytes. Paradoxically, c-Myb promotes B2 cell development yet limits numbers of IgM-producing antibody-secreting cells and levels of atheroprotective OxLDL-specific IgM antibodies.

New opportunities in design surface with scientific advances: however, the rapid pace of scientific discoveries combined with the complexity of technical barriers often impedes new product development. Bio-based technologies, for instance, typically require decisions across complex multiscale system organizations that are difficult for humans to understand and formalize computationally. This paper addresses such challenges in science and design by weaving phases of empirical discovery, analytical description, and technological development in an integrative “D3 Methodology.” The phases are bridged with human-guided computational processes suitable for human-in-the-loop design approaches. Optimization of biolibraries, which are sets of standardized biological parts for adaptation into new products, is used as a characteristic design problem for demonstrating the methodology. Results from this test case suggest that biolibraries with synthetic biological components can promote the development of high-performance bio-based products. These new products motivate further scientific studies to characterize designed synthetic biological components, thus illustrating reciprocity among science and design. Successes in implementing each phase suggest the D3 Methodology is a feasible route for bio-based research and development and for driving the scientific inquiries of today toward the novel technologies of tomorrow.

New opportunities in design often surface with scientific advances, however, the rapid pace of scientific findings in biological domains, and their complexity, may impede effective technological design. This paper addresses such challenges through weaving phases of scientific discovery, analytical description, and technological design in an integrative “d3 Methodology.” The method is implemented using human-guided automated processes developed with cognitive-based considerations. A case study of designing myosin bio-libraries is specifically investigated, and optimization results suggest that bio-libraries of designed synthetic isoforms have advantages over natural isoforms. The findings are motivating for future scientific endeavors to investigate the benefits of designed myosins, thus demonstrating reciprocity among design and science. The successes in implementing each d3 phase suggests the methodology is a feasible approach for nanoscale biosystems design, and is well-suited for driving the scientific inquiries of today towards the novel technologies of tomorrow.Copyright © 2015 by ASME

The Janus kinase (JAK) system is involved in numerous cell signaling processes and is highly expressed in cardiac tissue. The JAK isoform JAK2 is activated by numerous factors known to influence cardiac function and pathologic conditions. However, although abundant, the role of JAK2 in the regulation or maintenance of cardiac homeostasis remains poorly understood. Using the Cre-loxP system, we generated a cardiac-specific deletion of Jak2 in the mouse to assess the effect on cardiac function with animals followed up for a 4-month period after birth. These animals had marked mortality during this period, although at 4 months mortality in male mice (47%) was substantially higher compared with female mice (30%). Both male and female cardiac Jak2-deleted mice had hypertrophy, dilated cardiomyopathy, and severe left ventricular dysfunction, including a marked reduction in ejection fractions as assessed by serial echocardiography, although the responses in females were somewhat less severe. Defective cardiac function was associated with altered protein levels of sarcoplasmic reticulum calcium-regulatory proteins particularly in hearts from male mice that had depressed levels of SERCA2 and phosphorylated phospholamban. In contrast, SERCA2 was unchanged in hearts of female mice, whereas phosphorylated phospholamban was increased. Our findings suggest that cardiac JAK2 is critical for maintaining normal heart function, and its ablation produces a severe pathologic phenotype composed of myocardial remodeling, heart failure, and pronounced mortality.

Aim: To assess the adherence of antibiotic prescribing in emergency departments (ED) to hospital guidelines. Method: A four- week concurrent review was undertaken in the ED of three teaching hospitals. All parenteral antibiotic courses initiated in the ED were classified as adherent to guidelines, non-adherent to guidelines or indeterminate. Courses adhering to guidelines were then divided into four prescriber categories: intern, resident, registrar or consultant. A prescriber questionnaire was administered in one hospital to determine prescriber access to the Antibiotic Guidelines (Therapeutic Guidelines - 9th edition). Results: Of the 273 cases of parenteral antibiotics prescribed, 58 (21%) adhered to the hospital guidelines, 197 (72%) did not adhere and 18 (7%) were classified as indeterminate. After considering local prescribing patterns, the proportion of adherence was still only 54%. There were no significant differences in the proportion of adherence between the four prescriber categories. In the surveyed hospital, 71% of prescribers had access to the Antibiotic Guidelines 9th edition. Conclusion: There was low adherence to antibiotic guidelines within the ED. Prescriber experience was not a significant influence on this result. (author abstract)