Three Dimensional Quantification of Angiotensin II-Induced Murine Abdominal Aortic Aneurysms Using High Frequency Ultrasound

Abdominal aortic aneurysms (AAAs), a localized dilation of the vessel wall of 50% or more above normal, claims approximately 14,000 U.S. lives yearly due to aortic rupture. This commonly asymptomatic disease can only be treated by endovascular stent grafts or invasive surgery, usually after the AAA diameter reaches 5 cm. Because these treatment methods carry serious risk, stem cell therapy is being explored in order to provide a low risk option for managing smaller AAAs. To determine if stem cell therapy, once administered, could stabilize or reduce AAA growth, baseline 3D ultrasound measurements in a control group were first needed. High frequency ultrasound was used on apolipoprotein E-deficient (apoE-/-) mice given angiotensin II (AngII) from subcutaneously implanted osmotic mini pumps. This mouse model developed dissecting AAAs, containing a false and true lumen, which were clearly visualized and quantified using 3D ultrasound imaging. With this ultrasound technique, we found that aneurysm diameter, total volume, and false lumen volume all increased steadily over a period of 28 days once AAAs formed. These data suggest our noninvasive, 3D ultrasound technique can be used to monitor the progression of aneurysms that may be delayed once stem cell therapy is administered

A point mutation decouples the lipid transfer activities of microsomal triglyceride transfer protein.

Funder: G. Harold and Leila Y. Mathers Charitable Foundation; funder-id: http://dx.doi.org/10.13039/100001229Apolipoprotein B-containing lipoproteins (B-lps) are essential for the transport of hydrophobic dietary and endogenous lipids through the circulation in vertebrates. Zebrafish embryos produce large numbers of B-lps in the yolk syncytial layer (YSL) to move lipids from yolk to growing tissues. Disruptions in B-lp production perturb yolk morphology, readily allowing for visual identification of mutants with altered B-lp metabolism. Here we report the discovery of a missense mutation in microsomal triglyceride transfer protein (Mtp), a protein that is essential for B-lp production. This mutation of a conserved glycine residue to valine (zebrafish G863V, human G865V) reduces B-lp production and results in yolk opacity due to aberrant accumulation of cytoplasmic lipid droplets in the YSL. However, this phenotype is milder than that of the previously reported L475P stalactite (stl) mutation. MTP transfers lipids, including triglycerides and phospholipids, to apolipoprotein B in the ER for B-lp assembly. In vitro lipid transfer assays reveal that while both MTP mutations eliminate triglyceride transfer activity, the G863V mutant protein unexpectedly retains ~80% of phospholipid transfer activity. This residual phospholipid transfer activity of the G863V mttp mutant protein is sufficient to support the secretion of small B-lps, which prevents intestinal fat malabsorption and growth defects observed in the mttpstl/stl mutant zebrafish. Modeling based on the recent crystal structure of the heterodimeric human MTP complex suggests the G865V mutation may block triglyceride entry into the lipid-binding cavity. Together, these data argue that selective inhibition of MTP triglyceride transfer activity may be a feasible therapeutic approach to treat dyslipidemia and provide structural insight for drug design. These data also highlight the power of yolk transport studies to identify proteins critical for B-lp biology

Food Distribution and Consumption in Knoxville: Exploring Food-Related Local Planning Issues

Summary: City planners have traditionally made an effort to understand the interrelationships between urban activities and various support systems, such as transportation, water and sewer, waste management, communications and energy. Food is also an important urban support system with a complex system of supply, distribution, and consumption. An understanding of the nature of the food supply and distribution system seems important, but in the past has not been an area of concern for the planning profession. It was the intent of this project to develop a basis from which to seek an understanding of the Knoxville food support system and its implications for local planning policy in Knoxville. The thrust of the study was three-fold. First, food-related problems and issues were identified. Then, further work was undertaken in order to propose remedial measures or public programs that might be initiated by local units of government. Finally, the group considered the possibility of establishing some kind of public oversight of the local food supply and distribution function. The approach has been general and comprehensive. One assumption here is that before public action can be initiated, those with responsibility for maintaining the public interest must understand the system. Thus, an analysis which would describe the system comprehensively, while allowing an opportunity to detect interrelationships among system components, was utilized. Patterns of consumption, food services and programs, and marketing channels by food types were also explored. The development of information involves consultation with literature, academicians, public officials, and industry representatives

Microscopic Approach to Magnetism and Superconductivity of ff-Electron Systems with Filled Skutterudite Structure

In order to gain a deep insight into $f$-electron properties of filled skutterudite compounds from a microscopic viewpoint, we investigate the multiorbital Anderson model including Coulomb interactions, spin-orbit coupling, and crystalline electric field effect. For each case of $n$=1$\sim$13, where $n$ is the number of $f$ electrons per rare-earth ion, the model is analyzed by using the numerical renormalization group (NRG) method to evaluate magnetic susceptibility and entropy of $f$ electron. In order to make further step to construct a simplified model which can be treated even in a periodic system, we also analyze the Anderson model constructed based on the $j$-$j$ coupling scheme by using the NRG method. Then, we construct an orbital degenerate Hubbard model based on the $j$-$j$ coupling scheme to investigate the mechanism of superconductivity of filled skutterudites. In the 2-site model, we carefully evaluate the superconducting pair susceptibility for the case of $n$=2 and find that the susceptibility for off-site Cooper pair is clearly enhanced only in a transition region in which the singlet and triplet ground states are interchanged.Comment: 14 pages, 11 figures, Typeset with jpsj2.cl

Nonlinear Optical Microscopy of Murine Abdominal Aortic Aneurysm

Abdominal aortic aneurysm (AAA) is a cardiovascular disease characterized by dilation and weakening of the vessel wall. AAA rupture is responsible for approximately 14,000 deaths annually in the United States [1]. Nonlinear optical (NLO) microscopy presents new possibilities for analyzing AAA tissue samples from murine models. Common NLO techniques are two-photon excitation fluorescence (TPEF), which detects the intrinsic autofluorescent properties of elastin, and second-harmonic generation (SHG), which is specific for collagen fibrils. Elastin and collagen, two major extracellular matrix components, help the aortic wall withstand internal pressure. Murine AAAs were created through 1) subcutaneous continuous systemic infusion of angiotensin II (AngII) in hyperlipidemic apolipoprotein E-deficient mice and 2) by intraluminal infusion of elastase (low 0.5 U/ml and high 25 U/ml concentrations) into the infrarenal aorta of rats [2]. We imaged aneurysmal and control tissue using TPEF and SHG and compared the resulting images to sections stained with standard elastin and collagen markers. TPEF images revealed disorganized elastin sheets and SHG images indicated collagen turnover after aneurysm formation. We quantified the relative degree of elastin degradation and collagen content in the aortic media within a user-defined area on sections stained with Verhoeff-van Gieson (VVG) or Masson’s trichrome (MTC), as well as on TPEF and SHG images. Our analysis with VVG-stained sections shows that elastin content in AAA tissue is significantly decreased by 64% in AngII models (P=0.02), by 34% in low concentration elastase models (P=0.07), and by 99% in high concentration elastase models (P=0.03), relative to control aortic tissue

Pathologic gene network rewiring implicates PPP1R3A as a central regulator in pressure overload heart failure

Heart failure is a leading cause of mortality, yet our understanding of the genetic interactions underlying this disease remains incomplete. Here, we harvest 1352 healthy and failing human hearts directly from transplant center operating rooms, and obtain genome-wide genotyping and gene expression measurements for a subset of 313. We build failing and non-failing cardiac regulatory gene networks, revealing important regulators and cardiac expression quantitative trait loci (eQTLs). PPP1R3A emerges as a regulator whose network connectivity changes significantly between health and disease. RNA sequencing after PPP1R3A knockdown validates network-based predictions, and highlights metabolic pathway regulation associated with increased cardiomyocyte size and perturbed respiratory metabolism. Mice lacking PPP1R3A are protected against pressure-overload heart failure. We present a global gene interaction map of the human heart failure transition, identify previously unreported cardiac eQTLs, and demonstrate the discovery potential of disease-specific networks through the description of PPP1R3A as a central regulator in heart failure

African Ancestry and Its Correlation to Type 2 Diabetes in African Americans: A Genetic Admixture Analysis in Three U.S. Population Cohorts

The risk of type 2 diabetes is approximately 2-fold higher in African Americans than in European Americans even after adjusting for known environmental risk factors, including socioeconomic status (SES), suggesting that genetic factors may explain some of this population difference in disease risk. However, relatively few genetic studies have examined this hypothesis in a large sample of African Americans with and without diabetes. Therefore, we performed an admixture analysis using 2,189 ancestry-informative markers in 7,021 African Americans (2,373 with type 2 diabetes and 4,648 without) from the Atherosclerosis Risk in Communities Study, the Jackson Heart Study, and the Multiethnic Cohort to 1) determine the association of type 2 diabetes and its related quantitative traits with African ancestry controlling for measures of SES and 2) identify genetic loci for type 2 diabetes through a genome-wide admixture mapping scan. The median percentage of African ancestry of diabetic participants was slightly greater than that of non-diabetic participants (study-adjusted difference = 1.6%, P<0.001). The odds ratio for diabetes comparing participants in the highest vs. lowest tertile of African ancestry was 1.33 (95% confidence interval 1.13–1.55), after adjustment for age, sex, study, body mass index (BMI), and SES. Admixture scans identified two potential loci for diabetes at 12p13.31 (LOD = 4.0) and 13q14.3 (Z score = 4.5, P = 6.6×10−6). In conclusion, genetic ancestry has a significant association with type 2 diabetes above and beyond its association with non-genetic risk factors for type 2 diabetes in African Americans, but no single gene with a major effect is sufficient to explain a large portion of the observed population difference in risk of diabetes. There undoubtedly is a complex interplay among specific genetic loci and non-genetic factors, which may both be associated with overall admixture, leading to the observed ethnic differences in diabetes risk

Home visits by family physicians during the end-of-life: Does patient income or residence play a role?

BACKGROUND: With a growing trend for those with advanced cancer to die at home, there is a corresponding increase in need for primary medical care in that setting. Yet those with lower incomes and in rural regions are often challenged to have their health care needs met. This study examined the association between patient income and residence and the receipt of Family Physician (FP) home visits during the end-of-life among patients with cancer. METHODS: Data Sources/Study Setting. Secondary analysis of linked population-based data. Information pertaining to all patients who died due to lung, colorectal, breast or prostate cancer between 1992 and 1997 (N = 7,212) in the Canadian province of Nova Scotia (NS) was extracted from three administrative health databases and from Statistics Canada census records. Study Design. An ecological measure of income ('neighbourhood' median household income) was developed using census information. Multivariate logistic regression was then used to assess the association of income with the receipt of at least one home visit from a FP among all subjects and by region of residency during the end-of-life. Covariates in the initial multivariate model included patient demographics and alternative health services information such as total days spent as a hospital inpatient. Data Extraction Methods. Encrypted patient health card numbers were used to link all administrative health databases whereas the postal code was the link to Statistics Canada census information. RESULTS: Over 45% of all subjects received at least one home visit (n = 3265). Compared to those from low income areas, the log odds of receiving at least one home visit was significantly greater among subjects who reside in middle to high income neighbourhoods (for the highest income quintile, adjusted odds ratio [OR] = 1.37, 95% confidence interval [CI] = 1.15, 1.64; for upper-middle income, adjusted OR = 1.19, 95%CI = 1.02, 1.39; for middle income, adjusted OR = 1.33, 95%CI = 1.15, 1.54). This association was found to be primarily associated with residency outside of the largest metropolitan region of the province. CONCLUSION: The likelihood of receiving a FP home visit during the end-of-life is associated with neighbourhood income particularly among patients living outside of a major metropolitan region

Ants, Cataglyphis cursor, Use Precisely Directed Rescue Behavior to Free Entrapped Relatives

Although helping behavior is ubiquitous throughout the animal kingdom, actual rescue activity is particularly rare. Nonetheless, here we report the first experimental evidence that ants, Cataglyphis cursor, use precisely directed rescue behavior to free entrapped victims; equally important, they carefully discriminate between individuals in distress, offering aid only to nestmates. Our experiments simulate a natural situation, which we often observed in the field when collecting Catagyphis ants, causing sand to collapse in the process. Using a novel experimental technique that binds victims experimentally, we observed the behavior of separate, randomly chosen groups of 5 C. cursor nestmates under one of six conditions. In five of these conditions, a test stimulus (the “victim”) was ensnared with nylon thread and held partially beneath the sand. The test stimulus was either (1) an individual from the same colony; (2) an individual from a different colony of C cursor; (3) an ant from a different ant species; (4) a common prey item; or, (5) a motionless (chilled) nestmate. In the final condition, the test stimulus (6) consisted of the empty snare apparatus. Our results demonstrate that ants are able to recognize what, exactly, holds their relative in place and direct their behavior to that object, the snare, in particular. They begin by excavating sand, which exposes the nylon snare, transporting sand away from it, and then biting at the snare itself. Snare biting, a behavior never before reported in the literature, demonstrates that rescue behavior is far more sophisticated, exact and complexly organized than the simple forms of helping behavior already known, namely limb pulling and sand digging. That is, limb pulling and sand digging could be released directly by a chemical call for help and thus result from a very simple mechanism. However, it's difficult to see how this same releasing mechanism could guide rescuers to the precise location of the nylon thread, and enable them to target their bites to the thread itself

Status of Muon Collider Research and Development and Future Plans

The status of the research on muon colliders is discussed and plans are outlined for future theoretical and experimental studies. Besides continued work on the parameters of a 3-4 and 0.5 TeV center-of-mass (CoM) energy collider, many studies are now concentrating on a machine near 0.1 TeV (CoM) that could be a factory for the s-channel production of Higgs particles. We discuss the research on the various components in such muon colliders, starting from the proton accelerator needed to generate pions from a heavy-Z target and proceeding through the phase rotation and decay ($\pi \to \mu \nu_{\mu}$) channel, muon cooling, acceleration, storage in a collider ring and the collider detector. We also present theoretical and experimental R & D plans for the next several years that should lead to a better understanding of the design and feasibility issues for all of the components. This report is an update of the progress on the R & D since the Feasibility Study of Muon Colliders presented at the Snowmass'96 Workshop [R. B. Palmer, A. Sessler and A. Tollestrup, Proceedings of the 1996 DPF/DPB Summer Study on High-Energy Physics (Stanford Linear Accelerator Center, Menlo Park, CA, 1997)].Comment: 95 pages, 75 figures. Submitted to Physical Review Special Topics, Accelerators and Beam