Vascular Smooth Muscle as a Therapeutic Target in Disease Pathology

Our circulatory system is composed of numerous elements that are responsible for transport of blood and delivery of essential nutrients and gases to vital downstream tissues. Among these components that make up our circulation is vascular smooth muscle (VSM), the primary muscular and contractile element of blood vessels and regulator of many blood vessel functions. This is of particular importance as cardiovascular disease (CVD), the number one killer of individuals in America and worldwide, is primarily vascular in origin. Logically, identifying and characterizing feasible targets that could control CVD are highly appealing and much desired. With this in mind and given its centrality in control of vascular physiology, VSM has gained wide attention as a plausible target to combat elements of CVD. This book chapter focuses on VSM as a potential therapeutic target against CVD and will provide overview of vascular anatomy and physiology and brief discussions about the pivotal roles of VSM in CVD pathology, the influence of abnormal blood flow mechanics and hemodynamics in CVD, neural control of VSM and the vasculature, and possible novel cellular and molecular signaling targets that could be used to control and/or minimize CVD. This chapter hopes to serve as a valuable resource for basic and applied scientists as well as clinicians interested in understanding the crucial roles that VSM plays in vessel physiology and pathology

The Effects of Fish Trap Mesh Size on Reef Fish Catch off Southeastern Florida

Catch and mesh selectivity of wire-meshed fish traps were tested for eleven different mesh sizes ranging from 13 X 13 mm (0.5 x 0.5") to 76 x 152 mm (3 X 6"). A total of 1,810 fish (757 kg) representing 85 species and 28 families were captured during 330 trap hauls off southeastern Florida from December 1986 to July 1988. Mesh size significantly affected catches. The 1.5" hexagonal mesh caught the most fish by number, weight, and value. Catches tended to decline as meshes got smaller or larger. Individual fish size increased with larger meshes. Laboratory mesh retention experiments showed relationships between mesh shape and size and individual retention for snapper (Lutjanidae), grouper (Serranidae), jack (Carangidae), porgy (Sparidae), and surgeonfish (Acanthuridae). These relationships may be used to predict the effect of mesh sizes on catch rates. Because mesh size and shape greatly influenced catchability, regulating mesh size may provide a useful basis for managing the commercial trap fishery

DISTRIBUTED BROKERAGE OFFICES THROUGH INFORMATION TECHNOLOGY

This paper describes some novel ways in which Edward D. Jones and Co., a successful brokerage firm with 1650 offices nationwide, uses information technology to pursue a unique market niche: single-broker offices in communities too small to support a traditional, typically much larger, brokerage branch office. The paper focuses on the use of mainframes with "dumb" CRT terminals, rather than workstations or personal computers, to coordinate distributed operational work on a day-to-day basis.Information Systems Working Papers Serie

Proteostasis and the Regulation of Intra- and Extracellular Protein Aggregation by ATP-Independent Molecular Chaperones: Lens α-Crystallins and Milk Caseins

Conspectus: Molecular chaperone proteins perform a diversity of roles inside and outside the cell. One of the most important is the stabilization of misfolding proteins to prevent their aggregation, a process that is potentially detrimental to cell viability. Diseases such as Alzheimer\u27s, Parkinson\u27s, and cataract are characterized by the accumulation of protein aggregates. In vivo, many proteins are metastable and therefore under mild destabilizing conditions have an inherent tendency to misfold, aggregate, and hence lose functionality. As a result, protein levels are tightly regulated inside and outside the cell. Protein homeostasis, or proteostasis, describes the network of biological pathways that ensures the proteome remains folded and functional. Proteostasis is a major factor in maintaining cell, tissue, and organismal viability. We have extensively investigated the structure and function of intra- and extracellular molecular chaperones that operate in an ATP-independent manner to stabilize proteins and prevent their misfolding and subsequent aggregation into amorphous particles or highly ordered amyloid fibrils. These types of chaperones are therefore crucial in maintaining proteostasis under normal and stress (e.g., elevated temperature) conditions. Despite their lack of sequence similarity, they exhibit many common features, i.e., extensive structural disorder, dynamism, malleability, heterogeneity, oligomerization, and similar mechanisms of chaperone action. In this Account, we concentrate on the chaperone roles of α-crystallins and caseins, the predominant proteins in the eye lens and milk, respectively. Intracellularly, the principal ATP-independent chaperones are the small heat-shock proteins (sHsps). In vivo, sHsps are the first line of defense in preventing intracellular protein aggregation. The lens proteins αA- and αB-crystallin are sHsps. They play a crucial role in maintaining solubility of the crystallins (including themselves) with age and hence in lens proteostasis and, ultimately, lens transparency. As there is little metabolic activity and no protein turnover in the lens, crystallins are very long lived proteins. Lens proteostasis is therefore very different to that in normal, metabolically active cells. Crystallins undergo extensive post-translational modification (PTM), including deamidation, racemization, phosphorylation, and truncation, which can alter their stability. Despite this, the lens remains transparent for tens of years, implying that lens proteostasis is intimately integrated with crystallin PTMs. Many PTMs do not significantly alter crystallin stability, solubility, and functionality, which thereby facilitates lens transparency. In the long term, however, extensive accumulation of crystallin PTMs leads to large-scale crystallin aggregation, lens opacification, and cataract formation. Extracellularly, various ATP-independent molecular chaperones exist that exhibit sHsp-like structural and functional features. For example, caseins, the major milk proteins, exhibit chaperone ability by inhibiting the amorphous and amyloid fibrillar aggregation of a diversity of destabilized proteins. Caseins maintain proteostasis within milk by preventing deleterious casein amyloid fibril formation via incorporation of thousands of individual caseins into an amorphous structure known as the casein micelle. Hundreds of nanoclusters of calcium phosphate are sequestered within each casein micelle through interactions with short, highly phosphorylated casein sequences. This results in a stable biofluid that contains a high concentration of potentially amyloidogenic caseins and concentrations of calcium and phosphate that can be far in excess of the solubility of calcium phosphate. Casein micelle formation therefore performs vital roles in neonatal nutrition and calcium homeostasis in the mammary gland

Population Structure Influences Sexual Conflict in Wild Populations of Water Striders.

In sexual conflict, aggressive males frequently diminish the long-term reproductive success of females in efforts to gain a short-term advantage over rival males. This short-term advantage can selectively favour high-exploitation males. However, just as the over-exploitation of resources can lead to local extinction, the over-exploitation of females in the form of harassment by aggressive males can yield similar consequences resulting in reduced female fecundity, increased female mortality and overall decline in mating activity. This outcome may often be prevented by selection acting at multiple levels of biological organization. Directional selection favouring aggressive exploitation within groups can be balanced by directional selection amongst groups opposing exploitation. Such between-group selection has recently been demonstrated in laboratory studies of water striders, where the conditional dispersal of individuals increased variation amongst groups and influenced the balance of selection toward reduced male aggression. This multilevel selection (MLS) framework also provides predictive value when investigating natural populations differing in their relative strength of selection within versus among groups. For water striders, the consequences of local exploitation cause fitness differences between groups, favouring less aggressive males. Inconsistently flowing ephemeral streams consist of isolated pools that prevent aggressive male water striders from escaping the consequences of local exploitation. We, therefore, predicted that inconsistently flowing ephemeral streams would favour the evolution of less aggressive males than would perennial streams, which allow aggressive males to move more freely and to escape the group-level costs of their aggression. Comparing two neighbouring streams during the mating season, we found that males dispersed naturally between pools at much higher rates in the perennial stream than in the ephemeral stream. As predicted, we found that males from the perennial stream were significantly more aggressive than those from the ephemeral stream. We also found that dispersers were significantly more aggressive than non-dispersers within each stream. These field results illustrate the relevance of the MLS framework in our understanding of the evolution of sexual conflict

The X-ray Remnant of SN1987A

We present high resolution Chandra observations of the remnant of SN1987A in the Large Magellanic Cloud. The high angular resolution of the Chandra X-ray Observatory (CXO) permits us to resolve the X-ray remnant. We find that the remnant is shell-like in morphology, with X-ray peaks associated with some of the optical hot spots seen in HST images. The X-ray light curve has departed from the linear flux increase observed by ROSAT, with a 0.5-2.0 keV luminosity of 1.5 x 10^35 erg/s in January 2000. We set an upper limit of 2.3 x 10^34 ergs/s on the luminosity of any embedded central source (0.5 - 2 keV). We also present a high resolution spectrum, showing that the X-ray emission is thermal in origin and is dominated by highly ionized species of O, Ne, Mg, and Si.Comment: 16 pages, 3 figures, Accepted for publication in ApJ Letter

High energy from space

The following subject areas are covered: (1) important scientific problems for high energy astrophysics (stellar activity, the interstellar medium in galaxies, supernovae and endpoints of stellar evolution, nucleosynthesis, relativistic plasmas and matter under extreme conditions, nature of gamma-bursts, identification of black holes, active nuclei, accretion physics, large-scale structures, intracluster medium, nature of dark matter, and the X- and gamma-ray background); (2) the existing experimental programs (Advanced X-Ray Astrophysics Facility (AXAF), Gamma Ray Observatory (GRO), X-Ray Timing Explorer (XTE), High Energy Transient Experiment (HETE), U.S. participation in foreign missions, and attached Shuttle and Space Station Freedom payloads); (3) major missions for the 1990's; (4) a new program of moderate missions; (5) new opportunities for small missions; (6) technology development issues; and (7) policy issues