IntroductionAdvancing research and treatment for Alzheimer's disease (AD) and the search for effective treatments depend on a complex financial ecosystem involving federal, state, industry, advocacy, venture capital, and philanthropy funding approaches.MethodsWe conducted an expert review of the literature pertaining to funding and financing of translational research and drug development for AD.ResultsThe federal government is the largest public funder of research in AD. The National Institute on Aging, National Institute of Mental Health, National Institute of General Medical Sciences, and National Center for Advancing Translational Science all fund aspects of research in AD drug development. Non-National Institutes of Health federal funding comes from the National Science Foundation, Veterans Administration, Food and Drug Administration, and the Center for Medicare and Medicaid Services. Academic Medical Centers host much of the federally funded basic science research and are increasingly involved in drug development. Funding of the “Valley of Death” involves philanthropy and federal funding through small business programs and private equity from seed capital, angel investors, and venture capital companies. Advocacy groups fund both basic science and clinical trials. The Alzheimer Association is the advocacy organization with the largest research support portfolio relevant to AD drug development. Pharmaceutical companies are the largest supporters of biomedical research worldwide; companies are most interested in late stage de-risked drugs. Drugs progressing into phase II and III are candidates for pharmaceutical industry support through licensing, mergers and acquisitions, and co-development collaborations.DiscussionTogether, the funding and financing entities involved in supporting AD drug development comprise a complex, interactive, dynamic financial ecosystem. Funding source interaction is largely unstructured and available funding is insufficient to meet all demands for new therapies. Novel approaches to funding such as mega-funds have been proposed and more integration of component parts would assist in accelerating drug development.
The circulatory system of adult blue crabs, Callinectes sapidus, was mapped by either injecting barium sulfate into intact animals followed by radiography or by resin corrosion casts (Batsons Monomer). Seven arteries arise from the heart. The anterior aorta exits from the anterior dorsal surface of the heart and gives rise to the optic arteries; these arteries supply hemolymph to the supraesophageal ganglion and eyestalks. The paired anterolateral arteries also exit from the anterior dorsal surface of the heart and supply hemolymph to the gonads, hepatopancreas, stomach, antennal gland, mandibular muscles, and the hypodermis of the anterior cephalothorax. The paired hepatic arteries exit the heart anteriorly and ventrally and branch profusely within the hepatopancreas. A smaller side branch, the pyloric hepatic artery, supplies hemolymph to the pyloric stomach and midgut. The smallest artery, the posterior aorta, branches off the posterior ventral surface of the heart; it joins with the inferior abdominal artery in the region of the second abdominal segment and these arteries supply hemolymph to the hindgut and abdomen. The largest artery is the sternal artery, which exits from the ventral surface of the heart; the ventral thoracic artery branches off the sternal artery and supplies hemolymph to the chelae, the mouthparts, and to each pereiopod. The present study shows that the circulatory system is highly developed, with arteries dividing into smaller capillary-like vessels that ramify profusely within individual organs. The return vessels, the sinuses, are discrete channels rather than random open spaces, as previously described. The present study refines and advances descriptions of the circulatory system and is discussed in relation to recent work on hemolymph flow in crustaceans.
Growth and development can occur over a wide range of physical conditions in reptiles. Cardiovascular function must be critical to this ability. However, information on cardiovascular function in developing reptiles is lacking. Previous work indicated that in reptiles the effects of temperature on growth and metabolism are largely restricted to early development. This study examined whether the previously observed effects of temperature and different perinatal patterns of metabolism observed in amniotic vertebrates are correlated with cardiovascular function. Embryonic and hatchling carcass mass, heart mass and heart rate (HR) were compared for snapping turtle eggs (Chelydra serpentina) incubated at 24 degrees and 29 degrees C. Incubation time was shorter at 29 degrees C (56.2 days) than at 24 degrees C (71.1 days). Carcass and heart growth showed a sigmoidal pattern at both temperatures. However, cardiac growth showed a relative decrease as incubation proceeded. Incubation temperature significantly affected the HR pattern during development. The HR of embryos incubated at 24 degrees C was constant for most of incubation (51.8 +/- 4.8 min-1). A small decrease was observed just prior to and a large decrease immediately following hatching (posthatch, 22.3 +/- 4.1 min-1). At 29 degrees C embryonic HR was greater than at 24 degrees C early in development (72.3 +/- 3 min-1). The HR steadily decreased to values equivalent to those at 24 degrees C. The HRs of 24 degrees C and 29 degrees C hatchlings were not different. Cardiac output (estimated as the product of heart mass and HR) increased rapidly during early development and then slowed dramatically at both temperatures. These data are consistent with the suggestion that temperature exerts its effects primarily early in development. Furthermore, the changes in cardiovascular function are correlated with metabolic changes in hatching vertebrates.
Reports focusing on the behavioral responses of crabs to exposure to low salinity have involved choice chamber experiments or quantification of changes in activity. In addition to describing changes in locomotor activity in four species of crabs of differing osmoregulatory ability, the present study describes six behaviors: increased movement of the mouthparts, cleaning of the mouthparts with the chelae, cleaning of the antennae and antennules with the maxillipeds, flicking of the antennae, retraction of the antennules, and extension of the abdomen. Callinectes sapidus and Carcinus maenas are classed as efficient osmoregulators, and in general, showed an increase in these behaviors with decreasing salinity. Cancer magister, a weak regulator, and Libinia emarginata, an osmoconformer, exhibited these behaviors to a lesser degree and became inactive in the lower salinities, tending to adopt an isolation-type response. The differences in behaviors between the species correlated closely with previously reported changes in cardiovascular function and hemolymph flow. These overt reactions are discussed in relation to the osmoregulatory physiology and ecology of each crab species.
Invertebrate cardiovascular systems have historically been viewed as sluggish, poorly regulated, and “open”, where blood bathes the tissues directly as it moves through a system of ill-defined sinuses and/or lacunae without an endothelial boundary. When examining cardiovascular/circulatory morphology and physiology in a broader evolutionary context, one can question the very nature of the definition of a “closed” versus “open” circulatory system. Viewed in this context a number of invertebrates have evolved incomplete or even completely cell-lined vessels and or lacunae with a highly branched vasculature that allows for the production of significant driving pressures and flows to meet relatively high metabolic demands driven by active life styles. In light of our current understanding of invertebrate cardiovascular systems and their paralleled complexity to vertebrate systems, a number of long established paradigms must be questioned and new definitions presented to better align our understanding of the nature of “open” versus “closed” cardiovascular systems.
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