Relative abundance and size composition of Red sea urchin, Strongylocentrotus franciscanus, populations along the Mendocino county coast, 1991

Underwater surveys were conducted in the summer of 1991, as part of a three year survey, to determine density and size composition of red sea urchin, Strongylocentrotus franciscanus, populations along the Mendocino coast at three different depth zones. The study consisted of two parts: i) a broad scale survey, with 12 systematically chosen sites from Gualala to Mendocino and ii) a fine scale survey, with nine sites in the vicinity of Fort Bragg. The fine scale sites were selected to represent different habitat types and levels of commercial exploitation. The sites included the Point Cabrillo Marine Reserve (PCMR) as an unfished control and the Caspar Commercial Urchin Closure Area, established in 1989 to assess the effects of closure upon recovery of fished areas. The broad scale mean density was 0.71 red urchin m-2 (SD 1.9), a decline from the 1.3 and 1.1 red urchin m-2 found during the 1988 and 1989 surveys, respectively. The 4.6-m depth zone yielded only 0.17 m-2. No site in the broad scale survey bad greater than 2.2 red urchin m-2. Fine scale fished site mean density declined to 0.34 (SD 1.1) and the PCMR control site density increased to 7.0 m-2 (SD 6.2). Abundance was variable; however, as in past surveys the highest densities were generally found at the 10.7-m and 15.2-m depth zones. The presence of a mode in the 15-35 mm size interval indicated a recent recruitment event. However, continued declines in legal-sized (>89 mm) red sea urchins survey-wide demonstrate the need for more effective fishery management. (79pp.

Bull kelp, Nereocystis luetkeana, abundance in Van Damme Bay, Mendocino County, California

Size and density data were collected for Nereocystis luetkeana sporophytes from kelp beds in Van Damme Bay, Mendocino County during May, June and July 1990. Length and weight measurements were made on individual plants from representative size groups collected from depths of 6.1 m and 12.2 m. Mean sporophyte weight was 268 g (SD 393 g), while mean stipe length was 214 cm (SD 275 cm). Densities were determined separately for those plants which had reached the surface and for all plants within the water column. Sixty-five 12.7 m2 surface quadrats yielded mean surface densities of 2.2 (SD 1.5) and 2.7 plants/m2 (SD 1.3) in June and July, respectively. Individual plants were counted within 42 1x5 m plots along benthic transect lines yielding average densities of 2.7 (SD 4.5) and 5.2 plants/m2 (SD 3.0) in May and July, respectively. Combined density and size data from July 1990 and kelp bed area estimates from fall 1988 for Van Damme Bay yielded a biomass estimate of 640 metric tons distributed over 45.7 hectares. (15pp.

Results of Dover Sole tagging in waters off Northern California, 1969-1971

Three seasonal trawl tagging cruises were undertaken by the California Department of Fish and Game between 1969 and 1971 to determine the distribution, abundance and stock identity of Dover sole (Microstomus pacificus)in the area between Cape Mendocino in northern California and Cape Blanco in southern Oregon. A total of 4730 Dover sole was tagged and released. Through 1984 26% (1235) were recovered. Recapture rates from the tagging cruises were 32% for the spring cruise, 28% for fall, and 15% for winter. Only 13 of 1235 tags were recaptured outside of PMFC 2A and 1C areas (Cape Blanco to Cape Mendocino). The mean north-south dispersion of tagged Dover sole from point of release was 10.2 nautical miles (nm). The maximum distances moved from tagging sites were 215 nm southward and 211 nm northward. A stock unique for management purposes is indicated by the tag recoveries. A seasonal migration by female Dover sole to deep-water grounds in fall and winter was demonstrated. Several estimates of total mortality (Z) were generated by regression of recoveries on time-at-liberty for all recoveries and for shallow- and deep-water returns, separately. Values were 0.41, 0.61, and 0.31, respectively. (84pp.

The California Red Sea Urchin, Strongylocentrotus franciscanus, Fishery: Catch, Effort, and Management Trends

California's red sea urchin, Strongylocentrotus franciscanus, catch peaked at 23,577 metric tons (t) in 1988. Since then, catches and CPUE have trended downward at different rates in northern and southern California, with 10,086 t landed statewide in 1995. West coast sea urchin catches and CPUE from British Columbia, Can., to Baja California, Mex., have generally declined during this period which followed a decade of rapid fishery expansion. This expansion was in response to increasing demand from Japan fueled by rising prices based largely on a more favorable export currency exchange rate. West coast stock assessment methods have been based on integrating a combination of fisheries dependent data and population surveys into models at various levels of complexity. California management policy has centered on technical measures such as size limits and seasonal closures and has been largely ineffective in stabilizing declining catches

Relative abundance and size composition of red sea urchin, Strongylocentrotus franciscanus, populations along the Mendocino and Sonoma County coasts, 1989

Underwater surveys were conducted in the spring and summer of 1989, as part of a three year survey, to determine density and size composition of populations of the red sea urchin, Strongylocentrotus franciscanus, along the Mendocino and Sonoma County coasts at three different depth zones. The study was composed of two parts: i) a broad scale survey, consisting of 22 systematically chosen sites from Fort Ross to Mendocino and ii) a fine scale survey, consisting of seven sites in the vicinity of Fort Bragg. The fine scale sites were selected to represent different habitat types and levels of commercial exploitation. The sites included the Point Cabrillo Marine Reserve (PCMR) as a nonharvested control and the Caspar Closure Area, established in 1989 in an effort to assess the effects of closure upon recovery of previously harvested areas. The mean density for all broad scale sites was 1.1 red urchins/m2 (SD 2.4). The 15-ft. depth zone yielded only 0.5/m2. No site in the broad scale survey had greater than 4.1 red urchins/m2. Spring fine scale harvested sites yielded 1.5 red urchins/m2 (SD 2.8) while the PCMR had 7.8/m2 (SD 7.3). Summer fine scale harvested sites increased to 1.7 and the PCMR declined to 5.4/m2. Abundance was variable; however, highest densities were generally found at the 35-ft. and 50-ft. depth zones. Bimodality in red urchin size frequency distributions, indicative of canopy grouping (smaller urchins beneath the spines or tests of larger urchins), was apparent at PCMR, but not at harvested fine scale or broad scale sites. Broad scale sites had a similar percentage of juveniles as harvested fine scale summer and spring sites, at 7.3, 8.3 and 12.9%, respectively. Harvested sites continued to show a low level of recruitment during this second year of study. (Document has 114 pages) (114pp.

Prediction of brain extracellular fluid concentrations: application to understanding central nervous system pharmacokinetics and pharmacodynamics

This project was pursued to evaluate the applicability of in vivo brain extracellular fluid concentrations, obtained via brain-homogenate equilibrium dialysis, to assess extent of CNS penetration and provide estimates of CNS biophase concentrations. Parallel experimentation was conducted to define the impact of blood-brain barrier (BBB) efflux on opioid pharmacokinetics/pharmacodynamics (PK/PD), and to evaluate mathematical approaches for assessing efflux transport kinetics. Steady-state unbound plasma-to-unbound brain concentration ratios and in vivo P-gp efflux ratios were determined in mice and used to evaluate extent of CNS distribution for 34 drugs. PK/PD studies were conducted with seven opioids to estimate ED50, serum EC50, and brain EC50; relevant in vitro and clinical parameters were used to construct in vitro-to-preclinical and preclinical-to-clinical comparisons of opioid potency. PK/PD studies were conducted in P-gp-deficient mice to assess the influence of BBB efflux transport on CNS PK/PD for opioid substrates of P-gp. Comprehensive mathematical modeling was employed to evaluate the influence of efflux, or efflux inhibition, on brain exposure, and to evaluate several potential metrics of efflux. The unbound plasma-to-unbound brain concentration ratio proved to be a valuable parameter for assessing the CNS distribution of drugs (equivalent to or superior to the in vivo P-gp efflux ratio). Opioid PK/PD studies indicated that, for centrally-active agents, unbound brain EC50,u was the best descriptor of in vivo intrinsic potency, resulting in a in vitro-to-in vivo correlation of r2~0.8. P-gp-mediated efflux attenuated central activity of fentanyl, methadone, and loperamide by decreasing brain-to-plasma ratios, but did not influence brain EC50. BBB efflux also decreased fentanyl, methadone, and loperamide brain:plasma equilibration half-life by ~2-fold, consistent with mathematical predictions. Mathematical modeling revealed that 50% inhibition of BBB efflux results in brain exposure increasing less than or equal to 2-fold; conventional mathematical treatment of efflux inhibition data overestimates Km and IC50. New mathematical relationships for expressing efflux activity and calculating Km and IC50 developed in this project overcomes limitations of conventional mathematical treatment. Knowledge of unbound brain concentrations and the influence of BBB efflux transport is important in developing a comprehensive understanding of CNS PK/PD for individual compounds or for members of a compound set

Hypoxia-enhanced Blood-Brain Barrier Chip recapitulates human barrier function and shuttling of drugs and antibodies

The high selectivity of the human blood-brain barrier (BBB) restricts delivery of many pharmaceuticals and therapeutic antibodies to the central nervous system. Here, we describe an in vitro microfluidic organ-on-a-chip BBB model lined by induced pluripotent stem cell-derived human brain microvascular endothelium interfaced with primary human brain astrocytes and pericytes that recapitulates the high level of barrier function of the in vivo human BBB for at least one week in culture. The endothelium expresses high levels of tight junction proteins and functional efflux pumps, and it displays selective transcytosis of peptides and antibodies previously observed in vivo. Increased barrier functionality was accomplished using a developmentally-inspired induction protocol that includes a period of differentiation under hypoxic conditions. This enhanced BBB Chip may therefore represent a new in vitro tool for development and validation of delivery systems that transport drugs and therapeutic antibodies across the human BBB

Proteasome inhibition for treatment of leishmaniasis, Chagas disease and sleeping sickness

Chagas disease, leishmaniasis and sleeping sickness affect 20 million people worldwide and lead to more than 50,000 deaths annually. The diseases are caused by infection with the kinetoplastid parasites Trypanosoma cruzi, Leishmania spp. and Trypanosoma brucei spp., respectively. These parasites have similar biology and genomic sequence, suggesting that all three diseases could be cured with drugs that modulate the activity of a conserved parasite target. However, no such molecular targets or broad spectrum drugs have been identified to date. Here we describe a selective inhibitor of the kinetoplastid proteasome (GNF6702) with unprecedented in vivo efficacy, which cleared parasites from mice in all three models of infection. GNF6702 inhibits the kinetoplastid proteasome through a non-competitive mechanism, does not inhibit the mammalian proteasome or growth of mammalian cells, and is well-tolerated in mice. Our data provide genetic and chemical validation of the parasite proteasome as a promising therapeutic target for treatment of kinetoplastid infections, and underscore the possibility of developing a single class of drugs for these neglected diseases

Relationship between Drug/Metabolite Exposure and Impairment of Excretory Transport Function

The quantitative impact of excretory transport modulation on the systemic exposure to xenobiotics and derived metabolites is poorly understood. This article presents fundamental relationships between exposure and loss of a specific excretory process that contributes to overall clearance. The mathematical relationships presented herein were explored on the basis of hepatic excretory data for polar metabolites formed in the livers of various transporter-deficient rodents. Experimental data and theoretical relationships indicated that the fold change in exposure is governed by the relationship, 1/(1 – fe), where fe is the fraction excreted by a particular transport protein. Loss of function of a transport pathway associated with fe 0.5. These mathematical relationships may be extended to other organs, such as the intestine and kidney, as well as to systemic drug exposure. Finally, the relationship between exposure and fe is not only applicable to complete loss of function of a transport pathway but also can be extended to partial inhibition scenarios by modifying the equation with the ratio of the inhibitor concentration and inhibition constant