An anchoring factor targets protein phosphatase 2A to brain microtubules

Protein phosphatase 2A (PP2A) is a ubiquitously expressed serine/threonine phosphatase composed of a heterodimeric core enzyme that associates with a variety of regulatory subunits. A fraction of brain PP2A associates with microtubules and may play a role in regulating phosphorylation of microtubule-associated proteins. We examined the isoform specificity and the mechanism involved in the association of PP2A with brain microtubules. Only the R2alpha (B/PR55alpha) and R2beta (B/PR55beta) regulatory subunits associated with endogenous neural microtubules. Neither the R2gamma (B/PR55gamma) nor members of the R5 (B'/PR56) family of regulatory subunits co-sedimented with microtubules, although abundant amounts of these proteins were detected in brain. The efficient association of PP2A with microtubules in vitro was dependent on an anchoring activity present in a brain protein fraction containing microtubule-associated and microtubule-interacting proteins. Anchoring factor-dependent association of PP2A with microtubules was specific for the heterotrimeric form of PP2A. The core dimer and the isolated subunits of PP2A had very little affinity for microtubules. Characterization of a fraction enriched in the anchoring factor showed that the activity was a heat labile protein that does not correspond to classical microtubule-associated proteins. The anchoring factor associated with microtubules independently of PP2A. These results indicate the association of PP2A with microtubules can be mediated by an anchoring factor that interacts in an isoform-specific manner with heterotrimeric forms of the phosphatase.     

Evaluating sustainable development policies in rural coastal economies

Sustainable development (SD) policies targeting marine economic sectors, designed to alleviate poverty and conserve marine ecosystems, have proliferated in recent years. Many developing countries are providing poor fishing households with new fishing boats (fishing capital) that can be used further offshore as a means to improve incomes and relieve fishing pressure on nearshore fish stocks. These kinds of policies are a marine variant of traditional SD policies focused on agriculture. Here, we evaluate ex ante economic and environmental impacts of provisions of fishing and agricultural capital, with and without enforcement of fishing regulations that prohibit the use of larger vessels in nearshore habitats. Combining methods from development economics, natural resource economics, and marine ecology, we use a unique dataset and modeling framework to account for linkages between households, business sectors, markets, and local fish stocks. We show that the policies investing capital in local marine fisheries or agricultural sectors achieve income gains for targeted households, but knock-on effects lead to increased harvest of nearshore fish, making them unlikely to achieve conservation objectives in rural coastal economies. However, pairing an agriculture stimulus with increasing enforcement of existing fisheries’ regulations may lead to a win–win situation. While marine-based policies could be an important tool to achieve two of the United Nations Sustainable Development Goals (alleviate poverty and protect vulnerable marine resources), their success is by no means assured and requires consideration of land and marine socioeconomic linkages inherent in rural economies.

Coastal and island nations are adopting “blue growth” sustainable development (SD) policies to alleviate poverty and conserve vulnerable ocean resources. Generally speaking, SD policies manage resources and direct investments in order to meet current and future human needs and aspirations, without endangering the natural systems (1). The feasibility and potential of SD has been the focus of decades of academic research; many regard the consideration of economic, social, environmental, and institutional needs and linkages as fundamental to successful policy design and implementation (2–6). Given their novelty, what constitutes a blue growth policy is not universal (7), but like traditional SD policies that focus on land-based sectors such as agriculture, manufacturing, and energy sectors (8, 9), blue growth policies seek to achieve social, economic, and environmental goals simultaneously (10). Blue growth policies attempt to achieve these goals by supporting marine-based industries such as offshore fishing, aquaculture, shipping, and tourism (11, 12). The marine focus has reinvigorated SD efforts of international organizations (including the Global Environmental Facility, United Nations Food and Agriculture Organization, the European Union, and The World Bank) that have collectively invested hundreds of millions of dollars into the development and monitoring of blue growth programs (12–16).While small-scale artisanal fishers consider a variety of factors when making fishing decisions (17), evidence suggests allocation of time is, in part, based on relative returns to labor (18–21). Thus, some blue growth policies attempt to alter returns to fishing relative to alternative income-generating activities as a way to achieve both poverty alleviation and conservation objectives. For example, if poor fishing households are incentivized to participate in offshore fishing, it may lead to increased household incomes and reduced fishing pressure on overexploited nearshore fish stocks (22, 23). Policies enforcing and increasing the regulation of fishing activities are also considered important to achieving blue growth objectives (10, 24).Many SD policies are designed to reduce upfront costs of switching to more sustainable livelihoods. Historically, large-scale fisheries receive the majority of subsidy benefits (25), arguably to the detriment of small-scale fisheries who are often outcompeted by industrialized operations (26). Recently, however, developing countries including Kenya, the Philippines, India, Tanzania, Vietnam, and Indonesia have been investing in programs that bolster the fishing capacity of small-scale and artisanal fishermen (27–33). These programs are designed to help small-scale fishers access larger or better vessels and gear, allowing them to reach more plentiful fishing grounds, compete with commercial vessels, and relieve pressure on vulnerable nearshore fisheries.Despite the recent surge in popularity, we lack evidence that these marine-based SD policies will achieve both poverty reduction and conservation objectives when implemented in rural economies. The complexity of coupled natural–human systems makes it difficult to measure the ex post performance of SD policies, especially in marine environments (34, 35). Additionally, local market failures due to high transportation costs and poorly developed marketing infrastructure (36) can lead to locally defined prices that fluctuate with changes in local supply and demand; local prices may distort household responses to policies, leading to unintended environmental consequences (37–40). Because local market failures are more common in rural economies in developing countries, methods and lessons learned from studies of industrialized fisheries in developed countries may not be relevant. Rather, management of fisheries in rural coastal economies may be more successful if market imperfections, alternative livelihood options, and ecological feedback are considered (20, 41–47).Recent studies explore the causal impacts of land-based SD policy instruments in developing countries (48–56). A key finding of these studies is that community heterogeneity is an important factor in policy performance. However, findings from forestry research do not necessarily carry over to marine settings because fish resources are mobile and regenerate relatively quickly, and, typically, access rights to fisheries are not well defined. This study begins to address the need for research examining responses to SD policy in rural coastal economies.We use a coupled natural–human modeling framework to estimate the ex ante impacts of common SD policies. Our ex ante mechanistic approach that includes a general equilibrium local economy model captures important dynamic feedback between the economy and health of the fish stocks. Indeed, other researchers have studied the correlations between markets and ecosystems in coastal communities in developing countries (44, 57–59). However, the theoretical structure of our analysis approach allows us to examine the causal mechanisms between policy and its outcomes. Our model captures the feedback between economic sectors and households within the economy (Fig. 1, details in SI Appendix). This broad scope is necessary to estimate the extent to which policies targeting poor households in a community also impact nontargeted households (knock-on effects). For example, a policy supporting a subset of fishing households could be detrimental to other households that harvest from the same fish stocks and compete in the same input and output markets.Open in a separate windowFig. 1.A conceptual framework for the bioeconomic local general equilibrium model. Households are represented by four representative groups and may produce goods and services (e.g., agricultural, offshore and nearshore fish, retail, and restaurants) available in local, and possibly global, markets. The simulated policies provide different types of capital to poor households and may also restrict use of fishing capital.Here, we estimate the impacts of two common marine fisheries policies (provision of offshore fishing vessels and increased enforcement of fishing regulations) and an alternative agricultural policy (provision of agricultural capital) in a rural coastal economy. To estimate the impacts of these SD policies in coastal economies, we use a modeling approach that has been developed using theory from development economics, natural resource economics, and marine ecology (37, 60). Introducing new features to the framework, we develop a model of a rural economy capable of disentangling fisher participation in two distinct fishing activities and household consumption of two fish goods. We use microeconomic data collected from household and business surveys to parameterize and calibrate our model, allowing us to realistically estimate policy impacts. An inherent strength to our methodology is the ability to adjust the structure of the model to represent alternative economies. We demonstrate how the model can be used to predict policy outcomes for a typology of rural coastal economies.Although combining policies that simultaneously target marine and agricultural sectors is currently not part of the dialogue on the adoption of blue SD policies around the world (e.g., see The World Bank’s strategy document for its Blue Economy Program and PROBLUE (13)), we find that pairing policy instruments that target both sectors—increased enforcement of vessel regulations and capital investments in the agricultural sector—is better able to achieve both conservation and poverty reduction goals.Why is an agricultural policy combined with enforcement capabilities of marine fishing regulations able to achieve a win–win while marine-focused SD policies are not? Our coupled natural–human modeling framework highlights the mechanisms leading to this counterintuitive outcome. That is, investing in the agricultural sector increases the returns to agricultural labor, which in turn creates upward pressure on wages and encourages a reduction in labor allocated to nearshore fishing. At the same time, the increased wealth in the local economy due to greater agricultural productivity drives up demand for nearshore fish. Although higher prices of fish draw some labor back into the fishery, increased enforcement of vessel regulations prevents fishers from illegally using larger boats in the nearshore habitat as a means to increase harvests. Without coupling increased enforcement and agricultural subsidy, the higher demand for fish would lead to increased harvests in the nearshore environment and lower fish stocks over time.     

Attenuation of Gi- and Gq-mediated signaling by expression of RGS4 or GAIP in mammalian cells

Protein regulators of G protein signaling (RGS proteins) were discovered as negative regulators of heterotrimeric G protein-mediated signal transduction in yeast and worms. Experiments with purified recombinant proteins in vitro have established that RGS proteins accelerate the GTPase activity of certain G protein α subunits (the reaction responsible for their deactivation); they can also act as effector antagonists. We demonstrate herein that either of two such RGS proteins, RGS4 or GAIP, attenuated signal transduction mediated by endogenous receptors, G proteins, and effectors when stably expressed as tagged proteins in transfected mammalian cells. The pattern of selectivity observed in vivo was similar to that seen in vitro. RGS4 and GAIP both attenuated G_i-mediated inhibition of cAMP synthesis. RGS4 was more effective than GAIP in blocking G_q-mediated activation of phospholipase Cβ.     

Predictors of non-compliance in autologous hematopoietic SCT patients undergoing out-patient transplants

Non-compliance has received significant attention in medicine, yet few studies have examined its correlates in autologous hematopoietic SCT (AHSCT) patients. This study examined predictors of non-compliance in a sample of 151 AHSCT patients treated in an outpatient setting. Before AHSCT, participants completed a validated measure of mood and retrospective chart reviews were conducted to assess non-compliance during AHSCT, defined as refusal of oral hygiene, prescribed exercise programs, oral nutrition and/or prescribed medications. We found 121 patients (80%) were non-compliant with an aspect of the AHSCT regimen on 1 or more days; mean percentage of non-compliant days was 16.6 (s.d. 15.6). Men were more likely than women to be non-compliant (P<0.05); as were participants with an elevated depression score (P<0.05). Stepwise regression models identified significant predictors of non-compliance: gender, depression, global distress and nausea and vomiting severity (P-values all <0.01). Further analysis revealed that the interaction of the psychological variables with gender was a more robust predictor of non-compliance (P<0.001). For outpatient AHSCT, our findings suggest the need to broaden conceptualizations of risk factors for non-compliance and the importance of assessing patient barriers to compliance to ensure optimal treatment outcome.     

Lung heme oxygenase-1 is elevated in acute respiratory distress syndrome

OBJECTIVE: We aimed to quantify concentrations of inducible heme oxygenase (HO)-1 in the lungs of patients with acute respiratory distress syndrome (ARDS) and to investigate its role as a source of ferrous iron and as a signaling agent for iron regulation. Control of such processes by heme oxygenase has implications for the onset, progression, and resolution of ARDS. DESIGN: Retrospective analysis of archived samples. SETTING: Adult intensive care unit of a postgraduate teaching hospital. PATIENTS: Patients admitted to the adult intensive care unit who fulfilled the American-European Consensus Conference criteria for ARDS. INTERVENTIONS: Biochemical and immunohistochemical studies using bronchoalveolar lavage fluid or lung tissue were performed in patients with established ARDS and in those undergoing lung resection (controls). MEASUREMENTS AND MAIN RESULTS: Concentrations of heme oxygenase protein were significantly elevated in lung tissue (193.7 +/- 13.27 vs. 81.0 +/- 16.0%, p < .01) and in bronchoalveolar lavage fluid (2.4 x 10(5) vs. 1.4 x 10(5) densitometric units, p = .047) taken from patients with ARDS compared with controls. Concentrations of heme oxygenase protein in bronchoalveolar lavage fluid from patients with ARDS correlated positively and significantly with changes in the concentrations of ferritin (r = .697, p = .02) and the iron saturation of transferrin (r = .8, p = .014) but correlated negatively and significantly with concentrations of bleomycin-detectable (redox-active) iron (r = -.73, p = .031). Significantly elevated (p < .05) concentrations of heme oxygenase staining in cell types expressing this protein were detected in patients with ARDS, compared with concentrations in the same cells taken from controls undergoing lung resection. CONCLUSIONS: Heme oxygenase protein is elevated in the lungs of patients with ARDS and may contribute to the changes in iron mobilization, signaling, and regulation seen in this condition.     

Perirhinal cortex lesions produce variable patterns of retrograde amnesia in rats

Two experiments examined the contribution of the perirhinal cortex (PRh) to retrograde memory for the location of a platform in a water maze. In a previous study, we found that electrolytic lesions of the PRh produced retrograde amnesia, without a temporal gradient, for water-maze problems acquired 4 weeks and 2 days before surgery [Behav. Brain. Res. 114 (2000) 119]. In Experiment 1, we used the same mixed design as in our previous report (time of learning was a within-subjects factor), but PRh lesions were made by aspiration. Contrary to our earlier report, these PRh rats displayed good retention of both platform locations. Combined, these findings indicate that the lesion method may contribute importantly to the pattern of deficits observed. Experiment 2 was conducted similar to Experiment 1, except that a completely between-subjects design was used (time of learning was a between-subjects factor). Rats that received PRh lesions approximately 2 days after the last training session displayed impaired retention of the platform's location, whereas rats that received PRh lesions 4 weeks after training did not. This finding of a temporally graded retrograde amnesia is consistent with our earlier report, and further suggests that the involvement of the PRh in the retention of water-maze problems is time-limited. However, also consistent with our earlier report, the PRh-lesioned rats in Experiment 2 that displayed a retention deficit rapidly reacquired the task. This finding, combined with the negative findings in Experiment 1, suggests that the contribution of the PRh to retrograde memory for platform locations is subtle and may not be due to impaired spatial memory abilities. Additionally, the conflicting results of Experiments 1 and 2 underscore the importance of the design employed in studies of retrograde amnesia in animals.     

Retrograde amnesia after hippocampal damage: recent vs. remote memories in two tasks

We review evidence from experiments conducted in our laboratory on retrograde amnesia in rats with damage to the hippocampal formation. In a new experiment reported here, we show that N-methyl-D-aspartate (NMDA)-induced hippocampal damage produced retrograde amnesia for both hidden platform and two-choice visible platform discriminations in the Morris water task. For both problems there was a significant trend for longer training-surgery intervals to be associated with worse retention performance. Little support is offered by our work for the concept that there is a process involving hippocampal-dependent consolidation of memories in extrahippocampal permanent storage sites. Long-term memory consolidation may take place within the hippocampus. The hippocampus may be involved permanently in storage and/or retrieval of a variety of relational and nonrelational memories if it was intact at the time of learning, even involving information which is definitely not affected in anterograde amnesia after hippocampal damage.