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Niemann-Pick type A (NPA) disease is a fatal lysosomal neurodegenerative disorder caused by the deficiency in acid sphingomyelinase (ASM) activity. NPA patients present severe and progressive neurodegeneration starting at an early age. Currently, there is no effective treatment for this disease and NPA patients die between 2 and 3 years of age. NPA is characterized by an accumulation of sphingomyelin in lysosomes and dysfunction in the autophagy-lysosomal pathway. Recent studies show that c-Abl tyrosine kinase activity downregulates autophagy and the lysosomal pathway. Interestingly, this kinase is also activated in other lysosomal neurodegenerative disorders. Here, we describe that c-Abl activation contributes to the mechanisms of neuronal damage and death in NPA disease. Our data demonstrate that: 1) c-Abl is activated in-vitro as well as in-vivo NPA models; 2) imatinib, a clinical c-Abl inhibitor, reduces autophagy-lysosomal pathway alterations, restores autophagy flux, and lowers sphingomyelin accumulation in NPA patient fibroblasts and NPA neuronal models and 3) chronic treatment with nilotinib and neurotinib, two c-Abl inhibitors with differences in blood-brain barrier penetrance and target binding mode, show further benefits. While nilotinib treatment reduces neuronal death in the cerebellum and improves locomotor functions, neurotinib decreases glial activation, neuronal disorganization, and loss in hippocampus and cortex, as well as the cognitive decline of NPA mice. Our results support the participation of c-Abl signaling in NPA neurodegeneration and autophagy-lysosomal alterations, supporting the potential use of c-Abl inhibitors for the clinical treatment of NPA patients.

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The contribution of working forests to tropical conservation and development depends upon the maintenance of ecological integrity under ongoing land use. Assessment of ecological integrity requires an understanding of the structure, composition, and function and major drivers that govern their variability. Working forests in tropical river floodplains provide many goods and services, yet the data on the ecological processes that sustain these services is scant. In flooded forests of riverside Amazonian communities, we established 46 0.1-ha plots varying in flood duration, use by cattle and water buffalo, and time since agricultural abandonment (30-90 yr). We monitored three aspects of ecological integrity (stand structure, species composition, and dynamics of trees and seedlings) to evaluate the impacts of different trajectories of livestock activity (alleviation, stasis, and intensification) over nine years. Negative effects of livestock intensification were solely evident in the forest understory, and plots alleviated from past heavy disturbance increased in seedling density but had higher abundance of thorny species than plots maintaining low activity. Stand structure, dynamics, and tree species composition were strongly influenced by the natural pulse of seasonal floods, such that the defining characteristics of integrity were dependent upon flood duration (3-200 d). Forests with prolonged floods ≥ 140 d had not only lower species richness but also lower rates of recruitment and species turnover relative to forests with short floods <70 d. Overall, the combined effects of livestock intensification and prolonged flooding hindered forest regeneration, but overall forest integrity was largely related to the hydrological regime and age. Given this disjunction between factors mediating canopy and understory integrity, we present a subset of metrics for regeneration and recruitment to distinguish forest condition by livestock trajectory. Although our study design includes confounded factors that preclude a definitive assessment of the major drivers of ecological change, we provide much-needed data on the regrowth of a critical but poorly studied ecosystem. In addition to its emphasis on the dynamics of tropical wetland forests undergoing anthropogenic and environmental change, our case study is an important example for how to assess of ecological integrity in working forests of tropical ecosystems.

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The recent 70% decline in deforestation in the Brazilian Amazon suggests that it is possible to manage the advance of a vast agricultural frontier. Enforcement of laws, interventions in soy and beef supply chains, restrictions on access to credit, and expansion of protected areas appear to have contributed to this decline, as did a decline in the demand for new deforestation. The supply chain interventions that fed into this deceleration are precariously dependent on corporate risk management, and public policies have relied excessively on punitive measures. Systems for delivering positive incentives for farmers to forgo deforestation have been designed but not fully implemented. Territorial approaches to deforestation have been effective and could consolidate progress in slowing deforestation while providing a framework for addressing other important dimensions of sustainable development.

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Tropical rainforest regions have large hydropower generation potential that figures prominently in many nations' energy growth strategies. Feasibility studies of hydropower plants typically ignore the effect of future deforestation or assume that deforestation will have a positive effect on river discharge and energy generation resulting from declines in evapotranspiration (ET) associated with forest conversion. Forest loss can also reduce river discharge, however, by inhibiting rainfall. We used land use, hydrological, and climate models to examine the local "direct" effects (through changes in ET within the watershed) and the potential regional "indirect" effects (through changes in rainfall) of deforestation on river discharge and energy generation potential for the Belo Monte energy complex, one of the world's largest hydropower plants that is currently under construction on the Xingu River in the eastern Amazon. In the absence of indirect effects of deforestation, simulated deforestation of 20% and 40% within the Xingu River basin increased discharge by 4-8% and 10-12%, with similar increases in energy generation. When indirect effects were considered, deforestation of the Amazon region inhibited rainfall within the Xingu Basin, counterbalancing declines in ET and decreasing discharge by 6-36%. Under business-as-usual projections of forest loss for 2050 (40%), simulated power generation declined to only 25% of maximum plant output and 60% of the industry's own projections. Like other energy sources, hydropower plants present large social and environmental costs. Their reliability as energy sources, however, must take into account their dependence on forests.

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Land-use regulations are a critical component of forest governance and conservation strategies, but their effectiveness in shaping landholder behaviour is poorly understood. We conducted a spatial and temporal analysis of the Brazilian Forest Code (BFC) to understand the patterns of regulatory compliance over time and across changes in the policy, and the implications of these compliance patterns for the perceived costs to landholders and environmental performance of agricultural landscapes in the southern Amazon state of Mato Grosso. Landholdings tended to remain in compliance or not according to their status at the beginning of the study period. The perceived economic burden of BFC compliance on soya bean and beef producers (US$3-5.6 billion in net present value of the land) may in part explain the massive, successful campaign launched by the farm lobby to change the BFC. The ecological benefits of compliance (e.g. greater connectivity and carbon) with the BFC are diffuse and do not compete effectively with the economic benefits of non-compliance that are perceived by landholders. Volatile regulation of land-use decisions that affect billions in economic rent that could be captured is an inadequate forest governance instrument; effectiveness of such regulations may increase when implemented in tandem with positive incentives for forest conservation.

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Community forestry initiatives have been shown to reduce rural poverty while promoting the conservation and sustainable use of forests. However, a number of challenges face communities wanting to initiate or maintain formal, community-based forest management. Through a grounded theory approach, this paper uses three case studies of community forest management models in the eastern Amazon to create a framework showing challenges faced by communities at different phases of formal management. The framework shows that, in the development phase, four root problems (land ownership, knowledge acquisition, community organization, and adequate capital) need to be addressed to obtain legal management permission. With this permission in hand, further challenges to operationalization are presented (deterring illegal loggers, maintaining infrastructure, obtaining necessary managerial skills and accessing markets). The interrelatedness of these challenges emphasizes that all challenges need to be addressed in a holistic manner for communities to maintain a profitable and self-sufficient operation. This contradicts current development approaches that only address part of this framework. The framework proposed here can be used as a starting point for community forestry initiatives in other regions.

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A AMAZÕNIA está entrando em uma era de rápidas mudanças impulsionadas pela previsão de asfaltamento de rodovias que estimularão a expansão da fronteira agrícola e de exploração madeireira. O declínio do custo de transporte tem importantes implicações para a biodiversidade, emissão de gases que contribuem para o efeito estufa e prosperidade da sociedade da Amazônia a longo prazo. Para analisar esse contexto, foi desenvolvido um modelo de simulação de desmatamento na bacia Amazônica, sensível a diferentes cenários de políticas públicas frente à expansão da infra-estrutura de transporte pela região. Resultados do modelo indicam que, dentro de um cenário pessimista, o desmatamento projetado pode eliminar, até meados deste século, 40 por cento dos atuais 5,4 milhões de km² de florestas da Amazônia, liberando o equivalente a 32 Pg (10(9) toneladas) de carbono para atmosfera. A modelagem de cenários alternativos aponta que a expansão de uma rede de áreas protegidas, efetivamente implementadas, poderia reduzir em até 1/3 as perdas florestais projetadas. Contudo, outras medidas de conservação são ainda necessárias para se manter a integridade funcional das paisagens e bacias hidrográficas amazônicas. Atuais experimentos em conservação florestal em propriedades privadas, mercados de serviços ambientais e zoneamento agro-ecológico devem ser refinados e multiplicados a fim de se buscar uma conservação extensiva.

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