Despite broad interest in using payment for ecosystem services to promote changes in the use of natural capital, there are few expost assessments of impacts of payment for ecosystem services programs on ecosystem service provision, program cost, and changes in livelihoods resulting from program participation. In this paper, we evaluate the Paddy Land-to-Dry Land (PLDL) program in Beijing, China, and associated changes in service providers' livelihood activities. The PLDL is a land use conversion program that aims to protect water quality and quantity for the only surface water reservoir that serves Beijing, China's capital city with nearly 20 million residents. Our analysis integrates hydrologic data with household survey data and shows that the PLDL generates benefits of improved water quantity and quality that exceed the costs of reduced agricultural output. The PLDL has an overall benefitcost ratio of 1.5, and both downstream beneficiaries and upstream providers gain from the program. Household data show that changes in livelihood activities may offset some of the desired effects of the program through increased expenditures on agricultural fertilizers. Overall, however, reductions in fertilizer leaching from land use change dominate so that the program still has a positive net impact on water quality. This program is a successful example of water users paying upstream landholders to improve water quantity and quality through land use change. Program evaluation also highlights the importance of considering behavioral changes by program participants.social-ecological systems | sustainable household livelihoods | watershed management | sustainability | regional collaboration P ayment for ecosystem services (PES) can serve as an effective mechanism to translate external, nonmarket values of ecosystem services into financial incentives for local actors to provide such services (1), and has been highlighted as an innovative approach to integrate conservation and socioeconomic development (2-4). In principle, when the benefits derived from increased provision of ecosystem services exceed the cost of provision, PES mechanisms can make both ecosystem service beneficiaries and providers better off. Despite considerable promise and interest in the use of PES worldwide and increasing assessments of the benefits and costs of PES programs, there is little documentation of resulting changes in program participants' livelihoods. Livelihood changes can alter the total effect of a program through unintended changes in an area's economic structure or other natural capital assets (5-8). Taking stock of these socioeconomic impacts highlights the dynamic and distributional effects of PES programs, and is necessary for understanding the equity implications and overall efficiency of a program.Beijing faces a water crisis requiring urgent solutions, and PES programs are one strategy being used to protect water resources. The Miyun Reservoir is the only surface water source for domestic water in Beijing. Its main purpose is to supply...

In human mutant BRAF melanoma cells, the stemness transcription factor FOXD3 is rapidly induced by inhibition of ERK1/2 signaling and mediates adaptive resistance to RAF inhibitors. However, the mechanism underlying ERK signaling control of FOXD3 expression remains unknown. Here we show that SOX10 is both necessary and sufficient for RAF inhibitor-induced expression of FOXD3 in mutant BRAF melanoma cells. SOX10 activates the transcription of FOXD3 by binding to a regulatory element in FOXD3 promoter. Phosphorylation of SOX10 by ERK inhibits its transcription activity toward multiple target genes by interfering with the sumoylation of SOX10 at K55, which is essential for its transcription activity. Finally, depletion of SOX10 sensitizes mutant BRAF melanoma cells to RAF inhibitors in vitro and in vivo. Thus, our work discovers a novel phosphorylation-dependent regulatory mechanism of SOX10 transcription activity and completes an ERK1/2/SOX10/FOXD3/ERBB3 axis that mediates adaptive resistance to RAF inhibitors in mutant BRAF melanoma cells.

A major pharmacological barrier to peptide therapeutics is their susceptibility to proteolytic degradation and poor membrane permeability, which, in principle, can be overcome by nanoparticle-based delivery technologies. Proteins, by definition, are nano materials and have been clinically proven as an efficient delivery vehicle for small molecule drugs. Here we describe the design of a protein-based peptide drug carrier derived from the tetramerization domain of the chimeric oncogenic protein Bcr/Abl of chronic myeloid leukemia. A dodecameric peptide inhibitor of the p53-MDM2/MDMX interaction, termed PMI, was grafted to the N-terminal helical region of Bcr/Abl tetramer. To antagonize intracellular MDM2/MDMX for p53 activation, we extended this protein, PMI Bcr/Abl, by a C-terminal Arg-repeating hexapeptide to facilitate its cellular uptake. The resultant tetrameric protein PMI Bcr/Abl-R6 adopted an alpha-helical conformation in solution and bound to MDM2 at an affinity of 32 nM. PMI Bcr/Abl-R6 effectively induced apoptosis of HCT116 p53 +/+ cells in vitro in a p53-dependent manner and potently inhibited tumor growth in a nude mouse xenograft model by stabilizing p53 in vivo. Our proteinbased delivery strategy thus provides a clinically viable solution to p53-inspired anticancer therapy *

Summary DUSP6 functions as an important negative feedback component of the MAPK/ERK signaling pathway. Although DUSP6 expression is tightly regulated by ERK1/2 signaling, the molecular mechanism of this regulation remains partially understood. In this work, we show that the transcriptional repressor CIC functions downstream of the ERK1/2 signaling to negatively regulate DUSP6 expression. CIC directly represses DUSP6 transcription by binding to three cis -regulatory elements (CREs) in DUSP6 promoter. p90RSK, a downstream target of ERK1/2, phosphorylates CIC at S173 and S301 sites, which creates a 14-3-3 recognition motif, resulting in 14-3-3-mediated nuclear export of CIC and derepression of DUSP6. Finally, we demonstrate that the oncogenic CIC-DUX4 fusion protein acts as a transcriptional activator of DUSP6 and its nuclear/cytoplasmic distribution remains regulated by ERK1/2 signaling. These results complete an ERK1/2/p90RSK/CIC/DUSP6 negative feedback circuit and elucidate the molecular mechanism of how RTK/MAPK signaling harnesses the transcriptional repressor activity of CIC in mammalian cells.