Osteoclastic bone resorption requires cell-matrix contact, an event mediated by the αvβ3 integrin. The structural components of the integrin that mediate osteoclast function are, however, not in ...hand. To address this issue, we generated mice lacking the
β3 integrin
gene, which have dysfunctional osteoclasts. Here, we show the full rescue of
β3
–/–
osteoclast function following expression of a full-length β3 integrin. In contrast, truncated β3, lacking a cytoplasmic domain (hβ3Δc), is completely ineffective in restoring function to
β3
–/–
osteoclasts. To identify the components of the β3 cytoplasmic domain regulating osteoclast function, we generated six point mutants known, in other circumstances, to mediate β integrin signaling. Of the six, only the S
752
P substitution, which also characterizes a form of the human bleeding disorder Glanzmann’s thrombasthenia, fails to rescue
β3
–/–
osteoclasts or restore ligand-activated signaling in the form of c-src activation. Interestingly, the double mutation Y
747
F/Y
759
F, which disrupts platelet function, does not affect the osteoclast. Thus similarities and distinctions exist in the mechanisms by which the β3 integrin regulates platelets and osteoclasts.
INTRODUCTIONNiemann-Pick C (NPC) is an autosomal recessive disease due to defective NPC1 or NPC2 proteins resulting in endo-lysosomal storage of unesterified cholesterol in the central nervous system ...and liver. Acute liver disease in the newborn period may be self-limited or fatal. 2-hydroxypropyl-β-cyclodextrin (2HPBCD) is a cholesterol-binding agent that reduces lysosomal cholesterol storage. We have enrolled 3 infants 0-6 months old with direct hyperbilirubinemia due to NPC1 or NPC2 liver disease in a Phase I/II open label clinical trial of intravenous 2HPBCD. METHODSInfants received intravenous 2HPBCD twice a week for 6 weeks, followed by monthly infusion for 6-months. Primary outcome measure was reduction of plasma (3β,5α,6β-trihydroxy-cholan-24-oyl) glycine (TCG), a bile acid generated from cholesterol sequestered in lysosome. RESULTSThree participants completed this protocol. A fourth patient received intravenous 2HPBCD under an emergency investigational new drug study but later expired from her underlying condition. The three protocol patients are living and have improved liver enzymes and TCG. No patient has experienced a drug-related adverse event. CONCLUSIONIntravenous 2HPBCD was tolerated in three infants with liver disease due to NPC.
In the face of myriad environmental challenges associated with industrial agriculture, some farmers and researchers have looked to diversified farming systems as a promising alternative. Despite ...well-documented ecological benefits, diversification practices remain rare in many regions of the U.S, even amongst organic farmers. Our study focuses on organic farmers in the Central Coast region of California, an area that has played a crucial role in the rise of organic agriculture over the last several decades. Through 20 interviews with farmers who all grow lettuce and 8 interviews with technical assistance providers, we investigate the persistent barriers that growers in this region face in adopting diversification practices including cover cropping, compost application, crop rotation, insectary strips, and hedgerows. We find that high land rents, the predominance of short-term leases, stringent food safety standards, and other supply chain pressures significantly hamper the adoption of diversification practices. In order to surmount these barriers and increase adoption, solutions must be pursued at three interconnected levels: innovation at the farm level, and policy change at the technical and structural levels. Locally-informed, integrated, and innovative policies across these three levels must be explored to support the creation of a more resilient, sustainable, and equitable food system.
In the past few decades, farmers and researchers have firmly established that biologically diversified farming systems improve ecosystem services both on and off the farm, producing economic benefits ...for farmers and ecological benefits for surrounding landscapes. However, adoption of these practices has been slow, requiring a more nuanced examination of both barriers and opportunities to improve adoption rates. While previous research has demonstrated that both individual and structural factors shape farmers' decisions about whether to adopt diversification practices, this study aims to understand the interaction of these individual and structural factors, and how they relate to farm scale. Based on 20 interviews with organic lettuce growers on the Central Coast of California, as well as 8 interviews with technical assistance providers who work with these growers, we constructed a typology to help elucidate the distinct contexts that shape growers' decisions about diversification practices. This typology, which reflects the structural influence of land rent and supply chains, divides growers into three categories: limited resource, mid-scale diversified, or wholesale. In this economic context, limited resource and wholesale growers both experience significant barriers that constrain the adoption of diversification practices, while some mid-scale diversified growers have found a “sweet spot” for managing agroecosystems that can succeed in both economic and ecological terms. The key enabling factors that allow these farmers to choose diversification, however, are not directly related to their farm size, but have more to do with secure land tenure, adequate access to capital and resources, and buyers who share their values and are willing to pay a premium. By focusing on these key enabling factors with targeted policies, we believe it is possible to encourage diversification practices on farms at a variety of scales within California's Central Coast.
Non-crop vegetation, such as hedgerows and cover crops, are important on-farm diversification practices that support biodiversity and ecosystem services; however, information about their rates and ...patterns of adoption are scarce. We used satellite and aerial imagery coupled with machine learning classification to map the use of hedgerows/windbreaks and winter cover crops in California's Central Coast, a globally important agricultural area of intensive fresh produce production. We expected that adoption of both practices would be relatively low and unevenly distributed across the landscape, with higher levels of adoption found in marginal farmland and in less intensively cultivated areas where the pressure to remove non-crop vegetation may be lower. Our remote sensing classification revealed that only ~6% of farmland had winter cover crops in 2021 and 0.26% of farmland had hedgerows or windbreaks in 2018. Thirty-seven percent of ranch parcels had cover crops on at least 5% of the ranch while 22% of ranches had at least one hedgerow/windbreak. Nearly 16% of farmland had other annual winter crops, some of which could provide services similar to cover crops; however, 60% of farmland had bare soil over the winter study period, with the remainder of farmland classified as perennial crops or strawberries. Hotspot analysis showed significant areas of adoption of both practices in the hillier regions of all counties. Finally, qualitative interviews revealed that adoption patterns were likely driven by interrelated effects of topography, land values, and farming models, with organic, diversified farms implementing these practices in less ideal, lower-value farmland. This study demonstrates how remote sensing coupled with qualitative research can be used to map and interpret patterns of important diversification practices, with implications for tracking policy interventions and targeting resources to assist farmers motivated to expand adoption.
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