The low-density lipoprotein receptor–related protein (Lrp)-5 functions as a Wnt coreceptor. Here we show that mice with a targeted disruption of Lrp5 develop a low bone mass phenotype. In vivo and in vitro analyses indicate that this phenotype becomes evident postnatally, and demonstrate that it is secondary to decreased osteoblast proliferation and function in a Cbfa1-independent manner. Lrp5 is expressed in osteoblasts and is required for optimal Wnt signaling in osteoblasts. In addition, Lrp5-deficient mice display persistent embryonic eye vascularization due to a failure of macrophage-induced endothelial cell apoptosis. These results implicate Wnt proteins in the postnatal control of vascular regression and bone formation, two functions affected in many diseases. Moreover, these features recapitulate human osteoporosis-pseudoglioma syndrome, caused by LRP5 inactivation.
The Genome Sequence Archive (GSA) is a data repository for archiving raw sequence data, which provides data storage and sharing services for worldwide scientific communities. Considering explosive data growth with diverse data types, here we present the GSA family by expanding into a set of resources for raw data archive with different purposes, namely, GSA (https://ngdc.cncb.ac.cn/gsa/), GSA for Human (GSA-Human, https://ngdc.cncb.ac.cn/gsa-human/), and Open Archive for Miscellaneous Data (OMIX, https://ngdc.cncb.ac.cn/omix/). Compared with the 2017 version, GSA has been significantly updated in data model, online functionalities, and web interfaces. GSA-Human, as a new partner of GSA, is a data repository specialized in human genetics-related data with controlled access and security. OMIX, as a critical complement to the two resources mentioned above, is an open archive for miscellaneous data. Together, all these resources form a family of resources dedicated to archiving explosive data with diverse types, accepting data submissions from all over the world, and providing free open access to all publicly available data in support of worldwide research activities.
With the rapid development of sequencing technologies towards higher throughput and lower cost, sequence data are generated at an unprecedentedly explosive rate. To provide an efficient and easy-to-use platform for managing huge sequence data, here we present Genome Sequence Archive (GSA; http://bigd.big.ac.cn/gsa or http://gsa.big.ac.cn), a data repository for archiving raw sequence data. In compliance with data standards and structures of the International Nucleotide Sequence Database Collaboration (INSDC), GSA adopts four data objects (BioProject, BioSample, Experiment, and Run) for data organization, accepts raw sequence reads produced by a variety of sequencing platforms, stores both sequence reads and metadata submitted from all over the world, and makes all these data publicly available to worldwide scientific communities. In the era of big data, GSA is not only an important complement to existing INSDC members by alleviating the increasing burdens of handling sequence data deluge, but also takes the significant responsibility for global big data archive and provides free unrestricted access to all publicly available data in support of research activities throughout the world.
Adipose differentiation-related protein (ADFP; also known as ADRP or adipophilin), is a lipid droplet (LD) protein found in most cells and tissues. ADFP expression is strongly induced in cells with increased lipid load. We have inactivated the Adfp gene in mice to better understand its role in lipid accumulation. The Adfpdeficient mice have unaltered adipose differentiation or lipolysis in vitro or in vivo. Importantly, they display a 60% reduction in hepatic triglyceride (TG) and are resistant to diet-induced fatty liver. To determine the mechanism for the reduced hepatic TG content, we measured hepatic lipogenesis, very-low-density lipoprotein (VLDL) secretion, and lipid uptake and utilization, all of which parameters were shown to be similar between mutant and wild-type mice. The finding of similar VLDL output in the presence of a reduction in total TG in the Adfp-deficient liver is explained by the retention of TG in the microsomes where VLDL is assembled. Given that lipid droplets are thought to form from the outer leaflet of the microsomal membrane, the reduction of TG in the cytosol with concomitant accumulation of TG in the microsome of Adfp ؊/؊ cells suggests that ADFP may facilitate the formation of new LDs. In the absence of ADFP, impairment of LD formation is associated with the accumulation of microsomal TG but a reduction in TG in other subcellular compartments.Adipose differentiation-related protein (ADFP) was first isolated by differential hybridization screening of 1246 cells during their differentiation to adipocytes (29). Its mRNA is induced 100 fold during the process. Using 3T3L1 cells, Brasaemle et al. (3) showed that Adfp gene expression is induced early, at day 1 of adipocyte differentiation, and that mRNA levels are maintained throughout differentiation. In contrast, ADFP protein levels, initially upregulated, gradually go down after day 4 (3), suggesting that these levels are subject to significant translational or posttranslational regulation. At the same time, upregulation of perilipin (PLIN), another lipid droplet (LD) protein, is observed at day 4 of differentiation; it has been postulated that perilipin and ADFP might compete for LD localization during the differentiation of 3T3L1 cells (3, 36). ADFP protein is localized to the surface of the LD, though it also has been detected in the LD core by freeze fracture electron microscopy (49, 50).ADFP shares sequence homology with other LD proteins including perilipin and Tip47, collectively known as PAT domain-containing proteins (36, 43), as well as with another LD protein, S3-12 (53). S3-12 shares a 11-amino-acid repeat motif with ADFP, in addition to another region of homology to both ADFP and Tip47 at its carboxyl terminus (6,24,36). With the exception of perilipin, which is expressed only in fat and steroidogenic tissues, the other LD proteins are detected in a variety of cells and tissues (22). Perilipin is phosphorylated by protein kinase A during lipolysis, resulting in an altered conformation to allow hormone-sensitive lipase ...
The research reported in this article clarifies how employee-organization relationships (EORs) work. Specifically, the authors tested whether social exchange and job embeddedness mediate how mutual-investment (whereby employers offer high inducements to employees for their high contributions) and over-investment (high inducements without corresponding high expected contributions) EOR approaches, which are based on Tsui, Pearce, Porter, and Tripoli's (1997) framework, affect quit propensity and organizational commitment. Two studies evaluated these intervening mechanisms. Study 1 surveyed 953 Chinese managers attending part-time master of business administration (MBA) programs in China, whereas Study 2 collected cross-sectional and longitudinal data from 526 Chinese middle managers in 41 firms. Standard and multilevel causal modeling techniques affirmed that social exchange and job embeddedness translate EOR influence. A second multilevel test using lagged outcome measures further established that job embeddedness mediates long-term EOR effects over 18 months. These findings corroborate prevailing views that social exchange explains how mutual- and over-investment EORs motivate greater workforce commitment and loyalty. This study enriches EOR perspectives by identifying job embeddedness as another mediator that is more enduring than social exchange.
Inflammasome activation and subsequent pyroptosis are critical defense mechanisms against microbes. However, overactivation of inflammasome leads to death of the host. Although recent studies have uncovered the mechanism of pyroptosis following inflammasome activation, how pyroptotic cell death drives pathogenesis, eventually leading to death of the host, is unknown. Here, we identified inflammasome activation as a trigger for blood clotting through pyroptosis. We have shown that canonical inflammasome activation by the conserved type III secretion system (T3SS) rod proteins from Gramnegative bacteria or noncanonical inflammasome activation by lipopolysaccharide (LPS) induced systemic blood clotting and massive thrombosis in tissues. Following inflammasome activation, pyroptotic macrophages released tissue factor (TF), an essential initiator of coagulation cascades. Genetic or pharmacological inhibition of TF abolishes inflammasome-mediated blood clotting and protects against death. Our data reveal that blood clotting is the major cause of host death following inflammasome activation and demonstrate that inflammasome bridges inflammation with thrombosis.
The functional capacity of C5 variants with mutations at Arg885, together with their failure to undergo blockade by eculizumab, account for the poor response to this agent in patients who carry these mutations. (Funded by Alexion Pharmaceuticals and the Ministry of Health, Labor, and Welfare of Japan.).
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