Transcription factor C/EBPbeta isoform ratio regulates osteoclastogenesis through MafB

Disequilibrium between bone-forming osteoblasts and bone-resorbing osteoclasts is central to many bone diseases. Here, we show that dysregulated expression of translationally controlled isoforms of CCAAT/enhancer-binding protein beta (C/EBPbeta) differentially affect bone mass. Alternative translation initiation that is controlled by the mammalian target of rapamycin (mTOR) pathway generates long transactivating (LAP(*), LAP) and a short repressive (LIP) isoforms from a single C/EBPbeta transcript. Rapamycin, an inhibitor of mTOR signalling increases the ratio of LAP over LIP and inhibits osteoclastogenesis in wild type (WT) but not in C/EBPbeta null (c/ebpbeta(-/-)) or in LIP knock-in (L/L) osteoclast precursors. C/EBPbeta mutant mouse strains exhibit increased bone resorption and attenuated expression of MafB, a negative regulator of osteoclastogenesis. Ectopic expression of LAP and LIP in monocytes differentially affect the MafB promoter activity, MafB gene expression and dramatically affect osteoclastogenesis. These data show that mTOR regulates osteoclast formation by modulating the C/EBPbeta isoform ratio, which in turn affects osteoclastogenesis by regulating MafB expression

Immune competence and spleen size scale with colony status in the naked mole-rat

Naked mole-rats (NM-R; Heterocephalus glaber) live in multi-generational colonies with a social hierarchy, show low cancer incidence and long life-spans. Here we asked if such extreme physiology might have an immune component. The spleen is the largest lymphoid organ and plays an essential role in response to immunological insults and may participate in combating cancer and slowing ageing. We investigated the anatomy, molecular composition and function of the NM-R spleen using RNA-sequencing and histological analysis in healthy animals. We found that spleen size in healthy NM-Rs varies considerably. We therefore classified NM-Rs according to spleen size as NM-Rs with small spleens or enlarged spleens. Animals with enlarged spleens showed potentially better anti-microbial profiles and were much more likely to have a high rank within the colony. Splenomegaly was associated with infection in sick NM-Rs, but not in NM-Rs with enlarged spleens. In all healthy NM-Rs splenic erythropoiesis, megakaryopoiesis and myelopoiesis were increased, but B lymphopoiesis was reduced and splenic marginal zone showed markedly altered morphology when compared to other rodents. However, in NM-Rs lymphocytes were found in secondary sites such as lymph nodes, gut lymphoid nodules and thymus. Thus, the NM-R spleen is a major site of adult hematopoiesis under normal physiological conditions. Overall, the NM-R immune system seems to rely mainly on innate immune responses with a more restricted adaptive immune response. We propose that the anatomical plasticity of the spleen might be regulated by social interaction and gives immunological advantage to increase the life-span of higher ranked animals

The molecular mechanism and physiological role of silent nociceptor activation

Silent nociceptors are sensory afferents that are insensitive to noxious mechanical stimuli under normal conditions but become sensitized to such stimuli during inflammation. Using RNA-sequencing and quantitative RT-PCR we demonstrate that inflammation selectively upregulates the expression of the transmembrane protein TMEM100 in silent nociceptors and electrophysiology revealed that over-expression of TMEM100 is required and sufficient to un-silence silent nociceptors. Moreover, we show that mice lacking TMEM100 do not develop secondary hyperalgesia, i.e. pain hypersensitivity that spreads beyond the site of inflammation, in a mouse model of knee joint inflammation and that AAV-mediated overexpression of TMEM100 in articular afferents in the absence of inflammation is sufficient to induce secondary hyperalgesia in remote skin regions without causing knee joint pain. Thus, our work identifies TMEM100 as a key regulator of silent nociceptor un-silencing and reveals a physiological role for this hitherto enigmatic afferent subclass in triggering spatially remote secondary hyperalgesia during inflammation

The PHENIX Experiment at RHIC

The physics emphases of the PHENIX collaboration and the design and current status of the PHENIX detector are discussed. The plan of the collaboration for making the most effective use of the available luminosity in the first years of RHIC operation is also presented.Comment: 5 pages, 1 figure. Further details of the PHENIX physics program available at http://www.rhic.bnl.gov/phenix

Ontogeny of the circadian system during embryogenesis in rainbow trout (Oncorhynchus mykiss) and the effect of prolonged exposure to continuous illumination on daily rhythms of per1, clock, and aanat2 expression

It is widely held that the development of the circadian system during embryogenesis is important for future survival of an organism. Work in teleosts has been, to date, limited to zebrafish, which provides little insight into the diversity of this system within such a large vertebrate class. In this study, we analyzed the diel expression of per1, clock, and aanat2 in unfertilized rainbow trout oocytes and embryos maintained under either a 12:12 light:dark (LD) cycle or continuous illumination (LL) from fertilization. 24-h profiles in expression were measured at fertilization as well as 8, 21 42, and 57 days postfertilization (dpf). Both per1 and clock were expressed in unfertilized oocytes and all embryonic stages, while aanat2 expression was only measureable from 8 dpf. A reduction in both per1 and clock mean expression level between unfertilized oocytes/0-1dpf embryos and 8-9dpf embryos was suggestive of a transition from maternal RNA to endogenous mRNA expression. While aanat2 expression was not clearly associated with photic conditions, photoperiod treatment did alter the expression of per1 and clock expression/rhythmicity from as early as 8 dpf (per1), which could suggest the presence and functionality of an as yet unidentified “photoreceptor”. As a whole, this work demonstrates that clock systems are present and functional during embryonic development in rainbow trout. Further studies of their expression and regulation will help understand how the environment interacts with embryonic development in the species

The Policy Dystopia Model:an interpretive analysis of tobacco industry political activity

BACKGROUND: Tobacco industry interference has been identified as the greatest obstacle to the implementation of evidence-based measures to reduce tobacco use. Understanding and addressing industry interference in public health policy-making is therefore crucial. Existing conceptualisations of corporate political activity (CPA) are embedded in a business perspective and do not attend to CPA's social and public health costs; most have not drawn on the unique resource represented by internal tobacco industry documents. Building on this literature, including systematic reviews, we develop a critically informed conceptual model of tobacco industry political activity. METHODS AND FINDINGS: We thematically analysed published papers included in two systematic reviews examining tobacco industry influence on taxation and marketing of tobacco; we included 45 of 46 papers in the former category and 20 of 48 papers in the latter (n = 65). We used a grounded theory approach to build taxonomies of "discursive" (argument-based) and "instrumental" (action-based) industry strategies and from these devised the Policy Dystopia Model, which shows that the industry, working through different constituencies, constructs a metanarrative to argue that proposed policies will lead to a dysfunctional future of policy failure and widely dispersed adverse social and economic consequences. Simultaneously, it uses diverse, interlocking insider and outsider instrumental strategies to disseminate this narrative and enhance its persuasiveness in order to secure its preferred policy outcomes. Limitations are that many papers were historical (some dating back to the 1970s) and focused on high-income regions. CONCLUSIONS: The model provides an evidence-based, accessible way of understanding diverse corporate political strategies. It should enable public health actors and officials to preempt these strategies and develop realistic assessments of the industry's claims