Protein kinase Cα (PKCα) regulates bone architecture and osteoblast activity.

Bones' strength is achieved and maintained through adaptation to load bearing. The role of the protein kinase PKCα in this process has not been previously reported. However, we observed a phenotype in the long bones of Prkca(-/-) female but not male mice, in which bone tissue progressively invades the medullary cavity in the mid-diaphysis. This bone deposition progresses with age and is prevented by disuse but unaffected by ovariectomy. Castration of male Prkca(-/-) but not WT mice results in the formation of small amounts of intramedullary bone. Osteoblast differentiation markers and Wnt target gene expression were up-regulated in osteoblast-like cells derived from cortical bone of female Prkca(-/-) mice compared with WT. Additionally, although osteoblastic cells derived from WT proliferate following exposure to estradiol or mechanical strain, those from Prkca(-/-) mice do not. Female Prkca(-/-) mice develop splenomegaly and reduced marrow GBA1 expression reminiscent of Gaucher disease, in which PKC involvement has been suggested previously. From these data, we infer that in female mice, PKCα normally serves to prevent endosteal bone formation stimulated by load bearing. This phenotype appears to be suppressed by testicular hormones in male Prkca(-/-) mice. Within osteoblastic cells, PKCα enhances proliferation and suppresses differentiation, and this regulation involves the Wnt pathway. These findings implicate PKCα as a target gene for therapeutic approaches in low bone mass conditions

Spina bifida-predisposing heterozygous mutations in Planar Cell Polarity genes and Zic2 reduce bone mass in young mice

Fractures are a common comorbidity in children with the neural tube defect (NTD) spina bifida. Mutations in the Wnt/planar cell polarity (PCP) pathway contribute to NTDs in humans and mice, but whether this pathway independently determines bone mass is poorly understood. Here, we first confirmed that core Wnt/PCP components are expressed in osteoblasts and osteoclasts in vitro. In vivo, we performed detailed µCT comparisons of bone structure in tibiae from young male mice heterozygous for NTD-associated mutations versus WT littermates. PCP signalling disruption caused by Vangl2 (Vangl2Lp/+) or Celsr1 (Celsr1Crsh/+) mutations significantly reduced trabecular bone mass and distal tibial cortical thickness. NTD-associated mutations in non-PCP transcription factors were also investigated. Pax3 mutation (Pax3Sp2H/+) had minimal effects on bone mass. Zic2 mutation (Zic2Ku/+) significantly altered the position of the tibia/fibula junction and diminished cortical bone in the proximal tibia. Beyond these genes, we bioinformatically documented the known extent of shared genetic networks between NTDs and bone properties. 46 genes involved in neural tube closure are annotated with bone-related ontologies. These findings document shared genetic networks between spina bifida risk and bone structure, including PCP components and Zic2. Genetic variants which predispose to spina bifida may therefore independently diminish bone mass

Regional variability in the atmospheric nitrogen deposition signal and its transfer to the sediment record in Greenland lakes

Disruption of the nitrogen cycle is a major component of global environmental change. δ15N in lake sediments is increasingly used as a measure of reactive nitrogen input but problematically, the characteristic depleted δ15N signal is not recorded at all sites. We used a regionally replicated sampling strategy along a precipitation and N-deposition gradient in SW Greenland to assess the factors determining the strength of δ15N signal in lake sediment cores. Analyses of snowpack N and δ15N-NO3 and water chemistry were coupled with bulk sediment δ15N. Study sites cover a gradient of snowpack δ15N (ice sheet: −6‰; coast −10‰), atmospheric N deposition (ice sheet margin: ∼ 0.2 kg ha−1 yr−1; coast: 0.4 kg ha−1 yr−1) and limnology. Three 210Pb-dated sediment cores from coastal lakes showed a decline in δ15N of ca.−1‰ from ∼ 1860, reflecting the strongly depleted δ15N of snowpack N, lower in-lake total N (TN) concentration (∼ 300 μg N L−1) and a higher TN-load. Coastal lakes have 3.7–7.1× more snowpack input of nitrate than inland sites, while for total deposition the values are 1.7–3.6× greater for lake and whole catchment deposition. At inland sites and lakes close to the ice-sheet margin, a lower atmospheric N deposition rate and larger in-lake TN pool resulted in greater reliance on N-fixation and recycling (mean sediment δ15N is 0.5–2.5‰ in most inland lakes; n = 6). The primary control of the transfer of the atmospheric δ15N deposition signal to lake sediments is the magnitude of external N inputs relative to the in-lake N-pool

Freshwater umbrella - the effects of nitrogen deposition & climate change on freshwaters in the UK

In upland areas of the UK located away from direct human disturbance through agriculture, industrial activities and urban pollution, atmospheric pollution poses one of the major threats to the chemical and biological quality of lakes and streams. One of the most important groups of pollutants is nitrogen (N) compounds, including oxidised forms of N called NOx, generated mainly by fossil fuel combustion especially in motor vehicles, and reduced forms of N (ammonia gas or dissolved ammonium compounds) generated mainly from agricultural activities and livestock. These nitrogen compounds may dissolve in rain or soilwater to form acids, or may be taken up as nutrients by plants and soil microbes in upland catchments, and then subsequently released in acid form associated with nitrate leaching at a later date. It is well established that nitrate leaching contributes to acidification of upland waters, with damage to aquatic ecosystems including plants, invertebrates and fish. However it has recently been suggested that nitrate leaching may also be associated with nutrient enrichment of upland waters that contain biological communities adapted to very low nutrient levels

The Risk of West Nile Virus Infection Is Associated with Combined Sewer Overflow Streams in Urban Atlanta, Georgia, USA

BACKGROUND: At present, the factors favoring transmission and amplification of West Nile Virus (WNV) within urban environments are poorly understood. In urban Atlanta, Georgia, the highly polluted waters of streams affected by combined sewer overflow (CSO) represent significant habitats for the WNV mosquito vector Culex quinquefasciatus. However, their contribution to the risk of WNV infection in humans and birds remains unclear.\ud \ud OBJECTIVES: Our goals were to describe and quantify the spatial distribution of WNV infection in mosquitoes, humans, and corvids, such as blue jays and American crows that are particularly susceptible to WNV infection, and to assess the relationship between WNV infection and proximity to CSO-affected streams in the city of Atlanta, Georgia.\ud \ud MATERIALS AND METHODS: We applied spatial statistics to human, corvid, and mosquito WNV surveillance data from 2001 through 2007. Multimodel analysis was used to estimate associations of WNV infection in Cx. quinquefasciatus, humans, and dead corvids with selected risk factors including distance to CSO streams and catch basins, land cover, median household income, and housing characteristics.\ud \ud RESULTS: We found that WNV infection in mosquitoes, corvids, and humans was spatially clustered and statistically associated with CSO-affected streams. WNV infection in Cx. quinquefasciatus was significantly higher in CSO compared with non-CSO streams, and WNV infection rates among humans and corvids were significantly associated with proximity to CSO-affected streams, the extent of tree cover, and median household income.\ud \ud CONCLUSIONS: Our study strongly suggests that CSO-affected streams are significant sources of Cx. quinquefasciatus mosquitoes that may facilitate WNV transmission to humans within urban environments. Our findings may have direct implications for the surveillance and control of WNV in other urban centers that continue to use CSO systems as a waste management practice

New Approaches to Preventing, Diagnosing, and Treating Neonatal Sepsis

Karen Edmond and Anita Zaidi highlight new approaches that could reduce the burden of neonatal sepsis worldwide

Tracking progress towards equitable child survival in a Nicaraguan community: neonatal mortality challenges to meet the MDG 4

<p>Abstract</p> <p>Background</p> <p>Nicaragua has made progress in the reduction of the under-five mortality since 1980s. Data for the national trends indicate that this poor Central American country is on track to reach the Millennium Development Goal-4 by 2015. Despite this progress, neonatal mortality has not showed same progress. The aim of this study is to analyse trends and social differentials in neonatal and under-five mortality in a Nicaraguan community from 1970 to 2005.</p> <p>Methods</p> <p>Two linked community-based reproductive surveys in 1993 and 2002 followed by a health and demographic surveillance system providing information on all births and child deaths in urban and rural areas of León municipality, Nicaragua. A total of 49 972 live births were registered.</p> <p>Results</p> <p>A rapid reduction in under-five mortality was observed during the late 1970s (from 103 deaths/1000 live births) and the 1980s, followed by a gradual decline to the level of 23 deaths/1000 live births in 2005. This community is on track for the Millennium Development Goal 4 for improved child survival. However, neonatal mortality increased lately in spite of a good coverage of skilled assistance at delivery. After some years in the 1990s with a very small gap in neonatal survival between children of mothers of different educational levels this divide is increasing.</p> <p>Conclusions</p> <p>After the reduction of high under-five mortality that coincided with improved equity in survival in this Nicaraguan community, the current challenge is the neonatal mortality where questions of an equitable perinatal care of good quality must be addressed.</p

Cellular Radiosensitivity: How much better do we understand it?

Purpose: Ionizing radiation exposure gives rise to a variety of lesions in DNA that result in genetic instability and potentially tumorigenesis or cell death. Radiation extends its effects on DNA by direct interaction or by radiolysis of H2O that generates free radicals or aqueous electrons capable of interacting with and causing indirect damage to DNA. While the various lesions arising in DNA after radiation exposure can contribute to the mutagenising effects of this agent, the potentially most damaging lesion is the DNA double strand break (DSB) that contributes to genome instability and/or cell death. Thus in many cases failure to recognise and/or repair this lesion determines the radiosensitivity status of the cell. DNA repair mechanisms including homologous recombination (HR) and non-homologous end-joining (NHEJ) have evolved to protect cells against DNA DSB. Mutations in proteins that constitute these repair pathways are characterised by radiosensitivity and genome instability. Defects in a number of these proteins also give rise to genetic disorders that feature not only genetic instability but also immunodeficiency, cancer predisposition, neurodegeneration and other pathologies. Conclusions: In the past fifty years our understanding of the cellular response to radiation damage has advanced enormously with insight being gained from a wide range of approaches extending from more basic early studies to the sophisticated approaches used today. In this review we discuss our current understanding of the impact of radiation on the cell and the organism gained from the array of past and present studies and attempt to provide an explanation for what it is that determines the response to radiation