RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis

RANK ligand (RANKL), a TNF-related molecule, is essential for osteoclast formation, function and survival through interaction with its receptor RANK. Mammary glands of RANK- and RANKL-deficient mice develop normally during sexual maturation, but fail to form lobuloalveolar structures during pregnancy because of defective proliferation and increased apoptosis of mammary epithelium. It has been shown that RANKL is responsible for the major proliferative response of mouse mammary epithelium to progesterone during mammary lactational morphogenesis, and in mouse models, manipulated to induce activation of the RANK/RANKL pathway in the absence of strict hormonal control, inappropriate mammary proliferation is observed. However, there is no evidence so far of a functional contribution of RANKL to tumorigenesis. Here we show that RANK and RANKL are expressed within normal, pre-malignant and neoplastic mammary epithelium, and using complementary gain-of-function (mouse mammary tumour virus (MMTV)-RANK transgenic mice) and loss-of function (pharmacological inhibition of RANKL) approaches, define a direct contribution of this pathway in mammary tumorigenesis. Accelerated pre-neoplasias and increased mammary tumour formation were observed in MMTV-RANK transgenic mice after multiparity or treatment with carcinogen and hormone (progesterone). Reciprocally, selective pharmacological inhibition of RANKL attenuated mammary tumour development not only in hormone- and carcinogen-treated MMTV-RANK and wild-type mice, but also in the MMTV-neu transgenic spontaneous tumour model. The reduction in tumorigenesis upon RANKL inhibition was preceded by a reduction in pre-neoplasias as well as rapid and sustained reductions in hormone- and carcinogen-induced mammary epithelial proliferation and cyclin D1 levels. Collectively, our results indicate that RANKL inhibition is acting directly on hormone-induced mammary epithelium at early stages in tumorigenesis, and the permissive contribution of progesterone to increased mammary cancer incidence is due to RANKL-dependent proliferative changes in the mammary epithelium. The current study highlights a potential role for RANKL inhibition in the management of proliferative breast disease.     

Tumour necrosis factor-alpha in murine autoimmune 'lupus' nephritis

The (NZB x NZW)F1 hybrid mouse develops a severe autoimmune disease similar to systemic lupus erythematosus in humans. Both the human and murine form of the disease show strong associations with alleles of the major histocompatibility complex (MHC) gene products. The severe form of the disease found in F1 mice is due, in part, to dominant NZW gene(s) mapping with the H-2 complex (the murine MHC). Here we present evidence that the tumour necrosis factor (TNF-alpha) gene, which is located within the H-2 complex (the murine major histocompatibility complex), could be involved in the pathogenesis of lupus nephritis in F1 mice. Thus, a restriction fragment length polymorphism in the TNF-alpha gene correlates with the reduced levels of TNF-alpha produced by NZW mice. Furthermore, replacement therapy with recombinant TNF-alpha induces a significant delay in the development of the nephritis.     

Mineral composition of pigeon milk

Summary Mineral analysis of pigeon milk indicates its major elements to be P>Ca>K>Na>Mg (in that order) and trace elements Fe>Zn>Mn>Cu. Whereas the levels of Ca, K, Mg, Na and Mn remain fairly constant in the first week, those of P, Fe, Zn and Cu fall significantly during this period. Compared to cow's and human milk, pigeon milk has definitely higher levels of trace elements. Similarly, the trace mineral content of pigeon milk exceeds that of pigeon egg albumen or yolk. Except for Fe, Mn and Cu, pigeon milk is richer than adult pigeon feed in its mineral content. The Ca:P ratio of pigeon milk increases from 0.3 to 1.1 in the first five days. It appears that the high trace mineral content of pigeon milk is one of the factors contributing to the phenomenal postnatal growth of squabs.     

Electrophorèse de protéines musculaires de Lapin

Summary Saline extracts from rabbit's skeletal muscles obtained and dialyzed at the ionic strength 0.15 contain at least 11 electrophoretically distinct components. Five of these components (n, m, t, l, s) have properties which are comparable with some characteristics of the myogens ofWeber, another component (h) is probably myoalbumin. Muscular proteins which are more soluble at higher ionic strength are not homogenous: there must be not one but two or more electrophoretically different myosins. Much work is needed to establish accurate relations between electrophoretic and classical muscular proteins.     

Geochemical evidence from the Sudbury structure for crustal redistribution by large bolide impacts

Deformation and melting of the crust during the formation of large impact craters must have been important during the Earth's early evolution, but such processes remain poorly understood. The 1.8-billion-year-old Sudbury structure in Ontario, Canada, is greater than 200 km in diameter and preserves a complete impact section, including shocked basement rocks, an impact melt sheet and fallback material. It has generally been thought that the most voluminous impact melts represent the average composition of the continental crust, but here we show that the melt sheet now preserved as the Sudbury Igneous Complex is derived predominantly from the lower crust. We therefore infer that the hypervelocity impact caused a partial inversion of the compositional layering of the continental crust. Using geochemical data, including platinum-group-element abundances, we also show that the matrix of the overlying clast-laden Onaping Formation represents a mixture of the original surficial sedimentary strata, shock-melted lower crust and the impactor itself.     

Patterns and processes in reef fish diversity

A central aim of ecology is to explain the heterogeneous distribution of biodiversity on earth. As expectations of diversity loss grow, this understanding is also critical for effective management and conservation. Although explanations for biodiversity patterns are still a matter for intense debate, they have often been considered to be scale-dependent. At large geographical scales, biogeographers have suggested that variation in species richness results from factors such as area, temperature, environmental stability, and geological processes, among many others. From the species pools generated by these large-scale processes, community ecologists have suggested that local-scale assembly of communities is achieved through processes such as competition, predation, recruitment, disturbances and immigration. Here we analyse hypotheses on speciation and dispersal for reef fish from the Indian and Pacific oceans and show how dispersal from a major centre of origination can simultaneously account for both large-scale gradients in species richness and the structure of local communities.     

Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 are associated with systemic lupus erythematosus

TREX1 acts in concert with the SET complex in granzyme A-mediated apoptosis, and mutations in TREX1 cause Aicardi-Goutières syndrome and familial chilblain lupus. Here, we report monoallelic frameshift or missense mutations and one 3' UTR variant of TREX1 present in 9/417 individuals with systemic lupus erythematosus but absent in 1,712 controls (P = 4.1 x 10(-7)). We demonstrate that two mutant TREX1 alleles alter subcellular targeting. Our findings implicate TREX1 in the pathogenesis of SLE.     

Interleukin 7 receptor alpha chain (IL7R) shows allelic and functional association with multiple sclerosis

Multiple sclerosis is a demyelinating neurodegenerative disease with a strong genetic component. Previous genetic risk studies have failed to identify consistently linked regions or genes outside of the major histocompatibility complex on chromosome 6p. We describe allelic association of a polymorphism in the gene encoding the interleukin 7 receptor alpha chain (IL7R) as a significant risk factor for multiple sclerosis in four independent family-based or case-control data sets (overall P = 2.9 x 10(-7)). Further, the likely causal SNP, rs6897932, located within the alternatively spliced exon 6 of IL7R, has a functional effect on gene expression. The SNP influences the amount of soluble and membrane-bound isoforms of the protein by putatively disrupting an exonic splicing silencer.     

Today’s and tomorrow’s imaging and circulating biomarkers for pulmonary arterial hypertension

The pathobiology of pulmonary arterial hypertension (PAH) involves a remodeling process in distal pulmonary arteries, as well as vasoconstriction and in situ thrombosis, leading to an increase in pulmonary vascular resistance, right heart failure and death. Its etiology may be idiopathic, but PAH is also frequently associated with underlying conditions such as connective tissue diseases. During the past decade, more than welcome novel therapies have been developed and are in development, including those increasingly targeting the remodeling process. These therapeutic options modestly increase the patients' long-term survival, now approaching 60% at 5 years. However, non-invasive tools for confirming PAH diagnosis, and assessing disease severity and response to therapy, are tragically lacking and would help to select the best treatment. After exclusion of other causes of pulmonary hypertension, a final diagnosis still relies on right heart catheterization, an invasive technique which cannot be repeated as often as an optimal follow-up might require. Similarly, other techniques and biomarkers used for assessing disease severity and response to treatment generally lack specificity and have significant limitations. In this review, imaging as well as current and future circulating biomarkers for diagnosis, prognosis, and follow-up are discussed.