Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL

Autosomal recessive osteopetrosis is usually associated with normal or elevated numbers of nonfunctional osteoclasts. Here we report mutations in the gene encoding RANKL (receptor activator of nuclear factor-KB ligand) in six individuals with autosomal recessive osteopetrosis whose bone biopsy specimens lacked osteoclasts. These individuals did not show any obvious defects in immunological parameters and could not be cured by hematopoietic stem cell transplantation; however, exogenous RANKL induced formation of functional osteoclasts from their monocytes, suggesting that they could, theoretically, benefit from exogenous RANKL administration.     

Proliferation status defines functional properties of endothelial cells

Homeostasis of solid tissue is characterized by a low proliferative activity of differentiated cells while special conditions like tissue damage induce regeneration and proliferation. For some cell types it has been shown that various tissue-specific functions are missing in the proliferating state, raising the possibility that their proliferation is not compatible with a fully differentiated state. While endothelial cells are important players in regenerating tissue as well as in the vascularization of tumors, the impact of proliferation on their features remains elusive. To examine cell features in dependence of proliferation, we established human endothelial cell lines in which proliferation is tightly controlled by a doxycycline-dependent, synthetic regulatory unit. We observed that uptake of macromolecules and establishment of cell–cell contacts was more pronounced in the growth-arrested state. Tube-like structures were formed in vitro in both proliferating and non-proliferating conditions. However, functional vessel formation upon transplantation into immune-compromised mice was restricted to the proliferative state. Kaposi’s sarcoma-associated herpes virus (KSHV) infection resulted in reduced expression of endothelial markers. Upon transplantation of infected cells, drastic differences were observed: proliferation arrested cells acquired a high migratory activity while the proliferating counterparts established a tumor-like phenotype, similar to Kaposi Sarcoma lesions. The study gives evidence that proliferation governs endothelial functions. This suggests that several endothelial functions are differentially expressed during angiogenesis. Moreover, since proliferation defines the functional properties of cells upon infection with KSHV, this process crucially affects the fate of virus-infected cells.     

A new species and the phylogeny of the South American genus Gromphas Brullé, 1837 (Coleoptera: Scarabaeidae: Scarabaeinae: Phanaeini)

Gromphas jardim Cupello & Vaz-de-Mello sp. nov. is described from Bolivia and Central Brazil and is endemic to the biogeographic province of Rondônia. It resembles Gromphas amazonica and Gromphas inermis, but is distinguished primarily by the pattern of pronotal granulation and the form of the apical tubercle of male protibiae, which is modified in a tapered spur. Based on 31 morphological characters, a phylogenetic analysis returned a single most parsimonious tree where Gromphas is monophyletic and has the following internal topology: ((G. aeruginosa + G. lemoinei) (G. dichroa (G. inermis (G. amazonica + G. jardim)))).     

Low-energy acoustic plasmons at metal surfaces

Nearly two-dimensional (2D) metallic systems formed in charge inversion layers and artificial layered materials permit the existence of low-energy collective excitations, called 2D plasmons, which are not found in a three-dimensional (3D) metal. These excitations have caused considerable interest because their low energy allows them to participate in many dynamical processes involving electrons and phonons, and because they might mediate the formation of Cooper pairs in high-transition-temperature superconductors. Metals often support electronic states that are confined to the surface, forming a nearly 2D electron-density layer. However, it was argued that these systems could not support low-energy collective excitations because they would be screened out by the underlying bulk electrons. Rather, metallic surfaces should support only conventional surface plasmons-higher-energy modes that depend only on the electron density. Surface plasmons have important applications in microscopy and sub-wavelength optics, but have no relevance to the low-energy dynamics. Here we show that, in contrast to expectations, a low-energy collective excitation mode can be found on bare metal surfaces. The mode has an acoustic (linear) dispersion, different to the dependence of a 2D plasmon, and was observed on Be(0001) using angle-resolved electron energy loss spectroscopy. First-principles calculations show that it is caused by the coexistence of a partially occupied quasi-2D surface-state band with the underlying 3D bulk electron continuum and also that the non-local character of the dielectric function prevents it from being screened out by the 3D states. The acoustic plasmon reported here has a very general character and should be present on many metal surfaces. Furthermore, its acoustic dispersion allows the confinement of light on small surface areas and in a broad frequency range, which is relevant for nano-optics and photonics applications.     

Enzymatic capture of an extrahelical thymine in the search for uracil in DNA

The enzyme uracil DNA glycosylase (UNG) excises unwanted uracil bases in the genome using an extrahelical base recognition mechanism. Efficient removal of uracil is essential for prevention of C-to-T transition mutations arising from cytosine deamination, cytotoxic U*A pairs arising from incorporation of dUTP in DNA, and for increasing immunoglobulin gene diversity during the acquired immune response. A central event in all of these UNG-mediated processes is the singling out of rare U*A or U*G base pairs in a background of approximately 10(9) T*A or C*G base pairs in the human genome. Here we establish for the human and Escherichia coli enzymes that discrimination of thymine and uracil is initiated by thermally induced opening of T*A and U*A base pairs and not by active participation of the enzyme. Thus, base-pair dynamics has a critical role in the genome-wide search for uracil, and may be involved in initial damage recognition by other DNA repair glycosylases.     

Light on the structure of thromboxane A2 receptor heterodimers

The structure-based design of a mutant form of the thromboxane A(2) prostanoid receptor (TP) was instrumental in characterizing the structural determinants of the hetero-dimerization process of this G protein coupled receptor (GPCR). The results suggest that the hetero-dimeric complexes between the TPα and β isoforms are characterized by contacts between hydrophobic residues in helix 1 from both monomers. Functional characterization confirms that TPα-TPβ hetero-dimerization serves to regulate TPα function through agonist-induced internalization, with important implications in cardiovascular homeostasis. The integrated approach employed in this study can be adopted to gain structural and functional insights into the dimerization/oligomerization process of all GPCRs for which the structural model of the monomer can be achieved at reasonable atomic resolution.     

Origin of AIDS: contaminated polio vaccine theory refuted

Despite strong evidence to the contrary, speculation continues that the AIDS virus, human immunodeficiency virus type 1 (HIV-1), may have crossed into humans as a result of contamination of the oral polio vaccine (OPV). This 'OPV/AIDS theory' claims that chimpanzees from the vicinity of Stanleyville--now Kisangani in the Democratic Republic of Congo--were the source of a simian immunodeficiency virus (SIVcpz) that was transmitted to humans when chimpanzee tissues were allegedly used in the preparation of OPV. Here we show that SIVcpz is indeed endemic in wild chimpanzees of this region but that the circulating virus is phylogenetically distinct from all strains of HIV-1, providing direct evidence that these chimpanzees were not the source of the human AIDS pandemic.     

The knockout mouse project

Mouse knockout technology provides a powerful means of elucidating gene function in vivo, and a publicly available genome-wide collection of mouse knockouts would be significantly enabling for biomedical discovery. To date, published knockouts exist for only about 10% of mouse genes. Furthermore, many of these are limited in utility because they have not been made or phenotyped in standardized ways, and many are not freely available to researchers. It is time to harness new technologies and efficiencies of production to mount a high-throughput international effort to produce and phenotype knockouts for all mouse genes, and place these resources into the public domain.