SNX10 regulates osteoclastogenic cell fusion and osteoclast size in mice.

Bone-resorbing osteoclasts (OCLs) are formed by differentiation and fusion of monocyte precursor cells, generating large multinucleated cells. Tightly regulated cell fusion during osteoclastogenesis leads to formation of resorption-competent OCLs, whose sizes fall within a predictable physiological range. The molecular mechanisms that regulate the onset of OCL fusion and its subsequent arrest are, however, largely unknown.

Development and validation of a disease-specific quality of life questionnaire for patients with peripheral artery disease (QOLPAD).

Background: The aim of this study was to develop and validate a short and feasible questionnaire to measure health-related quality of life (HRQoL) in patients with peripheral artery disease (PAD). The content of the new instrument is intended to correspond with the simultaneously developed instrument Patient Benefit Index for PAD (PBI-PAD), which evaluates treatment goals and benefits in this patient group.

Methods: Fifty patients stated their disease burden on free-text questionnaires, which was used by an interdisciplinary expert panel to develop 12 items for the new instrument, named Quality of Life questionnaire for patients with peripheral artery disease (QOLPAD).

An SNX10-dependent mechanism downregulates fusion between mature osteoclasts.

Homozygosity for the R51Q mutation in sorting nexin 10 (SNX10) inactivates osteoclasts (OCLs) and induces autosomal recessive osteopetrosis in humans and in mice. We show here that the fusion of wild-type murine monocytes to form OCLs is highly regulated, and that its extent is limited by blocking fusion between mature OCLs. In contrast, monocytes from homozygous R51Q SNX10 mice fuse uncontrollably, forming giant dysfunctional OCLs that can become 10- to 100-fold larger than their wild-type counterparts.

Massive osteopetrosis caused by non-functional osteoclasts in R51Q SNX10 mutant mice.

The R51Q mutation in sorting nexin 10 (SNX10) was shown to cause a lethal genetic disease in humans, namely autosomal recessive osteopetrosis (ARO). We describe here the first R51Q SNX10 knock-in mouse model and show that mice homozygous for this mutation exhibit massive, early-onset, and widespread osteopetrosis. The mutant mice exhibit multiple additional characteristics of the corresponding human disease, including stunted growth, failure to thrive, missing or impacted teeth, occasional osteomyelitis, and a significantly-reduced lifespan.

Phosphorylation of the phosphatase PTPROt at Tyr is a molecular switch that controls osteoclast activity and bone mass in vivo.

Bone resorption by osteoclasts is essential for bone homeostasis. The kinase Src promotes osteoclast activity and is activated in osteoclasts by the receptor-type tyrosine phosphatase PTPROt. In other contexts, however, PTPROt can inhibit Src activity.

Diarrheagenic Escherichia coli and Shigella with High Rate of Extended-Spectrum Beta-Lactamase Production: Two Predominant Etiological Agents of Acute Diarrhea in Shiraz, Iran.

This study was conducted to find the etiology of acute diarrhea in Iranian children and determine the antimicrobial resistance patterns. The pathogenic bacteria were recovered from 110/269 (40.9%) diarrheal fecal samples with the following profiles: the most predominant pathogen was diarrheagenic Escherichia coli (DEC) (43.

The PTPROt tyrosine phosphatase functions as an obligate haploinsufficient tumor suppressor in vivo in B-cell chronic lymphocytic leukemia.

The tyrosine phosphatase PTPROt is a suggested tumor suppressor (TS) in B-cell chronic lymphocytic leukemia (CLL), and its expression is reduced in this disease. In order to examine how reduced PTPROt expression affects CLL in vivo we induced CLL in PTPROt-targeted mice. Unexpectedly, loss of both Ptprot alleles delayed disease detection and progression and lengthened survival relative to mice carrying two intact alleles, indicating that PTPROt fulfills a novel tumor-promoting role in CLL.

Protein tyrosine phosphatases ε and α perform nonredundant roles in osteoclasts.

Female mice lacking protein tyrosine phosphatase ε (PTP ε) are mildly osteopetrotic. Osteoclasts from these mice resorb bone matrix poorly, and the structure, stability, and cellular organization of their podosomal adhesion structures are abnormal. Here we compare the role of PTP ε with that of the closely related PTP α in osteoclasts.

Effect of white mineral trioxide aggregate compared with biomimetic carbonated apatite on dentine bridge formation and inflammatory response in a dental pulp model.

Aim:   To evaluate the effects of apatite precipitation on the biocompatibility and hard tissue induction properties of white mineral trioxide aggregate (WMTA) in a dental pulp model.

Methodology:   Pulp exposures were created on the axial walls of 32 sound canine teeth of eight dogs. Four additional sound teeth served as controls.

Distinct GATA6- and laminin-dependent mechanisms regulate endodermal and ectodermal embryonic stem cell fates.

This study investigates the establishment of alternative cell fates during embryoid body differentiation when ES cells diverge into two epithelia simulating the pre-gastrulation endoderm and ectoderm. We report that endoderm differentiation and endoderm-specific gene expression, such as expression of laminin 1 subunits, is controlled by GATA6 induced by FGF. Subsequently, differentiation of the non-polar primitive ectoderm into columnar epithelium of the epiblast is induced by laminin 1.

Akt/PKB regulates laminin and collagen IV isotypes of the basement membrane.

Basement membranes are important for epithelial differentiation, cell survival, and normal and metastatic cell migration. Much is known about their breakdown and remodeling, yet their positive regulation is poorly understood. Our previous analysis of a fibroblast growth factor (FGF) receptor mutation raised the possibility that protein kinase B (Akt/PKB) activated by FGF is connected to the expression of certain laminin and type IV collagen isotypes.

Fibroblast growth factor signaling and basement membrane assembly are connected during epithelial morphogenesis of the embryoid body.

Fibroblast growth factors and receptors are intimately connected to the extracellular matrix by their affinity to heparan sulfate proteoglycans. They mediate multiple processes during embryonic development and adult life. In this study, embryonic stem cell-derived embryoid bodies were used to model fibroblast growth factor signaling during early epithelial morphogenesis.

Fgfr2 is required for limb outgrowth and lung-branching morphogenesis.

The aim of this study was to clarify the role of Fgfr2 during later stages of embryonic development. Of two previously reported gene-targeting experiments, the more extensive Fgfr2 deletion was lethal shortly after implantation, because of trophoblast defects, whereas the less extensive one survived until midgestation with placental insufficiency and defective limb outgrowth [Xu, X., Weinstein, M.

Targeted disruption of fibroblast growth factor (FGF) receptor 2 suggests a role for FGF signaling in pregastrulation mammalian development.

We disrupted the fibroblast growth factor (FGF) receptor 2 (FGFR2) gene by introducing a neo cassette into the IIIc ligand binding exon and by deleting a genomic DNA fragment encoding its transmembrane domain and part of its kinase I domain. A recessive embryonic lethal mutation was obtained. Preimplantation development was normal until the blastocyst stage.

Analysis of the Hoxd-3 gene: structure and localization of its sense and natural antisense transcripts.

This study set out to investigate the structure and localized expression of the mouse homeobox-containing gene Hoxd-3. In addition to identifying a transcript of the type known from other Antennapedia (Antp)-like mammalian homeobox cDNAs, an antisense transcript was also detected. The antisense form of Hoxd-3 overlaps with 603 bp of the sense transcript including the homeobox.

Developmental localization of the splicing alternatives of fibroblast growth factor receptor-2 (FGFR2).

The gene for fibroblast growth factor receptor-2 (FGFR2) encodes two splice variants designated here as keratinocyte growth factor (KGFR) and bek. Their ligand-binding specificity is markedly different due to mutually exclusive alternative splicing. We asked whether alternative exon usage, in addition to influencing receptor specificity, could be correlated with transcriptional localization.

New murine homeoboxes: structure, chromosomal assignment, and differential expression in adult erythropoiesis.

The nucleotide sequence, chromosomal assignment, and preliminary transcriptional analysis of four murine homeoboxes is presented. Three of these are linked to the Hox-2 gene complex on chromosome 11, whereas the fourth, Hox-4, was assigned to mouse chromosome 12. A comparative analysis of homeobox sequences reveals that two of our sequences represent the previously described Hox-2.

Common origin of transmissible venereal tumors (TVT) in dogs.

We determined the sequence of the 1.5-kb insert upstream to c-myc in the transmissible venereal tumor (TVT) of dogs. The sequence is highly homologous to the 3' region of the mammalian repetitive LINE element.

Retention and loss of immunoglobulin heavy chain alleles in helper T cell hybridoma clones.

Retention or loss of immunoglobulin heavy chain genes was studied in 20 functional T cell hybridoma clones. DNA probes representing C mu, C alpha and JH genes, as well as VH subgroups II and III were hybridized with restriction enzyme fragments of hybridoma DNA by the Southern filter hybridization technique. Parental alleles of the hybridoma cells were distinguished on the basis of polymorphism of the lengths of restriction enzyme fragments.