Wnt signaling during synaptic development and plasticity

The formation of synaptic connections requires a dialogue between pre and postsynaptic cells to coordinate the assembly of the presynaptic release machinery and the postsynaptic receptive complexes. Signaling molecules of the Wnt family of proteins are central to this trans-synaptic dialogue. At the neuromuscular junction and central synapses, Wnts promote synaptic assembly by signaling to the developing pre and postsynaptic compartments. In addition, new studies reveal that expression of Wnt proteins and localization of their Fz receptors are regulated by neuronal activity. Importantly, Wnts mediates the synaptic changes induced by patterned neuronal activity or sensory experience in mature neurons. Here we review recent findings into the function of Wnt signaling at the synapse and its link to activity-dependent synaptic growth and function.     

Surface changes in denture soft liners with and without sealer coating following abrasion with mechanical brushing

Gerodontology 2010; doi: 10.1111/j.1741‐2358.2010.00375.x Surface changes in denture soft liners with and without sealer coating following abrasion with mechanical brushing Aim: To evaluate the surface alterations of soft liners with or without sealer coating following abrasion with mechanical brushing. Methods: Thirty specimens were made of a methacrylate‐ (Coe‐Soft) and a siloxane‐based material (Ufi‐Gel SC), and 15 received two coatings of surface sealer. The specimens were submitted to a mechanical brushing‐dentifrice assay under 200 g of force at 250 cycles/min. Mechanical brushing was simulated for a period of 1 (1250 cycles) and 6 months (5000 cycles). Surface roughness (Ra parameter) was measured, and scanning electron microscopy (SEM) images were obtained. Ra data were analysed by anova for repeated measures and Bonferroni’s test (alpha = 0.05). Results: Ra increased from baseline to 6 months regardless of sealer coating. At baseline, only Coe‐Soft without sealer had a higher Ra than the other groups. After 1 month, the Ra of Coe‐Soft with sealer was three‐fold higher than the Ra at baseline; the other groups showed no significant increase of Ra. SEM images showed degradation of the soft liners over time, except for the Ufi‐Gel SC with sealer, which displayed minimum alteration of surface texture. Conclusion: Sealer coating reduced the surface degradation of the tested soft liners, but the protective effect was more pronounced for the siloxane‐based material.     

The molecular identification of factor H and factor I molecules in rainbow trout provides insights into complement C3 regulation

The complement system in vertebrates plays a crucial role in the elimination of pathogens. To regulate complement on self-tissue and to prevent spontaneous activation and systemic depletion, complement is controlled by both fluid-phase and membrane-bound inhibitors. One such inhibitor, complement factor I (CFI) regulates complement by proteolytic cleavage of components C3b and C4b in the presence of specific cofactors. Complement factor H (CFH), the main cofactor for CFI, regulates the alternative pathway of complement activation by acting in the breakdown of C3b to iC3b. To gain further insight into the origin of C3 regulation in bony fish we have cloned and characterized the CFI and CFH1 cDNAs in the rainbow trout (Oncorhynchus mykiss). In this study we report the primary sequence, the tissue expression profile, the polypeptide domain architecture and the phylogenetic analysis of trout CFI and CFH1 genes. The deduced amino acid sequences of trout CFI and CFH1 polypeptides exhibit 42% and 32% identity with human orthologs, respectively. RNA expression analysis showed that CFI is expressed differentially in trout tissues, while liver is the main source of CFH1 expression. Our data indicate that factor H and I genes have emerged during evolution as early as the divergence of teleost fish.     

Curcumin attenuates hyperglycaemia-mediated AMPK activation and oxidative stress in cerebrum of streptozotocin-induced diabetic rat

Oxidative stress has been strongly implicated in the pathogenesis of diabetic encephalopathy (DE). Numerous studies have demonstrated a close relationship between oxidative stress and AMPK activation in various disorders, including diabetes-related brain disorders. Since curcumin has powerful antioxidant properties, this study investigated its effects on hyperglycaemia-mediated oxidative stress and AMPK activation in rats with DE. Diabetes was induced by a single intraperitoneal injection of streptozotocin (STZ-55 mg/kg BW). The diabetic rats were then orally administered curcumin (100 mg/kg BW) or vehicle for 8 weeks. The cerebra of the diabetic rats displayed upregulated protein expression of AdipoR1, p-AMPKα1, Tak1, GLUT4, NADPH oxidase sub-units, caspase-12 and 3-NT and increased lipid peroxidation in comparison with the controls and all of these effects were significantly attenuated with curcumin treatment, except for the increase in AdipoR1 expressions. These results provide a new insight into the beneficial effects of curcumin on hyperglycaemia-mediated DE, which are produced through the down-regulation of AMPK-mediated gluconeogenesis associated with its anti-oxidant property.     

Stem cell-based approaches for intervertebral disc regeneration

Degeneration of the intervertebral disc is an age-related progressive process considered to be the major cause of a series of spine disorders, such as low-back pain that affects the majority of adult population and causes a huge loss of time from work and medical expenses. Numerous regenerative approaches are being developed with the aim to halt or reverse degeneration, including intradiscal administration of nucleus pulposus cells and mesenchymal stem cells and anabolic growth factors. Each of the currently proposed approaches, however, has exhibited certain limitations or shortcomings, largely due to our limited understanding on the cell biology, turnover mechanisms of the intervertebral disc as well as the etiology of disc degeneration. Intervertebral disc, particularly the central nucleus pulposus, is the largest enclosed and avascular tissue in the body and owes a microenvironment under high mechanical and osmotic pressures, at severely hypoxia, and with very limited nutrient supply. In order to achieve an optimal outcome of new regenerative therapies in such a harsh circumstance, identifying and characterizing endogenous regenerative properties of normal and degenerate intervertebral disc, including stem/progenitor cells themselves and extracellular factors located within the stem cell niche, may provide effective insights into selecting the most suitable cell sources and improving or rebuilding the microenvironment favorable for endogenous or transplanted stem cells.     

Rostral densification in beaked whales: Diverse processes for a similar pattern

As compared to other odontocetes (toothed whales), the rostrum of beaked whales (family Ziphiidae) often displays extensive changes in the shape, thickness, and density of its constituent bones. Previous morphological observations suggested that these modifications appeared in parallel in different ziphiid lineages. However, very few data were available on the compactness and histology of these rostral bones, which precluded the study of the processes at work for the development of such structures, as well as the interpretation of their functional implications. In this work we review the bibliographic data on the anatomy of the ziphiid rostrum and we add new observations on adults of several extinct and extant taxa. These observations are based on CT scans and transverse histological sections. Our results confirm that different bones (vomer, mesethmoid, premaxilla, maxilla) are involved in the various morphologies displayed by ziphiid rostra. Strong density contrasts are detected between bones and/or inside the bones themselves; for example, parts of the rostrum reach densities in the range of Neoceti ear bones, which are among the densest bones known hitherto. Furthermore, the histology of the pachyostotic and osteosclerotic bones proves to change from one taxon to the other; the degree of Haversian remodeling varies strongly between species: it can be absent (e.g. Aporotus recurvirostris), partial (e.g. aff. Ziphirostrum), or complete (e.g., Mesoplodon densirostris). The atypical secondary osteons known to be responsible for bone hypermineralization in the rostrum of M. densirostris occurred also in Choneziphius sp. Confronted with a phylogenetic framework, these anatomical and histological observations indicate that the acquisition of compact (osteosclerotic) and/or swollen (pachyostotic) bone is the result of a broad convergence between taxa, in response to common selective pressures. The functional dimension of this question is discussed with respect to what is known about extant ziphiid ecology.     

A computational analysis of limb and body dimensions in Tyrannosaurus rex with implications for locomotion, ontogeny, and growth

The large theropod dinosaur Tyrannosaurus rex underwent remarkable changes during its growth from <10 kg hatchlings to >6000 kg adults in <20 years. These changes raise fascinating questions about the morphological transformations involved, peak growth rates, and scaling of limb muscle sizes as well as the body's centre of mass that could have influenced ontogenetic changes of locomotion in T. rex. Here we address these questions using three-dimensionally scanned computer models of four large, well-preserved fossil specimens as well as a putative juvenile individual. Furthermore we quantify the variations of estimated body mass, centre of mass and segment dimensions, to characterize inaccuracies in our reconstructions. These inaccuracies include not only subjectivity but also incomplete preservation and inconsistent articulations of museum skeletons. Although those problems cause ambiguity, we conclude that adult T. rex had body masses around 6000-8000 kg, with the largest known specimen ("Sue") perhaps ～9500 kg. Our results show that during T. rex ontogeny, the torso became longer and heavier whereas the limbs became proportionately shorter and lighter. Our estimates of peak growth rates are about twice as rapid as previous ones but generally support previous methods, despite biases caused by the usage of scale models and equations that underestimate body masses. We tentatively infer that the hindlimb extensor muscles masses, including the large tail muscle M. caudofemoralis longus, may have decreased in their relative size as the centre of mass shifted craniodorsally during T. rex ontogeny. Such ontogenetic changes would have worsened any relative or absolute decline of maximal locomotor performance. Regardless, T. rex probably had hip and thigh muscles relatively larger than any extant animal's. Overall, the limb "antigravity" muscles may have been as large as or even larger than those of ratite birds, which themselves have the most muscular limbs of any living animal.     

GnRH--a missing link between testosterone concentrations in yolk and plasma and its intergenerational effects

Despite the strong interest in hormone-mediated maternal effects two key questions concerning their mechanisms are as yet unanswered: First, whether the deposition of hormones in the egg yolk is coupled with the levels of these hormones in the maternal circulation, and second, whether epigenetic changes as induced by embryonic exposure to maternal yolk hormones impinge on yolk hormone deposition at adulthood. We investigated the responsiveness to gonadotropin-releasing hormone (GnRH) in female canaries whose embryonic exposure to yolk testosterone had been manipulated. This enabled us to study to what extent GnRH interlinks testosterone concentrations in female circulation and egg yolk as well as the intergenerational potential of hormone-mediated maternal effects. As expected, canary females responded to GnRH with a rise in plasma testosterone. The GnRH-responsiveness was positively correlated with the yolk testosterone content. Factors stimulating the release of GnRH will, therefore, lead to an increase of testosterone in both plasma and egg, posing a potential constraint on the yolk hormone deposition due to testosterone related trade-offs within the laying female. Exposure to elevated yolk testosterone levels as embryo reduced the GnRH-responsiveness in adulthood, potentially limiting environmental influences on yolk testosterone deposition, but the concentrations of yolk testosterone itself were not affected.     

Control of centrin stability by Aurora A

Aurora A is an oncogenic serine/threonine kinase which can cause cell transformation and centrosome amplification when over-expressed. Human breast tumors show excess Aurora A and phospho-centrin in amplified centrosomes. Here, we show that Aurora A mediates the phosphorylation of and localizes with centrin at the centrosome, with both proteins reaching maximum abundance from prophase through metaphase, followed by their precipitous loss in late stages of mitosis. Over-expression of Aurora A results in excess phospho-centrin and centrosome amplification. In contrast, centrosome amplification is not seen in cells over-expressing Aurora A in the presence of a recombinant centrin mutant lacking the serine phosphorylation site at residue 170. Expression of a kinase dead Aurora A results in a decrease in mitotic index and abrogation of centrin phosphorylation. Finally, a recombinant centrin mutation that mimics centrin phosphorylation increases centrin's stability against APC/C-mediated proteasomal degradation. Taken together, these results suggest that the stability of centrin is regulated in part by Aurora A, and that excess phosphorylated centrin may promote centrosome amplification in cancer.     

A multi-compartment, single and multiple dose pharmacokinetic study of the vaginal candidate microbicide 1% tenofovir gel

Background

Tenofovir (TFV) gel is being evaluated as a microbicide with pericoital and daily regimens. To inhibit viral replication locally, an adequate concentration in the genital tract is critical.

Methods and Findings

Forty-nine participants entered a two-phase study: single-dose (SD) and multi-dose (MD), were randomized to collection of genital tract samples (endocervical cells [ECC], cervicovaginal aspirate and vaginal biopsies) at one of seven time points [0.5, 1, 2, 4, 6, 8, or 24 hr(s)] post-dose following SD exposure of 4 mL 1% TFV gel and received a single dose. Forty-seven were randomized to once (QD) or twice daily (BID) dosing for 2 weeks and to collection of genital tract samples at 4, 8 or 24 hrs after the final dose, but two discontinued prior to gel application. Blood was collected during both phases at the seven times post-dose. TFV exposure was low in blood plasma for SD and MD; median C_max was 4.0 and 3.4 ng/mL, respectively (C≤29 ng/mL). TFV concentrations were high in aspirates and tissue after SD and MD, ranging from 1.2×10⁴ to 9.9×10⁶ ng/mL and 2.1×10² to 1.4×10⁶ ng/mL, respectively, and did not noticeably differ between proximal and distal tissue. TFV diphosphate (TFV-DP), the intracellular active metabolite, was high in ECC, ranging from 7.1×10³ to 8.8×10⁶ ng/mL. TFV-DP was detectable in approximately 40% of the tissue samples, ranging from 1.8×10² to 3.5×10⁴ ng/mL. AUC for tissue TFV-DP was two logs higher after MD compared to SD, with no noticeable differences when comparing QD and BID.

Conclusions

Single-dose and multiple-dose TFV gel exposure resulted in high genital tract concentrations for at least 24 hours post-dose with minimal systemic absorption. These results support further study of TFV gel for HIV prevention.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00561496","term_id":"NCT00561496"}}NCT00561496