Indices of environmental temperatures for primates in open habitats

Studies of thermoregulation in primates are under-represented in the literature, although there is sufficient evidence to suggest that temperature represents an important ecological constraint. One of the problems in examining thermoregulation in primates, however, is the difficulty in quantifying the thermal environment, since shade temperatures, solar radiation, humidity and wind speed all serve to alter an animals perceived temperature. Since animals respond to their perceived temperature, we need methods to account for each of these factors, both individually and collectively, if we are to understand the integrated impact of the thermal environment on primates. Here, we present a review of some thermal indices currently available. Black bulb temperatures can account for the effect of solar radiation, with wind chill equivalent temperatures and the heat index providing quantifiable estimates of the relative impact of wind speed and humidity, respectively. We present three potential indices of the perceived environmental temperature (PET) that account for the combined impact of solar radiation, humidity and wind speed on temperature, and perform a preliminary test of all of the climatic indices against behavioural data from a field study of chacma baboons (Papio cynocephalus ursinus) at De Hoop Nature Reserve, South Africa. One measure of the perceived environmental temperature, PET2, is an effective thermal index, since it enters the models for feeding and resting behaviour, and also accounts for levels of allogrooming. Solar radiation intensity is an important factor underlying these relationships, although the wind chill equivalent temperature and humidity enter the models for other behaviours. Future studies should thus be mindful of the impact of each of these elements of the thermal environment. A detailed understanding of primate thermoregulation will only come with the development of biophysical models of the thermal characteristics of the species and its environment. Until such developments, however, the indices presented here should permit a more detailed examination of the thermal environment, allowing thermoregulation to be given greater precedence in future studies of primate behaviour.     

Strain-rate sensitive mechanical properties of tendon fascicles from mice with genetically engineered alterations in collagen and decorin

Tendons have complex mechanical behaviors that are nonlinear and time dependent. It is widely held that these behaviors are provided by the tissue composition and structure. It is generally thought that type I collagen provides the primary elastic strength to tendon while proteoglycans, such as decorin, play a role in failure and viscoelastic properties. This study sought to quantify such structure-function relationships by comparing tendon mechanical properties between normal mice and mice genetically engineered for altered type I collagen content and absence of decorin. Uniaxial tensile ramp to failure experiments were performed on tail tendon fascicles at two strain rates, 0.5%/s and 50%/s. Mutations in type I collagen led to reduced failure load and stiffness with no changes in failure stress, modulus or strain rate sensitivity. Fascicles without decorin had similar elastic properties to normal fascicles, but reduced strain rate sensitivity. Fascicles from immature mice, with increased decorin content compared to adult fascicles, had inferior elastic properties but higher strain rate sensitivity. These results showed that tendon viscoelasticity is affected by decorin content but not by collagen alterations. This study provides quantitative evidence for structure-function relationships in tendon, including the role of proteoglycan in viscoelasticity.     

The modified super-ellipsoid yield criterion for human trabecular bone

Despite the importance of multiaxial failure of trabecular bone in many biomechanical applications, to date no complete multiaxial failure criterion for human trabecular bone has been developed. By using experimentally validated nonlinear high-resolution, micromechanical finite-element models as a surrogate for multiaxial loading experiments, we determined the three-dimensional normal strain yield surface and all combinations of the two-dimensional normal-shear strain yield envelope. High-resolution finite-element models of three human femoral neck trabecular bone specimens obtained through microcomputed tomography were used. In total, 889 multiaxial-loading cases were analyzed, requiring over 41,000 CPU hours on parallel supercomputers. Our results indicated that the multiaxial yield behavior of trabecular bone in strain space was homogeneous across the specimens and nearly isotropic. Analysis of stress-strain curves along each axis in the 3-D normal strain space indicated uncoupled yield behavior whereas substantial coupling was seen for normal-shear loading. A modified super-ellipsoid surface with only four parameters fit the normal strain yield data very well with an arithmetic error +/-SD less than -0.04 +/- 5.1%. Furthermore, the principal strains associated with normal-shear loading showed excellent agreement with the yield surface obtained for normal strain loading (arithmetic error +/- SD < 2.5 +/- 6.5%). We conclude that the four-parameter "Modified Super-Ellipsoid" yield surface presented here describes the multiaxial failure behavior of human femoral neck trabecular bone very well.     

(4-Piperidinylphenyl)aminoethyl amides as a novel class of non-covalent cathepsin K inhibitors

A series of (4-piperidinylphenyl)aminoethyl amides based on dipeptide anilines were synthesized and tested against cathepsin K, cathepsin L and cathepsin B. These new non-covalent inhibitors exhibited single-digit nM inhibition of the cysteine proteases. Compounds 3 and 7 demonstrated potency in both mouse and human osteoclast resorption assays.     

Novel pyrazolopyrimidine derivatives as GSK-3 inhibitors

A series of [1-aryl-1H-pyrazolo[3,4-d]pyrimidin-4-yl]arylhydrazones were discovered as novel inhibitors glycogen synthase kinase-3 (GSK-3). Based on initial modeling a detailed SAR was constructed. Modification of the interior binding aryl ring (Ar(1)) determined this to be a tight binding region with little room for modification. As predicted from the model, a large variety of modifications could be incorporated into the hydrazone aryl ring. This work led to GSK-3 inhibitors in the low nano-molar range.     

Proteomic, functional, and domain-based analysis of in vivo 14-3-3 binding proteins involved in cytoskeletal regulation and cellular organization

BACKGROUND: 14-3-3 proteins are abundant and conserved polypeptides that mediate the cellular effects of basophilic protein kinases through their ability to bind specific peptide motifs phosphorylated on serine or threonine. RESULTS: We have used mass spectrometry to analyze proteins that associate with 14-3-3 isoforms in HEK293 cells. This identified 170 unique 14-3-3-associated proteins, which show only modest overlap with previous 14-3-3 binding partners isolated by affinity chromatography. To explore this large set of proteins, we developed a domain-based hierarchical clustering technique that distinguishes structurally and functionally related subsets of 14-3-3 target proteins. This analysis revealed a large group of 14-3-3 binding partners that regulate cytoskeletal architecture. Inhibition of 14-3-3 phosphoprotein recognition in vivo indicates the general importance of such interactions in cellular morphology and membrane dynamics. Using tandem proteomic and biochemical approaches, we identify a phospho-dependent 14-3-3 binding site on the A kinase anchoring protein (AKAP)-Lbc, a guanine nucleotide exchange factor (GEF) for the Rho GTPase. 14-3-3 binding to AKAP-Lbc, induced by PKA, suppresses Rho activation in vivo. CONCLUSION: 14-3-3 proteins can potentially engage around 0.6% of the human proteome. Domain-based clustering has identified specific subsets of 14-3-3 targets, including numerous proteins involved in the dynamic control of cell architecture. This notion has been validated by the broad inhibition of 14-3-3 phosphorylation-dependent binding in vivo and by the specific analysis of AKAP-Lbc, a RhoGEF that is controlled by its interaction with 14-3-3.     

High altitude training of dogs results in elevated erythropoietin and endothelin-1 serum levels

Living at 2300-m altitude combined with intermittent training at 3500 m leads to cardiovascular alterations in dogs, including increase in systemic and pulmonary artery pressure. Despite moderate to marked hypoxemia at these altitudes, erythrocytosis does not develop. To study humoral mechanisms of acclimatisation to high altitude, erythropoietin (EPO), endothelin-1 (ET-1), big endothelin (Big-ET) and vascular endothelial growth factor (VEGF) were measured in dogs living at 2300 m and intermittently ascending to 3500 m, and compared to the values obtained in control dogs living at 700-900 m. While the median EPO and ET-1 level in dogs at 2300 m did not differ from the one measured at 700-900 m, exposure from 2300 to 3500 m resulted in significantly elevated EPO and ET-1 levels. Big-ET levels were significantly higher at 2300 and 3500 m compared to dogs at low altitude, but did not differ between 2300 and 3500 m. VEGF was significantly elevated in dogs at 2300 m compared to dogs at low altitude. The increases in EPO, VEGF, ET-1 and Big-ET are thought to reflect the effect of hypoxia on a cellular level in these dogs. Obviously, the mild elevation of EPO levels observed at 3500 m was not sufficient to cause erythrocytosis. Elevations of the vasoconstrictors Big-ET and ET-1 may play some, but not a central role in hypoxic vasoconstriction in these dogs. Finally, serum VEGF measurement may be a sensitive and useful test to assess hypoxic stress in dogs.     

Learning the codes of fly immunity

Insect antimicrobial response serves as an excellent model for studying human innate immunity. In this issue of Molecular Cell, Senger and colleagues demonstrate that a large number of immunity genes in Drosophila fat bodies can be regulated by a simple code, REL-GATA.     

Multivesicular body sorting: ubiquitin ligase Rsp5 is required for the modification and sorting of carboxypeptidase S

The multivesicular body (MVB) sorting pathway provides a mechanism for delivering transmembrane proteins into the lumen of the lysosome/vacuole. Recent studies demonstrated that ubiquitin modification acts in cis as a signal for the sorting of cargoes into this pathway. Here, we present results from a genetic selection designed to identify mutants that missort MVB cargoes. This selection identified a point mutation in ubiquitin ligase Rsp5 (Rsp5-326). At the permissive temperature, this mutant is specifically defective for ubiquitination and sorting of the ubiquitin-dependent MVB cargo precursor carboxypeptidase S (pCPS), but not ligand-induced ubiquitination of Ste2. A previous study implicated Tul1 as the ubiquitin ligase responsible for MVB sorting of pCPS. However, we detected no defect in either the sorting or ubiquitination of pCPS in tul1 mutants. We had previously shown that Fab1 phosphatidylinositol 3-phosphate 5-kinase is also required for MVB sorting of pCPS, but not Ste2. However, our analyses reveal that fab1 mutants do not exhibit a defect in ubiquitination of pCPS. Thus, both Rsp5 and Fab1 play distinct and essential roles in the targeting of biosynthetic MVB cargoes. However, whereas Rsp5 seems to be responsible for cargo ubiquitination, the precise role for Fab1 remains to be elucidated.