Pharmacological properties of canine intrapulmonary blood vessels

The contractile response of ring segments of large, medium, and small pulmonary arteries and veins of the dog to histamine, norepinephrine, and serotonin have been studied. The maximum contractile response to these drugs was normalized with respect to the maximal response obtained in stimulation with 127 mM K+. The small pulmonary artery was more reactive to histamine, norepinephrine, and serotonin when compared with large and medium pulmonary arteries. The medium and large pulmonary artery showed no difference in reactivity to histamine. However, the mean effective dose (ED50) values for these agonists among the different segments of pulmonary arteries showed no significant difference. The small and medium pulmonary veins demonstrated increased reactivity to histamine, but not norepinephrine and serotonin. The ED50 values also indicated that both small and medium veins were more sensitive to histamine when compared with the large pulmonary vein. The log concentration percent response curves for both small and medium pulmonary veins were displaced leftward (increased sensitivity) with respect to that for the large pulmonary vein. However, the reactivity and sensitivity to histamine between medium and small pulmonary veins were no different. The reactivity and sensitivity of different segments of pulmonary veins to norepinephrine and serotonin showed no significant differences among them. We conclude that histamine and other vasoactive substances, which are directly or indirectly related to mast cell degranulation, exert pharmacological effects on the pulmonary vasculature which possesses differential responsiveness at various levels of the vascular tree.     

Influence of isometric exercise on blood flow and sweating in glabrous and nonglabrous human skin.

The distribution of the reflex effects of isometric exercise on cutaneous vasomotor and sudomotor function is not clear. We examined the effects of isometric exercise by different muscle masses on skin blood flow (SkBF) and sweat rate (SR) in nonglabrous skin and in glabrous skin. The latter contains arteriovenous anastomoses (AVAs), which cause large fluctuations in SkBF. SkBF was measured by laser-Doppler flowmetry (LDF) and reported as cutaneous vascular conductance (CVC; LDF/mean arterial pressure). SR was measured by capacitance hygrometry. LDF and SR were measured at the sole, palm, forearm, and ventral leg during separate bouts of isometric handgrip (IHG) and isometric leg extension (ILE). CVC and its standard deviation decreased significantly during IHG and ILE in the palm and sole (P < 0.05) but not in the forearm or leg (P > 0.05). Only palmar SR increased significantly during IHG and ILE (P < 0.05). We conclude that the major reflex influences of isometric exercise on the skin include AVAs and palmar sweat glands and that this is true for both arm and leg exercise.     

Competitive interactions between felid species may limit the southern distribution of bobcats Lynx rufus

Bobcats are opportunistic felids occurring in a diverse range of habitats and with a widespread distribution from southern Canada to southern Mexico. To explore why the bobcat's distribution stops at the Isthmus of Tehuantepec, we modelled the ecological niches, projected as potential distributions, of the felid community (bobcat Lynx rufus, puma Puma concolor, jaguar Panthera onca, margay Leopardus wiedii, jaguarundi Herpailurus yagouaroundi, and ocelot Leopardus pardalis) in southern Mexico, using occurrence data, environmental maps, the computer algorithm GARP, and a GIS platform. The resulting geographical projection of the ecological niche of bobcats extends south of the Isthmus of Tehuantepec, suggesting that ecological conditions exist for the establishment of populations. The overlap of the modelled distribution of the bobcat was large with that of the puma (97%), but low with that of the ocelot (44%), margay (46%), jaguar (49%), and jaguarundi (52%), the latter three having relatively similar size and feeding habits to bobcats. Moreover, an independent analysis computing a geographic co‐occurrence index showed a similar trend of geographic avoidance (values 0.15), while all felids, except bobcats, showed a geographic co‐occurrence in southern Mexico (values ranging from ?1.91 to 4.71). The Isthmus of Tehuantepec, a lowland region with subtropical habitat, is unlikely to serve as a geographic and ecological barrier to bobcats. As mammal inventories have been conducted for over a century in this region with no records of bobcats, it is unlikely that bobcats are present but have just not been seen. Fossil records also provide no support for the presence of bobcats in that region in the past. Thus, competitive interactions with other felid species appear important in limiting the southern distribution of bobcats, preventing dispersal to a suitable but geographically reduced area south of the Isthmus of Tehuantepec.     

Association of TERC and OBFC1 Haplotypes with Mean Leukocyte Telomere Length and Risk for Coronary Heart Disease

Objective

To replicate the associations of leukocyte telomere length (LTL) with variants at four loci and to investigate their associations with coronary heart disease (CHD) and type II diabetes (T2D), in order to examine possible causal effects of telomere maintenance machinery on disease aetiology.

Methods

Four SNPs at three loci BICD1 (rs2630578 GγC), 18q12.2 (rs2162440 GγT), and OBFC1 (rs10786775 CγG, rs11591710 AγC) were genotyped in four studies comprised of 2353 subjects out of which 1148 had CHD and 566 T2D. Three SNPs (rs12696304 CγG, rs10936601G>T and rs16847897 GγC) at the TERC locus were genotyped in these four studies, in addition to an offspring study of 765 healthy students. For all samples, LTL had been measured using a real-time PCR-based method.

Results

Only one SNP was associated with a significant effect on LTL, with the minor allele G of OBFC1 rs10786775 SNP being associated with longer LTL (β=0.029, P=0.04). No SNPs were significantly associated with CHD or T2D. For OBFC1 the haplotype carrying both rare alleles (rs10786775G and rs11591710C, haplotype frequency 0.089) was associated with lower CHD prevalence (OR: 0.77; 95% CI: 0.61–0.97; P= 0.03). The TERC haplotype GTC (rs12696304G, rs10936601T and rs16847897C, haplotype frequency 0.210) was associated with lower risk for both CHD (OR: 0.86; 95% CI: 0.75-0.99; P=0.04) and T2D (OR: 0.74; 95% CI: 0.61–0.91; P= 0.004), with no effect on LTL. Only the last association remained after adjusting for multiple testing.

Conclusion

Of reported associations, only that between the OBFC1 rs10786775 SNP and LTL was confirmed, although our study has a limited power to detect modest effects. A 2-SNP OBFC1 haplotype was associated with higher risk of CHD, and a 3-SNP TERC haplotype was associated with both higher risk of CHD and T2D. Further work is required to confirm these results and explore the mechanisms of these effects.     

Modelling Viscous Fingering on a Parallel Computer

Diffusion limited aggregation (DLA) has proved very successful in modelling systems which display fractal characteristics, like viscous fingering. However, by nature, such simulations are very processor intensive, requiring large amounts of processor time even for relatively small models. We have performed simulations of viscous fingering on the NCUBE parallel computer which has hypercube architecture. We find that, as long as the number of processors used is much less than both the total number of walkers released and the overall dimensions of the model, the fractal dimensions obtained using serial and parallel algorithms give similar results whilst achieving a considerable speed-up in the parallel implementation. An average fractal dimension of 1.71 was obtained along with a speed-up of 106 (in the best case) and 83% efficiency using 128 processors.     

HIV Populations Are Large and Accumulate High Genetic Diversity in a Nonlinear Fashion

HIV infection is characterized by rapid and error-prone viral replication resulting in genetically diverse virus populations. The rate of accumulation of diversity and the mechanisms involved are under intense study to provide useful information to understand immune evasion and the development of drug resistance. To characterize the development of viral diversity after infection, we carried out an in-depth analysis of single genome sequences of HIV pro-pol to assess diversity and divergence and to estimate replicating population sizes in a group of treatment-naive HIV-infected individuals sampled at single (n = 22) or multiple, longitudinal (n = 11) time points. Analysis of single genome sequences revealed nonlinear accumulation of sequence diversity during the course of infection. Diversity accumulated in recently infected individuals at rates 30-fold higher than in patients with chronic infection. Accumulation of synonymous changes accounted for most of the diversity during chronic infection. Accumulation of diversity resulted in population shifts, but the rates of change were low relative to estimated replication cycle times, consistent with relatively large population sizes. Analysis of changes in allele frequencies revealed effective population sizes that are substantially higher than previous estimates of approximately 1,000 infectious particles/infected individual. Taken together, these observations indicate that HIV populations are large, diverse, and slow to change in chronic infection and that the emergence of new mutations, including drug resistance mutations, is governed by both selection forces and drift.     

Physical mapping of the von Recklinghausen neurofibromatosis region on chromosome 17

The von Recklinghausen neurofibromatosis (NF1) locus has been linked to chromosome 17, and recent linkage analyses place the gene on the proximal long arm. NF1 probably resides in 17q11.2, since two unrelated NF1 patients have been identified who possess constitutional reciprocal translocations involving 17q11.2 with chromosomes 1 and 22. We have used a somatic-cell hybrid from the t(17;22) individual, along with other hybrid cell lines, to order probes around the NF1 locus. An additional probe, 17L1, has been isolated from a NotI linking library made from flow-sorted chromosome 17 material and has been mapped to a region immediately proximal to the translocation breakpoint. While neither NF1 translocation breakpoint has yet been identified by pulse-field gel analysis, an overlap between two probes, EW206 and EW207, has been detected. Furthermore, we have identified the breakpoint in a non-NF1 translocation, SP-3, on the proximal side of the NF1 locus. This breakpoint has been helpful in creating a 1,000-kb pulsed-field map, which includes the closely linked NF1 probes HHH202 and TH17.19. The combined somatic-cell hybrid and pulsed-field gel analysis we report here favors the probe order D17Z1-HHH202-TH17.19-CRYB1-17L1-NF1- (EW206, EW207, EW203, L581, L946)-(ERBB2, ERBA1). The agreement in probe ordering between linkage analysis and physical mapping is excellent, and the availability of translocation breakpoints in NF1 should now greatly assist the cloning of this locus.     

Identification of a myosin VII-talin complex

Myosin VII (M7) plays a role in adhesion in both Dictyostelium and mammalian cells where it is a component of a complex of proteins that serve to link membrane receptors to the underlying actin cytoskeleton. The nature of this complex is not fully known, prompting a search for M7-binding proteins. Co-immunoprecipitation experiments reveal that Dictyostelium M7 (DdM7) interacts with talinA, an actin-binding protein with a known role in cell-substrate adhesion. No additional proteins are observed in the immunoprecipitate, indicating that the interaction is direct. The N-terminal region of the DdM7 tail that lies between the region of predicted coil and the first MyTH4 domain is found to harbor the talinA binding site. Localization experiments reveal that talinA does not serve as a membrane receptor for DdM7 and vice versa. These findings reveal that talinA is a major DdM7 binding partner and suggest that their interaction induces a conformational change in each that, in combination with membrane receptor binding, promotes the assembly of a high avidity receptor complex essential for adhesion of the cell to substrata.