Molecular pathway for cancer metastasis to bone

The molecular mechanism leading to the cancer metastasis to bone is poorly understood but yet determines prognosis and therapy. Here, we define a new molecular pathway that may account for the extraordinarily high osteotropism of prostate cancer. By using SPARC (secreted protein, acidic and rich in cysteine)-deficient mice and recombinant SPARC, we demonstrated that SPARC selectively supports the migration of highly metastatic relative to less metastatic prostate cancer cell lines to bone. Increased migration to SPARC can be traced to the activation of integrins alphaVbeta3 and alphaVbeta5 on tumor cells. Such activation is induced by an autocrine vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)-2 loop on the tumor cells, which also supports the growth and proliferation of prostate cancer cells. A consequence of SPARC recognition by alphaVbeta5 is enhanced VEGF production. Thus, prostate cancer cells expressing VEGF/VEGFR-2 will activate alphaVbeta3 and alphaVbeta5 on their surface and use these integrins to migrate toward SPARC in bone. Within the bone environment, SPARC engagement of these integrins will stimulate growth of the tumor and further production of VEGF to support neoangiogenesis, thereby favoring the development of the metastatic tumor. Supporting this model, activated integrins were found to colocalize with VEGFR-2 in tissue samples of metastatic prostate tumors from patients.     

Estradiol binding to maxi-K channels induces their down-regulation via proteasomal degradation

Estrogens exert their biological action via both genomic and non-genomic mechanisms. Proteins different from classical estradiol receptors are believed to mediate the latter effects. Here we demonstrate that the maxi-K channel functions as an estrogen-binding protein in transfected HEK293 cells. Whole-cell maxi-K channel currents and protein expression were attenuated by exposure to either 17alpha- or 17beta-estradiol. This effect was dose-dependent for 17beta-estradiol at concentrations ranging from 10 nm to 1 microm, while 17alpha-estradiol inhibited channel expression only at 1 microm. These effects were mediated by direct low affinity binding of estradiol to the maxi-K channel but not to its accessory beta1-subunit, as revealed by cell membrane estradiol binding assays. However, specific binding of estradiol to the channel was facilitated by the presence of the beta1 subunit. Addition of MG-132, a blocker of proteasomal degradation, stabilized channel expression. These data suggest that channel down-regulation is mediated by estrogen-induced proteasomal degradation, similar to the pathway used for estrogen receptor degradation. Membrane expression of endogenous maxi-K channels in cultured vascular smooth muscle cells was also attenuated by prolonged exposure to 17alpha- and 17beta-estradiol. Thus our studies demonstrate that estrogen binds to maxi-K channels and may directly regulate channel expression and function. These results will have important implications in understanding estradiol-induced effects in multiple tissues including vascular smooth muscle.     

Auditory feedback in learning and maintenance of vocal behaviour

Songbirds are one of the best-studied examples of vocal learners. Learning of both human speech and birdsong depends on hearing. Once learned, adult song in many species remains unchanging, suggesting a reduced influence of sensory experience. Recent studies have revealed, however, that adult song is not always stable, extending our understanding of the mechanisms involved in song maintenance, and their similarity to those active during song learning. Here we review some of the processes that contribute to song learning and production, with an emphasis on the role of auditory feedback. We then consider some of the possible neural substrates involved in these processes, particularly basal ganglia circuitry. Although a thorough treatment of human speech is beyond the scope of this article, we point out similarities between speech and song learning, and ways in which studies of these disparate behaviours complement each other in developing an understanding of general principles that contribute to learning and maintenance of vocal behaviour.     

Decreased CXCR3+ CD8 T cells in advanced human immunodeficiency virus infection suggest that a homing defect contributes to cytotoxic T-lymphocyte dysfunction

To exert their cytotoxic function, cytotoxic T-lymphocytes (CTL) must be recruited into infected lymphoid tissue where the majority of human immunodeficiency virus (HIV) replication occurs. Normally, effector T cells exit lymph nodes (LNs) and home to peripheral sites of infection. How HIV-specific CTL migrate into lymphoid tissue from which they are normally excluded is unknown. We investigated which chemokines and receptors mediate this reverse homing and whether impairment of this homing could contribute to CTL dysfunction as HIV infection progresses. Analysis of CTL chemokine receptor expression in the blood and LNs of untreated HIV-infected individuals with stable, chronic infection or advanced disease demonstrated that LNs were enriched for CXCR3(+) CD8 T cells in all subjects, suggesting a key role for this receptor in CTL homing to infected lymphoid tissue. Compared to subjects with chronic infection, however, subjects with advanced disease had fewer CXCR3(+) CD8 T cells in blood and LNs. CXCR3 expression on bulk and HIV-specific CD8 T cells correlated positively with CD4 count and negatively with viral load. In advanced infection, there was an accumulation of HIV-specific CD8 T cells at the effector memory stage; however, decreased numbers of CXCR3(+) CD8 T cells were seen across all maturation subsets. Plasma CXCL9 and CXCL10 were elevated in both infected groups in comparison to the levels in uninfected controls, whereas lower mRNA levels of CXCR3 ligands and CD8 in LNs were seen in advanced infection. These data suggest that both CXCR3(+) CD8 T cells and LN CXCR3 ligands decrease as HIV infection progresses, resulting in reduced homing of CTL into LNs and contributing to immune dysfunction.     

Fishing degrades size structure of coral reef fish communities

Fishing pressure on coral reef ecosystems has been frequently linked to reductions of large fishes and reef fish biomass. Associated impacts on overall community structure are, however, less clear. In size‐structured aquatic ecosystems, fishing impacts are commonly quantified using size spectra, which describe the distribution of individual body sizes within a community. We examined the size spectra and biomass of coral reef fish communities at 38 US‐affiliated Pacific islands that ranged in human presence from near pristine to human population centers. Size spectra ‘steepened’ steadily with increasing human population and proximity to market due to a reduction in the relative biomass of large fishes and an increase in the dominance of small fishes. Reef fish biomass was substantially lower on inhabited islands than uninhabited ones, even at inhabited islands with the lowest levels of human presence. We found that on populated islands size spectra exponents decreased (analogous to size spectra steepening) linearly with declining biomass, whereas on uninhabited islands there was no relationship. Size spectra were steeper in regions of low sea surface temperature but were insensitive to variation in other environmental and geomorphic covariates. In contrast, reef fish biomass was highly sensitive to oceanographic conditions, being influenced by both oceanic productivity and sea surface temperature. Our results suggest that community size structure may be a more robust indicator than fish biomass to increasing human presence and that size spectra are reliable indicators of exploitation impacts across regions of different fish community compositions, environmental drivers, and fisheries types. Size‐based approaches that link directly to functional properties of fish communities, and are relatively insensitive to abiotic variation across biogeographic regions, offer great potential for developing our understanding of fishing impacts in coral reef ecosystems.     

Experimentally-induced diabetes reduces nocturnal pineal melatonin content in the Syrian hamster

Male, Syrian hamsters were rendered diabetic by either alloxan (60 mg/kg, i.v.) or streptozotocin (65 mg/kg, i.p.). Diabetic animals had reduced pineal melatonin contents during the night. Basal daytime values were not significantly altered. Diabetes may decrease melatonin synthesis by reducing the availability of glucose for metabolism or by decreasing the transport of tryptophan into pinealocytes for the synthesis of melatonin.     

Photoperiodic and light spectral conditions which inhibit circulating concentrations of thyroxine in the male hamster

Adult male Syrian hamsters were exposed daily for 12 weeks to 11 h/day of cool white fluorescent light (350 +/- 50 microW/cm2) followed by an additional 3 h of near ultraviolet (339-317 nm), blue (435-500 nm), green (515-550 nm), yellow (558-636 nm) or red (653-668 nm) light at an irradiance of 0.2 microW/cm2 or to total darkness. Animals exposed to the wavelengths between 558-668 nm (yellow or red half peak bandwidths) or those receiving a total of 13 h of darkness/day had suppressed circulating levels of thyroxine (T4), a depressed free T4 index (FT4I) and a higher T3/T4 ratio compared to animals receiving a total of 14 h of white light (350 +/- 50 microW/cm2). These results suggest that specific wavelengths of light can affect the neuroendocrine-thyroid axis.     

Effects of different light wavelengths at equal irradiance on testis weight, protein content, and K-paranitrophenylphosphatase activity in the Syrian hamster

The effects of different light wavelengths at equal irradiance on testis weight, testis protein content, and testis K-paranitrophenylphosphatase (K-pNPPase) activity were studied in the Syrian hamster. One group (long photoperiod) was maintained on a light:dark cycle of 14:10, and another group (short photoperiod) on a cycle of 10:14. Five other groups were maintained on a cycle of 10:14 but with a one hour pulse of equally intense illumination in the middle of the dark period with UV, blue, green, yellow or red light. Animals exposed to a long photoperiod or UV, blue or green light pulses had significantly greater testis weights--up to eightfold greater than those in the yellow or red or short photoperiod groups. Organ protein content closely paralleled organ weight, but the protein/wet weight ratio was consistently higher in the large organ groups. K-pNPPase and Mg-pNPPase activities were significantly higher in the large organ groups, even when expressed per mg protein. Therefore, at a balanced irradiance of 0.2uW/cm2, light wavelength exerts a profound effect on testicular weight, protein content, and K-pNPPase and Mg-pNPPase activities. Testicular involution is a process that is selective with regard to protein biosynthesis.