HER-2/neu-mediated down-regulation of biglycan associated with altered growth properties

The extracellular matrix protein biglycan (Bgn) is a leucine-rich proteoglycan that is involved in the matrix assembly, cellular migration and adhesion, cell growth, and apoptosis. Although a distinct expression of Bgn was found in a number of human tumors, the role of this protein in the initiation and/or maintenance of neoplastic transformation has not been studied in detail. Using an in vitro model of oncogenic transformation, a down-regulation of Bgn expression as well as an altered secretion of different Bgn isoforms was found both in murine and human HER-2/neu oncogene-transformed cells when compared with HER-2/neu(-) cells. This was associated with a reduced growth, wound closure, and migration capacity. Vice versa, silencing of Bgn in HER-2/neu(-) fibroblasts increased the growth rate and migration capacity of these cells. Bgn expression was neither modulated in HER-2/neu(+) cells by transforming growth factor-β(1) nor by inhibition of the phosphoinositol 3-kinase and MAP kinase pathways. In contrast, inhibition of the protein kinase C (PKC) pathway led to the reconstitution of Bgn expression. In particular, the PKC target protein cAMP response element binding protein (CREB) is a major regulator of Bgn expression as the silencing of CREB by RNA interference was accompanied by ～5000-fold increase in Bgn-mRNA expression in HER-2/neu(+) cells. Thus, Bgn inhibits the major properties of HER-2/neu-transformed cells, which is inversely modulated by the PKC signaling cascade.     

Discrimination of jittered sonar echoes by the echolocating bat,Eptesicus fuscus: The shape of target images in echolocation

1. Behavioral experiments with jittering echoes examined acoustic images of sonar targets in the echolocating bat, Eptesicus fuscus, along the echo delay or target range axis. Echo phase, amplitude, bandwidth, and signal-to-noise ratio were manipulated to assess the underlying auditory processes for image formation. 2. Fine delay acuity is about 10 ns. Calibration and control procedures indicate that this represents temporal acuity rather than spectral discrimination. Jitter discrimination curves change in phase when the phase of one jittering echo is shifted by 180 degrees relative to the other, showing that echo phase is involved in delay estimation. At an echo detectability index of about 36 dB, fine acuity is 40 ns, which is approximately as predicted for the delay accuracy of an ideal receiver. 3. Compound performance curves for 0 degrees and 180 degrees phase conditions match the crosscorrelation function of the echoes. The locations of both 0 degrees and 180 degrees phase peaks in the performance curves shift along the time axis by an amount that matches neural amplitude-latency trading in Eptesicus, confirming a temporal basis for jitter discrimination.     

Genetic and physiological bases for phenological responses to current and predicted climates

We are now reaching the stage at which specific genetic factors with known physiological effects can be tied directly and quantitatively to variation in phenology. With such a mechanistic understanding, scientists can better predict phenological responses to novel seasonal climates. Using the widespread model species Arabidopsis thaliana, we explore how variation in different genetic pathways can be linked to phenology and life-history variation across geographical regions and seasons. We show that the expression of phenological traits including flowering depends critically on the growth season, and we outline an integrated life-history approach to phenology in which the timing of later life-history events can be contingent on the environmental cues regulating earlier life stages. As flowering time in many plants is determined by the integration of multiple environmentally sensitive gene pathways, the novel combinations of important seasonal cues in projected future climates will alter how phenology responds to variation in the flowering time gene network with important consequences for plant life history. We discuss how phenology models in other systems—both natural and agricultural—could employ a similar framework to explore the potential contribution of genetic variation to the physiological integration of cues determining phenology.     

Ceramide kinase regulates the migration of bone marrow-derived mesenchymal stem cells

Endogenous bone marrow-derived mesenchymal stem cells (BM-MSCs) are mobilized into peripheral blood and injured tissues by various growth factors and cytokines that are expressed in the injured tissues, such as substance P (SP), stromal cell derived factor-1 (SDF-1), and transforming growth factor-beta (TGF-β). Extracellular bioactive lipid metabolites such as ceramide-1-phosphate and sphingosine-1-phosphate also modulate BM-MSC migration as SP, SDF-1, and TGF-β. However, the roles of intrinsic lipid kinases of BM-MSCs in the stem cell migration are unclear. Here, we demonstrated that ceramide kinase mediates the chemotactic migration of BM-MSCs in response to SP, SDF-1, or TGF-β. Furthermore, a specific inhibitor of ceramide kinase inhibited TGF-β-induced migration of BM-MSCs and N-cadherin that is necessary for BM-MSCs migration in response to TGF-β. Therefore, these results suggest that the intracellular ceramide kinase is required for the BM-MSCs migration and the roles of the intrinsic ceramide kinase in the migration are associated with N-cadherin regulation.     

Spawning and nesting behavior of the waccamaw darter,Etheostoma perlongum

Synopsis The spawning and nesting behavior ofEtheostoma (Boleosoma) perlongum was investigated in the field and laboratory. Sexual dimorphism is highly developed in such features as genital papillae, first dorsal and paired fins, and nuptial coloration. A reproductive migration from mid-lake to shore occurs in the spring: males precede females to select nest sites under submerged sticks and other debris. The male excavates a depression beneath the submerged object. Gonad analysis indicates a single spawning season extending from March through June. Nests were found from late April to mid-June and were guarded by a single male for periods of 13 to 36 days. Males initiate courtship by lateral display, lead the female to the nest site and show the nest by inverting. The female responds by tail up, tail wag and circle; males also tail wag and circle. Spawning pairs invert, usually in unison, and orient head to head or, less often, head to tail. The female deposits eggs while holding her body in a weak S or J shape with the caudal peduncle held away from the spawning substrate while vibrating.     

Patterns of bird migration phenology in South Africa suggest northern hemisphere climate as the most consistent driver of change

Current knowledge of phenological shifts in Palearctic bird migration is largely based on data collected on migrants at their breeding grounds; little is known about the phenology of these birds at their nonbreeding grounds, and even less about that of intra‐African migrants. Because climate change patterns are not uniform across the globe, we can expect regional disparities in bird phenological responses. It is also likely that they vary across species, as species show differences in the strength of affinities they have with particular habitats and environments. Here, we examine the arrival and departure of nine Palearctic and seven intra‐African migratory species in the central Highveld of South Africa, where the former spend their nonbreeding season and the latter their breeding season. Using novel analytical methods based on bird atlas data, we show phenological shifts in migration of five species – red‐backed shrike, spotted flycatcher, common sandpiper, white‐winged tern (Palearctic migrants), and diederik cuckoo (intra‐African migrant) – between two atlas periods: 1987–1991 and 2007–2012. During this time period, Palearctic migrants advanced their departure from their South African nonbreeding grounds. This trend was mainly driven by waterbirds. No consistent changes were observed for intra‐African migrants. Our results suggest that the most consistent drivers of migration phenological shifts act in the northern hemisphere, probably at the breeding grounds.     

The Caribou Migration Model for Arctic Hadrosaurs (Dinosauria: Ornithischia): A Reassessment

The recovery of abundant dinosaur fossils from high paleolatitudes of northern Alaska has raised some hard questions in relation to any available model of dinosaur physiology. To explain the occurrence of hadrosaurs at high ancient latitudes, a model involving long-distance migration analogous to that of the modern caribou has been proposed. The model calls for seasonal movements over great latitudinal distances by these Cretaceous hadrosaurs. This model is reassessed in terms of the growth, body sizes, and inferred physiological ecology of the hadrosaurs and the caribou. Histological data suggest that juvenile hadrosaurs obtained from northern Alaska were greater than 1 year in age. Comparison of the relative sizes of juvenile and adult hadrosaurs with juvenile and adult caribou suggests, based on qualitative energetics, that the juvenile hadrosaurs were too small to participate in long-distance migration. The "hadrosaurs as caribou" model provides clues to the feeding ecology of North Slope hadrosaurs, if they are reinterpreted as year-round residents of high latitudes. However, it does not constitute a satisfactory basis on which to infer long-distance seasonal migrations by these animals.     

Mammalian and Malaria Parasite Cyclase-associated Proteins Catalyze Nucleotide Exchange on G-actin through a Conserved Mechanism

Cyclase-associated proteins (CAPs) are among the most highly conserved regulators of actin dynamics, being present in organisms from mammals to apicomplexan parasites. Yeast, plant, and mammalian CAPs are large multidomain proteins, which catalyze nucleotide exchange on actin monomers from ADP to ATP and recycle actin monomers from actin-depolymerizing factor (ADF)/cofilin for new rounds of filament assembly. However, the mechanism by which CAPs promote nucleotide exchange is not known. Furthermore, how apicomplexan CAPs, which lack many domains present in yeast and mammalian CAPs, contribute to actin dynamics is not understood. We show that, like yeast Srv2/CAP, mouse CAP1 interacts with ADF/cofilin and ADP-G-actin through its N-terminal α-helical and C-terminal β-strand domains, respectively. However, in the variation to yeast Srv2/CAP, mouse CAP1 has two adjacent profilin-binding sites, and it interacts with ATP-actin monomers with high affinity through its WH2 domain. Importantly, we revealed that the C-terminal β-sheet domain of mouse CAP1 is essential and sufficient for catalyzing nucleotide exchange on actin monomers, although the adjacent WH2 domain is not required for this function. Supporting these data, we show that the malaria parasite Plasmodium falciparum CAP, which is entirely composed of the β-sheet domain, efficiently promotes nucleotide exchange on actin monomers. Collectively, this study provides evidence that catalyzing nucleotide exchange on actin monomers via the β-sheet domain is the most highly conserved function of CAPs from mammals to apicomplexan parasites. Other functions, including interactions with profilin and ADF/cofilin, evolved in more complex organisms to adjust the specific role of CAPs in actin dynamics.     

Flt3 mutation activates p21WAF1/CIP1 gene expression through the action of STAT5

Metastin, a post-translationally modified variant of KiSS1, was recently identified as an endogenous peptide agonist for a novel G-protein coupled receptor, hOT7T175 (AXOR12, GPR54). In this study, we analyzed the role of KiSS1 and hOT7T175 in both pancreatic cancer tissues and pancreatic cancer cell lines. Furthermore, we synthesized novel short variant forms of metastin and tested the inhibitory effect of those variants on in vitro cell functions that are relevant to metastasis. Pancreatic cancer tissues showed significantly lower expression of KiSS1 mRNA than normal tissues (p=0.018), while cancer tissues showed significantly higher expression of hOT7T175 mRNA than normal pancreatic tissues (p=0.027). In human pancreatic cancer cell lines, KiSS1 mRNA was highly expressed in 2 out of 6 pancreatic cancer cell lines, while hOT7T175 mRNA was expressed in all cell lines at various degrees. PANC-1 cells showed the highest expression of hOT7T175. Exogenous metastin did not suppress cell proliferation but significantly reduced the in vitro migration of PANC-1 cells (p<0.01). Metastin induced activation of ERK1 in PANC-1 and AsPC-1 cells. Finally, we synthesized 3 novel short variant forms of metastin, FM053a2TFA, FM059a2TFA, and FM052a4TFA. These metastin variants significantly suppressed the migration of PANC-1 cells and activated ERK1. These data suggest that the metastin receptor, hOT7T175, is one of the promising targets for suppression of metastasis, and that small metastin variants could be an anti-metastatic agent to pancreatic cancer.