Association of the membrane estrogen receptor, GPR30, with breast tumor metastasis and transactivation of the epidermal growth factor receptor

The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases function as a common signaling conduit for membrane receptors that lack intrinsic enzymatic activity, such as G-protein coupled receptors and integrins. GPR30, an orphan member of the seven transmembrane receptor (7TMR) superfamily has been linked to specific estrogen binding, rapid estrogen-mediated activation of adenylyl cyclase and the release of membrane-tethered proHB-EGF. More recently, GPR30 expression in primary breast adenocarcinoma has been associated with pathological parameters commonly used to assess breast cancer progression, including the development of extramammary metastases. This newly appreciated mechanism of cross communication between estrogen and EGF is consistent with the observation that 7TMR-mediated transactivation of the EGFR is a recurrent signaling paradigm and may explain prior data reporting the EGF-like effects of estrogen. The molecular details surrounding GPR30-mediated release of proHB-EGF, the involvement of integrin beta1 as a signaling intermediary in estrogen-dependent EGFR action, and the possible implications of these data for breast cancer progression are discussed herein.     

The D-diastereomer of ShK toxin selectively blocks voltage-gated K+ channels and inhibits T lymphocyte proliferation

The polypeptide toxin ShK is a potent blocker of Kv1.3 potassium channels, which are crucial in the activation of human effector memory T cells (T(EM)); selective blockers constitute valuable therapeutic leads for the treatment of autoimmune diseases mediated by T(EM) cells, such as multiple sclerosis, rheumatoid arthritis, and type-1 diabetes. The critical motif on the toxin for potassium channel blockade consists of neighboring lysine and tyrosine residues. Because this motif is sufficient for activity, an ShK analogue was designed based on D-amino acids. D-allo-ShK has a structure essentially identical with that of ShK and is resistant to proteolysis. It blocked Kv1.3 with K(d) 36 nm (2,800-fold lower affinity than ShK), was 2-fold selective for Kv1.3 over Kv1.1, and was inactive against other K(+) channels tested. D-allo-ShK inhibited human T(EM) cell proliferation at 100-fold higher concentration than ShK. Its circulating half-life was only slightly longer than that of ShK, implying that renal clearance is the major determinant of its plasma levels. D-allo-ShK did not bind to the closed state of the channel, unlike ShK. Models of D-allo-ShK bound to Kv1.3 show that it can block the pore as effectively as ShK but makes different interactions with the vestibule, some of which are less favorable than for native ShK. The finding that an all-D analogue of a polypeptide toxin retains biological activity and selectivity is highly unusual. Being resistant to proteolysis and nonantigenic, this analogue should be useful in K(+) channel studies; all-d analogues with improved Kv1.3 potency and specificity may have therapeutic advantages.     

Uncoupling protein-2 modulates the lipid metabolic response to fasting in mice

Uncoupling protein-2 (UCP2) regulates insulin secretion by controlling ATP levels in beta-cells. Although UCP2 deficiency improves glycemic control in mice, increased expression of UCP2 interferes with glucose-stimulated insulin secretion. These observations link UCP2 to beta-cell dysfunction in type 2 diabetes with a perplexing evolutionary role. We found higher residual serum insulin levels and blunted lipid metabolic responses in fasted ucp2(-/-) mice, supporting the concept that UCP2 evolved to suppress insulin effects and to accommodate the fuel switch to fatty acids during starvation. In the absence of UCP2, fasting initially promotes peripheral lipolysis and hepatic fat accumulation at less than expected rates but culminates in protracted steatosis, indicating diminished hepatic utilization and clearance of fatty acids. We conclude that UCP2-mediated control of insulin secretion is a physiologically relevant mechanism of the metabolic response to fasting.     

The Alzheimer amyloid precursor protein (APP) and FE65, an APP-binding protein, regulate cell movement.

FE65 binds to the Alzheimer amyloid precursor protein (APP), but the function of this interaction has not been identified. Here, we report that APP and FE65 are involved in regulation of cell movement. APP and FE65 colocalize with actin and Mena, an Abl-associated signaling protein thought to regulate actin dynamics, in lamellipodia. APP and FE65 specifically concentrate with beta 1-integrin in dynamic adhesion sites known as focal complexes, but not in more static adhesion sites known as focal adhesions. Overexpression of APP accelerates cell migration in an MDCK cell wound--healing assay. Coexpression of APP and FE65 dramatically enhances the effect of APP on cell movement, probably by regulating the amount of APP at the cell surface. These data are consistent with a role for FE65 and APP, possibly in a Mena-containing macromolecular complex, in regulation of actin-based motility.     

Effects of Hunger on Foraging Behavior of Age-0 Smallmouth Bass in a Heterogeneous Environment

We examined how hunger affected habitat use by juvenile smallmouth bass, Micropterus dolomieu, as they moved among a variety of habitat patches. Hungry and satiated fish were placed in an artificial stream that contained three types of habitat patches: pools with uniform depth and low water velocities, mazes with uniform depth and moderate water velocities, and riffle-pool complexes with varying depth and the highest water velocities. Food was only available in the riffle-pool complexes. Hungry fish spent more time in the riffle-pool complex than satiated fish did. However, hungry and satiated fish did not differ in the time it took to exit the pool they were initially placed in, the number of patches entered, or the number of times they moved among patches. Both hungry and satiated fish frequently entered other patches after foraging successfully in the riffle-pool complexes. There was wide variation in foraging behavior among individuals in both treatment groups, and we consistently observed individuals that did not alter their foraging behavior in response to the difference in food availability among patches.     

Husbandry protocols for the Band‐tailed pigeon,Patagioenas fasciata albilinea,at the WCS,Bronx Zoo for future conservation management programs

From 2015 to 2016 we determined the husbandry protocols involved in the captive rearing of the Band‐tailed Pigeon (BTPI), Patagioenas fascinate albilinea, for use as a tool in the future management of like extant and extinct avian taxa. Current and historical ex‐situ conservation management of BTPIs and the closely related Passenger Pigeon, Ectopistes migratorius, is limited in scope and required further examination. Focus on the BTPI within zoos and private aviculture facilities is currently lacking. New pressures on the wild populations and future examination of the parameters involved in the possible restoration of the Passenger Pigeon may rely on a complete understanding of these conservation management techniques. Here we report on the establishment of a colony of BTPIs, at the Wildlife Conservation Society (WCS), and detail the progress attained. A confiscated group of BTPIs was presented to WCS and allowed us to set up the colony, document the husbandry involved, and monitor neonatal development and the factors that influence that development. The information has provided a better understanding of the BTPI and has implications for the future conservation management of this and like species.     

Detrimental effects of a novel flow regime on the functional trajectory of an aquatic invertebrate metacommunity

Novel flow regimes resulting from dam operations and overallocation of freshwater resources are an emerging consequence of global change. Yet, anticipating how freshwater biodiversity will respond to surging flow regime alteration requires overcoming two challenges in environmental flow science: shifting from local to riverscape‐level understanding of biodiversity dynamics, and from static to time‐varying characterizations of the flow regime. Here, we used time‐series methods (wavelets and multivariate autoregressive models) to quantify flow‐regime alteration and to link time‐varying flow regimes to the dynamics of multiple local communities potentially connected by dispersal (i.e., a metacommunity). We studied the Chattahoochee River below Buford dam (Georgia, U.S.A.), and asked how flow regime alteration by a large hydropower dam may control the long‐term functional trajectory of the downstream invertebrate metacommunity. We found that seasonal variation in hydropeaking synchronized temporal fluctuations in trait abundance among the flow‐altered sites. Three biological trait states describing adaptation to fast flows benefitted from flow management for hydropower, but did not compensate for declines in 16 “loser” traits. Accordingly, metacommunity‐wide functional diversity responded negatively to hydropeaking intensity, and stochastic simulations showed that the risk of functional diversity collapse within the next 4 years would decrease by 17% if hydropeaking was ameliorated, or by 9% if it was applied every other season. Finally, an analysis of 97 reference and 23 dam‐affected river sites across the U.S. Southeast suggested that flow variation at extraneous, human‐relevant scales (12‐hr, 24‐hr, 1‐week) is relatively common in rivers affected by hydropower dams. This study advances the notion that novel flow regimes are widespread, and simplify the functional structure of riverine communities by filtering out taxa with nonadaptive traits and by spatially synchronizing their dynamics. This is relevant in the light of ongoing and future hydrologic alteration due to climate non‐stationarity and the new wave of dams planned globally.     

The SOCS Box Encodes a Hierarchy of Affinities for Cullin5: Implications for Ubiquitin Ligase Formation and Cytokine Signalling Suppression

The SOCS (suppressors of cytokine signalling) family of proteins inhibits the cytokine-induced signalling cascade in part by promoting the ubiquitination of signalling intermediates that are then targeted for proteasomal degradation. This activity relies upon an interaction between the SOCS box domain, the adapter complex elonginBC and a member of the Cullin family, the scaffold protein of an E3 ubiquitin ligase. In this study, we dissected this interaction in vitro using purified components. We found that all eight SOCS proteins bound Cullin5 but required prior recruitment of elonginBC. Neither SOCS nor elonginBC bound Cullin5 when in isolation. Interestingly, the affinity of each SOCS-elonginBC complex for Cullin5 varied by 2 orders of magnitude across the SOCS family. Unexpectedly, the most potent suppressors of signalling, SOCS-1 and SOCS-3, bound most weakly to the E3 ligase scaffold, with affinities 100- and 10-fold lower, respectively, than the rest of the family. The remaining six SOCS proteins all bound Cullin5 with high affinity (K_d of ∼ 10 nM) due to a slower off-rate and hence a longer half-life of the complex. This difference in affinity may reflect a difference in mode of action as only SOCS-1 and SOCS-3 have been shown to suppress signalling using both SOCS box-dependent and SOCS box-independent mechanisms. This is not the case with the other six SOCS proteins, and our data imply the existence of two distinct subclasses of SOCS proteins with a high affinity for Cullin5, the E3 ligase scaffold, possibly reflecting complete dependence upon ubiquitination for suppression of cytokine signalling.     

Taxonomical classification and origin of Kamut® wheat

Bioagriculture and healthy lifestyle are trends of the twenty-first century. Bioagriculture involves the breeding of crops without using modern synthetic substances. Kamut brand wheat is one of the popular biocereals grown mainly in the USA and Europe. This cereal has the status of ancient wheat, not only because it has been grown since the era of the ancient Egyptian civilization, but also for its properties favorable for modern breeding programs and modern food marketing. In spite of Kamut’s^® interesting history and stable place in the market, it is not a common subject of genetic studies. It is also interesting that it has not been successfully taxonomically classified yet. There are a few studies which classify this tetraploid wheat as Triticum polonicum L., T. turanicum Jakubz., T. turgidum L. and T. durum Desf. These studies are based on cytological and comparative methods. We chose molecular (transposable element resistance gene analog polymorphism, diversity arrays technology, sequencing of genes SBEIIa, and ψLpx-A1_like) and statistical methods to classify Kamut^® wheat. According to our experiments we suggest that Kamut brand wheat originated as a natural hybrid between Triticum dicoccon conv. dicoccon and T. polonicum and is not original ancient Egyptian wheat. We suggest that Etruscan wheat has the same parents as Kamut^®.