Intercellular communication in the rat anterior pituitary gland: an in vivo and in vitro study

The concept of "stimulus-secretion coupling" suggested by Douglas and co-workers to explain the events related to monamine discharge by the adrenal medulla (5, 7) may be applied to other endocrine tissues, such as adrenal cortex (36), pancreatic islets (4), and magnocellular hypothalamic neurons (6), which exhibit a similar ion-dependent process of hormone elaboration. In addition, they share another feature, that of joining neighbor cells via membrane junctions (12, 26, and Fletcher, unpublished observation). Given this, and the reports that hormone secretion by the pars distalis also involves a secretagogue-induced decrease in membrane bioelectric potential accompanied by a rise in cellular [Ca++] (27, 34, 41), it was appropriate to test the possibility that cells of the anterior pituitary gland are united by junctions.     

High-throughput screen identifies disulfiram as a potential therapeutic for triple-negative breast cancer cells: Interaction with IQ motif-containing factors

Triple-negative breast cancer (TNBC) represents an aggressive subtype, for which radiation and chemotherapy are the only options. Here we describe the identification of disulfiram, an FDA-approved drug used to treat alcoholism, as well as the related compound thiram, as the most potent growth inhibitors following high-throughput screens of 3185 compounds against multiple TNBC cell lines. The average IC₅₀ for disulfiram was ~300 nM. Drug affinity responsive target stability (DARTS) analysis identified IQ motif-containing factors IQGAP1 and MYH9 as direct binding targets of disulfiram. Indeed, knockdown of these factors reduced, though did not completely abolish, cell growth. Combination treatment with 4 different drugs commonly used to treat TNBC revealed that disulfiram synergizes most effectively with doxorubicin to inhibit cell growth of TNBC cells. Disulfiram and doxorubicin cooperated to induce cell death as well as cellular senescence, and targeted the ESA⁺/CD24^-/low/CD44⁺ cancer stem cell population. Our results suggest that disulfiram may be repurposed to treat TNBC in combination with doxorubicin.     

Repeated oral administration of capsaicin increases anxiety-like behaviours with prolonged stress-response in rats

This study was conducted to examine the psycho-emotional effects of repeated oral exposure to capsaicin, the principal active component of chili peppers. Each rat received 1 mL of 0.02% capsaicin into its oral cavity daily, and was subjected to behavioural tests following 10 daily administrations of capsaicin. Stereotypy counts and rostral grooming were significantly increased, and caudal grooming decreased, in capsaicin-treated rats during the ambulatory activity test. In elevated plus maze test, not only the time spent in open arms but also the percent arm entry into open arms was reduced in capsaicin-treated rats compared with control rats. In forced swim test, although swimming duration was decreased, struggling increased in the capsaicin group, immobility duration did not differ between the groups. Repeated oral capsaicin did not affect the basal levels of plasma corticosterone; however, the stress-induced elevation of plasma corticosterone was prolonged in capsaicin treated rats. Oral capsaicin exposure significantly increased c-Fos expression not only in the nucleus tractus of solitarius but also in the paraventricular nucleus. Results suggest that repeated oral exposure to capsaicin increases anxiety-like behaviours in rats, and dysfunction of the hypothalamic-pituitary-adrenal axis may play a role in its pathophysiology.     

Mismatches between breeding phenology and resource abundance of resident alpine ptarmigan negatively affect chick survival

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Managing for multiple species: greater sage-grouse and sagebrush songbirds

Human activity has altered 33–50% of Earth's surface, including temperate grasslands and sagebrush rangelands, resulting in a loss of biodiversity. By promoting habitat for sensitive or wide-ranging species, less exigent species may be protected in an umbrella effect. The greater sage-grouse (Centrocercus urophasianus; sage-grouse) has been proposed as an umbrella for other sagebrush-obligate species because it has an extensive range that overlaps with many other species, it is sensitive to anthropogenic activity, it requires resources over large landscapes, and its habitat needs are known. The efficacy of the umbrella concept, however, is often assumed and rarely tested. Therefore, we surveyed sage-grouse pellet occurrence and sagebrush-associated songbird abundance in northwest Colorado, USA, to determine the amount of habitat overlap between sage-grouse and 4 songbirds (Brewer's sparrow [Spizella breweri], sage thrasher [Oreoscoptes montanus], sagebrush sparrow [Artemisiospiza nevadensis]), and green-tailed towhee [Pipilo chlorurus]). During May and June 2013–2015, we conducted standard point count breeding surveys for songbirds and counted sage-grouse pellets within 300 10-m radius plots. We modeled songbird abundance and sage-grouse pellet occurrence with multi-scaled environmental features, such as sagebrush cover and bare ground. To evaluate sage-grouse as an umbrella for sagebrush-associated passerines, we determined the correlation between probability of sage-grouse pellet occurrence and model-predicted songbird densities per sampling plot. We then classified the sage-grouse probability of occurrence as high (probability >0.5) and low (probability ≤0.5) and mapped model-predicted surfaces for each species in our study area. We determined average songbird density in areas of high and low probability of sage-grouse occurrence. Sagebrush cover at intermediate scales was an important predictor for all species, and ground cover was important for all species except sage thrashers. Areas with a higher probability of sage-grouse occurrence also contained higher densities of Brewer's sparrows, green-tailed towhees, and sage thrashers, but predicted sagebrush sparrow densities were lower in these areas. In northwest Colorado, sage-grouse may be an effective umbrella for Brewer's sparrows, green-tailed towhees, and sage thrashers, but sage-grouse habitat does not appear to capture areas that support high sagebrush sparrow densities. A multi-species focus may be the best management and conservation strategy for several species of concern, especially those with conflicting habitat requirements. © The Wildlife Society, 2019     

Assessing vegetation recovery from energy development using a dynamic reference approach

Ecologically relevant references are useful for evaluating ecosystem recovery, but references that are temporally static may be less useful when environmental conditions and disturbances are spatially and temporally heterogeneous. This challenge is particularly acute for ecosystems dominated by sagebrush (Artemisia spp.), where communities may require decades to recover from disturbance. We demonstrated application of a dynamic reference approach to studying sagebrush recovery using three decades of sagebrush cover estimates from remote sensing (1985–2018). We modelled recovery on former oil and gas well pads (n = 1200) across southwestern Wyoming, USA, relative to paired references identified by the Disturbance Automated Reference Toolset. We also used quantile regression to account for unmodelled heterogeneity in recovery, and projected recovery from similar disturbance across the landscape. Responses to weather and site‐level factors often differed among quantiles, and sagebrush recovery on former well pads increased more when paired reference sites had greater sagebrush cover. Little (<5%) of the landscape was projected to recover within 100 years for low to mid quantiles, and recovery often occurred at higher elevations with cool and moist annual conditions. Conversely, 48%–78% of the landscape recovered quickly (within 25 years) for high quantiles of sagebrush cover. Our study demonstrates advantages of using dynamic reference sites when studying vegetation recovery, as well as how additional inferences obtained from quantile regression can inform management.     

The Importance of the Human Footprint in Shaping the Global Distribution of Terrestrial,Freshwater and Marine Invaders

Human activities such as transport, trade and tourism are likely to influence the spatial distribution of non-native species and yet, Species Distribution Models (SDMs) that aim to predict the future broad scale distribution of invaders often rely on environmental (e.g. climatic) information only. This study investigates if and to what extent do human activities that directly or indirectly influence nature (hereafter the human footprint) affect the global distribution of invasive species in terrestrial, freshwater and marine ecosystems. We selected 72 species including terrestrial plants, terrestrial animals, freshwater and marine invasive species of concern in a focus area located in NW Europe (encompassing Great Britain, France, The Netherlands and Belgium). Species Distribution Models were calibrated with the global occurrence of species and a set of high-resolution (9×9 km) environmental (e.g. topography, climate, geology) layers and human footprint proxies (e.g. the human influence index, population density, road proximity). Our analyses suggest that the global occurrence of a wide range of invaders is primarily limited by climate. Temperature tolerance was the most important factor and explained on average 42% of species distribution. Nevertheless, factors related to the human footprint explained a substantial amount (23% on average) of species distributions. When global models were projected into the focus area, spatial predictions integrating the human footprint featured the highest cumulative risk scores close to transport networks (proxy for invasion pathways) and in habitats with a high human influence index (proxy for propagule pressure). We conclude that human related information–currently available in the form of easily accessible maps and databases—should be routinely implemented into predictive frameworks to inform upon policies to prevent and manage invasions. Otherwise we might be seriously underestimating the species and areas under highest risk of future invasions.     

FlgN Is Required for Flagellum-Based Motility by Bacillus subtilis

The assembly of the bacterial flagellum is exquisitely controlled. Flagellar biosynthesis is underpinned by a specialized type III secretion system that allows export of proteins from the cytoplasm to the nascent structure. Bacillus subtilis regulates flagellar assembly using both conserved and species-specific mechanisms. Here, we show that YvyG is essential for flagellar filament assembly. We define YvyG as an orthologue of the Salmonella enterica serovar Typhimurium type III secretion system chaperone, FlgN, which is required for the export of the hook-filament junction proteins, FlgK and FlgL. Deletion of flgN (yvyG) results in a nonmotile phenotype that is attributable to a decrease in hag translation and a complete lack of filament polymerization. Analyses indicate that a flgK-flgL double mutant strain phenocopies deletion of flgN and that overexpression of flgK-flgL cannot complement the motility defect of a ΔflgN strain. Furthermore, in contrast to previous work suggesting that phosphorylation of FlgN alters its subcellular localization, we show that mutation of the identified tyrosine and arginine FlgN phosphorylation sites has no effect on motility. These data emphasize that flagellar biosynthesis is differentially regulated in B. subtilis from classically studied Gram-negative flagellar systems and questions the biological relevance of some posttranslational modifications identified by global proteomic approaches.     

Differential Sensitivities of Fast- and Slow-Cycling Cancer Cells to Inosine Monophosphate Dehydrogenase 2 Inhibition by Mycophenolic Acid

As uncontrolled cell proliferation requires nucleotide biosynthesis, inhibiting enzymes that mediate nucleotide biosynthesis constitutes a rational approach to the management of oncological diseases. In practice, however, results of this strategy are mixed and thus elucidation of the mechanisms by which cancer cells evade the effect of nucleotide biosynthesis restriction is urgently needed. Here we explored the notion that intrinsic differences in cancer cell cycle velocity are important in the resistance toward inhibition of inosine monophosphate dehydrogenase (IMPDH) by mycophenolic acid (MPA). In short-term experiments, MPA treatment of fast-growing cancer cells effectively elicited G0/G1 arrest and provoked apoptosis, thus inhibiting cell proliferation and colony formation. Forced expression of a mutated IMPDH2, lacking a binding site for MPA but retaining enzymatic activity, resulted in complete resistance of cancer cells to MPA. In nude mice subcutaneously engrafted with HeLa cells, MPA moderately delayed tumor formation by inhibiting cell proliferation and inducing apoptosis. Importantly, we developed a lentiviral vector–based Tet-on label-retaining system that enables to identify, isolate and functionally characterize slow-cycling or so-called label-retaining cells (LRCs) in vitro and in vivo. We surprisingly found the presence of LRCs in fast-growing tumors. LRCs were superior in colony formation, tumor initiation and resistance to MPA as compared with fast-cycling cells. Thus, the slow-cycling compartment of cancer seems predominantly responsible for resistance to MPA.