Reduced protein expression of the phosphodiesterases PDE4A4 and PDE4A8 in AIP mutation positive somatotroph adenomas

© 2018 Type 4 phosphodiesterases (PDE4s) of the large PDE enzyme superfamily have unique specificity for cAMP and may, therefore, be relevant for somatotroph tumorigenesis. Somatotroph adenomas typically overexpress PDEs probably as part of a compensatory mechanism to reduce cAMP levels. The rat PDE4A5 isoform (human homolog PDE4A4) interacts with the AIP protein, coded by a tumour suppressor gene mutated in a subgroup of familial isolated pituitary adenomas (FIPAs). PDE4A8 is the closest related isoform of PDE4A4. We aimed to evaluate the expression of both PDE4A4 and PDE4A8 in GH cells of AIP-mutated adenomas and compare their expression with that in GH cells from sporadic AIP-mutation negative GH-secreting adenomas, where we had shown previously that both PDE4A4 and PDE4A8 isoforms had been over-expressed. Confocal immunofluorescence analysis showed that both PDE4A8 and PDE4A4 had lower expression in AIP-mutated somatotropinoma samples compared to sporadic GH-secreting tumours (P < 0.0001 for both). Based on the association of low PDE4A4 and PDE4A8 expression with germline AIP-mutations positive samples we suggest that lack of AIP hinders the upregulation of PDE4A8 and PDE4A4 protein seen in sporadic somatotrophinomas. These data point to a unique disturbance of the cAMP-PDE pathway in AIP-mutation positive adenomas, which may help to explain their well-described poor response to somatostatin analogues.Grant sponsor: NIH RO1-GM58553 to GBB, The Bolger Prostate Cancer Research Fund to GBB, and the National Cancer Institute of the National Institutes of Health to the University of Alabama at Birmingham Comprehensive Cancer Center under award number P30 CA013148 (for generation of monoclonal antibodies

Prior Mating Experience Modulates the Dispersal of Drosophila in Males More Than in Females

Cues from both an animal’s internal physiological state and its local environment may influence its decision to disperse. However, identifying and quantifying the causative factors underlying the initiation of dispersal is difficult in uncontrolled natural settings. In this study, we automatically monitored the movement of fruit flies and examined the influence of food availability, sex, and reproductive status on their dispersal between laboratory environments. In general, flies with mating experience behave as if they are hungrier than virgin flies, leaving at a greater rate when food is unavailable and staying longer when it is available. Males dispersed at a higher rate and were more active than females when food was unavailable, but tended to stay longer in environments containing food than did females. We found no significant relationship between weight and activity, suggesting the behavioral differences between males and females are caused by an intrinsic factor relating to the sex of a fly and not simply its body size. Finally, we observed a significant difference between the dispersal of the natural isolate used throughout this study and the widely-used laboratory strain, Canton-S, and show that the difference cannot be explained by allelic differences in the foraging gene

Substrate texture properties induce triatomine probing on bitten warm surfaces

<p>Abstract</p> <p>Background</p> <p>In this work we initially evaluated whether the biting process of <it>Rhodnius prolixus </it>relies on the detection of mechanical properties of the substrate. A linear thermal source was used to simulate the presence of a blood vessel under the skin of a host. This apparatus consisted of an aluminium plate and a nickel-chrome wire, both thermostatized and presented at 33 and 36°C, respectively. To evaluate whether mechanical properties of the substrate affect the biting behaviour of bugs, this apparatus was covered by a latex membrane. Additionally, we evaluated whether the expression of probing depends on the integration of bilateral thermal inputs from the antennae.</p> <p>Results</p> <p>The presence of a latex cover on a thermal source induced a change in the biting pattern shown by bugs. In fact, with latex covered sources it was possible to observe long bites that were never performed in response to warm metal surfaces. The total number of bites was higher in intact versus unilaterally antennectomized insects. These bites were significantly longer in intact than in unilaterally antennectomized insects.</p> <p>Conclusions</p> <p>Our results suggest that substrate recognition by simultaneous input through thermal and mechanical modalities is required for triggering maxillary probing activity.</p

Phorcotabanus cinereus (Wiedemann, 1821) (Diptera, Tabanidae), an ornithophilic species of tabanid in Central Amazon, Brazil

In Central Amazon, Brazil, the tabanid Phorcotabanus cinereus (Wiedemann) was recorded attacking the native duck Cairina moschata (Linnaeus) (Anseriformes, Anatidae). The flight and behavior of the tabanid during the attacks and the host's defenses were videotaped and analyzed in slow motion. The tabanid was recorded flying rapidly around the heads of the ducks before landing. Landing always took place on the beak, and then the tabanid walked to the fleshy caruncle on the basal part of the beak to bite and feed. Firstly the duck defends itself through lateral harsh head movements, and then, when it is being bitten, it defends itself by rubbing its head on the body, or dipping the head into water, when swimming. If disturbed, the fly resumed the same pattern of flight as before and would generally try to land again on the same host and bite in the same place. This feeding activity was observed predominantly between 9:30 am and 4:30 pm and always in open areas, near aquatic environments, from June 1996 to January 1997, the dry season in Central Amazon. To test the attractiveness of other animals to P. cinereus, mammals, caimans and domestic and wild birds were placed in suitable habitat and the response of V. cinereus observed. P. cinereus did not attack these animals, suggesting that this species has a preference for ducks, which are plentiful in the region

Immunogenic Salivary Proteins of Triatoma infestans: Development of a Recombinant Antigen for the Detection of Low-Level Infestation of Triatomines

Chagas disease, caused by Trypanosoma cruzi, is a neglected disease with 20 million people at risk in Latin America. The main control strategies are based on insecticide spraying to eliminate the domestic vectors, the most effective of which is Triatoma infestans. This approach has been very successful in some areas. However, there is a constant risk of recrudescence in once-endemic regions resulting from the re-establishment of T. infestans and the invasion of other triatomine species. To detect low-level infestations of triatomines after insecticide spraying, we have developed a new epidemiological tool based on host responses against salivary antigens of T. infestans. We identified and synthesized a highly immunogenic salivary protein. This protein was used successfully to detect differences in the infestation level of T. infestans of households in Bolivia and the exposure to other triatomine species. The development of such an exposure marker to detect low-level infestation may also be a useful tool for other disease vectors

The BINGO Project: III. Optical design and optimization of the focal plane

Context. The Baryon Acoustic Oscillations from Integrated Neutral Gas Observations (BINGO) telescope was designed to measure the fluctuations of the 21 cm radiation arising from the hyperfine transition of neutral hydrogen. It is also aimed at measuring the baryon acoustic oscillations (BAO) from such fluctuations, thereby serving as a pathfinder to future, deeper intensity mapping surveys. The requirements for the Phase 1 of the projects consider a large reflector system (two 40 m-class dishes in a crossed-Dragone configuration) illuminating a focal plane with 28 horns to measure the sky, with two circular polarizations in a drift scan mode to produce measurements of the radiation in intensity (I) as well as the circular (V) polarization. Aims. In this paper, we present the optical design for the instrument. We describe the optical arrangement of the horns in the focal plane to produce a homogeneous and well-sampled map after the end of Phase 1, as well as the intensity and polarization properties of the beams. Our analysis provides an optimal model for the location of the horns in the focal plane, producing a homogeneous and Nyquist-sampled map after the nominal survey time. Methods. We used the GRASP package to model the focal plane arrangement and performed several optimization tasks to arrive at the current configuration, including an estimation of the sidelobes corresponding to the diffraction patterns of the two mirrors. The final model for the focal plane was defined through a combination of neural network and other direct optimization methods. Results. We arrived at an optimal configuration for the optical system that includes the focal plane positioning and the beam behavior of the instrument. We present an estimate of the expected sidelobes both for intensity and polarization, as well as the effect of band averaging on the final sidelobes, as well as an estimation of the cross-polarization leakage for the final configuration. Conclusions. We conclude that the chosen optical design meets the requirements for the project in terms of polarization purity and area coverage as well as a homogeneity of coverage so that BINGO can perform a successful BAO experiment. We further conclude that the requirements on the placement and rms error on the mirrors are also achievable so that a successful experiment can be conducted

The Effect of Anandamide on Uterine Nitric Oxide Synthase Activity Depends on the Presence of the Blastocyst

Nitric oxide production, catalyzed by nitric oxide synthase (NOS), should be strictly regulated to allow embryo implantation. Thus, our first aim was to study NOS activity during peri-implantation in the rat uterus. Day 6 inter-implantation sites showed lower NOS activity (0.19±0.01 pmoles L-citrulline mg prot−1 h−1) compared to days 4 (0.34±0.03) and 5 (0.35±0.02) of pregnancy and to day 6 implantation sites (0.33±0.01). This regulation was not observed in pseudopregnancy. Both dormant and active blastocysts maintained NOS activity at similar levels. Anandamide (AEA), an endocannabinoid, binds to cannabinoid receptors type 1 (CB1) and type 2 (CB2), and high concentrations are toxic for implantation and embryo development. Previously, we observed that AEA synthesis presents an inverted pattern compared to NOS activity described here. We adopted a pharmacological approach using AEA, URB-597 (a selective inhibitor of fatty acid amide hydrolase, the enzyme that degrades AEA) and receptor selective antagonists to investigate the effect of AEA on uterine NOS activity in vitro in rat models of implantation. While AEA (0.70±0.02 vs 0.40±0.04) and URB-597 (1.08±0.09 vs 0.83±0.06) inhibited NOS activity in the absence of a blastocyst (pseudopregnancy) through CB2 receptors, AEA did not modulate NOS on day 5 pregnant uterus. Once implantation begins, URB-597 decreased NOS activity on day 6 implantation sites via CB1 receptors (0.25±0.04 vs 0.40±0.05). While a CB1 antagonist augmented NOS activity on day 6 inter-implantation sites (0.17±0.02 vs 0.27±0.02), a CB2 antagonist decreased it (0.17±0.02 vs 0.12±0.01). Finally, we described the expression and localization of cannabinoid receptors during implantation. In conclusion, AEA levels close to and at implantation sites seems to modulate NOS activity and thus nitric oxide production, fundamental for implantation, via cannabinoid receptors. This modulation depends on the presence of the blastocyst. These data establish cannabinoid receptors as an interesting target for the treatment of implantation deficiencies

Enhanced Leishmania braziliensis Infection Following Pre-Exposure to Sandfly Saliva

Parasites of the genus Leishmania cause a variety of diseases known as leishmaniasis, that are transmitted by bites of female sand flies that, during blood-feeding, inject humans with parasites and saliva. It was shown that, in mice, immunity to sand-fly saliva is able to protect against the development of leishmaniasis. We have investigated, in the present study, whether this finding extends the sand fly species Lutzomyia intermedia, which is responsible for transmission of Leishmania braziliensis, a parasite species able to cause destructive skin lesions that can be fatal if left untreated. We observed that mice injected with sand fly saliva develop a specific immune response against salivary proteins. Most importantly, however, this immune response was unable to protect mice against a challenge infection with L. braziliensis, indicating that exposure to this sand fly saliva is harmful to the host. Indeed, subjects with cutaneous leishmaniasis have a higher immune response against L. intermedia saliva. These findings indicate that the anti-saliva immune response to sand fly saliva plays an important role in the outcome of leishmaniasis caused by L. braziliensis, in both mice and humans, and emphasize possible hurdles in the development of vaccines based on sand fly saliva

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation