Homologous and heterologous desensitization of guanylyl cyclase-B signaling in GH3 somatolactotropes

The guanylyl cyclases, GC-A and GC-B, are selective receptors for atrial and C-type natriuretic peptides (ANP and CNP, respectively). In the anterior pituitary, CNP and GC-B are major regulators of cGMP production in gonadotropes and yet mouse models of disrupted CNP and GC-B indicate a potential role in growth hormone secretion. In the current study, we investigate the molecular and pharmacological properties of the CNP/GC-B system in somatotrope lineage cells. Primary rat pituitary and GH3 somatolactotropes expressed functional GC-A and GC-B receptors that had similar EC50 properties in terms of cGMP production. Interestingly, GC-B signaling underwent rapid homologous desensitization in a protein phosphatase 2A (PP2A)-dependent manner. Chronic exposure to either CNP or ANP caused a significant down-regulation of both GC-A- and GC-B-dependent cGMP accumulation in a ligand-specific manner. However, this down-regulation was not accompanied by alterations in the sub-cellular localization of these receptors. Heterologous desensitization of GC-B signaling occurred in GH3 cells following exposure to either sphingosine-1-phosphate or thyrotrophin-releasing hormone (TRH). This heterologous desensitization was protein kinase C (PKC)-dependent, as pre-treatment with GF109203X prevented the effect of TRH on CNP/GC-B signaling. Collectively, these data indicate common and distinct properties of particulate guanylyl cyclase receptors in somatotropes and reveal that independent mechanisms of homologous and heterologous desensitization occur involving either PP2A or PKC. Guanylyl cyclase receptors thus represent potential novel therapeutic targets for treating growth-hormone-associated disorders

Life expectancy inequalities in Wales before COVID-19: an exploration of current contributions by age and cause of death and changes between 2002 and 2018

Objectives The COVID-19 pandemic in Wales and the UK has highlighted significant and historic inequalities in health between social groups. To better understand the composition of these inequalities and inform planning after the pandemic, we undertook a decomposition of life expectancy inequalities between the most and least deprived quintiles for men and women by age and cause of death and explored trends between 2002 and 2018. Study design Statistical decomposition of life expectancy inequalities by age and cause of death using routine population mortality datasets. Methods We used routine statistics from the Office for National Statistics for the period 2002–2018 on population and deaths in Wales stratified by age, gender, Welsh Index of Multiple Deprivation (WIMD) 2019 quintile and cause of death, categorised by International Classification of Disease, version 10, code into 15 categories of public health relevance. We aggregated data to 3-year rolling figures to account for low numbers of events in some groups annually. Next, we estimated life expectancy at birth by quintile, gender and period using life table methods. Lastly, we performed a decomposition analysis using the Arriaga method to identify the specific disease categories and ages at which excess deaths occur in more disadvantaged areas to highlight potential areas for action. Results Life expectancy inequalities between the most and least WIMD quintiles rose for both genders between 2002 and 2018: from 4.69 to 6.02 years for women (an increase of 1.33 years) and from 6.34 to 7.42 years for men (an increase of 1.08 years). Exploratory analysis of these trends suggested that the following were most influential for women: respiratory disease (1.50 years), cancers (1.36 years), circulatory disease (1.35 years) and digestive disease (0.51 years). For men, the gap was driven by circulatory disease (2.01 years), cancers (1.39 years), respiratory disease (1.25 years), digestive disease (0.79 years), drug- and alcohol-related conditions (0.54 years) and external causes (0.54 years). Contributions for women from respiratory disease, cancers, dementia and drug- and alcohol-related conditions appeared to be increasing, while among men, there were rising contributions from respiratory, digestive and circulatory disease. Conclusions Life expectancy inequalities in Wales remain wide and have been increasing, particularly among women, with indications of worsening trends since 2010 following the introduction of fiscal austerity. As agencies recover from the pandemic, these findings should be considered alongside any resumption of services in Wales or future health and public policy

Description of the two-nucleon system on the basis of the Bargmann representation of the S matrix

For the effective-range function $k\cot \delta$, a pole approximation that involves a small number of parameters is derived on the basis of the Bargmann representation of the $S$ matrix. The parameters of this representation, which have a clear physical meaning, are related to the parameters of the Bargmann $S$ matrix by simple equations. By using a polynomial least-squares fit to the function $k\cot \delta$ at low energies, the triplet low-energy parameters of neutron-proton scattering are obtained for the latest experimental data of Arndt et al. on phase shifts. The results are $a_{t}=5.4030$fm, $r_{t}=1.7494$fm, and $v_{2}=0.163$fm$^{3}$. With allowance for the values found for the low-energy scattering parameters and for the pole parameter, the pole approximation of the function $k\cot \delta$ provides an excellent description of the triplet phase shift for neutron-proton scattering over a wide energy range ($T_{\text{lab}}\lesssim 1000$MeV), substantially improving the description at low energies as well. For the experimental phase shifts of Arndt et al., the triplet shape parameters $v_{n}$ of the effective-range expansion are obtained by using the pole approximation. The description of the phase shift by means of the effective-range expansion featuring values found for the low-energy scattering parameters proves to be fairly accurate over a broad energy region extending to energy values approximately equal to the energy at which this phase shift changes sign, this being indicative of a high accuracy and a considerable value of the effective-range expansion in describing experimental data on nucleon-nucleon scattering. The properties of the deuteron that were calculated by using various approximations of the effective-range function comply well with their experimental values.Comment: 39 pages, 3 figure

Natriuretic peptide activation of extracellular regulated kinase 1/2 (ERK1/2) pathway by particulate guanylyl cyclases in GH3 somatolactotropes.

The natriuretic peptides, Atrial-, B-type and C-type natriuretric peptides (ANP, BNP, CNP), are regulators of many endocrine tissues and exert their effects predominantly through the activation of their specific guanylyl cyclase receptors (GC-A and GC-B) to generate cGMP. Whereas cGMP-independent signalling has been reported in response to natriuretic peptides, this is mediated via either the clearance receptor (Npr-C) or a renal-specific NPR-Bi isoform, which both lack intrinsic guanylyl cyclase activity. Here, we report evidence of GC-B-dependent cGMP-independent signalling in pituitary GH3 cells. Stimulation of GH3 cells with CNP resulted in a rapid and sustained enhancement of ERK1/2 phosphorylation (P-ERK1/2), an effect that was not mimicked by dibutryl-cGMP. Furthermore, CNP-stimulated P-ERK1/2 occurred at concentrations below that required for cGMP accumulation. The effect of CNP on P-ERK1/2 was sensitive to pharmacological blockade of MEK (U0126) and Src kinases (PP2). Silencing of the GC-B1 and GC-B2 splice variants of the GC-B receptor by using targeted short interfering RNAs completely blocked the CNP effects on P-ERK1/2. CNP failed to alter GH3 cell proliferation or cell cycle distribution but caused a concentration-dependent increase in the activity of the human glycoprotein α-subunit promoter (αGSU) in a MEK-dependent manner. Finally, CNP also activated the p38 and JNK MAPK pathways in GH3 cells. These findings reveal an additional mechanism of GC-B signalling and suggest additional biological roles for CNP in its target tissues

Size-selective mortality during freshwater and marine life stages of steelhead related to freshwater growth in the Skagit River, Washington

Wild steelhead trout, Oncorhynchus mykiss, in the Puget Sound are currently in decline, and very little is known about the early life history of these threatened fish. This study evaluated consequences of early growth and survival to smolt or adult stages in different precipitation zones of the Skagit River Basin, Washington. The objectives of this study were to determine whether significant size-selective mortality (SSM) in wild steelhead could be detected between freshwater stages and returning adults; and if so, how the magnitude of SSM varied among juveniles rearing in different precipitation zones (snow and mixed rain-snow). Wild steelhead were sampled as juveniles, smolts, and adults, and scales were measured to compare back-calculated size distributions and growth rates of rearing juveniles with individuals that survived from an earlier life stage to the smolt and adult stages. Back-calculated size-at-annulus comparisons indicated that steelhead in the snow zone were significantly larger at annulus-1 than those in the mixed zone. Steelhead sampled as adults were significantly larger than those sampled as juveniles at annuli-1, -2, and -3, and larger than those sampled as smolts at annuli-2 and -3, Steelhead sampled as smolts were larger than those sampled as juveniles at annuli-1 and -2, but smolts and juveniles were the same size at annulus-3. The disparity in size-at-age-2 and -3 between steelhead sampled at earlier and later life stages suggested that fast growth during the second or third freshwater growing seasons was vitally important for survival to adulthood, and that both freshwater and marine survival could be attributed, in part, to size attained at earlier life stages in freshwater. Efforts for recovery of threatened Puget Sound steelhead could benefit by considering SSM in freshwater environments, and identifying factors that limit growth during early life stages

The Oldest Case of Decapitation in the New World (Lapa do Santo, East-Central Brazil)

We present here evidence for an early Holocene case of decapitation in the New World (Burial 26), found in the rock shelter of Lapa do Santo in 2007. Lapa do Santo is an archaeological site located in the Lagoa Santa karst in east-central Brazil with evidence of human occupation dating as far back as 11.7-12.7 cal kyBP (95.4% interval). An ultra-filtered AMS age determination on a fragment of the sphenoid provided an age range of 9.1-9.4 cal kyBP (95.4% interval) for Burial 26. The interment was composed of an articulated cranium, mandible and first six cervical vertebrae. Cut marks with a v-shaped profile were observed in the mandible and sixth cervical vertebra. The right hand was amputated and laid over the left side of the face with distal phalanges pointing to the chin and the left hand was amputated and laid over the right side of the face with distal phalanges pointing to the forehead. Strontium analysis comparing Burial 26's isotopic signature to other specimens from Lapa do Santo suggests this was a local member of the group. Therefore, we suggest a ritualized decapitation instead of trophy-taking, testifying for the sophistication of mortuary rituals among hunter-gatherers in the Americas during the early Archaic period. In the apparent absence of wealth goods or elaborated architecture, Lapa do Santo's inhabitants seemed to use the human body to express their cosmological principles regarding death