The interaction between protein kinase A and progesterone on basal and inflammation-induced myometrial oxytocin receptor expression

Our previous work has shown myometrial PKA activity declines in term and twin-preterm labour in association with an increase in the expression of the oxytocin receptor (OTR). Here we investigate the action of cAMP/PKA in basal conditions, with the addition of progesterone (P4) and/or IL-1β to understand how cAMP/PKA acts to maintain pregnancy and whether the combination of cAMP and P4 would be a viable therapeutic combination for the prevention of preterm labour (PTL). Further, given that we have previously found that cAMP enhances P4 action we wanted to test the hypothesis that changes in the cAMP effector system are responsible for the functional withdrawal of myometrial P4 action. Myometrial cells were grown from biopsies obtained from women at the time of elective Caesarean section before the onset of labour. The addition of forskolin, an adenylyl cyclase activator, repressed basal OTR mRNA levels at all doses and P4 only enhanced this effect at its highest dose. Forskolin repressed the IL-1β-induced increase in OTR mRNA and protein levels in a PKA-dependent fashion and repressed IL-1β-activation and nuclear transfer of NFκB and AP-1. P4 had similar effects and the combination P4 and forskolin had greater effects on OTR and NFκB than forskolin alone. While PKA knockdown had no effect on the ability of P4 to repress IL-1β-induced OTR expression it reversed the repressive effect of the combination of P4 and forskolin and resulted in a greater increase than observed with IL-1β alone. These studies suggest that cAMP acts via PKA to repress inflammation-driven OTR expression, but that when PKA activity is reduced, the combination of cAMP and P4 actually enhances the OTR response to inflammation, promoting the onset of labour and suggesting that changes in the cAMP effector system can induce a functional P4 withdrawal.

Development of an end-effector system for autonomous spraying applications and radiation surveying

This paper presents the design and testing of a scale proof-of-concept prototype robotic end-effector system for autonomous robotic shotcrete application and radiation surveying in underground uranium mining environments. The system presented consists of two functionally distinct prototype tools that achieve the independent tasks of autonomous robotic spray pattern control and surface radiation surveying. The first prototype tool presented is a novel, robotic shotcrete spraying tool that is capable of autonomously maintaining and adjusting its circular spray pattern diameter on target surfaces in response to changes in target surface distance. Control algorithms are presented that give the robotic shotcrete spraying tool the capability to produce advanced figure eight and spiral spraying patterns for surface preparation applications that involve spot filling deep surface cracks and pockets. Physical testing of the prototype tool empirically verified its ability to maintain circular spray pattern diameters at various target distances and demonstrated the application potential of the advanced figure eight and spiral spraying patterns. The second prototype tool presented is a Geiger–Müller tube-based radiation detection tool that uses lead shielding and a single-hole collimator in combination with precise robotic positioning to capture localized radiation measurements of surfaces within radiation-rich environments. Physical testing of the prototype tool demonstrated its ability to create radiation survey profiles that distinctly characterized the radiological profile of test target surfaces embedded with various radioactive sources.

Changes in cAMP effector predominance are associated with increased oxytocin receptor expression in twin but not infection-associated or idiopathic preterm labour

We previously reported that at term pregnancy, a decline in myometrial protein kinase A (PKA) activity leads to an exchange protein activated by cyclic AMP (Epac1)-dependent increase in oxytocin receptor (OTR) expression, promoting the onset of labour. Here, we studied the changes in the cyclic adenosine monophosphate (cAMP) effector system present in different phenotypes of preterm labour (PTL). Myometrial biopsies obtained from women with phenotypically distinct forms of PTL and the levels of PKA and OTR were examined. Although we found similar changes in the cAMP effector pathway in all forms of PTL, only in the case of twin PTL (T-PTL) was myometrial OTR levels increased in association with these results. Although there were several changes in the mRNA levels of components of the cAMP synthetic pathway, the total myometrial cAMP levels did not change with the onset of any subtype of PTL. With regards to the expression of cAMP-responsive genes, we found that the mRNA levels of 4 of the 5 cAMP-down-regulated genes were increased in T-PTL, similar to our findings in term labour. These data signify that although changes in the cAMP effector system were common to all forms of PTL, only in T-PTL were OTR levels increased. Similarly, the mRNA levels of cAMP-repressed genes were only increased in T-PTL supporting the concept that the decline in PKA levels influences myometrial function driving the onset of T-PTL.

The Lamprey’s Dilemma

This chapter focuses on the neural network, demonstrating how the principles described in the previous chapter are implemented in vertebrates, taking as a blueprint the oldest one: the lamprey. The reticulospinal neurons belong to the reticular formation located in the brainstem of the lamprey. These reticulospinal neurons act as the effector system. Apart from the peripheral input that comes back from the spinal cord, the reticular formation receives, among other things, input from the diencephalon and specifically the thalamus. This structure allows interfacing between sensory stimuli (visual, auditory, and olfactory) and the motor system. The other very important targets of the thalamus in the lamprey are the basal ganglia. The chapter then goes on to explain the diencephalic and telencephalic loops.

OPTIMIZATION OF KIDNEYS’ DETOXICATION FUNCTION OF SEPTIC PATIENTS IN THE PERIOD OF STABILIZATION OF TOXIC AUTOAGRESION

INTRODUCTION: Kidney injuries in the endogenous intoxication syndrome of septic genesis necessitates nephroprotective therapy.OBJECTIVES: The purpose of the work was to determine the effect of the combined use of sorbilact and L-arginine on the detoxification function of kidneys and the levels of separate indicators of endogenous intoxication syndrome.METHODS: Detoxication function of kidneys have been studied in patients of the following groups.The first group (І, control) consisted of 31 patients with systemic inflammatory response syndrome (SIRS, ICD-10: R-65.2).The second group (ІІ) consisted of 22 patients with endogenous intoxication syndrome who were treated according to Surviving Sepsis Campaign 2016 (standard therapy) [9].The third group (IІІ) consisted of 24 patients with endogenous intoxication syndrome, who received sorbilact in addition to standard therapy.The fourth group (IV) consisted of 21 patients with endogenous intoxication syndrome who received sorbilact and L-arginine in addition to standard therapy.Sorbilact infusion to patients of the III and IV groups was performed at a rate of 6-7 ml/kg body weight, intravenously dripping at a rate of 7-8 ml/min. After the end of the infusion of sorbilact, patients of the IV group were infused with 4.2% solution of L-arginine (“Tivortin” intravenous drip according to the instructions). Data was obtained and results gathered on the application of drugs in the period of stabilization (according to the state of regulation of water and ion balance by kidneys) of endogenous intoxication syndrome (fourth day of drugs’ application).As a single-celled receptor-effector system, a Paramecium caudatum culture was used. Low Molecular Weight Protein (LMWP) concentrations in blood and urine were determined using a modified method.RESULTS: Endogenous intoxication syndrome in patients of II-IV groups was characterized by the following indicators: total blood plasma toxicity (Pt) in the II group was 151 ± 6.4 toxicity units / ml, in group ІІ -147 ± 6.2 toxicity units / ml and 130 ± 6.6 toxicity units / ml in group IV. LMWP concentration in group ІІ was 0.61 ± 0.03 conditional units / ml, in ІІІ group - 0.52 ± 0.029 conditional units / ml and 0.43 ± 0.037 conditional units / ml in group IV.The following clearance detoxification function characteristics are established, which are integral indicators of its kidneys performance. Clearance of toxic substances (Ct) in the I group was 2.7 ± 0.06 ml / min, in the II group 2.1 ± 0.09 ml / min, in the III group - 2.9 ± 0.07 ml / min and 3.8 ± 0.08 ml / min in the IV group. Clearness of LMWP (C LMWP) in the 1st group was 15.91 ± 0.69, ml / min, in the II group 14.65 ± 0.79 ml / min, in group ІІІ - 25.61 ± 0.71 ml / min and 37.31 ± 0.7 ml / min in group IV.CONCLUSION: Under conditions of septic endotoxemia in the period of stabilization of endogenous intoxication syndrome optimization of standard therapy with the use of sorbilact and L-arginine is accompanied by the activation of the kidneys’detoxication function according to their clearance characteristics.

Effect of nutritional stress and sex on melanotic encapsulation rate in the sexually size dimorphic Cook Strait giant weta (Deinacrida rugosa)

Nutritional condition and sex are known to influence efficacy and investment in immune function. A poor diet is costly to immune function because it limits the resources (e.g., protein) available to effector systems (e.g., melanotic encapsulation), whereas males and females are expected to differ in how they allocate resources to fitness-related traits. Males are expected to invest less in immunity, and more in mating, than females, but this pattern could be reversed if fitness is more condition-dependent in males than in females. I tested the effects of nutritional condition and sex on melanotic encapsulation rate in the Cook Strait giant weta (Deinacrida rugosa Buller, 1871), an orthopteran insect exhibiting strong female-biased sexual size dimorphism that is, at least in part, the result of strong sexual selection for small male size. I found that male D. rugosa have a stronger encapsulation response than females, while nutritional condition has only a small positive effect on this particular effector system in both sexes. Whether the observed sex difference in encapsulation ability is due to a physiological constraint in females or whether males allocate more resources to this effector system because their fitness is more condition-dependent than female’s remains to be determined.