Neuronal correlates of kinematics-to-dynamics transformation in the supplementary motor area

It is widely acknowledged that movements are planned at the level of the kinematics. However, the central nervous system must ultimately transform kinematic plans into dynamics-related commands. How, when, and where the kinematics-to-dynamics (KD) transformation is processed represent fundamental and unanswered questions. We recorded from the supplementary motor area (SMA) of two monkeys as they executed visually instructed reaching movements. We specifically analyzed a delay period following the instruction but prior to the go signal (motor planning). During the delay, a group of neurons in the SMA progressively came to reflect the dynamics rather than the desired kinematics of the upcoming movement. This finding suggests that some neurons in the SMA participate in the KD transformation.     

The MAPK pathway triggers activation of Nek2 during chromosome condensation in mouse spermatocytes

Chromosome condensation during the G2/M progression of mouse pachytene spermatocytes induced by the phosphatase inhibitor okadaic acid (OA) requires the activation of the MAPK Erk1. In many cell systems, p90Rsks are the main effectors of Erk1/2 function. We have identified p90Rsk2 as the isoform that is specifically expressed in mouse spermatocytes and have shown that it is activated during the OA-triggered meiotic G2/M progression. By using the MEK inhibitor U0126, we have demonstrated that activation of p90Rsk2 during meiotic progression requires activation of the MAPK pathway. Immunofluorescence analysis indicates that activated Erks and p90Rsk2 are tightly associated with condensed chromosomes during the G2/M transition in meiotic cells. We also found that active p90Rsk2 was able to phosphorylate histone H3 at Ser10 in vitro, but that the activation of the Erk1/p90Rsk2 pathway was not necessary for phosphorylation of H3 in vivo. Furthermore, phosphorylation of H3 was not sufficient to cause condensation of meiotic chromosomes in mouse spermatocytes. Other proteins known to associate with chromatin may represent effectors of Erk1 and p90Rsk2 during chromosome condensation. Nek2 (NIMA-related kinase 2), which associates with chromosomes, plays an active role in chromatin condensation and is stimulated by treatment of pachytene spermatocytes with okadaic acid. We show that inhibition of the MAPK pathway by preincubation of spermatocytes with U0126 suppresses Nek2 activation, and that incubation of spermatocyte cell extracts with activated p90Rsk2 causes stimulation of Nek2 kinase activity. Furthermore, we show that the Nek2 kinase domain is a substrate for p90Rsk2 phosphorylation in vitro. These data establish a connection between the Erk1/p90Rsk2 pathway, Nek2 activation and chromosome condensation during the G2/M transition of the first meiotic prophase.     

Endovanilloid signaling in pain

Recent work has addressed the role of vanilloid receptor type 1 (VR1) in pain perception. VR1 activity is regulated both directly and indirectly by endogenous factors. For example, protein kinase C sensitizes human VR1 to mild decreases in pH, which are commonly encountered during inflammation, and renders the endocannabinoid anandamide a more potent 'endovanilloid'. Bradykinin and nerve growth factor release VR1 from the inhibitory control of phosphatidylinositol (4,5)-bisphosphate and anti-VR1 serum ameliorates thermal allodynia and hyperalgesia in diabetic mice. There is strong evidence that not only the sensitivity but also the density of expression of VR1 is enhanced during inflammatory conditions. These observations provide an empirical foundation which could explain the reduced inflammatory hyperalgesia in VR1 knockout mice, and they imply an important role for endovanilloid signaling via VR1 in the development of ongoing pain in humans that occurs in most inflammatory conditions. Conversely, downregulation of VR1 expression and/or activity is a promising therapeutic strategy for novel analgesic drugs.     

Combinatorial library of indinavir analogues: replacement for the aminoindanol at P2'

A 1X22X41 combinatorial library or 902 compounds of indinavir analogues was synthesized on the solid support to identify a replacement for the aminoindanol moiety at P2'. 2,6-Dimethyl-4-hydroxy phenol was discovered to be a good replacement for aminoindanol.     

Absence of endogenous interleukin-10 enhances the evolution of acute lung injury

Interleukin-10 (IL-10) exerts a wide spectrum of regulatory activities in the immune and inflammatory response. The aim of this study was to investigate the role of endogenous IL-10 on the modulation of the inflammatory response in mice subjected to carrageenan-induced lung injury. When compared to carrageenan-treated IL-10 wild-type (WT) mice, carrageenan-treated IL-10 knock-out mice (IL-10KO) mice experienced a higher rate of pleural exudation, and polymorphonuclear cell migration. Exudate levels of the pro-inflammatory cytokines tumour necrosis factor, interleukin-1beta and interleukin-6 were also greatly enhanced in IL-10KO mice in comparison to wild-type mice. Lung myeloperoxidase (MPO) activity was significantly reduced in IL-10WT mice when compared to IL-10KO mice-treated with carrageenan. The degree of oxidative and nitrosative damage was significantly higher in IL-10KO mice than in wild-type littermates, as indicated by elevated malondialdehyde levels and formation of nitrotyrosine and poly (ADP-ribose) synthetase (PARS). Staining of lung tissue sections obtained from carrageenan-treated IL-10WT with an anti-COX-2 antibody showed a positive staining of the inflamed tissue. Furthermore, expression of inducible nitric oxide synthase (iNOS) was found mainly in the macrophages of the inflamed lungs from carrageenan-treated IL-10WT mice. The intensity and degree of the staining for COX-2 and iNOS were markedly enhanced in tissue sections obtained from carrageenan-treated IL-10KO mice. Most notably, the degree of lung injury caused by carrageenan was also enhanced in IL-10KO mice. Taken together, our results clearly demonstrate that endogenous IL-10 exerts an anti-inflammatory role during acute inflammation and tissue damage associated with carrageenan-induced pleurisy, possibly by regulating neutrophil recruitment, and the subsequent cytokine and oxidant generation.     

Evolution of enzyme cascades from embryonic development to blood coagulation

Recent delineation of the serine protease cascade controlling dorsal-ventral patterning during Drosophila embryogenesis allows this cascade to be compared with those controlling clotting and complement in vertebrates and invertebrates. The identification of discrete markers of serine protease evolution has made it possible to reconstruct the probable chronology of enzyme evolution and to gain new insights into functional linkages among the cascades. Here, it is proposed that a single ancestral developmental/immunity cascade gave rise to the protostome and deuterostome developmental, clotting and complement cascades. Extensive similarities suggest that these cascades were built by adding enzymes from the bottom of the cascade up and from similar macromolecular building blocks.     

Pressure drops in a distensible model of end-to-side anastomosis in systemic-to-pulmonary shunts

The modified Blalock-Taussig shunt is a surgical procedure used as a palliation to treat complex congenital heart defects. It consists of an interposing prosthetic tube between the innominate/subclavian artery and the right pulmonary artery. Previous experience indicates that the pressure drop across the shunt is affected by the pulmonary pressure at the distal anastomosis combined with the distensibility of the anastomosis. In this study, a computational fluid-structure interaction approach is presented to investigate the haemodynamic behaviour. Steady-state fluid dynamics and structural analyses were carried out using commercial codes based on the finite element method (FIDAP and ABAQUS) coupled by means of a purposely-developed procedure to transfer boundary conditions. Both prosthetic tube and artery walls were characterised by non-linear material properties. Three different pulmonary pressures (2, 5 and 15 mmHg) and two volume flow rates (0.4 and 0.8 l/min) were investigated. Results indicate that the effects of distensibility at the distal anastomosis on the shunt pressure drop are relevant only when the distal anastomosis on the shunt pressure drop are relevant only when the distal anastomosis is not fully distended, which occurs when the pulmonary pressure is lower than 5 mmHg.     

Immunological evidence for progesterone and estradiol receptors in the freshwater crayfish Austropotamobius pallipes

In this article, we present evidence for progesterone and estradiol receptors (PR and ER, respectively) in the female of the crayfish Austropotamobius pallipes. To our knowledge, this is the first report of sex steroid receptors in crustaceans. By using immunohistochemistry and Western blotting approaches and employing three different antibodies against PR (human PR, chicken PR-hinge region, and chicken PR A/B domain) and antibodies against human ER, we showed the presence of PR in the ovary and hepatopancreas and ER in the hepatopancreas of the freshwater crayfish A. pallipes. The immunological characteristics and the tissue localization suggest a relatedness with both PR and ER in vertebrates along with their involvement in the modulation of reproductive functions in this crustaceans.     

Detection of grain protein content QTLs across environments in tetraploid wheats

Grain protein content (GPC) is an important quality factor in both durum and bread wheats. GPC is considered to be a polygenic trait influenced by environmental factors and management practice. The objectives of this study were both to compare the quantitative trait loci (QTL) for GPC in a population of 65 recombinant inbred lines of tetraploid wheats evaluated in three locations for several years (eight data sets), and to investigate the genetic relationship among GPC and grain yield. QTLs were determined based on the Messapia × dicoccoides linkage map which covers 217 linked loci on the 14 chromosomes with 42 additional loci as yet unassigned to linkage groups. The map extends to 1352 cM; the average distance between adjacent markers was 6.3 cM. Seven QTLs for GPC, located on the chromosome arms 4BS, 5AL, 6AS (two loci), 6BS, 7AS and 7BS, were detected that were significant in at least one environment at P<0.001 or in at least two environments at P<0.01. One QTL was significant in all but one environment, two were significant in four or five environments, and four were significant in two out of eight environments. Six out of seven protein content QTLs had pleiotropic effects or were associated to QTLs for grain yield and explained the negative correlation among GPC and yield components. The present results support the concept that studies conducted in a single environment are likely to underestimate the number of QTLs that can influence a trait and that the phenotypic data for a quantitative trait should be collected over a range of locations to identify putative QTLs and determine their phenotypic effects.     

beta-Endorphin modulation of pressor response to hyperventilation in hypertensive patients

After hyperventilation, systolic and diastolic blood pressure (BP) significantly decreased in 14 hypertensive patients (group 1), did not change in 9 (group 2) and increased in 8 (group 3). Basal BP, norepinephrine and dynorphin B levels were higher in group 1 than in groups 2 and 3. The decrease in BP after hyperventilation was associated with a decrease in plasma norepinephrine, Met-enkephalin and dynorphin B and an increase in beta-endorphin. Naloxone abolished the hyperventilation-induced BP and norepinephrine decreases. Our findings indicate that hyperventilation may select hypertensive patients with different sympatho-adrenergic activity and that the increase in beta-endorphin reduces BP response to hyperventilation in patients with high sympatho-adrenergic tone.