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1
Antoniewski, C. "Le co-activateur du récepteur nucléaire était... un ARN !" médecine/sciences 15, no. 10 (1999): 1153. http://dx.doi.org/10.4267/10608/1230.
2
Martella, Christophe, Laetitia Waast, and Claudine Pique. "Tax, marionnettiste de la transcription du HTLV-1." médecine/sciences 38, no. 4 (April 2022): 359–65. http://dx.doi.org/10.1051/medsci/2022039.
Анотація:
Les rétrovirus sont des virus dont le génome est constitué d’un ARN rétrotranscrit en ADN dans la cellule, qui s’intègre alors dans le génome cellulaire. La transcription du génome rétroviral intégré est ensuite réalisée par la machinerie de transcription de l’ARN polymérase II. Dans le cas du virus T-lymphotrope humain de type 1 (HTLV-1, pour human T-lymphotropic virus type 1), rétrovirus responsable de la leucémie aiguë de l’adulte et de maladies inflammatoires, la transcription est contrôlée par la protéine virale Tax. Celle-ci agit selon un mode d’action original car le mécanisme activateur ne repose pas sur une interaction directe avec le promoteur viral, mais sur le recrutement de différents facteurs et cofacteurs cellulaires de la transcription. Les facteurs cellulaires recrutés par Tax sont impliqués dans l’activation initiale du promoteur, mais également dans les étapes ultérieures du processus de transcription lui-même. Cette revue décrit ce mécanisme particulier de transcription virale, de la levée de la répression transcriptionnelle jusqu’à l’élongation des transcrits viraux néosynthétisés.
3
Blake, Timo, Anne Barnard, Stephen J. W. Busby, and Jeffrey Green. "Transcription Activation by FNR: Evidence for a Functional Activating Region 2." Journal of Bacteriology 184, no. 21 (November 1, 2002): 5855–61. http://dx.doi.org/10.1128/jb.184.21.5855-5861.2002.
Анотація:
ABSTRACT The FNR protein of Escherichia coli controls the transcription of target genes in response to anoxia via the assembly-disassembly of oxygen-labile iron-sulfur clusters. Previous work identified patches of surface-exposed amino acids (designated activating regions 1 and 3 [AR1 and AR3, respectively]) of FNR which allow it to communicate with RNA polymerase (RNAP) and thereby activate transcription. Previously it was thought that FNR lacks a functional activating region 2 (AR2), although selecting for mutations that compensate for defective AR1 or a miscoordinated iron-sulfur cluster can reactivate AR2. Here we show that the substitution of two surface-exposed lysine residues (Lys49 and Lys50) of FNR impaired transcription from class II (FNR box centered at −41.5) but not class I (FNR box centered at −71.5) FNR-dependent promoters. The degree of impairment was greater when a negatively charged residue (Glu) replaced either Lys49 or Lys50 than when uncharged amino acid Ala was substituted. Oriented heterodimers were used to show that only the downstream subunit of the FNR dimer was affected by the Lys→Ala substitutions at a class II promoter. Site-directed mutagenesis of a negatively charged patch (162EEDE165) within the N-terminal domain of the RNAP α subunit that interacts with the positively charged AR2 of the cyclic AMP receptor protein suggested that Lys49 and Lys50 of FNR interact with this region of the α subunit of RNAP. Thus, it was suggested that Lys49 and Lys50 form part of a functional AR2 in FNR.
4
Liu, Xinhuai, and Allan Herbison. "Kisspeptin Regulation of Arcuate Neuron Excitability in Kisspeptin Receptor Knockout Mice." Endocrinology 156, no. 5 (March 10, 2015): 1815–27. http://dx.doi.org/10.1210/en.2014-1845.
Анотація:
The G protein-coupled receptor 54 (GPR54) is critical for kisspeptin to activate GnRH neurons to modulate fertility. However, the often mismatching distribution of kisspeptin and GPR54 in the brain suggests that kisspeptin may also act on other receptors. The arcuate nucleus (ARN) is one brain region with a very high density of kisspeptin fibers but only limited evidence for the expression of GPR54. Using acute brain slice electrophysiology in combination with Gpr54 knockout (GPR54KO) mouse models, we examined whether actions of kisspeptin in the ARN were dependent upon GPR54. Cell-attached recordings from unidentified ARN neurons in wild-type mice revealed that approximately one third of neurons were either excited or inhibited by kisspeptin in a dose-dependent manner. The responses of ARN neurons to kisspeptin were exactly the same in GPR54KO mice despite effects of kisspeptin on GnRH neurons being abolished. To evaluate whether kisspeptin may be acting through neuropeptide FF receptors, the effects of an agonist RFamide-related peptide 3 (RFRP-3) and antagonists RF9 and BIBP-3226 were evaluated. Both the excitatory and inhibitory effects of kisspeptin were mimicked by the agonist RFRP-3. RF9 itself activated ARN neurons and suppressed only the inhibitory actions of kisspeptin. BIBP-3226 suppressed kisspeptin actions in 50% of neurons. Whole-cell recordings in GPR54KO mice demonstrated that both kisspeptin and RFRP-3 acted directly on the same ARN neurons and activated the same ion channels. Together, these studies demonstrate that kisspeptin can act partly through neuropeptide FF receptors to modulate neuronal activity independent of GPR54 in the mouse brain.
5
Xu, Bo, Hong Zheng, Xuefei Liu, and Kaushik P. Patel. "Activation of afferent renal nerves modulates RVLM-projecting PVN neurons." American Journal of Physiology-Heart and Circulatory Physiology 308, no. 9 (May 1, 2015): H1103—H1111. http://dx.doi.org/10.1152/ajpheart.00862.2014.
Анотація:
Renal denervation for the treatment of hypertension has proven to be successful; however, the underlying mechanism/s are not entirely clear. To determine if preautonomic neurons in the paraventricular nucleus (PVN) respond to afferent renal nerve (ARN) stimulation, extracellular single-unit recording was used to investigate the contribution of the rostral ventrolateral medulla (RVLM)-projecting PVN (PVN-RVLM) neurons to the response elicited during stimulation of ARN. In 109 spontaneously active neurons recorded in the PVN of anesthetized rats, 25 units were antidromically activated from the RVLM. Among these PVN-RVLM neurons, 84% (21/25) were activated by ARN stimulation. The baseline discharge rate was significantly higher in these neurons than those PVN-RVLM neurons not activated by ARN stimulation (16%, 4/25). The responsiveness of these neurons to baroreflex activation induced by phenylephrine and activation of cardiac sympathetic afferent reflex (CSAR) was also examined. Almost all of the PVN neurons that responded to ARN stimulation were sensitive to baroreflex (95%) and CSAR (100%). The discharge characteristics for nonevoked neurons (not activated by RVLM antidromic stimulation) showed that 23% of these PVN neurons responded to ARN stimulation. All the PVN neurons that responded to ARN stimulation were activated by N-methyl-d-aspartate, and these responses were attenuated by the glutamate receptor blocker AP5. These experiments demonstrated that sensory information originating in the kidney is integrated at the level of preautonomic neurons within the PVN, providing a novel mechanistic insight for use of renal denervation in the modulation of sympathetic outflow in disease states such as hypertension and heart failure.
6
de Croft, Simon, Ulrich Boehm, and Allan E. Herbison. "Neurokinin B Activates Arcuate Kisspeptin Neurons Through Multiple Tachykinin Receptors in the Male Mouse." Endocrinology 154, no. 8 (August 1, 2013): 2750–60. http://dx.doi.org/10.1210/en.2013-1231.
Анотація:
Abstract Kisspeptin neurons located in the arcuate nucleus (ARN) coexpress dynorphin and neurokinin B (NKB) and may interact to influence gonadotropin secretion. Using a kisspeptin-green fluorescent protein mouse model, the present study examined whether the neuropeptides kisspeptin, dynorphin, and NKB modulate the electrical activity of ARN kisspeptin neurons in the adult male mouse. Cell-attached recordings showed that kisspeptin itself had no effect on kisspeptin neuron firing. Dynorphin and the κ-opioid receptor agonist U50-488 evoked a potent suppression of all ARN kisspeptin neuron firing that was blocked completely by the κ-opioid receptor antagonist nor-Binaltorphimine. Both NKB and Senktide, a neurokinin 3 receptor agonist, exerted a potent stimulatory action on ∼95% of ARN kisspeptin neurons. Although the selective neurokinin 3 receptor antagonists SB222200 and SR142801 blocked the effects of Senktide on kisspeptin neurons, they surprisingly had no effect on NKB activation of firing. Studies with selective neurokinin 1 receptor (SDZ-NKT343) and neurokinin 2 receptor (GR94800) antagonists revealed that the activation of kisspeptin neurons by NKB was only blocked completely by a cocktail of antagonists against all 3 tachykinin receptors. Whole-cell recordings revealed that individual kisspeptin neurons were activated directly by all 3 tachykinins substance, P, neurokinin A, and NKB. These experiments show that dynorphin and NKB have opposing actions on the electrical activity of kisspeptin neurons supporting the existence of an interconnected network of kisspeptin neurons in the ARN. However, the effects of NKB result from an unexpected activation of multiple tachykinin receptors.
7
Derrien, Thomas, and Roderic Guigó. "De longs ARN non codants activateurs de la transcription des gènes." médecine/sciences 27, no. 4 (April 2011): 359–61. http://dx.doi.org/10.1051/medsci/2011274009.
8
Qi, Guan-Ming, Li-Xin Jia, Yu-Lin Li, Hui-Hua Li, and Jie Du. "Adiponectin Suppresses Angiotensin II-Induced Inflammation and Cardiac Fibrosis through Activation of Macrophage Autophagy." Endocrinology 155, no. 6 (June 1, 2014): 2254–65. http://dx.doi.org/10.1210/en.2013-2011.
Анотація:
Previous studies have indicated that adiponectin (APN) protects against cardiac remodeling, but the underlying mechanism remains unclear. The present study aimed to elucidate how APN regulates inflammatory responses and cardiac fibrosis in response to angiotensin II (Ang II). Male APN knockout (APN KO) mice and wild-type (WT) C57BL/6 littermates were sc infused with Ang II at 750 ng/kg per minute. Seven days after Ang II infusion, both APN KO and WT mice developed equally high blood pressure levels. However, APN KO mice developed more severe cardiac fibrosis and inflammation compared with WT mice. This finding was demonstrated by the up-regulation of collagen I, α-smooth muscle actin, IL-1β, and TNF-α and increased macrophage infiltration in APN KO mice. Moreover, there were substantially fewer microtubule-associated protein 1 light chain 3-positive autophagosomes in macrophages in the hearts of Ang II-infused APN KO mice. Additional in vitro studies also revealed that globular APN treatment induced autophagy, inhibited Ang II-induced nuclear factor-κB activity, and enhanced the expression of antiinflammatory cytokines, including IL-10, macrophage galactose N-acetyl-galactosamine specific lectin 2, found in inflammatory zone 1, and type-1 arginase in macrophages. In contrast, APN-induced autophagy and antiinflammatory cytokine expression was diminished in Atg5-knockdown macrophages or by Compound C, an inhibitor of adenosine 5′-monophosphate-activated protein kinase. Our study indicates that APN activates macrophage autophagy through the adenosine 5′-monophosphate-activated protein kinase pathway and suppresses Ang II-induced inflammatory responses, thereby reducing the extent of cardiac fibrosis.
9
Caverson, M. M., and J. Ciriello. "Contribution of paraventricular nucleus to afferent renal nerve pressor response." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 254, no. 3 (March 1, 1988): R531—R543. http://dx.doi.org/10.1152/ajpregu.1988.254.3.r531.
Анотація:
Experiments were done in alpha-chloralose-anesthetized, paralyzed, and artificially ventilated cats to determine the effect of afferent renal nerve (ARN) stimulation on the firing frequency of neurons in the paraventricular nucleus of the hypothalamus (PVH), whose axons project directly to the neurohypophysis (NH), and the contribution of these neurons to the pressor response elicited by ARN stimulation. In the first series of experiments, 474 single units were extracellularly recorded in the PVH region. Of these units 86 were antidromically excited by stimulation of the NH. Seventeen of the antidromic units (20%) responded orthodromically to ARN stimulation; 10 responded to ARN stimulation only, and 7 units responded to both ARN and buffer nerve stimulation. All PVH-NH-projecting neurons that responded to ARN stimulation were excited. In the second series the contribution of PVH neurons to the pressor response elicited by ARN stimulation was investigated in animals with the aortic depressor, carotid sinus, vagus, and cervical sympathetic nerves cut bilaterally. The ARN pressor response has previously been shown to be due to the activation of the sympathetic nervous system and to the release of arginine vasopressin (AVP). The primary and secondary (AVP component) components of the pressor response were attenuated by 51 and 69%, respectively, by bilateral injections of procaine hydrochloride into PVH or bilateral electrolytic lesions of PVH. Control injections of saline into PVH or electrolytic lesions of hypothalamic regions anterior, dorsal, or ventral to PVH did not alter the ARN pressor response. These experiments demonstrate that sensory information originating in renal receptors excites magnocellular neurosecretory neurons in PVH and suggest that this renal-paraventricular reflex loop may contribute to the elevated arterial pressure and AVP release during conditions when ARN are activated.
10
Li, Yuan, and Zong Jie Cui. "Photodynamic Activation of Cholecystokinin 1 Receptor with Different Genetically Encoded Protein Photosensitizers and from Varied Subcellular Sites." Biomolecules 10, no. 10 (October 8, 2020): 1423. http://dx.doi.org/10.3390/biom10101423.
Анотація:
Cholecystokinin 1 receptor (CCK1R) is activated by singlet oxygen (1O2) generated in photodynamic action with sulphonated aluminum phthalocyanine (SALPC) or genetically encoded protein photosensitizer (GEPP) KillerRed or mini singlet oxygen generator (miniSOG). A large number of GEPP with varied 1O2 quantum yields have appeared recently; therefore, in the present work, the efficacy of different GEPP to photodynamically activate CCK1R was examined, as monitored by Fura-2 calcium imaging. KillerRed, miniSOG, miniSOG2, singlet oxygen protein photosensitizer (SOPP), flavin-binding fluorescent protein from Methylobacterium radiotolerans with point mutation C71G (Mr4511C71G), and flavin-binding fluorescent protein from Dinoroseobacter shibae (DsFbFP) were expressed at the plasma membrane (PM) in AR4-2J cells, which express endogenous CCK1R. Light irradiation (KillerRed: white light 85.3 mW‧cm−2, 4’ and all others: LED 450 nm, 85 mW·cm−2, 1.5′) of GEPPPM-expressing AR4-2J was found to all trigger persistent calcium oscillations, a hallmark of permanent photodynamic CCK1R activation; DsFbFP was the least effective, due to poor expression. miniSOG was targeted to PM, mitochondria (MT) or lysosomes (LS) in AR4-2J in parallel experiments; LED light irradiation was found to all induce persistent calcium oscillations. In miniSOGPM-AR4-2J cells, light emitting diode (LED) light irradiation-induced calcium oscillations were readily inhibited by CCK1R antagonist devazepide 2 nM; miniSOGMT-AR4-2J cells were less susceptible, but miniSOGLS-AR4-2J cells were not inhibited. In conclusion, different GEPPPM could all photodynamically activate CCK1R. Intracellular GEPP photodynamic action may prove particularly suited to study intracellular GPCR.
11
Zhang, Xin, and Robert Schleif. "Catabolite Gene Activator Protein Mutations Affecting Activity of the araBAD Promoter." Journal of Bacteriology 180, no. 2 (January 15, 1998): 195–200. http://dx.doi.org/10.1128/jb.180.2.195-200.1998.
Анотація:
ABSTRACT We have studied catabolite gene activator protein (CAP) activation at the araBAD promoter, pBAD , in the absence of DNA looping. We ruled out the two most plausible indirect activation mechanisms: CAP-induced folding of upstream DNA back upon RNA polymerase, and CAP-induced stabilization of AraC binding to DNA. Therefore, a direct CAP-RNA polymerase interaction seemed likely. We sought and found CAP mutants defective in transcription activation at pBAD that retained normal DNA binding affinity. Some mutations altered residues in the interval from positions 150 to 164 that includes CAP activating region 1 (AR1), which has been shown to contact RNA polymerase at a number of promoters. Unexpectedly, additional mutations were found that altered residues in the region between positions 46 and 68 and at position 133. This includes the region known as activating region 3 (AR3). Mutations from both groups also affect the araFGH and rhaBADpromoters.
12
Davenport, Ross A., Maria Guerreiro, Daniel Frith, Claire Rourke, Sean Platton, Mitchell Cohen, Rupert Pearse, Chris Thiemermann, and Karim Brohi. "Activated Protein C Drives the Hyperfibrinolysis of Acute Traumatic Coagulopathy." Anesthesiology 126, no. 1 (January 1, 2017): 115–27. http://dx.doi.org/10.1097/aln.0000000000001428.
Анотація:
Abstract Background Major trauma is a leading cause of morbidity and mortality worldwide with hemorrhage accounting for 40% of deaths. Acute traumatic coagulopathy exacerbates bleeding, but controversy remains over the degree to which inhibition of procoagulant pathways (anticoagulation), fibrinogen loss, and fibrinolysis drive the pathologic process. Through a combination of experimental study in a murine model of trauma hemorrhage and human observation, the authors’ objective was to determine the predominant pathophysiology of acute traumatic coagulopathy. Methods First, a prospective cohort study of 300 trauma patients admitted to a single level 1 trauma center with blood samples collected on arrival was performed. Second, a murine model of acute traumatic coagulopathy with suppressed protein C activation via genetic mutation of thrombomodulin was used. In both studies, analysis for coagulation screen, activated protein C levels, and rotational thromboelastometry (ROTEM) was performed. Results In patients with acute traumatic coagulopathy, the authors have demonstrated elevated activated protein C levels with profound fibrinolytic activity and early depletion of fibrinogen. Procoagulant pathways were only minimally inhibited with preservation of capacity to generate thrombin. Compared to factors V and VIII, proteases that do not undergo activated protein C–mediated cleavage were reduced but maintained within normal levels. In transgenic mice with reduced capacity to activate protein C, both fibrinolysis and fibrinogen depletion were significantly attenuated. Other recognized drivers of coagulopathy were associated with less significant perturbations of coagulation. Conclusions Activated protein C–associated fibrinolysis and fibrinogenolysis, rather than inhibition of procoagulant pathways, predominate in acute traumatic coagulopathy. In combination, these findings suggest a central role for the protein C pathway in acute traumatic coagulopathy and provide new translational opportunities for management of major trauma hemorrhage.
13
Finocchiaro, Claudio, Germana Barone, Paolo Mazzoleni, Caterina Sgarlata, Isabella Lancellotti, Cristina Leonelli, and Marcello Romagnoli. "Artificial neural networks test for the prediction of chemical stability of pyroclastic deposits-based AAMs and comparison with conventional mathematical approach (MLR)." Journal of Materials Science 56, no. 1 (September 16, 2020): 513–27. http://dx.doi.org/10.1007/s10853-020-05250-w.
Анотація:
Abstract The investigation on the reticulation degree of volcanic alkali-activated materials, AAMs, were experimentally determined in terms of chemico-physical properties: weight loss after leaching test in water, ionic conductivity and pH of the leachate and compressive strength. Artificial neural network (ANN) was successfully applied to predict the chemical stability of volcanic alkali-activated materials. Nine input data per each chemico-physical parameter were used to train each ANN. The training series of specific volcanic precursors were tested also for the other one. Excellent correlations between experimental and calculated data of the same precursor type were found reaching values around one. The evidence of strong effect on chemical stability of the alkaline activator SiO2/Na2O molar ratio as well as the Si/Al ratio of precursor mixtures on the reticulation degree of ghiara-based formulation with respect to volcanic ash-based materials is presented. It must be noted that such effect was much less pronounced on the compressive strength values, appearing more insensitive the molar ratio of the alkaline activator. The comparison of the ANN results with more conventional multiple linear regression (MLR) testifies the higher prediction performance of the first method. MLRs results, less significant, are useful to confirm the powerful capacity of ANNs to identify the more suitable formulation using a set of experimental AAMs. This study, as few others, on the correlation between chemical stability and compressive strength of AAMs provide a great contribution in the direction of durability and in-life mechanical performance of these class of materials. Graphic abstract
14
Beppu, Satoru, Yasufumi Nakajima, Masayuki Shibasaki, Kyoko Kageyama, Toshiki Mizobe, Nobuaki Shime, and Naoyuki Matsuda. "Phosphodiesterase 3 Inhibition Reduces Platelet Activation and Monocyte Tissue Factor Expression in Knee Arthroplasty Patients." Anesthesiology 111, no. 6 (December 1, 2009): 1227–37. http://dx.doi.org/10.1097/aln.0b013e3181c155ce.
Анотація:
Background Tissue damage during surgery activates platelets and provokes a prothrombic state. The current study attempted to determine the impact of phosphodiesterase 3 inhibitors on platelet activation, platelet-leukocyte aggregate formation, and monocyte tissue factor expression during and after total knee arthroplasty. Methods Thirty-four patients undergoing scheduled total knee arthroplasty were randomly assigned to receive either the phosphodiesterase 3 inhibitor milrinone or the same amount of saline perioperatively. The effects of milrinone on platelet and leukocyte function in vitro were then assessed in healthy volunteers. Results Perioperative infusion of milrinone significantly attenuated platelet activation; phosphorylation of intraplatelet p38 mitogen-activated protein kinase, extracellular signal-regulated kinase 1/2, and Akt; and platelet-leukocyte aggregation. Furthermore, perioperative tissue factor expression on monocytes and fibrin monomer complex production were reduced by milrinone infusion in patients undergoing total knee arthroplasty. In vitro studies using adenosine diphosphate- and collagen-stimulated blood samples from healthy volunteers confirmed the antiplatelet effects and reduced monocyte tissue factor expression by milrinone. These studies further showed that platelet aggregation and integrin alpha(IIb)beta(3) activation were modified by intraplatelet phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase/extracellular signal-regulated kinase pathways, and that P-selectin expression on platelets and platelet-leukocyte aggregation were modulated by intraplatelet p38 mitogen-activated protein kinase pathway. Conclusion Continuous milrinone infusion has the potential to reduce platelet activation and monocyte tissue factor expression during the perioperative period in total knee arthroplasty. These events may be mediated in part by the ability of milrinone to reduce activation of intraplatelet mitogen-activated protein kinases and phosphatidylinositol 3-kinase. The clinical impact of phosphodiesterase 3 inhibition on perioperative hemostasis remains to be elucidated.
15
Han, Su Young, Timothy McLennan, Katja Czieselsky, and Allan E. Herbison. "Selective optogenetic activation of arcuate kisspeptin neurons generates pulsatile luteinizing hormone secretion." Proceedings of the National Academy of Sciences 112, no. 42 (October 6, 2015): 13109–14. http://dx.doi.org/10.1073/pnas.1512243112.
Анотація:
Normal reproductive functioning in mammals depends upon gonadotropin-releasing hormone (GnRH) neurons generating a pulsatile pattern of gonadotropin secretion. The neural mechanism underlying the episodic release of GnRH is not known, although recent studies have suggested that the kisspeptin neurons located in the arcuate nucleus (ARN) may be involved. In the present experiments we expressed channelrhodopsin (ChR2) in the ARN kisspeptin population to test directly whether synchronous activation of these neurons would generate pulsatile luteinizing hormone (LH) secretion in vivo. Characterization studies showed that this strategy targeted ChR2 to 70% of all ARN kisspeptin neurons and that, in vitro, these neurons were activated by 473-nm blue light with high fidelity up to 30 Hz. In vivo, the optogenetic activation of ARN kisspeptin neurons at 10 and 20 Hz evoked high amplitude, pulse-like increments in LH secretion in anesthetized male mice. Stimulation at 10 Hz for 2 min was sufficient to generate repetitive LH pulses. In diestrous female mice, only 20-Hz activation generated significant increments in LH secretion. In ovariectomized mice, 5-, 10-, and 20-Hz activation of ARN kisspeptin neurons were all found to evoke LH pulses. Part of the sex difference, but not the gonadal steroid dependence, resulted from differential pituitary sensitivity to GnRH. Experiments in kisspeptin receptor-null mice, showed that kisspeptin was the critical neuropeptide underlying the ability of ARN kisspeptin neurons to generate LH pulses. Together these data demonstrate that synchronized activation of the ARN kisspeptin neuronal population generates pulses of LH.
16
Biro, E., R. Nieuwland, P. P. Tak, L. M. Pronk, M. C. L. Schaap, A. Sturk, and C. E. Hack. "Activated complement components and complement activator molecules on the surface of cell-derived microparticles in patients with rheumatoid arthritis and healthy individuals." Annals of the Rheumatic Diseases 66, no. 8 (January 12, 2007): 1085–92. http://dx.doi.org/10.1136/ard.2006.061309.
17
Ciriello, J. "Afferent renal inputs onto subfornical organ neurons responsive to angiotensin II." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 272, no. 5 (May 1, 1997): R1684—R1689. http://dx.doi.org/10.1152/ajpregu.1997.272.5.r1684.
Анотація:
Experiments were done in pentobarbital sodium-anesthetized rats to investigate the effect of electrical stimulation of afferent renal nerves (ARN) on the discharge rate of subfornical organ (SFO) neurons that responded to changes in plasma levels of angiotensin II (ANG II) and projected directly to the paraventricular nucleus of the hypothalamus (PVH). Extracellular recordings were made from 76 histologically verified single neurons in the SFO that were excited by intracarotid infusions of ANG II. Of these units, 54.8% (23 of 42) responded with excitation to ARN stimulation (mean onset latency, 125 +/- 35 ms). None of the SFO units excited by plasma ANG II were found to be inhibited by ARN stimulation. An additional 34 units in the SFO that were excited by plasma ANG II were also antidromically activated by stimulation of the PVH. Of these neurons, 17.8% (6 of 34) were also excited by stimulation of ARN. The results indicate that inputs from ARN converge onto SFO neurons that alter their discharge rate during changes in plasma concentration of ANG II and project directly to the PVH. These data suggest that ARN may play an important role in body fluid balance and circulatory regulation by modulating the activity of SFO neurons that function in the detection of blood-borne signals resulting from the decrease in extracellular fluid volume and arterial pressure and that influence the activity of hypothalamic nuclei that contain neurosecretory neurons.
18
Holcroft, Carolyn C., та Susan M. Egan. "Roles of Cyclic AMP Receptor Protein and the Carboxyl-Terminal Domain of the α Subunit in Transcription Activation of theEscherichia coli rhaBAD Operon". Journal of Bacteriology 182, № 12 (15 червня 2000): 3529–35. http://dx.doi.org/10.1128/jb.182.12.3529-3535.2000.
Анотація:
ABSTRACT The Escherichia coli rhaBAD operon encodes the enzymes for catabolism of the sugar l-rhamnose. FullrhaBAD activation requires the AraC family activator RhaS (bound to a site that overlaps the −35 region of the promoter) and the cyclic AMP receptor protein (CRP; bound immediately upstream of RhaS at −92.5). We tested alanine substitutions in activating regions (AR) 1 and 2 of CRP for their effect onrhaBAD activation. Some, but not all, of the substitutions in both AR1 and AR2 resulted in approximately twofold defects in expression from rhaBAD promoter fusions. We also expressed a derivative of the α subunit of RNA polymerase deleted for the entire C-terminal domain (α-Δ235) and assayed expression from rhaBAD promoter fusions. The greatest defect (54-fold) occurred at a truncated promoter where RhaS was the only activator, while the defect at the full-length promoter (RhaS plus CRP) was smaller (13-fold). Analysis of a plasmid library expressing alanine substitutions at every residue in the carboxyl-terminal domain of the α subunit (α-CTD) identified 15 residues (mostly in the DNA-binding determinant) that were important at both the full-length and truncated promoters. Only one substitution was defective at the full-length but not the truncated promoter, and this residue was located in the DNA-binding determinant. Six substitutions were defective only at the promoter activated by RhaS alone, and these may define a protein-contacting determinant on α-CTD. Overall, our results suggest that CRP interaction with α-CTD may not be required for rhaBAD activation; however, α-CTD does contribute to full activation, probably through interactions with DNA and possibly RhaS.
19
Laver, Derek R., John Attia, Christopher Oldmeadow, and Anthony W. Quail. "Cardiac Calcium Release Channel (Ryanodine Receptor 2) Regulation by Halogenated Anesthetics." Anesthesiology 126, no. 3 (March 1, 2017): 495–506. http://dx.doi.org/10.1097/aln.0000000000001519.
Анотація:
Abstract Background Halogenated anesthetics activate cardiac ryanodine receptor 2–mediated sarcoplasmic reticulum Ca2+ release, leading to sarcoplasmic reticulum Ca2+ depletion, reduced cardiac function, and providing cell protection against ischemia-reperfusion injury. Anesthetic activation of ryanodine receptor 2 is poorly defined, leaving aspects of the protective mechanism uncertain. Methods Ryanodine receptor 2 from the sheep heart was incorporated into artificial lipid bilayers, and their gating properties were measured in response to five halogenated anesthetics. Results Each anesthetic rapidly and reversibly activated ryanodine receptor 2, but only from the cytoplasmic side. Relative activation levels were as follows: halothane (approximately 4-fold; n = 8), desflurane and enflurane (approximately 3-fold,n = 9), and isoflurane and sevoflurane (approximately 1.5-fold, n = 7, 10). Half-activating concentrations (Ka) were in the range 1.3 to 2.1 mM (1.4 to 2.6 minimum alveolar concentration [MAC]) with the exception of isoflurane (5.3 mM, 6.6 minimum alveolar concentration). Dantrolene (10 μM with 100 nM calmodulin) inhibited ryanodine receptor 2 by 40% but did not alter the Ka for halothane activation. Halothane potentiated luminal and cytoplasmic Ca2+ activation of ryanodine receptor 2 but had no effect on Mg2+ inhibition. Halothane activated ryanodine receptor 2 in the absence and presence (2 mM) of adenosine triphosphate (ATP). Adenosine, a competitive antagonist to ATP activation of ryanodine receptor 2, did not antagonize halothane activation in the absence of ATP. Conclusions At clinical concentrations (1 MAC), halothane desflurane and enflurane activated ryanodine receptor 2, whereas isoflurane and sevoflurane were ineffective. Dantrolene inhibition of ryanodine receptor 2 substantially negated the activating effects of anesthetics. Halothane acted independently of the adenine nucleotide–binding site on ryanodine receptor 2. The previously observed adenosine antagonism of halothane activation of sarcoplasmic reticulum Ca2+ release was due to competition between adenosine and ATP, rather than between halothane and ATP.
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Zhu, Qiqi, Haobo Li, Xiang Xie, Xiaozhen Chen, Ramoji Kosuru, Sisi Li, Qingquan Lian, et al. "Adiponectin Facilitates Postconditioning Cardioprotection through Both AMPK-Dependent Nuclear and AMPK-Independent Mitochondrial STAT3 Activation." Oxidative Medicine and Cellular Longevity 2020 (March 4, 2020): 1–17. http://dx.doi.org/10.1155/2020/4253457.
Анотація:
Myocardial ischemic postconditioning- (IPo-) mediated cardioprotection against myocardial ischemia-reperfusion (IR) injury needs the activation of signal transducer and activator of transcription 3 (STAT3), which involves adiponectin (APN). APN confers its biological effects through AMP-activated protein kinase- (AMPK-) dependent and AMPK-independent pathways. However, the role of AMPK in APN-mediated STAT3 activation in IPo cardioprotection is unknown. We hypothesized that APN-mediated STAT3 activation in IPo is AMPK-independent and that APN through AMPK-dependent STAT3 activation facilitates IPo cardioprotection. Here, Sprague-Dawley rats were subjected to myocardial IR without or with IPo and/or APN. APN or IPo significantly improved postischemic cardiac function and reduced myocardial injury and oxidative stress, and their combination further attenuated postischemic myocardial injuries. APN or its combination with IPo but not IPo alone significantly increased AMPK activation and both nuclear and mitochondrial STAT3 activation, while IPo significantly enhanced mitochondrial but not nuclear STAT3 activation. In primarily isolated cardiomyocytes, recombined globular APN (gAd), hypoxic postconditioning (HPo), or their combination significantly attenuated hypoxia/reoxygenation-induced cell injury and increased nuclear and/or mitochondrial STAT3 activation. STAT3 inhibition had no impact on gAd or gAd in combination with HPo-induced AMPK activation but abolished their cellular protective effects. AMPK inhibition did not affect HPo cardioprotection but abolished gAd cardioprotection and disabled gAd to facilitate/enhance HPo cardioprotection and STAT3 activation. These results suggest that APN confers cardioprotection through AMPK-dependent and AMPK-independent STAT3 activation, while IPo confers cardioprotection through AMPK-independent mitochondrial STAT3 activation. Joint use of APN and IPo synergistically attenuated myocardial IR injury by activating STAT3 via distinct signaling pathways.
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Mahamat, Assia Aboubakar, Moussa Mahamat Boukar, Nurudeen Mahmud Ibrahim, Tido Tiwa Stanislas, Numfor Linda Bih, Ifeyinwa Ijeoma Obianyo, and Holmer Savastano. "Machine Learning Approaches for Prediction of the Compressive Strength of Alkali Activated Termite Mound Soil." Applied Sciences 11, no. 11 (May 22, 2021): 4754. http://dx.doi.org/10.3390/app11114754.
Анотація:
Earth-based materials have shown promise in the development of ecofriendly and sustainable construction materials. However, their unconventional usage in the construction field makes the estimation of their properties difficult and inaccurate. Often, the determination of their properties is conducted based on a conventional materials procedure. Hence, there is inaccuracy in understanding the properties of the unconventional materials. To obtain more accurate properties, a support vector machine (SVM), artificial neural network (ANN) and linear regression (LR) were used to predict the compressive strength of the alkali-activated termite soil. In this study, factors such as activator concentration, Si/Al, initial curing temperature, water absorption, weight and curing regime were used as input parameters due to their significant effect in the compressive strength. The experimental results depict that SVM outperforms ANN and LR in terms of R2 score and root mean square error (RMSE).
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Pessi, Gabriella, and Dieter Haas. "Transcriptional Control of the Hydrogen Cyanide Biosynthetic Genes hcnABC by the Anaerobic Regulator ANR and the Quorum-Sensing Regulators LasR and RhlR inPseudomonas aeruginosa." Journal of Bacteriology 182, no. 24 (December 15, 2000): 6940–49. http://dx.doi.org/10.1128/jb.182.24.6940-6949.2000.
Анотація:
ABSTRACT Virulence factors of Pseudomonas aeruginosa include hydrogen cyanide (HCN). This secondary metabolite is maximally produced at low oxygen tension and high cell densities during the transition from exponential to stationary growth phase. The hcnABCgenes encoding HCN synthase were identified on a genomic fragment complementing an HCN-deficient mutant of P. aeruginosaPAO1. The hcnA promoter was found to be controlled by the FNR-like anaerobic regulator ANR and by the quorum-sensing regulators LasR and RhlR. Primer extension analysis revealed two transcription starts, T1 and T2, separated by 29 bp. Their function was confirmed by transcriptional lacZ fusions. The promoter sequence displayed an FNR/ANR box at −42.5 bp upstream of T2 and alux box centered around −42.5 bp upstream of T1. Expression of the hcn genes was completely abolished when this lux box was deleted or inactivated by two point mutations in conserved nucleotides. The lux box was recognized by both LasR [activated byN-(oxododecanoyl)-homoserine lactone] and RhlR (activated by N-butanoyl-homoserine lactone), as shown by expression experiments performed in quorum-sensing-defective P. aeruginosa mutants and in the N-acyl-homoserine lactone-negative heterologous host P. fluorescens CHA0. A second, less conserved lux box lying 160 bp upstream of T1 seems to account for enhanced quorum-sensing-dependent expression. Without LasR and RhlR, ANR could not activate the hcnpromoter. Together, these data indicate that expression of thehcn promoter from T1 can occur under quorum-sensing control alone. Enhanced expression from T2 appears to rely on a synergistic action between LasR, RhlR, and ANR.
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Lu, Chung-Dar, Harald Winteler, Ahmed Abdelal, and Dieter Haas. "The ArgR Regulatory Protein, a Helper to the Anaerobic Regulator ANR during Transcriptional Activation of thearcD Promoter in Pseudomonas aeruginosa." Journal of Bacteriology 181, no. 8 (April 15, 1999): 2459–64. http://dx.doi.org/10.1128/jb.181.8.2459-2464.1999.
Анотація:
ABSTRACT Pseudomonas aeruginosa, when deprived of oxygen, generates ATP from arginine catabolism by enzymes of the arginine deiminase pathway, encoded by the arcDABC operon. Under conditions of low oxygen tension, the transcriptional activator ANR binds to a site centered 41.5 bp upstream of the arcDtranscriptional start. ANR-mediated anaerobic induction was enhanced two- to threefold by extracellular arginine. This arginine effect depended, in trans, on the transcriptional regulator ArgR and, in cis, on an ArgR binding site centered at −73.5 bp in the arcD promoter. Binding of purified ArgR protein to this site was demonstrated by electrophoretic mobility shift assays and DNase I footprinting. This ArgR recognition site contained a sequence, 5′-TGACGC-3′, which deviated in only 1 base from the common sequence motif 5′-TGTCGC-3′ found in other ArgR binding sites of P. aeruginosa. Furthermore, an alignment of all known ArgR binding sites confirmed that they consist of two directly repeated half-sites. In the absence of ANR, arginine did not induce thearc operon, suggesting that ArgR alone does not activate the arcD promoter. According to a model proposed, ArgR makes physical contact with ANR and thereby facilitates initiation ofarc transcription.
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Kelchtermans, H., L. Geboes, T. Mitera, D. Huskens, G. Leclercq, and P. Matthys. "Activated CD4+CD25+ regulatory T cells inhibit osteoclastogenesis and collagen-induced arthritis." Annals of the Rheumatic Diseases 68, no. 5 (May 14, 2008): 744–50. http://dx.doi.org/10.1136/ard.2007.086066.
Анотація:
Objectives:Patients with rheumatoid arthritis (RA) have defective CD4+CD25+ regulatory T (Treg) cells and increased osteoclastogenesis. A similar situation has been described in collagen-induced arthritis (CIA). In this study, it was investigated whether a single transfer of polyclonally activated Treg cells inhibits CIA and osteoclastogenesis.Methods:Purified Treg cells were expanded in vitro with anti-CD3 and anti-CD28 antibody-coated beads and injected into DBA/1 mice. Mice were immunised with collagen type II (CII) in complete Freund adjuvant (CFA) and scores of arthritis were recorded. In vitro osteoclastogenesis assays were performed on splenocytes by stimulation with macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor (NF)κB ligand (RANKL). Levels of anti-CII antibody and cytokines were determined in the supernatant using ELISA and Bio-Plex protein array system.Results:It was found that 106 activated Treg cells significantly counteracted the development of CIA, which was accompanied by decreased serum levels of TNFα and IL6, but not by inhibition of autoimmune antibody responses. The differentiation of osteoclasts in splenocyte cultures was significantly reduced in the presence of prestimulated Treg cells. Expression of cytokines that are described to inhibit osteoclastogenesis, including granulocyte macrophage colony-stimulating factor (GM-CSF), interferon (IFN)γ, interleukin (IL)5 and IL10, were dramatically increased upon addition of Treg cells. Furthermore, splenocytes from mice that had been treated with Treg cells displayed an impaired capacity to develop into mature osteoclasts, suggesting that Treg cells abrogated osteoclastogenesis in vivo.Conclusions:Activated CD4+CD25+ Treg cells improve clinical symptoms of CIA, regulate cytokine production and inhibit osteoclastogenesis in vitro and in vivo.
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Peters, Christopher M., and James C. Eisenach. "Contribution of the Chemokine (C-C Motif) Ligand 2 (CCL2) to Mechanical Hypersensitivity after Surgical Incision in Rats." Anesthesiology 112, no. 5 (May 1, 2010): 1250–58. http://dx.doi.org/10.1097/aln.0b013e3181d3d978.
Анотація:
Background Neural glial signaling in the spinal cord may underlie pain and sensitization after peripheral injury. The authors test the role of a glial activator, the chemokine (C-C motif) ligand 2 (CCL2), on mechanical hypersensitivity after plantar incision in a rat model of postoperative pain. Methods Twenty-four hours after hind paw incision, rats were intrathecally administered an anti-CCL2 neutralizing antibody (3 and 10 microg) or control immunoglobulin G (10 microg). Mechanical hypersensitivity was assessed acutely and for several days after administration of anti-CCL2 antibody using von Frey filaments. Immunohistochemical analysis was conducted on spinal cord sections to examine the effects of treatment on measures of microglial activation, including levels of ionized calcium-binding adaptor molecule 1 and phosphorylated p38 mitogen-activated protein kinase. Results Neutralization of spinal CCL2 acutely reversed mechanical hypersensitivity within 30 min in a dose-dependent manner. A single administration also produced a sustained decrease in mechanical hypersensitivity 48 and 72 h after incision. Anti-CCL2 antibody reduced microglial activation as measured by the levels of ionized calcium-binding adaptor molecule 1 immunoreactivity and the number of microglia containing phosphorylated p38 mitogen-activated protein kinase 48 h after incision but not within 30 min of administration. Conclusions These results provide evidence that CCL2 contributes to the maintenance of mechanical hypersensitivity after plantar incision and establish a role for neural glial signaling in postoperative pain. The long-term effects of anti-CCL2 treatment correlate with reduced microglial activation. Spinal blockade of CCL2 may serve as a useful therapy for the treatment of certain aspects of postoperative pain.
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Sakai, Hiroyasu, Yu Watanabe, Mai Honda, Rika Tsuiki, Yusuke Ueda, Yuki Nagai, Minoru Narita, Miwa Misawa, and Yoshihiko Chiba. "Involvement of the Tyr Kinase/JNK Pathway in Carbachol-induced Bronchial Smooth Muscle Contraction in the Rat." Anesthesiology 118, no. 5 (May 1, 2013): 1076–85. http://dx.doi.org/10.1097/aln.0b013e318286d0ae.
Анотація:
Abstract Background: Tyrosine (Tyr) kinases and mitogen-activated protein kinases have been thought to participate in the contractile response in various smooth muscles. The aim of the current study was to investigate the involvement of the Tyr kinase pathway in the contraction of bronchial smooth muscle. Methods: Ring preparations of bronchi isolated from rats were suspended in an organ bath. Isometric contraction of circular smooth muscle was measured. Immunoblotting was used to examine the phosphorylation of c-Jun N-terminal kinasess (JNKs) in bronchial smooth muscle. Results: To examine the role of mitogen-activated protein kinase(s) in bronchial smooth muscle contraction, the effects of MPAK inhibitors were investigated in this study. The contraction induced by carbachol (CCh) was significantly inhibited by pretreatment with selective Tyr kinase inhibitors (genistein and ST638, n = 6, respectively), and a JNK inhibitor (SP600125, n = 6). The contractions induced by high K+ depolarization (n = 4), orthovanadate (a potent Tyr phosphatase inhibitor) and sodium fluoride (a G protein activator; NaF) were also significantly inhibited by selective Tyr kinase inhibitors and a JNK inhibitor (n = 4, respectively). However, the contraction induced by calyculin-A was not affected by SP600125. On the other hand, JNKs were phosphorylated by CCh (2.2 ± 0,4 [mean±SEM] fold increase). The JNK phosphorylation induced by CCh was significantly inhibited by SP600125 (n = 4). Conclusion: These findings suggest that the Tyr kinase/JNK pathway may play a role in bronchial smooth muscle contraction. Strategies to inhibit JNK activation may represent a novel therapeutic approach for diseases involving airway obstruction, such as asthma and chronic obstructive pulmonary disease.
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Ma, Yanzhuo, Yi Liu, Shaowei Liu, Yan Qu, Rutao Wang, Chenhai Xia, Haifeng Pei, et al. "Dynamic alteration of adiponectin/adiponectin receptor expression and its impact on myocardial ischemia/reperfusion in type 1 diabetic mice." American Journal of Physiology-Endocrinology and Metabolism 301, no. 3 (September 2011): E447—E455. http://dx.doi.org/10.1152/ajpendo.00687.2010.
Анотація:
The present study determined the dynamic change of adiponectin (APN, a cardioprotective adipokine), its receptor expression, and their impact upon myocardial ischemia/reperfusion (MI/R) injury during type 1 diabetes mellitus (T1DM) progression, and involved underlying mechanisms. Diabetic state was induced in mice via multiple intraperitoneal injections of low-dose streptozotocin. The dynamic change of plasma APN concentration and cardiac APN receptor-1 and -2 (AdipoR1/2) expression were assessed immediately after diabetes onset (0 wk) and 1, 3, 5, and 7 wk thereafter. Indicators of MI/R injury (infarct size, apoptosis, and LDH release) were determined at 0, 1, and 7 wk of DM duration. The effect of APN on MI/R injury was determined in mice subjected to different diabetic durations. Plasma APN levels (total and HMW form) increased, whereas cardiac AdipoR1 expression decreased early after T1DM onset. With T1DM progression, APN levels were reduced and cardiac AdipoR1 expression increased. MI/R injury was exacerbated with T1DM progression in a time-dependent manner. Administration of globular APN (gAD) failed to attenuate MI/R injury in 1-wk T1DM mice, while an AMP-activated protein kinase (AMPK) activator (AICAR) reduced MI/R injury. However, administration of gAD (and AICAR) reduced infarct size and cardiomyocyte apoptosis in 7-wk T1DM mice. In conclusion, our results demonstrate a dynamic dysfunction of APN/AdipoR1 during T1DM progression. Reduced cardiac AdipoR1 expression and APN concentration may be responsible for increased I/R injury susceptibility at early and late T1DM stages, respectively. Interventions bolstering AdipoR1 expression during early T1DM stages and APN supplementation during advanced T1DM stages may potentially reduce the myocardial ischemic injury in diabetic patients.
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Mrozek, Segolene, Boris Jung, Basil J. Petrof, Marion Pauly, Stephanie Roberge, Alain Lacampagne, Cécile Cassan, et al. "Rapid Onset of Specific Diaphragm Weakness in a Healthy Murine Model of Ventilator-induced Diaphragmatic Dysfunction." Anesthesiology 117, no. 3 (September 1, 2012): 560–67. http://dx.doi.org/10.1097/aln.0b013e318261e7f8.
Анотація:
Background Controlled mechanical ventilation is associated with ventilator-induced diaphragmatic dysfunction, which impedes weaning from mechanical ventilation. To design future clinical trials in humans, a better understanding of the molecular mechanisms using knockout models, which exist only in the mouse, is needed. The aims of this study were to ascertain the feasibility of developing a murine model of ventilator-induced diaphragmatic dysfunction and to determine whether atrophy, sarcolemmal injury, and the main proteolysis systems are activated under these conditions. Methods Healthy adult male C57/BL6 mice were assigned to three groups: (1) mechanical ventilation with end-expiratory positive pressure of 2-4 cm H2O for 6 h (n=6), (2) spontaneous breathing with continuous positive airway pressure of 2-4 cm H2O for 6 h (n=6), and (3) controls with no specific intervention (n=6). Airway pressure and hemodynamic parameters were monitored. Upon euthanasia, arterial blood gases and isometric contractile properties of the diaphragm and extensor digitorum longus were evaluated. Histology and immunoblotting for the main proteolysis pathways were performed. Results Hemodynamic parameters and arterial blood gases were comparable between groups and within normal physiologic ranges. Diaphragmatic but not extensor digitorum longus force production declined in the mechanical ventilation group (maximal force decreased by approximately 40%) compared with the control and continuous positive airway pressure groups. No histologic difference was found between groups. In opposition with the calpains, caspase 3 was activated in the mechanical ventilation group. Conclusion Controlled mechanical ventilation for 6 h in the mouse is associated with significant diaphragmatic but not limb muscle weakness without atrophy or sarcolemmal injury and activates proteolysis.
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Faridmehr, Iman, Moncef L. Nehdi, Mehdi Nikoo, Ghasan Fahim Huseien, and Togay Ozbakkaloglu. "Life-Cycle Assessment of Alkali-Activated Materials Incorporating Industrial Byproducts." Materials 14, no. 9 (May 5, 2021): 2401. http://dx.doi.org/10.3390/ma14092401.
Анотація:
Eco-friendly and sustainable materials that are cost-effective, while having a reduced carbon footprint and energy consumption, are in great demand by the construction industry worldwide. Accordingly, alkali-activated materials (AAM) composed primarily of industrial byproducts have emerged as more desirable alternatives to ordinary Portland cement (OPC)-based concrete. Hence, this study investigates the cradle-to-gate life-cycle assessment (LCA) of ternary blended alkali-activated mortars made with industrial byproducts. Moreover, the embodied energy (EE), which represents an important parameter in cradle-to-gate life-cycle analysis, was investigated for 42 AAM mixtures. The boundary of the cradle-to-gate system was extended to include the mechanical and durability properties of AAMs on the basis of performance criteria. Using the experimental test database thus developed, an optimized artificial neural network (ANN) combined with the cuckoo optimization algorithm (COA) was developed to estimate the CO2 emissions and EE of AAMs. Considering the lack of systematic research on the cradle-to-gate LCA of AAMs in the literature, the results of this research provide new insights into the assessment of the environmental impact of AAM made with industrial byproducts. The final weight and bias values of the AAN model can be used to design AAM mixtures with targeted mechanical properties and CO2 emission considering desired amounts of industrial byproduct utilization in the mixture.
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Sopicka-Lizer, Malgorzata, Tomasz Pawlik, Tomasz Włodek, and Marta Tańcula. "The Phase Evolution in the Si3N4-AlN System after High-Energy Mechanical Treatment of the Precursor Powder." Key Engineering Materials 403 (December 2008): 7–10. http://dx.doi.org/10.4028/www.scientific.net/kem.403.7.
Анотація:
The high-energy milling uses the mechanical energy to activate chemical reactions by developing structural changes in the powder particles. High-energy milling with an acceleration of 28g was applied for the mechanical activation of the aluminium and silicon nitrides mixture with yttria additive. The activated powders showed the significant damage of the crystal structure and limited formation of a solid solution. Sintering of the activated precursor demonstrated higher ability for densification and started at 300 °C lower temperature in comparison to the standard mixture. The phase evolution during sintering was dependent on the starting composition and degree of powder activation.
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Li, Ping, Megan M. Eaton, Joe Henry Steinbach та Gustav Akk. "The Benzodiazepine Diazepam Potentiates Responses of α1β2γ2L γ-Aminobutyric Acid Type A Receptors Activated by either γ-Aminobutyric Acid or Allosteric Agonists". Anesthesiology 118, № 6 (1 червня 2013): 1417–25. http://dx.doi.org/10.1097/aln.0b013e318289bcd3.
Анотація:
Abstract Background: The γ-aminobutyric acid (GABA) type A receptor is a target for several anesthetics, anticonvulsants, anxiolytics, and sedatives. Neurosteroids, barbiturates, and etomidate both potentiate responses to GABA and allosterically activate the receptor. We examined the ability of a benzodiazepine, diazepam, to potentiate responses to allosteric agonists. Methods: The GABA type A receptors were expressed in human embryonic kidney 293 cells and studied using whole-cell and single-channel patch clamp. The receptors were activated by the orthosteric agonist GABA and allosteric agonists pentobarbital, etomidate, and alfaxalone. Results: Diazepam is equally potent at enhancing responses to orthosteric and allosteric agonists. Diazepam EC50s were 25 ± 4, 26 ± 6, 33 ± 6, and 26 ± 3 nm for receptors activated by GABA, pentobarbital, etomidate, and alfaxalone, respectively (mean ± SD, 5–6 cells at each condition). Mutations to the benzodiazepine-binding site (α1(H101C), γ2(R144C), γ2(R197C)) reduced or removed potentiation for all agonists, and an inverse agonist at the benzodiazepine site reduced responses to all agonists. Single-channel data elicited by GABA demonstrate that in the presence of 1 μm diazepam the prevalence of the longest open-time component is increased from 13 ± 7 (mean ± SD, n = 5 patches) to 27 ± 8% (n = 3 patches) and the rate of channel closing is decreased from 129 ± 28 s−1 to 47 ± 6 s−1 (mean±SD) Conclusions: We conclude that benzodiazepines do not act by enhancing affinity of the orthosteric site for GABA but rather by increasing channel gating efficacy. The results also demonstrate the presence of interactions between allosteric activators and potentiators, raising a possibility of effects on dosage requirements or changes in side effects.
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Carles, Michel, Brant M. Wagener, Mathieu Lafargue, Jérémie Roux, Karen Iles, Dong Liu, Cilina Ann Rodriguez, et al. "Heat-shock Response Increases Lung Injury Caused by Pseudomonas aeruginosa via an Interleukin-10-dependent Mechanism in Mice." Anesthesiology 120, no. 6 (June 1, 2014): 1450–62. http://dx.doi.org/10.1097/aln.0000000000000235.
Анотація:
Abstract Background: The heat-shock response (HSR) protects from insults, such as ischemia–reperfusion injury, by inhibiting signaling pathways activated by sterile inflammation. However, the mechanisms by which the HSR activation would modulate lung damage and host response to a bacterial lung infection remain unknown. Methods: HSR was activated with whole-body hyperthermia or by intraperitoneal geldanamycin in mice that had their lungs instilled with Pseudomonas aeruginosa 24 h later (at least six mice per experimental group). Four hours after instillation, lung endothelial and epithelial permeability, bacterial counts, protein levels in bronchoalveolar lavage fluid, and lung myeloperoxidase activity were measured. Mortality rate 24 h after P. aeruginosa instillation was recorded. The HSR effect on the release of interleukin-10 and killing of P. aeruginosa bacteria by a mouse alveolar macrophage cell line and on neutrophil phagocytosis was also examined. Results: HSR activation worsened lung endothelial (42%) and epithelial permeability (50%) to protein, decreased lung bacterial clearance (71%), and increased mortality (50%) associated with P. aeruginosa pneumonia, an effect that was not observed in heat-shock protein–72-null mice. HSR-mediated decrease in neutrophil phagocytosis (69%) and bacterial killing (38%) by macrophages was interleukin-10 dependent, a mechanism confirmed by increased lung bacterial clearance and decreased mortality (70%) caused by P. aeruginosa pneumonia in heat-shocked interleukin-10-null mice. Conclusions: Prior HSR activation worsens lung injury associated with P. aeruginosa pneumonia in mice via heat-shock protein–72- and interleukin-10-dependent mechanisms. These results provide a novel mechanism for the immunosuppression observed after severe trauma that is known to activate HSR in humans.
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Larsen, Ole Halfdan, Christian Fenger-Eriksen, Kirsten Christiansen, Jørgen Ingerslev, and Benny Sørensen. "Diagnostic Performance and Therapeutic Consequence of Thromboelastometry Activated by Kaolin versus a Panel of Specific Reagents." Anesthesiology 115, no. 2 (August 1, 2011): 294–302. http://dx.doi.org/10.1097/aln.0b013e318220755c.
Анотація:
Background Thromboelastography/metry (TEG®; Haemoscope, Niles, IL/ROTEM®; Tem International GmbH, Munich, Germany) is increasingly used to guide transfusion therapy. This study investigated the diagnostic performance and therapeutic consequence of using kaolin-activated whole blood compared with a panel of specific TEM®-reagents to distinguish: dilutional coagulopathy, thrombocytopenia, hyperfibrinolysis, and heparinization. Methods Blood was drawn from 11 healthy volunteers. Dilutional coagulopathy was generated by 50% dilution with hydroxyethyl starch 130/0.4 whereas thrombocytopenia (mean platelet count 20 ×10⁹/l) was induced using a validated model. Hyperfibrinolysis and heparin contamination were generated by tissue plasminogen activator 2 nM and unfractionated heparin 0.1U/ml, respectively. Coagulation tests were run on ROTEM® delta. Results Kaolin-activated whole blood showed no differences between dilutional coagulopathy and thrombocytopenia (mean clotting time 450 s vs. 516 s, α-angle 47.1° vs. 41.5°, maximum clot firmness 35.0 mm vs. 34.2 mm, all P values ≥0.14). Hyperfibrinolysis specifically disclosed an increased maximum lysis (median: 100%, all P values less than 0.001), and heparin induced a distinctly prolonged clotting time (2283 s, all P values less than 0.02). The coagulopathies were readily distinguishable using a panel of TEM-reagents. In particular, dilutional coagulopathy was separated from thrombocytopenia using FIBTEM (maximum clot firmness 1.9 mm vs. 11.2 mm, P < 0.001). The run time of analysis to achieve diagnostic data was shorter applying a panel of TEM-reagents. A transfusion algorithm based on kaolin suggested platelets in case of dilutional coagulopathy, whereas an algorithm applying TEM-reagents suggested fibrinogen. Conclusion Monoanalysis with kaolin was unable to distinguish coagulopathies caused by dilution from that of thrombocytopenia. Algorithms based on the use of kaolin may lead to unnecessary transfusion with platelets, whereas the application of TEM-reagents may result in goal-directed fibrinogen substitution.
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Duvekot, Anne, Victor A. Viersen, Simone E. Dekker, Leo M. G. Geeraedts, Lothar A. Schwarte, Angelique M. E. Spoelstra-Man, Peter M. van de Ven, et al. "Low Cerebral Oxygenation Levels during Resuscitation in Out-of-hospital Cardiac Arrest Are Associated with Hyperfibrinolysis." Anesthesiology 123, no. 4 (October 1, 2015): 820–29. http://dx.doi.org/10.1097/aln.0000000000000806.
Анотація:
Abstract Background: The authors investigated whether patients with out-of-hospital cardiac arrest with an initial low cerebral oxygen level during cardiopulmonary resuscitation are more prone to develop hyperfibrinolysis than patients with normal cerebral oxygenation levels and which part of the fibrinolytic system is involved in this response. Methods: In 46 patients, hyperfibrinolysis was diagnosed immediately upon emergency department admission using rotational thromboelastometry and defined as a lysis more than 15%. Simultaneously, initial cerebral tissue oxygenation was measured using near-infrared spectroscopy, and oxygen desaturation was defined as a tissue oxygenation index (TOI) of 50% or less. Blood sample analysis included markers for hypoperfusion and fibrinolysis. Results: There was no difference in prehospital cardiopulmonary resuscitation duration between patients with or without hyperfibrinolysis. An initial TOI of 50% or less was associated with more clot lysis (91% [17 to 100%; n = 16]) compared with patients with a normal TOI (6% [4 to 11%]; n = 30; P < 0.001), with lower levels of plasminogen (151.6 ± 61.0 vs. 225.3 ± 47.0 μg/ml; P < 0.001) and higher levels of tissue plasminogen activator (t-PA; 18.3 ± 7.4 vs. 7.9 ± 4.7 ng/ml; P < 0.001) and plasminogen activator inhibitor-1 (19.3 ± 8.9 vs. 12.1 ± 6.1 ng/ml; P = 0.013). There were no differences in (activated) protein C levels among groups. The initial TOI was negatively correlated with t-PA (r = −0.69; P < 0001). Mortality rates were highest in patients with hyperfibrinolysis. Conclusion: Activation of the fibrinolytic system is more common in out-of-hospital cardiac arrest patients with an initial cerebral tissue oxygenation value of 50% or less during resuscitation and is linked to increased levels of t-PA rather than involvement of protein C.
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Stueber, Thomas, Mirjam J. Eberhardt, Christoph Hadamitzky, Annette Jangra, Stefan Schenk, Felicia Dick, Carsten Stoetzer, et al. "Quaternary Lidocaine Derivative QX-314 Activates and Permeates Human TRPV1 and TRPA1 to Produce Inhibition of Sodium Channels and Cytotoxicity." Anesthesiology 124, no. 5 (May 1, 2016): 1153–65. http://dx.doi.org/10.1097/aln.0000000000001050.
Анотація:
Abstract Background The relatively membrane-impermeable lidocaine derivative QX-314 has been reported to permeate the ion channels transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential cation channel, subfamily A, member 1 (TRPA1) to induce a selective inhibition of sensory neurons. This approach is effective in rodents, but it also seems to be associated with neurotoxicity. The authors examined whether the human isoforms of TRPV1 and TRPA1 allow intracellular entry of QX-314 to mediate sodium channel inhibition and cytotoxicity. Methods Human embryonic kidney 293 (HEK-293) cells expressing wild-type or mutant human (h) TRPV1 or TRPA1 constructs as well as the sodium channel Nav1.7 were investigated by means of patch clamp and ratiometric calcium imaging. Cytotoxicity was examined by flow cytometry. Results Activation of hTRPA1 by carvacrol and hTRPV1 by capsaicin produced a QX-314–independent reduction of sodium current amplitudes. However, permeation of QX-314 through hTRPV1 or hTRPA1 was evident by a concentration-dependent, use-dependent inhibition of Nav1.7 activated at 10 Hz. Five and 30 mM QX-314 activated hTRPV1 via mechanisms involving the intracellular vanilloid-binding domain and hTRPA1 via unknown mechanisms independent of intracellular cysteins. Expression of hTRPV1, but not hTRPA1, was associated with a QX-314–induced cytotoxicity (viable cells 48 ± 5% after 30 mM QX-314) that was ameliorated by the TRPV1 antagonist 4-(3-chloro-2-pyridinyl)-N-[4-(1,1-dimethylethyl)phenyl]-1-piperazinecarboxamide (viable cells 81 ± 5%). Conclusions The study data demonstrate that QX-314 directly activates and permeates the human isoforms of TRPV1 and TRPA1 to induce inhibition of sodium channels, but also a TRPV1-dependent cytotoxicity. These results warrant further validation of this approach in more intact preparations and may be valuable for the development of this concept into clinical practice.
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Stepan, Vinzenz, Saravanan Ramamoorthy, Nonthalee Pausawasdi, Craig D. Logsdon, Frederick K. Askari, and Andrea Todisco. "Role of small GTP binding proteins in the growth-promoting and antiapoptotic actions of gastrin." American Journal of Physiology-Gastrointestinal and Liver Physiology 287, no. 3 (September 2004): G715—G725. http://dx.doi.org/10.1152/ajpgi.00169.2003.
Анотація:
G17 has growth promoting and antiapoptotic effects on the AR4–2J pancreatic acinar cell line. We previously reported that whereas MAPK regulates G17-stimulation of AR4–2J cell proliferation, Akt mediates the antiapoptotic action of G17. We examined the signal-transduction pathways mediating G17 stimulation of AR4–2J cell growth and survival. G17 activated the small GTP binding proteins Ras, Rac, Rho, and Cdc42. Transduction of the cells with adenoviral vectors expressing dominant negative Akt, Ras, Rho, and Cdc42 but not dominant negative Rac inhibited AR4–2J cell proliferation and survival. Both exoenzyme C3 from Clostridium botulinum (C3), a toxin known to inactivate Rho, and PD98059, a MAPK inhibitor, reversed G17 inhibition of AR4–2J cell apoptosis. G17 induction of Akt activation was reduced by >60% by both dominant negative Ras and Rho and by 30% by dominant negative Cdc42. In contrast, G17-stimulated MAPK activation was blocked by >80% by dominant negative Ras but not by dominant negative Rho and Cdc42. Similar results were observed in the presence of C3. Dominant negative Rac failed to affect G17 induction of both Akt and MAPK, whereas it inhibited sorbitol by almost 50% but not G17-stimulated activation of p38 kinase. Thus G17 promotes AR4–2J cell growth and survival through the activation of multiple GTP binding proteins, which, in turn, regulate different protein kinase cascades. Whereas Ras activates Akt and MAPK, Rho and Cdc42 appear to regulate Akt and possibly other as yet unidentified kinases mediating the growth-stimulatory actions of G17.
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Twaroski, Danielle M., Yasheng Yan, Jessica M. Olson, Zeljko J. Bosnjak, and Xiaowen Bai. "Down-regulation of MicroRNA-21 Is Involved in the Propofol-induced Neurotoxicity Observed in Human Stem Cell–derived Neurons." Anesthesiology 121, no. 4 (October 1, 2014): 786–800. http://dx.doi.org/10.1097/aln.0000000000000345.
Анотація:
Abstract Background: Recent studies in various animal models have suggested that anesthetics such as propofol, when administered early in life, can lead to neurotoxicity. These studies have raised significant safety concerns regarding the use of anesthetics in the pediatric population and highlight the need for a better model to study anesthetic-induced neurotoxicity in humans. Human embryonic stem cells are capable of differentiating into any cell type and represent a promising model to study mechanisms governing anesthetic-induced neurotoxicity. Methods: Cell death in human embryonic stem cell–derived neurons was assessed using terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate in situ nick end labeling staining, and microRNA expression was assessed using quantitative reverse transcription polymerase chain reaction. miR-21 was overexpressed and knocked down using an miR-21 mimic and antagomir, respectively. Sprouty 2 was knocked down using a small interfering RNA, and the expression of the miR-21 targets of interest was assessed by Western blot. Results: Propofol dose and exposure time dependently induced significant cell death (n = 3) in the neurons and down-regulated several microRNAs, including miR-21. Overexpression of miR-21 and knockdown of Sprouty 2 attenuated the increase in terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate in situ nick end labeling–positive cells following propofol exposure. In addition, miR-21 knockdown increased the number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate in situ nick end labeling–positive cells by 30% (n = 5). Finally, activated signal transducer and activator of transcription 3 and protein kinase B (Akt) were down-regulated, and Sprouty 2 was up-regulated following propofol exposure (n = 3). Conclusions: These data suggest that (1) human embryonic stem cell–derived neurons represent a promising in vitro human model for studying anesthetic-induced neurotoxicity, (2) propofol induces cell death in human embryonic stem cell–derived neurons, and (3) the propofol-induced cell death may occur via a signal transducer and activator of transcription 3/miR-21/Sprouty 2–dependent mechanism.
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Ciriello, John. "Afferent renal inputs to paraventricular nucleus vasopressin and oxytocin neurosecretory neurons." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 275, no. 6 (December 1, 1998): R1745—R1754. http://dx.doi.org/10.1152/ajpregu.1998.275.6.r1745.
Анотація:
Extracellular single-unit recording experiments were done in pentobarbital sodium-anesthetized rats to investigate the effects of electrical stimulation of afferent renal nerves (ARN) and renal vein (RVO) or artery (RAO) occlusion on the discharge rate of putative arginine vasopressin (AVP) and oxytocin (Oxy) neurons in the paraventricular nucleus of the hypothalamus (PVH). PVH neurons antidromically activated by electrical stimulation of the neurohypophysis were classified as either AVP or Oxy secreting on the basis of their spontaneous discharge patterns and response to activation of arterial baroreceptors. Ninety-eight putative neurosecretory neurons in the PVH were tested for their response to electrical stimulation of ARN: 44 were classified as putative AVP and 54 as putative Oxy neurons. Of the 44 AVP neurons, 52% were excited, 7% were inhibited, and 41% were nonresponsive to ARN stimulation. Of the 54 Oxy neurons, 43% were excited, 6% inhibited, and 51% were not affected by ARN. An additional 45 neurosecretory neurons (29 AVP and 16 Oxy neurons) were tested for their responses to RVO and/or RAO. RVO inhibited 42% of the putative AVP neurons and 13% of the putative Oxy neurons. On the other hand, RAO excited 33% of the AVP and 9% of the Oxy neurons. No AVP or Oxy neurons were found to be excited by RVO or inhibited by RAO. These data indicate that sensory information originating in renal receptors alters the activity of AVP and Oxy neurons in the PVH and suggest that these renal receptors contribute to the hypothalamic control of AVP and Oxy release into the circulation.
39
Tang, Yi Xuan, Yeong Huei Lee, Mugahed Amran, Roman Fediuk, Nikolai Vatin, Ahmad Beng Hong Kueh, and Yee Yong Lee. "Artificial Neural Network-Forecasted Compression Strength of Alkaline-Activated Slag Concretes." Sustainability 14, no. 9 (April 26, 2022): 5214. http://dx.doi.org/10.3390/su14095214.
Анотація:
The utilization of ordinary Portland cement (OPC) in conventional concretes is synonymous with high carbon emissions. To remedy this, an environmentally friendly concrete, alkaline-activated slag concrete (AASC), where OPC is completely replaced by ground granulated blast-furnace slag (GGBFS) industrial waste, is one of the currently pursued research interests. AASC is not commonly used in the construction industry due to limitations in experience and knowledge on the mix proportions and mechanical properties. To circumvent great labour in the experimental works toward the determination of the optimal properties, this study, therefore, presents the compressive strength prediction of AASC by employing the back-propagation artificial neural network (ANN) modelling technique. To construct this model, a sufficiently equipped experimental databank was built from the literature covering varied mix proportion effects on the compressive strength of AASC. For this, four model variants with different input parameter considerations were examined and the ideal ANN architecture for each model with the best input number–hidden layer neuron number–output number format was identified to improve its prediction accuracy. From such a setting, the most accurate prediction model with the highest determination coefficient, R2, of 0.9817 was determined, with an ANN architecture of 8-18-1 containing inputs such as GGBFS, a fine to total aggregate ratio, sodium silicate, sodium hydroxide, mixing water, silica modulus of activator, percentage of sodium oxide and water–binder ratio. The prediction accuracy of the optimal ANN model was then compared to existing ANN-based models, while the variable selection was compared to existing AASC models with other machine learning algorithms, due to limitations in the ANN-based model. To identify the parametric influence, the individual relative importance of each input variable was determined through a sensitivity analysis using the connection weight approach, whose results indicated that the silica modulus of the activator and sodium silicate greatly affected the AASC compressive strength. The proposed methodology demonstrates that the ANN-based model can predict the AASC compressive strength with a high accuracy and, consequently, aids in promoting the utilization of AASC in the construction industry as green concrete without performing destructive tests. This prediction model can also accelerate the use of AASC without using a cement binder in the concrete matrix, leading to produce a sustainable construction material.
40
Bhagwat, Shripad V., Johanna Lahdenranta, Ricardo Giordano, Wadih Arap, Renata Pasqualini, and Linda H. Shapiro. "CD13/APN is activated by angiogenic signals and is essential for capillary tube formation." Blood 97, no. 3 (February 1, 2001): 652–59. http://dx.doi.org/10.1182/blood.v97.3.652.
Анотація:
Abstract In the hematopoietic compartment, the CD13/APN metalloprotease is one of the earliest markers of cells committed to the myeloid lineage where it is expressed exclusively on the surface of myeloid progenitors and their differentiated progeny. CD13/APN is also found in nonhematopoietic tissues, and its novel expression on the endothelial cells of angiogenic, but not normal, vasculature was recently described. Treatment of animals with CD13/APN inhibitors significantly impaired retinal neovascularization, chorioallantoic membrane angiogenesis, and xenograft tumor growth, indicating that CD13/APN plays an important functional role in vasculogenesis and identifying it as a critical regulator of angiogenesis. To investigate the mechanisms of CD13/APN induction in tumor vasculature, the regulation ofCD13/APN by factors contributing to angiogenic progression was studied. In this report, it is shown that endogenous CD13/APN levels in primary cells and cell lines are up-regulated in response to hypoxia, angiogenic growth factors, and signals regulating capillary tube formation during angiogenesis. Transcription of reporter plasmids containing CD13/APNproximal promoter sequences is significantly increased in response to the same angiogenic signals that regulate the expression of the endogenous gene and in human tumor xenografts, indicating that this fragment contains elements essential for the angiogenic induction ofCD13/APN expression. Finally, functional antagonists of CD13/APN interfere with tube formation but not proliferation of primary vascular endothelial cells, suggesting that CD13/APN functions in the control of endothelial cell morphogenesis. These studies clearly establish the CD13/APN metalloprotease as an important regulator of endothelial morphogenesis during angiogenesis.
41
Xu, Ting, Dai Li, Xin Zhou, Han-Dong Ouyang, Li-Jun Zhou, Hang Zhou, Hong-Mei Zhang, Xu-Hong Wei, Guosong Liu та Xian-Guo Liu. "Oral Application of Magnesium-l-Threonate Attenuates Vincristine-induced Allodynia and Hyperalgesia by Normalization of Tumor Necrosis Factor-α/Nuclear Factor-κB Signaling". Anesthesiology 126, № 6 (1 червня 2017): 1151–68. http://dx.doi.org/10.1097/aln.0000000000001601.
Анотація:
Abstract Background Antineoplastic agents, including vincristine, often induce neuropathic pain and magnesium deficiency clinically, but the causal link between them has not been determined. No drug is available for treating this form of neuropathic pain. Methods Injection of vincristine (0.1 mg · kg-1 · day-1, intraperitoneally, for 10 days) was used to induce nociceptive sensitization, which was accessed with von Frey hairs and the plantar tester in adult male Sprague–Dawley rats. Magnesium-l- threonate was administered through drinking water (604 mg · kg-1 · day-1). Extracellular and intracellular free Mg2+ were measured by Calmagite chromometry and flow cytometry. Molecular biologic and electrophysiologic experiments were performed to expose the underlying mechanisms. Results Vincristine injection induced allodynia and hyperalgesia (n = 12), activated tumor necrosis factor-α/nuclear factor-κB signaling, and reduced free Mg2+ in cerebrospinal fluid by 21.7 ± 6.3% (mean ± SD; n = 13) and in dorsal root ganglion neurons by 27 ± 6% (n = 11). Reducing Mg2+ activated tumor necrosis factor-α/nuclear factor-κB signaling in cultured dorsal root ganglion neurons. Oral application of magnesium-l-threonate prevented magnesium deficiency and attenuated both activation of tumor necrosis factor-α/nuclear factor-κB signaling and nociceptive sensitization (n = 12). Mechanistically, vincristine induced long-term potentiation at C-fiber synapses, up-regulated N-methyl-D-aspartate receptor type 2B subunit of N-methyl-d-aspartate receptor, and led to peptidergic C-fiber sprouting in spinal dorsal horn (n = 6 each). The vincristine-induced pathologic plasticity was blocked by intrathecal injection of nuclear factor-κB inhibitor (n = 6), mimicked by tumor necrosis factor-α, and substantially prevented by oral magnesium-l-threonate (n = 5). Conclusions Vincristine may activate tumor necrosis factor-α/nuclear factor-κB pathway by reduction of intracellular magnesium, leading to spinal pathologic plasticity and nociceptive sensitization. Oral magnesium-l-threonate that prevents the magnesium deficiency is a novel approach to prevent neuropathic pain induced by chemotherapy.
42
Dingle, J. T., M. E. Davies, B. Y. Mativi, and H. F. Middleton. "Immunohistological identification of interleukin-1 activated chondrocytes." Annals of the Rheumatic Diseases 49, no. 11 (November 1, 1990): 889–92. http://dx.doi.org/10.1136/ard.49.11.889.
43
López-Pedrera, Chary, Patricia Ruiz-Limón, Maria Ángeles Aguirre, Nuria Barbarroja, Carlos Pérez-Sánchez, Paula Buendía, Ines-Carmen Rodriguez-García, et al. "Global effects of fluvastatin on the prothrombotic status of patients with antiphospholipid syndrome." Annals of the Rheumatic Diseases 70, no. 4 (December 20, 2010): 675–82. http://dx.doi.org/10.1136/ard.2010.135525.
Анотація:
ObjectiveNumerous mechanisms have been proposed to explain the thrombotic/proinflammatory tendency of antiphospholipid syndrome (APS) patients. Prothrombotic monocyte activation by antiphospholipid antibodies involves numerous proteins and intracellular pathways. The anti-inflammatory, anticoagulant and immunoregulatory effects of statins have been aimed as a therapeutic tool in APS patients. This study delineates the global effects of fluvastatin on the prothrombotic tendency of monocytes from APS patients.MethodsForty-two APS patients with thrombosis and 35 healthy donors were included in the study. APS patients received 20 mg/day fluvastatin for 1 month. Blood samples were obtained before the start, at the end and 2 months after the end of treatment.ResultsAfter 1 month of treatment, monocytes showed a significant inhibition of tissue factor, protein activator receptors 1 and 2, vascular endothelial growth factor and Flt1 expression that was related to the inhibition of p38 mitogen-activated protein kinase (MAPK) and nuclear factor kappa B/Rel DNA-binding activity. Proteomic analysis showed proteins involved in thrombotic development (annexin II, RhoA and protein disulphide isomerase) with altered expression after fluvastatin administration. In-vitro studies indicated that the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase by fluvastatin might inhibit protein prenylation and MAPK activation.ConclusionThe data from this study support the belief that fluvastatin has multiple profound effects in monocyte activity, which might contribute to thrombosis prevention in APS patients.
44
Granel, B. "Juvenile temporal arteritis and activated protein C resistance." Annals of the Rheumatic Diseases 63, no. 2 (February 1, 2004): 215–16. http://dx.doi.org/10.1136/ard.2003.008227.
45
Otulakowski, Gail, Doreen Engelberts, Martin Post, Claire Masterson, and Brian P. Kavanagh. "Mechanical Ventilation Induces Desensitization of Lung Axl Tyrosine Kinase Receptors." Anesthesiology 129, no. 1 (July 1, 2018): 143–53. http://dx.doi.org/10.1097/aln.0000000000002140.
Анотація:
Abstract Background Lower tidal volumes are increasingly used in acute respiratory distress syndrome, but mortality has changed little in the last 20 yr. Therefore, in addition to ventilator settings, it is important to target molecular mediators of injury. Sepsis and other inflammatory states increase circulating concentrations of Gas6, a ligand for the antiinflammatory receptor Axl, and of a soluble decoy form of Axl. We investigated the effects of lung stretch on Axl signaling. Methods We used a mouse model of early injury from high tidal volume and assessed the effects of inhibiting Axl on in vivo lung injury (using an antagonist R428, n = 4/group). We further determined the effects of stretch on Axl activation using in vitro lung endothelial cells. Results High tidal volume caused mild injury (compliance decreased 6%) as intended, and shedding of the Axl receptor (soluble Axl in bronchoalveolar fluid increased 77%). The Axl antagonist R428 blocked the principal downstream Axl target (suppressor of cytokine signaling 3 [SOCS3]) but did not worsen lung physiology or inflammation. Cyclic stretch in vitro caused Axl to become insensitive to activation by its agonist, Gas6. Finally, in vitro Axl responses were rescued by blocking stretch-activated calcium channels (using guanidinium chloride [GdCl3]), and the calcium ionophore ionomycin replicated the effect of stretch. Conclusions These data suggest that lung endothelial cell overdistention activates ion channels, and the resultant influx of Ca2+ inactivates Axl. Downstream inactivation of Axl by stretch was not anticipated; preventing this would be required to exploit Axl receptors in reducing lung injury.
46
Purwono, Bambang, Naresh Kumar, and David StC Black. "Mannich reactions of activated 4,6-dimethoxyindoles." Arkivoc 2022, no. 4 (December 10, 2021): 58–69. http://dx.doi.org/10.24820/ark.5550190.p011.668.
47
Braun, T., J. Lepper, P. Lezuo, G. Schett, and J. Zwerina. "MAPK-activated protein kinase-2 regulates physiological bone turnover." Annals of the Rheumatic Diseases 70, Suppl 2 (February 22, 2011): A21—A22. http://dx.doi.org/10.1136/ard.2010.148965.21.
48
Lindau, D., A. Rabsteyn, I. Kotter, A. Igney, M. C. Boissier, H. G. Rammensee, and P. Decker. "Chromatin-activated neutrophils represent a major source of interferon." Annals of the Rheumatic Diseases 70, Suppl 2 (February 22, 2011): A38—A39. http://dx.doi.org/10.1136/ard.2010.148973.7.
49
Wickley, Peter J., Ryo Yuge, Brad A. Martin, Jacob S. Meyer та Derek S. Damron. "Propofol Activates and Allosterically Modulates Recombinant Protein Kinase Cϵ". Anesthesiology 111, № 1 (1 липня 2009): 36–43. http://dx.doi.org/10.1097/aln.0b013e3181a3274b.
Анотація:
Background Myocardial protection by anesthetics is known to involve activation of protein kinase C epsilon (PKC epsilon). A key step in the activation process is autophosphorylation of the enzyme at serine 729. This study's objectives were to identify the extent to which propofol interacts with PKC epsilon and to identify the molecular mechanism(s) of interaction. Methods Immunoblot analysis of recombinant PKC epsilon was used to assess autophosphorylation of PKC epsilon at serine 729 before and after exposure to propofol. An enzyme-linked immunosorbant assay kit was used for measuring PKC epsilon activity. Spectral shifts in fluorescence emission maxima of the C1B subdomain of PKC epsilon in combination with the fluorescent phorbol ester, sapintoxin D, was used to identify molecular interactions between propofol and the phorbol ester/diacylglycerol binding site on the enzyme. Results Propofol (1 microM) caused a sixfold increase in immunodetectable serine 729 phosphorylated PKC epsilon and increased catalytic activity of the enzyme in a dose-dependent manner. Dioctanoylglycerol-induced or phorbol myristic acetate-induced activation of recombinant PKC epsilon activity was enhanced by preincubation with propofol. Both propofol and phorbol myristic acetate quenched the intrinsic fluorescence spectra of the PKC epsilon C1B subdomain in a dose-dependent manner, and propofol caused a further leftward-shift in the fluorescence emission maxima of sapintoxin D after addition of the C1B subdomain. Conclusions These results demonstrate that propofol interacts with recombinant PKC epsilon causing autophosphorylation and activation of the enzyme. Moreover, propofol enhances phorbol ester-induced catalytic activity, suggesting that propofol binds to a region near the phorbol ester binding site allowing for allosteric modulation of PKC epsilon catalytic activity.
50
Bhagwat, Shripad V., Nenad Petrovic, Yasuhiro Okamoto, and Linda H. Shapiro. "The angiogenic regulator CD13/APN is a transcriptional target of Ras signaling pathways in endothelial morphogenesis." Blood 101, no. 5 (March 1, 2003): 1818–26. http://dx.doi.org/10.1182/blood-2002-05-1422.
Анотація:
Angiogenesis, the formation of new blood vessels, is a critical step for tumor growth and metastasis and an integral component of the pathologic inflammatory response in arthritis and the proliferative retinopathies. The CD13/aminopeptidase N (CD13/APN) metalloprotease is an important regulator of angiogenesis where its expression on activated blood vessels is induced by angiogenic signals. Here, we show that cytokine induction of CD13/APN in endothelial cells is regulated by distinct Ras effector pathways involving Ras/mitogen-activated protein kinase (MAPK) or PI-3K. Signals transduced by activated Ras, Raf, and mitogen-induced extracellular kinase (MEK) stimulate transcription from theCD13/APN proximal promoter. Inhibition of these pathways and extracellular signal–regulated serine/threonine kinase (ERK-2) and PI-3K by expression of dominant-negative proteins or chemical inhibitors prevented induction of CD13/APNtranscription in response to basic fibroblast growth factor (bFGF). We show that Ras-induced signal transduction is required for growth factor–induced angiogenesis, because inhibition of downstream mediators of Ras signaling (MEK or PI-3K) abrogated endothelial cell migration, invasion, and morphogenesis in vitro. Reintroduction of CD13/APN, a shared downstream target of these pathways, overrode the suppressive effect of these inhibitors and restored the function of endothelial cells in migration/invasion and capillary morphogenesis assays. Similarly, inhibition of MEK abrogated cell invasion and the formation of endothelial-lined capillaries in vivo, which was effectively rescued by addition of exogenous CD13/APN protein. These studies provide strong evidence that CD13/APN is an important target of Ras signaling in angiogenesis and is a limiting factor in angiogenic progression.