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Activity Leading (activity + leading)
Selected AbstractsProductive Chlamydia trachomatis lymphogranuloma venereum 434 infection in cells with augmented or inactivated autophagic activitiesFEMS MICROBIOLOGY LETTERS, Issue 2 2009Niseema Pachikara Abstract Autophagy, a eukaryotic cellular activity leading to the degradation of cellular components, serves as a defense mechanism against facultative intracellular bacteria as well as a growth niche for the obligate intracellular bacterium Coxiella burnetii. We here demonstrate that the obligate intracellular bacterial pathogen Chlamydia trachomatis lymphogranuloma venereum strongly induced autophagy in the middle of the chlamydial developmental cycle (24 h after infection), a time point with maximal level of chlamydial replication, but not during the early stages with low overall chlamydial metabolism (before 8 h). No autophagy induction was evident in cells exposed to heat- and UV-inactivated elementary bodies (EBs, the infectious form of Chlamydia) or to inocula from which EBs had been removed before inoculation. Blocking chlamydial development with chloramphenicol also prevented autophagy induction in cells infected with infectious EBs. It appears that autophagy is activated primarily in response to the metabolic stress consequent to chlamydial replication. However, autophagy-defective ATG5,/, cells supported chlamydial development as efficiently as autophagy-proficient ATG5+/+ cells. [source] Commonalities in the neurobiology between autism and fragile XJOURNAL OF INTELLECTUAL DISABILITY RESEARCH, Issue 10 2008R. Hagerman There is a close association between autism and fragile X syndrome (FXS) with 30% of males with FXS having autism and 2 to 7% of children with autism having the fragile X mutation. The protein that is missing or deficient in FXS, FMRP, is an RNA binding and transport protein which regulates the translation of many messages important for synaptic plasticity. Typically FMRP inhibits the translation of these messages, such that protein production increases when FMRP is absent. Some of these proteins are known to also cause autism when they are mutated including neuroligin 3 and 4 and the SHANK protein. Therefore, when FMRP is missing there is dysregulation of other proteins that are known to cause autism. FMRP is an important inhibitor of protein production in the metabotropic glutamate receptor 5 pathway (mGluR5) which leads to long term depression (LTD) or the weakening of synaptic connections. Therefore, when FMRP is missing there is enhanced mGluR5 activity leading to enhanced LTD and weak or immature synaptic connections. The use of mGluR5 antagonists to reverse the LTD in the animal models of FXS has led to reversal of the learning, behaviour and dendritic spine abnormalities in these animals. There are now initial studies taking place in humans regarding the use of mGluR5 antagonists to improve behaviour and cognition in FXS. It is likely that these mGluR5 antagonists will also be helpful in a subgroup of patients with non fragile X autism who have similar problems with hyperactivity, hyperarousal and anxiety to those seen in FXS. A second cause of autism is the fragile X premutation but this mechanism of involvement is related to RNA toxicity which perhaps stimulates neuroimmune problems and may mimic other causes of autism. Neurons with the premutation are more vulnerable to environmental toxicity and oxidative stress leading to early cell death. [source] Amphibolite facies retrograde metamorphism of the Zhujiachong eclogite, SE Dabieshan: 40Ar/39Ar age constraints from argon extraction using UV-laser microprobe, in vacuo crushing and stepwise heatingJOURNAL OF METAMORPHIC GEOLOGY, Issue 5 2010H.-N. QIU Abstract The Zhujiachong eclogite in the south-eastern Dabieshan ultra-high- P terrane has been overprinted during retrograde metamorphism, with the development of garnet-amphibolite mineral assemblages in most rocks in the outcrop. This study is focused on providing age constraints for the retrograde amphibolite facies and greenschist facies mineralogy by 40Ar/39Ar dating. By applying a novel approach of combining three different techniques for extracting argon: laser stepwise heating of single grains and small separates, a spot fusion technique by UV-laser ablation microprobe on polished sections and an in vacuo crushing technique for liberating radiogenic argon from fluid inclusions, it is demonstrated that an internally consistent thermal history can be derived. The 40Ar/39Ar ages indicate that phengite formed before 265 Ma, probably during the ultra-high- P event. Ages associated with amphibolite facies retrograde metamorphism range from 242 to 217 Ma by the analyses of amphibole. Ages of c. 230 Ma were found for the symplectite matrix that formed during retrogression from eclogite pyroxene. Late stage hydrothermal activity leading to the formation of coarse-grained paragonite and fluid inclusions in vein amphibole was dated at c. 200 Ma. These age results agree well with the mineral crystallization sequence observed from thin-sections of the retrograded eclogite: phengite , paragonite and amphibole in matrix , amphibole in the corona. [source] Regulation of dendritic spine morphology by an NMDA receptor-associated Rho GTPase-activating protein, p250GAPJOURNAL OF NEUROCHEMISTRY, Issue 4 2008Takanobu Nakazawa Abstract The NMDA receptor regulates spine morphological plasticity by modulating Rho GTPases. However, the molecular mechanisms for NMDA receptor-mediated regulation of Rho GTPases remain elusive. In this study, we show that p250GAP, an NMDA receptor-associated RhoGAP, regulates spine morphogenesis by modulating RhoA activity. Knock-down of p250GAP increased spine width and elevated the endogenous RhoA activity in primary hippocampal neurons. The increased spine width by p250GAP knock-down was suppressed by the expression of a dominant-negative form of RhoA. Furthermore, p250GAP is involved in NMDA receptor-mediated RhoA activation. In response to NMDA receptor activation, exogenously expressed green fluorescent protein (GFP)-tagged p250GAP was redistributed. Thus, these data suggest that p250GAP plays an important role in NMDA receptor-mediated regulation of RhoA activity leading to spine morphological plasticity. [source] Differential phosphorylation of myosin light chain (Thr)18 and (Ser)19 and functional implications in plateletsJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 10 2010T. M. GETZ Summary. Background:, Myosin IIA is an essential platelet contractile protein that is regulated by phosphorylation of its regulatory light chain (MLC) on residues (Thr)18 and (Ser)19 via the myosin light chain kinase (MLCK). Objective:, The present study was carried out to elucidate the mechanisms regulating MLC (Ser)19 and (Thr)18 phosphorylation and the functional consequence of each phosphorylation event in platelets. Results:, Induction of 2MeSADP-induced shape change occurs within 5 s along with robust phosphorylation of MLC (Ser)19 with minimal phosphorylation of MLC (Thr)18. Selective activation of G12/13 produces both slow shape change and comparably slow MLC (Thr)18 and (Ser)19 phosphorylation. Stimulation with agonists that trigger ATP secretion caused rapid MLC (Ser)19 phosphorylation while MLC (Thr)18 phosphorylation was coincident with secretion. Platelets treated with p160ROCK inhibitor Y-27632 exhibited a partial inhibition in secretion and had a substantial inhibition in MLC (Thr)18 phosphorylation without effecting MLC (Ser)19 phosphorylation. These data suggest that phosphorylation of MLC (Ser)19 is downstream of Gq/Ca2+ -dependent mechanisms and sufficient for shape change, whereas MLC (Thr)18 phosphorylation is substantially downstream of G12/13 -regulated Rho kinase pathways and necessary, probably in concert with MLC (Ser)19 phosphorylation, for full contractile activity leading to dense granule secretion. Overall, we suggest that the amplitude of the platelet contractile response is differentially regulated by a least two different signaling pathways, which lead to different phosphorylation patterns of the myosin light chain, and this mechanism results in a graded response rather than a simple on/off switch. [source] Novel Pirinixic Acids as PPAR, Preferential Dual PPAR,/, AgonistsMOLECULAR INFORMATICS, Issue 5 2009Heiko Zettl Abstract Pirinixic acid is a moderate agonist of both the alpha and the gamma subtype of the peroxisome proliferator activated receptor (PPAR). Previously, we have shown that ,-alkyl substitution leads to balanced low micromolar-active dual agonists of PPAR, and PPAR,. Taking ,-hexyl pirinixic acid as a new scaffold, we further optimized PPAR activity by enlargement of the lipophilic backbone by substituting the 2,3-dimethylphenyl with biphenylic moieties. Such a substitution pattern had only minor impact on PPAR, activity but further increased PPAR, activity leading to nanomolar activities. Supporting docking studies proposed that the (R)-enantiomer should fit the PPAR, ligand-binding pocket better and thus be more active than the (S)-enantiomer. Single enantiomers of selected active analogues were then prepared by enantio-selective synthesis and enantio-selective preparative HPLC, respectively. Biological data for the distinct enantiomers fully corroborated the docking experiments and substantiate a stereochemical impact on PPAR activation. [source] A six amino acid deletion, partially overlapping the VanSB G2 ATP-binding motif, leads to constitutive glycopeptide resistance in VanB-type Enterococcus faeciumMOLECULAR MICROBIOLOGY, Issue 3 2003Florence Depardieu Summary Enterococcus faecium clinical isolate BM4524, resistant to vancomycin and susceptible to teicoplanin, harboured a chromosomal vanB cluster, including the vanSB / vanRB two-component system regulatory genes. Enterococcus faecium strain BM4525, isolated two weeks later from the same patient, was resistant to high levels of both glycopeptides. The ddl gene of BM4525 had a 2 bp insertion leading to an impaired d -alanine: d -alanine ligase. Sequencing of the vanB operon in BM4525 also revealed an 18 bp deletion in the vanSB gene designated vanSB, . The resulting six amino acid deletion partially overlapped the G2 ATP-binding domain of the VanS B, histidine kinase leading to constitutive expression of the resistance genes. Sequence analysis indicated that the deletion occurred between two tandemly arranged heptanucleotide direct repeats, separated by 11 base-pairs. The VanS B , VanS B, and VanR B proteins were overproduced in Escherichia coli and purified. In vitro autophosphorylation of the VanS B and VanS B, histidine kinases and phosphotransfer to the VanR B response regulator did not differ significantly. However, VanS B, was deficient in VanR B phosphatase activity leading to accumulation of phosphorylated VanR B . Increased glycopeptide resistance in E. faecium BM4525 was therefore a result of the lack of production of d -alanyl- d -alanine ending pentapeptide and to constitutive synthesis of d -alanyl- d -lactate terminating peptidoglycan precursors, following loss of d -alanine: d -alanine ligase and of VanS B phosphatase activity respectively. We suggest that the heptanucleotide direct repeat in vanSB may favour the appearance of high level constitutively expressed vancomycin resistance through a ,slippage' type of genetic rearrangement in VanB-type strains. [source] An Unusual Complication of Sinus Arrest Following Right-Sided Stellate Ganglion Block: A Case ReportPAIN PRACTICE, Issue 3 2004Ashok K. Saxena MD Abstract: We present a case of a 29-year-old female patient who had presented to us for the management of her chronic right shoulder,hand pain and developed a sinus arrest following a right-sided stellate ganglion block (RSGB). This patient on receiving a diagnostic RSGB via the anterior paratracheal (C6) approach developed sinus arrest followed by apnea and unconsciousness. On institution of resuscitative measures involving tracheal intubation, positive pressure ventilation, cardiac massage, and intravenous atropine, spontaneous cardiac activity recovered in about 3 minutes. Other signs and symptoms resolved fully in a total of 10 minutes. She had persistent postural hypotension lasting for about 24 hours requiring bed rest and was discharged about 36 hours after the procedure, without any adverse sequelae. As the sinus node is supplied by the right-sided sympathetic chain, its blockade probably resulted in unopposed parasympathetic activity leading to asystole. Available evidence of the role of right stellate ganglion in regulation of cardiac electrophysiology and functioning is also discussed. [source] Sexuality and sexual activity in pregnancyBJOG : AN INTERNATIONAL JOURNAL OF OBSTETRICS & GYNAECOLOGY, Issue 8 2000Elias Bartellas Clinical Assistant Professor Objectives To evaluate women's sexual experience in pregnancy, and to describe their sources of information regarding sexuality during this period. Design Cross-sectional study. Setting The offices of obstetricians providing obstetric care in a tertiary care university hospital in St. John's, Newfoundland, Canada. Population One hundred and forty-one pregnant women. Methods Pregnant women anonymously completed self-administered questionnaires regarding sexuality and sexual activity during pregnancy. Responses were summarised using descriptive statistics, and comparisons were made between the trimesters of pregnancy. Multiple logistic regression was performed to assess the influences of a variety of factors on sexual activity. Results Vaginal intercourse and sexual activity overall decreased throughout pregnancy (P= 0.004 and 0.05, respectively) with the trimester of pregnancy being the only independent predictor. Most women reported a decrease in sexual desire (58%). Overall, 49% of women worried that sexual intercourse may harm the pregnancy. Concerns regarding sexual activity leading to preterm labour or premature rupture of membranes increased as the pregnancy progressed (P < 0.001 and P= 0.001, respectively). Only 29% of women discussed sexual activity in pregnancy with their doctor and 49% of these women raised the issue first, with 34% feeling uncomfortable in bringing up the topic themselves. Most women (76%) who had not discussed these issues with their doctor felt they should be discussed. Conclusions A reduction in sexual activity, vaginal intercourse and sexual desire occurs in many women as pregnancy progresses. Both the woman and her partner have concerns regarding complications in the pregnancy as a result of sexual intercourse. The majority of women wish to discuss these issues with their doctor, but are not always comfortable raising the topic themselves. [source] | |||||||||||||