Ameliorative Effects of Neurolytic Celiac Plexus Block on Stress and Inflammation in Rats with Partial Hepatectomy

Purpose: To investigate effects of neurolytic celiac plexus block (NCPB) on stress and inflammation in rats with partial hepatectomy (PH).Methods: A model of PH rat was established, and serum C-reactive protein (CRP); corticosterone (GC); adrenocorticotropin (ACTH); noradrenaline (NA); adrenalin (AD); aspartate transaminase (AST); alanine transaminase (ALT); as well as tumor necrosis factor-α (TNF-α); interleukin (IL)-1β and IL-6; high mobility group box1 (HMGB1); and nitric oxide (NO) concentrations in serum assessed after PH. Additionally, Western blotting was performed to determine the effect of NCPB on expressions of glucocorticoid receptors (GR), inhibitor of nuclear factor kappa B (IκB), p65, c-Jun and inducible nitric oxide synthase (iNOS) of PH rats, as well as assay effects of NCPB on nuclear translocation of GR, c- Jun and p65. DNA binding activities of nuclear factor kappa B (NF-κB) and activator protein 1 (AP-1) were also determined.Results: NCPB reduced AST and ALT (P < 0.05), decreased secretion of inflammatory cytokines and NO (P < 0.05), as well as decreased CRP, GC, ACTH, NA and AD after PH (p < 0.05). NCPB increased expressions of GR and IκB, but expressions of p65, c-Jun, and iNOS (p < 0.05). Additionally, NCPB increased nuclear translocation of GR (p < 0.01), but decreased nuclear translocation of p65 and c-Jun after PH (p < 0.05). Additionally, DNA binding activity of NF-κB and AP-1 was decreased by NCPB (p < 0.05).Conclusion: The results indicate that NCPB treatment can significantly inhibit stress and inflammation in PH rats.Keywords: Neurolytic celiac plexus block, Cytokine, Nuclear translocation, Partial hepatectomy, Stress, Inflammatio

Time series analysis of dengue fever and weather in Guangzhou, China

<p>Abstract</p> <p>Background</p> <p>Monitoring and predicting dengue incidence facilitates early public health responses to minimize morbidity and mortality. Weather variables are potential predictors of dengue incidence. This study explored the impact of weather variability on the transmission of dengue fever in the subtropical city of Guangzhou, China.</p> <p>Methods</p> <p>Time series Poisson regression analysis was performed using data on monthly weather variables and monthly notified cases of dengue fever in Guangzhou, China for the period of 2001-2006. Estimates of the Poisson model parameters was implemented using the Generalized Estimating Equation (GEE) approach; the quasi-likelihood based information criterion (QICu) was used to select the most parsimonious model.</p> <p>Results</p> <p>Two best fitting models, with the smallest QICu values, are selected to characterize the relationship between monthly dengue incidence and weather variables. Minimum temperature and wind velocity are significant predictors of dengue incidence. Further inclusion of minimum humidity in the model provides a better fit.</p> <p>Conclusion</p> <p>Minimum temperature and minimum humidity, at a lag of one month, are positively associated with dengue incidence in the subtropical city of Guangzhou, China. Wind velocity is inversely associated with dengue incidence of the same month. These findings should be considered in the prediction of future patterns of dengue transmission.</p

Mechanism of effector capture and delivery by the type IV secretion system from Legionella pneumophila

Legionella pneumophila is a bacterial pathogen that utilises a Type IV secretion (T4S) system to inject effector proteins into human macrophages. Essential to the recruitment and delivery of effectors to the T4S machinery is the membrane-embedded T4 coupling complex (T4CC). Here, we purify an intact T4CC from the Legionella membrane. It contains the DotL ATPase, the DotM and DotN proteins, the chaperone module IcmSW, and two previously uncharacterised proteins, DotY and DotZ. The atomic resolution structure reveals a DotLMNYZ hetero-pentameric core from which the flexible IcmSW module protrudes. Six of these hetero-pentameric complexes may assemble into a 1.6-MDa hexameric nanomachine, forming an inner membrane channel for effectors to pass through. Analysis of multiple cryo EM maps, further modelling and mutagenesis provide working models for the mechanism for binding and delivery of two essential classes of Legionella effectors, depending on IcmSW or DotM, respectively

Identification of the Allosteric Regulatory Site of Insulysin

Background: Insulin degrading enzyme (IDE) is responsible for the metabolism of insulin and plays a role in clearance of the Ab peptide associated with Alzheimer's disease. Unlike most proteolytic enzymes, IDE, which consists of four structurally related domains and exists primarily as a dimer, exhibits allosteric kinetics, being activated by both small substrate peptides and polyphosphates such as ATP.Principal Findings: the crystal structure of a catalytically compromised mutant of IDE has electron density for peptide ligands bound at the active site in domain 1 and a distal site in domain 2. Mutating residues in the distal site eliminates allosteric kinetics and activation by a small peptide, as well as greatly reducing activation by ATP, demonstrating that this site plays a key role in allostery. Comparison of the peptide bound IDE structure (using a low activity E111F IDE mutant) with unliganded wild type IDE shows a change in the interface between two halves of the clamshell-like molecule, which may enhance enzyme activity by altering the equilibrium between closed and open conformations. in addition, changes in the dimer interface suggest a basis for communication between subunits.Conclusions/Significance: Our findings indicate that a region remote from the active site mediates allosteric activation of insulysin by peptides. Activation may involve a small conformational change that weakens the interface between two halves of the enzyme.United States Public Health ServicesUniv Kentucky, Dept Mol & Cellular Biochem, Lexington, KY 40536 USAUniv Kentucky, Struct Biol Ctr, Lexington, KY USAUniversidade Federal de São Paulo, Dept Biophys, Escola Paulista Med, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Biophys, Escola Paulista Med, São Paulo, BrazilUnited States Public Health Services: NS38041United States Public Health Services: DA02243United States Public Health Services: DA016176United States Public Health Services: P20 RR20171United States Public Health Services: T32 DA016176Web of Scienc

Beta catenin and cytokine pathway dysregulation in patients with manifestations of the "PTEN hamartoma tumor syndrome"

Background. The "PTEN hamartoma tumor syndrome" (PHTS) includes a group of syndromes caused by germline mutations within the tumor suppressor gene "phosphatase and tensin homolog deleted on chromosome ten" (PTEN), characterized by multiple polyps in the gastrointestinal tract and by a highly increased risk of developing malignant tumours in many tissues. The current work clarifies the molecular basis of PHTS in three unrelated Italian patients, and sheds light on molecular pathway disregulation constitutively associated to PTEN alteration. Methods. We performed a combination of RT-PCR, PCR, sequencing of the amplified fragments, Real Time PCR and western blot techniques. Results. Our data provide the first evidence of β-catenin accumulation in blood cells of patients with hereditary cancer syndrome caused by germ-line PTEN alteration. In addition, for the first time we show, in all PHTS patients analysed, alterations in the expression of TNFα, its receptors and IL-10. Importantly, the isoform of TNFRI that lacks the DEATH domain (TNFRSF1β) was found to be overexpressed. Conclusion. In light of our findings, we suggest that the PTEN pathway disregulation could determine, in non-neoplastic cells of PHTS patients, cell survival and pro-inflammatory stimulation, mediated by the expression of molecules such as β-catenin, TNFα and TNFα receptors, which could predispose these patients to the development of multiple cancers

Prevalence and Risk Factors of Human Papillomavirus (HPV) Infection in Southern Chinese Women – A Population-Based Study

Background: Persistent high-risk type Human papillomavirus (HPV) infection is recognized as a necessary cause of cervical cancer. This study aimed to compare the HPV prevalence and risk factors between women residing in Hong Kong (HK) and Guangzhou (GZ) region of China. Methodology/Principal Findings: A total of 1,570 and 1,369 women were recruited from HK and GZ, respectively. The cytology samples were collected and tested for HPV infection. The overall and type-specific HPV prevalence and the potential risk factors for acquisition of HPV infection were studied. Women with normal cytology in the GZ cohort had significantly higher HPV prevalence (10%) than those in the HK cohort (6.2%, p<0.001). The patterns of the age-specific HPV prevalence were also different between the two cohorts. In the HK cohort, women at the age of 20-29 years old had the highest prevalence and a second peak was observed in the age of ≥60 years old. In the GZ cohort, the highest HPV prevalence was also observed in 20-29 years old but declined as the age increased and a second peak was not seen. HPV16 and HPV52 were the most common high-risk types found in the HK and GZ cohorts, respectively. Age was the most consistently observed independent risk factor for HPV infection in the HK, while the number of sexual partners had association in the GZ cohort. Conclusions/Significance: Our study provides the current status and the epidemiological characteristics of HPV prevalence in Southern Chinese women. The results strongly suggested that population education and the effective cervical cancer screening would be vital in the prevention of cervical cancer. © 2011 Liu et al.published_or_final_versio

hnRNP I Inhibits Notch Signaling and Regulates Intestinal Epithelial Homeostasis in the Zebrafish

Regulated intestinal stem cell proliferation and differentiation are required for normal intestinal homeostasis and repair after injury. The Notch signaling pathway plays fundamental roles in the intestinal epithelium. Despite the fact that Notch signaling maintains intestinal stem cells in a proliferative state and promotes absorptive cell differentiation in most species, it remains largely unclear how Notch signaling itself is precisely controlled during intestinal homeostasis. We characterized the intestinal phenotypes of brom bones, a zebrafish mutant carrying a nonsense mutation in hnRNP I. We found that the brom bones mutant displays a number of intestinal defects, including compromised secretory goblet cell differentiation, hyperproliferation, and enhanced apoptosis. These phenotypes are accompanied by a markedly elevated Notch signaling activity in the intestinal epithelium. When overexpressed, hnRNP I destabilizes the Notch intracellular domain (NICD) and inhibits Notch signaling. This activity of hnRNP I is conserved from zebrafish to human. In addition, our biochemistry experiments demonstrate that the effect of hnRNP I on NICD turnover requires the C-terminal portion of the RAM domain of NICD. Our results demonstrate that hnRNP I is an evolutionarily conserved Notch inhibitor and plays an essential role in intestinal homeostasis

Interaction of Pyrrolobenzodiazepine (PBD) Ligands with Parallel Intermolecular G-Quadruplex Complex Using Spectroscopy and ESI-MS

Studies on ligand interaction with quadruplex DNA, and their role in stabilizing the complex at concentration prevailing under physiological condition, has attained high interest. Electrospray ionization mass spectrometry (ESI-MS) and spectroscopic studies in solution were used to evaluate the interaction of PBD and TMPyP4 ligands, stoichiometry and selectivity to G-quadruplex DNA. Two synthetic ligands from PBD family, namely pyrene-linked pyrrolo[2,1-c][1,4]benzodiazepine hybrid (PBD1), mixed imine-amide pyrrolobenzodiazepine dimer (PBD2) and 5,10,15,20-tetrakis(N-methyl-4-pyridyl)porphyrin (TMPyP4) were studied. G-rich single-stranded oligonucleotide d(5′GGGGTTGGGG3′) designated as d(T2G8), from the telomeric region of Tetrahymena Glaucoma, was considered for the interaction with ligands. ESI-MS and spectroscopic methods viz., circular dichroism (CD), UV-Visible, and fluorescence were employed to investigate the G-quadruplex structures formed by d(T2G8) sequence and its interaction with PBD and TMPyP4 ligands. From ESI-MS spectra, it is evident that the majority of quadruplexes exist as d(T2G8)2 and d(T2G8)4 forms possessing two to ten cations in the centre, thereby stabilizing the complex. CD band of PBD1 and PBD2 showed hypo and hyperchromicity, on interaction with quadruplex DNA, indicating unfolding and stabilization of quadruplex DNA complex, respectively. UV-Visible and fluorescence experiments suggest that PBD1 bind externally where as PBD2 intercalate moderately and bind externally to G-quadruplex DNA. Further, melting experiments using SYBR Green indicate that PBD1 unfolds and PBD2 stabilizes the G-quadruplex complex. ITC experiments using d(T2G8) quadruplex with PBD ligands reveal that PBD1 and PBD2 prefer external/loop binding and external/intercalative binding to quadruplex DNA, respectively. From experimental results it is clear that the interaction of PBD2 and TMPyP4 impart higher stability to the quadruplex complex