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111.
Streptococcus pneumoniae (the pneumococcus) colonizes the human nasopharynx and is a significant pathogen worldwide. Pneumolysin (Ply) is a multi-functional, extracellular virulence factor produced by this organism that is critical for pathogenesis. Despite the absence of any apparent secretion or cell surface attachment motifs, Ply localizes to the cell envelope of actively growing cells. We sought to characterize the consequences of this surface localization. Through functional assays with whole cells and subcellular fractions, we determined that Ply activity and its release into the extracellular environment are inhibited by peptidoglycan (PG) structure. The ability of PG to inhibit Ply release was dependent on the stem peptide composition of this macromolecule, which was manipulated by mutation of the murMN operon that encodes proteins responsible for branched stem peptide synthesis. Additionally, removal of choline-binding proteins from the cell surface significantly reduced Ply release to levels observed in a mutant with a high proportion of branched stem peptides suggesting a link between this structural feature and surface-associated choline-binding proteins involved in PG metabolism. Of clinical relevance, we also demonstrate that a hyperactive, mosaic murMN allele associated with penicillin resistance causes decreased Ply release with concomitant increases in the amount of branched stem peptides. Finally, using a murMN deletion mutant, we observed that increased Ply release is detrimental to virulence during a murine model of pneumonia. Taken together, our results reveal a novel role for branched stem peptides in pneumococcal pathogenesis and demonstrate the importance of controlled Ply release during infection. These results highlight the importance of PG composition in pathogenesis and may have broad implications for the diverse PG structures observed in other bacterial pathogens. 相似文献
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113.
Deysi V. T. Wong Roberto C. P. Lima-Júnior Cibele B. M. Carvalho Vanessa F. Borges Carlos W. S. Wanderley Amanda X. C. Bem Caio A. V. G. Leite Maraiza A. Teixeira Gabriela L. P. Batista Rangel L. Silva Thiago M. Cunha Gerly A. C. Brito Paulo R. C. Almeida Fernando Q. Cunha Ronaldo A. Ribeiro 《PloS one》2015,10(10)
Intestinal mucositis is a common side effect of irinotecan-based anticancer regimens. Mucositis causes cell damage, bacterial/endotoxin translocation and production of cytokines including IL–1 and IL–18. These molecules and toll-like receptors (TLRs) activate a common signaling pathway that involves the Myeloid Differentiation adaptor protein, MyD88, whose role in intestinal mucositis is unknown. Then, we evaluated the involvement of TLRs and MyD88 in the pathogenesis of irinotecan-induced intestinal mucositis. MyD88-, TLR2- or TLR9-knockout mice and C57BL/6 (WT) mice were given either saline or irinotecan (75 mg/kg, i.p. for 4 days). On day 7, animal survival, diarrhea and bacteremia were assessed, and following euthanasia, samples of the ileum were obtained for morphometric analysis, myeloperoxidase (MPO) assay and measurement of pro-inflammatory markers. Irinotecan reduced the animal survival (50%) and induced a pronounced diarrhea, increased bacteremia, neutrophil accumulation in the intestinal tissue, intestinal damage and more than twofold increased expression of MyD88 (200%), TLR9 (400%), TRAF6 (236%), IL–1β (405%), IL–18 (365%), COX–2 (2,777%) and NF-κB (245%) in the WT animals when compared with saline-injected group (P<0.05). Genetic deletion of MyD88, TLR2 or TLR9 effectively controlled the signs of intestinal injury when compared with irinotecan-administered WT controls (P<0.05). In contrast to the MyD88-/- and TLR2-/- mice, the irinotecan-injected TLR9-/- mice showed a reduced survival, a marked diarrhea and an enhanced expression of IL–18 versus irinotecan-injected WT controls. Additionally, the expression of MyD88 was reduced in the TLR2-/- or TLR9-/- mice. This study shows a critical role of the MyD88-mediated TLR2 and TLR9 signaling in the pathogenesis of irinotecan-induced intestinal mucositis. 相似文献
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115.
Ricardo Filipe Alves Costa Adhemar Longatto-Filho Céline Pinheiro Luiz Carlos Zeferino José Humberto Fregnani 《PloS one》2015,10(9)
Background
The Cervical Cancer Database of the Brazilian National Health Service (SISCOLO) contains information regarding all cervical cytological tests and, if properly explored, can be used as a tool for monitoring and managing the cervical cancer screening program. The aim of this study was to perform a historical analysis of the cervical cancer screening program in Brazil from 2006 to 2013.Material and Methods
The data necessary to calculate quality indicators were obtained from the SISCOLO, a Brazilian health system tool. Joinpoint analysis was used to calculate the annual percentage change.Results
We observed important trends showing decreased rates of low-grade squamous intraepithelial lesions (LSIL) and high-grade squamous intraepithelial lesions (HSIL) and an increased rate of rejected exams from 2009 to 2013. The index of positivity was maintained at levels below those indicated by international standards; very low frequencies of unsatisfactory cases were observed over the study period, which partially contradicts the low rate of positive cases. The number of positive cytological diagnoses was below that expected, considering that developed countries with low frequencies of cervical cancer detect more lesions annually.Conclusions
The evolution of indicators from 2006 to 2013 suggests that actions must be taken to improve the effectiveness of cervical cancer control in Brazil. 相似文献116.
Michele Carbonelli Chiara La Morgia Giacomo Savini Maria Lucia Cascavilla Enrico Borrelli Filipe Chicani Carolina do V. F. Ramos Solange R. Salomao Vincenzo Parisi Jerry Sebag Francesco Bandello Alfredo A. Sadun Valerio Carelli Piero Barboni 《PloS one》2015,10(6)
Purpose
To investigate the thickness of the retinal layers and to assess the prevalence of macular microcysts (MM) in the inner nuclear layer (INL) of patients with mitochondrial optic neuropathies (MON).Methods
All patients with molecularly confirmed MON, i.e. Leber’s Hereditary Optic Neuropathy (LHON) and Dominant Optic Atrophy (DOA), referred between 2010 and 2012 were enrolled. Eight patients with MM were compared with two control groups: MON patients without MM matched by age, peripapillary retinal nerve fiber layer (RNFL) thickness, and visual acuity, as well as age-matched controls. Retinal segmentation was performed using specific Optical coherence tomography (OCT) software (Carl Zeiss Meditec). Macular segmentation thickness values of the three groups were compared by one-way analysis of variance with Bonferroni post hoc corrections.Results
MM were identified in 5/90 (5.6%) patients with LHON and 3/58 (5.2%) with DOA. The INL was thicker in patients with MON compared to controls regardless of the presence of MM [133.1±7μm vs 122.3±9μm in MM patients (p<0.01) and 128.5±8μm vs. 122.3±9μm in no-MM patients (p<0.05)], however the outer nuclear layer (ONL) was thicker in patients with MM (101.4±1mμ) compared to patients without MM [77.5±8mμ (p<0.001)] and controls [78.4±7mμ (p<0.001)]. ONL thickness did not significantly differ between patients without MM and controls.Conclusion
The prevalence of MM in MON is low (5-6%), but associated with ONL thickening. We speculate that in MON patients with MM, vitreo-retinal traction contributes to the thickening of ONL as well as to the production of cystic spaces. 相似文献117.
Flávio Teles Tarcilo Machado da Silva Francisco Pessoa da Cruz Júnior Vitor Hugo Honorato Henrique de Oliveira Costa Ana Paula Fernandes Barbosa Sabrina Gomes de Oliveira Zenaldo Porfírio Alexandre Braga Libório Raquel Lerner Borges Camilla Fanelli 《PloS one》2015,10(1)
The pathogenic role of inflammation and oxidative stress in chronic kidney disease (CKD) is well known. Anti-inflammatories and antioxidant drugs has demonstrated significant renoprotection in experimental nephropathies. Moreover, the inclusion of natural antioxidants derived from food and herbal extracts (such as polyphenols, curcumin and lycopene) as an adjuvant therapy for slowing CKD progression has been largely tested. Brazilian propolis is a honeybee product, whose anti-inflammatory, antimicrobial and antioxidant effects have been widely shown in models of sepsis, cancer, skin irritation and liver fibrosis. Furthermore, previous studies demonstrated that this compound promotes vasodilation and reduces hypertension. However, potential renoprotective effects of propolis in CKD have never been investigated. The aim of this study was to evaluate the effects of a subtype of Brazilian propolis, the Red Propolis (RP), in the 5/6 renal ablation model (Nx). Adult male Wistar rats underwent Nx and were divided into untreated (Nx) and RP-treated (Nx+RP) groups, after 30 days of surgery; when rats already exhibited marked hypertension and proteinuria. Animals were observed for 90 days from the surgery day, when Nx+RP group showed significant reduction of hypertension, proteinuria, serum creatinine retention, glomerulosclerosis, renal macrophage infiltration and oxidative stress, compared to age-matched untreated Nx rats, which worsened progressively over time. In conclusion, RP treatment attenuated hypertension and structural renal damage in Nx model. Reduction of renal inflammation and oxidative stress could be a plausible mechanism to explain this renoprotection. 相似文献
118.
Kazunari Kaizu Wiet de?Ronde Joris Paijmans Koichi Takahashi Filipe Tostevin Pieter?Rein ten?Wolde 《Biophysical journal》2014,106(4):976-985
Biological systems often have to measure extremely low concentrations of chemicals with high precision. When dealing with such small numbers of molecules, the inevitable randomness of physical transport processes and binding reactions will limit the precision with which measurements can be made. An important question is what the lower bound on the noise would be in such measurements. Using the theory of diffusion-influenced reactions, we derive an analytical expression for the precision of concentration estimates that are obtained by monitoring the state of a receptor to which a diffusing ligand can bind. The variance in the estimate consists of two terms, one resulting from the intrinsic binding kinetics and the other from the diffusive arrival of ligand at the receptor. The latter term is identical to the fundamental limit derived by Berg and Purcell (Biophys. J., 1977), but disagrees with a more recent expression by Bialek and Setayeshgar. Comparing the theoretical predictions against results from particle-based simulations confirms the accuracy of the resulting expression and reaffirms the fundamental limit established by Berg and Purcell. 相似文献
119.
Borges R Pereda D Beltrán B Prunell M Rodríguez M Machado JD 《Cellular and molecular neurobiology》2010,30(8):1359-1364
Chromaffin granules are similar organelles to the large dense core vesicles (LDCV) present in many secretory cell types including
neurons. LDCV accumulate solutes at high concentrations (catecholamines, 0.5–1 M; ATP, 120–300 mM; or Ca2+, 40 mM (Bulenda and Gratzl Biochemistry 24:7760–7765, 1985). Solutes seem to aggregate to a condensed matrix to elude osmotic lysis. The affinity of solutes for LDCV matrix is responsible
for the delayed release of catecholamines during exocytosis. The aggregation of solutes occurs due to a specific H+ pump denominated V-ATPase that maintains an inner acidic media (pH ≈5.5). This pH gradient against cytosol is also responsible
for the vesicular accumulation of amines and Ca2+. When this gradient is reduced by modulation of the V-ATPase activity, catecholamines and Ca2+ are moved toward the cytosol. In addition, some drugs largely accumulate inside LDCV and not only impair the accumulation
of natural solutes, but also act as false neurotransmitters when they are co-released with catecholamines. There is much experimental
evidence to conclude that the physiological modulation of vesicle pH and the manipulation of intravesicular media with drugs
affect the LDCV cargo and change the kinetics of exocytosis. Here, we will present some experimental data demonstrating the
participation of drugs in the kinetics of exocytosis through changes in the composition of vesicular media. We also offer
a model to explain the regulation of exocytosis by the intravesicular media that conciliate the experimentally obtained data. 相似文献
120.
Pereira F Carneiro J Matthiesen R van Asch B Pinto N Gusmão L Amorim A 《Nucleic acids research》2010,38(22):e203
The quest for a universal and efficient method of identifying species has been a longstanding challenge in biology. Here, we show that accurate identification of species in all domains of life can be accomplished by multiplex analysis of variable-length sequences containing multiple insertion/deletion variants. The new method, called SPInDel, is able to discriminate 93.3% of eukaryotic species from 18 taxonomic groups. We also demonstrate that the identification of prokaryotic and viral species with numeric profiles of fragment lengths is generally straightforward. A computational platform is presented to facilitate the planning of projects and includes a large data set with nearly 1800 numeric profiles for species in all domains of life (1556 for eukaryotes, 105 for prokaryotes and 130 for viruses). Finally, a SPInDel profiling kit for discrimination of 10 mammalian species was successfully validated on highly processed food products with species mixtures and proved to be easily adaptable to multiple screening procedures routinely used in molecular biology laboratories. These results suggest that SPInDel is a reliable and cost-effective method for broad-spectrum species identification that is appropriate for use in suboptimal samples and is amenable to different high-throughput genotyping platforms without the need for DNA sequencing. 相似文献