The role of immunoglobulins and their transporters in urogenital Chlamydial infections

Chlamydia trachomatis infections of the male and female reproductive tracts are the world's leading sexually transmitted bacterial disease, and can lead to damaging pathology, scarring and infertility. The resolution of chlamydial infection requires the development of adaptive immune responses to infection, and includes cell-mediated and humoral immunity. Whilst cluster of differentiation (CD)4+ T cells are known to be essential in clearance of infection [1], they are also associated with immune cell infiltration, autoimmunity and infertility in the testes [2-3]. Conversely, antibodies are less associated with inflammation, are readily transported into the reproductive tracts, and can offer lumenal neutralization of chlamydiae prior to infection. Antibodies, or immunoglobulins (Ig), play a supportive role in the resolution of chlamydial infections, and this thesis sought to define the function of IgA and IgG, against a variety of chlamydial antigens expressed during the intracellular and extracellular stages of the chlamydial developmental cycle. Transport of IgA and IgG into the mucosal lumen is facilitated by receptor-mediated transcytosis yet the expression profile (under normal conditions and during urogenital chlamydial infection) of the polymeric immunoglobulin receptor (pIgR) and the neonatal Fc receptor (FcRn) remains unknown. The expression profile of pIgR and FcRn in the murine male reproductive tract was found to be polarized to the lower and upper reproductive tract tissues respectively. This demonstrates that the two receptors have a tissue tropism, which must be considered when targeting pathogens that colonize different sites. In contrast, the expression of pIgR and FcRn in the female mouse was found to be distributed in both the upper and lower reproductive tracts. When urogenitally infected with Chlamydia muridarum, both male and female reproductive tracts up-regulated expression of pIgR and down-regulated expression of FcRn. Unsurprisingly, the up-regulation of pIgR increased the concentration of IgA in the lumen. However, down-regulation of FcRn, prevented IgG uptake and led to an increase or pooling of IgG in lumenal secretions. As previous studies have identified the importance of pIgR-mediated delivery of IgA, as well as the potential of IgA to bind and neutralize intracellular pathogens, IgA against a variety of chlamydial antigens was investigated. The protection afforded by IgA against the extracellular antigen major outer membrane protein (MOMP), was found to be dependent on pIgR expression in vitro and in vivo. It was also found that in the absence of pIgR, no protection was afforded to mice previously immunized with MOMP. The protection afforded from polyclonal IgA against the intracellular chlamydial antigens; inclusion membrane protein A (IncA), inclusion membrane proteins (IncMem) and secreted chlamydial protease-like activity factor (CPAF) were produced and investigated in vitro. Antigen-specific intracellular IgA was found to bind to the respective antigen within the infected cell, but did not significantly reduce inclusion formation (p > 0.05). This suggests that whilst IgA specific for the selected antigens was transported by pIgR to the chlamydial inclusion, it was unable to prevent growth. Similarly, immunization of male mice with intracellular chlamydial antigens (IncA or IncMem), followed by depletion CD4+ T cells, and subsequent urogenital C. muridarum challenge, provided minimal pIgR-mediated protection. Wild type male mice immunized with IncA showed a 57 % reduction (p < 0.05), and mice deficient in pIgR showed a 35 % reduction (p < 0.05) in reproductive tract chlamydial burden compared to control antigen, and in the absence of CD4+ T cells. This suggests that pIgR and secretory IgA (SIgA) were playing a protective role (21 % pIgR-mediated) in unison with another antigen-specific immune mechanism (36 %). Interestingly, IgA generated during a primary respiratory C. muridarum infection did not provide a significant amount of protection to secondary urogenital C. muridarum challenge. Together, these data suggest that IgA specific for an extracellular antigen (MOMP) can play a strong protective role in chlamydial infections, and that IgA targeting intracellular antigens is also effective but dependent on pIgR expression in tissues. However, whilst not investigated here, IgA targeting and blocking other intracellular chlamydial antigens, that are more essential for replication or type III secretion, may be more efficacious in subunit vaccines. Recently, studies have demonstrated that IgG can neutralize influenza virus by trafficking IgG-bound virus to lysosomes [4]. We sought to determine if this process could also traffic chlamydial antigens for degradation by lysosomes, despite Chlamydia spp. actively inhibiting fusion with the host endocytic pathway. As observed in pIgR-mediated delivery of anti-IncA IgA, FcRn similarly transported IgG specific for IncA which bound the inclusion membrane. Interestingly, FcRn-mediated delivery of anti-IncA IgG significantly decreased inclusion formation by 36 % (p < 0.01), and induced aberrant inclusion morphology. This suggests that unlike IgA, IgG can facilitate additional host cellular responses which affect the intracellular niche of chlamydial growth. Fluorescence microscopy revealed that IgG also bound the inclusion, but unlike influenza studies, did not induce the recruitment of lysosomes. Notably, anti-IncA IgG recruited sequestosomes to the inclusion membrane, markers of the ubiquitin/proteasome pathway and major histocompatibility complex (MHC) class I loading. To determine if the protection against C. muridarum infection afforded by IncA IgG in vitro translated in vivo, wild type mice and mice deficient in functional FcRn and MHC-I, were immunized, depleted of CD4+, and urogenitally infected with C. muridarum. Unlike in pIgR-deficient mice, the protection afforded from IncA immunization was completely abrogated in mice lacking functional FcRn and MHC-I/CD8+. Thus, both anti-IncA IgA and IgG can bind the inclusion in a pIgR and FcRn-mediated manner, respectively. However, only IgG mediates a higher reduction in chlamydial infection in vitro and in vivo suggesting more than steric blocking of IncA had occurred. Unlike anti-MOMP IgA, which reduced chlamydial infection of epithelial cells and male mouse tissues, IgG was found to enhance infectivity in vitro, and in vivo. Opsonization of EBs with MOMP-IgG enhanced inclusion formation of epithelial cells in a MOMP-IgG dose-dependent and FcRn-dependent manner. When MOMP-IgG opsonized EBs were inoculated into the vagina of female mice, a small but non-significant (p > 0.05) enhancement of cervicovaginal C. muridarum shedding was observed three days post infection in mice with functional FcRn. Interestingly, infection with opsonized EBs reduced the intensity of the peak of infection (day six) but protracted the duration of infection by 60 % in wild type mice only. Infection with EBs opsonized in IgG also significantly increased (p < 0.05) hydrosalpinx formation in the oviducts and induced lymphocyte infiltration uterine horns. As MOMP is an immunodominant antigen, and is widely used in vaccines, the ability of IgG specific to extracellular chlamydial antigens to enhance infection and induce pathology needs to be considered. Together, these data suggest that immunoglobulins play a dichotomous role in chlamydial infections, and are dependent on antigen specificity, FcRn and pIgR expression. FcRn was found to be highly expressed in upper male reproductive tract, whilst pIgR was dominantly expressed in the lower reproductive tract. Conversely, female mice expressed FcRn and pIgR in both the lower and upper reproductive tracts. In response to a normal chlamydial infection, pIgR is up-regulated increasing secretory IgA release, but FcRn is down-regulated preventing IgG uptake. Similarly to other studies [5-6], we demonstrate that IgA and IgG generated during primary chlamydial infections plays a minor role in recall immunity, and that antigen-specific subunit vaccines can offer more protection. We also show that both IgA and IgG can be used to target intracellular chlamydial antigens, but that IgG is more effective. Finally, IgA against the extracellular antigen MOMP can afford protection, whist IgG plays a deleterious role by increasing infectivity and inducing damaging immunopathology. Further investigations with additional antigens or combination subunit vaccines will enhance our understanding the protection afforded by antibodies against intracellular and extracellular pathogenic antigens, and help improve the development of an efficacious chlamydial vaccine.

In the wake of the war canoe ; a stirring record of forty years' successful labour, peril & adventure amongst the savage Indian tribes of the Pacific coast, and the piratical headhunting Haidas of the Queen Charlotte Islands, B.C., with an introduction by the Lord Bishop of Derry.

http://www.archive.org/details/inwakeofwarcanoe00collrich

Early promoted : a memoir of the Rev. William Spiller Cox by Edward W Cox

http://www.archive.org/details/earlypromotedame00coxwuoft

The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection):a randomised placebo-controlled trial

Lowering LDL cholesterol with statin regimens reduces the risk of myocardial infarction, ischaemic stroke, and the need for coronary revascularisation in people without kidney disease, but its effects in people with moderate-to-severe kidney disease are uncertain. The SHARP trial aimed to assess the efficacy and safety of the combination of simvastatin plus ezetimibe in such patients.

Serial chimerism analyses indicate that mixed haemopoietic chimerism influences the probability of graft rejection and disease recurrence following allogeneic stem cell transplantation (SCT) for severe aplastic anaemia (SAA): indication for routine assessment of chimerism post SCT for SAA

Ninety-one patients were studied serially for chimeric status following allogeneic stem cell transplantation (SCT) for severe aplastic anaemia (SAA) or Fanconi Anaemia (FA). Short tandem repeat polymerase chain reaction (STR-PCR) was used to stratify patients into five groups: (A) complete donor chimeras (n = 39), (B) transient mixed chimeras (n = 15) (C) stable mixed chimeras (n = 18), (D) progressive mixed chimeras (n = 14) (E) recipient chimeras with early graft rejection (n = 5). As serial sampling was not possible in Group E, serial chimerism results for 86 patients were available for analysis. The following factors were analysed for association with chimeric status: age, sex match, donor type, aetiology of aplasia, source of stem cells, number of cells engrafted, conditioning regimen, graft-versus-host disease (GvHD) prophylaxis, occurrence of acute and chronic GvHD and survival. Progressive mixed chimeras (PMCs) were at high risk of late graft rejection (n = 10, P <0.0001). Seven of these patients lost their graft during withdrawal of immunosuppressive therapy. STR-PCR indicated an inverse correlation between detection of recipient cells post-SCT and occurrence of acute GvHD (P = 0.008). PMC was a bad prognostic indicator of survival (P = 0.003). Monitoring of chimeric status during cyclosporin withdrawal may facilitate therapeutic intervention to prevent late graft rejection in patients transplanted for SAA.

Effect of post-weld-annealing on the tensile deformation characteristics of laser-welded NiTi thin foil

Laser welding is an important process for fabricating complex components involving NiTi shape memory
alloy. As welding is a thermal process, the amount of heat input and the rate of cooling have significant
impact on the microstructure and hence the resultant characteristics of NiTi. In this study, the effect of
laser welding and post-weld-annealing from 573 K to 1173 K on the thermal phase transformation behaviors,
tensile deformation and micro-hardness characteristics of the laser-welded NiTi thin foils were investigated.
It was found that the as-welded sample exhibited inferior super-elasticity compared to the base
material, and the super-elasticity could be partially restored by annealing at 573 K. On the other hand,
annealing of the weldment above the recrystallization temperature would lower the super-elasticity.

Effect of post-weld heat-treatment on the oxide film and corrosion behaviour of laser-welded shape memory NiTi wires

Post-weld heat-treatment (PWHT) was applied to NiTi weldments to improve the corrosion behaviour by modifying the microstructure and surface composition. The surface oxide film on the weldments is principally TiO2, together with some Ti, TiO, and Ti2O3. The surface Ti/Ni ratio of the weldments after PWHT is increased. The oxide film formed in Hanks’ solution is thicker on the weldments after PWHT. The pitting resistance of the weldments is increased by PWHT. The galvanic effect in the weldments is very small. The weldment with PWHT at 350 °C shows the best corrosion resistance among other heat-treated weldments in this study.

Reduction of environmentally induced cracking of laser-welded shape memory NiTi wires via post-weld heat-treatment

In this study, the environmentally induced cracking behaviour of the NiTi weldment with and without post-weld heat-treatment (PWHT) in Hanks’ solution at 37.5 °C at OCP were studied by tensile and cyclic slow-strain-rate tests (SSRT), and compared with those tested in oil (an inert environment). Our previous results in the tensile and cyclic SSRT showed that the weldment without PWHT showed high susceptibility to the hydrogen cracking, as evidenced by the degradation of tensile and super-elastic properties when testing in Hanks' solution. The weldment after PWHT was much less susceptible to hydrogen attack in Hanks' solution as no obvious degradation in the tensile and super-elastic properties was observed, and only a very small amount of micro-cracks were found in the fracture surface. The susceptibility to hydrogen cracking of the NiTi weldment could be alleviated by applying PWHT at the optimized temperature of 350 °C after laser welding.

Genome scan meta-analysis of schizophrenia and bipolar disorder, part II:Schizophrenia

Schizophrenia is a common disorder with high heritability and a 10-fold increase in risk to siblings of probands. Replication has been inconsistent for reports of significant genetic linkage. To assess evidence for linkage across studies, rank-based genome scan meta-analysis (GSMA) was applied to data from 20 schizophrenia genome scans. Each marker for each scan was assigned to 1 of 120 30-cM bins, with the bins ranked by linkage scores (1 = most significant) and the ranks averaged across studies (R(avg)) and then weighted for sample size (N(sqrt)[affected casess]). A permutation test was used to compute the probability of observing, by chance, each bin's average rank (P(AvgRnk)) or of observing it for a bin with the same place (first, second, etc.) in the order of average ranks in each permutation (P(ord)). The GSMA produced significant genomewide evidence for linkage on chromosome 2q (PAvgRnk

Effect of Post-weld Heat-treatment on the Stress Corrosion Cracking Behaviour of Laser-welded Shape Memory NiTi Wires in Hanks’ Solution

In this study, the stress-corrosion cracking (SCC) behaviour of laser-welded NiTi wires before and after post-weld heat-treatment (PWHT) was investigated. The samples were subjected to slow strain rate testing (SSRT) under tensile loading in Hanks’ solution at 37.5 °C (or 310.5 K) at a constant anodic potential (200 mVSCE). The current density of the samples during the SSRT was captured by a potentiostat, and used as an indicator to determine the susceptibility to SCC. Fractography was analyzed using scanning-electron microscopy (SEM). The experimental results showed that the laser-welded sample after PWHT was immune to the SCC as evidenced by the stable current density throughout the SSRT. This is attributed to the precipitation of fine and coherent nano-sized Ni4Ti3 precipitates in the welded regions (weld zone, WZ and heat-affected zone, HAZ) after PWHT, resulting in (i) enrichment of TiO2 content in the passive film and (ii) higher resistance against the local plastic deformation in the welded regions.

Herschel key program HERITAGE:A far-infrared source catalog for the Magellanic Clouds

Observations from the HERschel Inventory of the Agents of Galaxy Evolution (HERITAGE ) have been used to identify dusty populations of sources in the Large and Small Magellanic Clouds (LMC and SMC). We conducted the study using the HERITAGE catalogs of point sources available from the Herschel Science Center from both the Photodetector Array Camera and Spectrometer (PACS; 100 and 160 μm) and Spectral and Photometric Imaging Receiver (SPIRE; 250, 350, and 500 μm) cameras. These catalogs are matched to each other to create a Herschel band-merged catalog and then further matched to archival Spitzer IRAC and MIPS catalogs from the Spitzer Surveying the Agents of Galaxy Evolution (SAGE) and SAGE-SMC surveys to create single mid- to far-infrared (far-IR) point source catalogs that span the wavelength range from 3.6 to 500 μm. There are 35,322 unique sources in the LMC and 7503 in the SMC. To be bright in the FIR, a source must be very dusty, and so the sources in the HERITAGE catalogs represent the dustiest populations of sources. The brightest HERITAGE sources are dominated by young stellar objects (YSOs), and the dimmest by background galaxies. We identify the sources most likely to be background galaxies by first considering their morphology (distant galaxies are point-like at the resolution of Herschel) and then comparing the flux distribution to that of the Herschel Astrophysical Terahertz Large Area Survey (ATLAS ) survey of galaxies. We find a total of 9745 background galaxy candidates in the LMC HERITAGE images and 5111 in the SMC images, in agreement with the number predicted by extrapolating from the ATLAS flux distribution. The majority of the Magellanic Cloud-residing sources are either very young, embedded forming stars or dusty clumps of the interstellar medium. Using the presence of 24 μm emission as a tracer of star formation, we identify 3518 YSO candidates in the LMC and 663 in the SMC. There are far fewer far-IR bright YSOs in the SMC than the LMC due to both the SMC's smaller size and its lower dust content. The YSO candidate lists may be contaminated at low flux levels by background galaxies, and so we differentiate between sources with a high ("probable") and moderate ("possible ") likelihood of being a YSO. There are 2493/425 probable YSO candidates in the LMC/SMC. Approximately 73% of the Herschel YSO candidates are newly identified in the LMC, and 35% in the SMC. We further identify a small population of dusty objects in the late stages of stellar evolution including extreme and post-asymptotic giant branch, planetary nebulae, and supernova remnants. These populations are identified by matching the HERITAGE catalogs to lists of previously identified objects in the literature. Approximately half of the LMC sources and one quarter of the SMC sources are too faint to obtain accurate ample FIR photometry and are unclassified.

Campaign speech of W.D. Mayfield [for re-election as State Superintendent of Education]

This speech was given by Mr. Mayfield while running for re-election to the office of State Superintendent of Education. He gives evidence and reasons that he should be re-elected. He also talks about his future plans for if he does get re-elected.

Letters to Reverend William Proudfoot, 1823, 1842-1843, 1846

A 2 ½ page letter addressed to The Editor of the Presbyterian Magazine, care of [illegible], London, C.W. The writer describes the Village of Chippawa and its location in Ontario. He writes that there are many people there of Scotch [Scottish] descent. He says that a congregation was formed and 39 names were on the roll. The letter is from J.P. [John Porteous] with an added note from Wm. Porteous. The letter is from St. Catharines. There is one postmark – St. Catharines, April 6, 1823 A 1 ½ page letter addressed to Rev. W. Proudfoot, Ed. Of Presbyterian Mag., London, C.W. This letter is from Walter Mitchell in St. Catharines. He sends a list of peoples’ names and the amounts that they have paid toward the Presbyterian Magazine. Mr. Mitchell is acting as an agent for the magazine. This letter has 1 postmark – St. Catharines, Sept. 13, 1842 A 2 page letter addressed to Rev. W. Proudfoot, London, C.W. This letter is from John Jennings of St. Catharines. The writer claims that he is ill but he makes plans to meet Reverend Proudfoot in Toronto in order to go to a meeting in Rochester. The writer expects that Reverend Proudfoot will preach in Rochester. The letter has 1 postmark – St. Catharines, Aug. 14, 1843. A 2 page letter addressed to The Rev. Professor Proudfoot, London, C.W. from John Porteaus of St. Catharines. The writer says that he will not preach in Detroit. He says that the people of Detroit are expecting Mr. Dalrymple [who was sent as a missionary to Canada from Scotland in 1846] and also, he doesn’t want to leave his congregation for 2 Sabbaths. The letter has 2 postmarks – St. Catharines, August 1846 [this postmark is very faint] and Hamilton, August 2, 1846.