Enhanced upper genital tract pathologies by blocking Tim-3 and PD-L1 signaling pathways in mice intravaginally infected with Chlamydia muridarum

<p>Abstract</p> <p>Background</p> <p>Although Tim-3 & PD-L1 signaling pathways play important roles in negatively regulating immune responses, their roles in chlamydial infection have not been evaluated.</p> <p>Methods</p> <p>Neutralization antibodies targeting Tim-3 and PD-L1 were used to treat mice. Following an intravaginal infection with <it>C. muridarum </it>organisms, mice with or without the dual antibody treatment were compared for live chlamydial organism shedding from the lower genital tract and inflammatory pathology in the upper genital tract.</p> <p>Results</p> <p>Mice treated with anti-Tim-3 and anti-PD-L1 antibodies displayed a time course of live organism shedding similar to that of mice treated with equivalent amounts of isotype-matched IgG molecules. The combined antibody blocking failed to alter either the lower genital tract cytokine or systemic humoral and cellular adaptive responses to <it>C. muridarum </it>infection. However, the antibody blocking significantly enhanced <it>C. muridarum</it>-induced pathologies in the upper genital tract, including more significant hydrosalpinx and inflammatory infiltration in uterine horn and oviduct tissues.</p> <p>Conclusions</p> <p>The Tim-3 and PD-L1-mediated signaling can significantly reduce pathologies in the upper genital tract without suppressing immunity against chlamydial infection, suggesting that Tim-3 and PD-L1-mediated negative regulation may be manipulated to attenuate tubal pathologies in women persistently infected with <it>C. trachomatis </it>organisms.</p

Using virtual reality in criminological research

Since the pioneering early studies of the 1990s hinted at its promise as a research method, virtual reality (VR) technology has increasingly been used by social scientists. Given recent developments that have greatly enhanced realism, reduced costs, and increased possibilities for application, VR seems well on its way to become an established research tool in the social sciences. However, as with other ethodological innovations, the field of criminology hasbeen slow to catch on. To address this gap, this article explores the potential of VR as a tool for crime research. It provides readers with a brief and non-technical description of VR and its main elements and reviews severalapplications of VR in social scientific research that are potentially relevant for criminologists. By way of illustration, we identify and discuss in more detail different areas in which we think the field of criminology can particularly benefit from VR and offer suggestions for research. Some of the equipment available on the consumer market is also reviewed.In conjunction, the different sections should equip readers interested in applying VR in their own research with a fundamental understanding of what it entails and how it can be applied

Age-Related Comparisons of Evolution of the Inflammatory Response After Intracerebral Hemorrhage in Rats

In the hours to days after intracerebral hemorrhage (ICH), there is an inflammatory response within the brain characterized by the infiltration of peripheral neutrophils and macrophages and the activation of brain-resident microglia and astrocytes. Despite the strong correlation of aging and ICH incidence, and increasing information about cellular responses, little is known about the temporal- and age-related molecular responses of the brain after ICH. Here, we monitored a panel of 27 genes at 6 h and 1, 3, and 7 days after ICH was induced by injecting collagenase into the striatum of young adult and aged rats. Several molecules (CR3, TLR2, TLR4, IL-1β, TNFα, iNOS, IL-6) were selected to reflect the classical activation of innate immune cells (macrophages, microglia) and the potential to exacerbate inflammation and damage brain cells. Most of the others are associated with the resolution of innate inflammation, alternative pathways of macrophage/microglial activation, and the repair phase after acute injury (TGFβ, IL-1ra, IL-1r2, IL-4, IL-13, IL-4Rα, IL-13Rα1, IL-13Rα2, MRC1, ARG1, CD163, CCL22). In young animals, the up-regulation of 26 in 27 genes (not IL-4) was detected within the first week. Differences in timing or levels between young and aged animals were detected for 18 of 27 genes examined (TLR2, GFAP, IL-1β, IL-1ra, IL-1r2, iNOS, IL-6, TGFβ, MMP9, MMP12, IL-13, IL-4Rα, IL-13Rα1, IL-13Rα2, MRC1, ARG1, CD163, CCL22), with a generally less pronounced or delayed inflammatory response in the aged animals. Importantly, within this complex response to experimental ICH, the induction of pro-inflammatory, potentially harmful mediators often coincided with resolving and beneficial molecules

C. elegans Agrin Is Expressed in Pharynx, IL1 Neurons and Distal Tip Cells and Does Not Genetically Interact with Genes Involved in Synaptogenesis or Muscle Function

Agrin is a basement membrane protein crucial for development and maintenance of the neuromuscular junction in vertebrates. The C. elegans genome harbors a putative agrin gene agr-1. We have cloned the corresponding cDNA to determine the primary structure of the protein and expressed its recombinant fragments to raise specific antibodies. The domain organization of AGR-1 is very similar to the vertebrate orthologues. C. elegans agrin contains a signal sequence for secretion, seven follistatin domains, three EGF-like repeats and two laminin G domains. AGR-1 loss of function mutants did not exhibit any overt phenotypes and did not acquire resistance to the acetylcholine receptor agonist levamisole. Furthermore, crossing them with various mutants for components of the dystrophin-glycoprotein complex with impaired muscle function did not lead to an aggravation of the phenotypes. Promoter-GFP translational fusion as well as immunostaining of worms revealed expression of agrin in buccal epithelium and the protein deposition in the basal lamina of the pharynx. Furthermore, dorsal and ventral IL1 head neurons and distal tip cells of the gonad arms are sources of agrin production, but no expression was detectable in body muscles or in the motoneurons innervating them. Recombinant worm AGR-1 fragment is able to cluster vertebrate dystroglycan in cultured cells, implying a conservation of this interaction, but since neither of these proteins is expressed in muscle of C. elegans, this interaction may be required in different tissues. The connections between muscle cells and the basement membrane, as well as neuromuscular junctions, are structurally distinct between vertebrates and nematodes

Current management of the gastrointestinal complications of systemic sclerosis.

Systemic sclerosis is a multisystem autoimmune disorder that involves the gastrointestinal tract in more than 90% of patients. This involvement can extend from the mouth to the anus, with the oesophagus and anorectum most frequently affected. Gut complications result in a plethora of presentations that impair oral intake and faecal continence and, consequently, have an adverse effect on patient quality of life, resulting in referral to gastroenterologists. The cornerstones of gastrointestinal symptom management are to optimize symptom relief and monitor for complications, in particular anaemia and malabsorption. Early intervention in patients who develop these complications is critical to minimize disease progression and improve prognosis. In the future, enhanced therapeutic strategies should be developed, based on an ever-improving understanding of the intestinal pathophysiology of systemic sclerosis. This Review describes the most commonly occurring clinical scenarios of gastrointestinal involvement in patients with systemic sclerosis as they present to the gastroenterologist, with recommendations for the suggested assessment protocol and therapy in each situation

The peculiar motions of early-type galaxies in two distant regions .1. Cluster and galaxy selection

The EFAR project is a study of 736 candidate elliptical galaxies in 84 clusters lying in two regions, toward Hercules-Corona Borealis and Perseus-Pisces-Cetus, at distances cz ≈ 6000-15,000 km s-1. In this paper (the first of a series), we present an introduction to the EFAR project and describe in detail the selection of the clusters and galaxies in our sample. Fundamental data for the galaxies and clusters are given, including accurate new positions for each galaxy and redshifts for each cluster. The galaxy selection functions are determined by using diameters measured from Schmidt sky survey images for 2185 galaxies in the cluster fields. Future papers in this series will present the spectroscopic and photometric observations of this sample, investigate the properties of the fundamental plane for elliptical galaxies, and determine the large-scale peculiar velocity fields in these two regions of the universe

The peculiar motions of early-type galaxies in two distant regions - III. The photometric data

We present R-band CCD photometry for 776 galaxies observed in the EFAR project. The photometry is compared with photoelectric data, showing that a common zero-point good to better than 1 per cent and a precision of 0.03 mag per zero-point have been achieved. We give the circularly averaged surface brightness profiles and the photometric parameters of the 762 programme galaxies, D n diameters (at 20.5 mag arcsec -2), half-luminosity radii R e, total magnitudes m T and average effective surface brightnesses 〈SB e〉. The photometric parameters are derived using the seeing-convolved, R 1/4-plus-exponential fitting algorithm described in Paper IV which optimally combines multiple profiles and corrects for sky subtraction errors. The parameters of the two-component fits are also given. We find that the diameters D n span the range 4.8-90 arcsec, with 〈logD n〉 = 1.30 or 20 arcsec. The run of the effective radii R e is 1.6-71.2 arcsec, with 〈log R e〉 = 0.84 or 6.9 arcsec. The total magnitudes m T extend from 10.57 to 15.97 mag, with a mean of 13.85 mag. The effective surface brightnesses 〈SB e〉 span the range 17.78-22.35 mag arcsec -2 with a mean of 19.89 mag arcsec -2. The mean photometric precisions of D n diameters, magnitudes and surface brightnesses are 0.9 per cent, 0.017 mag and 0.017 mag arcsec -2 respectively. In addition, the fitting scheme quantifies and minimizes the many systematic biases affecting the determination of galaxy photometric parameters. We find simple R 1/4 fits for only 14 per cent of the total, and simple exponential fits for ≉ 1 per cent of the total. The spread in sky values measured from the different profiles of the same object is less than 1 per cent in 85 per cent of the cases. In 80 per cent of the fits a reduced χ 2 of less than 12 is obtained. More than 90 per cent of the galaxies have at least one profile extending to more than 4 half-luminosity radii. More than 90 per cent of the galaxies are well resolved, having at least one profile where R e > 2Γ, where Γ is the FWHM of the point-spread function. More than 80 per cent of the profiles have a global signal-to-noise ratio larger than 300. The extrapolation needed to derive total magnitudes is less than 10 per cent for 80 per cent of the fits. More than 80 per cent of the galaxies have mean effective surface brightness larger than the observed sky brightness. In 90 per cent of the profiles the estimate of the contamination of the sky by the galaxy light is less than 1 per cent. Summarizing, the extensive internal comparisons, together with Monte Carlo simulations (see Paper IV), show that we derive total magnitudes and half-luminosity radii to better than 0.15 mag and 25 per cent respectively for 90 per cent of our sample. In contrast, external comparisons show that data in the literature can be strongly affected by systematic errors due to large extrapolations, small radial range, sky subtraction errors, seeing effects, and the use of a simple R 1/4 fit. The resulting errors can easily amount to more than 0.5 mag in the total magnitudes and 50 per cent in the half-luminosity radii. The errors on the combined quantity FP = log R e - 0.3 〈SB e〉 which enters the Fundamental Plane equation remain, however, always smaller than 0.03 dex. The galaxy type classification, based on all of the information available to us, shows that 31 per cent of the sample objects, visually selected from photographic images to be of early type, are in fact spiral or barred galaxies. The 69 per cent of galaxies classified as early-type can be subdivided into cD (8 per cent), E (12 per cent with a simple R 1/4 law best fit), and E/S0 (48 per cent with a disc-plus-bulge best fit). The photographic diameters D W measured in Paper I correlate with D n diameters or, equivalently, with the Fundamental Plane quantity FP = log R e - 0.3 〈SB e〉, with 23 per cent scatter for the early-type sample. © 1997 RAS