Recent thymic emigrants are the youngest subset of peripheral T cells and their involvement in combating persistent bacterial infections has not been explored. Here, we hypothesized that CD4+ recent ...thymic emigrants are essential immune mediators during persistent Salmonella infection. To test this, we thymectomized adult mice either prior to, or during, persistent Salmonella infection. We found that thymic output is crucial in the formation of protective immune responses during the early formation of a Salmonella infection but is dispensable once persistent Salmonella infection is established. Further, we show that thymectomized mice demonstrate increased infection-associated mortality and bacterial burdens. Unexpectedly, numbers of Salmonella-specific CD4+ T cells were significantly increased in thymectomized mice compared to sham control mice. Lastly, we found that T cells from thymectomized mice may be impaired in producing the effector cytokine IL-17 at early time points of infection, compared to thymically intact mice. Together, these results imply a unique role for thymic output in the formation of immune responses against a persistent, enteric pathogen.
Objective. The aim of our study was to evaluate the association between patellar alignment (using standard MRI images of extended knees) and MRI indices of patellofemoral (PF) osteoarthritis (OA) ...features. Methods. In this cross-sectional observational study, subjects were recruited to participate in the Boston Osteoarthritis of the Knee Study (BOKS). The association of patellar alignment patellar length ratio (PLR), sulcus angle (SA), lateral patellar tilt angle (LPTA) and bisect offset (BO) with measures of PF OA cartilage morphology and bone marrow lesion (BML) in the medial and lateral PF compartment were examined using a logistic regression model while adjusting for age, sex and BMI. Results. Study sample comprised 126 males (mean age 68.0, BMI 31.2) and 87 females (mean age 64.7, BMI 31.6). All measurements of patellar alignment were statistically significantly associated with cartilage morphology and BML in the lateral compartment of PF joint. PLR and SA were significantly associated with medial cartilage loss. With increasing PLR there was an increased prevalence of lateral and medial cartilage loss as well as of lateral BML. Increasing SA was positively associated with increased lateral and medial cartilage loss and lateral BML. LPTA range was negatively associated with lateral cartilage loss and BML. More laterally displaced patella (higher BO) was associated with increased lateral cartilage loss and BML. Conclusions. The results of our study clearly indicated that patellar alignment is associated with manifestations of PF OA such as cartilage thickness loss and BML.
A numerical imperfection study is carried out on a hot rolled tubular brace member under displacement controlled amplitudes. An appropriate range of global and local imperfections is used in the ...finite element analyses to evaluate the initial-post buckling compressive strength, lateral storey drift, energy dissipation and mid-length lateral deformation of the brace member. The purpose of this study is to assess the impact of the geometrical imperfection on the numerical performance, and to determine an amplitude range that can be used unequivocally for numerical modelling of brace members. It is shown that the amplitude of global imperfections has an effect on the initial response, whereas the amplitude of local imperfections has influence on the resistance capacity of the brace member at higher ductility level. Based on the results, a refined range of amplitude of global and local imperfections is proposed. This range is found to have a good agreement with design standards. In addition, an already established equation to find lateral deformation is compared to results from the analyses and found that the equation with some modification can be used accurately in design. In this paper, a modification factor is proposed in the equation to find the lateral deformation to account for the imperfection amplitude in the numerical analyses of brace members.
The lifespan and economic viability of tidal energy devices are constrained, in part, by the complex degradation of the tidal turbine blade materials due to prolonged immersion in a hostile sub-sea ...environment. Seawater penetration is a significant degradation mechanism in composite materials. This work aims to investigate the influence of microstructure and hydrostatic pressure on water absorption in four polymer composites which are candidate materials for use in tidal energy devices. These materials are: a glass fibre powder epoxy, a carbon fibre powder epoxy, glass fibre Ampreg epoxy and a chopped fibre glass fibre Polyether Ether Ketone. X-ray computed tomography is used to characterise the voids, resin-rich areas and other manufacturing defects present in each material. These defects are known to significantly alter the rate of moisture diffusion, as well as the total uptake of water at saturation. The samples are then exposed to accelerated water aging and hydrostatic pressurisation in order to simulate a range of expected sub-sea operating conditions. The material micro-structure, the matrix material and pressurisation level are shown to strongly influence both the moisture absorption rate and total water uptake. Significant volumetric changes are also noted for all samples, both during and after aging. X-ray computed tomography scans of specimens also provide a unique insight into the role of voids in storing water once a material has reached saturation.
Summary Objectives To examine whether categories of anatomic alignment (varus, neutral, valgus) measured from knee X-rays agree with similar categories of mechanical alignment from the full limb film ...and whether varus anatomic malalignment predicts medial joint space loss on knee X-rays as well as varus mechanical alignment. Methods We used data from the Osteoarthritis Initiative (OAI) (full limb and flexed knee X-rays) to examine agreement of anatomic and mechanical alignment and data from Boston Osteoarthritis of the Knee Study (BOKS) to evaluate the association of full limb mechanical alignment vs knee X-ray anatomic alignment with joint space loss. A 4° offset was used to correct for the more valgus angulation of the anatomic alignment. Results Of 143 subjects whose knee X-rays and full limb films were publicly released from the OAI, the agreement of varus, neutral and valgus alignment was only moderate ( κ = 0.43, P < 0.001). In BOKS, varus mechanical and anatomic alignments measured from full limb and knee X-rays respectively both predicted a high risk of medial joint space loss vs neutral alignment – for mechanical alignment, odds ratio (OR) = 4.82 95% confidence interval (CI) 1.93, 12.00 and for anatomic alignment OR = 4.25 (95% CI 2.08, 8.72). Conclusions While agreement of alignment from knee X-ray to full limb film was only moderate, varus malalignment measured from a flexed knee predicted the likelihood of progression well. Flexed knee alignment may be more relevant to knee osteoarthritis (OA) risk than that of a fully extended knee, but a measurement of alignment from a short limb is an imperfect surrogate for full limb alignment.
The intestinal epithelium constitutes an innate barrier which, upon injury, undergoes self-repair processes known as restitution. Although bile acids are known as important regulators of epithelial ...function in health and disease, their effects on wound healing processes are not yet clear. Here we set out to investigate the effects of the colonic bile acids, deoxycholic acid (DCA) and ursodeoxycholic acid (UDCA), on epithelial restitution. Wound healing in T
cell monolayers grown on transparent, permeable supports was assessed over 48 h with or without bile acids. Cell migration was measured in Boyden chambers. mRNA and protein expression were measured by RT-PCR and Western blotting. DCA (50-150 µM) significantly inhibited wound closure in cultured epithelial monolayers and attenuated cell migration in Boyden chamber assays. DCA also induced nuclear accumulation of the farnesoid X receptor (FXR), whereas an FXR agonist, GW4064 (10 µM), inhibited wound closure. Both DCA and GW4064 attenuated the expression of CFTR Cl
channels, whereas inhibition of CFTR activity with either CFTR-
-172 (10 µM) or GlyH-101 (25 µM) also prevented wound healing. Promoter/reporter assays revealed that FXR-induced downregulation of CFTR is mediated at the transcriptional level. In contrast, UDCA (50-150 µM) enhanced wound healing in vitro and prevented the effects of DCA. Finally, DCA inhibited and UDCA promoted mucosal healing in an in vivo mouse model. In conclusion, these studies suggest bile acids are important regulators of epithelial wound healing and are therefore good targets for development of new drugs to modulate intestinal barrier function in disease treatment. NEW & NOTEWORTHY The secondary bile acid, deoxycholic acid, inhibits colonic epithelial wound healing, an effect which appears to be mediated by activation of the nuclear bile acid receptor, FXR, with subsequent downregulation of CFTR expression and activity. In contrast, ursodeoxycholic acid promotes wound healing, suggesting it may provide an alternative approach to prevent the losses of barrier function that are associated with mucosal inflammation in IBD patients.
This work presents details of manufacturing and testing of a carbon fibre polyetheretherketone induction-welded hat-stiffened panel. Mechanical testing is carried out to evaluate the performance of ...the welded assembly and results are compared with similar testing of an adhesively bonded panel. The results show that the welded panel and the bonded panel had similar load-bearing capacity (<2% difference) and stiffness (<1% difference). Optical microscopy is used to verify the weld quality and identify manufacturing artefacts associated with induction welding. Inspection of the panel after welding shows that the induction welding process caused minor warpage, voids and delamination in the panel. The work addresses the lack of data relating to demonstrator scale welded assemblies in the literature, demonstrates that continuous induction welding is a suitable assembly technique for aerospace and automotive components under uniaxial in-plane compressive loading and identifies process-induced artefacts that may occur during induction welding.
The native rock pool mosquito, Aedes atropalpus (Coquillett), and the invasive Aedes japonicus (Theobald) have been found in many types of artificial and natural containers throughout North America. ...Little is known about the ecology of these two species in habitats where they co-occur, although multiple investigators have reported the decline of the native species concurrent with the introduction and spread of the invasive species. Here we report the results of riverine rock pool collections (n=503) in the southern Appalachian Mountains between 2009–2015. Surface water temperatures strongly predicted the presence of each species across a broad range of observed temperatures (11–39.8° C). For every unit of increase in temperature (°C) the odds of collecting Ae. atropalpus larvae increased by 0.34 while the odds of collecting Ae. japonicus larvae decreased by 0.28. No Ae. japonicus larvae or pupae were collected at temperatures greater than 36° C; however, immature Ae. atropalpus were found in rock pools with temperatures up to 39.8° C. In contrast, Ae. japonicus were highly abundant in cooler rock pools (<17° C) where Ae. atropalpus were infrequent or absent. Our findings suggest that in spite of the successful invasion by Ae. japonicus, Ae. atropalpus remains well established in the southern Appalachian Mountains. Given the strong correlation of temperature with the presence of the two species and the contrasting absence of each species at observed temperature extremes, the role of thermal conditions should be carefully explored in the context of other ecological factors likely influencing the range and abundance of these mosquitoes.
Intestinal epithelia are critical for maintaining gastrointestinal homeostasis. Epithelial barrier injury, causing inflammation and vascular damage, results in inflammatory hypoxia, and thus, healing ...occurs in an oxygen-restricted environment. The transcription factor hypoxia-inducible factor (HIF)-1 regulates genes important for cell survival and repair, including the cell adhesion protein β1-integrin. Integrins function as αβ-dimers, and α-integrin-matrix binding is critical for cell migration. We hypothesized that HIF-1 stabilization accelerates epithelial migration through integrin-dependent pathways. We aimed to examine functional and posttranslational activity of α-integrins during HIF-1-mediated intestinal epithelial healing. Wound healing was assessed in T84 monolayers over 24 h with/without prolyl-hydroxylase inhibitor (PHDi) (GB-004), which stabilizes HIF-1. Gene and protein expression were measured by RT-PCR and immunoblot, and α-integrin localization was assessed by immunofluorescence. α-integrin function was assessed by antibody-mediated blockade, and integrin α6 regulation was determined by HIF-1α chromatin immunoprecipitation. Models of mucosal wounding and 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis were used to examine integrin expression and localization in vivo. PHDi treatment accelerated wound closure and migration within 12 h, associated with increased integrin α2 and α6 protein, but not α3. Functional blockade of integrins α2 and α6 inhibited PHDi-mediated accelerated wound closure. HIF-1 bound directly to the integrin α6 promoter. PHDi treatment accelerated mucosal healing, which was associated with increased α6 immunohistochemical staining in wound-associated epithelium and wound-adjacent tissue. PHDi treatment increased α6 protein levels in colonocytes of TNBS mice and induced α6 staining in regenerating crypts and reepithelialized inflammatory lesions. Together, these data demonstrate a role for HIF-1 in regulating both integrin α2 and α6 responses during intestinal epithelial healing.
HIF-1 plays an important role in epithelial restitution, selectively inducing integrins α6 and α2 to promote migration and proliferation, respectively. HIF-stabilizing prolyl-hydroxylase inhibitors accelerate intestinal mucosal healing by inducing epithelial integrin expression.
This paper examines the cyclic performance of axially loaded tubular members used as bracing elements to provide lateral seismic resistance in steel framed structures. An experimental study into the ...response of members with square and rectangular hollow sections, made from cold-formed steel, is described. Three cross-sectional geometries were employed to represent a range of local and overall slenderness. Fifteen specimens, with normalised slendernesses between 0.4 and 3.2, were tested under cyclic axial displacements of increasing amplitude. In addition, twenty-one short specimens were tested under displacement-controlled monotonic tension loading, focusing primarily on the relationship between the tensile resistance of the material and that of the cross-section. Based on the results obtained in both sets of tests, and with due consideration of existing design provisions, the paper assesses the influence of section and member properties on the structural parameters that are most important for seismic design. These include the tensile capacity, initial and post-buckling compressive resistance, ductility capacity, energy dissipation, and mid-length lateral deformations of bracing members.
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