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BackgroundWe sought to describe trends in extracorporeal membrane oxygenation (ECMO) use, and define the impact on PGD incidence and early mortality in lung transplantation.MethodsPatients were enrolled from August 2011 to June 2018 at 10 transplant centers in the multi-center Lung Transplant Outcomes Group prospective cohort study. PGD was defined as Grade 3 at 48 or 72 hours, based on the 2016 PGD ISHLT guidelines. Logistic regression and survival models were used to contrast between group effects for event (i.e., PGD and Death) and time-to-event (i.e., death, extubation, discharge) outcomes respectively. Both modeling frameworks accommodate the inclusion of potential confounders.ResultsA total of 1,528 subjects were enrolled with a 25.7% incidence of PGD. Annual PGD incidence (14.3%-38.2%, p=.0002), median LAS (38.0-47.7 p=.009) and the use of ECMO salvage for PGD (5.7%-20.9%, p=.007) increased over the course of the study. PGD was associated with increased 1 year mortality (OR 1.7 [95% C.I. 1.2, 2.3], p=.0001). Bridging strategies were not associated with increased mortality compared to non-bridged patients (p=.66); however, salvage ECMO for PGD was significantly associated with increased mortality (OR 1.9 [1.3, 2.7], p=.0007). Restricted mean survival time comparison at 1-year demonstrated 84.1 days lost in venoarterial salvaged recipients with PGD when compared to those without PGD (ratio 1.3 [1.1, 1.5]) and 27.2 days for venovenous with PGD (ratio 1.1 [1.0, 1.4]).ConclusionsPGD incidence continues to rise in modern transplant practice paralleled by significant increases in recipient severity of illness. Bridging strategies have increased but did not affect PGD incidence or mortality. PGD remains highly associated with mortality and is increasingly treated with salvage ECMO.

Proximal sesamoid bone (PSB) fractures are the most common musculoskeletal injury in race-horses. X-ray CT imaging can detect expressed radiological features in horses that experienced catastrophic fractures. Our objective was to assess whether expressed radiomic features in the PSBs of 50 horses can be used to develop machine learning models for predicting PSB fractures. The μCTs of intact contralateral PSBs from 50 horses, 30 of which suffered catastrophic fractures, and 20 controls were studied. From the 129 intact μCT images of PSBs, 102 radiomic features were computed using a variety of voxel resampling dimensions. Decision Trees and Wrapper methods were used to identify the 20 top expressed features, and six machine learning algorithms were developed to model the risk of fracture. The accuracy of all machine learning models ranged from 0.643 to 0.903 with an average of 0.754. On average, Support Vector Machine, Random Forest (RUS Boost), and Log-regression models had higher performance than K-means Nearest Neighbor, Neural Network, and Random Forest (Bagged Trees) models. Model accuracy peaked at 0.5 mm and decreased substantially when the resampling resolution was greater than or equal to 1 mm. We find that, for this in vitro dataset, it is possible to differentiate between unfractured PSBs from case and control horses using μCT images. It may be possible to extend these findings to the assessment of fracture risk in standing horses.

OBJECTIVE To examine whether proximal sesamoid bone (PSB) articular cartilage and bone osteoarthritic changes or palmar osteochondral disease (POD) scores were associated with exercise history and catastrophic PSB fracture in Thoroughbred racehorses. SAMPLE PSBs from 16 Thoroughbred racehorses (8 with and 8 without PSB fracture). PROCEDURES Exercise history was collected, and total career high-speed furlongs was used as the measure of total exercise per horse. At necropsy, medial and lateral condyles of the third metacarpus from each forelimb were assigned a POD score, followed by imaging with micro-CT for evaluation of osteophyte size. Three investigators that were blinded to the type of PSB (fracture or no fracture) used the Osteoarthritis Research Society International (OARSI) scoring system to evaluate acellularity, chondrocyte necrosis, cartilage fibrillation, chondrone formation, safranin O stain uptake, and tidemark advancement of 1 central sagittal tissue section/PSB (4 PSBs/horse). Cartilage thickness and bone necrosis were scored on the basis of histologic examination. RESULTS POD score, osteophyte size score, percentage of bone necrosis, tidemark advancement, chondrone formation, and total OARSI score were greater in horses with more accrued total career high-speed furlongs. Scores for POD, osteophyte size, fibrillation, acellularity, chondrone formation, and total OARSI were greater for horses with PSB fracture. CONCLUSIONS AND CLINICAL RELEVANCE OARSI scoring revealed that more advanced osteoarthritic changes strongly correlated with total career high-speed furlongs and PSB fracture. However, the effect of exercise was dominant, suggesting that exercise history will be important to include in future models that aim to assess risk factors for catastrophic PSB fracture.

BACKGROUND Proximal sesamoid bone (PSB) fractures are the most common fatal musculoskeletal injury in North American racehorses. Computed tomography has the potential to detect morphological changes in bone structure but can be challenging to analyse reliably and quantitatively. OBJECTIVES To develop a radiomics platform that allows the comparison of features from micro-CTs (µCT) of PSBs in horses that sustained catastrophic fractures with horses that did not. To compare features calculated with a radiomics approach with features calculated from a previously published study that used quantitative µCT in the same specimens. STUDY DESIGN Retrospective study of cadaver specimens of µCT images of PSBs using prospectively applied radiomics. METHODS Radiomics features were computed on standardised CT datasets to benchmark the software. Features from µCT images of PSBs from eight horses that sustained PSB fracture and eight controls were computed using the contralateral, intact forelimb from horses sustaining PSB fracture (cases, n = 19) and all available forelimbs for controls (n = 30). Two-hundred and fifteen radiomic features were calculated, and similar or comparable features were compared with those reported in a previous study that used the same specimens. RESULTS Morphologic features computed with the radiomics approach, such as volume, minor axis dimensions and anisotropy were highly correlated with previously published data. A high number of imperceptible radiomic features, such as entropy, coarseness and histogram features were also found to be significantly different (P

Neurofilaments are structural proteins that are concentrated in the body and axons of neurons. Damage to the neurons or axons as a result of trauma or infectious diseases leads to the release of neurofilaments into blood and cerebrospinal fluid (CSF). This case-control study was carried out to compare serum levels of phosphorylated neurofilament heavy chain (pNF-H) between clinically healthy Thoroughbred (TB) horses and TB horses that suffered catastrophic musculoskeletal injuries (cMSI), and to investigate the correlation between putative risk factors and serum concentrations of pNF-H in injured horses. Blood samples were collected from clinically healthy horses and from horses that suffered cMSI. The concentration of pNF-H in serum samples was determined using the Phosphorylated Neurofilament H Sandwich enzyme-linked immunosorbent assay kit. A total of 343 horses were enrolled in the study (148 cases and 195 controls). The median serum concentration of pNF-H for controls was 0.0 ng/ml and for cases was 0.07 ng/ml. No significant difference was observed between the 2 groups in racing. The number of lifetime starts was correlated with serum pNF-H concentration in case horses. The serum concentration of pNF-H was higher in case horses that experienced cMSI while training than while racing. The number of lifetime starts is a proxy measure for several risk factors related to cumulative exercise load during the career of racehorses. Measurement of serum concentrations of pNF-H in TB racehorses does not support the hypothesis that subclinical neurologic injury or conditions are associated with catastrophic injury of TB racehorses.

T cell polyfunctionality is a hallmark of protective immunity against pathogens and cancer, yet the molecular mechanism governing it remains mostly elusive. We found that canonical Wnt agonists inhibited human memory CD8+ T cell differentiation while simultaneously promoting the generation of highly polyfunctional cells. Downstream effects of Wnt activation persisted after removal of the drug, and T cells remained polyfunctional following subsequent cell division, indicating the effect is epigenetically regulated. Wnt activation induced a gene expression pattern that is enriched with stem cell–specific gene signatures and upregulation of protein arginine methyltransferase 1 (PRMT1), a known epigenetic regulator. PRMT1+CD8+ T cells are associated with enhanced polyfunctionality, especially the ability to produce IL-2. In contrast, inhibition of PRMT1 ameliorated the effects of Wnt on polyfunctionality. Chromatin immunoprecipitation revealed that H4R3me2a, a permissive transcription marker mediated by PRMT1, increased at the IL-2 promoter loci following Wnt activation. In vivo, Wnt-treated T cells exhibited superior polyfunctionality and persistence. When applied to cytomegalovirus (CMV) donor–seropositive, recipient-seronegative patients (D+/R–) lung transplant patient samples, Wnt activation enhanced CMV-specific T cell polyfunctionality, which is important in controlling CMV diseases. These findings reveal a molecular mechanism governing T cell polyfunctionality and identify PRMT1 as a potential target for T cell immunotherapy.

Neurofilaments heavy chain proteins (pNF-H) have been identified as useful serum biomarkers for humans and animals with neurologic conditions, some of which can lead to poor performance, and athletic injuries. However, there are no published reports that describe a reference range for serum pNF-H levels in healthy racehorses. This cross-sectional study was carried out to determine the serum concentration of pNF-H in 1,349 samples collected from 1,291 clinically healthy standardbred (SB) racehorses. Data on age, time of sampling (pre-race or post-race), and finishing position during a race were collected. The concentration of pNF-H in serum samples was determined using an enzyme-linked immunosorbent assay (ELISA). The appropriate statistical techniques were used to determine the median serum concentration of pNF-H in these horses, if the serum concentration of pNF-H changed with age, if there were changes in the serum concentration of pNF-H during a race, and if there was an association between serum concentration of pNF-H, and the finishing position for the horse. The median serum concentration of pNF-H in this group of clinically healthy SB horses was 0.0 ng/mL. The concentration of pNF-H in serum was not associated with the age of the horses in this study as was determined by regression analysis. There was no significant change in the serum concentration of pNF-H before and after a race in paired samples. There was no association of serum concentration of pNF-H and the finishing position of the horses after the race. The data from this study supports use of0.412 ng/mL as a reference interval for measurement of serum levels of pNF-H in SB racehorses as 95% of the collected samples fell into the range 0.0-0.412 ng/mL.

Introduction: Histone Deacetylase 3 (HDAC3) is a Class I member of the histone deacetylase family that is recruited to nuclear enhancers. HDAC3 is located within the cell nucleus, where it constitutes the sole endogenous HDAC interacting with the nuclear-receptor corepressor complex containing NCOR and SMRT (NCOR2). As such, HDAC3 has a unique role in modulating the transcriptional activity of nuclear receptors. We have previously demonstrated its involvement in the inflammatory response in Lipopolysaccharide A (LPS)-stimulated human MH-S alveolar macrophages in vitro, and its interaction with pro-inflammatory IL-12 and anti-inflammatory IL-10. Similarly, our previous work using the broad spectrum HDAC inhibitor trichostatin A has demonstrated therapeutic efficacy reducing the pathogenesis of acute gram negative pneumonia in-vivo. With the current project, we aim to identify the HDAC3 interactome in LPS-stimulated human pulmonary epithelial cells type II (A549), the first immune defense in pathogens invading the lungs. Methods: Human A549 cells were transfected with a BioID2-tagged HDAC3 plasmid, and were divided in three groups: a. Untreated, b. stimulated with LPS, and c. stimulated with LPS and treated with Entinostat (MS275, a HDAC1/3 inhibitor). Cells were lysed, and total and biotinylated protein were submitted for quantitative Liquid Chromatography/Mass Spectrometry analysis to identify the peptides that directly bind with HDAC3. Data were searched against the Swiss Protein Human database, and False Discovery Rate (FDR) was set at 1%. Results: The dataset yielded 395,776 peptide matches. After peptide sequencing by database searching and validation, and FDR exclusion, we identified 2,666 proteins. Of these, 33 have been annotated to function in the NF-kB signaling pathway and/or NF-kB-regulated transcriptional activity.Conclusion: Protein acetylation is a reversible post-translational modification that is known to stabilize protein structure and modify function and localization. With the current project we have identified several potential proteins in the HDAC3 interactome that may be targeted early in the NF-κB activation process to disrupt HDAC3-substrate interaction and potentially downstream signaling. Nuclear activation of NF-κB is known to be involved in the early stages of Acute Respiratory Distress Syndrome and is a target of intense study for the development of novel therapeutics.

A longitudinal retrospective study was carried out to investigate the attrition of Thoroughbred (TB) and Standardbred (SB) horses racing at New York racetracks during the 2016 to 2019 seasons. The data were collected from the New York State Gaming Commission (NYSGC) Equine Breakdown, Death, Injury and Incident (EBDII), The Jockey Club InCompass Solutions, and The United States Trotting Association Pathway databases. Survival analysis was used to compare the predisposing factors by breed of the horse. The study included 431 horses (360 TB and 71 SB). There was a significant difference between the average incidence of attrition events per start for TB (0.304) and SB (0.035) horses. There was a significant difference in the median age to attrition between TB (4.2 years) and SB (7.5 years) horses. There was also a significant difference between the average number of starts to attrition for TB (13.6) and SB (125.5) horses. Among the causes of attrition events in the two breeds musculoskeletal injuries and medical conditions were significantly higher among TB horses, while sudden death was significantly higher among SB horses. The multivariate analysis showed that the hazard of attrition was affected by the age of the horse, age at first start, whether the horse was intact male, type of activity (racing training or other) and the breed of the horse. SB horses were less likely to experience attrition events in comparison to TB horses.

Conventional track circuit condition monitoring systems are fixed at the wayside, with each installation reporting on a single track circuit. In this work, we present a custom-built, sensitive, magnetic field detection system, which can be fitted to the underside of a rail vehicle. With this system installed, some characteristics of an operating track circuit can be monitored from the vehicle whilst it is in motion. By using appropriate analysis techniques, it is possible to identify the signatures of equipment relating to audio frequency track circuits, the topic of this work. Analysing the signatures of track circuit equipment demonstrated that there were clear differences between track circuit assets. By building on other research into the behaviours of failing track circuits, and continuing to conduct this research, the authors believe that it is possible, and beneficial, to perform condition monitoring of track circuits from low-cost equipment mounted on the train. Coupling this with advanced analysis techniques will allow predictive maintenance of track circuits with very little capital outlay.

BACKGROUND Fracture of the proximal sesamoid bones continues to be the most common fatal musculoskeletal injury in US racehorses. Identifying factors that influence fracture risk could lead to screening techniques to reduce catastrophic injury rates and improve animal welfare. OBJECTIVES To identify morphological differences between proximal sesamoid bones of the contralateral limb of fracture and control horses and assess the feasibility of computed tomography (CT) to detect traits associated with proximal sesamoid bone fracture. We hypothesised that horses with proximal sesamoid bone fracture would have greater bone density. STUDY DESIGN Cross-sectional cadaver morphological study. METHODS Proximal sesamoid bone morphology was measured using high-resolution micro-CT images from 16 Thoroughbred racehorses (eight fracture, eight control) euthanised on New York racetracks. Nominal logistic regression models and receiver operating characteristic curves were created to assess the ability of CT-derived morphological traits to accurately classify fracture horses vs. controls. RESULTS Bone volume fraction was greater in the fracture group (90.39 ± 1.76%) as compared to controls (87.20 ± 2.79%, P

Though it is well understood that all internal upheaval within a polity is a consequence of agency interacting with structure, the importance of the former has perhaps become too pushed to the rear...

The insurgent movement that calls itself the Communist Party of Peru Partido Comunista del Peru (PCP) and is called by others Shining Path is both a paradox and an anachronism. Shining Path had its origins in 1962 and 1963, in the provincial Ayacucho organization of Peru's then single-line Communist Party. The PCP, Shining Path, Guzman holds, is following the correct communist line almost alone and will eventually be vindicated by revolutionary triumph in Peru. Shining Path, in effect, pursues ideology at the expense of reality, convinced that its own "scientific interpretation of history" represents the real interests of the proletariat and will inevitably triumph. The United States government played a significant role in this process out of concern for Peru's domestic crises, including the insurgency, and committed some $90 million in economic and military assistance as well. Expenses may include some arms brought in by the mostly Colombian drug smuggling planes.

Neurofilaments (NFs) are structural proteins of neurons that are released in significant quantities in the cerebrospinal fluid and blood as a result of neuronal degeneration or axonal damage. Therefore, NFs have potential as biomarkers for neurologic disorders. Neural degeneration increases with age and has the potential to confound the utility of NFs as biomarkers in the diagnosis of neurologic disorders. We investigated this relationship in horses with and without neurological diagnosis. While controlling for horse type (draft, pleasure, and racing), we evaluated the relationship between serum heavy-chain phosphorylated neurofilaments (pNF-H) and age, sex, and serum vitamin E concentrations. Serum pNF-H concentrations increased by 0.002 ng/ml for each year increase in age. There were significant differences in the serum pNF-H concentration among the type of activity performed by the horse. The highest serum pNF-H concentration was found in horses performing heavy work activity (racehorse) and with lower serum pNF-H concentration found among light (pleasure riding) and moderate (draft) activity. There was no significant association between the pNF-H concentration and sex or vitamin E concentration. Serum pNF-H concentration was elevated among horses afflicted with EMND and EPM when compared with control horses without evidence of neurologic disorders. Accordingly, serum pNF-H concentration can serve as a useful biomarker to complement the existing diagnostic work-up of horses suspected of having EPM or EMND.

Postmortem evaluation of racehorses has focused primarily on musculoskeletal injuries; however, horses also die suddenly on the track (sudden death [SD]). Although cardiac conditions are frequently suspected as a cause of death, SD racehorses are often autopsy negative; however, previous studies have been limited due to inconsistent or insufficient cardiac sampling and lack of controls. SD in New York (NY) and Maryland (MD) racehorses was evaluated in an observational case vs control study comparing clinical information, postmortem evaluation including cardiac dissection, and cardiac conduction system histopathology. In the study period, there were 40 cases of SD. In NY, SD occurred in 12% (37/316) of submissions, and 36 (11%) cases of SD were exercise associated (EASD); 3 EASD cases occurred in MD. In NY/MD EASD cases with histologic examination of the heart, 11 of 36 (31%) had significant lesions, including mesenteric artery rupture (1), axial trauma (2), systemic inflammation (2), pulmonary hemorrhage (1), and cardiac disease (5). Mild myocardial fibrosis, mild inflammation, coronary arteriosclerosis, and variation in cardiac nodal connective tissue were present in both SD cases and controls and thus were not considered to be causes of SD. While not excluding a genetic basis for SD, analysis of the genotypes (GGP Equine 70 K Array) of cases and controls did not reveal significant differences in allele frequencies at any locus. Most SD racehorses were autopsy negative; further research using standardized protocols and controls is needed to understand the underlying causes of SD, which is crucial to protecting the viability of racing.

© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Prostate cancer is a multifocal disease with characteristic heterogeneity and foci that can range from low grade indolent to aggressive disease. The latter is characterised by the well-established histopathological Gleason grading system used in the current clinical care. Nevertheless, a large discrepancy exists on initial biopsy and after the final radical prostatectomy. Moreover, there is no reliable imaging modality to study these foci, in particular at the level of the cells and surrounding matrix. Extracellular matrix (ECM) remodelling is significant in cancer progression with collagen as the dominant structural component providing mechanical strength and flexibility of tissue. In this study, the collagen assembly in prostate tissue was investigated with second harmonic generation (SHG) microscopy: malignant foci demonstrated a reticular pattern, with a typical collagen pattern for each Gleason score. The orientation of collagen for each biopsy was computed by applying a ratio of the anisotropic and isotropic collagen fibres. This value was found to be distinct for each Gleason score. The findings suggest that this approach can not only be used to detect prostate cancer, but also can act as a potential biomarker for cancer aggressiveness. (Figure presented.).

Muscle invasive urinary bladder cancer is one of the most lethal cancers and its detection at the time of transurethral resection remains limited and diagnostic methods are urgently needed. We have developed a muscle invasive transitional cell carcinoma (TCC) model of the bladder using porcine bladder scaffold and the human bladder cancer cell line 5637. The progression of implanted cancer cells to muscle invasion can be monitored by measuring changes in the spectrum of endogenous fluorophores such as reduced nicotinamide dinucleotide (NADH) and flavins. We believe this could act as a useful tool for the study of fluorescence dynamics of developing muscle invasive bladder cancer in patients. Published by The Optical Society under the terms of the Creative Commons Attribution 4.0 License. Further distribution of this work must maintain attribution to the author(s) and the published article's title, journal citation, and DOI.

Injury is a leading cause of death and disability worldwide. Both can be reduced by prompt, systematic care. However, assessing or comparing outcomes over time or between regions is difficult without consistent injury severity assessments. The Abbreviated Injury Scale (AIS) is a severity-weighted injury classification system. AIS-derived summary scores can describe the severity of injured individuals and populations, and underpin many aspects of injury care. Injury diagnosis and management change over time. This thesis aims to develop and evaluate AIS-derived tools enabling the consistent prediction of fatal and non-fatal outcomes following injury, and to identify principles ensuring ongoing AIS relevancy.

Peru exhibits a deeply ingrained Hispanic tradition as the South American center of the Spanish Empire. This tradition contributed, after a reluctant independence, to instability, military regimes, and authoritarian governments for most of Peru's history as a republic. Peruvians are still divided by the legacy of Alberto Fujimori's government, a highly controversial elected regime that provided the benefits of pacification and economic stabilization on the one hand, but autocratic governance and pervasive corruption on the other. Peru's continuing democratic process owes much to the Paniagua-led transition. The wave of democracy that Peru was inaugurated by the transitional government led by president of congress and longtime Alignment Process representative Valentin Paniagua, who took the oath of office on November 22, 2000. The Velasco military government was a significant catalyst for social change. Most notable was the enactment of a large-scale agrarian-reform program, which effectively eliminated large, private landholdings; in the process, it reconfigured a rural landscape that was archaic and exploitative.

While the significance and influence of Appia's writings and his storyboard scenarios of Wagnerian operas are uncontested, their origin has been explained almost universally as instigated by a combination of his musical inspiration and the technological development of electric stage lighting. While light was clearly at the heart of this new scenography, it was not as a result of the new electrical, incandescent lamps of Edison and Swan that had begun to populate the theatres of Europe and North America from the early 1880s as most commentators would suggest, but rather due to an older, pre-existing lighting technology with which Appia was acquainted. In 1886, at the age of 24, Appia embarked on a four-year period during which he was primarily resident in Dresden. It was a formative time in his education, which despite being instrumental in the development of a new scenic art, has received surprisingly little critical attention. Appia's writings and drawings for the staging of Wagnerian drama first conceiv...

This paper focuses on issues arising from the making of an experimental interactive 360-degree video that emerged from a relational ‘immersive’ site-specific theatre project for a public audience that was staged in historic grounds in South Florida, USA in April 2017. This work was undertaken with academics from University of Miami, Kim Grinfeder and Stephen Di Benedetto. The specific nature of the performance event, the filming of aspects of this experience and the post-production processes each raise significant questions relating to the development of methods of ‘interactive’ digital storytelling for ‘immersive’ audience experience. The role of theatre practice and performance design in developing these mediated experiences seems to be an important element that has largely been ignored in thinking about how digital immersive experiences might be created.

Between January 1, 2013 and December 31, 2015, findings of a New York State Gaming Commission–Cornell University postmortem examination program were utilized in a multi-disciplinary mortality review process to review 129 racing fatalities at Thoroughbred racetracks operated by the New York Racing Association (NYRA). Musculoskeletal fractures comprised 79% of the fatalities; cardiopulmonary conditions accounted for 12% of the fatalities. Other causes of death included gastrointestinal (3%), respiratory (5%), and central nervous system (2%) conditions. Fetlock failure represented 50% of the musculoskeletal fatalities. The general distribution of these findings was very similar to that reported by the California Animal Health and Food Safety Laboratory System during the same period. These findings, used in conjunction with a comprehensive mortality review process and regulatory reform, have contributed to a significant reduction of the incidence of Thoroughbred racing fatalities at NYRA racetracks during the period of this review.

© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Bladder cancer is among the most common cancers in the UK and conventional detection techniques suffer from low sensitivity, low specificity, or both. Recent attempts to address the disparity have led to progress in the field of autofluorescence as a means to diagnose the disease with high efficiency, however there is still a lot not known about autofluorescence profiles in the disease. The multi-functional diagnostic system “LAKK-M” was used to assess autofluorescence profiles of healthy and cancerous bladder tissue to identify novel biomarkers of the disease. Statistically significant differences were observed in the optical redox ratio (a measure of tissue metabolic activity), the amplitude of endogenous porphyrins and the NADH/porphyrin ratio between tissue types. These findings could advance understanding of bladder cancer and aid in the development of new techniques for detection and surveillance. (Figure presented.).

OBJECTIVEIt has long been recognized that autoimmunity is often associated with immunodeficiency. The mechanism underlying this paradox is not well understood. Bcl-3 (B-cell lymphoma 3) is an atypical member of the IκB (inhibitor of the nuclear factor-κB) family that is required for lymphoid organogenesis and germinal center responses. Mice deficient in Bcl-3 are immunodeficient because of the microarchitectural defects of their lymphoid organs. The goal of this study is to define the potential roles of Bcl-3 in type 1 diabetes.RESEARCH DESIGN AND METHODSBcl-3–deficient NOD mice were generated by backcrossing Bcl-3–deficient C57BL/6 mice to NOD mice. Spontaneous and induced type 1 diabetes were studied in these mice by both pathologic and immunologic means. The effect of Bcl-3 on inflammatory gene transcription was evaluated in a promoter reporter assay.RESULTSWe found that Bcl-3–deficient NOD and C57BL/6 mice were, paradoxically, more susceptible to autoimmune diabetes than wild-type mice. The increase in diabetes susceptibility was caused by Bcl-3 deficiency in hematopoietic cells but not nonhematopoietic cells. Bcl-3 deficiency did not significantly affect anti-islet Th1 or Th2 autoimmune responses, but markedly increased inflammatory chemokine and T helper 17 (Th17)-type cytokine expression. Upon transfection, Bcl-3 significantly inhibited the promoter activities of inflammatory chemokine and cytokine genes.CONCLUSIONSThese results indicate that in addition to mediating lymphoid organogenesis, Bcl-3 prevents autoimmune diabetes by inhibiting inflammatory chemokine and cytokine gene transcription. Thus, a single Bcl3 gene mutation leads to both autoimmunity and immunodeficiency.

This paper focuses on the research project, Projecting Performance, in which off-stage technical operators take on the role of performer through the live manipulation of digital ‘sprites’ in a theatrical environment. The sprites are projected onto gauzes in the stage space and operators control them with graphics tablets and pens to perform with on-stage dancers. Operators have frequently described experiences of dislocation or translocation during the experience of operating and this paper investigates the reasons for such reports. It presents the tripartite models of Zich and Castronova from the fields of theatre studies and human-computer interaction respectively, cross-referencing them to analyse the relationship between performer-operator and sprite. Merleau-Ponty's phenomenological theories are then employed through the writings of Crowther and Fraleigh to explore the experience of the performer-operator. The paper proposes an understanding of the digital interface in Projecting Performance as embodied and experienced both visually and kinaesthetically by the performer-operator.

In this introductory chapter, McKinney and Palmer survey the newly emerged field of expanded scenography and consider the underlying concepts by which it can be defined. Taking their lead from Krauss’s approach to expanded sculpture they identify evidence of the re-structurings of theatrical scenography that have led to new ways of thinking about the spatial, material and design-based aspects of performance both in and beyond the theatre. However, scenography in its expanded form is not simply a by-product of theatre but a mode of encounter and exchange founded on spatial and material relations between bodies, objects and environments. McKinney and Palmer prioritise the perspective of the spectator to focus on the spatial, multisensorial and material aspects of contemporary performance and they propose three interrelated and overlapping concepts; relationality, affectivity and materiality, as a theoretical framework. This re-focusing of the scenographic lens illuminates the evental, processual nature of much contemporary scenography and brings into sharper definition the characteristics of expanded scenography as a new field.

Toll-like receptors (TLRs) trigger the production of inflammatory cytokines and shape adaptive and innate immunity to pathogens. We report the identification of B cell leukemia (Bcl)–3 as an essential negative regulator of TLR signaling. By blocking ubiquitination of p50, a member of the nuclear factor (NF)-κB family, Bcl-3 stabilizes a p50 complex that inhibits gene transcription. As a consequence, Bcl-3–deficient mice and cells were found to be hypersensitive to TLR activation and unable to control responses to lipopolysaccharides. Thus, p50 ubiquitination blockade by Bcl-3 limits the strength of TLR responses and maintains innate immune homeostasis. These findings indicate that the p50 ubiquitination pathway can be selectively targeted to control deleterious inflammatory diseases.

This article builds on the binary rhythms of transparency and reflectivity described by Bolter and Gromala (2003) as being central to the design of interfaces in digital artifacts. It starts from the concept of experience design and suggests that the experience of the interface might better be considered in terms of the ‘sensuous manifold’. The authors present the interactive kinetic light installation, Dancing in the Streets, as an example of how this sensuous manifold could be seen to work in practice. Many participants described this work as being ‘transparent’ and ‘magical’. The article analyses elements of the installation in relation to transparency/reflectivity to assess the reasons behind these descriptions, and to explore how the sensuous manifold experience was achieved for participants. The location of the installation is defined as a ‘non-place’ whose uncanniness contributed to the potential for ambiguity and liminality. The use of light as a medium for urban scenography was also a critical factor in the design of the interface. The images and their behaviour in relation to the participants created the final element of the artwork. The installation was successful in getting the people of York dancing in the streets. In doing so, it foregrounds the concept of the sensuous manifold as a useful concept for experience designers.