Kinin System Activation in Vasculitis

The kinin system is activated when high-molecular-weight kininogen (HK) is cleaved by plasma kallikrein thus generating bradykinin. Bradykinin is a potent proinflammatory peptide that induces plasma leakage, blood pressure drop, liberation of inflammatory cytokines and pain. Vasculitis is an autoimmune systemic inflammatory disease, characterized by leukocyte inflammation in and around vessel walls leading to perturbed vessel patency and tissue damage. Many different organs may be afflicted but most commonly the kidney, respiratory tract and skin are involved. Some patients with severe vasculitis have circulating antibodies against neutrophil enzymes called anti-neutrophil-cytoplasmic antibodies (ANCAs). Theoretically kinin system activation may explain some of the inflammation seen during vasculitis. In this thesis we demonstrate, for the first time, activation of the kinin system in patients with vasculitis. Elevated kinin levels were demonstrated in the circulation and kinins were detected at sites of inflammation. We also found that neutrophil-derived proteinase 3 (PR3) cleaves HK liberating a novel vasoactive kinin, termed PR3-kinin. PR3-kinin binds to and activates kinin B1-receptors both in vitro and in vivo. In addition, PR3-ANCAs from patients with vasculitides inhibit PR3-induced HK proteolysis and subsequent PR3-kinin release. In the MRLlpr/lpr mouse, that develops systemic inflammation and vasculitis, we demonstrate B1-receptor upregulation both systemically, on circulating leukocyte-derived microparticles (MPs), and locally, in the renal vasculitic lesions. In conclusion, we demonstrate kinin system activation in vasculitis and suggest that it may partake in the pathogenesis of this inflammatory condition. We therefore propose that inhibiting kinin system activation by blockage of B1-receptors may prove to be effective by reducing the inflammatory response during vasculitis

G protein-coupled Estrogen Receptor 1 (GPER1)/GPR30 Increases ERK1/2 Activity Through PDZ-dependent and -independent Mechanisms

G protein-coupled receptor 30 (GPR30), also called G protein-coupled estrogen receptor 1 (GPER1), is thought to play important roles in breast cancer and cardiometabolic regulation, but many questions remain about ligand activation, effector coupling, and subcellular localization. We showed recently that GPR30 interacts through the C-terminal type I PDZ motif with SAP97 and protein kinase A (PKA)-anchoring protein (AKAP) 5, which anchor the receptor in the plasma membrane and mediate an apparently constitutive decrease in cAMP production independently of Gi/o. Here, we show that GPR30 also constitutively increases ERK1/2 activity. Removing the receptor PDZ motif or knocking down specifically AKAP5 inhibited the increase, showing that this increase also requires the PDZ interaction. However, the increase was inhibited by pertussis toxin (PTX) as well as by wortmannin, but not by AG1478, indicating that Gi/o and phosphoinositide 3-kinase (PI3K) mediate the increase independently of epidermal growth factor receptor (EGFR) transactivation. FK506 and okadaic acid also inhibited the increase, implying that a protein phosphatase is involved. The proposed GPR30 agonist G-1 also increased ERK1/2 activity, but this increase was only observed at a level of receptor expression below that required for the constitutive increase. Furthermore, deleting the PDZ motif did not inhibit the G-1-stimulated increase. Based on these results, we propose that GPR30 increases ERK1/2 activity via two Gi/o-mediated mechanisms; a PDZ-dependent apparently constitutive mechanism, and a PDZ-independent G-1-stimulated mechanism

High Stakes Decision Making: Normative, Descriptive and Prescriptive Considerations

This paper reviews the state of the art of research on individual decision-making in high-stakes, low-probability settings. A central theme of the discussion is that optimally resolving high-stakes decisions poses a formidable challenge not only to naïve decision makers, but also to users of more sophisticated tools such as decision analysis.. Such problems are difficult to resolve because precise information about probabilities is not available, and the dynamics of the decision are complex. When faced with such problems, naïve decision-makers fall prey to a wide range of potentially harmful biases, such as not recognizing a high-stakes problem, ignoring the information about probabilities that does exist, and responding to complexity by accepting the status quo. We offer an agenda for future research focusing on how the process and outcomes of high-stakes decision making might be improved

Synovial monocytes contribute to chronic inflammation in childhood-onset arthritis via IL-6/STAT signalling and cell-cell interactions

IntroductionMonocytes are key effector cells in inflammatory processes. We and others have previously shown that synovial monocytes in childhood-onset arthritis are activated. However, very little is known about how they contribute to disease and attain their pathological features. Therefore, we set out to investigate the functional alterations of synovial monocytes in childhood-onset arthritis, how they acquire this phenotype, and whether these mechanisms could be used to tailorize treatment.MethodsThe function of synovial monocytes was analysed by assays believed to reflect key pathological events, such as T-cell activation-, efferocytosis- and cytokine production assays using flow cytometry in untreated oligoarticular juvenile idiopathic arthritis (oJIA) patients (n=33). The effect of synovial fluid on healthy monocytes was investigated through mass spectrometry and functional assays. To characterize pathways induced by synovial fluid, we utilized broad-spectrum phosphorylation assays and flow cytometry, as well as inhibitors to block specific pathways. Additional effects on monocytes were studied through co-cultures with fibroblast-like synoviocytes or migration in transwell systems.ResultsSynovial monocytes display functional alterations with inflammatory and regulatory features, e.g., increased ability to induce T-cell activation, resistance to cytokine production following activation with LPS and increased efferocytosis. In vitro, synovial fluid from patients induced the regulatory features in healthy monocytes, such as resistance to cytokine production and increased efferocytosis. IL-6/JAK/STAT signalling was identified as the main pathway induced by synovial fluid, which also was responsible for a majority of the induced features. The magnitude of synovial IL-6 driven activation in monocytes was reflected in circulating cytokine levels, reflecting two groups of low vs. high local and systemic inflammation. Remaining features, such as an increased ability to induce T-cell activation and markers of antigen presentation, could be induced by cell-cell interactions, specifically via co-culture with fibroblast-like synoviocytes.ConclusionsSynovial monocytes in childhood-onset arthritis are functionally affected and contribute to chronic inflammation, e.g., via promoting adaptive immune responses. These data support a role of monocytes in the pathogenesis of oJIA and highlight a group of patients more likely to benefit from targeting the IL-6/JAK/STAT axis to restore synovial homeostasis

Co-Induction in Relational Semantics

AbstractAn application of the mathematical theory of maximum fixed points of monotonic set operators to relational semantics is presented. It is shown how an important proof method which we call co-induction, a variant of Park's (1969) principle of fixpoint induction, can be used to prove the consistency of the static and the dynamic relational semantics of a small functional programming language with recursive functions

Cancer Incidence in World Trade Center Rescue and Recovery Workers, 2001–2008

Background: World Trade Center (WTC) rescue and recovery workers were exposed to a complex mix of pollutants and carcinogens. Objective: The purpose of this investigation was to evaluate cancer incidence in responders during the first 7 years after 11 September 2001. Methods: Cancers among 20,984 consented participants in the WTC Health Program were identified through linkage to state tumor registries in New York, New Jersey, Connecticut, and Pennsylvania. Standardized incidence ratios (SIRs) were calculated to compare cancers diagnosed in responders to predicted numbers for the general population. Multivariate regression models were used to estimate associations with degree of exposure. Results: A total of 575 cancers were diagnosed in 552 individuals. Increases above registry-based expectations were noted for all cancer sites combined (SIR = 1.15; 95% CI: 1.06, 1.25), thyroid cancer (SIR = 2.39; 95% CI: 1.70, 3.27), prostate cancer (SIR = 1.21; 95% CI: 1.01, 1.44), combined hematopoietic and lymphoid cancers (SIR = 1.36; 95% CI: 1.07, 1.71), and soft tissue cancers (SIR = 2.26; 95% CI: 1.13, 4.05). When restricted to 302 cancers diagnosed ≥ 6 months after enrollment, the SIR for all cancers decreased to 1.06 (95% CI: 0.94, 1.18), but thyroid and prostate cancer diagnoses remained greater than expected. All cancers combined were increased in very highly exposed responders and among those exposed to significant amounts of dust, compared with responders who reported lower levels of exposure. Conclusion: Estimates should be interpreted with caution given the short follow-up and long latency period for most cancers, the intensive medical surveillance of this cohort, and the small numbers of cancers at specific sites. However, our findings highlight the need for continued follow-up and surveillance of WTC responders

Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia.

Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = -0.71 to -1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = -0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10-6, 1.7 × 10-9, 3.5 × 10-12 and 1.0 × 10-4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes

TorchAudio 2.1: Advancing speech recognition, self-supervised learning, and audio processing components for PyTorch

TorchAudio is an open-source audio and speech processing library built for PyTorch. It aims to accelerate the research and development of audio and speech technologies by providing well-designed, easy-to-use, and performant PyTorch components. Its contributors routinely engage with users to understand their needs and fulfill them by developing impactful features. Here, we survey TorchAudio's development principles and contents and highlight key features we include in its latest version (2.1): self-supervised learning pre-trained pipelines and training recipes, high-performance CTC decoders, speech recognition models and training recipes, advanced media I/O capabilities, and tools for performing forced alignment, multi-channel speech enhancement, and reference-less speech assessment. For a selection of these features, through empirical studies, we demonstrate their efficacy and show that they achieve competitive or state-of-the-art performance

Neuroanatomical abnormalities in first-episode psychosis across independent samples: a multi-centre mega-analysis

Abstract Background Neuroanatomical abnormalities in first-episode psychosis (FEP) tend to be subtle and widespread. The vast majority of previous studies have used small samples, and therefore may have been underpowered. In addition, most studies have examined participants at a single research site, and therefore the results may be specific to the local sample investigated. Consequently, the findings reported in the existing literature are highly heterogeneous. This study aimed to overcome these issues by testing for neuroanatomical abnormalities in individuals with FEP that are expressed consistently across several independent samples. Methods Structural Magnetic Resonance Imaging data were acquired from a total of 572 FEP and 502 age and gender comparable healthy controls at five sites. Voxel-based morphometry was used to investigate differences in grey matter volume (GMV) between the two groups. Statistical inferences were made at p < 0.05 after family-wise error correction for multiple comparisons. Results FEP showed a widespread pattern of decreased GMV in fronto-temporal, insular and occipital regions bilaterally; these decreases were not dependent on anti-psychotic medication. The region with the most pronounced decrease – gyrus rectus – was negatively correlated with the severity of positive and negative symptoms. Conclusions This study identified a consistent pattern of fronto-temporal, insular and occipital abnormalities in five independent FEP samples; furthermore, the extent of these alterations is dependent on the severity of symptoms and duration of illness. This provides evidence for reliable neuroanatomical alternations in FEP, expressed above and beyond site-related differences in anti-psychotic medication, scanning parameters and recruitment criteria