Wedgebox analysis of four-lepton events from neutralino pair production at the LHC

`Wedgebox' plots constructed by plotting the di-electron invariant mass versus the di-muon invariant mass from pp -> e^+e^- mu^+ mu^- + missing energy signature LHC events. Data sets of such events are obtained across the MSSM input parameter space in event-generator simulations, including cuts designed to remove SM backgrounds. Their study reveals several general features: (1)Regions in the MSSM input parameter space where a sufficient number of events are expected so as to be able to construct a clear wedgebox plot are delineated. (2)The presence of box shapes on a wedgebox plot either indicates the presence of heavy Higgs bosons decays or restricts the location to a quite small region of low \mu and M_2 values \lsim 200 GeV, a region denoted as the `lower island'. In this region, wedgebox plots can be quite complicated and change in pattern rather quickly as one moves around in the (\mu, M_2) plane. (3)Direct neutralino pair production from an intermediate Z^{0*} may only produce a wedge-shape since only \widetilde{\chi}_2^0\widetilde{\chi}_3^0 decays can contribute significantly. (4)A double-wedge or wedge-protruding-from-a-box pattern on a wedgebox plot, which results from combining a variety of MSSM production processes, yields three distinct observed endpoints, almost always attributable to \widetilde{\chi}_{2,3,4}^0 \to \widetilde{\chi}_1^0 \ell^+\ell^- decays, which can be utilized to determine a great deal of information about the neutralino and slepton mass spectra and related MSSM input parameters. Wedge and double-wedge patterns are seen in wedgebox plots in another region of higher \mu and M_2 values, denoted as the`upper island.' Here the pattern is simpler and more stable as one moves across the (\mu, M_2) input parameter space.Comment: 28 pages (LaTeX), 8 figures (encapsulated postscript

Plasma membrane H⁺ -ATPase regulation is required for auxin gradient formation preceding phototropic growth.

Phototropism is a growth response allowing plants to align their photosynthetic organs toward incoming light and thereby to optimize photosynthetic activity. Formation of a lateral gradient of the phytohormone auxin is a key step to trigger asymmetric growth of the shoot leading to phototropic reorientation. To identify important regulators of auxin gradient formation, we developed an auxin flux model that enabled us to test in silico the impact of different morphological and biophysical parameters on gradient formation, including the contribution of the extracellular space (cell wall) or apoplast. Our model indicates that cell size, cell distributions, and apoplast thickness are all important factors affecting gradient formation. Among all tested variables, regulation of apoplastic pH was the most important to enable the formation of a lateral auxin gradient. To test this prediction, we interfered with the activity of plasma membrane H⁺ -ATPases that are required to control apoplastic pH. Our results show that H⁺ -ATPases are indeed important for the establishment of a lateral auxin gradient and phototropism. Moreover, we show that during phototropism, H⁺ -ATPase activity is regulated by the phototropin photoreceptors, providing a mechanism by which light influences apoplastic pH

Change in Emotional and Theory of Mind Processing in Borderline Personality Disorder: A Pilot Study.

Changes in emotional processing (EP) and in theory of mind (TOM) are central across treatment approaches for patients with borderline personality disorder (BPD). Although the assessment of EP relies on the observation of a patient's self-criticism in a two-chair dialogue, an individual's TOM assessments is made based on responses to humorous stimuli based on false beliefs. For this pilot study, we assessed eight patients with BPD before and after a 3-month-long psychiatric treatment, using functional magnetic resonance imaging and behavioral tasks. We observed arousal increase within the session of the two-chair dialogue (d = 0.36), paralleled by arousal decrease between sessions (d = 0.80). We found treatment-associated trends for neural activity reduction in brain areas central for EP and TOM. Our exploratory findings using an integrative assessment procedure of changes in EP and TOM point toward evidence for treatment effects at the brain systems level related to behavioral modulation

Dialectical behavior therapy skills training affects defense mechanisms in borderline personality disorder: An integrative approach of mechanisms in psychotherapy.

Objective: Borderline personality disorder (BPD) is characterized by immature defense mechanisms. Dialectical behavior therapy (DBT) is an effective treatment for BPD. However, understanding the underlying mechanisms of change is still limited. Using a transtheoretical framework, we investigated the effect of DBT skills training on defense mechanisms. Method: In this randomized controlled trial, 16 of 31 BPD outpatients received DBT skills training adjunctive to individual treatment as usual (TAU), while the remaining 15 received only individual TAU. Pre-post changes of defense mechanisms, assessed with the Defense Mechanism Rating Scale, were compared between treatment conditions using ANCOVAs. Partial correlations and linear regressions were conducted to explore associations between defenses and symptom outcome. Results: Overall defense function improved significantly more in the skills training condition (F(1, 28) = 4.57, p = .041). Borderline defenses decreased throughout skills training, but not throughout TAU only (F(1, 28) = 5.09, p = .032). In the skills training condition, an increase in narcissistic defenses was associated with higher symptom scores at discharge (β = 0.58, p = .02). Conclusions: Although DBT does not explicitly target defense mechanisms, skills training may have favorable effects on defense function in BPD. Our findings contribute to an integrative understanding of mechanisms of change in BPD psychotherapy

Zilucoplan in immune-mediated necrotising myopathy: a phase 2, randomised, double-blind, placebo-controlled, multicentre trial

BACKGROUND: Immune-mediated necrotising myopathy is an autoimmune myopathy characterised by proximal muscle weakness, high creatine kinase concentrations, and autoantibodies recognising 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) or the signal recognition particle (SRP). No approved therapies exist for people with immune-mediated necrotising myopathy. Previous studies have suggested that complement activation might be pathogenic in immune-mediated necrotising myopathy; therefore, zilucoplan, a complement C5 (C5) inhibitor, could be a potential therapy. We aimed to evaluate the efficacy, safety, and tolerability of zilucoplan in adult participants with anti-HMGCR or anti-SRP autoantibody-positive immune-mediated necrotising myopathy. METHODS: IMNM-01 was a phase 2, multicentre, randomised, double-blind, placebo-controlled study done at 15 hospital sites across the USA, the UK, France, and the Netherlands. Participants aged 18–74 years were eligible for inclusion if they had a clinically confirmed diagnosis of immune-mediated necrotising myopathy, positive serology for anti-HMGCR or anti-SRP autoantibodies, clinical evidence of weakness, serum total creatine kinase concentration of more than 1000 U/L at screening, and no change in glucocorticoids or other immunosuppressive therapies for 30 days before baseline or expected during the first 8 weeks of the study. Participants were randomly assigned (1:1) to receive daily subcutaneous zilucoplan (0·3 mg/kg) or placebo for 8 weeks by use of a computerised randomisation algorithm; with optional enrolment in the study open-label extension. Randomisation was stratified by autoantibody status. Participants and study staff were masked to treatment group assignment. Primary efficacy endpoint (in the intent-to-treat population, defined as all participants who were randomly assigned to a treatment group) was percent change from baseline to week 8 in creatine kinase concentrations. Safety analyses were performed on the safety population (participants who received at least one dose of study drug during the main study, irrespective of whether they continued to the extension period—study participants were analysed on the basis of the treatment received). This study is registered with ClinicalTrials.gov, NCT04025632. FINDINGS: Between Nov 7, 2019, and Jan 7, 2021, we randomly assigned 27 participants (13 female and 14 male) to receive zilucoplan (n=12) or placebo (n=15). All 27 participants completed the 8-week main study. At week 8 there were no significant differences between treatment groups in median percent change of creatine kinase concentrations versus baseline (–15·1% [IQR –31·1 to 3·2] in the zilucoplan group vs –16·3% [–43·8 to 5·9] in the placebo group; p=0·46) and no clinically relevant improvement over time within the treatment group despite target engagement based on mode of action. There were no unexpected adverse safety or tolerability findings. Treatment-emergent adverse events were reported in nine (75%) of 12 participants in the zilucoplan group, and in 13 (87%) of 15 participants in the placebo group, and serious treatment-emergent adverse events were reported in zero participants in the zilucoplan group and three (20%) participants in the placebo group. The most frequent treatment-emergent adverse events were headache (four [33%] participants in the zilucoplan group and four [27%] participants in the placebo group) and nausea (three [25%] participants in the zilucoplan group and three [20%] participants in the placebo group). INTERPRETATION: C5 inhibition does not appear to be an efficacious treatment modality for people with immune-mediated necrotising myopathy. Rather than being the primary driver for disease activity, complement activation might be secondary to muscle injury. FUNDING: Ra Pharmaceuticals (now part of UCB Pharma)

Thrombosis in vasculitis: from pathogenesis to treatment

In recent years, the relationship between inflammation and thrombosis has been deeply investigated and it is now clear that immune and coagulation systems are functionally interconnected. Inflammation-induced thrombosis is by now considered a feature not only of autoimmune rheumatic diseases, but also of systemic vasculitides such as Behçet’s syndrome, ANCA-associated vasculitis or giant cells arteritis, especially during active disease. These findings have important consequences in terms of management and treatment. Indeed, Behçet’syndrome requires immunosuppressive agents for vascular involvement rather than anticoagulation or antiplatelet therapy, and it is conceivable that also in ANCA-associated vasculitis or large vessel-vasculitis an aggressive anti-inflammatory treatment during active disease could reduce the risk of thrombotic events in early stages. In this review we discuss thrombosis in vasculitides, especially in Behçet’s syndrome, ANCA-associated vasculitis and large-vessel vasculitis, and provide pathogenetic and clinical clues for the different specialists involved in the care of these patients