On-brane data for braneworld stars

Stellar structure in braneworlds is markedly different from that in ordinary general relativity. As an indispensable first step towards a more general analysis, we completely solve the ``on brane'' 4-dimensional Gauss and Codazzi equations for an arbitrary static spherically symmetric star in a Randall--Sundrum type II braneworld. We then indicate how this on-brane boundary data should be propagated into the bulk in order to determine the full 5-dimensional spacetime geometry. Finally, we demonstrate how this procedure can be generalized to solid objects such as planets.Comment: 5 pages, RevTeX4, v2: Main algorithm and results substantially simplified, further discussion and references adde

Numerical Solutions of ideal two-fluid equations very closed to the event horizon of Schwarzschild black hole

The 3+1 formalism of Thorne, Price and Macdonald has been used to derive the linear two-fluid equations describing transverse and longitudinal waves propagating in the two-fluid ideal collisionless plasmas surrounding a Schwarzschild black hole. The plasma is assumed to be falling in radial direction toward the event horizon. The relativistic two-fluid equations have been reformulate, in analogy with the special relativistic formulation as explained in an earlier paper, to take account of relativistic effects due to the event horizon. Here a WKB approximation is used to derive the local dispersion relation for these waves and solved numerically for the wave number k.Comment: 16 pages, 15 figures. arXiv admin note: text overlap with arXiv:0902.3766, arXiv:0807.459

Can electro-magnetic field, anisotropic source and varying Λ\Lambda be sufficient to produce wormhole spacetime ?

It is well known that solutions of general relativity which allow for traversable wormholes require the existence of exotic matter (matter that violates weak or null energy conditions [WEC or NEC]). In this article, we provide a class of exact solution for Einstein-Maxwell field equations describing wormholes assuming the erstwhile cosmological term $\Lambda$ to be space variable, viz., $\Lambda = \Lambda (r)$. The source considered here not only a matter entirely but a sum of matters i.e. anisotropic matter distribution, electromagnetic field and cosmological constant whose effective parts obey all energy conditions out side the wormhole throat. Here violation of energy conditions can be compensated by varying cosmological constant. The important feature of this article is that one can get wormhole structure, at least theoretically, comprising with physically acceptable matters.Comment: Some changes have been mad

Transverse Wave Propagation in Relativistic Two-fluid Plasmas in de Sitter Space

We investigate transverse electromagnetic waves propagating in a plasma in the de Sitter space. Using the 3+1 formalism we derive the relativistic two-fluid equations to take account of the effects due to the horizon and describe the set of simultaneous linear equations for the perturbations. We use a local approximation to investigate the one-dimensional radial propagation of Alfv\'en and high frequency electromagnetic waves and solve the dispersion relation for these waves numerically.Comment: 19 pages, 12 figure

Microglia actively remove NR1 autoantibody-bound NMDA receptors and associated post-synaptic proteins in neuron microglia co-cultures

Autoantibodies against the NR1 subunit of NMDA receptors (NMDARs) have been shown to promote crosslinking and internalization of bound receptors in NMDAR encephalitis (NMDARE). This internalization-mediated loss of NMDARs is thought to be the major mechanism leading to pathogenic outcomes in patients. However, the role of bound autoantibody in engaging the resident immune cells, microglia, remains poorly understood. Here, using a patient-derived monoclonal NR1 autoantibody (hNR1-mAb) and a co-culture system of microglia and neurons, we could show that hNR1-mAb bound to hippocampal neurons led to microglia-mediated removal of hNR1-mAb bound NMDARs. These complexes were found to accumulate inside endo-lysosomal compartments of microglia. Utilizing another patient isolated monoclonal autoantibody, against the α1-subunit of GABA(A) receptors (α1-GABA(A)-mAb), such removal of receptors was found to be specific to the antibody-bound receptor targets. Interestingly, along with receptor removal, we also observed a reduction in synapse number, more specifically in the numbers of post-synaptic proteins like PSD95 and Homer 1, when microglia were present in the culture. Importantly, mutations in the Fc region of hNR1-mAb, blocking its Fcγ receptor (FcγR) and complement binding, attenuated hNR1-mAb driven loss of NMDARs and synapses, indicating that microglia engagement by bound hNR1-mAb is critical for receptor and synapse loss. Our data argues for an active involvement of microglia in removal of NMDARs and other receptors in individuals with autoimmune encephalitis, thereby contributing to the etiology of these diseases

Long-term safety of Ixekizumab in adults with psoriasis, psoriatic arthritis, or axial spondyloarthritis: a post-hoc analysis of final safety data from 25 randomized clinical trials

Background We report long-term, end-of-study program safety outcomes from 25 randomized clinical trials (RCTs) in adult patients with psoriasis (PsO), psoriatic arthritis (PsA), or axial spondyloarthritis (axSpA) [including ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA)] who received ≥ 1 dose of Ixekizumab (IXE) over 5 years (PsO) or up to 3 years (PsA, axSpA). Methods This integrated safety analysis consists of data from patients who received any dose of IXE, across 25 RCTs (17 PsO, 4 PsA, 4 axSpA). Rates of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs) and selected adverse events (AEs) of interest were analyzed for all pooled studies by years of therapy and overall, through March 2022. Results were reported as exposure-adjusted incidence rates (IRs) per 100 patient-years (PY) overall and at successive year intervals. Results Six thousand eight hundred ninety two adult patients with PsO, 1401 with PsA, and 932 with axSpA (including AS and nr-axSpA), with a cumulative IXE exposure of 22,371.1 PY were included. The most commonly reported TEAE across indications was nasopharyngitis (IRs per 100 PY: 8.8 (PsO), 9.0 (PsA), 8.4 (axSpA)). SAEs were reported by 969 patients with PsO (IR 5.4), 134 patients with PsA (IR 6.0), and 101 patients with axSpA (IR 4.8). Forty-five deaths were reported (PsO, n = 36, IR 0.2; PsA, n = 6, IR 0.3; axSpA, n = 3, IR 0.1). TEAEs did not increase during IXE exposure: IRs per 100 PY, PsO: 88.9 to 63.2 (year 0–1 to 4–5), PsA: 87 to 67.3 (year 0–1 to 2–3), axSpA: 82.1 to 55.4 (year 0–1 to >  = 2). IRs per 100 PY of discontinuation from IXE due to AE were 2.9 (PsO), 5.1 (PsA), and 3.1 (axSpA). IRs per 100 PY of injection site reactions were 5.9 (PsO), 11.6 (PsA) and 7.4 (axSpA); Candida: 1.9 (PsO), 2.0 (PsA), and 1.2 (axSpA); depression, major adverse cerebro-cardiovascular events and malignancies: ≤ 1.6 across all indications. Adjudicated IRs per 100 PY of inflammatory bowel disease were ≤ 0.8 across indications (0.1 [PsO]; 0.1 [PsA]; 0.8 [axSpA]). Conclusions In this integrated safety analysis, consisting of over 22,000 PY of exposure, the long-term safety profile of IXE was found to be consistent with previous, earlier reports, with no new safety signals identified

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Genetics of grain yield and its components in wheat under heat stress

Heat stress is a matter of a great concern for the wheat crop. Heat stress usually either hastens crop development or shortens the grain filling duration, which severely reduces grain yield. Being a complex trait, understanding the genetics and gene interactions of stress tolerance are the two primary requirements for improving yield levels. Genetic analysis through generation mean analysis helps to find out the nature of gene actions involved in a concerned trait by providing an estimate of main gene effects (additive and dominance) along with their digenic interactions (additive × additive, additive × dominance, and dominance × dominance). In the present investigation, we elucidated the inheritance pattern of different yield contributing traits under heat stress using different cross combinations which could be helpful for selecting a suitable breeding strategy. Thus six generations of five crosses were sown normal (non-stress, TS) and late (heat stress, LS) in a randomized block design with three replications during two crop seasons. The model was not adequate for late sown conditions indicating the expression of epistatic genes under stress conditions. The traits i.e. Days to heading (DH), Days to anthesis (DA), Days to maturity (DM), Grain filling duration (GFD), Grain yield (GY), Thousand grain weight (TGW), Grain weight per spike (GWS) and Heat susceptibility index (HSI) under heat stress conditions were found under the control of additive gene action with dominance × dominance interaction, additive gene action with additive × dominance epistatic effect, dominance gene action with additive × additive interaction effect, additive and dominance gene action with dominance × dominance interaction effect, additive gene action with additive × dominance epistatic effect, additive gene action with additive × additive interaction effect and dominance gene action with additive × additive interaction effect, respectively

A novel formulation of inhaled sodium cromoglicate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial

Background Cough can be a debilitating symptom of idiopathic pulmonary fibrosis (IPF) and is difficult to treat. PA101 is a novel formulation of sodium cromoglicate delivered via a high-efficiency eFlow nebuliser that achieves significantly higher drug deposition in the lung compared with the existing formulations. We aimed to test the efficacy and safety of inhaled PA101 in patients with IPF and chronic cough and, to explore the antitussive mechanism of PA101, patients with chronic idiopathic cough (CIC) were also studied. Methods This pilot, proof-of-concept study consisted of a randomised, double-blind, placebo-controlled trial in patients with IPF and chronic cough and a parallel study of similar design in patients with CIC. Participants with IPF and chronic cough recruited from seven centres in the UK and the Netherlands were randomly assigned (1:1, using a computer-generated randomisation schedule) by site staff to receive PA101 (40 mg) or matching placebo three times a day via oral inhalation for 2 weeks, followed by a 2 week washout, and then crossed over to the other arm. Study participants, investigators, study staff, and the sponsor were masked to group assignment until all participants had completed the study. The primary efficacy endpoint was change from baseline in objective daytime cough frequency (from 24 h acoustic recording, Leicester Cough Monitor). The primary efficacy analysis included all participants who received at least one dose of study drug and had at least one post-baseline efficacy measurement. Safety analysis included all those who took at least one dose of study drug. In the second cohort, participants with CIC were randomly assigned in a study across four centres with similar design and endpoints. The study was registered with ClinicalTrials.gov (NCT02412020) and the EU Clinical Trials Register (EudraCT Number 2014-004025-40) and both cohorts are closed to new participants. Findings Between Feb 13, 2015, and Feb 2, 2016, 24 participants with IPF were randomly assigned to treatment groups. 28 participants with CIC were enrolled during the same period and 27 received study treatment. In patients with IPF, PA101 reduced daytime cough frequency by 31·1% at day 14 compared with placebo; daytime cough frequency decreased from a mean 55 (SD 55) coughs per h at baseline to 39 (29) coughs per h at day 14 following treatment with PA101, versus 51 (37) coughs per h at baseline to 52 (40) cough per h following placebo treatment (ratio of least-squares [LS] means 0·67, 95% CI 0·48–0·94, p=0·0241). By contrast, no treatment benefit for PA101 was observed in the CIC cohort; mean reduction of daytime cough frequency at day 14 for PA101 adjusted for placebo was 6·2% (ratio of LS means 1·27, 0·78–2·06, p=0·31). PA101 was well tolerated in both cohorts. The incidence of adverse events was similar between PA101 and placebo treatments, most adverse events were mild in severity, and no severe adverse events or serious adverse events were reported. Interpretation This study suggests that the mechanism of cough in IPF might be disease specific. Inhaled PA101 could be a treatment option for chronic cough in patients with IPF and warrants further investigation