Vasculitis in juvenile-onset systemic lupus erythematosus

© 2019 Smith, Lythgoe and Hedrich. Juvenile-onset systemic lupus erythematosus (JSLE) is a rare, heterogeneous multisystem autoimmune disease that can affect any organ, and present with diverse clinical and serological manifestations. Vasculitis can be a feature of JSLE. It more commonly presents as cutaneous vasculitis than visceral vasculitis, which can affect the central nervous system, peripheral nervous system, lungs, gut, kidneys, heart and large vessels. The incidence and prevalence of vasculitis in JSLE has not been well described to date. Symptoms of vasculitis can be non-specific and overlap with other features of JSLE, requiring careful consideration for the diagnosis to be achieved and promptly treated. Biopsies are often required to make a definitive diagnosis and differentiate JSLE related vasculitis from other manifestations of JSLE, vasculopathies and JSLE related antiphospholipid syndrome. Visceral vasculitis can be life threatening, and its presence at the time of JSLE diagnosis is associated with permanent organ damage, which further highlights the importance of prompt recognition and treatment. This review will focus on the presentation, diagnosis, management and outcomes of vasculitis in JSLE, highlighting gaps in the current evidence base

Sugar beet (Beta vulgaris) guard cells responses to salinity stress: a proteomic analysis

Soil salinity is a major environmental constraint affecting crop growth and threatening global food security. Plants adapt to salinity by optimizing the performance of stomata. Stomata are formed by two guard cells (GCs) that are morphologically and functionally distinct from the other leaf cells. These microscopic sphincters inserted into the wax-covered epidermis of the shoot balance CO2 intake for photosynthetic carbon gain and concomitant water loss. In order to better understand the molecular mechanisms underlying stomatal function under saline conditions, we used proteomics approach to study isolated GCs from the salt-tolerant sugar beet species. Of the 2088 proteins identified in sugar beet GCs, 82 were differentially regulated by salt treatment. According to bioinformatics analysis (GO enrichment analysis and protein classification), these proteins were involved in lipid metabolism, cell wall modification, ATP biosynthesis, and signaling. Among the significant differentially abundant proteins, several proteins classified as “stress proteins” were upregulated, including non-specific lipid transfer protein, chaperone proteins, heat shock proteins, inorganic pyrophosphatase 2, responsible for energized vacuole membrane for ion transportation. Moreover, several antioxidant enzymes (peroxide, superoxidase dismutase) were highly upregulated. Furthermore, cell wall proteins detected in GCs provided some evidence that GC walls were more flexible in response to salt stress. Proteins such as L-ascorbate oxidase that were constitutively high under both control and high salinity conditions may contribute to the ability of sugar beet GCs to adapt to salinity by mitigating salinity-induced oxidative stress

Is the Multiverse Hypothesis capable of explaining the Fine Tuning of Nature Laws and Constants? The Case of Cellular Automata

The objective of this paper is analyzing to which extent the multiverse hypothesis provides a real explanation of the peculiarities of the laws and constants in our universe. First we argue in favor of the thesis that all multiverses except Tegmark's > are too small to explain the fine tuning, so that they merely shift the problem up one level. But the > is surely too large. To prove this assessment, we have performed a number of experiments with cellular automata of complex behavior, which can be considered as universes in the mathematical multiverse. The analogy between what happens in some automata (in particular Conway's >) and the real world is very strong. But if the results of our experiments can be extrapolated to our universe, we should expect to inhabit -- in the context of the multiverse -- a world in which at least some of the laws and constants of nature should show a certain time dependence. Actually, the probability of our existence in a world such as ours would be mathematically equal to zero. In consequence, the results presented in this paper can be considered as an inkling that the hypothesis of the multiverse, whatever its type, does not offer an adequate explanation for the peculiarities of the physical laws in our world. A slightly reduced version of this paper has been published in the Journal for General Philosophy of Science, Springer, March 2013, DOI: 10.1007/s10838-013-9215-7.Comment: 30 pages, 16 figures, 5 tables. Slightly reduced version published in Journal for General Philosophy of Scienc

Calcium sensor kinase activates potassium uptake systems in gland cells of Venus flytraps

The Darwin plant Dionaea muscipula is able to grow on mineral-poor soil, because it gains essential nutrients from captured animal prey. Given that no nutrients remain in the trap when it opens after the consumption of an animal meal, we here asked the question of how Dionaea sequesters prey-derived potassium. We show that prey capture triggers expression of a K+ uptake system in the Venus flytrap. In search of K+ transporters endowed with adequate properties for this role, we screened a Dionaea expressed sequence tag (EST) database and identified DmKT1 and DmHAK5 as candidates. On insect and touch hormone stimulation, the number of transcripts of these transporters increased in flytraps. After cRNA injection of K+-transporter genes into Xenopus oocytes, however, both putative K+ transporters remained silent. Assuming that calcium sensor kinases are regulating Arabidopsis K+ transporter 1 (AKT1), we coexpressed the putative K+ transporters with a large set of kinases and identified the CBL9-CIPK23 pair as the major activating complex for both transporters in Dionaea K+ uptake. DmKT1 was found to be a K+-selective channel of voltage-dependent high capacity and low affinity, whereas DmHAK5 was identified as the first, to our knowledge, proton-driven, high-affinity potassium transporter with weak selectivity. When the Venus flytrap is processing its prey, the gland cell membrane potential is maintained around -120 mV, and the apoplast is acidified to pH 3. These conditions in the green stomach formed by the closed flytrap allow DmKT1 and DmHAK5 to acquire prey-derived K+, reducing its concentration from millimolar levels down to trace levels

Genetic dissection of granulomatous enterocolitis and arthritis in the intramural peptidoglycan-polysaccharide-treated rat model of IBD:

Inflammatory arthropathies are common extraintestinal manifestations of inflammatory bowel diseases (IBD). As genetic susceptibility plays an important role in the etiology of IBD, we questioned how granulomatous enterocolitis and arthritis are genetically controlled in an experimental animal model displaying both conditions

Mirror Symmetry and Other Miracles in Superstring Theory

The dominance of string theory in the research landscape of quantum gravity physics (despite any direct experimental evidence) can, I think, be justified in a variety of ways. Here I focus on an argument from mathematical fertility, broadly similar to Hilary Putnam's 'no miracles argument' that, I argue, many string theorists in fact espouse. String theory leads to many surprising, useful, and well-confirmed mathematical 'predictions' - here I focus on mirror symmetry. These predictions are made on the basis of general physical principles entering into string theory. The success of the mathematical predictions are then seen as evidence for framework that generated them. I attempt to defend this argument, but there are nonetheless some serious objections to be faced. These objections can only be evaded at a high (philosophical) price.Comment: For submission to a Foundations of Physics special issue on "Forty Years Of String Theory: Reflecting On the Foundations" (edited by G. `t Hooft, E. Verlinde, D. Dieks and S. de Haro)

CD14(+) monocytes contribute to inflammation in chronic nonbacterial osteomyelitis (CNO) through increased NLRP3 inflammasome expression

The pathophysiology of chronic nonbacterial osteomyelitis (CNO) remains incompletely understood. Increased NLRP3 inflammasome activation and IL-1β release in monocytes from CNO patients was suggested to contribute to bone inflammation. Here, we dissect immune cell infiltrates and demonstrate the involvement of monocytes across disease stages. Differences in cell density and immune cell composition may help to discriminate between BOM and CNO. However, differences are subtle and infiltrates vary in CNO. In contrast to other cells involved, monocytes are a stable element during all stages of CNO, which makes them a promising candidate in the search for “drivers” of inflammation. Furthermore, we link increased expression of inflammasome components NLRP3 and ASC in monocytes with site-specific DNA hypomethylation around the corresponding genes NLRP3 and PYCARD. Our observations deliver further evidence for the involvement of pro-inflammatory monocytes in the pathophysiology of CNO. Cellular and molecular alterations may serve as disease biomarkers and/or therapeutic targets

4-Aminopyridine is a promising treatment option for patients with gain-of-function KCNA2-encephalopathy

Developmental and epileptic encephalopathies are devastating disorders characterized by epilepsy, intellectual disability, and other neuropsychiatric symptoms, for which available treatments are largely ineffective. Following a precision medicine approach, we show for KCNA2-encephalopathy that the K+ channel blocker 4-aminopyridine can antagonize gain-of-function defects caused by variants in the KV1.2 subunit in vitro, by reducing current amplitudes and negative shifts of steady-state activation and increasing the firing rate of transfected neurons. In n-of-1 trials carried out in nine different centers, 9 of 11 patients carrying such variants benefitted from treatment with 4-aminopyridine. All six patients experiencing daily absence, myoclonic, or atonic seizures became seizure-free (except some remaining provoked seizures). Two of six patients experiencing generalized tonic-clonic seizures showed marked improvement, three showed no effect, and one worsening. Nine patients showed improved gait, ataxia, alertness, cognition, or speech. 4-Aminopyridine was well tolerated up to 2.6 mg/kg per day. We suggest 4-aminopyridine as a promising tailored treatment in KCNA2-(gain-of-function)–encephalopathy and provide an online tool assisting physicians to select patients with gain-of-function mutations suited to this treatment