Ectodysplasin A (EDA) - EDA receptor signalling and its pharmacological modulation.

The TNF family ligand ectodysplasin A (EDA) regulates the induction, morphogenesis and/or maintenance of skin-derived structures such as teeth, hair, sweat glands and several other glands. Deficiencies in the EDA - EDA receptor (EDAR) signalling pathway cause hypohidrotic ectodermal dysplasia (HED). This syndrome is characterized by the absence or malformation of several skin-derived appendages resulting in hypotrychosis, hypodontia, heat-intolerance, dry skin and dry eyes, susceptibility to airways infections and crusting of various secretions. The EDA-EDAR system is an important effector of canonical Wnt signalling in developing skin appendages. It functions by stimulating NF-κB-mediated transcription of effectors or inhibitors of the Wnt, Sonic hedgehog (SHH), fibroblast growth factor (FGF) and transforming growth factor beta (TGFβ) pathways that regulate interactions within or between epithelial and mesenchymal cells and tissues. In animal models of Eda-deficiency, soluble EDAR agonists can precisely correct clinically relevant symptoms with low side effects even at high agonist doses, indicating that efficient negative feedback signals occur in treated tissues. Hijacking of the placental antibody transport system can help deliver active molecules to developing foetuses in a timely manner. EDAR agonists may serve to treat certain forms of ectodermal dysplasia

The Big Occulting Steerable Satellite (BOSS)

Natural (such as lunar) occultations have long been used to study sources on small angular scales, while coronographs have been used to study high contrast sources. We propose launching the Big Occulting Steerable Satellite (BOSS), a large steerable occulting satellite to combine both of these techniques. BOSS will have several advantages over standard occulting bodies. BOSS would block all but about 4e-5 of the light at 1 micron in the region of interest around the star for planet detections. Because the occultation occurs outside the telescope, scattering inside the telescope does not degrade this performance. BOSS could be combined with a space telescope at the Earth-Sun L2 point to yield very long integration times, in excess of 3000 seconds. If placed in Earth orbit, integration times of 160--1600 seconds can be achieved from most major telescope sites for objects in over 90% of the sky. Applications for BOSS include direct imaging of planets around nearby stars. Planets separated by as little as 0.1--0.25 arcseconds from the star they orbit could be seen down to a relative intensity as little as 1e-9 around a magnitude 8 (or brighter) star. Other applications include ultra-high resolution imaging of compound sources, such as microlensed stars and quasars, down to a resolution as little as 0.1 milliarcseconds.Comment: 25pages, 4 figures, uses aaspp4, rotate, and epsfig. Submitted to the Astrophysical Journal. For more details see http://erebus.phys.cwru.edu/~boss

Characterizing the Existence of Optimal Proof Systems and Complete Sets for Promise Classes.

In this paper we investigate the following two questions: Q1: Do there exist optimal proof systems for a given language L? Q2: Do there exist complete problems for a given promise class C? For concrete languages L (such as TAUT or SAT) and concrete promise classes C (such as NP∩coNP, UP, BPP, disjoint NP-pairs etc.), these ques-tions have been intensively studied during the last years, and a number of characterizations have been obtained. Here we provide new character-izations for Q1 and Q2 that apply to almost all promise classes C and languages L, thus creating a unifying framework for the study of these practically relevant questions. While questions Q1 and Q2 are left open by our results, we show that they receive affirmative answers when a small amount on advice is avail-able in the underlying machine model. This continues a recent line of research on proof systems with advice started by Cook and Kraj́ıček [6]

Analysis of polyphenolic composition and stability of magistral preparation based on salviae officinalis folium

A magistral preparation based on the sage leaf decoction or infusion is one of the most popular herbal prescriptions prepared in pharmacies in Lower Silesia (Poland) for gargling in the case of pharyngitis or mouth infections. Other components of this preparation are boric acid, aluminum(III) acetotartrate or Burow's solution, and glycerol. The study aimed to investigate the polyphenolic composition and relations between herbal and chemical ingredients that are present in this mixture in comparison with the traditional aqueous galenic forms - infusion and decoction. The analysis was performed using high-performance liquid chromatography with diode-array detector (HPLC-DAD) and electrospray ionization mass spectrometry (ESI-MS) methods. The main polyphenolic ingredients of sage leaf were rosmarinic acid (RA) and luteolin 7-O-β-glucuronide. The RA predominance was observed in the infusion, decoction and magistral preparation. Comparing the contents of analyzed polyphenols, it was confirmed that their levels in the decoction were higher than in the infusion. Thus, the pharmacological activity of the examined magistral preparation results from the presence of boric acid, aluminum(III) salts and polyphenolic components of sage leaf hot water extract. The succeeding study showed that in the presence of excess salts of aluminum(III) and boric acid, sage polyphenols are partially soluble in an aqueous medium (mainly phenolic acids) and complexed as precipitated sediment (especially flavonoids). The aqueous solutions of this preparation obtained according to the recommendation are cloudy, which suggests limited solubility of the formed complexes. Therefore, the therapeutic activity should be associated with the presence of water-soluble caffeic acid esters like rosmarinic acid. The influence of luteolin glycosides coordination complexes is not evident. The obtained results also confirm the stability of the examined prescription formulation in the conditions of cold storage (4-6OC) within 7 days from its production

Familial Glucocorticoid Deficiency: New Genes and Mechanisms

PhDMutations in the melanocortin 2 receptor (MC2R) and its accessory protein (MRAP), in the ACTH signalling pathway, and the antioxidant genes nicotinamide nucleotide transhydrogenase (NNT) and thioredoxin reductase 2 (TXNRD2) have been associated with familial glucocorticoid deficiency (FGD). Using a tandem affinity purification and mass spectrometry approach to identify interacting partners of MC2R and MRAP failed to identify putative candidate genes for further FGD cases. However in a male patient a homozygous mutation in another antioxidant gene, glutathione peroxidase 1 (GPX1), was identified. In vitro studies showed H295R cells with knockdown of GPX1 had 50% less basal GPX activity and were less viable than wild-type when exposed to oxidative stress. Adrenals from Gpx1-/- mice showed no gross morphological changes and corticosterone levels were not significantly different from their wild-type counterparts (in contrast to the Nnt mutants). Sequencing of >100 FGD patients did not reveal any other GPX1 mutations. This equivocal data lead to the hypothesis that there could be a second gene defect present in this proband contributing to his disease. Whole exome sequencing revealed a homozygous loss-of-function mutation in peroxiredoxin 3 PRDX3 (p.Q67X) in this patient, that was also present in his unaffected brother. In vitro studies revealed both single and double knockdown of the two genes in H295R cells reduced cell viability, but redox homeostasis and cortisol production were unaffected. GPXs and PRDXs work simultaneously to reduce H2O2, preventing cellular damage. My data suggest that loss of PRDX3 alone is insufficient to cause adrenal failure and further that mutation in GPX1, either alone or in combination with PRDX3 mutation, may tip the redox balance to cause FGD.Medical Research Council and Barts and the London Charit

Inhibition of Membrane-Bound BAFF by the Anti-BAFF Antibody Belimumab.

B cell activating factor of the TNF family (BAFF, also known as BLyS), a cytokine that regulates homeostasis of peripheral B cells, is elevated in the circulation of patients with autoimmune diseases such as systemic lupus erythematosus (SLE). BAFF is synthetized as a membrane-bound protein that can be processed to a soluble form after cleavage at a furin consensus sequence, a site that in principle can be recognized by any of the several proteases of the pro-protein convertase family. Belimumab is a human antibody approved for the treatment of SLE, often cited as specific for the soluble form of BAFF. Here we show in different experimental systems, including in a monocytic cell line (U937) that naturally expresses BAFF, that belimumab binds to membrane-bound BAFF with similar EC50 as the positive control atacicept, which is a decoy receptor for both BAFF and the related cytokine APRIL (a proliferation inducing ligand). In U937 cells, binding of both reagents was only detectable in furin-deficient U937 cells, showing that furin is the main BAFF processing protease in these cells. In CHO cells expressing membrane-bound BAFF lacking the stalk region, belimumab inhibited the activity of membrane-bound BAFF less efficiently than atacicept, while in furin-deficient U937 cells, belimumab inhibited membrane-bound BAFF and residual soluble BAFF as efficiently as atacicept. These reagents did not activate complement or antibody-dependent cell cytotoxicity upon binding to membrane-bound BAFF in vitro. In conclusion, our data show that belimumab can inhibit membrane-bound BAFF, and that BAFF in U937 cells is processed by furin

Réservoir extra-digestif d’entérobactéries productrices de bêtalactamase à spectre élargi chez des patients non infectés: étude à partir d’une recherche systématique dans les urines et d’autres prélèvements à visée diagnostique

Notre objectif était d’étudier le réservoir extra-digestif d’entérobactéries productrices de β-lactamases à spectre élargi (EBLSE) en les recherchant dans des prélèvements à visée diagnostique (PVD) pour lesquels les colonies bactériennes isolées sur les milieux de cultures utilisés ne sont pas obligatoirement analysées (identification bactérienne et antibiogramme) en routine. Pendant une période de 5 semaines, des identifications et des antibiogrammes ont été réalisés de manière systématique pour les colonies correspondant à des entérobactéries isolées dans certains PVD comme les urines, les prélèvements respiratoires, et un groupe de prélèvements appelé “divers”. Les prélèvements pour lesquels un antibiogramme a été réalisé conformément à la pratique de routine du laboratoire ont été considérés comme infectés. Les prélèvements pour lesquels les entérobactéries ont été recherchées et étudiées suivant le protocole de l’étude ont été considérés comme colonisés. Au cours de l’étude, 2 312 urines, 327 prélèvements respiratoires et 1 887 prélèvements divers ont été envoyés au laboratoire. Parmi les 114 urines colonisées par au moins une entérobactérie, 13 (11,4 %) comportaient une EBLSE, alors que cette proportion était de 5,1 % (35/682) dans les urines infectées (p < 0,01). Parmi les prélèvements respiratoires et divers, 3 EBLSE ont été isolées dans 55 prélèvements colonisés par au moins une entérobactérie. Au total, la recherche systématique d’EBLSE dans les PVD a permis une augmentation de 27,7 % du nombre de patients identifiés comme porteurs de ces bactéries. D’autres études pourraient être utiles pour évaluer l’intérêt de mettre en place une telle stratégie comme alternative au dépistage rectal habituellement pratiqué

Ophthalmic evaluation of diagnosed cases of eye cystinosis: A tertiary care center’s experience

Background: We aimed to identify diagnosed cases of ocular cystinosis and describe clinical, epidemiological and therapeutic characteristics. Methods: This is a descriptive and retrospective case series. All patients underwent a full check-up examination every 4–6 months by ophthalmologists, nephrologists and other required specialists. Results: Of the seven cases, six (85.7%) were females and one (14.2%) was male. The infantile nephropathic form of cystinosis was observed in five patients and the juvenile nephropathic form in two patients. No patients with the ocular form of cystinosis were identified. Corneal cystine crystals (CCC) were found in all analyzed patients. Severe ocular and general complications of the disease that had been standing for years, connected to the infantile nephropathic form, delayed diagnosis or inappropriate treatment, were observed only in two patients. All patients received topical therapy. No adverse events related to the therapy were observed. Conclusions: Cystinosis is a rare, progressive disease. Early diagnosis and treatment prevent serious complications from numerous systemic organs. Patients require constant systematic monitoring by various specialists

Shrinking Point Bifurcations of Resonance Tongues for Piecewise-Smooth, Continuous Maps

Resonance tongues are mode-locking regions of parameter space in which stable periodic solutions occur; they commonly occur, for example, near Neimark-Sacker bifurcations. For piecewise-smooth, continuous maps these tongues typically have a distinctive lens-chain (or sausage) shape in two-parameter bifurcation diagrams. We give a symbolic description of a class of "rotational" periodic solutions that display lens-chain structures for a general $N$-dimensional map. We then unfold the codimension-two, shrinking point bifurcation, where the tongues have zero width. A number of codimension-one bifurcation curves emanate from shrinking points and we determine those that form tongue boundaries.Comment: 27 pages, 6 figure

Chromatin signatures at transcriptional start sites separate two equally populated yet distinct classes of intergenic long noncoding RNAs

Background: Mammalian transcriptomes contain thousands of long noncoding RNAs (lncRNAs). Some lncRNAs originate from intragenic enhancers which, when active, behave as alternative promoters producing transcripts that are processed using the canonical signals of their host gene. We have followed up this observation by analyzing intergenic lncRNAs to determine the extent to which they might also originate from intergenic enhancers. Results: We integrated high-resolution maps of transcriptional initiation and transcription to annotate a conservative set of intergenic lncRNAs expressed in mouse erythroblasts. We subclassified intergenic lncRNAs according to chromatin status at transcriptional initiation regions, defined by relative levels of histone H3K4 mono- and trimethylation. These transcripts are almost evenly divided between those arising from enhancer-associated (elncRNA) or promoter-associated (plncRNA) elements. These two classes of 5′ capped and polyadenylated RNA transcripts are indistinguishable with regard to their length, number of exons or transcriptional orientation relative to their closest neighboring gene. Nevertheless, elncRNAs are more tissue-restricted, less highly expressed and less well conserved during evolution. Of considerable interest, we found that expression of elncRNAs, but not plncRNAs, is associated with enhanced expression of neighboring protein-coding genes during erythropoiesis. Conclusions: We have determined globally the sites of initiation of intergenic lncRNAs in erythroid cells, allowing us to distinguish two similarly abundant classes of transcripts. Different correlations between the levels of elncRNAs, plncRNAs and expression of neighboring genes suggest that functional lncRNAs from the two classes may play contrasting roles in regulating the transcript abundance of local or distal loci