Inhibition of the inositol kinase Itpkb augments calcium signaling in lymphocytes and reveals a novel strategy to treat autoimmune disease

Emerging approaches to treat immune disorders target positive regulatory kinases downstream of antigen receptors with small molecule inhibitors. Here we provide evidence for an alternative approach in which inhibition of the negative regulatory inositol kinase Itpkb in mature T lymphocytes results in enhanced intracellular calcium levels following antigen receptor activation leading to T cell death. Using Itpkb conditional knockout mice and LMW Itpkb inhibitors these studies reveal that Itpkb through its product IP4 inhibits the Orai1/Stim1 calcium channel on lymphocytes. Pharmacological inhibition or genetic deletion of Itpkb results in elevated intracellular Ca2+ and induction of FasL and Bim resulting in T cell apoptosis. Deletion of Itpkb or treatment with Itpkb inhibitors blocks T-cell dependent antibody responses in vivo and prevents T cell driven arthritis in rats. These data identify Itpkb as an essential mediator of T cell activation and suggest Itpkb inhibition as a novel approach to treat autoimmune disease

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

On the mechanisms governing gas penetration into a tokamak plasma during a massive gas injection

A new 1D radial fluid code, IMAGINE, is used to simulate the penetration of gas into a tokamak plasma during a massive gas injection (MGI). The main result is that the gas is in general strongly braked as it reaches the plasma, due to mechanisms related to charge exchange and (to a smaller extent) recombination. As a result, only a fraction of the gas penetrates into the plasma. Also, a shock wave is created in the gas which propagates away from the plasma, braking and compressing the incoming gas. Simulation results are quantitatively consistent, at least in terms of orders of magnitude, with experimental data for a D 2 MGI into a JET Ohmic plasma. Simulations of MGI into the background plasma surrounding a runaway electron beam show that if the background electron density is too high, the gas may not penetrate, suggesting a possible explanation for the recent results of Reux et al in JET (2015 Nucl. Fusion 55 093013)

Empresas constuctoras presentaron sus ofertas para el nuevo hospital de Abra Pampa

This article from the newspaper/news website "La Hora de Jujuy" describes the bidding process, and lists the amounts of six bids, for the construction of a new hospital in Abra Pampa called "Nuestra Señora del Rosario." Bids (presumably in Argentine dollars) range from $4.56 to$5.83 million. The bidders include Forbice Estudio y Construcciones, Dinarco S.A., Mogro Construcciones, Villanueva e Hijos S.A., Savio Construcciones S.A., and Prima Ingeniería-Ramella.La

Substitution of rare-earth alloying elements by ubiquitous elements in magnesium alloys: In depth study of the precipitation kinetics and hardening mechanisms of a binary alloy Mg-Ca

Mechanical, Maritime and Materials EngineeringTechnische Materiaalwetenschappe

Fish of Deolali. Part III. On two new species and notes on some other forms

Volume: 40Start Page: 20End Page: 3

Factura sin destinatario, 1930 marzo 6, Madrid, de Fábrica y Almacén de Relojes La Hora

Factura impresa escrita a manoAlcance y contenido: Versa sobre la compra de un relojEn el membrete: Fuencarral, 23, Madrid. Casa fundada en el año 1860. Grandes talleres de composturasMembrete del establecimiento con fotografías en blanco y negro de la fachada y del interior del mismo, de MoratallaPapel color cremaEn la parte inferior: "Cisneros, Puebla, 14. 2000-12-29

Recortes de periódicos del Centro de Investigaciones Regionales de Mesoamérica, 1978

Cien textos crudos extraídos de artículos periodísticos de Guatemala y un archivo con sus metadatos. Las noticias datan del 26 de abril al 31 de mayo de 1978. Los artículos son una pequeña parte de la colección "Recortes de periódicos" del Centro de investigaciones regionales de Mesoamérica (CIRMA). A hundred raw text extracted from journal articles from Guatemala and a file with their metadata. The news are from April 26th to May 31st, 1978. The articles are a small part of the collection "Newspaper clippings" from the Center of Regional Research of Mesoamerica (CIRMA)

[La hora del cuento (Barcelona.1994)]

Copia digital. España : Ministerio de Cultura y Deporte. Subdirección General de Cooperación Bibliotecari