Research towards novel immunotherapeutic vectors: calixarene scaffolds

The aim of this project was to generate a new type of therapeutic delivery system and immunogenic vector, based on calixarenes, that is able to not only deliver immunogenic peptide but also act as a potential cancer vaccine. The introduction presents calixarenes derivatives in the context of supramolecular chemistry. Their properties on the nanoscale allow them to be potential adjuvants for cancer immunotherapeutics

Syndecan-4 knockout leads to reduced extracellular transglutaminase-2 and protects against tubulointerstitial fibrosis

Transglutaminase type 2 (TG2) is an extracellular matrix crosslinking enzyme with a pivotal role in kidney fibrosis. The interaction of TG2 with the heparan sulfate proteoglycan syndecan-4 (Sdc4) regulates the cell surface trafficking, localization, and activity of TG2 in vitro but remains unstudied in vivo. We tested the hypothesis that Sdc4 is required for cell surface targeting of TG2 and the development of kidney fibrosis in CKD. Wild-type and Sdc4-null mice were subjected to unilateral ureteric obstruction and aristolochic acid nephropathy (AAN) as experimental models of kidney fibrosis. Analysis of renal scarring by Masson trichrome staining, kidney hydroxyproline levels, and collagen immunofluorescence demonstrated progressive fibrosis associated with increases in extracellular TG2 and TG activity in the tubulointerstitium in both models. Knockout of Sdc-4 reduced these effects and prevented AAN-induced increases in total and active TGF-b1. In wild-type mice subjected to AAN, extracellular TG2 colocalized with Sdc4 in the tubular interstitium and basement membrane, where TG2 also colocalized with heparan sulfate chains. Heparitinase I, which selectively cleaves heparan sulfate, completely abolished extracellular TG2 in normal and diseased kidney sections. In conclusion, the lack of Sdc4 heparan sulfate chains in the kidneys of Sdc4-null mice abrogates injury-induced externalization of TG2, thereby preventing profibrotic crosslinking of extracellular matrix and recruitment of large latent TGF-b1. This finding suggests that targeting the TG2- Sdc4 interaction may provide a specific interventional strategy for the treatment of CKD

Osteopetrosis and related osteoclast disorders in adults:A review and knowledge gapsOn behalf of the European calcified tissue society and ERN BOND

Osteopetrosis refers to a group of related rare bone diseases characterized by a high bone mass due to impaired bone resorption by osteoclasts. Despite the high bone mass, skeletal strength is compromised and the risk of fracture is high, particularly in the long bones. Osteopetrosis was classically categorized by inheritance pattern into autosomal recessive forms (ARO), which are severe and diagnosed within the first years of life, an intermediate form and an autosomal dominant (ADO) form; the latter with variable clinical severity and typically diagnosed during adolescence or in young adulthood. Subsequently, the AD form was shown to be a result of mutations in the gene CLCN7 encoding for the ClC-7 chloride channel). Traditionally, the diagnosis of osteopetrosis was made on radiograph appearance alone, but recent molecular and genetic advances have enabled a greater fidelity in classification of osteopetrosis subtypes. In the more severe ARO forms (e.g., malignant infantile osteopetrosis MIOP) typical clinical features have severe consequences and often result in death in early childhood. Major complications of ADO are atypical fractures with delay or failure of repair and challenge in orthopedic management. Bone marrow failure, dental abscess, deafness and visual loss are often underestimated and neglected in relation with lack of awareness and expertise. Accordingly, the care of adult patients with osteopetrosis requires a multidisciplinary approach ideally in specialized centers. Apart from hematopoietic stem cell transplantation in certain infantile forms, the treatment of patients with osteopetrosis, has not been standardized and remains supportive. Further clinical studies are needed to improve our knowledge of the natural history, optimum management and impact of osteopetrosis on the lives of patients living with the disorder

Raças fisiológicas e linhagens de uma população contemporânea de Magnaporthe oryzae associada à brusone do arroz irrigado no Sul do Brasil.

Objetivou-se identificar raças fisiológicas, com base em séries diferenciadoras, e linhagens, com base em marcadores microssatélites, em uma população de Magnaporthe oryzae do sul do Brasil

Constraints on s→dγs\to d \gamma from Radiative Hyperon and Kaon Decays

The quark-level process $b \to s \gamma$ has been used extensively to place constraints on new interactions. These same interactions can be further constrained from the enhancement they induce in the quark-level $s \to d \gamma$ transition, to the extent that the short distance contributions can be separated from the long distance contributions. We parameterize what is known about the long distance amplitudes and subtract it from the data in radiative hyperon and kaon decays to constrain new interactions.Comment: Latex 11 page

The standard model at low energies

The hadronic sector of the standard model at low energies is described by a non--decoupling effective field theory, chiral perturbation theory. An introduction is given to the construction of effective chiral Lagrangians, both in the purely mesonic sector and with inclusion of baryons. The connection between the relativistic formulation and the heavy baryon approach to chiral perturbation theory with baryons is reviewed.Comment: Lectures given at the 6th Indian-Summer School on Intermediate Energy Physics, Prague, Aug. 1993, Latex, 26 pages (with a4.sty), UWThPh-1993-3

Structural insights into crista junction formation by the Mic60-Mic19 complex

Mitochondrial cristae membranes are the oxidative phosphorylation sites in cells. Crista junctions (CJs) form the highly curved neck regions of cristae and are thought to function as selective entry gates into the cristae space. Little is known about how CJs are generated and maintained. We show that the central coiled-coil (CC) domain of the mitochondrial contact site and cristae organizing system subunit Mic60 forms an elongated, bow tie–shaped tetrameric assembly. Mic19 promotes Mic60 tetramerization via a conserved interface between the Mic60 mitofilin and Mic19 CHCH (CC-helix-CC-helix) domains. Dimerization of mitofilin domains exposes a crescent-shaped membrane-binding site with convex curvature tailored to interact with the curved CJ neck. Our study suggests that the Mic60-Mic19 subcomplex traverses CJs as a molecular strut, thereby controlling CJ architecture and function