Human helminth therapy to treat inflammatory disorders - where do we stand?

Parasitic helminths have evolved together with the mammalian immune system over many millennia and as such they have become remarkably efficient modulators in order to promote their own survival. Their ability to alter and/or suppress immune responses could be beneficial to the host by helping control excessive inflammatory responses and animal models and pre-clinical trials have all suggested a beneficial effect of helminth infections on inflammatory bowel conditions, MS, asthma and atopy. Thus, helminth therapy has been suggested as a possible treatment method for autoimmune and other inflammatory disorders in humans

Institutional guidelines and ongoing studies in management of liver tumours: the experience of the European Institute of Oncology

An institutional task force on upper gastrointestinal tumours is active at the European Institute of Oncology (EIO). Members decided to collate the institutional guidelines on management of liver tumours (primary and metastatic) into a document. This article is aimed at presenting the current treatment guidelines as well as ongoing research protocols and trials in this field at the EIO

iPSC-derived neuronal models of PANK2-associated neurodegeneration reveal mitochondrial dysfunction contributing to early disease

Mutations in PANK2 lead to neurodegeneration with brain iron accumulation. PANK2 has a role in the biosynthesis of coenzyme A (CoA) from dietary vitamin B5, but the neuropathological mechanism and reasons for iron accumulation remain unknown. In this study, atypical patient-derived fibroblasts were reprogrammed into induced pluripotent stem cells (iPSCs) and subsequently differentiated into cortical neuronal cells for studying disease mechanisms in human neurons. We observed no changes in PANK2 expression between control and patient cells, but a reduction in protein levels was apparent in patient cells. CoA homeostasis and cellular iron handling were normal, mitochondrial function was affected; displaying activated NADH-related and inhibited FADH-related respiration, resulting in increased mitochondrial membrane potential. This led to increased reactive oxygen species generation and lipid peroxidation in patient-derived neurons. These data suggest that mitochondrial deficiency is an early feature of the disease process and can be explained by altered NADH/FADH substrate supply to oxidative phosphorylation. Intriguingly, iron chelation appeared to exacerbate the mitochondrial phenotype in both control and patient neuronal cells. This raises caution for the use iron chelation therapy in general when iron accumulation is absent

A wide-field photometric study of the globular cluster system of NGC 4636

We investigate the unusually rich cluster system of NGC4636 with wide-field Washington photometry. The globular cluster luminosity function can be followed roughly 1 mag beyond the turn-over magnitude. This corresponds to a distance modulus of m-M=31.24+-0.17, 0.4 mag larger than the distance determined from surface brightness fluctuations. The high specific frequency is confirmed, yet the exact value remains uncertain because of the uncertain distance: it varies between 5.6+-1.2 and 8.9+-1.2. The globular cluster system has a clearly bimodal color distribution. The color peak positions show no radial dependence and are in good agreement with the values found for other galaxies studied in the same filter system. However, a luminosity dependence is found: brighter clusters with an ``intermediate'' color exist. The clusters exhibit a shallow radial distribution within 7'.Within the same radial interval, the galaxy light has a distinctly steeper profile. Because of the difference in the cluster and light distribution the specific frequency increases considerably with radius. At 7' and 9' the density profiles of the red and blue clusters, respectively, change strongly which indicates that we reach the outer rim of the cluster system at approximately 11'. This feature is seen for the first time in a globular cluster system. While the radial distribution of the cluster and field populations are rather different, this is not true for the ellipticity of the system: the elongation as well as the position angle of the cluster system agree well with the galaxy light. We compare the radial distribution of globular clusters with the light profiles for a sample of elliptical galaxies. The difference observed in NGC 4636 is typical of an elliptical galaxy of this luminosity.Comment: Accepted for publication in A&A, 16 pages, 15 figure

Cell-free H-cluster Synthesis and [FeFe] Hydrogenase Activation: All Five CO and CN− Ligands Derive from Tyrosine

[FeFe] hydrogenases are promising catalysts for producing hydrogen as a sustainable fuel and chemical feedstock, and they also serve as paradigms for biomimetic hydrogen-evolving compounds. Hydrogen formation is catalyzed by the H-cluster, a unique iron-based cofactor requiring three carbon monoxide (CO) and two cyanide (CN−) ligands as well as a dithiolate bridge. Three accessory proteins (HydE, HydF, and HydG) are presumably responsible for assembling and installing the H-cluster, yet their precise roles and the biosynthetic pathway have yet to be fully defined. In this report, we describe effective cell-free methods for investigating H-cluster synthesis and [FeFe] hydrogenase activation. Combining isotopic labeling with FTIR spectroscopy, we conclusively show that each of the CO and CN− ligands derive respectively from the carboxylate and amino substituents of tyrosine. Such in vitro systems with reconstituted pathways comprise a versatile approach for studying biosynthetic mechanisms, and this work marks a significant step towards an understanding of both the protein-protein interactions and complex reactions required for H-cluster assembly and hydrogenase maturation