Alpha-Synuclein Autoimmune Decline in Prodromal Multiple System Atrophy and Parkinson’s Disease

Multiple-system trophy (MSA) and Parkinson’s Disease (PD) are both progressive, neurodegenerative diseases characterized by neuropathological deposition of aggregated alpha-synuclein (αSyn). The causes behind this aggregation are still unknown. We have reported aberrancies in MSA and PD patients in naturally occurring autoantibodies (nAbs) against αSyn (anti-αSyn-nAbs), which are important partakers in anti-aggregatory processes, immune-mediated clearance, and anti-inflammatory functions. To elaborate further on the timeline of autoimmune aberrancies towards αSyn, we investigated here the Immunoglobulin (Ig) affinity profile and subclass composition (IgG-total, IgG1-4 and IgM) of anti-αSyn-nAbs in serum samples from prodromal (p) phases of MSA and PD. Using an electrochemiluminescence competition immunoassay, we confirmed that the repertoire of high-affinity anti-αSyn-nAbs is significantly reduced in pMSA and pPD. Further, we demonstrated that pPD had increased anti-αSyn IgG-total levels compared to pMSA and controls, concordant with increased anti-αSyn IgG1 levels in pPD. Anti-αSyn IgG2 and IgG4 levels were reduced in pMSA and pPD compared with controls, whereas anti-αSyn IgG3 levels were reduced in pMSA compared to pPD and controls. The results indicate that the impaired reactivity towards αSyn occurs prior to disease onset. The apparent lack of high-affinity anti-αSyn nAbs may result in reduced clearance of αSyn, leading to aggregation of the protein. Thus, this study provides novel insights into possible causes behind the pathogenesis in synucleinopathies such as MSA and PD.     

Tumor Infiltration with CD20+CD73+ B Cells Correlates with Better Outcome in Colorectal Cancer

Immunotherapy has become increasingly important in the treatment of colorectal cancer (CRC). Currently, CD73, also known as ecto-5′-nucleotidase (NT5E), has gained considerable interest as a potential therapeutic target. CD73 is one of the key enzymes catalyzing the conversion of extracellular ATP into adenosine, which in turn exerts potent immune suppressive effects. However, the role of CD73 expression on various cell types within the CRC tumor microenvironment remains unresolved. The expression of CD73 on various cell types has been described recently, but the role of CD73 on B-cells in CRC remains unclear. Therefore, we analyzed CD73 on B-cells, especially on tumor-infiltrating B-cells, in paired tumor and adjacent normal tissue samples from 62 eligible CRC patients. The highest expression of CD73 on tumor-infiltrating B-cells was identified on class-switched memory B-cells, followed by naive B-cells, whereas no CD73 expression was observed on plasmablasts. Clinicopathological correlation analysis revealed that higher CD73⁺ B-cells infiltration in the CRC tumors was associated with better overall survival. Moreover, metastasized patients showed a significantly decreased number of tumor-infiltrating CD73⁺ B-cells. Finally, neoadjuvant therapy correlated with reduced CD73⁺ B-cell numbers and CD73 expression on B-cells in the CRC tumors. As promising new immune therapies are being developed, the role of CD73⁺ B-cells and their subsets in the development of colorectal cancer should be further explored to find new therapeutic options.     

Enabling Coarse X-ray Fluorescence Imaging Scans with Enlarged Synchrotron Beam by Means of Mosaic Crystal Defocusing Optics

Trace elements, functionalized nanoparticles and labeled entities can be localized with sub-mm spatial resolution by X-ray fluorescence imaging (XFI). Here, small animals are raster scanned with a pencil-like synchrotron beam of high energy and low divergence and the X-ray fluorescence is recorded with an energy-dispersive detector. The ability to first perform coarse scans to identify regions of interest, followed by a close-up with a sub-mm X-ray beam is desirable, because overall measurement time and X-ray dose absorbed by the (biological) specimen can thus be minimized. However, the size of X-ray beams at synchrotron beamlines is usually strongly dependent on the actual beamline setup and can only be adapted within specific pre-defined limits. Especially, large synchrotron beams are non-trivial to generate. Here, we present the concept of graphite-based, convex reflection optics for the one-dimensional enlargement of a 1 mm wide synchrotron beam by a factor of 5 to 10 within a 1 m distance. Four different optics are tested and characterized and their reflection properties compared to ray tracing simulations. The general shape and size of the measured reflection profiles agree with expectations. Enhancements with respect to homogeneity and efficiency can be expected with improved optics manufacturing. A mouse phantom is used for a proof-of-principle XFI experiment demonstrating the applicability of coarse and fine scans with the suggested optics design.     

Effects of Long-Term Temozolomide Treatment on Glioblastoma and Astrocytoma WHO Grade 4 Stem-like Cells

Glioblastoma leads to a fatal course within two years in more than two thirds of patients. An essential cornerstone of therapy is chemotherapy with temozolomide (TMZ). The effect of TMZ is counteracted by the cellular repair enzyme O⁶-methylguanine-DNA methyltransferase (MGMT). The MGMT promoter methylation, the main regulator of MGMT expression, can change from primary tumor to recurrence, and TMZ may play a significant role in this process. To identify the potential mechanisms involved, three primary stem-like cell lines (one astrocytoma with the mutation of the isocitrate dehydrogenase (IDH), CNS WHO grade 4 (HGA)), and two glioblastoma (IDH-wildtype, CNS WHO grade 4) were treated with TMZ. The MGMT promoter methylation, migration, proliferation, and TMZ-response of the tumor cells were examined at different time points. The strong effects of TMZ treatment on the MGMT methylated cells were observed. Furthermore, TMZ led to a loss of the MGMT promoter hypermethylation and induced migratory rather than proliferative behavior. Cells with the unmethylated MGMT promoter showed more aggressive behavior after treatment, while HGA cells reacted heterogenously. Our study provides further evidence to consider the potential adverse effects of TMZ chemotherapy and a rationale for investigating potential relationships between TMZ treatment and change in the MGMT promoter methylation during relapse.     

A Java Framework to Specify Faultloads for Fault Injection Campaigns

In an operational environment, the identification and reproduction of faults may be hard to be done, specially in complex systems. Use of fault injection accelerates this process, improving the test of fault tolerance mechanisms. However, there are a significant amount of fault injectors available, using several different approaches. This diversity of tools, each one with different methods to describe faultloads for fault injection campaigns, imposes severe obstacles to the efficient use of such fault injectors. In this context, this paper presents jFaultload, which applies Java for the specification of faultloads and translates them to specific formats that are appropriate to each available fault injector. Fault injectors for communication systems were integrated in the environment and completes the test scenario. The service under test used to demonstrate the usability and expressiveness of our solution is a video streaming session using RTP Protocol.     

Stereoisomere Aromastoffe

Zusammenfassung Es werden Methoden zur racemisie-rungsfreien Stereodifferenzierung der 2-Methylbuttersäure (direkt bzw. nach Esterhydrolyse) aus Äpfeln und apfelhaltigen Lebensmitteln beschrieben. Die Enantiomerenverteilung der 2-Methylbuttersäure kann direkt an permethylierter-Cyclodextrinphase gaschromatogra-phisch bestimmt werden. Es wird stets hoher Enantiomerenüberschuß zugunsten des (S)-Isomeren der Säure nachgewiesen. Proben von naturidentischem und natürlichem (biotechnologisch hergestelltem) 2-Methyl-buttersäureethylester sowie Äpfel, Apfelsaft, Apfellikör, Calvados, Apfelwein, Apfelmarmelade und Joghurts mit Apfelzusatz werden untersucht. Ein Zusatz von naturidentischen, racemischen 2-Methylbuttersäureestern ist einfach nachweisbar.

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Stereoisomeric flavour compounds. XLII. Enantiomer distribution of 2-methylbutanoic acid in apples and apple-containing food

Summary The direct Stereodifferentiation of 2-methyl-butanoic acid and its esters (after hydrolysis) from apples and apple-containing food is described, using permethyl-ated-cyclodextrin as the chiral CGC phase. In all cases, high enantiomeric excess in favour of the (S)-enantiomer was ascertained. The method is applicable to apples, apple juice, apple liquor, calvados, apple wine, apple jam and apple-containing yoghurts. The addition of race-mic (nature-identical) esters may be easily detected.

     

Chemical natures and distributions of metal impurities in multicrystalline silicon materials

We present a comprehensive summary of our observations of metal‐rich particles in multicrystalline silicon (mc‐Si) solar cell materials from multiple vendors, including directionally‐solidified ingot‐grown, sheet, and ribbon, as well as multicrystalline float zone materials contaminated during growth. In each material, the elemental nature, chemical states, and distributions of metal‐rich particles are assessed by synchrotron‐based analytical x‐ray microprobe techniques. Certain universal physical principles appear to govern the behavior of metals in nearly all materials: (a) Two types of metal‐rich particles can be observed (metal silicide nanoprecipitates and metal‐rich inclusions up to tens of microns in size, frequently oxidized), (b) spatial distributions of individual elements strongly depend on their solubility and diffusivity, and (c) strong interactions exist between metals and certain types of structural defects. Differences in the distribution and elemental nature of metal contamination between different mc‐Si materials can largely be explained by variations in crystal growth parameters, structural defect types, and contamination sources. Copyright © 2006 John Wiley & Sons, Ltd.