Genetic Insights into the Impact of Complement in Alzheimer’s Disease

The presence of complement activation products at sites of pathology in post-mortem Alzheimer’s disease (AD) brains is well known. Recent evidence from genome-wide association studies (GWAS), combined with the demonstration that complement activation is pivotal in synapse loss in AD, strongly implicates complement in disease aetiology. Genetic variations in complement genes are widespread. While most variants individually have only minor effects on complement homeostasis, the combined effects of variants in multiple complement genes, referred to as the “complotype”, can have major effects. In some diseases, the complotype highlights specific parts of the complement pathway involved in disease, thereby pointing towards a mechanism; however, this is not the case with AD. Here we review the complement GWAS hits; CR1 encoding complement receptor 1 (CR1), CLU encoding clusterin, and a suggestive association of C1S encoding the enzyme C1s, and discuss difficulties in attributing the AD association in these genes to complement function. A better understanding of complement genetics in AD might facilitate predictive genetic screening tests and enable the development of simple diagnostic tools and guide the future use of anti-complement drugs, of which several are currently in development for central nervous system disorders.

Prompt and delayed gamma rays induced by epithermal and fast neutrons with indium

The emission of prompt and delayed gamma rays from (n,γ) and (n,n´γ) reactions induced by irradiation of indium with epithermal and fast neutrons was investigated with the instrument FaNGaS operated at Heinz-Maier-Leibnitz Zentrum (MLZ) in Garching. The average neutron energy of the neutron spectrum was 2.30 MeV. The measurement was done at an angle of 90° between neutron beam and detector. A total of 136 prompt gamma lines from which 42 are related to the capture of epithermal and fast neutrons and 94 to the inelastic scattering of fast neutrons were detected together with the delayed gamma lines of the activation products 113mIn, 114m2In, 115mIn, 116m2In and 116mIn. Intensities and neutron spectrum averaged isotopic partial cross section of the gamma lines are presented. Additionally the neutron spectrum averaged cross sections of the reactions, 113In(n,n´)113mIn, 113In(n,γ)114m2In, 115In(n,n´)15mIn, 115In(n, γ)116m2In and 115In(n, γ)116mIn were determined from the corresponding delayed gamma rays of the formed isotopes as 143 ± 22, 288 ± 13 194 ± 18, 201 ± 10 and 508 ± 24 mb respectively. The various results obtained were found consistent with the literature data. However, our measurement indicate the need to reevaluate the cross section of the 115In(n,γ)116m2In reaction for thermal neutrons.

Radioactive Fission Waste from Molybdenum-99 Production and Proliferation Risks

Molybdenum-99 (99Mo) is a parent radioisotope of Technetium-99m (99mTc) widely used in nuclear diagnostics. The production of this radioisotope by PT. INUKI generated radioactive fission waste (RFW) that theoretically contains239Pu and235U, posing a nuclear proliferation risk. This paper discusses the determination of radionuclides inventory in the RFW and the proposed strategy for its management. The radionuclides inventory in the RFW was calculated using ORIGEN 2.1 code. The input parameters were obtained from one batch of 99Mo production using high enriched uranium in PT. INUKI. The result showed that the RFW contained activation products, actinides, and fission products, including239Pu and235U. This result was then used for consideration of the management of the RFW. The concentration of 235U was reduced by a down-blending method. The proposed strategy to further manage the down-blended RFW was converting it to U3O8 solid form, placed in a canister, and eventually stored in the interim storage for high-level waste located in The Radioactive Waste Technology Center.

Aluminum Oxide Catalysts and Supports Obtained by Thermal Activation

The paper considers the main methods used to obtain aluminum oxides; the advantages of using hydrargillite thermal activation products for the synthesis of catalysts, supports and sorbents; the factors affecting the properties of thermal activation products and aluminum oxides obtained by thermal activation; and examples of the efficient application of hydrargillite centrifugal thermal activation products in the synthesis of catalysts, supports and sorbents.

Spectroscopic and chemical investigations on volatile fission and activation products within the fuel-cladding interface of irradiated pressurised water reactor fuel rod segments

In Germany, the present waste management concept foresees the direct disposal of spent nuclear fuel (SNF) in deep geological repositories for high-level waste available by 2050, at best. Until then, SNF is encapsulated in dual-purpose casks and stored in dry interim storage facilities. Licenses for both casks and facilities will expire after 40 years following loading of the cask and emplacement of the first cask in the storage location. Yet, due to considerable delays in the site selection process and the estimated duration for construction and commissioning of a final repository of at least 2 decades, a prolonged dry interim storage of SNF is inevitable (ESK, 2015). Concerning these considerable timespans, integrity of the cladding is of utmost importance regarding the ultimately conditioning of the fuel assemblies for final disposal. Various processes strain the structural integrity of Zircaloy cladding during reactor operation and beyond such as delayed hydride cracking, fuel-cladding chemical interactions or irradiation damage induced by α-emitters present in the fuel pellet's rim zone (Ewing, 2015). Especially with higher burn-up, the gap between fuel and cladding closes and results in the formation of an interaction layer, in which precipitates of fission and activation products are present, displaying an interface for degradation processes. For chemical analysis and speciation of these agglomerates, Zircaloy-4 and SNF specimens were sampled from fuel rod segments irradiated in commercial pressurised water reactors during the 1980s. Zircaloy-4 specimens were taken from an UOX (50.4 GWdtHM-1) and mixed oxide fuel (MOX) (38.0 GWdtHM-1). In addition, SNF fragments were sampled from the closed gap of both fuel types to examine volatile activation and fission products, which had been segregated from the centre to the pellet periphery during irradiation and thus contribute to the possible chemically assisted cladding degradation effect of the precipitates within the fuel-cladding interface. Spectroscopic analysis of precipitates within the interface layer between fuel and cladding were performed by optical microscopy, X-ray absorption and X-ray photoelectron spectroscopy, as well as by energy-dispersive scanning electron microscopy. Moreover, the radionuclide inventory of the respective Zircaloy-4, fuel and interaction layers was determined using liquid scintillation counting, γ-spectroscopy, gas mass spectrometry, ion chromatography and inductive-coupled plasma mass spectrometry and compared to results received by MCNP/CINDER and webKORIGEN calculations. In this study, we provide results regarding the speciation and chemical composition of previously identified Cs-U-O-Zr-Cl-I bearing compounds found in the interaction layer of irradiated nuclear fuel and inventory analyses of radionuclides present therein, with particular emphasis on Cl-36 and I-129. Furthermore, the agglomerates within the fuel-cladding interface were characterised for the first time utilising synchrotron radiation-based Cl K-edge and I K-edge measurements, resulting in compounds with structural similarities to CsCl and CsI. The outcomes obtained from this study provide further insights into the complex chemistry within the fuel-cladding interface with respect to the aging management and integrity of SNF under the conditions of interim storage. In future studies we will examine whether the different compounds at the fuel-cladding interface have the potential to affect the mechanical properties of Zircaloy cladding.

Increased activation product of complement 4 protein in plasma of individuals with schizophrenia

Structural variation in the complement 4 gene (C4) confers genetic risk for schizophrenia. The variation includes numbers of the increased C4A copy number, which predicts increased C4A mRNA expression. C4-anaphylatoxin (C4-ana) is a C4 protein fragment released upon C4 protein activation that has the potential to change the blood–brain barrier (BBB). We hypothesized that elevated plasma levels of C4-ana occur in individuals with schizophrenia (iSCZ). Blood was collected from 15 iSCZ with illness duration < 5 years and from 14 healthy controls (HC). Plasma C4-ana was measured by radioimmunoassay. Other complement activation products C3-ana, C5-ana, and terminal complement complex (TCC) were also measured. Digital-droplet PCR was used to determine C4 gene structural variation state. Recombinant C4-ana was added to primary brain endothelial cells (BEC) and permeability was measured in vitro. C4-ana concentration was elevated in plasma from iSCZ compared to HC (mean = 654 ± 16 ng/mL, 557 ± 94 respectively, p = 0.01). The patients also carried more copies of the C4AL gene and demonstrated a positive correlation between plasma C4-ana concentrations and C4A gene copy number. Furthermore, C4-ana increased the permeability of a monolayer of BEC in vitro. Our findings are consistent with a specific role for C4A protein in schizophrenia and raise the possibility that its activation product, C4-ana, increases BBB permeability. Exploratory analyses suggest the novel hypothesis that the relationship between C4-ana levels and C4A gene copy number could also be altered in iSCZ, suggesting an interaction with unknown genetic and/or environmental risk factors.

Altered fibrin clot structure contributes to thrombosis risk in severe COVID-19

The high incidence of thrombotic events suggests a possible role of the contact system pathway in COVID-19 pathology. Here, we demonstrate altered levels of factor XII (FXII) and its activation products in two independent cohorts of critically ill COVID-19 patients in comparison to patients suffering from severe acute respiratory distress syndrome due to influenza virus (ARDS-influenza). Compatible with this data, we report rapid consumption of FXII in COVID-19, but not in ARDS-influenza, plasma. Interestingly, the kaolin clotting time was not prolonged in COVID-19 as compared to ARDS-influenza. Using confocal and electron microscopy, we show that increased FXII activation rate, in conjunction with elevated fibrinogen levels, triggers formation of fibrinolysis-resistant, compact clots with thin fibers and small pores in COVID-19. Accordingly, we observed clot lysis in 30% of COVID-19 patients and 84% of ARDS influenza subjects. Analysis of lung tissue sections revealed wide-spread extra- and intra-vascular compact fibrin deposits in COVID-19. Together, our results indicate that elevated fibrinogen levels and increased FXII activation rate promote thrombosis and thrombolysis resistance via enhanced thrombus formation and stability in COVID-19.

Determination of in situ detection efficiency for IM-NAA of non-standard geometrical samples

The k0-based internal mono-standard (IM) method was first proposed for the concentration analysis of samples of non-standard geometry in the 2000s. The method has demonstrated several advantages such as the elimination of gamma-ray self-attenuation and geometrical effects. On the other hand, the accuracy of the method principally depends on the in situ relative detection efficiency, which requires to be obtained in each measurement. Therefore, the relative detection efficiency is always under consideration for the improvement of the analysis results. The present paper describes a simple and automatic procedure for the determination of the relative efficiency using one or more activation products emitting gamma rays over a considered range of the spectrum. The procedure can be applied for INAA and PGNAA analysis.

Multiple-Organ Complement Deposition on Vascular Endothelium in COVID-19 Patients

Increased levels of circulating complement activation products have been reported in COVID-19 patients, but only limited information is available on complement involvement at the tissue level. The mechanisms and pathways of local complement activation remain unclear. The aim of this study was to investigate the deposition of complement components in the lungs, kidneys, and liver in patients with COVID-19 patients and to determine the pathway/s of complement activation. We performed immunofluorescence analyses of autopsy specimens of lungs, kidney, and liver from 12 COVID-19 patients who died of acute respiratory failure. Snap-frozen samples embedded in OCT were stained with antibodies against complement components and activation products, IgG, and spike protein of SARS-CoV-2. Lung deposits of C1q, C4, C3, and C5b-9 were localized in the capillaries of the interalveolar septa and on alveolar cells. IgG displayed a similar even distribution, suggesting classical pathway activation. The spike protein is a potential target of IgG, but its uneven distribution suggests that other viral and tissue molecules may be targeted by IgG. FB deposits were also seen in COVID-19 lungs and are consistent with activation of the alternative pathway, whereas MBL and MASP-2 were hardly detectable. Analysis of kidney and liver specimens mirrored findings observed in the lung. Complement deposits were seen on tubules and vessels of the kidney with only mild C5b-9 staining in glomeruli, and on the hepatic artery and portal vein of the liver. Complement deposits in different organs of deceased COVID-19 patients caused by activation of the classical and alternative pathways support the multi-organ nature of the disease and the contribution of the complement system to inflammation and tissue damage.