Teriflunomide Preserves Neuronal Activity and Protects Mitochondria in Brain Slices Exposed to Oxidative Stress

Teriflunomide (TFN) limits relapses in relapsing–remitting multiple sclerosis (RRMS) by reducing lymphocytic proliferation through the inhibition of the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) and the subsequent modulation of de novo pyrimidine synthesis. Alterations of mitochondrial function as a consequence of oxidative stress have been reported during neuroinflammation. Previously, we showed that TFN prevents alterations of mitochondrial motility caused by oxidative stress in peripheral axons. Here, we aimed to validate TFN effects on mitochondria and neuronal activity in hippocampal brain slices, in which cellular distribution and synaptic circuits are largely preserved. TFN effects on metabolism and neuronal activity were investigated by assessing oxygen partial pressure and local field potential in acute slices. Additionally, we imaged mitochondria in brain slices from the transgenic Thy1-CFP/COX8A)S2Lich/J (mitoCFP) mice using two-photon microscopy. Although TFN could not prevent oxidative stress-related depletion of ATP, it preserved oxygen consumption and neuronal activity in CNS tissue during oxidative stress. Furthermore, TFN prevented mitochondrial shortening and fragmentation of puncta-shaped and network mitochondria during oxidative stress. Regarding motility, TFN accentuated the decrease in mitochondrial displacement and increase in speed observed during oxidative stress. Importantly, these effects were not associated with neuronal viability and did not lead to axonal damage. In conclusion, during conditions of oxidative stress, TFN preserves the functionality of neurons and prevents morphological and motility alterations of mitochondria.     

Immune Checkpoint Blockade in Advanced Cutaneous Squamous Cell Carcinoma: What Do We Currently Know in 2020?

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer that predominantly arises in chronically sun-damaged skin. Immunosuppression, genetic disorders such as xeroderma pigmentosum (XP), exposure to certain drugs and environmental noxae have been identified as major risk factors. Surgical removal of cSCC is the therapy of choice and mostly curative in early stages. However, a minority of patients develop locally advanced tumors or distant metastases that are still challenging to treat. Immune checkpoint blockade (ICB) targeting CTLA-4, PD-L1 and PD-1 has tremendously changed the field of oncological therapy and especially the treatment of skin cancers as tumors with a high mutational burden. In this review, we focus on the differences between cSCC and cutaneous melanoma (CM) and their implications on therapy, summarize the current evidence on ICB for the treatment of advanced cSCC and discuss the chances and pitfalls of this therapy option for this cancer entity. Furthermore, we focus on special subgroups of interest such as organ transplant recipients, patients with hematologic malignancies, XP and field cancerization.     

Overview of R&D at TLK for process and analytical issues on tritium management in breeder blankets of ITER and DEMO

Safe, reliable, and efficient tritium management in the breeder blanket will have to face unprecedented technological challenges. Beside the efficiency for tritium recovery from the breeder blanket (Tritium Extraction (TES) and Coolant Purification Systems (CPS)), the accuracy for tritium tracking between the inner and the outer fuel cycle must also be demonstrated. This paper focuses on the recent R&D carried out at the Tritium Laboratory Karlsruhe to tackle these issues. For ITER, the recently consolidated TES and CPS designs comprise adsorption columns and getter beds operated in semi-continuous mode. Different approaches for the tritium accountancy stage (TAS) have been evaluated. Balancing static (batch-wise gas collection at the TBM outlets and the tritium plant) or dynamic (in/on-line) approaches with respect to the expected analytical performances and integration issues, the first conceptual design of the TAS for EU TBMs is presented. For DEMO, the overall strategy for tritium recovery and tracking has been revisited. The necessity for on-line real-time tritium accountancy and improved process efficiency suggest the use of continuous processes such as permeator and catalytic membrane reactor. The main benefits combining the PERMCAT process with advanced membranes is discussed with respect to process improvements and facilitated accountancy using spectroscopic methods.     

Interlaboratory study on lipid oxidation during accelerated storage trials with rapeseed and sunflower oil analyzed by conjugated dienes as primary oxidation products

Accelerated storage tests are frequently used to assess the oxidative stability of foods and related systems due to its reproducibility. Various methods and experimental conditions are used to measure lipid oxidation. Differences between laboratories make it necessary to determine the repeatability and reproducibility of oxidation tests performed under the same conditions. The objective of the present interlaboratory study was to evaluate the outcome of a storage test for two different bulk oils, sunflower oil (SFO) and rapeseed oil (RSO), during a period of 9 weeks at 20°C, 30°C, 40°C, and 60°C. Sixteen laboratories were provided with bottled oils and conducted the storage tests according to a detailed protocol. Lipid oxidation was monitored by the formation of conjugated dienes (CD) and the activation energy (E_a) was determined for comparative purposes and statistically evaluated. An increase in CD formation was observed for both oils when the storage temperature was increased in all laboratories. The E_a,1 ranged from 47.9 to 73.3 kJ mol⁻¹ in RSO and from 27.8 to 62.6 kJ mol⁻¹ in SFO, with average values of 58.2 and 46.8 kJ mol⁻¹, respectively. The reproducibility coefficients were 10.9% and 18.2% for RSO and SFO, respectively. Practical applications: In order to compare results on oxidative stability of foods derived from different studies, the reproducibility of storage tests and methods employed to evaluate the oxidation level should be considered. This study provides fundamental data on the reproducibility of lipid oxidation under accelerated storage conditions and defines important parameters to be considered for the conduction of experiments.     

Mechanical gradient interphase by interdiffusion and antiplasticisation effect—study of an epoxy/thermoplastic system

A stoichiometric amine-epoxy formulation was cured in the presence of a thermoplastic, namely poly(vinylpyrrolidone) (PVP). The epoxy system consisted of the resin diglycidyl ether of bisphenol A (DGEBA) and the aromatic curing agent 4,4′-diaminodiphenylsulfone (DDS). As shown for this system in a former study by Oyama et al. [Oyama HT, Lesko JJ, Wightman JP. J Polym Sci B 1997;35:331-46. [36]], preferential absorption of amine molecules by PVP can occur. In the present study, the focus is on the variations of local elastic properties within the epoxy interphase adjacent to the PVP layer. The curing was performed close to the glass transition temperature, T_α, of the PVP film, namely at 170 °C. Variations of the local amine concentration were tracked using energy-dispersive analysis of X-rays (EDX), by taking benefit of the sulfur contained in DDS. Using temperature-dependent dynamic mechanical analysis (DMA), a series of epoxy reference samples of different amine-epoxy concentration ratios, r, was investigated in order to work out the relationship between r and the epoxy storage modulus at room temperature. In the excess-epoxy regime, r<1, the modulus is observed to increase with departure from the stoichiometric ratio, r=1. Considering the respective suppression of the β-transition, the observed characteristic can be explained by an antiplasticisation effect. Depth-sensing indentation (DSI) experiments across the epoxy/PVP interphase provided evidence for strong modulus variations. In consistency with the EDX and the DMA data, in the vicinity of the PVP layer the local epoxy modulus is increased. The total change of the epoxy Young's modulus is ∼1.1 GPa. However, the total width of the modulus decay of ∼175 μm is ∼2.5 times larger than the one of the DDS concentration gradient. This finding is discussed in terms of additional spatial variations of the DGEBA concentration as well as long-range diffusion currents of DDS induced by the interdiffusion processes and their effect on the final network of crosslinks.     

High Iron and Iron Household Protein Contents in Perineuronal Net-Ensheathed Neurons Ensure Energy Metabolism with Safe Iron Handling

A subpopulation of neurons is less vulnerable against iron-induced oxidative stress and neurodegeneration. A key feature of these neurons is a special extracellular matrix composition that forms a perineuronal net (PN). The PN has a high affinity to iron, which suggests an adapted iron sequestration and metabolism of the ensheathed neurons. Highly active, fast-firing neurons—which are often ensheathed by a PN—have a particular high metabolic demand, and therefore may have a higher need in iron. We hypothesize that PN-ensheathed neurons have a higher intracellular iron concentration and increased levels of iron proteins. Thus, analyses of cellular and regional iron and the iron proteins transferrin (Tf), Tf receptor 1 (TfR), ferritin H/L (FtH/FtL), metal transport protein 1 (MTP1 aka ferroportin), and divalent metal transporter 1 (DMT1) were performed on Wistar rats in the parietal cortex (PC), subiculum (SUB), red nucleus (RN), and substantia nigra (SNpr/SNpc). Neurons with a PN (PN⁺) have higher iron concentrations than neurons without a PN: PC 0.69 mM vs. 0.51 mM, SUB 0.84 mM vs. 0.69 mM, SN 0.71 mM vs. 0.63 mM (SNpr)/0.45 mM (SNpc). Intracellular Tf, TfR and MTP1 contents of PN⁺ neurons were consistently increased. The iron concentration of the PN itself is not increased. We also determined the percentage of PN⁺ neurons: PC 4%, SUB 5%, SNpr 45%, RN 86%. We conclude that PN⁺ neurons constitute a subpopulation of resilient pacemaker neurons characterized by a bustling iron metabolism and outstanding iron handling capabilities. These properties could contribute to the low vulnerability of PN⁺ neurons against iron-induced oxidative stress and degeneration.     

Effects of Cadmium Exposure on Gut Villi in Danio rerio

In aquatic organisms, cadmium exposure occurs from ovum to death and the route of absorption is particularly wide, being represented by skin, gills and gastrointestinal tract, through which contaminated water and/or preys are ingested. It is known that cadmium interferes with the gut; however, less information is available on cadmium effects on an important component of the gut, namely goblet cells, specialized in mucus synthesis. In the present work, we studied the effects of two sublethal cadmium concentrations on the gut mucosa of Danio rerio. Particular attention was paid to changes in the distribution of glycan residues, and in metallothionein expression in intestinal cells. The results show that cadmium interferes with gut mucosa and goblet cells features. The effects are dose- and site-dependent, the anterior gut being more markedly affected than the midgut. Cadmium modifies the presence and/or distribution of glycans in the brush border and cytoplasm of enterocytes and in the goblet cells’ cytoplasm and alters the metallothionein expression and localization. The results suggest a significant interference of cadmium with mucosal efficiency, representing a health risk for the organism in direct contact with contamination and indirectly for the trophic chain.     

Introducing Glycolinkers for the Functionalization of Cytotoxic Drugs and Applications in Antibody–Drug Conjugation Chemistry

Antibody–drug conjugates (ADCs) are promising alternatives to naked antibodies for selective drug‐delivery applications and treatment of diseases such as cancer. Construction of ADCs relies upon site‐selective, efficient and mild conjugation technologies. The choice of a chemical linker is especially important, as it affects the overall properties of the ADC. We envisioned that hydrophilic bifunctional chemical linkers based on carbohydrates would be a useful class of derivatization agents for the construction of linker–drug conjugates and ADCs. Herein we describe the synthesis of carbohydrate‐based derivatization agents, glycolinker–drug conjugates featuring the tubulin inhibitor monomethyl auristatin E and an ADC based on an anti‐EGFR antibody. In addition, an initial in vitro cytotoxicity evaluation of the individual components and the ADC is provided against EGFR‐positive cancer cells.     

Electrochemical routes for environmentally friendly recycling of rare-earth-based (Sm–Co) permanent magnets

Journal of Applied Electrochemistry - The consumption of critical raw materials, especially those in permanent magnets of Nd–Fe–B and Sm–Co-type, has significantly grown in the...     

Viscosity‐molecular weight relationship for cellulose solutions in either NMMO monohydrate or cuen

The intrinsic viscosities, [η], of nine cellulose samples, with molar masses from 50 × 10³ to 1 390 × 10³ were determined in the solvents NMMO*H₂O (N‐methyl morpholin N‐oxide hydrate) at 80°C and in cuen (copper II‐ethlenediamine) at 25°C. The evaluation of these results with respect to the Kuhn–Mark–Houwink relations shows that the data for NMMO*H₂O fall on the usual straight line in the double logarithmic plots only for M ≤ 158 10³; the corresponding [η]/M relation reads log ([η]/mL g⁻¹) = –1.465 + 0.735 log M. Beyond that molar mass [η] remains almost constant up to M ≈ 10⁶ and increases again thereafter. In contrast to NMMO*H₂O the cellulose solutions in cuen behave normal and the Kuhn–Mark–Houwink relation reads log ([η]/mL g⁻¹) = −1.185 + 0.735 log M. Possible reasons for the dissimilarities of the behavior of cellulose in these two solvents are being discussed. The comparison of three different methods for the determination of [η] from viscosity measurements at different polymer concentrations, c, demonstrates the advantages of plotting the natural logarithm of the relative viscosities as a function of c. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011