Mismatch Repair-Deficient Crypt Foci in Lynch Syndrome – Molecular Alterations and Association with Clinical Parameters

Lynch syndrome is caused by germline mutations of DNA mismatch repair (MMR) genes, most frequently MLH1 and MSH2. Recently, MMR-deficient crypt foci (MMR-DCF) have been identified as a novel lesion which occurs at high frequency in the intestinal mucosa from Lynch syndrome mutation carriers, but very rarely progress to cancer. To shed light on molecular alterations and clinical associations of MMR-DCF, we systematically searched the intestinal mucosa from Lynch syndrome patients for MMR-DCF by immunohistochemistry. The identified lesions were characterised for alterations in microsatellite-bearing genes with proven or suspected role in malignant transformation. We demonstrate that the prevalence of MMR-DCF (mean 0.84 MMR-DCF per 1 cm² mucosa in the colorectum of Lynch syndrome patients) was significantly associated with patients’ age, but not with patients’ gender. No MMR-DCF were detectable in the mucosa of patients with sporadic MSI-H colorectal cancer (n = 12). Microsatellite instability of at least one tested marker was detected in 89% of the MMR-DCF examined, indicating an immediate onset of microsatellite instability after MMR gene inactivation. Coding microsatellite mutations were most frequent in the genes HT001 (ASTE1) with 33%, followed by AIM2 (17%) and BAX (10%). Though MMR deficiency alone appears to be insufficient for malignant transformation, it leads to measurable microsatellite instability even in single MMR-deficient crypts. Our data indicate for the first time that the frequency of MMR-DCF increases with patients’ age. Similar patterns of coding microsatellite instability in MMR-DCF and MMR-deficient cancers suggest that certain combinations of coding microsatellite mutations, including mutations of the HT001, AIM2 and BAX gene, may contribute to the progression of MMR-deficient lesions into MMR-deficient cancers.     

Hydraulic stress parameters of a cased caddis larva (Drusus biguttatus) using spatio-temporally filtered velocity measurements

Hydrobiologia - By studying hydraulic stress parameters of larvae of the cased caddisfly Drusus biguttatus (Pictet, 1834) in a tributary of the Schwarze Sulm (Carinthia, Austria), we aimed on (1)...     

Sex differentiation in seasonal distribution of the starry smooth-hound Mustelus asterias

This mark-recapture study of starry smooth-hound Mustelus asterias tagged during the summer months near the Dutch coast demonstrates a large-scale spatial sex differentiation in their circannual migration patterns and small-scale spatial sex differentiation during summer. Overwintering occurs in the North Sea, English Channel and Bay of Biscay, with significantly more males in the Northern North Sea and more females in the Bay of Biscay. During summer, sheltered sea arms off the Dutch coast were almost exclusively used by adult females. In subsequent summers post-release, both sexes were mostly confined to the Southern North Sea, suggesting philopatry.     

Catalytic Polysulfide Conversion and Physiochemical Confinement for Lithium–Sulfur Batteries

The lithium–sulfur (Li–S) battery is widely regarded as a promising energy storage device due to its low price and the high earth‐abundance of the materials employed. However, the shuttle effect of lithium polysulfides (LiPSs) and sluggish redox conversion result in inefficient sulfur utilization, low power density, and rapid electrode deterioration. Herein, these challenges are addressed with two strategies 1) increasing LiPS conversion kinetics through catalysis, and 2) alleviating the shuttle effect by enhanced trapping and adsorption of LiPSs. These improvements are achieved by constructing double‐shelled hollow nanocages decorated with a cobalt nitride catalyst. The N‐doped hollow inner carbon shell not only serves as a physiochemical absorber for LiPSs, but also improves the electrical conductivity of the electrode; significantly suppressing shuttle effect. Cobalt nitride (Co₄N) nanoparticles, embedded in nitrogen‐doped carbon in the outer shell, catalyze the conversion of LiPSs, leading to decreased polarization and fast kinetics during cycling. Theoretical study of the Li intercalation energetics confirms the improved catalytic activity of the Co₄N compared to metallic Co catalyst. Altogether, the electrode shows large reversible capacity (1242 mAh g^?1 at 0.1 C), robust stability (capacity retention of 658 mAh g^?1 at 5 C after 400 cycles), and superior cycling stability at high sulfur loading (4.5 mg cm^?2).     

Iron-Doping of Copper Oxide Nanoparticles Lowers Their Toxic Potential on C6 Glioma Cells

Neurochemical Research - Copper oxide nanoparticles (CuO-NPs) are well known for their cytotoxicity which in part has been attributed to the release of copper ions from CuO-NPs. As iron-doping has...     

Time-resolved methods in Biophysics. 1. A novel pump and probe surface-enhanced resonance Raman approach for studying biological photoreceptors.

This article describes a method, based on surface-enhanced resonance Raman (SERR) spectroscopy, for studying the reaction dynamics of photoreceptors immobilized on metal electrodes. Time resolution and fresh sample conditions are achieved by synchronizing the rotational and translational motion of a novel kinematic electrode with the duration and time delay between the pump and probe events. The power and sensitivity of the method is illustrated by studying the photocycle of the sensory photoreceptor NpSRII and its sensitivity to the applied electric field. The results are compared with time-resolved resonance Raman measurements in solution.     

Deactivation of Src family kinases: hypothesis testing using a Monte Carlo sensitivity analysis of systems-level properties.

Src family tyrosine kinases play a key role in many cellular signalling networks, but due to the high complexity of these networks their precise function remains elusive. Many factors involved in Src regulation, such as specific kinases and phosphatases, are still unknown. Mathematical models have been constructed to improve the understanding of the system and its dynamic behavior. Using a computational random parameter search, we characterized and compared the dynamics of three alternative models in order to assess their likelihoods. For this, we investigated how systems-level properties such as bistability and excitable behavior relate to kinetic and physiological parameters and how robust these properties were. Our results suggest the existence of a putative negative feedback loop in the Src system. A previously suggested role for PTPalpha in the deactivation of Src was not supported by the model.     

Attenuated autonomic function in multiple organ dysfunction syndrome across three age groups.

Multiple organ dysfunction syndrome (MODS) is the failure of several organs after a trigger event. The mortality is high, at up to 70%. We hypothesize that autonomic dysfunction may substantially contribute to the development of MODS and speculate that there is an age dependence of autonomic dysfunction in MODS. A total of 90 consecutively admitted MODS patients were assigned to this study. Three variables of autonomic function were analyzed: heart rate variability (HRV), baroreflex sensitivity (BRS) and chemoreflex sensitivity (CRS). The patient cohort was divided into three age groups. The main finding was that BRS, CRS and almost all indices of HRV were attenuated in comparison to normal range data and there was no age dependence for HRV indices or CRS, but there was for BRS. In conclusion, autonomic function in MODS is attenuated. The influence of MODS on autonomic function overwhelms the age dependence of autonomic function observed in healthy subjects.     

Cloning and characterization of r3b; members of the r3 superfamily of late blight resistance genes show sequence and functional divergence

Massive resistance (R) gene stacking is considered to be one of the most promising approaches to provide durable resistance to potato late blight for both conventional and genetically modified breeding strategies. The R3 complex locus on chromosome XI in potato is an example of natural R gene stacking, because it contains two closely linked R genes (R3a and R3b) with distinct resistance specificities to Phytophthora infestans. Here, we report about the positional cloning of R3b. Both transient and stable transformations of susceptible tobacco and potato plants showed that R3b conferred full resistance to incompatible P. infestans isolates. R3b encodes a coiled-coil nucleotide-binding site leucine-rich repeat protein and exhibits 82% nucleotide identity with R3a located in the same R3 cluster. The R3b gene specifically recognizes Avr3b, a newly identified avirulence factor from P. infestans. R3b does not recognize Avr3a, the corresponding avirulence gene for R3a, showing that, despite their high sequence similarity, R3b and R3a have clearly distinct recognition specificities. In addition to the Rpi-mcd1/Rpi-blb3 locus on chromosome IV, the R3 locus on chromosome XI is the second example of an R-gene cluster with multiple genes recognizing different races of P. infestans.     

Branched-chain amino acids increase arterial blood ammonia in spite of enhanced intrinsic muscle ammonia metabolism in patients with cirrhosis and healthy subjects

Branched-chain amino acids (BCAA) are used in attempts to reduce blood ammonia in patients with cirrhosis and intermittent hepatic encephalopathy based on the hypothesis that BCAA stimulate muscle ammonia detoxification. We studied the effects of an oral dose of BCAA on the skeletal muscle metabolism of ammonia and amino acids in 14 patients with cirrhosis and in 7 healthy subjects by combining [(13)N]ammonia positron emission tomography (PET) of the thigh muscle with measurements of blood flow and arteriovenous (A-V) concentrations of ammonia and amino acids. PET was used to measure the metabolism of blood-supplied ammonia and the A-V measurements were used to measure the total ammonia metabolism across the thigh muscle. After intake of BCAA, blood ammonia increased more than 30% in both groups of subjects (both P < 0.05). Muscle clearance of blood-supplied ammonia (PET) was unaffected (P = 0.75), but the metabolic removal rate (PET) increased significantly because of increased blood ammonia in both groups (all P < 0.05). The total ammonia clearance across the leg muscle (A-V) increased by more than 50% in both groups, and the flux (A-V) of ammonia increased by more than 45% (all P < 0.05). BCAA intake led to a massive glutamine release from the muscle (cirrhotic patients, P < 0.05; healthy subjects, P = 0.12). In conclusion, BCAA enhanced the intrinsic muscle metabolism of ammonia but not the metabolism of blood-supplied ammonia in both the patients with cirrhosis and in the healthy subjects.