Molecular characterization and temporal expression profiling of presenilins in the developing porcine brain

<p>Abstract</p> <p>Background</p> <p>The transmembrane presenilin (PSEN) proteins, PSEN1 and PSEN2, have been proposed to be the catalytic components of the γ-secretase protein complex, which is an intramembranous multimeric protease involved in development, cell regulatory processes, and neurodegeneration in Alzheimer's disease. Here we describe the sequencing, chromosomal mapping, and polymorphism analysis of PSEN1 and PSEN2 in the domestic pig (<it>Sus scrofa domesticus</it>).</p> <p>Results</p> <p>The porcine presenilin proteins showed a high degree of homology over their entire sequences to the PSENs from mouse, bovine, and human. PSEN1 and PSEN2 transcription was examined during prenatal development of the brain stem, hippocampus, cortex, basal ganglia, and cerebellum at embryonic days 60, 80, 100, and 114, which revealed distinct temporal- and tissue-specific expression profiles. Furthermore, immunohistochemical analysis of PSEN1 and PSEN2 showed similar localization of the proteins predominantly in neuronal cells in all examined brain areas.</p> <p>Conclusion</p> <p>The data provide evidence for structural and functional conservation of PSENs in mammalian lineages, and may suggest that the high sequence similarity and colocalization of PSEN1 and PSEN2 in brain tissue reflect a certain degree of functional redundancy. The data show that pigs may provide a new animal model for detailed analysis of the developmental functions of the PSENs.</p

Nedd8 processing enzymes in Schizosaccharomyces pombe

BACKGROUND: Conjugation of the ubiquitin-like modifier Nedd8 to cullins is critical for the function of SCF-type ubiquitin ligases and thus facilitates ubiquitin conjugation and ultimately degradation of SCF substrates, including several cell cycle regulators. Like ubiquitin, Nedd8 is produced as a precursor that must first be processed before it becomes active. In Saccharomyces cerevisiae this is carried out exclusively by the enzyme Yuh1. RESULTS: Here we show that in the fission yeast, Schizosaccharomyces pombe, the Yuh1 orthologue, Uch1, is not the sole Nedd8 processing enzyme. Instead it appears that deubiquitylating enzymes can efficiently process the Nedd8 precursor in vivo. CONCLUSIONS: Several enzymes contribute to Nedd8 precursor processing including a number of deubiquitylating enzymes

Severe and ChRonic Atopic dermatitis Treatment CoHort (SCRATCH):A Danish Real-world Evidence Atopic Dermatitis Treatment Registry

Data from real-world use of new systemic treatments in atopic dermatitis (AD) is important for assessing safety and efficacy. The aim of this study is to describe the baseline characteristics of adult patients with moderate-to-severe AD enrolled in the Danish nationwide Severe and ChRonic Atopic dermatitis Treatment CoHort (SCRATCH) database, between October 2017 and August 2021. A total of 282 adult patients were included. Most (62%) were men, the median age at baseline was 43 years (interquartile range (IQR) 29–54 years), and median age at onset of AD was 1 year (IQR 0–6 years). The median Eczema Area and Severity Index at treatment initiation was 19.1 (IQR 11.9–25.7); median Patient Oriented Eczema Measure 21.0 (IQR 16.0–25.0); median Dermatology Life Quality Index 13.0 (IQR 7.0–19.0); and median itch and sleep numerical rating scale scores 8.0 (IQR 6.0–9.0) and 6.0 (IQR 4.0–8.0). Differences were found between the sexes. This registry will provide a source for future efficacy and safety studies

Evidence for an extended scattered disk

By telescopic tracking, we have established that the orbit of the trans-neptunian object (2000 CR$_{105}$) has a perihelion of $\simeq$44 AU, and is thus outside the domain controlled by strong gravitational close encounters with Neptune. Because this object is on a very large, eccentric orbit (with semimajor axis $a\simeq$216 AU and eccentricity $e\simeq$0.8) this object must have been placed on this orbit by a gravitational perturbation which is {\it not} direct gravitational scattering off of any of the giant planets (on their current orbits). The existence of this object may thus have profound cosmogonic implications for our understanding of the formation of the outer Solar System. We discuss some viable scenarios which could have produced it, including long-term diffusive chaos and scattering off of other massive bodies in the outer Solar System. This discovery implies that there must be a large population of trans-neptunian objects in an `extended scattered disk' with perihelia above the previously-discussed 38 AU boundary.Comment: 22 test pages, 4 figures, 2 tables. Submitted to Icarus, 26 March 200

Lysates of Methylococcus capsulatus Bath induce a lean-like microbiota, intestinal FoxP3+RORγt+IL-17+ Tregs and improve metabolism

Interactions between host and gut microbial communities are modulated by diets and play pivotal roles in immunological homeostasis and health. We show that exchanging the protein source in a high fat, high sugar, westernized diet from casein to whole-cell lysates of the non-commensal bacterium Methylococcus capsulatus Bath is sufficient to reverse western diet-induced changes in the gut microbiota to a state resembling that of lean, low fat diet-fed mice, both under mild thermal stress (T22 °C) and at thermoneutrality (T30 °C). Concomitant with microbiota changes, mice fed the Methylococcus-based western diet exhibit improved glucose regulation, reduced body and liver fat, and diminished hepatic immune infiltration. Intake of the Methylococcu-based diet markedly boosts Parabacteroides abundances in a manner depending on adaptive immunity, and upregulates triple positive (Foxp3+RORγt+IL-17+) regulatory T cells in the small and large intestine. Collectively, these data point to the potential for leveraging the use of McB lysates to improve immunometabolic homeostasis.publishedVersio

Stationary Black Holes: Uniqueness and Beyond

The spectrum of known black-hole solutions to the stationary Einstein equations has been steadily increasing, sometimes in unexpected ways. In particular, it has turned out that not all black-hole-equilibrium configurations are characterized by their mass, angular momentum and global charges. Moreover, the high degree of symmetry displayed by vacuum and electro-vacuum black-hole spacetimes ceases to exist in self-gravitating non-linear field theories. This text aims to review some developments in the subject and to discuss them in light of the uniqueness theorem for the Einstein-Maxwell system.Comment: Major update of the original version by Markus Heusler from 1998. Piotr T. Chru\'sciel and Jo\~ao Lopes Costa succeeded to this review's authorship. Significantly restructured and updated all sections; changes are too numerous to be usefully described here. The number of references increased from 186 to 32

Creatine-induced activation of antioxidative defence in myotube cultures revealed by explorative NMR-based metabonomics and proteomics

<p>Abstract</p> <p>Background</p> <p>Creatine is a key intermediate in energy metabolism and supplementation of creatine has been used for increasing muscle mass, strength and endurance. Creatine supplementation has also been reported to trigger the skeletal muscle expression of insulin like growth factor I, to increase the fat-free mass and improve cognition in elderly, and more explorative approaches like transcriptomics has revealed additional information. The aim of the present study was to reveal additional insight into the biochemical effects of creatine supplementation at the protein and metabolite level by integrating the explorative techniques, proteomics and NMR metabonomics, in a systems biology approach.</p> <p>Methods</p> <p>Differentiated mouse myotube cultures (C2C12) were exposed to 5 mM creatine monohydrate (CMH) for 24 hours. For proteomics studies, lysed myotubes were analyzed in single 2-DGE gels where the first dimension of protein separation was pI 5-8 and second dimension was a 12.5% Criterion gel. Differentially expressed protein spots of significance were excised from the gel, desalted and identified by peptide mass fingerprinting using MALDI-TOF MS. For NMR metabonomic studies, chloroform/methanol extractions of the myotubes were subjected to one-dimensional ¹H NMR spectroscopy and the intracellular oxidative status of myotubes was assessed by intracellular DCFH₂oxidation after 24 h pre-incubation with CMH.</p> <p>Results</p> <p>The identified differentially expressed proteins included vimentin, malate dehydrogenase, peroxiredoxin, thioredoxin dependent peroxide reductase, and 75 kDa and 78 kDa glucose regulated protein precursors. After CMH exposure, up-regulated proteomic spots correlated positively with the NMR signals from creatine, while down-regulated proteomic spots were negatively correlated with these NMR signals. The identified differentially regulated proteins were related to energy metabolism, glucose regulated stress, cellular structure and the antioxidative defence system. The suggested improvement of the antioxidative defence was confirmed by a reduced intracellular DCFH₂oxidation with increasing concentrations of CMH in the 24 h pre-incubation medium.</p> <p>Conclusions</p> <p>The explorative approach of this study combined with the determination of a decreased intracellular DCFH₂oxidation revealed an additional stimulation of cellular antioxidative mechanisms when myotubes were exposed to CMH. This may contribute to an increased exercise performance mediated by increased ability to cope with training-induced increases in oxidative stress.</p

The Canada-France Ecliptic Plane Survey - Full Data Release: The orbital structure of the Kuiper belt

We report the orbital distribution of the trans-neptunian objects (TNOs) discovered during the Canada-France Ecliptic Plane Survey, whose discovery phase ran from early 2003 until early 2007. The follow-up observations started just after the first discoveries and extended until late 2009. We obtained characterized observations of 321 sq.deg. of sky to depths in the range g ~ 23.5--24.4 AB mag. We provide a database of 169 TNOs with high-precision dynamical classification and known discovery efficiency. Using this database, we find that the classical belt is a complex region with sub-structures that go beyond the usual splitting of inner (interior to 3:2 mean-motion resonance [MMR]), outer (exterior to 2:1 MMR), and main (in between). The main classical belt (a=40--47 AU) needs to be modeled with at least three components: the `hot' component with a wide inclination distribution and two `cold' components (stirred and kernel) with much narrower inclination distributions. The hot component must have a significantly shallower absolute magnitude (Hg) distribution than the other two components. With 95% confidence, there are 8000+1800-1600 objects in the main belt with Hg <= 8.0, of which 50% are from the hot component, 40% from the stirred component and 10% from the kernel; the hot component's fraction drops rapidly with increasing Hg. Because of this, the apparent population fractions depend on the depth and ecliptic latitude of a trans-neptunian survey. The stirred and kernel components are limited to only a portion of the main belt, while we find that the hot component is consistent with a smooth extension throughout the inner, main and outer regions of the classical belt; the inner and outer belts are consistent with containing only hot-component objects. The Hg <= 8.0 TNO population estimates are 400 for the inner belt and 10,000 for the outer belt within a factor of two.Comment: 59 pages, 9 figures, 7 table