Klinisches Bild, Entwicklungsparameter und Kernspintomographie des Gehirns bei Globoidzellleukodystrophie

Bei Morbus Krabbe bzw. Globoidzellleukodystrophie handelt es sich um eine seltene lysosomale Speichererkrankung, die durch einen genetisch bedingten Mangel des Enzyms β-Galactocerebrosidase hervorgerufen wird. Bisher war vor allem die klassische infantile Form beschrieben und bekannt. Es wurde davon ausgegangen, dass diese über 90 Prozent der Krabbe-Erkrankung ausmacht. Neuere Arbeiten wiesen darauf hin, dass andere Formen mit späterem Beginn dadurch vermutlich unterschätzt werden. Für Deutschland gab es bisher keine systematische Untersuchung klinischer und kernspintomographischer Daten über das gesamte Spektrum der Krankheitsformen in dieser Größenordnung. Daher war eine Fragestellung dieser Arbeit wie sich die Häufigkeiten der verschiedenen Krankheitsformen tatsächlich darstellen. Durch diese Arbeit mit einem für die seltene Erkrankung verhältnismäßig großen Kollektiv von knapp 40 Patienten konnte gezeigt werden, dass die späten Krankheitsformen mit einem Onset nach dem ersten Lebensjahr über 20 Prozent ausmachen und bisher in ihrer Häufigkeit unterschätzt wurden. Insgesamt 38 Fragebögen zu klinischen Daten gingen in die Auswertung dieser Arbeit ein. Außerdem lagen von 27 dieser Patienten insgesamt 38 MRTs vor. Da von einigen der Patienten mehrere Verlaufs-MRT-Bilder vorlagen, konnten damit auch Aussagen zu den MRT-Veränderungen im Krankheitsverlauf getroffen werden und Strukturen, die früh bzw. spät im Krankheitsverlauf betroffen sind, identifiziert werden. Sowohl die Erstsymptome, der Krankheitsverlauf, vor allem auch die Geschwindigkeit der Progredienz, als auch das kernspintomographische Pattern variieren je nach Alter bei Onset und definieren damit die Krankheitsform. Während die infantile Form vor allem Irritabilität, Unruhe und Reizbarkeit sowie Entwicklungsrückschritte als Erstsymptome aufweist, zeigte diese Arbeit, dass alle späteren Formen mit Auffälligkeiten in der Grobmotorik, in der Regel einer Gangstörung beginnen. Gerade zu Beginn der Erkrankung bzw. in der Diagnostik kommt dem MRT eine wichtige Bedeutung zu (infantil: diffuse Beteiligung der weißen Substanz und spezifisch cerebellärer Strukturen, later onset: parieto-occipitale weiße Substanz und Splenium, adult: motorische Bahnen). Vor allem wenn die Erkrankung noch nicht weit fortgeschritten ist und die Symptome noch relativ unspezifisch sind, kann die Erkennung des MRT-Patterns entscheidend für die Prognose des Patienten sein, da eine frühe Diagnosestellung bei den Krankheitsformen mit späterem Onset die Therapie einer HSZT ermöglichen kann. Für die Patienten mit infantiler Krankheitsform konnte bisher keine Evidenz für eine Empfehlung der HSZT gefunden werden. Da es entscheidend ist, frühzeitig den Verdacht auf diese Erkrankung zu stellen, ist es wichtig, dass die zu Beginn konsultierten Ärzte diese Diagnose bei relativ unspezifischen Erstsymptomen dennoch in Betracht ziehen und schnell in entsprechende Zentren zur Diagnosestellung überweisen. Damit diese Erkrankung in Betracht gezogen wird, ist es wichtig die Ärzte entsprechend zu sensibilisieren und die unterschiedlichen Gesichter des Morbus Krabbe verstärkt zu thematisieren

Constraining the geodynamic evolution of the Alps with sedimentary provenance and detrital thermochronometer data, II. Detrital thermochronology

This project was designed to disentangle sedimentary signals controlled by changes in the lithosphere, the upper crust, and climate change in the European Alps. The hypothesis was that if lithospheric reorganisation in the Alps (such as slab break-off or tearing) occurred, it would lead to spatio-temporal changes in buoyancy, influencing the location of rock uplift and erosion. Specifically, we wanted to test this hypothesis using a multi-proxy provenance approach (sedimentary provenance tools, detrital thermochronology) at key stratigraphic time slices (28, 25, 20, 17, 15, and 12 Ma) from the northern and southern foreland basins. Foreland basin deposits represent a rich archive of erosional processes controlled by tectonics, climate, and lithology. This presentation concerns part II of the study, the detrital thermochronology, which we use as "tracer thermochronology". Applications of tracer thermochronology exploit a known or assumed surface thermochronometric age map (based on either interpolated observed or modelled bedrock ages) to determine the provenance of detrital grains within fluvial or glacial catchments. The goal is to interpret the erosion pattern and processes within the sampled catchment. Before reconstructing and interpreting past erosion patterns and exhumation from detrital zircon fission-track (ZFT) age distributions and modelled bedrock ZFT ages back in time, we produce a frame of reference for today's situation. We do this by investigating signals from 26 modern river samples (21 previous [1,2] and nine new samples) and the present-day erosion pattern and mineral fertility in the Alps. We discuss observed and predicted (based on possible erosion scenarios) ZFT age distributions and potential pitfalls of the method (such as poor bedrock control in some areas of the Alps and challenges in combining previous and new data). Modern river results are consistent for adjacent, similar-size catchments and with expected erosion patterns. Most samples show a higher proportion of younger ZFT ages than would be predicted for uniform erosion and zircon fertility scenarios. Furthermore, we show preliminary results from stratigraphic sections from north and south of the Alps

Witness: The Modern Writer as Witness

Editor\u27s Note [Excerpt] The United States, as a society, is on the brink of profound and positive change. Demographically and culturally, things are improving, and the reason is obvious to people who study history: Conflict pushes us to be better, to strive for principled goals. Consider the inspired eco-advocacy of Greta Thunberg. Or the swearing in of most diverse class of lawmakers in history into the 116th Congress. Or billionaire Robert F. Smith’s pledge to pay off every Morehouse College (in Atlanta, Georgia) student’s debt. Indeed, there are many good people helping and great moments happening in spite of a bleak 24-hour news cycle designed to ruin happiness and to limit our understanding of our human potential. We at Witness see this yearning for transformation in the works we selected. The doorway must be crossed, and the voices and characters we featured in our Winter 2019 issue stand at the vestibule, ready for the light to warm them, primed to fight for that necessary illumination.https://digitalscholarship.unlv.edu/witness/1000/thumbnail.jp

Denoising diffusion-based MR to CT image translation enables whole spine vertebral segmentation in 2D and 3D without manual annotations

Background: Automated segmentation of spinal MR images plays a vital role both scientifically and clinically. However, accurately delineating posterior spine structures presents challenges. Methods: This retrospective study, approved by the ethical committee, involved translating T1w and T2w MR image series into CT images in a total of n=263 pairs of CT/MR series. Landmark-based registration was performed to align image pairs. We compared 2D paired (Pix2Pix, denoising diffusion implicit models (DDIM) image mode, DDIM noise mode) and unpaired (contrastive unpaired translation, SynDiff) image-to-image translation using "peak signal to noise ratio" (PSNR) as quality measure. A publicly available segmentation network segmented the synthesized CT datasets, and Dice scores were evaluated on in-house test sets and the "MRSpineSeg Challenge" volumes. The 2D findings were extended to 3D Pix2Pix and DDIM. Results: 2D paired methods and SynDiff exhibited similar translation performance and Dice scores on paired data. DDIM image mode achieved the highest image quality. SynDiff, Pix2Pix, and DDIM image mode demonstrated similar Dice scores (0.77). For craniocaudal axis rotations, at least two landmarks per vertebra were required for registration. The 3D translation outperformed the 2D approach, resulting in improved Dice scores (0.80) and anatomically accurate segmentations in a higher resolution than the original MR image. Conclusion: Two landmarks per vertebra registration enabled paired image-to-image translation from MR to CT and outperformed all unpaired approaches. The 3D techniques provided anatomically correct segmentations, avoiding underprediction of small structures like the spinous process.Comment: 35 pages, 7 figures, Code and a model weights available https://doi.org/10.5281/zenodo.8221159 and https://doi.org/10.5281/zenodo.819869

Nucleic acid recognition by Toll-like receptors is coupled to stepwise processing by cathepsins and asparagine endopeptidase

TLR3, TLR7, and TLR9 are cleaved in the same step-wise manner in all immune cell types examined

Nucleolar-nucleoplasmic shuttling of TARG1 and its control by DNA damage-induced poly-ADP-ribosylation and by nucleolar transcription

Macrodomains are conserved protein folds associated with ADP-ribose binding and turnover. ADP-ribosylation is a posttranslational modification catalyzed primarily by ARTD (aka PARP) enzymes in cells. ARTDs transfer either single or multiple ADP-ribose units to substrates, resulting in mono- or poly-ADP-ribosylation. TARG1/C6orf130 is a macrodomain protein that hydrolyzes mono-ADP-ribosylation and interacts with poly-ADP-ribose chains. Interactome analyses revealed that TARG1 binds strongly to ribosomes and proteins associated with rRNA processing and ribosomal assembly factors. TARG1 localized to transcriptionally active nucleoli, which occurred independently of ADP-ribose binding. TARG1 shuttled continuously between nucleoli and nucleoplasm. In response to DNA damage, which activates ARTD1/2 (PARP1/2) and promotes synthesis of poly-ADP-ribose chains, TARG1 re-localized to the nucleoplasm. This was dependent on the ability of TARG1 to bind to poly-ADP-ribose. These findings are consistent with the observed ability of TARG1 to competitively interact with RNA and PAR chains. We propose a nucleolar role of TARG1 in ribosome assembly or quality control that is stalled when TARG1 is re-located to sites of DNA damage

Plasma concentrations of soluble IL-2 receptor α (CD25) are increased in type 1 diabetes and associated with reduced C-peptide levels in young patients.

AIMS/HYPOTHESIS: Type 1 diabetes is a common autoimmune disease that has genetic and environmental determinants. Variations within the IL2 and IL2RA (also known as CD25) gene regions are associated with disease risk, and variation in expression or function of these proteins is likely to be causal. We aimed to investigate if circulating concentrations of the soluble form of CD25, sCD25, an established marker of immune activation and inflammation, were increased in individuals with type 1 diabetes and if this was associated with the concentration of C-peptide, a measure of insulin production that reflects the degree of autoimmune destruction of the insulin-producing beta cells. METHODS: We used immunoassays to measure sCD25 and C-peptide in peripheral blood plasma from patient and control samples. RESULTS: We identified that sCD25 was increased in patients with type 1 diabetes compared with controls and replicated this result in an independent set of 86 adult patient and 80 age-matched control samples (p = 1.17 × 10(-3)). In 230 patients under 20 years of age, with median duration-of-disease of 6.1 years, concentrations of sCD25 were negatively associated with C-peptide concentrations (p = 4.8 × 10(-3)). CONCLUSIONS/INTERPRETATION: The 25% increase in sCD25 in patients, alongside the inverse association between sCD25 and C-peptide, probably reflect the adverse effects of an on-going, actively autoimmune and inflammatory immune system on beta cell function in patients