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Impact of an irreversible β-galactosylceramidase inhibitor on the lipid profile of zebrafish embryos

Abstract

Not specified

Authors: Jessica Guerra, Mirella Belleri, Giulia Paiardi, Chiara Tobia, Davide Capoferri, Marzia Corli, Elisa Scalvini, Marco Ghirimoldi, Marcello Manfredi, Rebecca C. Wade, Marco Presta, Luca Mignani

Date Published: 1st Dec 2024

Publication Type: Journal

Computational screening of the effects of mutations on protein-protein off-rates and dissociation mechanisms by τRAMD

Abstract (Expand)

Abstract The dissociation rate, or its reciprocal, the residence time (τ), is a crucial parameter for understanding the duration and biological impact of biomolecular interactions. Accurate prediction …tions. Accurate prediction of τ is essential for understanding protein-protein interactions (PPIs) and identifying potential drug targets or modulators for tackling diseases. Conventional molecular dynamics simulation techniques are inherently constrained by their limited timescales, making it challenging to estimate residence times, which typically range from minutes to hours. Building upon its successful application in protein-small molecule systems, τ-Random Acceleration Molecular Dynamics (τRAMD) is here investigated for estimating dissociation rates of protein-protein complexes. τRAMD enables the observation of unbinding events on the nanosecond timescale, facilitating rapid and efficient computation of relative residence times. We tested this methodology for three protein-protein complexes and their extensive mutant datasets, achieving good agreement between computed and experimental data. By combining τRAMD with MD-IFP (Interaction Fingerprint) analysis, dissociation mechanisms were characterized and their sensitivity to mutations investigated, enabling the identification of molecular hotspots for selective modulation of dissociation kinetics. In conclusion, our findings underscore the versatility of τRAMD as a simple and computationally efficient approach for computing relative protein-protein dissociation rates and investigating dissociation mechanisms, thereby aiding the design of PPI modulators.

Authors: Giulia D’Arrigo, Daria B. Kokh, Ariane Nunes-Alves, Rebecca C. Wade

Date Published: 1st Dec 2024

Publication Type: Journal

Comprehensive characterization of the neurogenic and neuroprotective action of a novel TrkB agonist using mouse and human stem cell models of Alzheimer’s disease

Abstract (Expand)

Abstract Background Neural stem cell (NSC) proliferation and differentiation in the mammalian brain decreases to minimal levels postnatally. Nevertheless, neurogenic niches persist in the adult cortex …rtheless, neurogenic niches persist in the adult cortex and hippocampus in rodents, primates and humans, with adult NSC differentiation sharing key regulatory mechanisms with development. Adult neurogenesis impairments have been linked to Alzheimer’s disease (AD) pathology. Addressing these impairments by using neurotrophic factors is a promising new avenue for therapeutic intervention based on neurogenesis. However, this possibility has been hindered by technical difficulties of using in-vivo models to conduct screens, including working with scarce NSCs in the adult brain and differences between human and mouse models or ethical limitations. Methods Here, we use a combination of mouse and human stem cell models for comprehensive in-vitro characterization of a novel neurogenic compound, focusing on the brain-derived neurotrophic factor (BDNF) pathway. The ability of ENT-A011, a steroidal dehydroepiandrosterone derivative, to activate the tyrosine receptor kinase B (TrkB) receptor was tested through western blotting in NIH-3T3 cells and its neurogenic and neuroprotective action were assessed through proliferation, cell death and Amyloid-β (Aβ) toxicity assays in mouse primary adult hippocampal NSCs, mouse embryonic cortical NSCs and neural progenitor cells (NPCs) differentiated from three human induced pluripotent stem cell lines from healthy and AD donors. RNA-seq profiling was used to assess if the compound acts through the same gene network as BDNF in human NPCs. Results ENT-A011 was able to increase proliferation of mouse primary adult hippocampal NSCs and embryonic cortical NSCs, in the absence of EGF/FGF, while reducing Aβ-induced cell death, acting selectively through TrkB activation. The compound was able to increase astrocytic gene markers involved in NSC maintenance, protect hippocampal neurons from Αβ toxicity and prevent synapse loss after Aβ treatment. ENT-A011 successfully induces proliferation and prevents cell death after Aβ toxicity in human NPCs, acting through a core gene network shared with BDNF as shown through RNA-seq. Conclusions Our work characterizes a novel BDNF mimetic with preferable pharmacological properties and neurogenic and neuroprotective actions in Alzheimer’s disease via stem cell-based screening, demonstrating the promise of stem cell systems for short-listing competitive candidates for further testing.

Authors: Despoina Charou, Thanasis Rogdakis, Alessia Latorrata, Maria Valcarcel, Vasileios Papadogiannis, Christina Athanasiou, Alexandros Tsengenes, Maria Anna Papadopoulou, Dimitrios Lypitkas, Matthieu D. Lavigne, Theodora Katsila, Rebecca C. Wade, M. Zameel Cader, Theodora Calogeropoulou, Achille Gravanis, Ioannis Charalampopoulos

Date Published: 1st Dec 2024

Publication Type: Journal

Dusty Common Envelope Evolution

Abstract (Expand)

We present the first hydrodynamical simulations of common envelope evolution that include the formation of dust and the effect of radiation pressure on dust grains. We performed smoothed particle … hydrodynamics simulations of the CE evolution for two systems made of a 1.7 M⊙ and 3.7 M⊙ AGB star primary with a 0.6 M⊙ binary companion. The results of our calculations indicate that dust formation has a negligible impact on the gas dynamics essentially because dust forms in the already unbound material. The expansion and cooling of the envelope yield very early and highly efficient production of dust. In our formalism, which does not consider dust destruction, almost 100% of the available carbon that is not locked in CO condensates in dust grains. This massive dust production, thus, strongly depends on the envelope mass and composition, in particular, its C/O ratio, and has a considerable impact on the observational aspect of the object, resulting in a photospheric radius that is approximatively one order of magnitude larger than that of a non-dusty system.

Authors: Lionel Siess, Luis C. Bermúdez-Bustamante, Orsola De Marco, Daniel J. Price, Miguel González-Bolívar, Chunliang Mu, Mike Y. M. Lau, Ryosuke Hirai, Taïssa Danilovich

Date Published: 1st Dec 2024

Publication Type: Journal

Improving DNA-Barcoding Databases: A Framework for Error Detection and Correction in the Barcode of Life Data System (BOLD)

Abstract

Not specified

Authors: Alexander Suhrkamp, Alexandros Stamatakis

Date Published: 1st Dec 2024

Publication Type: Master's Thesis

Digital-Tier Strategy Improves Newborn Screening for Glutaric Aciduria Type 1

Abstract (Expand)

Glutaric aciduria type 1 (GA1) is a rare inherited metabolic disease increasingly included in newborn screening (NBS) programs worldwide. Because of the broad biochemical spectrum of individuals with …dividuals with GA1 and the lack of reliable second-tier strategies, NBS for GA1 is still confronted with a high rate of false positives. In this study, we aim to increase the specificity of NBS for GA1 and, hence, to reduce the rate of false positives through machine learning methods. Therefore, we studied NBS profiles from 1,025,953 newborns screened between 2014 and 2023 at the Heidelberg NBS Laboratory, Germany. We identified a significant sex difference, resulting in twice as many false-positives male than female newborns. Moreover, the proposed digital-tier strategy based on logistic regression analysis, ridge regression, and support vector machine reduced the false-positive rate by over 90% compared to regular NBS while identifying all confirmed individuals with GA1 correctly. An in-depth analysis of the profiles revealed that in particular false-positive results with high associated follow-up costs could be reduced significantly. In conclusion, understanding the origin of false-positive NBS and implementing a digital-tier strategy to enhance the specificity of GA1 testing may significantly reduce the burden on newborns and their families from false-positive NBS results.

Authors: Elaine Zaunseder, Julian Teinert, Nikolas Boy, Sven F. Garbade, Saskia Haupt, Patrik Feyh, Georg F. Hoffmann, Stefan Kölker, Ulrike Mütze, Vincent Heuveline

Date Published: 1st Dec 2024

Publication Type: Journal

Dielectrophoretic force-enhanced thermal convection within a horizontal cylindrical annulus

Abstract (Expand)

This study investigates, both experimentally and numerically the flow of a dielectric fluid confined between two concentric, differentially heated, horizontally aligned cylinders subjected to a 200 Hz …ed to a 200 Hz alternating radial electric field. A wide-gap annular setup with a length 20 times larger than the gap size is utilized in this investigation. The study focuses exclusively on the outward heating configuration, meaning the inner cylinder is hotter than the outer one. The electric field, in conjunction with the temperature gradient, triggers thermal electro-hydrodynamic instability caused by the application of dielectrophoretic force. when the applied electric tension exceeds a critical value for specific temperature gradients between the cylinders, the flow symmetry in the gap is disturbed. The instability manifests as periodically oscillating vortices occurring on top of the gap. A notable increase in heat transfer efficiency accompanies the onset of instability. The experimental and numerical results demonstrate quantitative and qualitative agreement.

Authors: M. H. Hamede, J. Roller, A. Meyer, V. Heuveline, C. Egbers

Date Published: 1st Dec 2024

Publication Type: Journal

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