Chapter 5-Parkinson's disease - A role of non-enzymatic posttranslational modifications in disease onset and progression?

Parkinson's disease (PD) is a still incurable neurodegenerative disorder with a highly complex etiology. While about 10% of cases are associated with single-gene mutations, the majority of PD is thought to originate from a combination of factors such as environmental impact, lifestyle and aging. Even though investigations into the genetically caused cases have uncovered major pathomechanisms of the disease there still exists a wide gap concerning the molecular impact of the other risk factors. All of them are known to have a major impact on the oxidative burden of the cell and thus strongly influence the non-enzymatic posttranslational modifications (nePTMs) of proteins. These modifications are by now known to dramatically alter the stability of proteins, their interactomes, and also their functions. However, the knowledge of nePTMs and their possible causative role in the pathoetiology of PD is just starting to emerge again guided by research on PD-associated genes. In this short review, we will thus concentrate on known nePTMs of two PD-associated genes, SCNA and DJ-1, and discuss their role in the pathoetiology of PD. In the future, it will, however, be essential to unravel the complete environmental proteome to understand the impact of nePTMs on PD etiology. This might open up new pathways urgently needed to develop new diagnostic and therapeutic tools for this still incurable disease

Improving automated model reconstruction across phylogenetically diverse genome-scale metabolic models

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Distribution of sialic acids on mucins and gels: a defense mechanism

Moist mucosal epithelial interfaces that are exposed to external environments are dominated by sugar epitopes, some of which (e.g., sialic acids) are involved in host defense. In this study, we determined the abundance and distribution of two sialic acids to assess differences in their availability to an exogenous probe in isolated mucins and mucous gels. We used atomic force microscopy to obtain force maps of human preocular mucous and purified ocular mucins by probing and locating the interactions between tip-tethered lectins Maackia amurensis and Sambucus nigra and their respective receptors, α-2,3 and α-2,6 N-acetylneuraminic (sialic) acids. The rupture force distributions were not affected by neighboring sugar-bearing molecules. Energy contours for both lectin-sugar bonds were fitted to a two-barrier model, suggesting a conformational change before dissociation. In contrast to data from purified mucin molecules, the preocular gels presented numerous large clusters (19,000 ± 4000 nm2) of α-2,6 sialic acids, but very few small clusters (2000 ± 500 nm2) of α-2,3 epitopes. This indicates that mucins, which are rich in α-2,3 sialic acids, are only partially exposed at the surface of the mucous gel. Microorganisms that recognize α-2,3 sialic acids will encounter only isolated ligands, and the adhesion of other microorganisms will be enhanced by large islands of neighboring α-2,6 sialic acids. We have unveiled an additional level of mucosal surface heterogeneity, specifically in the distribution of pro- and antiadhesive sialic acids that protect underlying epithelia from viruses and bacteria

Programmable Periodicity of Quantum Dot Arrays with DNA Origami Nanotubes

To fabricate quantum dot arrays with programmable periodicity, functionalized DNA origami nanotubes were developed. Selected DNA staple strands were biotin-labeled to form periodic binding sites for streptavidin-conjugated quantum dots. Successful formation of arrays with periods of 43 and 71 nm demonstrates precise, programmable, large-scale nanoparticle patterning; however, limitations in array periodicity were also observed. Statistical analysis of AFM images revealed evidence for steric hindrance or site bridging that limited the minimum array periodicity

Surface Roughness and Effective Stick-Slip Motion

The effect of random surface roughness on hydrodynamics of viscous incompressible liquid is discussed. Roughness-driven contributions to hydrodynamic flows, energy dissipation, and friction force are calculated in a wide range of parameters. When the hydrodynamic decay length (the viscous wave penetration depth) is larger than the size of random surface inhomogeneities, it is possible to replace a random rough surface by effective stick-slip boundary conditions on a flat surface with two constants: the stick-slip length and the renormalization of viscosity near the boundary. The stick-slip length and the renormalization coefficient are expressed explicitly via the correlation function of random surface inhomogeneities. The effective stick-slip length is always negative signifying the effective slow-down of the hydrodynamic flows by the rough surface (stick rather than slip motion). A simple hydrodynamic model is presented as an illustration of these general hydrodynamic results. The effective boundary parameters are analyzed numerically for Gaussian, power-law and exponentially decaying correlators with various indices. The maximum on the frequency dependence of the dissipation allows one to extract the correlation radius (characteristic size) of the surface inhomogeneities directly from, for example, experiments with torsional quartz oscillators.Comment: RevTeX4, 14 pages, 3 figure

Morphology and Nanomechanics of Sensory Neurons Growth Cones following Peripheral Nerve Injury

A prior peripheral nerve injury in vivo, promotes a rapid elongated mode of sensory neurons neurite regrowth in vitro. This in vitro model of conditioned axotomy allows analysis of the cellular and molecular mechanisms leading to an improved neurite re-growth. Our differential interference contrast microscopy and immunocytochemistry results show that conditioned axotomy, induced by sciatic nerve injury, did not increase somatic size of adult lumbar sensory neurons from mice dorsal root ganglia sensory neurons but promoted the appearance of larger neurites and growth cones. Using atomic force microscopy on live neurons, we investigated whether membrane mechanical properties of growth cones of axotomized neurons were modified following sciatic nerve injury. Our data revealed that neurons having a regenerative growth were characterized by softer growth cones, compared to control neurons. The increase of the growth cone membrane elasticity suggests a modification in the ratio and the inner framework of the main structural proteins

A reversible state of hypometabolism in a human cellular model of sporadic Parkinson's disease

Sporadic Parkinson's Disease (sPD) is a progressive neurodegenerative disorder caused by multiple genetic and environmental factors. Mitochondrial dysfunction is one contributing factor, but its role at different stages of disease progression is not fully understood. Here, we showed that neural precursor cells and dopaminergic neurons derived from induced pluripotent stem cells (hiPSCs) from sPD patients exhibited a hypometabolism. Further analysis based on transcriptomics, proteomics, and metabolomics identified the citric acid cycle, specifically the alpha-ketoglutarate dehydrogenase complex (OGDHC), as bottleneck in sPD metabolism. A follow-up study of the patients approximately 10 years after initial biopsy demonstrated a correlation between OGDHC activity in our cellular model and the disease progression. In addition, the alterations in cellular metabolism observed in our cellular model were restored by interfering with the enhanced SHH signal transduction in sPD. Thus, inhibiting overactive SHH signaling may have potential as neuroprotective therapy during early stages of sPD. Mitochondrial dysfunction is a contributing factor in Parkinson's disease. Here the authors carry out a multilayered omics analysis of Parkinson's disease patient-derived neuronal cells, which reveals a reversible hypometabolism mediated by alpha-ketoglutarate dehydrogenase deficiency, which is correlated with disease progression in the donating patients

Representing the function and sensitivity of coastal interfaces in earth system models

© The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Ward, N. D., Megonigal, J. P., Bond-Lamberty, B., Bailey, V. L., Butman, D., Canuel, E. A., Diefenderfer, H., Ganju, N. K., Goni, M. A., Graham, E. B., Hopkinson, C. S., Khangaonkar, T., Langley, J. A., McDowell, N. G., Myers-Pigg, A. N., Neumann, R. B., Osburn, C. L., Price, R. M., Rowland, J., Sengupta, A., Simard, M., Thornton, P. E., Tzortziou, M., Vargas, R., Weisenhorn, P. B., & Windham-Myers, L. Representing the function and sensitivity of coastal interfaces in earth system models. Nature Communications, 11(1), (2020): 2458, doi:10.1038/s41467-020-16236-2.Between the land and ocean, diverse coastal ecosystems transform, store, and transport material. Across these interfaces, the dynamic exchange of energy and matter is driven by hydrological and hydrodynamic processes such as river and groundwater discharge, tides, waves, and storms. These dynamics regulate ecosystem functions and Earth’s climate, yet global models lack representation of coastal processes and related feedbacks, impeding their predictions of coastal and global responses to change. Here, we assess existing coastal monitoring networks and regional models, existing challenges in these efforts, and recommend a path towards development of global models that more robustly reflect the coastal interface.Funding for this work was provided by Pacific Northwest National Laboratory (PNNL) Laboratory Directed Research & Development (LDRD) as part of the Predicting Ecosystem Resilience through Multiscale Integrative Science (PREMIS) Initiative. PNNL is operated by Battelle for the U.S. Department of Energy under Contract DE-AC05-76RL01830. Additional support to J.P.M. was provided by the NSF-LTREB program (DEB-0950080, DEB-1457100, DEB-1557009), DOE-TES Program (DE-SC0008339), and the Smithsonian Institution. This manuscript was motivated by discussions held by co-authors during a three-day workshop at PNNL in Richland, WA: The System for Terrestrial Aquatic Research (STAR) Workshop: Terrestrial-Aquatic Research in Coastal Systems. The authors thank PNNL artist Nathan Johnson for preparing the figures in this manuscript and Terry Clark, Dr. Charlette Geffen, and Dr. Nancy Hess for their aid in organizing the STAR workshop. The authors thank all workshop participants not listed as authors for their valuable insight: Lihini Aluwihare (contributed to biogeochemistry discussions and development of concept for Fig. 3), Gautam Bisht (contributed to modeling discussion), Emmett Duffy (contributed to observational network discussions), Yilin Fang (contributed to modeling discussion), Jeremy Jones (contributed to biogeochemistry discussions), Roser Matamala (contributed to biogeochemistry discussions), James Morris (contributed to biogeochemistry discussions), Robert Twilley (contributed to biogeochemistry discussions), and Jesse Vance (contributed to observational network discussions). A full report on the workshop discussions can be found at https://www.pnnl.gov/publications/star-workshop-terrestrial-aquatic-research-coastal-systems

cAMP/PKA Regulates Osteogenesis, Adipogenesis and Ratio of RANKL/OPG mRNA Expression in Mesenchymal Stem Cells by Suppressing Leptin

BACKGROUND: Mesenchymal stem cells (MSCs) are a pluripotent cell type that can differentiate into adipocytes, osteoblasts and other cells. The reciprocal relationship between adipogenesis and osteogenesis was previously demonstrated; however, the mechanisms remain largely unknown. METHODS AND FINDINGS: We report that activation of PKA by 3-isobutyl-1 methyl xanthine (IBMX) and forskolin enhances adipogenesis, the gene expression of PPARgamma2 and LPL, and downregulates the gene expression of Runx2 and osteopontin, markers of osteogenesis. PKA activation also decreases the ratio of Receptor Activator of the NF-kappaB Ligand to Osteoprotegerin (RANKL/OPG) gene expression - the key factors of osteoclastogenesis. All these effects are mediated by the cAMP/PKA/CREB pathway by suppressing leptin, and may contribute to PKA stimulators-induced in vivo bone loss in developing zebrafish. CONCLUSIONS: Using MSCs, the center of a newly proposed bone metabolic unit, we identified cAMP/PKA signaling, one of the many signaling pathways that regulate bone homeostasis via controlling cyto-differentiation of MSCs and altering RANKL/OPG gene expression

Effect of Fibrin Glue on the Biomechanical Properties of Human Descemet's Membrane

10.1371/journal.pone.0037456PLoS ONE75