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Journal of Biomechanical Engineering Jul 2023The cartilage endplates (CEPs) on the superior and inferior surfaces of the intervertebral disk (IVD), are the primary nutrient transport pathways between the disk and...
The cartilage endplates (CEPs) on the superior and inferior surfaces of the intervertebral disk (IVD), are the primary nutrient transport pathways between the disk and the vertebral body. Passive diffusion is responsible for transporting small nutrient and metabolite molecules through the avascular CEPs. The baseline solute diffusivities in healthy CEPs have been previously studied, however alterations in CEP diffusion associated with IVD degeneration remain unclear. This study aimed to quantitatively compare the solute diffusion in healthy and degenerated human CEPs using a fluorescence recovery after photobleaching (FRAP) approach. Seven healthy CEPs and 22 degenerated CEPs were collected from five fresh-frozen human cadaveric spines and 17 patients undergoing spine fusion surgery, respectively. The sodium fluorescein diffusivities in CEP radial and vertical directions were measured using the FRAP method. The CEP calcification level was evaluated by measuring the average X-ray attenuation. No difference was found in solute diffusivities between radial and axial directions in healthy and degenerated CEPs. Compared to healthy CEPs, the average solute diffusivity was 44% lower in degenerated CEPs (Healthy: 29.07 μm2/s (CI: 23.96-33.62 μm2/s); degenerated: 16.32 μm2/s (CI: 13.84-18.84 μm2/s), p < 0.001). The average solute diffusivity had an inverse relationship with the degree of CEP calcification as determined by the normalized X-ray attenuation values (ß = -22.19, R2 = 0.633; p < 0.001). This study suggests that solute diffusion through the disk and vertebral body interface is significantly hindered by CEP calcification, providing clues to help further understand the mechanism of IVD degeneration.
Topics: Humans; Cartilage; Intervertebral Disc; Intervertebral Disc Degeneration; Biological Transport; Diffusion; Calcinosis
PubMed: 36752723
DOI: 10.1115/1.4056871 -
Acta Biomaterialia Jul 2024Magnetic resonance elastography (MRE) and diffusion-weighted imaging (DWI) are complementary imaging techniques that detect disease based on viscoelasticity and water...
Magnetic resonance elastography (MRE) and diffusion-weighted imaging (DWI) are complementary imaging techniques that detect disease based on viscoelasticity and water mobility, respectively. However, the relationship between viscoelasticity and water diffusion is still poorly understood, hindering the clinical translation of combined DWI-MRE markers. We used DWI-MRE to study 129 biomaterial samples including native and cross-linked collagen, glycosaminoglycans (GAGs) with different sulfation levels, and decellularized specimens of pancreas and liver, all with different proportions of solid tissue, or solid fractions. We developed a theoretical framework of the relationship between mechanical loss and tissue-water mobility based on two parameters, solid and fluid viscosity. These parameters revealed distinct DWI-MRE property clusters characterizing weak, moderate, and strong water-network interactions. Sparse networks interacting weakly with water, such as collagen or diluted decellularized tissue, resulted in marginal changes in water diffusion over increasing solid viscosity. In contrast, dense networks with larger solid fractions exhibited both free and hindered water diffusion depending on the polarity of the solid components. For example, polar and highly sulfated GAGs as well as native soft tissues hindered water diffusion despite relatively low solid viscosity. Our results suggest that two fundamental properties of tissue networks, solid fraction and network polarity, critically influence solid and fluid viscosity in biological tissues. Since clinical DWI and MRE are sensitive to these viscosity parameters, the framework we present here can be used to detect tissue remodeling and architectural changes in the setting of diagnostic imaging. STATEMENT OF SIGNIFICANCE: The viscoelastic properties of biological tissues provide a wealth of information on the vital state of cells and host matrix. Combined measurement of viscoelasticity and water diffusion by medical imaging is sensitive to tissue microarchitecture. However, the relationship between viscoelasticity and water diffusion is still poorly understood, hindering full exploitation of these properties as a combined clinical biomarker. Therefore, we analyzed the parameter space accessible by diffusion-weighted imaging (DWI) and magnetic resonance elastography (MRE) and developed a theoretical framework for the relationship between water mobility and mechanical parameters in biomaterials. Our theory of solid material properties related to particle motion can be translated to clinical radiology using clinically established MRE and DWI.
Topics: Viscosity; Water; Diffusion; Animals; Elasticity; Elasticity Imaging Techniques; Humans; Diffusion Magnetic Resonance Imaging; Collagen; Glycosaminoglycans; Liver
PubMed: 38729549
DOI: 10.1016/j.actbio.2024.05.007 -
Scientific Reports Sep 2023Misfolded proteins in Alzheimer's disease and Parkinson's disease follow a well-defined connectomics-based spatial progression. Several anti-tau and anti-alpha synuclein...
Misfolded proteins in Alzheimer's disease and Parkinson's disease follow a well-defined connectomics-based spatial progression. Several anti-tau and anti-alpha synuclein (aSyn) antibodies have failed to provide clinical benefit in clinical trials despite substantial target engagement in the experimentally accessible cerebrospinal fluid (CSF). The proposed mechanism of action is reducing neuronal uptake of oligomeric protein from the synaptic cleft. We built a quantitative systems pharmacology (QSP) model to quantitatively simulate intrasynaptic secretion, diffusion and antibody capture in the synaptic cleft, postsynaptic membrane binding and internalization of monomeric and oligomeric tau and aSyn proteins. Integration with a physiologically based pharmacokinetic (PBPK) model allowed us to simulate clinical trials of anti-tau antibodies gosuranemab, tilavonemab, semorinemab, and anti-aSyn antibodies cinpanemab and prasineuzumab. Maximal target engagement for monomeric tau was simulated as 45% (semorinemab) to 99% (gosuranemab) in CSF, 30% to 99% in ISF but only 1% to 3% in the synaptic cleft, leading to a reduction of less than 1% in uptake of oligomeric tau. Simulations for prasineuzumab and cinpanemab suggest target engagement of free monomeric aSyn of only 6-8% in CSF, 4-6% and 1-2% in the ISF and synaptic cleft, while maximal target engagement of aggregated aSyn was predicted to reach 99% and 80% in the synaptic cleft with similar effects on neuronal uptake. The study generates optimal values of selectivity, sensitivity and PK profiles for antibodies. The study identifies a gradient of decreasing target engagement from CSF to the synaptic cleft as a key driver of efficacy, quantitatively identifies various improvements for drug design and emphasizes the need for QSP modelling to support the development of tau and aSyn antibodies.
Topics: Humans; Network Pharmacology; Antibodies, Monoclonal; Biological Transport; Diffusion; Parkinson Disease
PubMed: 37658103
DOI: 10.1038/s41598-023-41382-0 -
Journal of Molecular Biology Feb 2024The width of the periplasmic space of Gram-negative bacteria is only about 25-30 nm along the long axis of the cell, which affects free diffusion of (macro)molecules....
The width of the periplasmic space of Gram-negative bacteria is only about 25-30 nm along the long axis of the cell, which affects free diffusion of (macro)molecules. We have performed single-particle displacement measurements and diffusion simulation studies to determine the impact of confinement on the apparent mobility of proteins in the periplasm of Escherichia coli. The diffusion of a reporter protein and of OsmY, an osmotically regulated periplasmic protein, is characterized by a fast and slow component regardless of the osmotic conditions. The diffusion coefficient of the fast fraction increases upon osmotic upshift, in agreement with a decrease in macromolecular crowding of the periplasm, but the mobility of the slow (immobile) fraction is not affected by the osmotic stress. We observe that the confinement created by the inner and outer membranes results in a lower apparent diffusion coefficient, but this can only partially explain the slow component of diffusion in the particle displacement measurements, suggesting that a fraction of the proteins is hindered in its mobility by large periplasmic structures. Using particle-based simulations, we have determined the confinement effect on the apparent diffusion coefficient of the particles for geometries akin the periplasmic space of Gram-negative bacteria.
Topics: Diffusion; Escherichia coli; Escherichia coli Proteins; Osmotic Pressure; Periplasm; Single Molecule Imaging
PubMed: 38143021
DOI: 10.1016/j.jmb.2023.168420 -
Annual Review of Cell and Developmental... Oct 2023In 1952, Alan Turing published the reaction-diffusion (RD) mathematical framework, laying the foundations of morphogenesis as a self-organized process emerging from... (Review)
Review
In 1952, Alan Turing published the reaction-diffusion (RD) mathematical framework, laying the foundations of morphogenesis as a self-organized process emerging from physicochemical first principles. Regrettably, this approach has been widely doubted in the field of developmental biology. First, we summarize Turing's line of thoughts to alleviate the misconception that RD is an artificial mathematical construct. Second, we discuss why phenomenological RD models are particularly effective for understanding skin color patterning at the meso/macroscopic scales, without the need to parameterize the profusion of variables at lower scales. More specifically, we discuss how RD models () recapitulate the diversity of actual skin patterns, () capture the underlying dynamics of cellular interactions, () interact with tissue size and shape, () can lead to ordered sequential patterning, () generate cellular automaton dynamics in lizards and snakes, () predict actual patterns beyond their statistical features, and () are robust to model variations. Third, we discuss the utility of linear stability analysis and perform numerical simulations to demonstrate how deterministic RD emerges from the underlying chaotic microscopic agents.
Topics: Animals; Skin Pigmentation; Models, Biological; Morphogenesis; Cell Communication; Vertebrates; Diffusion; Body Patterning
PubMed: 37843926
DOI: 10.1146/annurev-cellbio-120319-024414 -
European Radiology Mar 2024Whether the alternation of the glymphatic system exists in neurodevelopmental disease still remains unclear. In this study, we investigated structural and functional...
OBJECTIVES
Whether the alternation of the glymphatic system exists in neurodevelopmental disease still remains unclear. In this study, we investigated structural and functional changes in the glymphatic system in the treatment-naïve attention-deficit/hyperactivity disorder (ADHD) children by quantitatively measuring the Virchow-Robin spaces (VRS) volume and diffusion tensor image-analysis along the perivascular space (DTI-ALPS).
METHODS
Forty-seven pediatric ADHD patients and 52 age- and gender-matched typically developing (TD) children were recruited in this prospective study. The VRS volume was calculated using a semi-automated approach in axial T2-weighted images. Diffusivities along the x-, y-, and z-axes in the projection, association, and subcortical neural fiber areas were measured. The ALPS index, a ratio that accentuated water diffusion along the perivascular space, was calculated. The Mann-Whitney U test was used to compare the quantitative parameters; Pearson's correlation was used to analyze the correlation with clinical symptoms.
RESULTS
The cerebral VRS volume (mean, 15.514 mL vs. 11.702 mL) and the VRS volume ratio in the ADHD group were larger than those in the TD group (all p < 0.001). The diffusivity along the x-axis in association fiber area and ALPS index were significantly smaller in the ADHD group vs. TD group (mean, 1.40 vs.1.59, p < 0.05 after false discovery rate adjustment). Besides, the ALPS index was related to inattention symptoms of ADHD (r = - 0.323, p < 0.05).
CONCLUSIONS
Our study suggests that the glymphatic system alternation may participate in the pathogenesis of ADHD, which may be a new research direction for exploring the mechanisms of psycho-behavioral developmental disorders. Moreover, the VRS volume and ALPS index could be used as the metrics for diagnosing ADHD.
CLINICAL RELEVANCE STATEMENT
Considering the potential relevance of the glymphatic system for exploring the mechanisms of attention deficit/hyperactivity, the Virchow-Robin spaces volume and the analysis along the perivascular space index could be used as additional metrics for diagnosing the disorder.
KEY POINTS
• Increased Virchow-Robin space volume and decreased analysis along the perivascular space index were found in the treatment-naïve attention-deficit/hyperactivity disorder children. • The results of this study indicate that the glymphatic system alternation may have a valuable role in the pathogenesis of attention-deficit/hyperactivity disorder. • The analysis along the perivascular space index is correlated with inattention symptoms of attention-deficit/hyperactivity disorder children.
Topics: Humans; Child; Attention Deficit Disorder with Hyperactivity; Prospective Studies; Benchmarking; Diffusion; Image Processing, Computer-Assisted
PubMed: 37673963
DOI: 10.1007/s00330-023-10220-2 -
Bio Systems May 2024Most nutrient uptake problems are modeled by the convection-diffusion equation (CDE) abiding by Fick's law. Because nutrients needed by plants exist in the soil solution...
Most nutrient uptake problems are modeled by the convection-diffusion equation (CDE) abiding by Fick's law. Because nutrients needed by plants exist in the soil solution as a form of ions and the soil is a typical fractal structure of heterogeneity, it makes the solute transport appear anomalous diffusion in soil. Taking anomalous diffusion as a transport process, we propose time and space fractional nutrient uptake models based on the classic Nye-Tinker-Barber model. There does not appear apparent sub-diffusion of nitrate in the time fractional model until four months and the time fractional models are appropriate for describing long-term dynamics and slow sorption reaction; the space fractional model can capture super-diffusion in short term and it is suitable for describing nonlocal phenomena and daily variations driven by transpiration and metabolism; the anomalous diffusion more apparently appears near the root surface in the modeling simulation.
Topics: Plant Roots; Diffusion; Models, Biological; Nutrients; Biological Transport; Soil; Nitrates; Computer Simulation
PubMed: 38599512
DOI: 10.1016/j.biosystems.2024.105210 -
Bioinformatics (Oxford, England) Sep 2023As an important player in transcriptome regulation, microRNAs may effectively diffuse somatic mutation impacts to broad cellular processes and ultimately manifest...
MOTIVATION
As an important player in transcriptome regulation, microRNAs may effectively diffuse somatic mutation impacts to broad cellular processes and ultimately manifest disease and dictate prognosis. Previous studies that tried to correlate mutation with gene expression dysregulation neglected to adjust for the disparate multitudes of false positives associated with unequal sample sizes and uneven class balancing scenarios.
RESULTS
To properly address this issue, we developed a statistical framework to rigorously assess the extent of mutation impact on microRNAs in relation to a permutation-based null distribution of a matching sample structure. Carrying out the framework in a pan-cancer study, we ascertained 9008 protein-coding genes with statistically significant mutation impacts on miRNAs. Of these, the collective miRNA expression for 83 genes showed significant prognostic power in nine cancer types. For example, in lower-grade glioma, 10 genes' mutations broadly impacted miRNAs, all of which showed prognostic value with the corresponding miRNA expression. Our framework was further validated with functional analysis and augmented with rich features including the ability to analyze miRNA isoforms; aggregative prognostic analysis; advanced annotations such as mutation type, regulator alteration, somatic motif, and disease association; and instructive visualization such as mutation OncoPrint, Ideogram, and interactive mRNA-miRNA network.
AVAILABILITY AND IMPLEMENTATION
The data underlying this article are available in MutMix, at http://innovebioinfo.com/Database/TmiEx/MutMix.php.
Topics: Humans; Diffusion; Glioma; MicroRNAs; Mutation; RNA, Messenger
PubMed: 37624931
DOI: 10.1093/bioinformatics/btad520 -
The Journal of Physical Chemistry. B Aug 2023We utilized the momentum transfer ()-dependence of quasi-elastic neutron scattering (QENS) to measure the dynamics of water and ethanol confined in graphene oxide (GO)...
We utilized the momentum transfer ()-dependence of quasi-elastic neutron scattering (QENS) to measure the dynamics of water and ethanol confined in graphene oxide (GO) powder or membranes at different temperatures and in different orientations. We found reduced diffusivities (up to 30% in the case of water) and a depression of dynamic transition temperatures. While water showed near Arrhenius behavior with an almost bulk-like activation barrier in a temperature range of 280-310 K, the diffusivity of ethanol showed little temperature dependence. For both water and ethanol, we found evidence for immobile and mobile fractions of the confined liquid. The mobile fraction exhibited jump diffusion, with a jump length consistent with the expected average spacing of hydroxide groups in the GO surfaces. From anisotropy measurements, we found weak anisotropy in the diffusivity of the mobile species and in the fraction and geometry of immobile species.
PubMed: 37556231
DOI: 10.1021/acs.jpcb.2c08960 -
Molecular Pharmaceutics May 2024The development, storage, transport, and subcutaneous delivery of highly concentrated monoclonal antibody formulations pose significant challenges due to the high...
The development, storage, transport, and subcutaneous delivery of highly concentrated monoclonal antibody formulations pose significant challenges due to the high solution viscosity and low diffusion of the antibody molecules in crowded environments. These issues often stem from the self-associating behavior of the antibody molecules, potentially leading to aggregation. In this work, we used a dissipative particle dynamics-based coarse-grained model to investigate the diffusion behavior of IgG1 antibody molecules in aqueous solutions with 15 and 32 mM NaCl and antibody concentrations ranging from 10 to 400 mg/mL. We determined the coarse-grained interaction parameters by matching the calculated structure factor with the computational and experimental data from the literature. Our results indicate Fickian diffusion for antibody concentrations of 10 and 25 mg/mL and anomalous diffusion for concentrations exceeding 50 mg/mL. The anomalous diffusion was observed for ∼0.33 to 0.4 μs, followed by Fickian diffusion for all antibody concentrations. We observed a strong linear correlation between the diffusion behavior of the antibody molecules (diffusion coefficient and anomalous diffusion exponent α) and the amount of aggregates present in the solution and between the amount of aggregates and the Coulomb interaction energy. The investigation of underlying mechanisms for anomalous diffusion revealed that in crowded environments at high antibody concentrations, the attractive interaction between electrostatically complementary regions of the antibody molecules could further bring the neighboring molecules closer to one another, ultimately resulting in aggregate formation. Further, the Coulomb attraction can continue to draw more molecules together, forming larger aggregates.
Topics: Diffusion; Antibodies, Monoclonal; Immunoglobulin G; Viscosity; Protein Aggregates
PubMed: 38572979
DOI: 10.1021/acs.molpharmaceut.3c00973