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International Journal of Environmental... Aug 2023The Achilles tendon is the thickest and strongest tendon of the human body, and it is frequently injured during sports activity. The incidence of Achilles tendon... (Review)
Review
The Achilles tendon is the thickest and strongest tendon of the human body, and it is frequently injured during sports activity. The incidence of Achilles tendon pathologies has increased over recent decades, especially in the last few years, because of increased sports participation among the general population and due to the diffusion of competitive sports at a high level. Tendinopathies are common in athletes and in middle-aged overweight patients. The term "tendinopathy" refers to a condition characterised clinically by pain and swelling, with functional limitations of tendon and nearby structures, and consequently to chronic failure of healing response process. Tendinopathies can produce marked morbidity, and at present, scientifically validated management modalities are limited. Despite the constantly increasing interest and number of studies about Achilles tendinopathy (AT), there is still not a consensual point of view on which is the best treatment, and its management is still controversial. AT can be treated conservatively primarily, with acceptable results and clinical outcomes. When this approach fails, surgery should be considered. Several surgical procedures have been described for both conditions with a relatively high rate of success with few complications and the decision for treatment in patients with AT should be tailored on patient's needs and level of activity. The aim of this article is to give insights about the pathogenesis and most used and recent treatment options for AT.
Topics: Middle Aged; Humans; Achilles Tendon; Tendinopathy; Athletes; Diffusion; Musculoskeletal Diseases
PubMed: 37681821
DOI: 10.3390/ijerph20176681 -
Science Advances Aug 2023Lipid synthesis is necessary for formation of epithelial barriers and homeostasis with external microbes. An analysis of the response of human keratinocytes to several...
Lipid synthesis is necessary for formation of epithelial barriers and homeostasis with external microbes. An analysis of the response of human keratinocytes to several different commensal bacteria on the skin revealed that induced a large increase in essential lipids including triglycerides, ceramides, cholesterol, and free fatty acids. A similar response occurred in mouse epidermis and in human skin affected with acne. Further analysis showed that this increase in lipids was mediated by short-chain fatty acids produced by and was dependent on increased expression of several lipid synthesis genes including . Inhibition or RNA silencing of peroxisome proliferator-activated receptor-α (PPARα), but not PPARβ and PPARγ, blocked this response. The increase in keratinocyte lipid content improved innate barrier functions including antimicrobial activity, paracellular diffusion, and transepidermal water loss. These results reveal that metabolites from a common commensal bacterium have a previously unappreciated influence on the composition of epidermal lipids.
Topics: Humans; Animals; Mice; Epidermis; Skin; Keratinocytes; Ceramides; Diffusion
PubMed: 37595033
DOI: 10.1126/sciadv.adg6262 -
Nature Sep 2023Transient receptor potential (TRP) channels are a large, eukaryotic ion channel superfamily that control diverse physiological functions, and therefore are attractive...
Transient receptor potential (TRP) channels are a large, eukaryotic ion channel superfamily that control diverse physiological functions, and therefore are attractive drug targets. More than 210 structures from more than 20 different TRP channels have been determined, and all are tetramers. Despite this wealth of structures, many aspects concerning TRPV channels remain poorly understood, including the pore-dilation phenomenon, whereby prolonged activation leads to increased conductance, permeability to large ions and loss of rectification. Here, we used high-speed atomic force microscopy (HS-AFM) to analyse membrane-embedded TRPV3 at the single-molecule level and discovered a pentameric state. HS-AFM dynamic imaging revealed transience and reversibility of the pentamer in dynamic equilibrium with the canonical tetramer through membrane diffusive protomer exchange. The pentamer population increased upon diphenylboronic anhydride (DPBA) addition, an agonist that has been shown to induce TRPV3 pore dilation. On the basis of these findings, we designed a protein production and data analysis pipeline that resulted in a cryogenic-electron microscopy structure of the TRPV3 pentamer, showing an enlarged pore compared to the tetramer. The slow kinetics to enter and exit the pentameric state, the increased pentamer formation upon DPBA addition and the enlarged pore indicate that the pentamer represents the structural correlate of pore dilation. We thus show membrane diffusive protomer exchange as an additional mechanism for structural changes and conformational variability. Overall, we provide structural evidence for a non-canonical pentameric TRP-channel assembly, laying the foundation for new directions in TRP channel research.
Topics: Anhydrides; Data Analysis; Diffusion; Protein Subunits; TRPV Cation Channels; Microscopy, Atomic Force; Molecular Targeted Therapy; Cryoelectron Microscopy; Protein Structure, Quaternary; Protein Multimerization
PubMed: 37648856
DOI: 10.1038/s41586-023-06470-1 -
Nature Feb 2024Many peptide hormones form an α-helix on binding their receptors, and sensitive methods for their detection could contribute to better clinical management of disease....
Many peptide hormones form an α-helix on binding their receptors, and sensitive methods for their detection could contribute to better clinical management of disease. De novo protein design can now generate binders with high affinity and specificity to structured proteins. However, the design of interactions between proteins and short peptides with helical propensity is an unmet challenge. Here we describe parametric generation and deep learning-based methods for designing proteins to address this challenge. We show that by extending RFdiffusion to enable binder design to flexible targets, and to refining input structure models by successive noising and denoising (partial diffusion), picomolar-affinity binders can be generated to helical peptide targets by either refining designs generated with other methods, or completely de novo starting from random noise distributions without any subsequent experimental optimization. The RFdiffusion designs enable the enrichment and subsequent detection of parathyroid hormone and glucagon by mass spectrometry, and the construction of bioluminescence-based protein biosensors. The ability to design binders to conformationally variable targets, and to optimize by partial diffusion both natural and designed proteins, should be broadly useful.
Topics: Biosensing Techniques; Computer-Aided Design; Deep Learning; Diffusion; Glucagon; Luminescent Measurements; Mass Spectrometry; Parathyroid Hormone; Peptides; Protein Structure, Secondary; Proteins; Substrate Specificity; Models, Molecular
PubMed: 38109936
DOI: 10.1038/s41586-023-06953-1 -
Nature Feb 2024To coordinate cellular physiology, eukaryotic cells rely on the rapid exchange of molecules at specialized organelle-organelle contact sites. Endoplasmic...
To coordinate cellular physiology, eukaryotic cells rely on the rapid exchange of molecules at specialized organelle-organelle contact sites. Endoplasmic reticulum-mitochondrial contact sites (ERMCSs) are particularly vital communication hubs, playing key roles in the exchange of signalling molecules, lipids and metabolites. ERMCSs are maintained by interactions between complementary tethering molecules on the surface of each organelle. However, due to the extreme sensitivity of these membrane interfaces to experimental perturbation, a clear understanding of their nanoscale organization and regulation is still lacking. Here we combine three-dimensional electron microscopy with high-speed molecular tracking of a model organelle tether, Vesicle-associated membrane protein (VAMP)-associated protein B (VAPB), to map the structure and diffusion landscape of ERMCSs. We uncovered dynamic subdomains within VAPB contact sites that correlate with ER membrane curvature and undergo rapid remodelling. We show that VAPB molecules enter and leave ERMCSs within seconds, despite the contact site itself remaining stable over much longer time scales. This metastability allows ERMCSs to remodel with changes in the physiological environment to accommodate metabolic needs of the cell. An amyotrophic lateral sclerosis-associated mutation in VAPB perturbs these subdomains, likely impairing their remodelling capacity and resulting in impaired interorganelle communication. These results establish high-speed single-molecule imaging as a new tool for mapping the structure of contact site interfaces and reveal that the diffusion landscape of VAPB at contact sites is a crucial component of ERMCS homeostasis.
Topics: Humans; Amyotrophic Lateral Sclerosis; Endoplasmic Reticulum; Mitochondria; Mitochondrial Membranes; Signal Transduction; Vesicular Transport Proteins; Microscopy, Electron; Imaging, Three-Dimensional; Binding Sites; Diffusion; Time Factors; Mutation; Homeostasis; Movement
PubMed: 38267577
DOI: 10.1038/s41586-023-06956-y -
Soft Matter Jan 2024Run-and-tumble processes successfully model several living systems. While studies have typically focused on particles with isotropic tumbles, recent examples exhibit...
Run-and-tumble processes successfully model several living systems. While studies have typically focused on particles with isotropic tumbles, recent examples exhibit "tumble-turns", in which particles undergo 90° tumbles and so possess explicitly anisotropic dynamics. We study the consequences of such tumble-turn anisotropicity at both short and long-time scales. We model run-and-tumble-turn particles as self-propelled particles subjected to an angular potential that favors directions of movement parallel to Cartesian axes. Using agent-based simulations, we study the effects of the interplay between rotational diffusion and an aligning potential on the particles' trajectories, which leads to the right-angled turns. We demonstrate that the long-time effect is to alter the tumble-turn time, which governs the long-time dynamics. In particular, when normalized by this timescale, trajectories become independent of the underlying details of the potential. As such, we develop a simplified continuum theory, which quantitatively agrees with agent-based simulations. We find that the purely diffusive hydrodynamic limit still exhibits anisotropic features at intermediate times and conclude that the transition to diffusive dynamics precedes the transition to isotropic dynamics. By considering short-range repulsive and alignment particle-particle interactions, we show how the anisotropic features of a single particle are inherited by the global order of the system. We hope this work will shed light on how active systems can extend local anisotropic properties to macroscopic scales, which might be important in biological processes occurring in anisotropic environments.
PubMed: 38226730
DOI: 10.1039/d3sm00589e -
Alzheimer's Research & Therapy Oct 2023There has been increasing interest in cortical microstructure as a complementary and earlier measure of neurodegeneration than macrostructural atrophy, but few papers...
BACKGROUND
There has been increasing interest in cortical microstructure as a complementary and earlier measure of neurodegeneration than macrostructural atrophy, but few papers have related cortical diffusion imaging to post-mortem neuropathology. This study aimed to characterise the associations between the main Alzheimer's disease (AD) neuropathological hallmarks and multiple cortical microstructural measures from in vivo diffusion MRI. Comorbidities and co-pathologies were also investigated.
METHODS
Forty-three autopsy cases (8 cognitively normal, 9 mild cognitive impairment, 26 AD) from the National Alzheimer's Coordinating Center and Alzheimer's Disease Neuroimaging Initiative databases were included. Structural and diffusion MRI scans were analysed to calculate cortical minicolumn-related measures (AngleR, PerpPD, and ParlPD) and mean diffusivity (MD). Neuropathological hallmarks comprised Thal phase, Braak stage, neuritic plaques, and combined AD neuropathological changes (ADNC-the "ABC score" from NIA-AA recommendations). Regarding comorbidities, relationships between cortical microstructure and severity of white matter rarefaction (WMr), cerebral amyloid angiopathy (CAA), atherosclerosis of the circle of Willis (ACW), and locus coeruleus hypopigmentation (LCh) were investigated. Finally, the effect of coexistent pathologies-Lewy body disease and TAR DNA-binding protein 43 (TDP-43)-on cortical microstructure was assessed.
RESULTS
Cortical diffusivity measures were significantly associated with Thal phase, Braak stage, ADNC, and LCh. Thal phase was associated with AngleR in temporal areas, while Braak stage was associated with PerpPD in a wide cortical pattern, involving mainly temporal and limbic areas. A similar association was found between ADNC (ABC score) and PerpPD. LCh was associated with PerpPD, ParlPD, and MD. Co-existent neuropathologies of Lewy body disease and TDP-43 exhibited significantly reduced AngleR and MD compared to ADNC cases without co-pathology.
CONCLUSIONS
Cortical microstructural diffusion MRI is sensitive to AD neuropathology. The associations with the LCh suggest that cortical diffusion measures may indirectly reflect the severity of locus coeruleus neuron loss, perhaps mediated by the severity of microglial activation and tau spreading across the brain. Recognizing the impact of co-pathologies is important for diagnostic and therapeutic decision-making. Microstructural markers of neurodegeneration, sensitive to the range of histopathological features of amyloid, tau, and monoamine pathology, offer a more complete picture of cortical changes across AD than conventional structural atrophy.
Topics: Humans; Alzheimer Disease; Lewy Body Disease; Brain; DNA-Binding Proteins; Atrophy
PubMed: 37794477
DOI: 10.1186/s13195-023-01309-3