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Frontiers in Neuroscience 2024The foot sole endures high magnitudes of pressure for sustained periods which results in transient but habitual cutaneous ischemia. Upon unloading, microvascular...
INTRODUCTION
The foot sole endures high magnitudes of pressure for sustained periods which results in transient but habitual cutaneous ischemia. Upon unloading, microvascular reactivity in cutaneous capillaries generates an influx of blood flow (PORH: post-occlusive reactive hyperemia). Whether pressure induced cutaneous ischemia from loading the foot sole impacts mechanoreceptor sensitivity remains unknown.
METHODS
Pressure induced ischemia was attained using a custom-built-loading device that applied load to the whole right foot sole at 2 magnitudes (15 or 50% body weight), for 2 durations (2 or 10 minutes) in thirteen seated participants. Mechanoreceptor sensitivity was assessed using Semmes-Weinstein monofilaments over the third metatarsal (3MT), medial arch (MA), and heel. Perceptual thresholds (PT) were determined for each site prior to loading and then applied repeatedly to a metronome to establish the time course to return to PT upon unload, defined as PT recovery time. Microvascular flux was recorded from an in-line laser speckle contrast imager (FLPI-2, Moor Instruments Inc.) to establish PORH peak and recovery rates at each site.
RESULTS
PT recovery and PORH recovery rate were most influenced at the heel and by load duration rather than load magnitude. PT recovery time at the heel was significantly longer with 10 minutes of loading, regardless of magnitude. Heel PORH recovery rate was significantly slower with 10minutes of loading. The 3MT PT recovery time was only longer after 10 minutes of loading at 50% body weight. Microvascular reactivity or sensitivity was not influenced with loading at the MA. A simple linear regression found that PORH recovery rate could predict PT recovery time at the heel (=0.184, <0.001).
CONCLUSION
In populations with degraded sensory feedback, such as diabetic neuropathy, the risk for ulcer development is heightened. Our work demonstrated that prolonged loading in healthy individuals can impair skin sensitivity, which highlights the risks of prolonged loading and is likely exacerbated in diabetes. Understanding the direct association between sensory function and microvascular reactivity in age and diabetes related nerve damage, could help detect early progressions of neuropathy and mitigate ulcer development.
PubMed: 38629048
DOI: 10.3389/fnins.2024.1329832 -
The Science of the Total Environment Jun 2024There is a growing interest in the impact of acoustic pollution on aquatic ecosystems. Currently, research has primarily focused on hearing species, particularly fishes... (Review)
Review
There is a growing interest in the impact of acoustic pollution on aquatic ecosystems. Currently, research has primarily focused on hearing species, particularly fishes and mammals. However, species from lower trophic levels, including many invertebrates, are less studied despite their ecological significance. Among these taxa, studies examining the effects of sound on holozooplankton are extremely rare. This literature review examines the effects of sound on both marine and freshwater zooplankton. It highlights two differences: the few used organisms and the types of sound source. Marine studies focus on the effects of very intense acute sound on copepods, while freshwater studies focus on less intense chronic sound on cladocerans. But, in both, various negative effects are reported. The effects of sound remain largely unknown, although previous studies have shown that zooplankton can detect vibrations using mechanoreceptors. The perception of their environment can be affected by sounds, potentially causing stress. Limited research suggests that sound may affect the physiology, behaviour, and fitness of zooplankton. Following this review, I highlight the potential to use methods from ecology, ecotoxicology, and parasitology to study the effects of sound at the individual level, including changes in physiology, development, survival, and behaviour. Responses to sound, which could alter species interactions and population dynamics, are expected to have larger-scale implications with bottom-up effects, such as changes in food web dynamics and ecosystem functioning. To improve the study of the effect of sound, to better use zooplankton as biological models and as bioindicators, researchers need to better understand how they perceive their acoustic environment. Consequently, an important challenge is the measurement of particle motion to establish useable dose-response relationships and particle motion soundscapes.
Topics: Zooplankton; Animals; Ecosystem; Sound; Environmental Monitoring; Copepoda
PubMed: 38621539
DOI: 10.1016/j.scitotenv.2024.172489 -
Journal of Zhejiang University.... Apr 2024Cells within tissues are subject to various mechanical forces, including hydrostatic pressure, shear stress, compression, and tension. These mechanical stimuli can be... (Review)
Review
Cells within tissues are subject to various mechanical forces, including hydrostatic pressure, shear stress, compression, and tension. These mechanical stimuli can be converted into biochemical signals through mechanoreceptors or cytoskeleton-dependent response processes, shaping the microenvironment and maintaining cellular physiological balance. Several studies have demonstrated the roles of Yes-associated protein (YAP) and its homolog transcriptional coactivator with PDZ-binding motif (TAZ) as mechanotransducers, exerting dynamic influence on cellular phenotypes including differentiation and disease pathogenesis. This regulatory function entails the involvement of the cytoskeleton, nucleoskeleton, integrin, focal adhesions (FAs), and the integration of multiple signaling pathways, including extracellular signal-regulated kinase (ERK), wingless/integrated (WNT), and Hippo signaling. Furthermore, emerging evidence substantiates the implication of long non-coding RNAs (lncRNAs) as mechanosensitive molecules in cellular mechanotransduction. In this review, we discuss the mechanisms through which YAP/TAZ and lncRNAs serve as effectors in responding to mechanical stimuli. Additionally, we summarize and elaborate on the crucial signal molecules involved in mechanotransduction.
Topics: Mechanotransduction, Cellular; Adaptor Proteins, Signal Transducing; Hippo Signaling Pathway; RNA, Long Noncoding; Intracellular Signaling Peptides and Proteins
PubMed: 38584091
DOI: 10.1631/jzus.B2300497 -
Nature Communications Apr 2024The roles of Aβ low-threshold mechanoreceptors (LTMRs) in transmitting mechanical hyperalgesia and in alleviating chronic pain have been of great interest but remain...
The roles of Aβ low-threshold mechanoreceptors (LTMRs) in transmitting mechanical hyperalgesia and in alleviating chronic pain have been of great interest but remain contentious. Here we utilized intersectional genetic tools, optogenetics, and high-speed imaging to specifically examine functions of Split labeled mouse Aβ-LTMRs in this regard. Genetic ablation of Split-Aβ-LTMRs increased mechanical nociception but not thermosensation in both acute and chronic inflammatory pain conditions, indicating a modality-specific role in gating mechanical nociception. Local optogenetic activation of Split-Aβ-LTMRs triggered nociception after tissue inflammation, whereas their broad activation at the dorsal column still alleviated mechanical hypersensitivity of chronic inflammation. Taking all data into consideration, we propose a model, in which Aβ-LTMRs play distinctive local and global roles in transmitting or alleviating mechanical hyperalgesia of chronic pain, respectively. Our model suggests a strategy of global activation plus local inhibition of Aβ-LTMRs for treating mechanical hyperalgesia.
Topics: Mice; Animals; Hyperalgesia; Chronic Pain; Nociception; Mechanoreceptors; Inflammation
PubMed: 38575590
DOI: 10.1038/s41467-024-47245-0 -
Scientific Reports Apr 2024The small muscle protein, X-linked (SMPX) gene encodes a cytoskeleton-associated protein, highly expressed in the inner ear hair cells (HCs), possibly regulating...
The small muscle protein, X-linked (SMPX) gene encodes a cytoskeleton-associated protein, highly expressed in the inner ear hair cells (HCs), possibly regulating auditory function. In the last decade, several mutations in SMPX have been associated with X-chromosomal progressive non syndromic hearing loss in humans and, in line with this, Smpx-deficient animal models, namely zebrafish and mouse, showed significant impairment of inner ear HCs development, maintenance, and functioning. In this work, we uncovered smpx expression in the neuromast mechanosensory HCs of both Anterior and Posterior Lateral Line (ALL and PLL, respectively) of zebrafish larvae and focused our attention on the PLL. Smpx was subcellularly localized throughout the cytoplasm of the HCs, as well as in their primary cilium. Loss-of-function experiments, via both morpholino-mediated gene knockdown and CRISPR/Cas9 F0 gene knockout, revealed that the lack of Smpx led to fewer properly differentiated and functional neuromasts, as well as to a smaller PLL primordium (PLLp), the latter also Smpx-positive. In addition, the kinocilia of Smpx-deficient neuromast HCs appeared structurally and numerically altered. Such phenotypes were associated with a significant reduction in the mechanotransduction activity of the neuromast HCs, in line with their positivity for Smpx. In summary, this work highlights the importance of Smpx in lateral line development and, specifically, in proper HCs differentiation and/or maintenance, and in the mechanotransduction process carried out by the neuromast HCs. Because lateral line HCs are both functionally and structurally analogous to the cochlear HCs, the neuromasts might represent an invaluable-and easily accessible-tool to dissect the role of Smpx in HCs development/functioning and shed light on the underlying mechanisms involved in hearing loss.
Topics: Humans; Animals; Mice; Zebrafish; Lateral Line System; Mechanotransduction, Cellular; Hair Cells, Auditory; Hearing Loss; Muscle Proteins
PubMed: 38570547
DOI: 10.1038/s41598-024-58138-z -
Cell Reports Apr 2024Type I spiral ganglion neurons (SGNs) convey sound information to the central auditory pathway by forming synapses with inner hair cells (IHCs) in the mammalian cochlea....
Type I spiral ganglion neurons (SGNs) convey sound information to the central auditory pathway by forming synapses with inner hair cells (IHCs) in the mammalian cochlea. The molecular mechanisms regulating the formation of the post-synaptic density (PSD) in the SGN afferent terminals are still unclear. Here, we demonstrate that brain-specific angiogenesis inhibitor 1 (BAI1) is required for the clustering of AMPA receptors GluR2-4 (glutamate receptors 2-4) at the PSD. Adult Bai1-deficient mice have functional IHCs but fail to transmit information to the SGNs, leading to highly raised hearing thresholds. Despite the almost complete absence of AMPA receptor subunits, the SGN fibers innervating the IHCs do not degenerate. Furthermore, we show that AMPA receptors are still expressed in the cochlea of Bai1-deficient mice, highlighting a role for BAI1 in trafficking or anchoring GluR2-4 to the PSDs. These findings identify molecular and functional mechanisms required for sound encoding at cochlear ribbon synapses.
Topics: Animals; Receptors, AMPA; Mice; Spiral Ganglion; Hearing; Cochlea; Post-Synaptic Density; Mice, Knockout; Hair Cells, Auditory, Inner; Mice, Inbred C57BL; Synapses; Receptors, G-Protein-Coupled
PubMed: 38564333
DOI: 10.1016/j.celrep.2024.114025 -
BioRxiv : the Preprint Server For... Mar 2024Cells apply forces to extracellular matrix (ECM) ligands through transmembrane integrin receptors: an interaction which is intimately involved in cell motility, wound...
Cells apply forces to extracellular matrix (ECM) ligands through transmembrane integrin receptors: an interaction which is intimately involved in cell motility, wound healing, cancer invasion and metastasis. These small (pN) forces exerted by cells have been studied by molecular tension fluorescence microscopy (MTFM), which utilizes a force-induced conformational change of a probe to detect mechanical events. MTFM has revealed the force magnitude for integrins receptors in a variety of cell models including primary cells. However, force dynamics and specifically the force loading rate (LR) have important implications in receptor signaling and adhesion formation and remain poorly characterized. Here, we develop a LR probe which is comprised of an engineered DNA structures that undergoes two mechanical transitions at distinct force thresholds: a low force threshold at 4.7 pN corresponding to hairpin unfolding and a high force threshold at 56 pN triggered through duplex shearing. These transitions yield distinct fluorescence signatures observed through single-molecule fluorescence microscopy in live-cells. Automated analysis of tens of thousands of events from 8 cells showed that the bond lifetime of integrins that engage their ligands and transmit a force >4.7 pN decays exponentially with a τ of 45.6 sec. A small subset of these events (<10%) mature in magnitude to >56pN with a median loading rate of 1.3 pNs with these mechanical ramp events localizing at the periphery of the cell-substrate junction. Importantly, the LR probe design is modular and can be adapted to measure force ramp rates for a broad range of mechanoreceptors and cell models, thus aiding in the study of mechanotransduction.
PubMed: 38558970
DOI: 10.1101/2024.03.15.585042 -
Cureus Feb 2024The hemodynamic milieu differs throughout the vascular tree because of varying vascular geometry and blood velocities. Accordingly, the risk of turbulence, which is... (Review)
Review
The hemodynamic milieu differs throughout the vascular tree because of varying vascular geometry and blood velocities. Accordingly, the risk of turbulence, which is dictated by the Reynolds and Dean numbers, also varies. Relatively high blood viscosity is needed to prevent turbulence in the left ventricle and aorta, where high-velocity blood changes direction several times. Low blood viscosity is needed in the capillaries, where erythrocytes pass through vessels with a diameter smaller than their own. In addition, higher blood viscosity is necessary when the cardiac output and peak blood velocity increase as a part of a sympathetic response or anemia, which occurs following significant hemorrhage. Blood viscosity, as reflected in systemic vascular resistance and vascular wall shear stress, is sensed, respectively, by cardiomyocyte stretching in the left ventricle and mechanoreceptors for wall shear stress in the carotid sinus. By controlling blood volume and red blood cell mass, the renin-aldosterone-angiotensin system and the systemic vascular resistance response control the hematocrit, the strongest intrinsic determinant of blood viscosity. These responses provide gross control of blood viscosity. Fine-tuning of blood viscosity in transient conditions is provided by hormonal control of erythrocyte deformability. The short half-life of some of these hormones limits their activity to specific vascular beds. Hormones that modulate blood viscosity include erythropoietin, angiotensin II, brain natriuretic factor, epinephrine, prostacyclin E2, antidiuretic hormone, and nitric oxide.
PubMed: 38558582
DOI: 10.7759/cureus.55237 -
Proceedings of the National Academy of... Apr 2024Although sudden sensorineural hearing loss (SSNHL) is a serious condition, there are currently no approved drugs for its treatment. Nevertheless, there is a growing...
Although sudden sensorineural hearing loss (SSNHL) is a serious condition, there are currently no approved drugs for its treatment. Nevertheless, there is a growing understanding that the cochlear pathologies that underlie SSNHL include apoptotic death of sensory outer hair cells (OHCs) as well as loss of ribbon synapses connecting sensory inner hair cells (IHCs) and neurites of the auditory nerve, designated synaptopathy. Noise-induced hearing loss (NIHL) is a common subtype of SSNHL and is widely used to model hearing loss preclinically. Here, we demonstrate that a single interventive application of a small pyridoindole molecule (AC102) into the middle ear restored auditory function almost to prenoise levels in a guinea pig model of NIHL. AC102 prevented noise-triggered loss of OHCs and reduced IHC synaptopathy suggesting a role of AC102 in reconnecting auditory neurons to their sensory target cells. Notably, AC102 exerted its therapeutic properties over a wide frequency range. Such strong improvements in hearing have not previously been demonstrated for other therapeutic agents. In vitro experiments of a neuronal damage model revealed that AC102 protected cells from apoptosis and promoted neurite growth. These effects may be explained by increased production of adenosine triphosphate, indicating improved mitochondrial function, and reduced levels of reactive-oxygen species which prevents the apoptotic processes responsible for OHC death. This action profile of AC102 might be causal for the observed hearing recovery in in vivo models.
Topics: Guinea Pigs; Animals; Hearing Loss, Noise-Induced; Hearing; Cochlea; Noise; Hearing Loss, Sensorineural; Hair Cells, Auditory, Outer; Auditory Threshold
PubMed: 38557194
DOI: 10.1073/pnas.2314763121 -
Frontiers in Cell and Developmental... 2024Tunicates, the sister group of vertebrates, offer a unique perspective for evolutionary developmental studies (Evo-Devo) due to their simple anatomical organization.... (Review)
Review
Tunicates, the sister group of vertebrates, offer a unique perspective for evolutionary developmental studies (Evo-Devo) due to their simple anatomical organization. Moreover, the separation of tunicates from vertebrates predated the vertebrate-specific genome duplications. As adults, they include both sessile and pelagic species, with very limited mobility requirements related mainly to water filtration. In sessile species, larvae exhibit simple swimming behaviors that are required for the selection of a suitable substrate on which to metamorphose. Despite their apparent simplicity, tunicates display a variety of mechanoreceptor structures involving both primary and secondary sensory cells (., coronal sensory cells). This review encapsulates two decades of research on tunicate mechanoreception focusing on the coronal organ's sensory cells as prime candidates for understanding the evolution of vertebrate hair cells of the inner ear and the lateral line organ. The review spans anatomical, cellular and molecular levels emphasizing both similarity and differences between tunicate and vertebrate mechanoreception strategies. The evolutionary significance of mechanoreception is discussed within the broader context of Evo-Devo studies, shedding light on the intricate pathways that have shaped the sensory system in chordates.
PubMed: 38550380
DOI: 10.3389/fcell.2024.1359207