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Communications Biology May 2024Pending questions regarding cochlear amplification and tuning are hinged upon the organ of Corti (OoC) active mechanics: how outer hair cells modulate OoC vibrations....
Pending questions regarding cochlear amplification and tuning are hinged upon the organ of Corti (OoC) active mechanics: how outer hair cells modulate OoC vibrations. Our knowledge regarding OoC mechanics has advanced over the past decade thanks to the application of tomographic vibrometry. However, recent data from live cochlea experiments often led to diverging interpretations due to complicated interaction between passive and active responses, lack of image resolution in vibrometry, and ambiguous measurement angles. We present motion measurements and analyses of the OoC sub-components at the close-to-true cross-section, measured from acutely excised gerbil cochleae. Specifically, we focused on the vibrating patterns of the reticular lamina, the outer pillar cell, and the basilar membrane because they form a structural frame encasing active outer hair cells. For passive transmission, the OoC frame serves as a rigid truss. In contrast, motile outer hair cells exploit their frame structures to deflect the upper compartment of the OoC while minimally disturbing its bottom side (basilar membrane). Such asymmetric OoC vibrations due to outer hair cell motility explain how recent observations deviate from the classical cochlear amplification theory.
Topics: Animals; Gerbillinae; Hair Cells, Auditory, Outer; Vibration; Organ of Corti; Cochlea; Basilar Membrane
PubMed: 38762693
DOI: 10.1038/s42003-024-06293-4 -
Disease Models & Mechanisms May 2024Diabetic nephropathy (DN) is a substantial healthcare challenge as a complication of diabetes, owing to the high risk of morbidity and mortality involved. Although...
Diabetic nephropathy (DN) is a substantial healthcare challenge as a complication of diabetes, owing to the high risk of morbidity and mortality involved. Although significant progress has been made in understanding the pathogenesis of DN, more efficient models are required to develop new therapeutics. Here, we created a DN model in zebrafish by crossing diabetic Tg(acta1:dnIGF1R-EGFP) and proteinuria-tracing Tg(l-fabp::VDBP-GFP) lines, named zMIR/VDBP. Overfed adult zMIR/VDBP fish developed severe hyperglycemia and proteinuria, which were not observed in wild-type zebrafish. Renal histopathology revealed human DN-like characteristics, such as glomerular basement membrane thickening, foot process effacement, and glomerular sclerosis. Glomerular dysfunction is restored upon calorie restriction. RNA sequencing (RNA-seq) analysis demonstrated that zebrafish DN kidneys exhibited transcriptional patterns similar to human DN pathogenesis. Notably, the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway was activated, a phenomenon observed in the early phase of human DN. In addition, metformin improved hyperglycemia and proteinuria in DN zebrafish by modulating AKT phosphorylation. Our results indicated that zMIR/VDBP fish are suitable for elucidating the mechanisms underlying human DN and could be a powerful tool for therapeutic discovery.
PubMed: 38747698
DOI: 10.1242/dmm.050438 -
Clinical and Experimental Medicine May 2024The role of mast cells in physiologic and pathological processes extends far beyond the allergy processes: they are involved in wound healing, chronic inflammation, and... (Review)
Review
The role of mast cells in physiologic and pathological processes extends far beyond the allergy processes: they are involved in wound healing, chronic inflammation, and tumor growth. This short article emphasizes the role played by mast cells in age-related macular degeneration (AMD). Mast cells can induce angiogenesis and are present around Bruch's membrane during the early and late stages of choroidal neovascularization in AMD. Proteolytic enzymes released by mast cells lead to thinning of the choroid in AMD as well as degradation of vascular basement membranes and Bruch's membrane, which in turn could result in retinal pigment epithelial death and choriocapillaris degeneration in geographical atrophy and exudative AMD.
Topics: Humans; Mast Cells; Choroid; Macular Degeneration; Choroidal Neovascularization; Bruch Membrane
PubMed: 38727918
DOI: 10.1007/s10238-024-01361-9 -
Frontiers in Immunology 2024studies often use two-dimensional (2D) monolayers, but 3D cell organization, such as in spheroids, better mimics the complexity of solid tumors. To metastasize, cancer... (Comparative Study)
Comparative Study
BACKGROUND
studies often use two-dimensional (2D) monolayers, but 3D cell organization, such as in spheroids, better mimics the complexity of solid tumors. To metastasize, cancer cells undergo the process of epithelial-to-mesenchymal transition (EMT) to become more invasive and pro-angiogenic, with expression of both epithelial and mesenchymal markers.
AIMS
We asked whether EMMPRIN/CD147 contributes to the formation of the 3D spheroid structure, and whether spheroids, which are often used to study proliferation and drug resistance, could better model the EMT process and the metastatic properties of cells, and improve our understanding of the role of EMMPRIN in them.
METHODS
We used the parental mouse CT26 colon carcinoma (CT26-WT) cells, and infected them with a lentivirus vector to knock down EMMPRIN expression (CT26-KD cells), or with an empty lentivirus vector (CT26-NC) that served as a negative control. In some cases, we repeated the experiments with the 4T1 or LLC cell lines. We compared the magnitude of change between CT26-KD and CT26-WT/NC cells in different metastatic properties in cells seeded as monolayers or as spheroids formed by the scaffold-free liquid overlay method.
RESULTS
We show that reduced EMMPRIN expression changed the morphology of cells and their spatial organization in both 2D and 3D models. The 3D models more clearly demonstrated how reduced EMMPRIN expression inhibited proliferation and the angiogenic potential, while it enhanced drug resistance, invasiveness, and EMT status, and moreover it enhanced cell dormancy and prevented CT26-KD cells from forming metastatic-like lesions when seeded on basement membrane extract (BME). Most interestingly, this approach enabled us to identify that EMMPRIN and miR-146a-5p form a negative feedback loop, thus identifying a key mechanism for EMMPRIN activities. These results underline EMMPRIN role as a gatekeeper that prevents dormancy, and suggest that EMMPRIN links EMT characteristics to the process of spheroid formation.
CONCLUSIONS
Thus, 3D models can help identify mechanisms by which EMMPRIN facilitates tumor and metastasis progression, which might render EMMPRIN as a promising target for anti-metastatic tumor therapy.
Topics: Basigin; Spheroids, Cellular; Animals; Colonic Neoplasms; Mice; Epithelial-Mesenchymal Transition; Cell Line, Tumor; Neoplasm Metastasis
PubMed: 38725999
DOI: 10.3389/fimmu.2024.1374088 -
ESC Heart Failure May 2024The development of new drugs and device therapies has led to remarkable advancements in heart failure (HF) treatment in the past couple of decades. However, it becomes... (Review)
Review
The development of new drugs and device therapies has led to remarkable advancements in heart failure (HF) treatment in the past couple of decades. However, it becomes increasingly evident that guideline-directed medical therapy cannot be one-size-fits-all across a wide range of ejection fractions (EFs) and various aetiologies. Therefore, classifications solely relying on EF and natriuretic peptide make optimization of treatment challenging, and there is a growing exploration of new indicators that enable efficient risk stratification of HF patients. Particularly when considering HF as a multi-organ interaction syndrome, the cardiorenal interaction plays a central role in its pathophysiology, and albuminuria has gained great prominence as its biomarker, independent from glomerular filtration rate. Albuminuria has been shown to exhibit a linear correlation with cardiovascular disease and HF prognosis in multiple epidemiological studies, ranging from normal (<30 mg/g) to high levels (>300 mg/g). However, on the other hand, it is only recently that the details of the pathological mechanisms that give rise to albuminuria have begun to be elucidated, including the efficient compaction/tightening of the glomerular basement membrane by podocytes and mesangial cells. Interestingly, renal disease, diabetes, and HF damage these components associated with albuminuria, and experimental models have demonstrated that recently developed HF drugs reduce albuminuria by ameliorating these pathological phenotypes. In this review, facing the rapid expansion of horizons in HF treatment, we aim to clarify the current understanding of the pathophysiology of albuminuria and explore the comprehensive understanding of albuminuria by examining the clinically established evidence to date, the pathophysiological mechanisms leading to its occurrence, and the outcomes of clinical studies utilizing various drug classes committed to specific pathological mechanisms to put albuminuria as a novel axis to depict the pathophysiology of HF.
PubMed: 38725278
DOI: 10.1002/ehf2.14811 -
Matrix Biology : Journal of the... May 2024Proteinuria, the presence of high molecular weight proteins in the urine, is a primary indicator of chronic kidney disease. Proteinuria results from increased molecular...
Proteinuria, the presence of high molecular weight proteins in the urine, is a primary indicator of chronic kidney disease. Proteinuria results from increased molecular permeability of the glomerular filtration barrier combined with saturation or defects in tubular protein reabsorption. Any solute that passes into the glomerular filtrate traverses the glomerular endothelium, the glomerular basement membrane, and the podocyte slit diaphragm. Damage to any layer from the filter has reciprocal effects on other layers to increase glomerular permeability. The GBM is thought to act as a compressible ultrafilter that has increased molecular selectivity with increased pressure due to compression that reduced the porosity of the GBM with increased pressure. In multiple forms of chronic kidney disease, crosslinking enzymes are upregulated and may act to increase GBM stiffness. Here we show that enzymatically crosslinking porcine GBM with transglutaminase increases the stiffness of the GBM and mitigates pressure-dependent reductions in molecular sieving coefficient. This was modeled mathematically using a modified membrane transport model accounting for GBM compression. Changes in the mechanical properties of the GBM may contribute to proteinuria through pressure-dependent effects on GBM porosity.
PubMed: 38723871
DOI: 10.1016/j.matbio.2024.05.002 -
Anatomy & Cell Biology May 2024Striated muscle insertions into the skin and mucosa are present in the head, neck, and pelvic floor. We reexamined the histology of these tissues to elucidate their role...
Striated muscle insertions into the skin and mucosa are present in the head, neck, and pelvic floor. We reexamined the histology of these tissues to elucidate their role in transmission of the force. We examined histological sections of 25 human fetuses (gestational ages of ~11-19 weeks and ~26-40 weeks) and 6 cadavers of elderly individuals. Facial muscle insertion or terminal almost always formed as an interdigitation with another muscle or as a circular arrangement in which muscle fiber insertions were sandwiched and mechanically supported by other muscle fibers (like an in-series muscle). Our examination of the face revealed some limited exceptions in which muscle fibers that approached the dermis were always in the nasalis and mentalis muscles, and often in the levator labii superioris alaeque nasi muscle. The buccinator muscle was consistently inserted into the basement membrane of the oral mucosa. Parts of the uvulae muscle in the soft palate and of the intrinsic vertical muscle of the tongue were likely to direct toward the mucosa. In contrast, the pelvic floor did not contain striated muscle fibers that were directed toward the skin or mucosa. Although 'cutaneous muscle' is a common term, the actual insertion of a muscle into the skin or mucosa seemed to be very rare. Instead, superficial muscle insertion often consisted of interdigitated muscle bundles that had different functional vectors. In this case, the terminal of one muscle bundle was sandwiched and fixed mechanically by other bundles.
PubMed: 38720632
DOI: 10.5115/acb.24.048 -
PloS One 2024Essential for muscle fiber formation and hypertrophy, muscle stem cells, also called satellite cells, reside beneath the basal lamina of the muscle fiber. Satellite...
Essential for muscle fiber formation and hypertrophy, muscle stem cells, also called satellite cells, reside beneath the basal lamina of the muscle fiber. Satellite cells have been commonly identified by the expression of the Paired box 7 (Pax7) due to its specificity and the availability of antibodies in tetrapods. In fish, the identification of satellite cells remains difficult due to the lack of specific antibodies in most species. Based on the development of a highly sensitive in situ hybridization (RNAScope®) for pax7, we showed that pax7+ cells were detected in the undifferentiated myogenic epithelium corresponding to the dermomyotome at day 14 post-fertilization in rainbow trout. Then, from day 24, pax7+ cells gradually migrated into the deep myotome and were localized along the muscle fibers and reach their niche in satellite position of the fibres after hatching. Our results showed that 18 days after muscle injury, a large number of pax7+ cells accumulated at the wound site compared to the uninjured area. During the in vitro differentiation of satellite cells, the percentage of pax7+ cells decreased from 44% to 18% on day 7, and some differentiated cells still expressed pax7. Taken together, these results show the dynamic expression of pax7 genes and the follow-up of these muscle stem cells during the different situations of muscle fiber formation in trout.
Topics: Animals; Oncorhynchus mykiss; PAX7 Transcription Factor; Satellite Cells, Skeletal Muscle; Cell Differentiation; Regeneration; Muscle Development; Gene Expression Regulation, Developmental
PubMed: 38718005
DOI: 10.1371/journal.pone.0300850 -
Investigative Ophthalmology & Visual... May 2024We aimed to identify structural differences in normal eyes, early age-related macular degeneration (AMD), and intermediate AMD eyes using optical coherence tomography... (Comparative Study)
Comparative Study
PURPOSE
We aimed to identify structural differences in normal eyes, early age-related macular degeneration (AMD), and intermediate AMD eyes using optical coherence tomography (OCT) in a well-characterized, large cross-sectional cohort.
METHODS
Subjects ≥ 60 years with healthy normal eyes, as well as early or intermediate AMD were enrolled in the Alabama Study on Age-related Macular Degeneration 2 (ALSTAR2; NCT04112667). Using Spectralis HRA + OCT2, we obtained macular volumes for each participant. An auto-segmentation software was used to segment six layers and sublayers: photoreceptor inner and outer segments, subretinal drusenoid deposits (SDDs), retinal pigment epithelium + basal lamina (RPE + BL), drusen, and choroid. After manually refining the segmentations of all B-scans, mean thicknesses in whole, central, inner and outer rings of the ETDRS grid were calculated and compared among groups.
RESULTS
This study involved 502 patients, 252 were healthy, 147 had early AMD, and 103 had intermediate AMD eyes (per Age-Related Eye Disease Study [AREDS] 9-step). Intermediate AMD eyes exhibited thicker SDD and drusen, thinner photoreceptor inner segments, and RPE compared to healthy and early AMD eyes. They also had thicker photoreceptor outer segments than early AMD eyes. Early AMD eyes had thinner photoreceptor outer segments than normal eyes but a thicker choroid than intermediate AMD eyes. Using the Beckman scale, 42% of the eyes initially classified as early AMD shifted to intermediate AMD, making thickness differences for photoreceptor outer segments and choroid insignificant.
CONCLUSIONS
With AMD stages, the most consistent structural differences involve appearance of drusen and SDD, followed by RPE + BL thickness, and then thickness of photoreceptor inner and outer segments. Structural changes in the transition from aging to intermediate AMD include alterations in the outer retinal bands, including the appearance of deposits on either side of the RPE.
Topics: Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; Choroid; Cross-Sectional Studies; Macular Degeneration; Retinal Drusen; Retinal Photoreceptor Cell Outer Segment; Retinal Pigment Epithelium; Tomography, Optical Coherence; Visual Acuity
PubMed: 38717424
DOI: 10.1167/iovs.65.5.17 -
Brazilian Journal of Medical and... 2024Anti-glomerular basement membrane (GBM) disease is a rare and severe vasculitis that affects the glomerular and pulmonary capillaries and has an incidence of less than 2...
Anti-glomerular basement membrane (GBM) disease is a rare and severe vasculitis that affects the glomerular and pulmonary capillaries and has an incidence of less than 2 cases per million individuals per year. Anti-GBM disease is mediated by autoantibodies against the α3 chain of type IV collagen. In the majority of cases, the autoantibodies are of the immunoglobulin G (IgG) class, with rare cases being mediated by immunoglobulin M (IgM) or immunoglobulin A (IgA); there are less than 15 IgA-mediated cases reported in the literature worldwide. The classic form of this disease manifests with rapidly progressive glomerulonephritis (RPGN), with or without pulmonary hemorrhage, and the diagnosis consists of identifying high titers of autoantibodies in the serum and/or deposited in the tissues. IgA antibodies are not identified in routine immunoassay tests, and renal biopsy with immunofluorescence is essential for diagnosis. We present a case of RPGN due to anti-GBM disease with linear IgA deposition, whose diagnosis was made exclusively by renal biopsy and with an unfavorable prognosis.
Topics: Humans; Anti-Glomerular Basement Membrane Disease; Immunoglobulin A; Autoantibodies; Glomerulonephritis; Biopsy; Male; Female
PubMed: 38716984
DOI: 10.1590/1414-431X2024e13466