Meissner's corpuscles are essential mechanoreceptors that detect low-frequency vibrations. However, the internal fluid dynamic processes that convert directional mechanical stimuli into neural signals are not yet fully understood. This study aims to clarify the direction-specific sensing mechanism by analyzing internal fluid flow and shear stress distribution under different vibration modes. A biomimetic microfluidic platform was developed and coupled with a dynamic mesh computational fluid dynamics (CFD) model to simulate the response of the corpuscle to 20 Hz normal and tangential vibrations. The simulation results showed clear differences in fluid behavior. Normal vibration produced localized vortices and peak wall shear stress greater than 0.0054 Pa along the short axis. In contrast, tangential vibration generated stable laminar flow with a lower average shear stress of about 0.0012 Pa along the long axis. These results suggest that the internal structure of the Meissner corpuscle is important for converting mechanical inputs from different directions into specific fluid patterns. This study provides a physical foundation for understanding mechanotransduction and supports the design of biomimetic sensors with improved directional sensitivity for use in smart skin and soft robotic systems.

T cells develop from circulating precursor cells, which enter the thymus and migrate through specialized subcompartments that support their maturation and selection[1]. In humans, this process starts in early fetal development and is highly active until thymic involution in adolescence. To map the microanatomical underpinnings of this process in pre- and early postnatal stages, we established a quantitative morphological framework for the thymus-the Cortico-Medullary Axis-and used it to perform a spatially resolved analysis. Here, by applying this framework to a curated multimodal single-cell atlas, spatial transcriptomics and high-resolution multiplex imaging data, we demonstrate establishment of the lobular cytokine network, canonical thymocyte trajectories and thymic epithelial cell distributions by the beginning of the the second trimester of fetal development. We pinpoint tissue niches of thymic epithelial cell progenitors and distinct subtypes associated with Hassall's corpuscles and identify divergence in the timing of medullary entry between CD4 and CD8 T cell lineages. These findings provide a basis for a detailed understanding of T lymphocyte development and are complemented with a holistic toolkit for cross-platform imaging data analysis, annotation and OrganAxis construction (TissueTag), which can be applied to any tissue.

In recent years, Varicocele (VC) has been recognized as a common cause of male infertility that can be treated by surgery or drugs. How to reduce the damage of VC to testicular spermatogenic function has attracted extensive attention in recent years. Among them, overexpressed ROS and high levels of inflammation may play a key role in VC-induced testicular damage. As the key mediated innate immune pathways, cGAS-STING shaft under pathological conditions, such as in cell and tissue damage stress can be cytoplasmic DNA activation, induce the activation of NLRP3 inflammatory corpuscle, triggering downstream of the inflammatory cascade reaction. Chlorogenic acid (CGA), as a natural compound from a wide range of sources, has strong anti-inflammatory and antioxidant activities, and is a potential effective drug for the treatment of varicocele infertility. The aim of this study is to investigate the role of CGA in the spermatogenic dysfunction of the rat testis induced by VC and the potential mechanisms. The results of this study have shown that CGA gavage treatment ameliorated the pathological damage of seminiferous tubules, increased the number of sperm in the lumen, and increased the expression levels of Occludin and ZO-1, which indicated the therapeutic effect of CGA on spermatogenic dysfunction in the testis of VC rats. Meanwhile, the damage of mitochondrial structure was alleviated and the expression levels of ROS, NLRP3 and pro-inflammatory cytokines (IL-1β, IL-6, IL-18) were significantly reduced in the testicular tissues of model rats after CGA treatment. In addition, we demonstrated for the first time the high expression status of cGAS and STING in testicular tissues of VC model rats, and this was ameliorated to varying degrees after CGA treatment. In conclusion, this study suggests that CGA can improve the spermatogenic function of the testis by reducing mitochondrial damage and inhibiting the activation of the cGAS-STING axis, inhibiting the activation of the NLRP3 inflammasome, and improving the inflammatory damage of the testis, highlighting the potential of CGA as a therapeutic agent for varicocele infertility.

T cells develop from circulating precursors, which enter the thymus and migrate throughout specialised sub-compartments to support maturation and selection. This process starts already in early fetal development and is highly active until the involution of the thymus in adolescence. To map the micro-anatomical underpinnings of this process in pre- vs. post-natal states, we undertook a spatially resolved analysis and established a new quantitative morphological framework for the thymus, the Cortico-Medullary Axis. Using this axis in conjunction with the curation of a multimodal single-cell, spatial transcriptomics and high-resolution multiplex imaging atlas, we show that canonical thymocyte trajectories and thymic epithelial cells are highly organised and fully established by post-conception week 12, pinpoint TEC progenitor states, find that TEC subsets and peripheral tissue genes are associated with Hassall's Corpuscles and uncover divergence in the pace and drivers of medullary entry between CD4 vs. CD8 T cell lineages. These findings are complemented with a holistic toolkit for spatial analysis and annotation, providing a basis for a detailed understanding of T lymphocyte development.

The nephron is composed of distinct segments that perform unique physiological functions. Little is known about how multipotent nephron progenitor cells differentiate into different nephron segments. It is well known that β-catenin signaling regulates the maintenance and commitment of mesenchymal nephron progenitors during kidney development. However, it is not fully understood how it regulates nephron segmentation after nephron progenitors undergo mesenchymal-to-epithelial transition. To address this, we performed β-catenin loss-of-function and gain-of-function studies in epithelial nephron progenitors in the mouse kidney. Consistent with a previous report, the formation of the renal corpuscle was defective in the absence of β-catenin. Interestingly, we found that epithelial nephron progenitors lacking β-catenin were able to form presumptive proximal tubules but that they failed to further develop into differentiated proximal tubules, suggesting that β-catenin signaling plays a critical role in proximal tubule development. We also found that epithelial nephron progenitors lacking β-catenin failed to form the distal tubules. Expression of a stable form of β-catenin in epithelial nephron progenitors blocked the proper formation of all nephron segments, suggesting tight regulation of β-catenin signaling during nephron segmentation. This work shows that β-catenin regulates the formation of multiple nephron segments along the proximo-distal axis of the mammalian nephron.

Thymic malignancies are rare mediastinal cancers, classified according to the World Health Organization's histopathologic classification which distinguishes thymomas from thymic carcinomas. One key consideration when discussing immunotherapy for thymic epithelial tumors is that one-third of patients diagnosed with thymomas present at the time of diagnosis with autoimmune disorders, the most common being myasthenia gravis. The first step in the understanding of autoimmunity in thymic epithelial tumors is to distinguish true autoimmune disorders from paraneoplastic syndromes; besides pathophysiology, clinical correlates, impact on oncological management and survival may differ strongly. Autoimmune disorders are related to a deregulation in the physiological role of the thymus (i.e. to induce central tolerance to tissue self-antigens) through control of differentiation and subsequent positive and negative selection of immature T cells; from a clinical standpoint, in thymomas, once autoimmune disorders are present, they may not regress significantly after thymectomy. PD-L1 expression, while observed in more than 90% of epithelial cells of the normal thymus with a medullar tropism respecting Hassall's corpuscles, has also been identified in thymomas and thymic carcinomas using various immunohistochemistry protocols. Immune checkpoint inhibitors of the PD-1/PD-L1 axis have been assessed in advanced and metastatic thymic epithelial tumors, mainly thymic carcinomas. Several case reports have been published, and four trials have assessed the efficacy and safety of these inhibitors. Immunotherapy is not standard given the frequent occurrence of severe autoimmune disorders, and clinical trials are ongoing.

Inflammatory response serves an important role in diabetic nephropathy (DN); however, the mechanism of inflammatory response results in renal damage is not yet clear. The aim of the present study was to investigate the role of the thioredoxin interacting protein (TXNIP)/NOD‑like receptor protein 3 (NLRP3) axis‑mediated activation of NLRP3 inflammasome in DN. A diabetic rat model was induced by streptozotocin injection. Hematoxylin and eosin (H&E) staining and streptavidin‑peroxidase staining were then used to examine the kidney tissue morphology, and TXNIP and NLRP3 protein expression levels, respectively. Furthermore, RNA interference technology was applied to silence the TXNIP gene. TXNIP and NLRP3 inflammasome activation‑associated proteins and mRNAs were detected by western blot analysis and RT‑qPCR, respectively. Enzyme‑linked immunosorbent assay was also used to examine interleukin (IL)‑1 and IL‑18 expression, while flow cytometry was performed to detect reactive oxygen species production. The data revealed that TXNIP and NLRP3 were overexpressed in kidney tissue of DN rats, and the level of antioxidant genes was downregulated. It was also observed that glucose promoted TXNIP expression and activation of NLRP3 inflammasome in a time‑dependent and dose‑dependent manner, therefore promoting inflammatory responses. Silencing of TXNIP gene resulted in the downregulation of NLRP3 inflammasome activation, and inhibited the expression levels of IL‑1 and IL‑18 in a high‑glucose environment. Furthermore, low expression of TXNIP promoted the levels of antioxidant genes and reduced the ROS levels. Taken together, the high‑glucose environment was able to upregulated the level of inflammatory factors by promoting the expression of TXNIP and the activation of NLRP3 inflammasome, consequently participating in DN.

Objective: To investigate the expression and significance of NLRP3/IL-1β/TGF-β(1) signal axis in a rat model of silicosis and pulmonary fibrosis. Methods: Eighty healthy Wistar male rats of SPF grade were randomly divided into 4 groups: high (100 mg/ml) , medium (50 mg/ml) , low (25 mg/ml) concentration SiO(2) dusting group and normal negative control. Group, 20 in each group. Five rats were sacrificed at 7 d, 14 d, 28 d and 56 d after SiO(2) dusting. The degree of alveolitis and the degree of pulmonary fibrosis were observed. The enzyme-linked immunosorbent assay (ELISA) was used to detect IL-1β in lung tissue. The expressions of NLRP3 and Caspase-1 in lung tissue of rats were detected by Western Blot. Results: The alveolitis score and fibrosis degree of the rats in the dust-receiving group were significantly higher than those in the control group at 7 d, 14 d, 28 d and 56 d, and the difference was statistically significant (P<0.01) . The concentrations of IL-1β, IL-18 and TGF-β1 in 14 d, 28 d and 56 d were significantly higher than those in the control group (P<0.01) . The expressions of NLRP3 and Caspase-1 in lung tissue of rats exposed to dust were 7 d and 14 d, 28 d, 56d were higher than the control group (P<0.01) ; the expression levels of NLRP3, Caspase-1, IL-1β, IL-18 and TGF-β(1) in the low, medium and high concentration SiO(2) dusting group were 7 d, 14 d and The difference between the two groups was statistically significant (P<0.05) , and both showed a time-effect relationship with the increase of dusting time. Conclusion: NLRP3 and its downstream factors Caspase-1, IL-1β, IL-18 and TGF-β1 are highly expressed in the lung tissue of rats with silicosis and pulmonary fibrosis, suggesting that the NLRP3/IL-1β/TGF-β(1) signal axis may be associated with silicosis. Pulmonary fibrosis has a close relationship and plays a role in the formation of silicosis.

The detailed distribution of Pacinian corpuscles was evaluated by viewing the transverse sections of all fingers and thumbs, including the interdigital areas, from eight hands of five fetuses of gestational age 28-33 weeks (crown-rump length 230-290 mm). Among the 40 fingers and thumbs, serial sections were prepared for 3D reconstructions of nerve elements in the distal and middle phalangeal segments of three fifth fingers; in these three fingers, the distal segment contained 45-75 Pacinian corpuscles. These Pacinian corpuscles were 0.2-1.0 mm in length and 0.05-0.3 mm in thickness, oriented along the proximodistal axis and arranged along the palmar digital nerve branches. Other than beneath the digital skin, small corpuscles (<0.1 mm in thickness) were observed within the tendon sheath of the flexors in the middle or distal segment of five fetuses and in the nail beds of four fetuses. Clusters of 5-20 corpuscles formed bouquet- or tree-like arrangements along neurovascular bundles in the fingers, thumbs and interdigital areas. Because the space beneath the skin was thick and loose in the interdigital area, trees in the interdigital area were up to 2 mm long. Regardless of site, the central core of each corpuscle was positive for S100 protein, while the core and parts of the capillaries in the corpuscle were weakly positive for nestin. Because corpuscles in the tendon sheath and nail bed, as well as bouquet- and tree-like arrangements of corpuscles, have not been reported in adults, these morphologies are likely specific to fetuses. Anat Rec, 2017. © 2017 Wiley Periodicals, Inc. Anat Rec, 301:154-165, 2018. © 2017 Wiley Periodicals, Inc.

The Pacinian corpuscle (PC) is a cutaneous mechanoreceptor sensitive to high-frequency vibrations (20-1000Hz). The PC is of importance due to its integral role in somatosensation and the critical need to understand PC function for haptic feedback system development. Previous theoretical and computational studies have modeled the physiological response of the PC to sustained or vibrating mechanical stimuli, but they have used estimates of the receptor's mechanical properties, which remain largely unmeasured. In this study, we used micropipette aspiration (MPA) to determine an apparent Young's modulus for PCs isolated from a cadaveric human hand. MPA was applied in increments of 5mm H2O (49Pa), and the change in protrusion length of the PC into the pipette was recorded. The protrusion length vs. suction pressure data were used to calculate the apparent Young's modulus. Using 10 PCs with long-axis lengths of 2.99±0.41mm and short-axis lengths of 1.45±0.22mm, we calculated a Young's modulus of 1.40±0.86kPa. Our measurement is on the same order of magnitude as those approximated in previous models, which estimated the PC to be on the same order of magnitude as skin or isolated cells, so we recommend that a modulus in the kPa range be used in future studies.

Using histological sections of 12 hands from 12 human fetuses at 20-34 weeks of gestation (150-290 mm) and 14 fingers (index and small) from seven donated cadavers of elderly individuals (aged 78-95 years), we compared the features of Vater-Pacinian corpuscles between these two stages of life. Corpuscles with thin, tightly packed lamellae appeared to undergo a change to thick, loosely packed lamellae at 23-32 weeks. The typical fetal corpuscle had two parts: (1) a rod-like proximal part (0.2-0.6 mm in length) extending along the proximodistal axis of the finger, and (2) a distal end (0.1 mm) after acute bending of the proximal part. Corpuscles were associated with palmar digital nerves in the fingers, but were also present along the dorsal nerves in the thumb. A flower bouquet- or tree-like arrangement including 5-10 corpuscles extended to the dermis of the skin along a perforating artery. Serial sections of the thumb and fifth finger revealed approximately 80-180 corpuscles in the distal phalangeal segment. In elderly individuals, the corpuscles were distributed along the palmar digital nerve, but (1) their density was much lower than in fetuses and (2) a bouquet- or tree-like arrangement was rarely seen. In the distal segment, there were fewer than 40 adult corpuscles, being 0.2-0.5 mm thick and 1.0-2.5 mm long. Wavy or coiled corpuscles were evident. Because of the considerable differences in the distribution and number of corpuscles between the fetus and adult, they appear to undergo considerable depletion with age, especially along thin, superficial nerve branches.

Fibroblast growth factor 23 (FGF23), a hormone required for phosphorus metabolism, was recently proposed to act on Ca2+ uptake; however, the available evidence of how FGF23 controls the body fluid Ca2+ homeostasis needs to be further clarified. The use of zebrafish as a model system revealed that FGF23 is specifically expressed in the corpuscles of Stannius (CS), an organ involved in Ca2+ homeostasis in fish, and that its expression is stimulated by ambient water with a high Ca2+ level. The overexpression of FGF23 inhibited Ca2+ uptake by downregulating the messenger RNA (mRNA) expression of epithelium calcium channel. Calcium-sensing receptor (CaSR), which senses changes in extracellular Ca2+ levels and modulates calciotropic hormones in organs controlling Ca2+ homeostasis in vertebrates, was found to be coexpressed with FGF23 in the CS. In addition, upregulated expression of FGF23 mRNA was detected in morphants of stanniocalcin 1 (stc1, another hypocalcemic factor synthesized in the CS), and knockdown of CaSR suppressed such upregulation and enhanced Ca2+ uptake. Taken together, our data indicate that FGF23 functions as a hypocalcemic hormone in zebrafish and that the CaSR/STC1-FGF23 axis is involved in body fluid Ca2+ homeostasis in vertebrates.

Cutaneous mechanoreceptors transduce different tactile stimuli into neural signals that produce distinct sensations of touch. The Pacinian corpuscle (PC), a cutaneous mechanoreceptor located deep within the dermis of the skin, detects high frequency vibrations that occur within its large receptive field. The PC is comprised of lamellae that surround the nerve fiber at its core. We hypothesized that a layered, anisotropic structure, embedded deep within the skin, would produce the nonlinear strain transmission and low spatial sensitivity characteristic of the PC. A multiscale finite-element model was used to model the equilibrium response of the PC to indentation. The first simulation considered an isolated PC with fiber networks aligned with the PC's surface. The PC was subjected to a 10 μm indentation by a 250 μm diameter indenter. The multiscale model captured the nonlinear strain transmission through the PC, predicting decreased compressive strain with proximity to the receptor's core, as seen experimentally by others. The second set of simulations considered a single PC embedded epidermally (shallow) or dermally (deep) to model the PC's location within the skin. The embedded models were subjected to 10 μm indentations at a series of locations on the surface of the skin. Strain along the long axis of the PC was calculated after indentation to simulate stretch along the nerve fiber at the center of the PC. Receptive fields for the epidermis and dermis models were constructed by mapping the long-axis strain after indentation at each point on the surface of the skin mesh. The dermis model resulted in a larger receptive field, as the calculated strain showed less indenter location dependence than in the epidermis model.

Thermodynamic properties of the one-dimensional (1D) quantum well (QW) with miscellaneous permutations of the Dirichlet (D) and Neumann (N) boundary conditions (BCs) at its edges in the perpendicular to the surfaces electric field [Formula: see text] are calculated. For the canonical ensemble, analytical expressions involving theta functions are found for the mean energy and heat capacity [Formula: see text] for the box with no applied voltage. Pronounced maximum accompanied by the adjacent minimum of the specific heat dependence on the temperature T for the pure Neumann QW and their absence for other BCs are predicted and explained by the structure of the corresponding energy spectrum. Applied field leads to the increase of the heat capacity and formation of the new or modification of the existing extrema what is qualitatively described by the influence of the associated electric potential. A remarkable feature of the Fermi grand canonical ensemble is, at any BC combination in zero fields, a salient maximum of [Formula: see text] observed on the T axis for one particle and its absence for any other number N of corpuscles. Qualitative and quantitative explanation of this phenomenon employs the analysis of the chemical potential and its temperature dependence for different N. It is proved that critical temperature [Formula: see text] of the Bose-Einstein (BE) condensation increases with the applied voltage for any number of particles and for any BC permutation except the ND case at small intensities [Formula: see text] what is explained again by the modification by the field of the interrelated energies. It is shown that even for the temperatures smaller than [Formula: see text] the total dipole moment [Formula: see text] may become negative for the quite moderate [Formula: see text]. For either Fermi or BE system, the influence of the electric field on the heat capacity is shown to be suppressed with N growing. Different asymptotic cases of, e.g., the small and large temperatures and low and high voltages are derived analytically and explained physically. Parallels are drawn to the similar properties of the 1D harmonic oscillator, and similarities and differences between them are discussed.