Mapping Somatosensory Afferent Circuitry to Bone Identifies Neurotrophic Signals Required for Fracture Healing.

The profound pain accompanying bone fracture is mediated by somatosensory neurons, which also appear to be required to initiate bone regeneration following fracture. Surprisingly, the precise neuroanatomical circuitry mediating skeletal nociception and regeneration remains incompletely understood. Here, we characterized somatosensory dorsal root ganglia (DRG) afferent neurons innervating murine long bones before and after experimental long bone fracture in mice. Retrograde labeling of DRG neurons by an adeno-associated virus with peripheral nerve tropism showed AAV-tdT signal. Single cell transcriptomic profiling of 6,648 DRG neurons showed highest labeling across CGRP+ neuron clusters (6.9-17.2%) belonging to unmyelinated C fibers, thinly myelinated Aδ fibers and Aß-Field LTMR (9.2%). Gene expression profiles of retrograde labeled DRG neurons over multiple timepoints following experimental stress fracture revealed dynamic changes in gene expression corresponding to the acute inflammatory ( S100a8 , S100a9 ) and mechanical force ( Piezo2 ). Reparative phase after fracture included morphogens such as Tgfb1, Fgf9 and Fgf18 . Two methods to surgically or genetically denervate fractured bones were used in combination with scRNA-seq to implicate defective mesenchymal cell proliferation and osteodifferentiation as underlying the poor bone repair capacity in the presence of attenuated innervation. Finally, multi-tissue scRNA-seq and interactome analyses implicated neuron-derived FGF9 as a potent regulator of fracture repair, a finding compatible with in vitro assessments of neuron-to-skeletal mesenchyme interactions.

The Mohawk homeobox gene represents a marker and osteo-inhibitory factor in calvarial suture osteoprogenitor cells.

The regeneration of the mammalian skeleton's craniofacial bones necessitates the action of intrinsic and extrinsic inductive factors from multiple cell types, which function hierarchically and temporally to control the differentiation of osteogenic progenitors. Single-cell transcriptomics of developing mouse calvarial suture recently identified a suture mesenchymal progenitor population with previously unappreciated tendon- or ligament-associated gene expression profile. Here, we developed a Mohawk homeobox (MkxCG; R26RtdT) reporter mouse and demonstrated that this reporter identifies an adult calvarial suture resident cell population that gives rise to calvarial osteoblasts and osteocytes during homeostatic conditions. Single-cell RNA sequencing (scRNA-Seq) data reveal that Mkx+ suture cells display a progenitor-like phenotype with expression of teno-ligamentous genes. Bone injury with Mkx+ cell ablation showed delayed bone healing. Remarkably, Mkx gene played a critical role as an osteo-inhibitory factor in calvarial suture cells, as knockdown or knockout resulted in increased osteogenic differentiation. Localized deletion of Mkx in vivo also resulted in robustly increased calvarial defect repair. We further showed that mechanical stretch dynamically regulates Mkx expression, in turn regulating calvarial cell osteogenesis. Together, we define Mkx+ cells within the suture mesenchyme as a progenitor population for adult craniofacial bone repair, and Mkx acts as a mechanoresponsive gene to prevent osteogenic differentiation within the stem cell niche.

Neuronal regulation of bone and tendon injury repair: a focused review.

Beyond the sensation of pain, peripheral nerves have been shown to play crucial roles in tissue regeneration and repair. As a highly innervated organ, bone can recover from injury without scar formation, making it an interesting model in which to study the role of nerves in tissue regeneration. As a comparison, tendon is a musculoskeletal tissue that is hypo-innervated, with repair often resulting in scar formation. Here, we reviewed the significance of innervation in three stages of injury repair (inflammatory, reparative, and remodeling) in two commonly injured musculoskeletal tissues: bone and tendon. Based on this focused review, we conclude that peripheral innervation is essential for phases of proper bone and tendon repair, and that nerves may dynamically regulate the repair process through interactions with the injury microenvironment via a variety of neuropeptides or neurotransmitters. A deeper understanding of neuronal regulation of musculoskeletal repair, and the crosstalk between nerves and the musculoskeletal system, will enable the development of future therapies for tissue healing.

Accumulating evidence has shown that, across organs systems, peripheral nerves regulate the process of tissue repair and regeneration. This is particularly relevant in the context of musculoskeletal injuries such as those affecting the bone and tendon. The question then arises: what is the function of peripheral innervation in the repair of bone and tendon injuries? This review offers an in-depth look at the ways in which nerves regulate the healing of bone and tendon injuries at various stages of recovery. A deeper comprehension of the influence of nerves on the repair of these tissues could pave the way for the development of future therapeutic strategies for tissue healing.

Web-Based Compassion Interventions for Family Caregivers' Mental Well-Being: A Systematic Review and Meta-Analysis.

OBJECTIVES: To assess the effectiveness of web-based compassion interventions on the mental well-being of family caregivers. DESIGN: Systematic review and meta-analysis. SETTING AND PARTICIPANTS: Randomized controlled trials of web-based compassion intervention for family caregivers. METHODS: MEDLINE, Embase, PsycINFO, Web of Science, Cochrane Library, and Proquest were searched from database inception until manuscript submission date. Eligible studies included family caregivers participating in web-based compassionate interventions with reported mental wellness indicators, such as self-compassion. Two independent researchers conducted a literature review, extracted data, and assessed the quality of each study using the risk of bias 2 tool. Random effects meta-analysis was performed to pool the data, followed by subgroup analyses, sensitivity analyses, and Egger's tests. RESULTS: Of 1095 studies evaluated, 8 randomized controlled trials (encompassing 1978 participants) were included, with 75% exhibiting low risk of bias and high-quality evidence. Meta-analysis results indicated positive effects of web-based compassion interventions on family caregivers' self-compassion [standardized mean difference (SMD), 0.33; 95% CI, 0.08-0.58; P = .009] and mindfulness (SMD, 0.46; 95% CI, 0.03-0.90; P = .04). These interventions also demonstrated a positive impact on reducing stress (SMD, -0.32; 95% CI, -0.59 to -0.04; P = .02) and anxiety (SMD, -0.28; 95% CI, -0.47 to -0.09; P = .003). Subgroup analyses highlighted superior self-compassion outcomes for caregivers supporting individuals with mental illness and cancer compared with those caring for individuals with Alzheimer's disease. Interventions lasting ≥8 weeks were the most common and effective. CONCLUSIONS AND IMPLICATIONS: Web-based compassion interventions benefit family caregivers by enhancing self-compassion, mindfulness, and reducing anxiety and stress. More well-designed studies are suggested for future clinical applications.

Uncovering the Dominant Role of an Extended Asymmetric Four-Coordinated Water Network in the Hydrogen Evolution Reaction.

In situ and accurate measurement of the structure and dynamics of interfacial water in the hydrogen evolution reaction (HER) is a well-known challenge because of the coupling of water among varied structures and its dual role as reactants and solvents. Further, the interference of bulk water and intricate interfacial interactions always hinders the probing of interfacial water. Surface-enhanced infrared absorption spectroscopy is extremely sensitive for the measurement of interfacial water; herein, we develop a nanoconfinement strategy by introducing nonaqueous ionic liquids to decouple and tailor the water structure in the electric double layer and further combined with molecular dynamics simulations, successfully gaining the correlation between isolated water, water clusters, and the water network with HER activity. Our results clearly disclosed that the potential-dependent asymmetric four-coordinated water network, whose connectivity could be regulated by hydrophilic and hydrophobic cations, was positively correlated with HER activity, which provided a pioneering guidance framework for revealing the function of water in catalysis, energy, and surface science.

Adipose tissue-derived human mesenchymal stromal cells can better suppress complement lysis, engraft and inhibit acute graft-versus-host disease in mice.

BACKGROUND: Acute graft-versus-host disease (aGvHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT). Transplantation of immunosuppressive human mesenchymal stromal cells (hMSCs) can protect against aGvHD post-HSCT; however, their efficacy is limited by poor engraftment and survival. Moreover, infused MSCs can be damaged by activated complement, yet strategies to minimise complement injury of hMSCs and improve their survival are limited. METHODS: Human MSCs were derived from bone marrow (BM), adipose tissue (AT) and umbilical cord (UC). In vitro immunomodulatory potential was determined by co-culture experiments between hMSCs and immune cells implicated in aGvHD disease progression. BM-, AT- and UC-hMSCs were tested for their abilities to protect aGvHD in a mouse model of this disease. Survival and clinical symptoms were monitored, and target tissues of aGvHD were examined by histopathology and qPCR. Transplanted cell survival was evaluated by cell tracing and by qPCR. The transcriptome of BM-, AT- and UC-hMSCs was profiled by RNA-sequencing. Focused experiments were performed to compare the expression of complement inhibitors and the abilities of hMSCs to resist complement lysis. RESULTS: Human MSCs derived from three tissues divergently protected against aGvHD in vivo. AT-hMSCs preferentially suppressed complement in vitro and in vivo, resisted complement lysis and survived better after transplantation when compared to BM- and UC-hMSCs. AT-hMSCs also prolonged survival and improved the symptoms and pathological features of aGvHD. We found that complement-decay accelerating factor (CD55), an inhibitor of complement, is elevated in AT-hMSCs and contributed to reduced complement activation. We further report that atorvastatin and erlotinib could upregulate CD55 and suppress complement in all three types of hMSCs. CONCLUSION: CD55, by suppressing complement, contributes to the improved protection of AT-hMSCs against aGvHD. The use of AT-hMSCs or the upregulation of CD55 by small molecules thus represents promising new strategies to promote hMSC survival to improve the efficacy of transplantation therapy. As complement injury is a barrier to all types of hMSC therapy, our findings are of broad significance to enhance the use of hMSCs for the treatment of a wide range of disorders.

Revealing the Nanoarchitectonics of Amyloid ß-Aggregation on Two-Dimensional Biomimetic Membranes by Surface-Enhanced Infrared Absorption Spectroscopy.

The in vivo folding of amyloid ß (Aß) is influenced by many factors among which biomembrane interfaces play an important role. Here, using surface-enhanced infrared absorption (SEIRA) spectroscopy and atomic force microscopy (AFM), the adsorption, structure, and morphology of Aß42 aggregating on different two-dimensional interfaces were investigated. Results show that interfaces facilitate the aggregation of Aß42 and are conducive to the formation of homogeneous aggregates, while the aggregates vary on different interfaces. On hydrophobic interfaces, strong hydrophobic interactions with the C-terminus of Aß42 result in the formation of small oligomers with a small proportion of the ß-sheet structure. On hydrophilic interfaces, hydrogen-bonding interactions and electrostatic interactions promote the formation of large aggregate particles with ß-sheet structure. The hydration repulsion plays an important role in the interaction of Aß42 with interfaces. These findings help to understand the nature of Aß42 adsorption and aggregation on the biomembrane interface and the origin of heterogeneity and polymorphism of Aß42 aggregates.

Molecular Nature of Structured Water in the Light-Induced Interfacial Capacitance Changes at the Bioelectric Interface.

Uncovering the function of structured water in the interfacial capacitance at the molecular level is the basis for the development of the concept and model of the electric double layer; however, the limitation of the available technology makes this task difficult. Herein, using surface-enhanced infrared absorption spectroscopy combined with electrochemistry, we revealed the contribution of the cleavage of loosely bonded tetrahedral water to the enhancement of model membrane capacitance. Upon further combination with ionic perturbation, we found that the interface hydrogen bonding environment in the stern layer was greatly significant for the light-induced cleavage of tetrahedral water and thus the conversion of optical signals into electrical signals. Our work has taken an important step toward gaining experimental insight into the relationship between water structure and capacitance at the bioelectric interface.

Image Inpainting by End-to-End Cascaded Refinement With Mask Awareness.

Inpainting arbitrary missing regions is challenging because learning valid features for various masked regions is nontrivial. Though U-shaped encoder-decoder frameworks have been witnessed to be successful, most of them share a common drawback of mask unawareness in feature extraction because all convolution windows (or regions), including those with various shapes of missing pixels, are treated equally and filtered with fixed learned kernels. To this end, we propose our novel mask-aware inpainting solution. Firstly, a Mask-Aware Dynamic Filtering (MADF) module is designed to effectively learn multi-scale features for missing regions in the encoding phase. Specifically, filters for each convolution window are generated from features of the corresponding region of the mask. The second fold of mask awareness is achieved by adopting Point-wise Normalization (PN) in our decoding phase, considering that statistical natures of features at masked points differentiate from those of unmasked points. The proposed PN can tackle this issue by dynamically assigning point-wise scaling factor and bias. Lastly, our model is designed to be an end-to-end cascaded refinement one. Supervision information such as reconstruction loss, perceptual loss and total variation loss is incrementally leveraged to boost the inpainting results from coarse to fine. Effectiveness of the proposed framework is validated both quantitatively and qualitatively via extensive experiments on three public datasets including Places2, CelebA and Paris StreetView.

Efficient photocatalytic degradation of acrylonitrile by Sulfur-Bismuth co-doped F-TiO2/SiO2 nanopowder.

In this study, a simple sol-gel method was applied for preparing effectual photocatalyst of S-Bi co-doped F-TiO2/SiO2 (S-Bi-F-TiO2/SiO2) nanopowder. Optimal preparation conditions were obtained by optimizing the calcination temperature and the ratio of S and Bi. The synthesized powder was characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), energy dispersive spectrometer (EDS), X-ray photoelectron spectroscopy (XPS), brunauer-emmett-teller (BET), UV-Visible diffuse-reflectance spectroscopy (UV-Vis DRS), photoluminescence spectroscopy (PL) and ammonia adsorption and temperature-programmed desorption (NH3-TPD). The photocatalytic activity was evaluated by the degradation of acrylonitrile under simulated visible light irradiation. S-Bi-F-TiO2/SiO2 nanopowder possess excellent photocatalytic properties under visible light for the degradation of acrylonitrile, when the calcination temperature was 450 °C for 2 h and the ratio of S and Bi was 0.02: 0.007. The degradation efficiency of acrylonitrile reached to 81.9% within 6 min of visible light irradiation. Compared with F-TiO2/SiO2 sample, NH3-TPD and PL results revealed the higher photocatalytic activity for S-Bi-F-TiO2/SiO2, which is mainly due to the increase strength and number of surface acid site with S doping. The co-doping with S & Bi improved the separation of electron-hole pairs and enhanced the photocatalytic oxidizing species. The UV-Vis DRS showed stronger absorption in S-Bi co-doped F-TiO2/SiO2 catalyst as compared to F-TiO2/SiO2 catalyst. XPS results demonstrated the presence of various surface species viz. oxygen vacancies, Ti3+, Ti4+, O2- and OH group.

The Safety and Efficacy of Inspiratory Muscle Training for Patients With Acute Myocardial Infarction Undergoing Percutaneous Coronary Intervention: Study Protocol for a Randomized Controlled Trial.

Background: Uncommonly high rates of pneumonia in patients with acute myocardial infarction (AMI) undergoing primary percutaneous coronary intervention (PCI) have been observed during recent years. Inspiratory muscle training (IMT) could reduce pneumonia in patients undergoing coronary artery bypass grafting and other cardiac surgeries. The relationship between IMT and AMI is unknown. Here, we describe the feasibility and potential benefit of IMT in patients at high risk for pneumonia with AMI who have undergone primary PCI. Methods: Our study is a prospective, randomized, controlled, single-center clinical trial. A total of 60 participants will be randomized into an IMT group and control group with 30 participants in each group. Participants in the IMT group will undergo training for 15 min per session, twice a day, from 12 to 24 h after primary PCI, until 30 days post-randomization; usual care will be provided for the control group. The primary endpoint is the change in inspiratory muscle strength, the secondary endpoint included feasibility, pneumonia, major adverse cardiovascular events, length of stay, pulmonary function tests measure, and quality of life. Discussion: Our study is designed to evaluate the feasibility of IMT and its effectiveness in improving inspiratory muscle strength in participants with AMI who have undergone primary PCI. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT04491760.

Seasonal expression of luteinizing hormone receptor and follicle stimulating hormone receptor in testes of the wild ground squirrels (Citellus dauricus Brandt).

The objective of this study was to evaluate whether luteinizing hormone (LH), follicle stimulating hormone (FSH) and their receptors luteinizing hormone receptor (LHR) and follicle stimulating hormone receptor (FSHR) play roles in the seasonal spermatogenesis of the wild ground squirrels. To that end, we characterized the testicular immunolocalization of LHR and FSHR, their expression on both mRNA and protein levels, as well as serum concentrations of LH and FSH in male wild ground squirrels throughout the annual reproductive cycle. Histologically, all types of spermatogenic cells including mature spermatozoa were identified in the breeding season (April), while spermatogonia and primary spermatocytes were observed in the non-breeding season (June), and spermatogonia, primary spermatocytes and secondary spermatocytes were found in pre-hibernation (September). LHR was present in Leydig cells during the whole periods with more intense staining in the breeding season; Stronger immunostaining of FSHR was observed in Sertoli cells during the breeding season compared to the non-breeding season and pre-hibernation. Consistently, the mRNA and protein levels of LHR and FSHR were higher in testes of the breeding season, and then decreased to a relatively lower level in the non-breeding season and pre-hibernation. Meanwhile, serum LH and FSH concentrations were significantly higher in the breeding season than those in the non-breeding season and pre-hibernation. These results suggested that gonadotropins and its receptors, LHR and FSHR may be involved in the regulation of seasonal changes in testicular functions of the wild ground squirrels.

Seasonal expressions of follicle-stimulating hormone receptor and luteinizing hormone receptor in the scented gland of the male muskrat (Ondatra zibethicus).

Accumulating evidence has shown that follicle-stimulating hormone (FSH) and luteinizing hormone (LH) may influence the functions of nongonadal tissues in addition to their classic target gonads. Our previous studies revealed that the scented glands of male muskrats expressed prolactin receptor, steroidogenic enzymes, and inhibin/activin subunits. To further seek the evidence of the activities of pituitary gonadotropins in scented glands, we investigated the seasonal expression patterns of FSH receptor (FSHR) and LH/choriogonadotropin receptor (LHCGR). The weight and size of scented glands during the breeding season were significantly higher than those during the nonbreeding season. Immunohistochemical studies showed that FSHR was present in the serous cells of scented glands, whereas LHCGR was present in the interstitial cells. The protein and mRNA expression levels of FSHR and LHCGR were significantly higher in the scented glands during the breeding season than those during the nonbreeding season. Importantly, the levels of circulating FSH and LH were remarkably higher during the breeding season. Taken together, these results suggested that gonadotropins may affect the function of muskrat scented gland via the locally expressed receptors in a season-dependent manner.

Seasonal expression of P450arom and estrogen receptors in scented glands of muskrats (Ondatra zibethicus).

Male muskrats have one pair of scented glands that grow and involute annually. To investigate the annual changes in the scented gland, we measured the expressions of aromatase cytochrome P-450 (P450arom) and estrogen receptors (ERs) in the scented glands. P450arom was expressed in glandular cells and epithelial cells in the scented glands during the breeding season, and only in glandular cells during the nonbreeding season. ERα and ERß were also detected in different types of cells in the scented gland during the breeding and nonbreeding seasons. Both mRNA and protein levels of P450arom, ERα, and ERß were higher in the scented glandular tissues during the breeding season than those during the nonbreeding season. In addition, small RNA sequencing showed that the predicted targets of the significantly changed microRNAs might be the genes encoding P450arom and ERs. In conclusion, the seasonal changes in the expression of P450arom and ERs may be involved in the regulation of scented gland functions.