Mesenchymal stem cells (MSCs) are a common kind of multipotent cell in vivo, but their heterogeneity limits their further applications. To identify MSC subpopulations and clarify their relationships, ...we performed cell mapping of bone-marrow-derived MSCs through single-cell RNA (scRNA) sequencing. In our study, three main subpopulations, namely, the stemness subpopulation, functional subpopulation, and proliferative subpopulation, were identified using marker genes and further bioinformatic analyses. Developmental trajectory analysis showed that the stemness subpopulation was the root and then became either the functional subpopulation or the proliferative subpopulation. The functional subpopulation showed stronger immunoregulatory and osteogenic differentiation abilities but lower proliferation and adipogenic differentiation. MSCs at different passages or isolated from different donors exhibited distinct cell mapping profiles, which accounted for their corresponding different functions. This study provides new insight into the biological features and clinical use of MSCs at the single-cell level, which may contribute to expanding their application in the clinic.
Gratings, one of the most important energy dispersive devices, are the fundamental building blocks for the majority of optical and optoelectronic systems. The grating period is the key parameter that ...limits the dispersion and resolution of the system. With the rapid development of large X-ray science facilities, gratings with periodicities below 50 nm are in urgent need for the development of ultrahigh-resolution X-ray spectroscopy. However, the wafer-scale fabrication of nanogratings through conventional patterning methods is difficult. Herein, we report a maskless and high-throughput method to generate wafer-scale, multilayer gratings with period in the sub-50 nm range. They are fabricated by a vacancy epitaxy process and coated with X-ray multilayers, which demonstrate extremely large angular dispersion at approximately 90 eV and 270 eV. The developed new method has great potential to produce ultrahigh line density multilayer gratings that can pave the way to cutting edge high-resolution spectroscopy and other X-ray applications.
Abstract
Ankylosing spondylitis (AS) is a type of rheumatic disease characterized by chronic inflammation and pathological osteogenesis in the entheses. Previously, we demonstrated that enhanced ...osteogenic differentiation of MSC from AS patients (AS-MSC) resulted in pathological osteogenesis, and that during the enhanced osteogenic differentiation course, AS-MSC induced TNF-α-mediated local inflammation. However, whether TNF-α in turn affects AS-MSC remains unknown. Herein, we further demonstrate that a high-concentration TNF-α treatment triggers enhanced directional migration of AS-MSC in vitro and in vivo, which enforces AS pathogenesis. Mechanistically, TNF-α leads to increased expression of ELMO1 in AS-MSC, which is mediated by a METTL14 dependent m
6
A modification in
ELMO1
3′UTR. Higher ELMO1 expression of AS-MSC is found in vivo in AS patients, and inhibiting ELMO1 in SKG mice produces therapeutic effects in this spondyloarthritis model. This study may provide insight into not only the pathogenesis but also clinical therapy for AS.
A reliable, efficient and electrically-pumped Si-based laser is considered as the main challenge to achieve the integration of all key building blocks with silicon photonics. Despite the impressive ...advances that have been made in developing 1.3-μm Si-based quantum dot (QD) lasers, extending the wavelength window to the widely used 1.55-μm telecommunication region remains difficult. In this study, we develop a novel photonic integration method of epitaxial growth of III-V on a wafer-scale InP-on-Si (100) (InPOS) heterogeneous substrate fabricated by the ion-cutting technique to realize integrated lasers on Si substrate. This ion-cutting plus epitaxial growth approach decouples the correlated root causes of many detrimental dislocations during heteroepitaxial growth, namely lattice and domain mismatches. Using this approach, we achieved state-of-the-art performance of the electrically-pumped, continuous-wave (CW) 1.55-µm Si-based laser with a room-temperature threshold current density of 0.65 kA/cm
, and output power exceeding 155 mW per facet without facet coating in CW mode. CW lasing at 120 °C and pulsed lasing at over 130 °C were achieved. This generic approach is also applied to other material systems to provide better performance and more functionalities for photonics and microelectronics.
Improving health and delaying aging is the focus of medical research. Previous studies have shown that mesenchymal stem cell (MSC) senescence is closely related to organic aging and the development ...of aging-related diseases such as osteoarthritis (OA). m6A is a common RNA modification that plays an important role in regulating cell biological functions, and ALKBH5 is one of the key m6A demethylases. However, the role of m6A and ALKBH5 in MSC senescence is still unclear. Here, we found that the m6A level was enhanced and ALKBH5 expression was decreased in aging MSCs induced by multiple replications, H
O
stimulation or UV irradiation. Downregulation of ALKBH5 expression facilitated MSC senescence by enhancing the stability of CYP1B1 mRNA and inducing mitochondrial dysfunction. In addition, IGF2BP1 was identified as the m6A reader restraining the degradation of m6A-modified CYP1B1 mRNA. Furthermore, Alkbh5 knockout in MSCs aggravated spontaneous OA in mice, and overexpression of Alkbh5 improved the efficacy of MSCs in OA. Overall, this study revealed a novel mechanism of m6A in MSC senescence and identified promising targets to protect against aging and OA.
The rapidly emerging human health crisis associated with the Zika virus (ZIKV) epidemic and its link to severe complications highlights the growing need to identify the mechanisms by which ZIKV ...accesses hosts. Interferon response protects host cells against viral infection, while the cellular factors that mediate this defense are the products of interferon-stimulated genes (ISGs). Although hundreds of ISGs have been identified, only a few have been characterized for their antiviral potential, target specificity and mechanisms of action. In this work, we focused our investigation on the possible antiviral effect of a novel ISG, C19orf66 in response to ZIKV infection and the associated mechanisms. We found that ZIKV infection could induce C19orf66 expression in ZIKV-permissive cells, and such an overexpression of C19orf66 remarkably suppressed ZIKV replication. Conversely, the depletion of C19orf66 led to a significant increase in viral replication. Furthermore, C19orf66 was found to interact and co-localize with ZIKV nonstructural protein 3 (NS3), thus inducing NS3 degradation via a lysosome-dependent pathway. Taken together, this study identified C19orf66 as a novel ISG that exerts antiviral effects against ZIKV by specifically degrading a viral nonstructural protein. These findings uncovered an intriguing mechanism of C19orf66 that targeting NS3 protein of ZIKV, providing clues for understanding the actions of innate immunity, and affording the possible availability of new drug targets that can be used for therapeutic intervention.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Osteoporosis is a common systemic skeletal disorder resulting in bone fragility and increased fracture risk. It is still necessary to explore its detailed mechanisms and identify novel targets for ...the treatment of osteoporosis. Previously, we found that a lncRNA named
in human could negatively regulate the lipoblast/adipocyte differentiation. However, it is still unclear whether
affects osteoblast differentiation and whether
is associated with osteoporosis. Our current research found that
was decreased in the bones and BMSCs, a major origin of osteoblast, of osteoporosis patients. Mechanistically,
promotes the osteoblast differentiation by interacting with UPF1 to degrade
mRNA. Moreover, a decreased bone mass and impaired bone repair ability were observed in
heterozygous mice, manifesting in osteoporosis. The systemic supplement of
-overexpressing adenoviruses significantly ameliorated bone loss in an osteoporosis mouse model. In conclusion,
promotes osteoblast differentiation by targeting the UPF1/SMAD7 axis and protects against osteoporosis.
Static force, ultrasonic amplitude, feed rate, and rolling spacing parameters of 42CrMo steel treated by the ultrasonic surface rolling process (USRP) were optimized by the Grey-Taguchi method. Nine ...sets of experiments based on an orthogonal array design and grey relational analysis were used to obtain the optimum combination of mechanical properties for USRP. The influence of processing parameters on mechanical properties was investigated based on the grey relational analysis. The results indicated that the feed rate is the dominant parameter affecting the mechanical properties, followed by rolling space, ultrasonic amplitude, and static force. The effects of plastic strain caused by USRP on the compressive residual stress and microhardness were investigated. The effects of the dislocation and cementite evolution on the mechanical properties were investigated to determine the origin of the best and worst mechanical properties. For the best mechanical property, the level and depth of distribution of compressive residual stress and tensile strain hardening capacity are the highest, which is benefited from the optimum synergistic of the elastic-plastic deformation, dislocation evolution, gradient distribution, and cementite evolution. For the worst mechanical property, a large amount of cementite is distributed within and around martensitic laths, increasing brittleness and the lowest comprehensive mechanical properties. These findings can provide a reference for accurately controlling the processing parameters of USRP and improving their mechanical properties.
Abstract
Sustained inflammatory invasion leads to joint damage and progressive disability in several autoimmune rheumatic diseases. In recent decades, targeting M1 macrophage polarization has been ...suggested as a promising therapeutic strategy for autoimmune arthritis. P300/CBP-associated factor (PCAF) is a histone acetyltransferase (HAT) that exhibits a strong positive relationship with the proinflammatory microenvironment. However, whether PCAF mediates M1 macrophage polarization remains poorly studied, and whether targeting PCAF can protect against autoimmune arthritis in vivo remains unclear. Commonly used drugs can cause serious side effects in patients because of their extensive and nonspecific distribution in the human body. One strategy for overcoming this challenge is to develop drug nanocarriers that target the drug to desirable regions and reduce the fraction of drug that reaches undesirable targets. In this study, we demonstrated that PCAF inhibition could effectively inhibit M1 polarization and alleviate arthritis in mice with collagen-induced arthritis (CIA) via synergistic NF-κB and H3K9Ac blockade. We further designed dextran sulfate (DS)-based nanoparticles (DSNPs) carrying garcinol (a PCAF inhibitor) to specifically target M1 macrophages in inflamed joints of the CIA mouse model via SR-A–SR-A ligand interactions. Compared to free garcinol, garcinol-loaded DSNPs selectively targeted M1 macrophages in inflamed joints and significantly improved therapeutic efficacy in vivo. In summary, our study indicates that targeted PCAF inhibition with nanoparticles might be a promising strategy for treating autoimmune arthritis via M1 macrophage polarization inhibition.
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