Due to the poor self-regeneration of brain tissue, stem cell transplantation therapy is purported to enable the replacement of lost neurons after traumatic brain injury (TBI). The main challenge of ...brain regeneration is whether the transplanted cells can survive and carry out neuronal functions in the lesion area. The brain is a complex neuronal network consisting of various types of cells that significantly influence on each other, and the survival of the implanted stem cells in brain is critically influenced by the surrounding cells. Although stem cell-based therapy is developing rapidly, most previous studies just focus on apply single type of stem cells as cell source. Here, we found that co-culturing human umbilical cord mesenchymal stem cells (hUC-MSCs) directly with the activated astrocytes benefited to the proliferation and neuron differentiation of hUC-MSCs in vitro. In this study, hUC-MSCs and the activated astrocytes were seeded in RADA16-BDNF peptide scaffold (R-B-SPH scaffold), a specifical self-assembling peptide hydrogel, in which the environment promoted the differentiation of typical neuron-like cells with neurites extending in three-dimensional directions. Moreover, the results showed co-culture of hUC-MSCs and activated astrocytes promoted more BDNF secretion which may benefit to both neural differentiation of ectogenic hUC-MSCs and endogenic neurogenesis. In order to promote migration of the transplanted hUC-MSCs to the host brain, the hUC-MSCs were forced with CXC chemokine receptor 4 (CXCR4). We found that the moderate-sized lesion cavity, but not the large cavity caused by TBI was repaired via the transplantation of hUC-MSCs
and activated astrocytes embedded in R-B-SPH scaffolds. The functional neural repair for TBI demonstrated in this study is mainly due to the transplantation system of double cells, hUC-MSCs and activated astrocytes. We believe that this novel cell transplantation system offers a promising treatment option for cell replacement therapy for TBI.
In this reach, we specifically linked RGIDKRHWNSQ, a functional peptide derived from BDNF, to the C-terminal of RADARADARADARADA (RADA16) to structure a functional self-assembling peptide hydrogel scaffold, RADA16-BDNF (R-B-SPH scaffold) for the better transplantation of the double cell unit. Also, the novel scaffold was used as cell-carrier for transplantation double cell unit (hUC-MSCs/astrocyte) for treating traumatic brain injury. The results of this study showing that R-B-SPH scaffold was pliancy and flexibility to fit the brain lesion cavity and promotes the outgrowth of axons and dendrites of the neurons derived from hUC-MSCs in vitro and in vivo, indicating the 3D R-B-SPH scaffold provided a suitable microenvironment for hUC-MSC survival, proliferation and differentiation. Also, our results showing the double-cells transplantation system (hUC-MSCs/astrocyte) may be a novel cell-based therapeutic strategy for neuroregeneration after TBI with potential value for clinical application.
General strategies for the chemical synthesis of organic compounds, especially of architecturally complex natural products, are not easily identified. Here we present a method to establish a strategy ...for such syntheses, which uses network analysis. This approach has led to the identification of a versatile synthetic intermediate that facilitated syntheses of the diterpenoid alkaloids weisaconitine D and liljestrandinine, and the core of gomandonine. We also developed a web-based graphing program that allows network analysis to be easily performed on molecules with complex frameworks. The diterpenoid alkaloids comprise some of the most architecturally complex and functional-group-dense secondary metabolites isolated. Consequently, they present a substantial challenge for chemical synthesis. The synthesis approach described here is a notable departure from other single-target-focused strategies adopted for the syntheses of related structures. Specifically, it affords not only the targeted natural products, but also intermediates and derivatives in the three families of diterpenoid alkaloids (C-18, C-19 and C-20), and so provides a unified synthetic strategy for these natural products. This work validates the utility of network analysis as a starting point for identifying strategies for the syntheses of architecturally complex secondary metabolites.
Methane (CH
4
) is an important greenhouse gas; however, there is a lack of large-scale studies on ground-level CH
4
concentrations. We estimated global ground-level CH
4
concentrations based on the ...CH
4
columns from the Copernicus Sentinel-5 precursor satellite (S5P) and vertical profiles of CH
4
concentrations simulated from the Atmospheric Chemical Transport Model (GEOS-Chem). The proposed approach had achieved a high predictive accuracy for monthly ground-level CH
4
concentrations, with a correlation coefficient of 0.93 (p < 0.01) and RMSE of 29.93 ppb between the estimated CH
4
concentrations and those of ground measurements from the World Data Centre for Greenhouse Gases (WDCGG). Compared with the S5P CH
4
columns, the estimated ground-level CH
4
concentration has a close spatial relationship with emissions. The high CH
4
concentrations occurred in eastern China, northern India, western Russia, eastern U.S., and central Europe. Furthermore, the estimated ground-level CH
4
concentrations could reflect the seasonal variations of the observations, with correlation coefficients from 0.14 to 0.92. Our findings highlight the importance of satellite observations on atmospheric CH
4
in understanding the spatial and temporal emissions.
Osteoarthritis (OA) is an age-related degenerative disease accompanied by an increasing number of senescent cells and chronic low-grade inflammation. Rhoifolin (ROF) showed considerable inhibition to ...inflammation, but its role in chondrocyte senescence and OA progress has not been fully characterized. We aimed to evaluate the protective effects of ROF on OA through a series of in vitro and in vivo experiments.
The role of ROF in the expression of senescence-associated secretory phenotype (SASP) factors was investigated using RT-qPCR, western blotting, and ELISA. Chondrocyte senescence was assessed by SA-β-gal staining. We applied molecular docking to screen candidate proteins regulated by ROF. Meanwhile, SASP factors and cellular senescence were further assessed after the transfection of Nrf2 siRNA. In the anterior cruciate ligament transection (ACLT) rat model, X-ray, hematoxylin-eosin (HE), and Masson's staining were performed to evaluate the therapeutic effects of ROF on OA.
We found that ROF inhibited SASP factors expression and senescence phenotype in IL-1β-treated chondrocytes. Furthermore, ROF suppressed IL-1β-induced activation of the NF-κB pathway cascades. Also, molecular docking and knock-down studies demonstrated that ROF might bind to Nrf2 to suppress the NF-κB pathway. In vivo, ROF ameliorated the OA process in the ACLT rat model.
ROF inhibits SASP factors expression and senescence phenotype in chondrocytes and ameliorates the progression of OA via the Nrf2/NF-κB axis, which supports ROF as a potential therapeutic agent for the treatment of OA.
When an ordered spin system of a given dimensionality undergoes a second order phase transition, the dependence of the order parameter, i.e., magnetization on temperature, can be well described by ...thermal excitations of elementary collective spin excitations (magnons). However, the behavior of magnons themselves, as a function of temperature and across the transition temperature T_{C}, is an unknown issue. Utilizing spin-polarized high resolution electron energy loss spectroscopy, we monitor the high-energy (terahertz) magnons, excited in an ultrathin ferromagnet, as a function of temperature. We show that the magnons' energy and lifetime decrease with temperature. The temperature-induced renormalization of the magnons' energy and lifetime depends on the wave vector. We provide quantitative results on the temperature-induced damping and discuss the possible mechanism, e.g., multimagnon scattering. A careful investigation of physical quantities determining the magnons' propagation indicates that terahertz magnons sustain their propagating character even at temperatures far above T_{C}.
We propose and study a simple and innovative non-parametric approach to estimate the age-of-onset distribution for a disease from a cross-sectional sample of the population that includes individuals ...with prevalent disease. First, we estimate the joint distribution of two event times, the age of disease onset and the survival time after disease onset. We accommodate that individuals had to be alive at the time of the study by conditioning on their survival until the age at sampling. We propose a computationally efficient expectation-maximization (EM) algorithm and derive the asymptotic properties of the resulting estimates. From these joint probabilities we then obtain non-parametric estimates of the age-at-onset distribution by marginalizing over the survival time after disease onset to death. The method accommodates categorical covariates and can be used to obtain unbiased estimates of the covariate distribution in the source population. We show in simulations that our method performs well in finite samples even under large amounts of truncation for prevalent cases. We apply the proposed method to data from female participants in the Washington Ashkenazi Study to estimate the age-at-onset distribution of breast cancer associated with carrying BRCA1 or BRCA2 mutations.
Notch-1 inhibits apoptosis in some transformed cells through incompletely understood mechanisms. Notch-1 can increase nuclear factor-kappa B (NF-κB) activity through a variety of mechanisms. ...Overexpression of cleaved Notch-1 in T-cell acute lymphoblastic leukemia cells activates NF-κB via interaction with the I kappa B kinase (IKK) signalosome. Concomitant activation of the Notch and NF-κB pathways has been described in a large series of cervical cancer specimens. Here, we show that wild-type, spontaneously expressed Notch-1 stimulates NF-κB activity in CaSki cervical cancer cells by associating with the IKK signalosome through IKKα. A significant fraction of tumor necrosis factor (TNF)-α-stimulated IκB kinase activity in CaSki cells is Notch-1-dependent. In addition, Notch-1 is found in the nucleus in association with IKKα at IKKα-stimulated promoters and is required for association of IKKα with these promoters under basal and TNF-α-stimulated conditions. Notch-1–IKKα complexes are found in normal human keratinocytes as well, suggesting that IKK regulation is a physiological function of Notch-1. Both Notch-1 and IKKα knockdown sensitize CaSki cells to cisplatin-induced apoptosis to equivalent extents. Our data indicate that Notch-1 regulates NF-κB in cervical cancer cells at least in part via cytoplasmic and nuclear IKK-mediated pathways.
To evaluate the effect of dehydroepiandrosterone (DHEA) therapy on the ovarian response and pregnancy outcome in patients with diminished ovarian reserve (DOR). Eligible studies, published before ...August 31, 2015, were identified from PubMed, EMBASE, the Cochrane library. Outcome measures were the number of retrieved oocytes, cancellation rate of IVF cycles, clinical pregnancy rate and miscarriage rate. We adopted Revman 5.0 software to pool the data from the eligible studies. A total of 9 studies, four were RCTs, four retrospective studies, one prospective studies, including 540 cases and 668 controls, were available for analysis. The pooled analysis showed that the clinical pregnancy rates were increased significantly in DOR patients who were pre-treated with DHEA (OR=1.47, 95% CI: 1.09–1.99), whereas no differences were found in the number of oocytes retrieved, the cancellation rate of IVF cycles and the miscarriage rate between the cases and controls (WMD= −0.69, 95% CI: −2.18–0.81; OR=0.74, 95% CI: 0.51–1.08; OR=0.34, 95% CI: 0.10–1.24). However, it is worth noting that when data were restricted to RCTs, there was a non-significant difference in the clinical pregnancy rate (OR=1.08, 95% CI: 0.67–1.73). We concluded that DHEA supplementation in DOR patients might improve the pregnancy outcomes. To further confirm this effect, more randomized controlled trials with large sample sizes are needed.
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