ANKZF1 knockdown inhibits glioblastoma progression by promoting intramitochondrial protein aggregation through mitoRQC.

Protein homeostasis is fundamental to the development of tumors. Ribosome-associated quality-control (RQC) is able to add alanine and threonine to the stagnant polypeptide chain C-terminal (CAT-tail) when protein translation is hindered, while Ankyrin repeat and zinc-finger domain-containing-protein 1 (ANKZF1) can counteract the formation of the CAT-tail, preventing the aggregation of polypeptide chains. In particular, ANKZF1 plays an important role in maintaining mitochondrial protein homeostasis by mitochondrial RQC (mitoRQC) after translation stagnation of precursor proteins targeting mitochondria. However, the role of ANKZF1 in glioblastoma is unclear. Therefore, the current study was aimed to investigate the effects of ANKZF1 in glioblastoma cells and a nude mouse glioblastoma xenograft model. Here, we reported that knockdown of ANKZF1 in glioblastoma cells resulted in the accumulation of CAT-tail in mitochondria, leading to the activated mitochondrial unfolded protein response (UPRmt) and inhibits glioblastoma malignant progression. Excessive CAT-tail sequestered mitochondrial chaperones HSP60, mtHSP70 and proteases LONP1 as well as mitochondrial respiratory chain subunits ND1, Cytb, mtCO2 and ATP6, leading to mitochondrial oxidative phosphorylation dysfunction, membrane potential impairment, and mitochondrial apoptotic pathway activation. Our study highlights ANKZF1 as a valuable target for glioblastoma intervention and provides an innovative insight for the treatment of glioblastoma through the regulating of mitochondrial protein homeostasis.

SP140 inhibitor suppressing TRIM22 expression regulates glioma progress through PI3K/AKT signaling pathway.

BACKGROUND: SP gene family, consisting of SP100, SP110, SP140, and SP140L, has been implicated in the initiation and advancement of numerous malignancies. Nevertheless, their clinical significance in glioma remains incompletely understood. METHOD: Expression levels and prognostic significance of SP family members were evaluated in the TCGA and CGGA datasets. Multifactorial analysis was used to identify SP gene family members that can independently impact the prognosis of glioma patients. A SP140-based predictive risk model/nomogram was developed in TCGA dataset and validated in CGGA dataset. The model's performance was evaluated through receiver operating characteristic (ROC) curves, calibration plots, and decision curve analyses. Phenotypic associations of SP140 and TRIM22 were examined through CancerSEA and TIMER. The effect of SP140 inhibitor in glioma progress and TRIM22/PI3K/AKT signaling pathway was confirmed in U251/U87 glioma cells. RESULTS: The SP family members exhibited elevated expression in gliomas and were negatively correlated with prognosis. SP140 emerged as an independent prognostic factor, and a SP140-based nomogram/predictive risk model demonstrated high accuracy. SP140 inhibitor, GSK761, lead to the suppression of TRIM22 expression and the PI3K/AKT signaling pathway. GSK761 also restrain glioma proliferation, migration, and invasion. Furthermore, SP140 and TRIM22 coexpressed in glioma cells with high level of vascular proliferation, TRIM22 is closely associated with the immune cell infiltration. CONCLUSION: SP140-based nomogram proved to be a practical tool for predicting the survival of glioma patients. SP140 inhibitor could suppress glioma progress via TRIM22/PI3K/AKT signaling pathway.

Acetylation of mtHSP70 at Lys595/653 affecting its interaction between GrpEL1 regulates glioblastoma progression via UPRmt.

BACKGROUND: The mitochondrial unfolded protein response (UPRmt) is a vital biological process that regulates mitochondrial protein homeostasis and enables glioblastoma cells to cope with mitochondrial oxidative stress in the tumor microenvironment. We previously reported that the binding of mitochondrial stress-70 protein (mtHSP70) to GrpE protein homolog 1 (GrpEL1) is involved in the regulation of the UPRmt. However, the mechanisms regulating their binding remain unclear. Herein, we examined the UPRmt in glioblastoma and explored whether modulating the interaction between mtHSP70 and GrpEL1 affects the UPRmt. METHODS: Western blot analysis, aggresome staining, and transmission electron microscopy were used to detect the activation of the UPRmt and protein aggregates within mitochondria. Molecular dynamics simulations were performed to investigate the impact of different mutations in mtHSP70 on its binding to GrpEL1. Endogenous site-specific mutations were introduced into mtHSP70 in glioblastoma cells using CRISPR/Cas9. In vitro and in vivo experiments were conducted to assess mitochondrial function and glioblastoma progression. RESULTS: The UPRmt was activated in glioblastoma cells in response to oxidative stress. mtHSP70 regulated mitochondrial protein homeostasis by facilitating UPRmt-progress protein import into the mitochondria. Acetylation of mtHSP70 at Lys595/653 enhanced its binding to GrpEL1. Missense mutations at Lys595/653 increased mitochondrial protein aggregates and inhibited glioblastoma progression in vitro and in vivo. CONCLUSIONS: We identified an innovative mechanism in glioblastoma progression by which acetylation of mtHSP70 at Lys595/653 influences its interaction with GrpEL1 to regulate the UPRmt. Mutations at Lys595/653 in mtHSP70 could potentially serve as therapeutic targets and prognostic indicators of glioblastoma.

APE1 regulates mitochondrial DNA damage repair after experimental subarachnoid haemorrhage in vivo and in vitro.

BACKGROUND: Subarachnoid haemorrhage (SAH) can result in a highly unfavourable prognosis. In recent years, the study of SAH has focused on early brain injury (EBI), which is a crucial progress that contributes to adverse prognosis. SAH can lead to various complications, including mitochondrial dysfunction and DNA damage. Apurinic/apyrimidinic endonuclease 1 (APE1) is an essential protein with multifaceted functionality integral to DNA repair and redox signalling. However, the role of APE1 in mitochondrial DNA damage repair after SAH is still unclear. METHODS: Our study involved an in vivo endovascular perforation model in rats and an in vitro neuron oxyhaemoglobin intervention. Then, the effects of APE1 on mitochondrial DNA damage repair were analysed by western blot, immunofluorescence, quantitative real-time PCR, mitochondrial bioenergetics measurement and neurobehavioural experiments. RESULTS: We found that the level of APE1 decreased while the mitochondria DNA damage and neuronal death increased in a rat model of SAH. Overexpression of APE1 improved short-term and long-term behavioural impairment in rats after SAH. In vitro, after primary neurons exposed to oxyhaemoglobin, APE1 expression significantly decreased along with increased mitochondrial DNA damage, a reduction in the subunit of respiratory chain complex levels and subsequent respiratory chain dysfunction. Overexpression of APE1 relieved energy metabolism disorders in the mitochondrial of neurons and reduced neuronal apoptosis. CONCLUSION: In conclusion, APE1 is involved in EBI after SAH by affecting mitochondrial apoptosis via the mitochondrial respiratory chain. APE1 may potentially play a vital role in the EBI stage after SAH, making it a critical target for treatment.

The efficacy and tolerability of inhaled nitrous oxide in major depressive disorder: a systematic review and meta-analysis.

BACKGROUND: Nitrous oxide (N2O) has been initially confirmed by clinical trials to benefit to patients with major depressive disorder (MDD). However, there needs to be a meta-analysis to compare the efficacy and tolerability of N2O in MDD. METHODS: PubMed, EMBASE, and Cochrane Library were searched for relevant studies up to Jan 1st, 2023. The meta-analysis mainly compared the outcome of the change in depression severity scores, response, remission, and adverse events in patients with MDD receiving 50% N2O and placebo. RESULTS: Four studies with 133 patients were eventually identified. We found that the N2O group and control group showed an overall significant difference in the change in depression severity score for patients at 2 h, 24 h, and 2 weeks or more (2 h, SMD = - 0.64, 95% CI - 0.01 to - 0.28, p < 0.0001) (24 h, SMD = - 0.65, 95% CI - 1.01 to - 0.29, p < 0.0001) (2 weeks, SMD = - 0.76, 95% CI - 1.16 to - 0.36, p < 0.0001). For the response and remission rate, the long-term effect of N2O was also statistically significant (for the response, RR = 2.33, 95% CI 1.23 to 4.44, p = 0.01) (for the remission, RR = 4.68, 95% CI 1.49 to 14.68, p = 0.008). For safety outcomes, patients treated with N2O had higher odds of nausea or vomiting (RR = 10.15, 95% CI 1.96 to 52.59, p = 0.009). CONCLUSION: Our study suggested that N2O has a rapid and long-lasting antidepressant effect in patients with MDD. However, the efficacy of lower or titrated concentration of N2O should be further investigated.

Enhancing Unsupervised Anomaly Detection With Score-Guided Network.

Anomaly detection plays a crucial role in various real-world applications, including healthcare and finance systems. Owing to the limited number of anomaly labels in these complex systems, unsupervised anomaly detection methods have attracted great attention in recent years. Two major challenges faced by the existing unsupervised methods are as follows: 1) distinguishing between normal and abnormal data when they are highly mixed together and 2) defining an effective metric to maximize the gap between normal and abnormal data in a hypothesis space, which is built by a representation learner. To that end, this work proposes a novel scoring network with a score-guided regularization to learn and enlarge the anomaly score disparities between normal and abnormal data, enhancing the capability of anomaly detection. With such score-guided strategy, the representation learner can gradually learn more informative representation during the model training stage, especially for the samples in the transition field. Moreover, the scoring network can be incorporated into most of the deep unsupervised representation learning (URL)-based anomaly detection models and enhances them as a plug-in component. We next integrate the scoring network into an autoencoder (AE) and four state-of-the-art models to demonstrate the effectiveness and transferability of the design. These score-guided models are collectively called SG-Models. Extensive experiments on both synthetic and real-world datasets confirm the state-of-the-art performance of SG-Models.

Synergistic binding of actinomycin D and echinomycin to DNA mismatch sites and their combined anti-tumour effects.

Combination cancer chemotherapy is one of the most useful treatment methods to achieve a synergistic effect and reduce the toxicity of dosing with a single drug. Here, we use a combination of two well-established anticancer DNA intercalators, actinomycin D (ActD) and echinomycin (Echi), to screen their binding capabilities with DNA duplexes containing different mismatches embedded within Watson-Crick base-pairs. We have found that combining ActD and Echi preferentially stabilised thymine-related T:T mismatches. The enhanced stability of the DNA duplex-drug complexes is mainly due to the cooperative binding of the two drugs to the mismatch duplex, with many stacking interactions between the two different drug molecules. Since the repair of thymine-related mismatches is less efficient in mismatch repair (MMR)-deficient cancer cells, we have also demonstrated that the combination of ActD and Echi exhibits enhanced synergistic effects against MMR-deficient HCT116 cells and synergy is maintained in a MMR-related MLH1 gene knockdown in SW620 cells. We further accessed the clinical potential of the two-drug combination approach with a xenograft mouse model of a colorectal MMR-deficient cancer, which has resulted in a significant synergistic anti-tumour effect. The current study provides a novel approach for the development of combination chemotherapy for the treatment of cancers related to DNA-mismatches.

A two-step approach for calculating chloride diffusion coefficient in concrete with both natural and recycled concrete aggregates.

This paper presents an analytical approach to calculate the effective diffusion coefficient of chlorides in concrete with both natural and recycled concrete aggregates. In the approach the concrete is treated as a composite consisting of three phases, namely mortar, natural aggregate plus interfacial transition zone, and recycled concrete aggregate plus interfacial transition zone. The effective diffusion coefficient of chlorides in the composite is calculated through two steps. The first step is to calculate the effective diffusion coefficients of chlorides in the natural aggregate plus interfacial transition zone and in the recycled concrete aggregate plus interfacial transition zone by using multilayer spherical approximation, the results of which provide the information about the quality of recycled concrete aggregate in terms of chloride penetration resistance. The second step is to calculate the effective diffusion coefficient of chlorides in the three-phase concrete composite by using effective medium approximation, the results of which provide the information about the influence of recycled concrete aggregate on the diffusivity of recycled aggregate concrete. The analytical expression of the effective diffusion coefficient is derived and carefully compared with the results obtained from both the experiments and numerical simulations, which demonstrates that the present analytical model is rational and reliable. The analytical expression presented can be used to predict the service life of recycled aggregate concrete exposed to chloride environment.

Efficacy and safety of stereotactic body radiotherapy for painful bone metastases: Evidence from randomized controlled trials.

Background: Pain relief is one of the main objectives of radiotherapy for cancer patients with bone metastases. Stereotactic body radiotherapy (SBRT) enables precise delivery of a higher dosage to the target area. Several trials have reported comparisons between SBRT and conventional radiotherapy (cRT) in patients with painful bone metastasis. However, the results of those investigations were inconsistent, and no systematic review or meta-analysis has been done till now. Methods: We systematically searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and Clinicaltrials.gov up to May 1, 2022 for relevant studies. Patients with painful bone metastasis who received SBRT or cRT were included. The primary outcome was the patients' pain response rate at three months. The secondary outcomes included the rate of pain responders at one month and six months, oral morphine equivalent dose (OMED) use, and any adverse events. STATA software 12.0 was used for the statistical analysis. Results: We collected 533 patients' data from 4 randomized controlled trials (RCTs), there was a significant difference of pain response rate at 3 months between two groups (RR = 1.41, 95% CI: 1.12-1.77, I2 = 0.0%, P = 0.003). However, no significant difference was found in pain response rate at 1 month (RR = 1.19, 95% CI: 0.91-1.54, I2 = 31.5%, P = 0.201) and 6 months (RR = 1.25, 95% CI: 0.93-1.69, I2 = 0.0%, P = 0.140). OMED consumption was not significantly different in patients treated with SBRT compared with control group (WMD = -1.11, 95% CI: -17.51-15.28, I2 = 0.0%, P = 0.894). For safety outcome, no statistical difference was found between SBRT and cRT (RR = 0.72, 95% CI: 0.46-1.14, I2=20.1%, P = 0.162). Conclusion: This study shows that for painful bone metastases, patients with SBRT experienced better pain relief 3 months after radiation than patients with cRT, and SBRT did not increase the incidence of adverse events. Systematic review registration: https://inplasy.com/inplasy-2022-6-0099/, identifier INPLASY202260099.

Molecular Simulation Study on Mechanical Properties of Microcapsule-Based Self-Healing Cementitious Materials.

Microcapsule-based self-healing concrete can effectively repair micro-cracks in concrete and improve the strength and durability of concrete structures. In this paper, in order to study the effect of epoxy resin on the cement matrix at a microscopic level, molecular dynamics were used to simulate the mechanical and interfacial properties of microcapsule-based self-healing concrete in which uniaxial tension was carried out along the z-axis. The radial distribution function, interface binding energy, and hydrogen bonding of the composite were investigated. The results show that the epoxy resin/C-S-H composite has the maximum stress strength when TEPA is used as the curing agent. Furthermore, the interface binding energy between epoxy resin and cement matrix increases with increasing strain before the stress reaches its peak value. The cured epoxy resin can enhance both the interfacial adhesion and the ductility of the composite, which can meet the needs of crack repair of microcapsule-based self-healing cementitious materials.

Niclosamide suppresses T­cell acute lymphoblastic leukemia growth through activation of apoptosis and autophagy.

T­cell acute lymphoblastic leukemia (T­ALL) is a common pediatric malignancy, characterized by the abnormal presence of immature T­cell progenitors. Conventional treatments for T­ALL fail to prevent or cure the disease, with a high­risk of recurrence after the first remission. Thus, medical options are in demand to develop novel therapies for patients suffering with T­ALL. Niclosamide, a traditional oral anti­helminthic drug, has been reported to be a potential anticancer agent that regulates intracellular signaling pathways. Few studies have yet investigated the effects of niclosamide on the development of T­ALL. Here, the present study aimed to investigate the anti­leukemia effects of niclosamide on T­ALL. We first hypothesized that the suppressive effects of niclosamide on the tumor growth of T­ALL are exerted by regulating autophagy and apoptosis. Following niclosamide treatment, T­ALL cell viability was evaluated using MTT assay, and apoptosis with Annexin V/propidium iodide staining. In T­ALL cells treated with niclosamide, changes in apoptosis­ and autophagy­related proteins were analyzed by western blotting. In addition, in an in vivo model, T­ALL xenograft mice were used to study the anti­leukemia effects of niclosamide. The results showed that niclosamide significantly reduced the viability of Jurkat and CCRF­CEM T­ALL cells in both a dose­ and time­dependent manner. Niclosamide significantly activated the early and late phases of apoptosis in Jurkat (at 2 µM) and CCRF­CEM cells (at 1 µM). Furthermore, niclosamide upregulated protein expression of cleaved caspase­3 and LC3B, while downregulated those of Bcl­2 and p62, in a dose­dependent manner in both Jurkat and CCRF­CEM cells. The in vivo results showed that niclosamide treatment significantly suppressed tumor growth and the disease progression in T­ALL xenograft mice by activating cleaved caspase­3 and LC3B. We conclude that niclosamide plays an anti­leukemia role, and that it represents a novel approach for the treatment of T­ALL.

Comparative Analyses of Single-Cell Transcriptomic Profiles between In Vitro Totipotent Blastomere-like Cells and In Vivo Early Mouse Embryonic Cells.

The developmental potential within pluripotent cells in the canonical model is restricted to embryonic tissues, whereas totipotent cells can differentiate into both embryonic and extraembryonic tissues. Currently, the ability to culture in vitro totipotent cells possessing molecular and functional features like those of an early embryo in vivo has been a challenge. Recently, it was reported that treatment with a single spliceosome inhibitor, pladienolide B (plaB), can successfully reprogram mouse pluripotent stem cells into totipotent blastomere-like cells (TBLCs) in vitro. The TBLCs exhibited totipotency transcriptionally and acquired expanded developmental potential with the ability to yield various embryonic and extraembryonic tissues that may be employed as novel mouse developmental cell models. However, it is disputed whether TBLCs are 'true' totipotent stem cells equivalent to in vivo two-cell stage embryos. To address this question, single-cell RNA sequencing was applied to TBLCs and cells from early mouse embryonic developmental stages and the data were integrated using canonical correlation analyses. Differential expression analyses were performed between TBLCs and multi-embryonic cell stages to identify differentially expressed genes. Remarkably, a subpopulation within the TBLCs population expressed a high level of the totipotent-related genes Zscan4s and displayed transcriptomic features similar to mouse two-cell stage embryonic cells. This study underscores the subtle differences between in vitro derived TBLCs and in vivo mouse early developmental cell stages at the single-cell transcriptomic level. Our study has identified a new experimental model for stem cell biology, namely 'cluster 3', as a subpopulation of TBLCs that can be molecularly defined as near totipotent cells.

Behavior of Alkali-Activated Fly Ash through Underwater Placement.

Underwater concrete is a cohesive self-consolidated concrete used for concreting underwater structures such as bridge piers. Conventional concrete used anti-washout admixture (AWA) to form a high-viscosity underwater concrete to minimise the dispersion of concrete material into the surrounding water. The reduction of quality for conventional concrete is mainly due to the washing out of cement and fine particles upon casting in the water. This research focused on the detailed investigations into the setting time, washout effect, compressive strength, and chemical composition analysis of alkali-activated fly ash (AAFA) paste through underwater placement in seawater and freshwater. Class C fly ash as source materials, sodium silicate, and sodium hydroxide solution as alkaline activator were used for this study. Specimens produced through underwater placement in seawater showed impressive performance with strength 71.10 MPa on 28 days. According to the Standard of the Japan Society of Civil Engineers (JSCE), the strength of specimens for underwater placement must not be lower than 80% of the specimen's strength prepared in dry conditions. As result, the AAFA specimens only showed 12.11% reduction in strength compared to the specimen prepared in dry conditions, thus proving that AAFA paste has high potential to be applied in seawater and freshwater applications.

Interfacial Binding Energy between Calcium-Silicate-Hydrates and Epoxy Resin: A Molecular Dynamics Study.

Microcapsules encapsulated within epoxy as a curing agent have been successfully applied in self-healing materials, in which the healing performance significantly depends on the binding behaviour of the epoxy curing agent with the cement matrix. In this paper, the binding energy was investigated by molecular dynamics simulation, which could overcome the shortcomings of traditional microscopic experimental methods. In addition to the construction of different molecular models of epoxy, curing agents, and dilutants, seven models were established to investigate the effects of chain length, curing agent, and epoxy resin chain direction on the interfacial binding energy. The results showed that an increase of chain length exhibited had limited effect on the binding energy, while the curing agent and the direction of the epoxy significantly affected the interfacial binding energy. Among different factors, the curing agent tetrethylenepentamine exhibited the highest value of interfacial binding energy by an increment of 31.03 kcal/mol, indicating a better binding ability of the microcapsule core and the cement matrix. This study provides a microscopic insight into the interface behaviour between the microcapsule core and the cement matrix.

Properties of a New Insulation Material Glass Bubble in Geo-Polymer Concrete.

This paper details analytical research results into a novel geopolymer concrete embedded with glass bubble as its thermal insulating material, fly ash as its precursor material, and a combination of sodium hydroxide (NaOH) and sodium silicate (Na2SiO3) as its alkaline activator to form a geopolymer system. The workability, density, compressive strength (per curing days), and water absorption of the sample loaded at 10% glass bubble (loading level determined to satisfy the minimum strength requirement of a load-bearing structure) were 70 mm, 2165 kg/m3, 52.58 MPa (28 days), 54.92 MPa (60 days), and 65.25 MPa (90 days), and 3.73 %, respectively. The thermal conductivity for geopolymer concrete decreased from 1.47 to 1.19 W/mK, while the thermal diffusivity decreased from 1.88 to 1.02 mm2/s due to increased specific heat from 0.96 to 1.73 MJ/m3K. The improved physicomechanical and thermal (insulating) properties resulting from embedding a glass bubble as an insulating material into geopolymer concrete resulted in a viable composite for use in the construction industry.

Anomaly Detection of Time Series With Smoothness-Inducing Sequential Variational Auto-Encoder.

Deep generative models have demonstrated their effectiveness in learning latent representation and modeling complex dependencies of time series. In this article, we present a smoothness-inducing sequential variational auto-encoder (VAE) (SISVAE) model for the robust estimation and anomaly detection of multidimensional time series. Our model is based on VAE, and its backbone is fulfilled by a recurrent neural network to capture latent temporal structures of time series for both the generative model and the inference model. Specifically, our model parameterizes mean and variance for each time-stamp with flexible neural networks, resulting in a nonstationary model that can work without the assumption of constant noise as commonly made by existing Markov models. However, such flexibility may cause the model fragile to anomalies. To achieve robust density estimation which can also benefit detection tasks, we propose a smoothness-inducing prior over possible estimations. The proposed prior works as a regularizer that places penalty at nonsmooth reconstructions. Our model is learned efficiently with a novel stochastic gradient variational Bayes estimator. In particular, we study two decision criteria for anomaly detection: reconstruction probability and reconstruction error. We show the effectiveness of our model on both synthetic data sets and public real-world benchmarks.

miR-524-5p reduces the progression of the BRAF inhibitor-resistant melanoma.

BRAF inhibitors were approved for the treatment of BRAF-mutant melanoma. However, most patients acquire the resistance to BRAF inhibitors after several months of treatment. miR-524-5p is considered as a tumor suppressor in many cancers, including melanoma. In this study, we investigated the biological functions of miR-524-5p in melanoma with acquired resistance to BRAF inhibitor and evaluated the endogenous miR-524-5p expression as a biomarker for melanoma. The results showed that the expression of miR-524-5p was 0.481-fold lower in melanoma tissues (n = 117) than in nevus tissues (n = 40). Overexpression of miR-524-5p significantly reduced proliferative, anchorage-independent growth, migratory and invasive abilities of BRAF inhibitor-resistant melanoma cells. Moreover, the introduction of miR-524-5p led to a reduced development of BRAF inhibitor-resistant melanoma in vivo. Remarkably, the MAPK/ERK signaling pathway was decreased after treatment with miR-524-5p. Furthermore, next-generation sequencing analysis implied that the complement system, leukocyte extravasation, liver X receptor/retinoid-X-receptor activation, and cAMP-mediated signaling may be related to miR-524-5p-induced pathways in the resistant cells. The miR-524-5p level was higher on average in complete response and long-term partial response patients than in progressive disease and short-term partial response patients treated with BRAF inhibitors. Our results proposed that miR-524-5p could be considered as a target for treatment BRAF inhibitor-resistant melanoma and a prognostic marker in the response of patients to BRAF inhibitors for melanoma.

Self-Sensing Carbon Nanotube Composites Exposed to Glass Transition Temperature.

This paper reported the effect of high temperature on the electro-mechanical behavior of carbon nanotube (CNT) reinforced epoxy composites. CNT/epoxy composites were fabricated by dispersing CNTs in the epoxy matrix using a solution casting method. Electrical conductivity measurements obtained for the CNT/epoxy composites indicated a steadily increasing directly proportional relationship with CNT concentration with a percolation threshold at 0.25 wt %, reaching a maximum of up to 0.01 S/m at 2.00 wt % CNTs. The electro-mechanical behavior of CNT/epoxy composites were investigated at a room temperature under the static and cyclic compressive loadings, resulting that the change in resistance of CNT/epoxy composites was reduced as increasing CNT concentration with good repeatability. This is due to well-networked CNTs conducting pathways created within the solid epoxy matrix observed by scanning electron microscopy. Temperature significantly affects the electro-mechanical behavior of CNT/epoxy composites. In particular, the electro-mechanical behavior of CNT/epoxy composites below the glass transition temperature showed the similar trend with those at room temperature, whereas the electro-mechanical behavior of CNT/epoxy composites above the glass transition temperature showed an opposite change in resistance with poor repeatability due to unstable CNT network in epoxy matrix.

YY1 and HDAC9c transcriptionally regulate p38-mediated mesenchymal stem cell differentiation into osteoblasts.

Mesenchymal stem cells (MSCs) have a high self-renewal potential and can differentiate into various types of cells, including adipocytes, osteoblasts, and chondrocytes. Previously, we reported that the enhancer of zeste homolog 2 (EZH2), the catalytic component of the Polycomb-repressive complex 2, and HDAC9c mediate the osteogenesis and adipogenesis of MSCs. In the current study, we identify the role of p38 in osteogenic differentiation from a MAPK antibody array screen and investigate the mechanisms underlying its transcriptional regulation. Our data show that YY1, a ubiquitously expressed transcription factor, and HDAC9c coordinate p38 transcriptional activity to promote its expression to facilitate the osteogenic potential of MSCs. Our results show that p38 mediates osteogenic differentiation, and this has significant implications in bone-related diseases, bone tissue engineering, and regenerative medicine.

Total body irradiation tremendously impair the proliferation, differentiation and chromosomal integrity of bone marrow-derived mesenchymal stromal stem cells.

Total body irradiation (TBI) is frequently used in hematopoietic stem cell transplantation (HSCT) and is associated with many complications due to radiation injury to the normal cells, including normal stem cells. Nevertheless, the effects of TBI on the mesenchymal stromal stem cell (MSC) are not fully understood. Bone marrow-derived MSCs (BM-MSCs) isolated from normal adults were irradiated with 200 cGy twice daily for consecutive 3 days, a regimen identical to that used in TBI-conditioning HSCT. The characteristics, differentiation potential, cytogenetics, hematopoiesis-supporting function, and carcinogenicity of the irradiated BM-MSCs were then compared to the non-irradiated control. The irradiated and non-irradiated MSCs shared similar morphology, phenotype, and hematopoiesis-supporting function. However, irradiated MSCs showed much lower proliferative and differentiative potential. Irradiation also induced clonal cytogenetic abnormalities of MSCs. Nevertheless, the carcinogenicity of irradiated MSCs is low in vitro and in vivo. In parallel with the ex vivo irradiation experiments, decreased proliferative and differentiative abilities and clonal cytogenetic abnormalities can also be found in MSCs isolated from transplant recipients who had received TBI-based conditioning previously. Thus, TBI used in HSCT drastically injury MSCs and may contribute to the development of some long-term complications associated with clonal cytogenetic abnormality and poor adipogenesis and osteogenesis after TBI.