Analysis and experiment of a pneumatic-hydraulic composite support system for in-situ mirror processing and testing.

To address the deformation issues caused by the self-gravity and machining stresses in the process of large-aperture mirror fabrication, this paper proposes an in-situ switchable pneumatic-hydraulic hybrid supporting system that enables the seamless transition between machining and testing. By facilitating in-situ switching, this system not only reduces the machining time of large-aperture mirrors, thereby enhancing production efficiency, but also mitigates the risks associated with traditional switching methods that may result in mirror damage due to human error. Three typical working conditions of the hybrid supporting system, namely hydraulic machining support, air-floating testing support, and three-point rigid support, are investigated in terms of mirror loading through a finite element simulation. Additionally, an experimental platform is constructed to validate the proposed system. The experimental results affirm the feasibility of the designed pneumatic-hydraulic hybrid supporting system. This system will serve as a technological support to advance the rapid development of large-aperture space telescope manufacturing techniques.

The mechanism of the WNT5A and FZD4 receptor mediated WNT/ß-catenin pathway in the degeneration of ALS spinal cord motor neurons.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with unknown etiology, characterized by motor neuron degeneration, and there is no highly effective treatment. The canonical WNT/ß-catenin signaling pathway has a critical role in the physiological and pathophysiological processes of the central nervous system. In this study, we investigated the regulatory mechanism of the WNT/ß-catenin signaling pathway from the perspective of ligand-receptor binding and its relationship with the degeneration of ALS motor neurons. We used hSOD1-G93A mutant ALS transgenic mice and hSOD1-G93A mutant NSC34 cells combined with morphological and molecular biology techniques to determine the role of the WNT/ß-catenin pathway in ALS. Our findings demonstrated that WNT5A regulates the WNT/ß-catenin signaling pathway by binding to the FZD4 receptor in the pathogenesis of ALS and affects the proliferation and apoptosis of ALS motor neurons. Therefore, these findings may lead to the development of novel therapies to support the survival of ALS motor neurons.

Spatiotemporal evolution of pyroptosis and canonical inflammasome pathway in hSOD1G93A ALS mouse model.

BACKGROUND: Evidences indicate that inflammasome compounds participate in amyotrophic lateral sclerosis (ALS), a fatal progressive motoneuron degenerative disease. Researchers have observed the expressions of nucleotide oligomerization domain (NOD)-like receptor protein 3 (NLRP3) related inflammasome components in specific regions of the central nervous system in different ALS models, but the cellular spatiotemporal evolution of this canonical inflammasome pathway and pyroptosis during ALS progression are unclear. METHODS: The spinal cords of hSOD1G93A mice (ALS mice) and age-matched littermates (CON mice) were dissected at pre-symptomatic stage (60 d), early- symptomatic stage (95 d), symptomatic stage (108 d) and late-symptomatic stage (122 d) of the disease. By using Nissl staining, double immunofluorescence labelling, qRT-PCR or western blot, we detected morphology change and the expression, cellular location of GSDMD, NLRP3, caspase-1 and IL-1ß in the ventral horn of lumbar spinal cords over the course of disease. RESULTS: Neural morphology changes and GSDMD+/NeuN+ double positive cells were observed in ventral horn from ALS mice even at 60 d of age, even though there were no changes of GSDMD mRNA and protein expressions at this stage compared with CON mice. With disease progression, compared with age-matched CON mice, increased expressions of GSDMD, NLRP3, activated caspase-1 and IL-1ß were detected. Double immunofluorescence labeling revealed that NLRP3, caspase-1, IL-1ß positive signals mainly localized in ventral horn neurons at pre- and early-symptomatic stages. From symptomatic stage to late-symptomatic stage, robust positive signals were co-expressed in reactive astrocytes and microglia. CONCLUSIONS: Early activation of the canonical NLRP3 inflammasome induced pyroptosis in ventral horn neurons, which may participate in motor neuron degeneration and initiate neuroinflammatory processes during ALS progression.

Evaluating automated entity extraction with respect to drug and non-drug treatment strategies.

OBJECTIVES: Treatment used in a randomized clinical trial is a critical data element both for physicians at the point of care and reviewers who are evaluating different interventions. Much of existing work on treatment extraction from the biomedical literature has focused on the extraction of pharmacological interventions. However, non-pharmacological interventions (e.g., exercise, diet, etc.) that are frequently used to address chronic conditions are less well studied. The goal of this study is to compare knowledge-based and machine learning strategies for the extraction of both drug and non-drug treatments. METHODS: We collected 800 randomized clinical trial abstracts each for breast cancer and diabetes from PubMed. The treatments in the result/conclusion sentences of the abstracts were manually annotated and marked as drug/non-drug treatments. We then designed three methods to identify the treatments and evaluated the systems with respect to drug/non-drug treatments. The first method is solely based on knowledge base (here we used MetaMap). The second method is based on a machine learning model trained mainly on contextual features (ML_only). The third method is a combination approach that integrates the previous two approaches. RESULTS/DISCUSSION: Results show that MetaMap, when used with high precision semantic types, has better performance for drug compared to non-drug treatments (F1 = 0.77 vs. 0.64). The ML_only approach has smaller performance difference between drug and non-drug treatments compared with the KB-based approach (F1 = 0.02 vs. 0.05, 0.07, and 0.13). The combination approach achieves significantly better performance than all MetaMap approaches alone for total treatments (F1 = 0.76 vs. 0.72, p < 0.001). The performance gain mainly comes from the non-drug treatments (0.03-0.08 improvement in F1), while the drug treatments do not benefit much from the combination approach (0-0.03 improvement in F1). CONCLUSION: These results suggest that a knowledge-based approach should be employed for medical conditions that are primarily treated with drugs whereas conditions that are treated with either a combination of drug and non-drug interventions or primarily non-drug interventions should use automated tools that combine machine learning and a knowledge-based approach to achieve optimal performance.

Gestational B-vitamin supplementation alleviates PM2.5-induced autism-like behavior and hippocampal neurodevelopmental impairment in mice offspring.

Gestational exposure to PM2.5 is a worldwide environmental issue associated with long-lasting behavior abnormalities and neurodevelopmental impairments in the hippocampus of offspring. PM2.5 may induce hippocampus injury and lead to autism-like behavior such as social communication deficits and stereotyped repetitive behavior in children through neuroinflammation and neurodegeneration. Here, we investigated the preventive effect of B-vitamin on PM2.5-induced deleterious effects by focusing on anti-inflammation, antioxidant, synaptic remodeling and neurodevelopment. Pregnant mice were randomly divided into three groups including control group (mice subject to PBS only), model group (mice subject to both 30 µL PM2.5 of 3.456 µg/µL and 10 mL/(kg·d) PBS), and intervention group (mice subject to both 30 µL PM2.5 of 3.456 µg/µL and 10 mL/(kg·d) B-vitamin supplementation (folic acid, vitamin B6 and vitamin B12 with concentrations at 0.06, 1.14 and 0.02 mg/mL, respectively)). In the current study B-vitamin significantly alleviated neurobehavioral impairment reflected in reduced social communication disorders, stereotyped repetitive behavior, along with learning and spatial memory impairment in PM2.5-stimulated mice offspring. Next, B-vitamin corrected synaptic loss and reduced mitochondrial damage in hippocampus of mice offspring, demonstrated by normalized synapse quantity, synaptic cleft, postsynaptic density (PSD) thickness and length of synaptic active area. Furthermore, significantly down-regulated expression of pro-inflammatory cytokines including NF-κB, TNF-α and IL-1ß, and lipid peroxidation were found. We observed elevated levels of oxidant-related genes (SOD, GSH and GSH-Px). Moreover, decreased cleaved caspase-3 and TUNEL-positive cells suggested inhibited PM2.5-induced apoptosis by B-vitamin. Furthermore, B-vitamin increased neurogenesis by increasing EdU-positive cells in the subgranular zone (SGZ) of offspring. Collectively, our results suggest that B-vitamin supplementation exerts preventive effect on autism-like behavior and neurodevelopmental impairment in hippocampus of mice offspring gestationally exposed to PM2.5, to which alleviated mitochondrial damage, increased anti-inflammatory and antioxidant capacity and synaptic efficiency, reduced neuronal apoptosis and improved hippocampal neurogenesis may contribute.

Screening the expression characteristics of several miRNAs in G93A-SOD1 transgenic mouse: altered expression of miRNA-124 is associated with astrocyte differentiation by targeting Sox2 and Sox9.

MicroRNAs (miRNAs) are suspected to be a contributing factor in amyotrophic lateral sclerosis (ALS). Here, we assess the altered expression of miRNAs and the effects of miR-124 in astrocytic differentiation in neural stem cells of ALS transgenic mice. Differentially expressed miRNA-positive cells (including miR-124, miR-181a, miR-22, miR-26b, miR-34a, miR-146a, miR-219, miR-21, miR-200a, and miR-320) were detected by in situ hybridization and qRT-PCR in the spinal cord and the brainstem. Our results demonstrated that miR-124 was down-regulated in the spinal cord and brainstem. In vitro, miR-124 was down-regulated in neural stem cells and up-regulated in differentiated neural stem cells in G93A-superoxide dismutase 1 (SOD1) mice compared with WT mice by qRT-PCR. Meanwhile, Sox2 and Sox9 protein levels showed converse change with miR-124 in vivo and vitro. After over-expression or knockdown of miR-124 in motor neuron-like hybrid (NSC34) cells of mouse, Sox2 and Sox9 proteins were noticeably down-regulated or up-regulated, whereas Sox2 and Sox9 mRNAs remained virtually unchanged. Moreover, immunofluorescence results indicated that the number of double-positive cells of Sox2/glial fibrillary acidic protein (GFAP) and Sox9/glial fibrillary acidic protein (GFAP) was higher in G93A-SOD1 mice compared with WT mice. We also found that many Sox2- and Sox9-positive cells were nestin positive in G93A-SOD1 mice, but not in WT mice. Furthermore, differentiated neural stem cells from G93A-SOD1 mice generated a greater proportion of astrocytes and lower proportion of neurons than those from WT mice. MiR-124 may play an important role in astrocytic differentiation by targeting Sox2 and Sox9 in ALS transgenic mice. Cover Image for this issue: doi: 10.1111/jnc.14171.

HMGB1 enhances embryonic neural stem cell proliferation by activating the MAPK signaling pathway.

Neural stem cells (NSCs) are involved in neural tube formation. As the high-mobility group box 1 (HMGB1) protein is involved in neurulation and is present at elevated levels in neural tube defects (NTDs) induced by hyperthermia, we have now investigated the effects of HMGB1 on proliferation, differentiation, and MAPK signaling pathways of NSCs in vitro. We constructed a lentivirus vector with HMGB1 siRNA and used it to infect NSCs. Down-regulation of HMGB1 expression was confirmed. Proliferation of NSCs was determined by MTS and nestin/BrdU double-labeling. Differentiation of NSCs was assessed using ß-tubulinIII and GFAP. Knockdown of HMGB1 significantly suppressed NSC proliferation but hardly affected differentiation, which was regulated by decreased expression of MAPK signaling pathways. Thus, HMGB1 has beneficial effects on neurulation and may serve as a new target for the prevention of NTDs.

Functional genes and microorganisms controlling in situ methylmercury production and degradation in marine sediments: A case study in the Eastern China Coastal Seas.

Dominant microorganisms and functional genes, including hgcA, hgcB, merA, and merB, have been identified to be responsible for mercury (Hg) methylation or methylmercury (MeHg) demethylation. However, their in situ correlation with MeHg levels and the processes of Hg methylation and MeHg demethylation in coastal areas remains poorly understood. In this study, four functional genes related to Hg methylation and MeHg demethylation (hgcA, hgcB, merA, and merB) were all detected in the sediments of the Eastern China Coastal Seas (ECCSs) (representative coastal seas highly affected by human activities) using metagenomic approaches. HgcA was identified to be the key gene controlling the in situ net production of MeHg in the ECCSs. Based on metagenomic analysis and incubation experiments, sulfate-reducing bacteria were identified as the dominant microorganisms controlling Hg methylation in the ECCSs. In addition, hgcA gene was positively correlated with the MeHg content and Hg methylation rates, highlighting the potential roles of Hg methylation genes and microorganisms influenced by sediment physicochemical properties in MeHg cycling in the ECCSs. These findings highlighted the necessity of conducting similar studies in other natural systems for elucidating the molecular mechanisms underlying MeHg production in aquatic environments.

Wnt Signaling is altered by spinal cord neuronal dysfunction in amyotrophic lateral sclerosis transgenic mice.

Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disease characterized by progressive degeneration of the motor neurons in the cortex, brainstem, and spinal cord. The etiology and mechanisms of selective motor neuron loss in ALS remain unknown. Wnt signaling is involved in neurodegenerative processes but little is known about the kinetic changes in Wnt signaling during ALS progression. In this study we used transcriptional microarray analysis to examine the expression of Wnt signaling components in the spinal cords of ALS transgenic SOD1(G93A) mice at different stages. We found that ALS onset led to the upregulation of Wnt signaling components and target genes involved in growth regulation and proliferation. We also determined the expression of Wnt inhibitory factor-1 (Wif1) and Wnt4 in the spinal cord of ALS transgenic mice at different stages by Western blot and immunofluorescence analysis. The protein levels of Wif1 and Wnt4 in the spinal cords of ALS transgenic mice were upregulated compared to those in wild-type mice. Moreover, the expression of Wif1 and Wnt4 in mature GFAP+ astrocytes was increased at the end stage of ALS. Our findings demonstrate that Wnt signaling is altered by spinal cord neuronal dysfunction in adult ALS transgenic mice, which provides new insight into ALS pathogenesis.

Role of Wnt1 and Fzd1 in the spinal cord pathogenesis of amyotrophic lateral sclerosis-transgenic mice.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by chronic progressive degeneration of motor neurons resulting in muscular atrophy, paralysis, and ultimately death. We have investigated the expression of Wnt1 and Fzd1 in the spinal cords of SOD1G93A ALS transgenic mice, SOD1G93A-transfected N2a cells, and primary cultured astrocytes from SOD1G93A transgenic mice. In addition, we provided further insight into the role of Wnt1 and Fzd1 in the pathogenesis of ALS transgenic mice and discuss the mechanisms underlying the Wnt signal pathway which may be useful in the treatment of ALS. The results indicate the involvement of Wnt1 and Fzd1 in the pathogenesis and development of ALS.

Research space telescope deployable mechanism variable diameter internal drive device elastic collision contact characteristics in the inter-stage transition.

To address the problem of elastic contact discrepancies between a variable-diameter internal drive device and a non-continuous surface during the transition, caused by the vibrations resulting from elastic collision impact when the motion speed of the elastic body increases, the following steps were taken. First, we established models for elastic collision, impact, and vibration during the inter-stage transition to analyze how motion speed and preload affect the elastic contact characteristics between the two components. Subsequently, we employed the finite element method to further analyze the elastic contact state, using identical loads but varying motion speeds and radial preloads as boundary conditions. Finally, an experimental prototype was developed to validate the elastic contact state of the elastic body during the inter-stage transition. The results indicated that the amplitude of elastic body vibration increased with higher motion speed, while it decreased with higher radial preload. Therefore, it is necessary to adjust radial preload at different times to ensure effective elastic contact between the elastic body and the non-continuous surface during the inter-stage transition. This approach not only enhances deployment speed but also guarantees the stability of the inter-stage transition.

Efficacy of Alveolar Type II Epithelial Cell Transplantation for Pulmonary Fibrosis: A Meta-Analysis.

Background: Cell transplantation is a promising therapeutic strategy for pulmonary fibrosis. In order to clarify the alveolar type II epithelial cell potential utility in the treatment of lung disease, we conducted a meta-analysis, to evaluate alveolar type II epithelial cells in animal models of lung injury and pulmonary fibrosis. Methods: This review followed the recommendations from the PRISMA statements, Comprehensive retrieval method was used to search Embase, PubMed, Cochrane, Chinese Knowledge Infrastructure, VIP and Wanfang databases. A total of 7 studies and 286 model rats were included. Two researchers independently screened the identified studies, based on inclusion and exclusion criteria. All analyses were conducted using Review Manager V.5.3 software. The combined standard mean difference (SMD) and 95% confidence interval (CI) of data from the included studies were calculated using fixed or random-effects models. Results: The analysis of three outcome indexes showed that the heterogeneity of the oxygen saturation group was high (I2=85%), the lung weight group (I2=64%) was close to moderate heterogeneity, and the lung hydroxyproline content group (I2=0) was not heterogeneous. Conclusion: Meta-analysis showed that transplantation of alveolar type II epithelial cells has beneficial effects, and no obvious adverse reactions. Alveolar type II epithelial cell transplantation can significantly reduce the intervention group and lung hydroxyproline content weight, improve the blood oxygen saturation, lung histo-pathology showed significant improvement in pulmonary fibrosis.

Induced Pluripotent Stem Cells and Their Applications in Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that results in the loss of motor function in the central nervous system (CNS) and ultimately death. The mechanisms underlying ALS pathogenesis have not yet been fully elucidated, and ALS cannot be treated effectively. Most studies have applied animal or single-gene intervention cell lines as ALS disease models, but they cannot accurately reflect the pathological characteristics of ALS. Induced pluripotent stem cells (iPSCs) can be reprogrammed from somatic cells, possessing the ability to self-renew and differentiate into a variety of cells. iPSCs can be obtained from ALS patients with different genotypes and phenotypes, and the genetic background of the donor cells remains unchanged during reprogramming. iPSCs can differentiate into neurons and glial cells related to ALS. Therefore, iPSCs provide an excellent method to evaluate the impact of diseases on ALS patients. Moreover, patient-derived iPSCs are obtained from their own somatic cells, avoiding ethical concerns and posing only a low risk of immune rejection. The iPSC technology creates new hope for ALS treatment. Here, we review recent studies on iPSCs and their applications in disease modeling, drug screening and cell therapy in ALS, with a particular focus on the potential for ALS treatment.

Activation of the Wnt/ß-catenin signaling pathway is associated with glial proliferation in the adult spinal cord of ALS transgenic mice.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive and fatal loss of motor neurons. In ALS, there is a significant cell proliferation in response to neurodegeneration; however, the exact molecular mechanisms of cell proliferation and differentiation are unclear. The Wnt signaling pathway has been shown to be involved in neurodegenerative processes. Wnt3a, ß-catenin, and Cyclin D1 are three key signaling molecules of the Wnt/ß-catenin signaling pathway. We determined the expression of Wnt3a, ß-catenin, and Cyclin D1 in the adult spinal cord of SOD1(G93A) ALS transgenic mice at different stages by RT-PCR, Western blot, and immunofluorescence labeling techniques. We found that the mRNA and protein of Wnt3a and Cyclin D1 in the spinal cord of the ALS mice were upregulated compared to those in wild-type mice. In addition, ß-catenin translocated from the cell membrane to the nucleus and subsequently activated transcription of the target gene, Cyclin D1. BrdU and Cyclin D1 double-positive cells were increased in the spinal cord of these mice. Moreover, Wnt3a, ß-catenin, and Cyclin D1 were also expressed in both neurons and astrocytes. The expression of Wnt3a, ß-catenin or Cyclin D1 in mature GFAP(+) astrocytes increased. Moreover, BrdU/Cyclin D1/GFAP triple-positive cells were detected in the ALS mice. Our findings suggest that neurodegeneration activates the Wnt/ß-catenin signaling pathway, which is associated with glial proliferation in the adult spinal cord of ALS transgenic mice. This mechanism may be significant in clinical gene therapy.

[Effect of Toxoplasma gondii infection on the embryonic neural stem cells in rats].

OBJECTIVE: To investigate the effect of Toxoplasma gondii infection on the proliferation, differentiation and migration of the embryonic neural stem cells (NSCs) in early pregnancy of rat. METHODS: Twelve pregnant Sprague-Dawley rats were randomly divided into control and infection groups. Rats in the infection group were each inoculated intraperitoneally with 1 x 10(5) T. gondii RH strain tachyzoites at day 1 (E1 day). Same amount of physiological saline was intraperitoneally injected for rats in control group. At E5 day, blood samples were taken from caudal vein and Giemsa staining of blood cells was performed to find T. gondii. At E9, E10 and E11 day, two rats in each group per time point were sacrificed and reverse transcription PCR (RT-PCR) was performed to detect B1 gene expression of T. gondii in amniotic fluid to confirm T. gondii infection. NSCs were cultured in vitro. The proliferation level was detected by methyl thiazolyl tetrazolium (MTT) assay. After differentiation culture of NSCs, the immunofluorescence assay was conducted to detect the expression of nestin, microtubule-associated protein 2 (MAP2) and glial fibrillary acidic protein (GFAP) to calculate the ratio of NSCs which differentiated to neurons and astrocytes. The embryonic nerve tissues at E9, E10 and E11 day in each group were taken to make frozen sections. The immunofluorescence assay was carried out to detect the expression of neuronal cell adhesion molecule (NCAM) in the nerve tissues at different developmental stages. RESULTS: Both the results of blood smears and RT-PCR confirmed that the pregnant rats and embryos were all infected by T. gondii in infection group. The morphology of the cultured NSCs under microscope was consistent with the characteristics of the normal NSCs. In addition, the NSC biomarker nestin protein was stained positive. The MTT assay showed that the proliferation level was lower in infection group than that of the control, and statistical differences were found between the two groups at day 3 and 4 after passages (P < 0.05). The immunofluorescence staining of MAP2 and GFAP showed that the percentage of neuron differentiation was 15.15% (55/363) in control group and 8.73% (31/355) in infection group, respectively, with a statistical difference (P < 0.05), and the percentage of astrocyte differentiation was 53.35% (199/374) and 67.48% 249/369), respectively (P > 0.05). In both groups, NCAM protein was found expressed at E9, E10 and E11 day in embryo nerve tissues. The fluorescence became stronger with time. The expression level in control group was significantly higher than that in infection group (P < 0.01). CONCLUSION: T. gondii infection at early gestation may inhibit the proliferation, differentiation and migration of neural stem cells in rats.

Methodological information extraction from randomized controlled trial publications: a pilot study.

Most biomedical information extraction (IE) approaches focus on entity types such as diseases, drugs, and genes, and relations such as gene-disease associations. In this paper, we introduce the task of methodological IE to support fine-grained quality assessment of randomized controlled trial (RCT) publications. We draw from the Ontology of Clinical Research (OCRe) and the CONSORT reporting guidelines for RCTs to create a categorization of relevant methodological characteristics. In a pilot annotation study, we annotate a corpus of 70 full-text publications with these characteristics. We also train baseline named entity recognition (NER) models to recognize these items in RCT publications using several training sets with different negative sampling strategies. We evaluate the models at span and document levels. Our results show that it is feasible to use natural language processing (NLP) and machine learning for fine-grained extraction of methodological information. We propose that our models, after improvements, can support assessment of methodological quality in RCT publications. Our annotated corpus, models, and code are publicly available at https://github.com/kellyhoang0610/RCTMethodologyIE.

Wnt5a protects motor neurons in amyotrophic lateral sclerosis by regulating the Wnt/Ca2+ signaling pathway.

OBJECTIVES: We aimed to detect the expression profile of downstream signaling molecules of non-canonical Wnt pathway in SOD1G93A transgenic mice (ALS mice) and SOD1G93A mutant motor neuron-like hybrid (NSC-34) cells. Characterizing the molecular mechanism of the Wnt5a-mediated non-canonical Wnt/Ca2+ signaling pathway in motor neuron (MN) degeneration may provide a feasible approach to effective treatment of amyotrophic lateral sclerosis (ALS). METHODS: The expressions of CaMKII-α, CaMKII-ß and TAK1 in the spinal cord of SOD1G93A ALS transgenic mice at different ages were determined using western blotting and immunofluorescence. The level of Ca2+ and cell apoptosis were assessed with flow cytometry and cell viability was evaluated using MTS assay. Cell proliferation was analyzed by the EdU cell proliferation assay. Neurite length was measured after treatment with retinoic acid. RESULTS: CaMKII-α, CaMKII-ß, and TAK1 were down-regulated in the spinal cord of ALS mice. Ca2+ level and CaMKII-α, CaMKII-ß, and TAK1 were down-regulated in SOD1G93A mutant NSC-34 cells. Expression of Ca2+, CaMKII-α, CaMKII-ß, and TAK1 were up-regulated in SOD1G93A mutant NSC-34 cells after Wnt5a overexpression and down-regulated after Wnt5a knockdown. Overexpression of Wnt5a promoted cell viability and proliferation but inhibited cell apoptosis. Contrastingly, Wnt5a knockdown inhibited cell viability and proliferation but promoted cell apoptosis. CaMKII inhibitor KN-93 and CaMKII activator oleic acid reversed changes in cell viability, proliferation, apoptosis, and neurite outgrowth induced by Wnt5a overexpression and knockdown. CONCLUSIONS: This study demonstrates that Wnt5a protects MNs in ALS by regulating cell viability, proliferation, apoptosis, and neurite growth through the Wnt/Ca2+ signaling pathway. Our data indicate that the non-canonical Wnt/Ca2+ signaling pathway regulated by Wnt5a is involved in MN degeneration in ALS.

The Biogenesis of miRNAs and Their Role in the Development of Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects upper and lower motor neurons. As there is no effective treatment for ALS, it is particularly important to screen key gene therapy targets. The identifications of microRNAs (miRNAs) have completely changed the traditional view of gene regulation. miRNAs are small noncoding single-stranded RNA molecules involved in the regulation of post-transcriptional gene expression. Recent advances also indicate that miRNAs are biomarkers in many diseases, including neurodegenerative diseases. In this review, we summarize recent advances regarding the mechanisms underlying the role of miRNAs in ALS pathogenesis and its application to gene therapy for ALS. The potential of miRNAs to target diverse pathways opens a new avenue for ALS therapy.

Potential Roles of the WNT Signaling Pathway in Amyotrophic Lateral Sclerosis.

The WNT signaling pathway plays an important role in the physiological and pathophysiological processes of the central nervous system and the neurodegenerative disease amyotrophic lateral sclerosis (ALS). We reviewed the literature pertinent to WNT/ß-catenin signaling in ALS from cellular studies, animal models, and human clinical trials. WNT, WNT receptors, and other components of the WNT signaling pathway are expressed in both ALS patients and transgenic mice, and are involved in the pathogenesis of ALS. Studies have shown that abnormal activation of the WNT/ß-catenin signaling pathway is related to neuronal degeneration and glial cell proliferation. WNT/Ca2+ signaling is associated with the pro-inflammatory phenotype of microglia; data on the muscle skeletal receptor Tyr kinase receptor in superoxide dismutase-1-G93A mice indicate that gene therapy is necessary for successful treatment of ALS. The varying profiles of lipoprotein receptor-related protein 4 antibodies in different ethnic groups suggest that individual treatment and multifactorial personalized approaches may be necessary for effective ALS therapy. In conclusion, the WNT signaling pathway is important to the ALS disease process, making it a likely therapeutic target.

Sapitinib Reverses Anticancer Drug Resistance in Colon Cancer Cells Overexpressing the ABCB1 Transporter.

The efficacy of anti-cancer drugs in patients can be attenuated by the development of multi-drug resistance (MDR) due to ATP-binding cassette (ABC) transporters overexpression. In this in vitro study, we determined the reversal efficacy of the epidermal growth factor receptor (EFGR) inhibitor, saptinib, in SW620 and SW720/Ad300 colon cancer cells and HEK293/ABCB1 cells which overexpress the ABCB1 transporter. Sapitinib significantly increased the efficacy of paclitaxel and doxorubicin in ABCB1 overexpressing cells without altering the expression or the subcellular location of the ABCB1 transporter. Sapitinib significantly increased the accumulation of [3H]-paclitaxel in SW620/AD300 cells probably by stimulating ATPase activity which could competitively inhibit the uptake of [3H]-paclitaxel. Furthermore, sapitinib inhibited the growth of resistant multicellular tumor spheroids (MCTS). The docking study indicated that sapitinib interacted with the efflux site of ABCB1 transporter by π-π interaction and two hydrogen bonds. In conclusion, our study suggests that sapitinib surmounts MDR mediated by ABCB1 transporter in cancer cells.