Training-Free Transformer Architecture Search With Zero-Cost Proxy Guided Evolution.

Transformers have shown remarkable performance, however, their architecture design is a time-consuming process that demands expertise and trial-and-error. Thus, it is worthwhile to investigate efficient methods for automatically searching high-performance Transformers via Transformer Architecture Search (TAS). In order to improve the search efficiency, training-free proxy based methods have been widely adopted in Neural Architecture Search (NAS). Whereas, these proxies have been found to be inadequate in generalizing well to Transformer search spaces, as confirmed by several studies and our own experiments. This paper presents an effective scheme for TAS called TRansformer Architecture search with ZerO-cost pRoxy guided evolution (T-Razor) that achieves exceptional efficiency. First, through theoretical analysis, we discover that the synaptic diversity of multi-head self-attention (MSA) and the saliency of multi-layer perceptron (MLP) are correlated with the performance of corresponding Transformers. The properties of synaptic diversity and synaptic saliency motivate us to introduce the ranks of synaptic diversity and saliency that denoted as DSS++ for evaluating and ranking Transformers. DSS++ incorporates correlation information among sampled Transformers to provide unified scores for both synaptic diversity and synaptic saliency. We then propose a block-wise evolution search guided by DSS++ to find optimal Transformers. DSS++ determines the positions for mutation and crossover, enhancing the exploration ability. Experimental results demonstrate that our T-Razor performs competitively against the state-of-the-art manually or automatically designed Transformer architectures across four popular Transformer search spaces. Significantly, T-Razor improves the searching efficiency across different Transformer search spaces, e.g., reducing required GPU days from more than 24 to less than 0.4 and outperforming existing zero-cost approaches. We also apply T-Razor to the BERT search space and find that the searched Transformers achieve competitive GLUE results on several Neural Language Processing (NLP) datasets. This work provides insights into training-free TAS, revealing the usefulness of evaluating Transformers based on the properties of their different blocks.

Clinical effects of cocktail injection on the thoracolumbar fascia injury during percutaneous vertebroplasty for osteoporotic vertebral compression fractures: a single-center, retrospective case-control study.

BACKGROUND: Nowadays, there is a lack of effective intraoperative treatment for thoracolumbar fascia injury (TFI) of osteoporotic vertebral compression fractures (OVCFs), which may lead to postoperative residual pain. We aimed to evaluate the clinical effects of cocktail injection on the TFI during percutaneous vertebroplasty (PVP) for OVCFs. METHODS: A retrospective study of OVCFs with TFI underwent PVP with cocktail injection (Cocktail group, 58 cases) or PVP (Routine group, 64 cases) was conducted. The surgical outcomes, visual analog scale (VAS) score, oswestry disability index (ODI), incidence of residual pain at 1 day and 7 days postoperatively, the rate and duration of taking painkillers during 7 days postoperatively after PVP were compared between them. RESULTS: No differences in baseline data, volume of bone cement injected and bone cement leakage were observed between the two groups, while the operation time of the routine group (44.3 ± 7.8 min) was less than that (47.5 ± 9.1 min) of the cocktail group (P < 0.05). However, the VAS scores (2.4 ± 0.8, 2.2 ± 0.7), ODI (25.2 ± 4.2, 22.3 ± 2.9), the incidence of residual pain (8.6%, 3.4%) at 1 and 7 days postoperatively, the rate (6.9%) and duration ( 2.5 ± 0.6 ) of taking painkillers during 7 days postoperatively in the cocktail group were better than those (3.4 ± 1.0, 2.9 ± 0.7, 34.1 ± 4.7, 28.6 ± 3.6, 23.4%, 15.6%, 28.1%, 4.2 ± 1.4) in the routine group (P < 0.05), respectively. CONCLUSION: PVP combined with cocktail injection increased the operation time in the treatment of OVCFs with TFI, but it can more effectively relieve pain, reduce the risk of residual pain at 1 day and 7 days postoperatively, and decrease the use and duration of taking painkillers.

Exploration of the mechanisms of Callicarpa nudiflora Hook. et Arn against influenza A virus (H1N1) infection.

BACKGROUND: In our preliminary research on screening traditional Chinese medicine extracts for anti-H1N1 activity, we discovered that the 75 % ethanol extract of Callicarpa nudiflora Hook. & Arn (C. nudiflora) exhibited promising anti-H1N1 infection activity. However, the underlying active components and mechanism of action remain to be elucidated. AIM OF THE STUDY: This experiment further explores the potential active components and mechanisms of action of C. nudiflora against H1N1. METHODS: In this study, the composition of the C. nudiflora was determined using UPLC-Q-Orbitrap-MS/MS. The inhibitory effect of C. nudiflora on H1N1 was investigated using a Madin-Darby canine kidney (MDCK) cell model infected with H1N1, and the protective effect of C. nudiflora on H1N1-infected mice was examined using a Balb/c mouse model infected with H1N1. The potential mechanisms of action were demonstrated at the mRNA and protein levels. RESULTS: A total of 21 compounds were detected in C. nudiflora, which was found to act on the replication stages of H1N1. Moreover, C. nudiflora improved the survival rate of H1N1-infected mice, enhanced the organ index, alleviated the trend of weight loss, reduced lung viral load, mitigated lung tissue damage, and regulated CD4/CD8 and Th1/Th2 immune balance. Molecular mechanism studies revealed that C. nudiflora can regulate the expression of key genes in the toll-like receptor and STAT signaling pathway. CONCLUSION: C. nudiflora can inhibit H1N1 replication. It also can exert a regulatory effect on the immune response of H1N1-infected mice, and mitigate inflammatory damage by modulating the expression of key genes in the toll-like receptor and STAT signaling pathways, indicating its potential for development as an anti-H1N1 drug.

MAT as a promising therapeutic strategy against triple-negative breast cancer via inhibiting PI3K/AKT pathway.

Triple-negative breast cancer (TNBC), a highly aggressive and heterogeneous subtype of breast cancer, lacks effective treatment options. Sophora flavescens Aiton, a Chinese medicinal plant, is often used in traditional Chinese medicine to treat cancer. Matrine (MAT) is an alkaloid extracted from Sophora flavescens. It has good anticancer effects, and thus can be explored as a new therapeutic agent in TNBC research. We performed bioinformatics analysis to analyze the differentially expressed genes between normal breast tissues and TNBC tissues, and comprehensive network pharmacology analyses. The activity and invasion ability of TNBC cells treated with MAT were analyzed. Apoptosis and cell cycle progression were determined using cytometry. We used Monodansylcadaverine (MDC) staining to determine the condition of autophagosomes. Finally, the expression levels of the key target proteins of the PI3K/AKT pathway were determined using western blotting. The proliferation and invasion ability of MDA-MB-231 and MDA-MB-468 can be effectively inhibited by MAT. The results of flow cytometry indicated that MAT arrested the TNBC cell cycle and induced apoptosis. In addition, we confirmed that MAT inhibited the expression of BCL-2 while up-regulating the expression of cleaved caspase-3. Moreover, enhanced intensity of MDC staining and high LC3-II expression were observed, which confirmed that MAT induced autophagy in TNBC cells. Western blotting showed that MAT inhibited the PI3K/AKT pathway and downregulated the expressions of PI3K, AKT, p-AKT, and PGK1. This study provides feasible methods, which include bioinformatics analysis and in vitro experiments, for the identification of compounds with anti-TNBC properties. MAT inhibited the PI3K/AKT signaling pathway, arrested cell cycle, as well as promoted cell apoptosis and autophagy. These experiments provide evidence for the anti-TNBC effect of MAT and identified potential targets against TNBC.

Comparison of Wiltse Approach of Pedicle Screw Fixation With or Without Vertebroplasty in the Treatment of Genant III Degree Osteoporotic Thoracolumbar Fractures: Analysis of Clinical Findings, Radiographic Parameters, and Follow-Up Complications.

STUDY DESIGN: A retrospective case-control study. OBJECTIVE: This study aimed to compare the effects of the Wiltse approach of pedicle screw fixation (PSF) either in combination with or without vertebroplasty (VP) in the treatment of Genant III degree osteoporotic thoracolumbar fractures (Genant III-OTLFs). METHODS: A retrospective study of Genant III-OTLFs was performed from January 2018 to December 2019, including 54 cases of PSF + VP and 56 cases of PSF. Clinical indicators [visual analog scale (VAS) score, Oswestry disability index (ODI)], radiographic parameters [local kyphosis angle (LKA), percentage of anterior, central, and posterior vertebral heights (AVH%, CVH%, and PVH%, respectively)] and follow-up complications [adjacent vertebral fracture (AVF), residual pain (RP), vertebral height loss (VHL), and internal fixation failure (IFF)] were compared between the 2 groups. RESULTS: No differences in surgical outcomes, clinical indicators, and radiographic parameters were observed between the 2 groups during the preoperation period and 7 days post-operatively (P > .05). However, the VAS score [2.0 (.6), 1.9 (.5)], ODI [23.7 (4.0), 22.6 (3.0)], LKA [9.5 (1.8), 10.6 (3.0)], AVH% [90.1 (2.7), 87.7 (6.0)], CVH% [92.5 (2.6), 91.3 (3.7)], and PVH% [93.4 (2.0), 92.7 (2.4)] at 1 year post-operatively and last follow-up of the PSF + VP group were better than those of the PSF group [2.5 (.8), 3.1 (1.1), 26.6 (3.8), 29.6 (4.6), 12.2 (1.6), 16.6 (3.2), 84.9 (4.0), 69.9 (6.6), 88.1 (3.1), 78.2 (5.1), 89.7 (2.3), 84.8 (4.6)], respectively (P < .001). During follow-up, the incidence of AVF had no difference (P > .05), while that of RP (32.1 vs 14.8%), VHL (33.9 vs 9.3%) and IFF (17.9 vs 5.6%) had statistical differences between them (P < .05). CONCLUSION: The Wiltse approach of PSF combined with VP for Genant III-OTLFs can not only effectively relieve pain, restore vertebral height, and correcte kyphosis, but also better maintain vertebral height, delay kyphosis progression, and reduce complications during follow-up.

Hierarchical Poly(3,4-ethylenedioxythiophene):Poly(styrenesulfonate)/Reduced graphene oxide/Polypyrrole hybrid electrode with excellent rate capability and cycling stability for fiber-shaped supercapacitor.

Fiber-shaped supercapacitor (FSSC) is considered as a promising energy storage device for wearable electronics due to its high power density and outstanding safety. However, it is still a great challenge to simultaneously achieve high specific capacitance especially at rapid charging/discharging rate and long-term cycling stability of fiber electrode in FSSC for practical application. Here, a ternary poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate)/reduced graphene oxide/polypyrrole (PEDOT:PSS/rGO/PPy) fiber electrode was constructed by in situ chemical polymerization of pyrrole on hydrothermally-assembled and acid-treated PEDOT:PSS/rGO (PG) hybrid hydrogel fiber. In this case, the porous PG hybrid fiber framework possesses combined advantages of highly-conductive PEDOT and flexible two-dimensional (2D) small-sized rGO sheets, which provides large surface area for the deposition of high-pseudocapacitance PPy, multiscale electrons/ions transport channels for the efficient utilization of active sites, and buffering layers to accommodate the structure change during electrochemical process. Attributed to the synergy, as-obtained ternary fiber electrode presents ultrahigh volumetric/areal specific capacitance (389 F cm-3 at 1 A cm-3 or 983 mF cm-2 at 2.5 mA cm-2) and outstanding rate performance (56 %, 1-20 A cm-3). In addition, 80 % preservation of initial capacitance after 8000 cycles for the corresponding FSSC also illustrates its greatly improved cycle stability compared with 64 % of binary PEDOT:PSS/PPy based counterpart. Accordingly, here proposed strategy promises a new opportunity to develop high-activity and durable electrode materials with potential applications in supercapacitor and beyond.

Application of the NanoString nCounter System as an Alternative Method to Investigate Molecular Mechanisms Involved in Host Plant Responses to Plasmodiophora brassicae.

Clubroot, caused by the soilborne pathogen Plasmodiophora brassicae, is an important disease of canola (Brassica napus) and other crucifers. The recent application of RNA sequencing (RNA-seq) technologies to study P. brassicae−host interactions has generated large amounts of gene expression data, improving knowledge of the molecular mechanisms of pathogenesis and host resistance. Quantitative PCR (qPCR) analysis has been widely applied to examine the expression of a limited number of genes and to validate the results of RNA-seq studies, but may not be ideal for analyzing larger suites of target genes or increased sample numbers. Moreover, the need for intermediate steps such as cDNA synthesis may introduce variability that could affect the accuracy of the data generated by qPCR. Here, we report the validation of gene expression data from a previous RNA-seq study of clubroot using the NanoString nCounter System, which achieves efficient gene expression quantification in a fast and simple manner. We first confirm the robustness of the NanoString system by comparing the results with those generated by qPCR and RNA-seq and then discuss the importance of some candidate genes for resistance or susceptibility to P. brassicae in the host. The results show that the expression of genes measured using NanoString have a high correlation with the values obtained using the other two technologies, with R > 0.90 and p < 0.01, and the same expression patterns for most genes. The three methods (qPCR, RNA-seq, and NanoString) were also compared in terms of laboratory procedures, time, and cost. We propose that the NanoString nCounter System is a robust, sensitive, highly reproducible, and simple technology for gene expression analysis. NanoString could become a common alternative to qPCR to validate RNA-seq data or to create panels of genes for use as markers of resistance/susceptibility when plants are challenged with different P. brassicae pathotypes.

Identification of Arabidopsis Phospholipase A Mutants With Increased Susceptibility to Plasmodiophora brassicae.

Clubroot, caused by the obligate parasite Plasmodiophora brassicae, is one of the most devastating diseases of canola (Brassica napus) in Canada. The identification of novel genes that contribute to clubroot resistance is important for the sustainable management of clubroot, as these genes may be used in the development of resistant canola cultivars. Phospholipase As (PLAs) play important roles in plant defense signaling and stress tolerance, and thus are attractive targets for crop breeding. However, since canola is an allopolyploid and has multiple copies of each PLA gene, it is time-consuming to test the functions of PLAs directly in this crop. In contrast, the model plant Arabidopsis thaliana has a simpler genetic background and only one copy of each PLA. Therefore, it would be reasonable and faster to validate the potential utility of PLA genes in Arabidopsis first. In this study, we identified seven homozygous atpla knockout/knockdown mutants of Arabidopsis, and tested their performance following inoculation with P. brassicae. Four mutants (pla1-iiα, pla1-iγ3, pla1-iii, ppla-iiiß, ppla-iiiδ) developed more severe clubroot than the wild-type, suggesting increased susceptibility to P. brassicae. The homologs of these Arabidopsis PLAs (AtPLAs) in B. napus (BnPLAs) were identified through Blast searches and phylogenic analysis. Expression of the BnPLAs was subsequently examined in transcriptomic datasets generated from canola infected by P. brassicae, and promising candidates for further characterization identified.

Efficient Recycling Blast Furnace Slag by Constructing Ti-Embedded Layered Double Hydroxide as Visible-Light-Driven Photocatalyst.

In this work, a strategy of heat treatment-precipitation has been developed to recycle Ti-containing metallurgical solid waste by forming Ti-embedded MgAl layered double hydroxide (TMA-LDH). This facile and simple route is featured by the dedicated utilization of the composition of slag with high overall recovery efficiency. Importantly, as-obtained product exhibits visible light response distinctly different from that of pristine MA-LDH ascribed to the Fe doping inherited from initial slag. Its mesoporous nanostructure also provides more microchannels for mass and carrier transfer. As such, excellent photocatalytic activity towards degradation of tetracycline hydrochloride is achieved, and 88% removal could be obtained in 60 min. Furthermore, 44% increase in efficiency than that of Ti-excluded LDH also indicates the synergistically promoting effect of Ti incorporation. Mechanism investigation suggests that Ti incorporation regulates the electronic structure of pristine LDH with more active sites, and favors the formation of radicals with improved oxidative ability for photocatalysis.

Attention-Based Neural Architecture Search for Person Re-Identification.

Recent years have witnessed significant progress of person reidentification (reID) driven by expert-designed deep neural network architectures. Despite the remarkable success, such architectures often suffer from high model complexity and time-consuming pretraining process, as well as the mismatches between the image classification-driven backbones and the reID task. To address these issues, we introduce neural architecture search (NAS) into automatically designing person reID backbones, i.e., reID-NAS, which is achieved via automatically searching attention-based network architectures from scratch. Different from traditional NAS approaches that originated for image classification, we design a reID-based search space as well as a search objective to fit NAS for the reID tasks. In terms of the search space, reID-NAS includes a lightweight attention module to precisely locate arbitrary pedestrian bounding boxes, which is automatically added as attention to the reID architectures. In terms of the search objective, reID-NAS introduces a new retrieval objective to search and train reID architectures from scratch. Finally, we propose a hybrid optimization strategy to improve the search stability in reID-NAS. In our experiments, we validate the effectiveness of different parts in reID-NAS, and show that the architecture searched by reID-NAS achieves a new state of the art, with one order of magnitude fewer parameters on three-person reID datasets. As a concomitant benefit, the reliance on the pretraining process is vastly reduced by reID-NAS, which facilitates one to directly search and train a lightweight reID model from scratch.

Maternal serum-derived exosomal lactoferrin as a marker in detecting and predicting ventricular septal defect in fetuses.

Among different types of congenital heart diseases, ventricular septal defect is the most frequently diagnosed type and is frequently missed in early prenatal screening programs. Herein, we explored the role of maternal serum-derived exosomes in detecting and predicting ventricular septal defect in fetuses in the early stage of pregnancy. A total of 104 pregnant women consisting of 52 ventricular septal defect cases and 52 healthy controls were recruited. TMT/iTRAQ proteomic analysis uncovered 15 maternal serum exosomal proteins, which showed differential expression between ventricular septal defect and control groups. Among these, four down-regulated proteins, lactoferrin, SBSN, DCD, and MBD3, were validated by Western blot. The protein lactoferrin was additionally verified by ELISA which was able to distinguish ventricular septal defects from controls with area under the ROC curve (AUC) 0.804 (p < 0.001). Our findings reveal that lactoferrin in maternal serum-derived exosomes may be a potential biomarker for non-invasive prenatal diagnosis of fetal ventricular septal defects.

Boosting the efficiency and stability of CoMoS4 by N incorporation for electrocatalytic hydrogen evolution.

Here, an in situ N incorporation method was developed to boost the efficiency and durability of CoMoS4 electrocatalyst for hydrogen evolution. Theoretical and experimental results reveal that such modification not only reduces the energy barrier of H* desorption by decreasing the electron densities around active metal sites, but also decreases the leaching rates of the metal ions with enhanced stability.

Comparative Transcriptome Analysis of Rutabaga (Brassica napus) Cultivars Indicates Activation of Salicylic Acid and Ethylene-Mediated Defenses in Response to Plasmodiophora brassicae.

Clubroot, caused by Plasmodiophora brassicae Woronin, is an important soilborne disease of Brassica napus L. and other crucifers. To improve understanding of the mechanisms of resistance and pathogenesis in the clubroot pathosystem, the rutabaga (B. napus subsp. rapifera Metzg) cultivars 'Wilhelmsburger' (resistant) and 'Laurentian' (susceptible) were inoculated with P. brassicae pathotype 3A and their transcriptomes were analyzed at 7, 14, and 21 days after inoculation (dai) by RNA sequencing (RNA-seq). Thousands of transcripts with significant changes in expression were identified in each host at each time-point in inoculated vs. non-inoculated plants. Molecular responses at 7 and 14 dai supported clear differences in the clubroot response mechanisms of the two genotypes. Both the resistant and the susceptible cultivars activated receptor-like protein (RLP) genes, resistance (R) genes, and genes involved in salicylic acid (SA) signaling as clubroot defense mechanisms. In addition, genes related to calcium signaling and genes encoding leucine-rich repeat (LRR) receptor kinases, the respiratory burst oxidase homolog (RBOH) protein, and transcription factors such as WRKYs, ethylene responsive factors, and basic leucine zippers (bZIPs), appeared to be upregulated in 'Wilhelmsburger' to restrict P. brassicae development. Some of these genes are essential components of molecular defenses, including ethylene (ET) signaling and the oxidative burst. Our study highlights the importance of activation of genes associated with SA- and ET-mediated responses in the resistant cultivar. A set of candidate genes showing contrasting patterns of expression between the resistant and susceptible cultivars was identified and includes potential targets for further study and validation through approaches such as gene editing.

The Therapeutic Potential of Small Activating RNAs for Colorectal Carcinoma.

Small double-strand RNAs have been recognized as master regulators of gene expression. In contrast to the evolutionary conserved RNA interference machinery, which degrades or inhibits the translation of target mRNAs, small activating RNA (saRNA) activates the specific gene in a target dependent manner through a similar mechanism as RNAi. Recently, saRNA mediated expression regulation of specific genes has been extensively studied in cancer researches. Of particular interest is the application of the RNA mediated gene activation within colorectal cancer (CRC) development, due to the high incidence of the CRC. In this review, we summarize the current knowledge of saRNA mediated genetic activation and its underlying mechanisms. Furthermore, we highlight the advantages of the utilization of saRNAs induced gene expression as an investigating tool in colorectal cancer research. Finally, the possibility and the challenge of the saRNA application as a potential therapy for colorectal cancer are addressed.

Cordyceps militaris fraction inhibits the invasion and metastasis of lung cancer cells through the protein kinase B/glycogen synthase kinase 3ß/ß-catenin signaling pathway.

Cordyceps militaris is widely used as a traditional Chinese medicine health supplement, and is also used in the development of anticancer agents. In our previous studies, it was revealed that C. militaris fraction (CMF) possessed an antitumor effect against K562 cells in vitro, induced apoptosis and caused cell cycle arrest in the S phase. The published results also demonstrated that CMF-induced apoptosis was involved in mitochondrial dysfunction. The aim of the present study was to investigate the anti-invasion and anti-metastasis effects of CMF in NCI-H1299 and Lewis lung cancer (LLC) cell lines, which have high metastatic potential. MTT and clone formation assays were initially used to investigate the inhibitory effect of CMF on the viability of NCI-H1299 and LLC cells. The results of cell adhesion, wound healing, migration and Matrigel invasion assays in vitro indicated that NCI-H1299 cells (treated with 1, 3, 10 or 30 µg/ml CMF) and LLC cells (treated with 0.1, 0.3, 1 or 3 µg/ml CMF) demonstrated a concentration-dependent reduction in cell migration and invasion compared with the control. In vivo experiments demonstrated that the oral administration of CMF (65, 130 or 260 mg/kg) decreased the tumor growth and decreased the lung and liver metastasis in an LLC xenograft model, compared with untreated mice. Furthermore, western blot analysis was used to investigate the mechanism of the effect of CMF on the migration of NCI-H1299 cells and metastasis in the xenograft model. The results revealed that CMF may promote glycogen synthase kinase 3ß (GSK-3ß)-mediated degradation of ß-catenin inhibited the phosphorylation of upstream protein kinase B (Akt), which resulted in the attenuation of the expression of matrix metalloproteinase (MMP)-2 and MMP-9. These results suggested that CMF may possess potential for the treatment of lung cancer metastasis via the Akt/GSK-3ß/ß-catenin pathway.

The role of Cdk5-mediated Drp1 phosphorylation in Aß1-42 induced mitochondrial fission and neuronal apoptosis.

Alzheimer's disease, one of the most common neurodegenerative diseases, is pathologically characterized by Amyloid beta containing plaques and neurofibrillary tangles. Amyloid beta (Aß) induces neuronal apoptosis through the intracellular Ca2+ increase, subsequent hyperactivation of cyclin-dependent kinase 5 (Cdk5) and mitochondrial abnormality. Recently, Cdk5 was identified as an upstream regulator of mitochondrial fission during neuronal apoptosis, but the underlying mechanism remains unclear. Here, in vitro phosphorylation assays showed that Cdk5 could phosphorylate the recombinant Drp1 at Serine 579. Aß1-42 stimulation increased the phosphorylation level of Drp1 at Serine 579 in mouse cortical neurons. Cdk5 inhibitor roscovitine and knockdown of Cdk5 by a lentiviral vector expressing shRNA targeting Cdk5 (Lenti-Cdk5-shRNA) efficiently prevented Aß1-42 induced Drp1 phosphorylation in neurons. In addition, Aß1-42 stimulation induced markedly mitochondrial fission in neurons. Roscovitine, Lenti-Cdk5-shRNA and expression of phospho-defect mutatant GFP-Drp1-S579A in neurons attenuated Aß1-42 induced mitochondrial fission, whereas expression of phospho-mimetic mutant GFP-Drp1-S579D alone resulted in mitochondiral fission similar to Aß1-42 stimulation. Moreover, Roscovitine and Lenti-Cdk5-shRNA suppressed the cleavage of caspase-3 and protected neurons against Aß1-42 induced neuronal apoptosis.Thus, our data indicate that Drp1 is a direct target of Cdk5, and Cdk5-mediated phosphorylation of Drp1 at Serine 579 regulates Aß1-42 induced mitochondrial fission and neuronal toxicity.

Activation of KLF4 expression by small activating RNA promotes migration and invasion in colorectal epithelial cells.

RNA activation mediated by small double-stranded RNAs targeting promoter sequence named small activating RNAs (saRNAs) is one of the mechanisms for gene activation. Artificial regulation of gene expression through RNA activation does not affect the alteration of the genomic DNA sequences or exogenous plasmid DNA, therefore it is a relative manageable approach for gene perturbation. KLF4 is a member of zinc-finger transcription factors and its functions in colorectal cells are still controversial. In order to elucidate the functions of KLF4, we synthesized saRNAs that target the promoter regions of KLF4 and transfected into varied colorectal epithelial cell lines. We found the KLF4 gene expression is specifically increased in the human normal epithelial cell NCM460 and colorectal epithelial cancer cell Caco-2 and HCT116, but not in other human colorectal epithelial cell lines. In addition, we observed that saRNAs induced overexpression of KLF4 could promote cell migration/invasion in NCM460 and HCT116 cell lines. This effect is mediated partly by inducing EMT and facilitating nuclear translocation of ß-catenin.

Structural elucidation and immunostimulatory activity of a new polysaccharide from Cordyceps militaris.

A new polysaccharide (CMPB90-1) was isolated from cultured Cordyceps militaris by alkaline extraction. The chemical structure of CMPB90-1 was determined by analysis of physicochemical and spectral data. The backbone of CMPB90-1 is composed of (1→6)-linked α-d-glucopyranosyl and (1→3)-linked α-d-glucopyranosyl residues, with branching at O-6, which consists of (1→4)-linked ß-d-mannopyranosyl and (1→6)-linked α-d-glucopyranosyl residues, respectively. ß-d-Galactopyranosyl residues is the terminal unit. In vitro immunomodulatory assay revealed that CMPB90-1 promoted proliferation of splenic lymphocytes, enhanced cytotoxicity of NK cells and promoted lymphocyte secretion of the cytokine interleukin-2. Besides, CMPB90-1 upregulated T-cell subpopulation, strengthened phagocytosis function of macrophages and induced their M1 polarization. The mechanism of the effects might be due to the activation of TLR2, MAPK and NF-κB pathways. The results proposed that CMPB90-1 can be researched and developed as a new functional food.

A small graphene oxide sheet/polyvinylidene fluoride bilayer actuator with large and rapid responses to multiple stimuli.

A high-performance actuator should be able to deliver large-shape deformations, fast actuations and sensitive responses to multiple stimuli. Here, we report such an actuator constructed from one layer of polyvinylidene fluoride (PVDF) with a high coefficient of thermal expansion (CTE), and another layer of small sheets of graphene oxide (SGO) with a negative CTE. The opposite deformations of both actuation layers make the SGO/PVDF bilayer actuator highly sensitive to the temperature stimulus with a large bending sensitivity of 1.5 cm-1 °C-1. Upon irradiation with 60 mW cm-2 infrared light, this SGO/PVDF bilayer actuator displayed an extremely rapid tip displacement rate of 140 mm s-1. Furthermore, this actuator can also sensitively respond to moisture because of its SGO layer, showing a curvature change from -22 to 13 cm-1 upon changing the relative humidity (RH) from 11% to 86%. This actuator can generate a contractile or relaxed stress 18 times that of mammalian skeletal muscle, under light irradiation or moisture with a response time as short as 1 s, being capable of lifting an object with a weight 80 times that of itself. Furthermore, it also showed excellent stability and repeatability.

An optimized two-vial formulation lipid nanoemulsion of paclitaxel for targeted delivery to tumor.

The discovery of new intravenous drug delivery carrier for water-insoluble drug is a challenging task. In this paper, novel two-vial formulation of paclitaxel (PTX)-loaded lipid nanoemulsions (TPLEs) with particle sizes of 110nm (TPLE-1), 220nm (TPLE-2) and 380nm (TPLE-3), which were formed by mixing a PEG400 solution of PTX and 10% (w/w) blank lipid emulsions (BLEs) with different particle size prior to use, were developed and comparatively evaluated for their pharmaceutics, pharmacokinetics, biodistribution, in vitro and in vivo anticancer efficiency. Among them, TPLE-1 displayed higher PTX-loading, slower PTX-release and larger PTX-distribution in oil-phase, significantly reduced extraction by RES organs, increased tumor-uptake, showed stronger cytotoxicity against MCF-7 cells and more potent anticancer efficacy on MCF-7 tumor-bearing nude mice, and had greater plasma AUC0-∞ value, smaller plasma clearance (CL), longer mean residence time (MRT) and elimination half-life (T1/2) in SD rats. It also exhibited the same in vivo efficacy as Taxol® and even produced less hemolysis and intravenous irritation. Moreover, its LD50 was 4.3-fold higher than that of Taxol®. All results demonstrate that TPLE-1 is a promising candidate drug due to its high tumor-accumulation and effectiveness, low toxicity, good safety and druggability in clinical application for the cancer therapy.