Search

Abstract The current first-line treatment for repairing cartilage defects in clinical practice is the creation of microfractures (MF) to stimulate the release of mesenchymal stem cells (MSCs); however, this method has many limitations. Recent studies have found that MSC-derived extracellular vesicles (MSC-EVs) play an important role in tissue regeneration. This study aimed to verify whether MSC-EVs promote cartilage damage repair mediated by MFs and to explore the repair mechanisms. In vitro experiments showed that human umbilical cord Wharton’s jelly MSC-EVs (hWJMSC-EVs) promoted the vitality of chondrocytes and the proliferation and differentiation ability of bone marrow-derived MSCs. This was mainly because hWJMSC-EVs carry integrin beta-1 (ITGB1), and cartilage and bone marrow-derived MSCs overexpress ITGB1 after absorbing EVs, thereby activating the transforming growth factor-β/Smad2/3 axis. In a rabbit knee joint model of osteochondral defect repair, the injection of different concentrations of hWJMSC-EVs into the joint cavity showed that a concentration of 50 µg/ml significantly improved the formation of transparent cartilage after MF surgery. Extraction of regenerated cartilage revealed that the changes in ITGB1, transforming growth factor-β, and Smad2/3 were directly proportional to the repair of regenerated cartilage. In summary, this study showed that hWJMSC-EVs promoted cartilage repair after MF surgery. Graphical abstract

Abstract Background RNA pseudouridylation is a critical post‐transcriptional modification that influences gene expression and impacts various biological functions. Despite its significance, the role of mRNA pseudouridylation in cancer remains poorly understood. This study investigates the impact of pseudouridine synthase 7 (PUS7)‐mediated pseudouridylation of Alpha‐ketoglutarate‐dependent Dioxygenase alkB Homolog 3 (ALKBH3) mRNA in gastric cancer. Methods Immunohistochemistry and Western blotting were used to assess PUS7 protein levels in human gastric cancer tissues. The relationship between PUS7 and gastric cancer progression was examined using 3D colony formation assays and subcutaneous xenograft models. Real‐time quantitative PCR (RT‐qPCR), Western blotting, and polysome profiling assays were conducted to investigate how PUS7 regulates ALKBH3. A locus‐specific pseudouridine (Ψ) detection assay was used to identify Ψ sites on ALKBH3 mRNA. Results Our findings indicate a significant reduction of PUS7 in gastric cancer tissues compared to adjacent non‐tumour tissues. Functional analyses reveal that PUS7 inhibits gastric cancer cell proliferation and tumour growth via its catalytic activity. Additionally, PUS7 enhances the translation efficiency of ALKBH3 mRNA by modifying the U696 site with pseudouridine, thereby attenuating tumour growth. Importantly, ALKBH3 functions as a tumour suppressor in gastric cancer, with its expression closely correlated with PUS7 levels in tumour tissues. Conclusions PUS7‐dependent pseudouridylation of ALKBH3 mRNA enhances its translation, thereby suppressing gastric cancer progression. These findings highlight the potential significance of mRNA pseudouridylation in cancer biology and suggest a therapeutic target for gastric cancer. Highlights PUS7 enhances the translation efficiency of ALKBH3 through its pseudouridylation activity on ALKBH3 mRNA, thereby inhibiting gastric tumourigenesis. The expression levels of PUS7 and ALKBH3 are significantly correlated in gastric tumours, which may be potential prognostic predictors and therapeutic targets for patients with gastric cancer.

Abstract Background Osteochondral injury is a common sports injury, and hyaline cartilage does not regenerate spontaneously when injured. However, there is currently no gold standard for treating osteochondral defects. Osteochondral autograft transplantation (OAT) is widely used in clinical practice and is best used to treat small osteochondral lesions in the knee that are 0.05). Conclusions In a porcine model, ADTT and OAT are both effective treatments for osteochondral defects in weight bearing areas. ADTT may be useful as an alternative procedure to OAT for treating osteochondral defects.

Abstract Colon-targeted oral drug delivery systems (CDDSs) are desirable for the treatment of ulcerative colitis (UC), which is a disease with high relapse and remission rates associated with immune system inflammation and dysregulation localized within the lining of the large bowel. However, the success of current available approaches used for colon-targeted therapy is limited. Budesonide (BUD) is a corticosteroid drug, and its rectal and oral formulations are used to treat UC, but the inconvenience of rectal administration and the systemic toxicity of oral administration restrict its long-term use. In this study, we designed and prepared colon-targeted solid lipid nanoparticles (SLNs) encapsulating BUD to treat UC by oral administration. A negatively charged surfactant (NaCS-C12) was synthesized to anchor cellulase-responsive layers consisting of polyelectrolyte complexes (PECs) formed by negatively charged NaCS and cationic chitosan onto the SLNs. The release rate and colon-specific release behavior of BUD could be easily modified by regulating the number of coated layers. We found that the two-layer BUD-loaded SLNs (SLN-BUD-2L) with a nanoscale particle size and negative zeta potential showed the designed colon-specific drug release profile in response to localized high cellulase activity. In addition, SLN-BUD-2L exhibited excellent anti-inflammatory activity in a dextran sulfate sodium (DSS)-induced colitis mouse model, suggesting its potential anti-UC applications.

Gastric cancer: Gene shutdown helps spread to the liver Reduced activity of a key cell control gene mediates an interaction between gastric cancer cells and immune system cells called macrophages that allows the cancer to spread to the liver. Cancer cells migrating to the liver is a major cause of death for gastric cancer patients, but the mechanisms driving this process have been unclear. Researchers in China led by Tianhua Zhou and Wei Zhuo at Zhejiang University School of Medicine, Hangzhou, studied the activity of genes and their corresponding proteins in patients’ cancer cells, and analyzed gene activity in mouse models of gastric cancer. They found that the gene that generates a protein called MAPK4 is significantly reduced in the cancer cells. This allows the cells to interact with macrophages, promoting their spread to the liver.

Extended circulation of anticancer nanodrugs in blood stream is essential for their clinical applications. However, administered nanoparticles are rapidly sequestered and cleared by cells of the mononuclear phagocyte system (MPS). In this study, we developed a biomimetic nanosystem that is able to efficiently escape MPS and target tumor tissues. The fabricated nanoparticles (TM-CQ/NPs) were coated with fibroblast cell membrane expressing tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL). Coating with this functionalized membrane reduced the endocytosis of nanoparticles by macrophages, but increased the nanoparticle uptake in tumor cells. Importantly, this membrane coating specifically induced tumor cell apoptosis via the interaction of TRAIL and its cognate death receptors. Meanwhile, the encapsulated chloroquine (CQ) further suppressed the uptake of nanoparticles by macrophages, and synergized with TRAIL to induce tumor cell apoptosis. The vigorous antitumor efficacy in two mice tumor models confirmed our nanosystem was an effective approach to address the MPS challenge for cancer therapy. Together, our TM-CQ/NPs nanosystem provides a feasible approach to precisely target tumor tissues and improve anticancer efficacy.

Cancer cells exploit immune checkpoint pathways, such as PD-1/PD-L1, to evade elimination by the immune system. Here, the authors demonstrate that TMUB1 regulates post-translational modifications of PD-L1 and that targeting the TMUB1/PD-L1 interaction promotes anti-tumour T cells responses

This study identifies the evolutionarily conserved Exportin 4 as an essential regulator in the nuclear export of circRNAs. Defective circRNA export results in R-loop formation and DNA damage in cells, as well as testis and neurological defects in mice.

Developing heterogeneous catalysts with identifiable catalytic sites provides opportunities to explore their structure–activity relationship. Covalent organic framework (COF) represents an emerging class of porous materials that have exhibited great potential in various applications. Herein, a single‐site heterogeneous photocatalyst consisting of 2D COF ultrathin nanobelts coordinated with single Cu–O/N sites (defined as Cu–COF) is synthesized and investigated for visible‐light‐driven CO2 reduction. The relatively weak N and O binding sites from the imine and methoxy groups of the organic linkers result in active Cu–O/N sites for charge transfer and CO2 reduction. The resultant Cu–COF with 0.2 wt% Cu only serves as a bifunctional photocatalyst for visible‐light‐driven CO2 reduction in the absence of a photosensitizer with triethanolamine as the sacrificial reagent. A high CO selectivity of 94% is obtained. This study further demonstrates the great potential of COFs in heterogeneous catalysis with the abundant choices of functional groups in the organic linkers.

Abstract PCIF1 (phosphorylated CTD interacting factor 1) is the first reported RNA N6,2′-O-dimethyladenosine (m6Am) methyltransferase. However, the pathological significance of PCIF1 and m6Am modification remains unknown. Here we find that both PCIF1 expression and m6Am modification are significantly elevated in gastric cancer tissues. Increased PCIF1 is associated with gastric cancer progression, and predicts poor prognosis. Silence of PCIF1 inhibits the proliferation and invasion of gastric cancer cells, and suppresses tumor growth and metastasis in mouse model. m6Am-seq analysis reveals TM9SF1 (transmembrane 9 superfamily member 1) as a target of PCIF1. PCIF1 modifies TM9SF1 mRNA with m6Am leading to decreased TM9SF1 translation. TM9SF1 reverses the effects of PCIF1 on gastric cancer cell aggressiveness. Collectively, our work uncovers an oncogenic function of PCIF1, providing insights into the critical role of m6Am modification in cancer progression.

Fusobacterium nucleatum contributes to host epitranscriptomic modifications and colorectal cancer (CRC) development. Here, the authors show that Fusobacterium nucleatum reduces global m6A modifications to promote CRC metastasis through a YAP/FOXD3/METTL3/KIF26B axis.

Abstract Primary cilia are antenna-like subcellular structures to act as signaling platforms to regulate many cellular processes and embryonic development. m1A RNA modification plays key roles in RNA metabolism and gene expression; however, the physiological function of m1A modification remains largely unknown. Here we find that the m1A demethylase ALKBH3 significantly inhibits ciliogenesis in mammalian cells by its demethylation activity. Mechanistically, ALKBH3 removes m1A sites on mRNA of Aurora A, a master suppressor of ciliogenesis. Depletion of ALKBH3 enhances Aurora A mRNA decay and inhibits its translation. Moreover, alkbh3 morphants exhibit ciliary defects, including curved body, pericardial edema, abnormal otoliths, and dilation in pronephric ducts in zebrafish embryos, which are significantly rescued by wild-type alkbh3, but not by its catalytically inactive mutant. The ciliary defects caused by ALKBH3 depletion in both vertebrate cells and embryos are also significantly reversed by ectopic expression of Aurora A mRNA. Together, our data indicate that ALKBH3-dependent m1A demethylation has a crucial role in the regulation of Aurora A mRNA, which is essential for ciliogenesis and cilia-associated developmental events in vertebrates.

Alpha-fetoprotein producing gastric carcinomas (AFPGC) are rare and aggressive. Here, the authors profile AFPGC tumours using whole exome sequencing, and find amplifications in CCNE1 and ERBB2 that are associated with poor outcomes but are potential therapeutic targets, as shown in patient-derived xenografts.

Summary: The lacquer tree (Toxicodendron vernicifluum (Stokes) F.A. Barkley) is an important tree with economic, industrial, and medicinal values. Here, we generated the reference genome of T. vernicifluum at the chromosome level with 491.93 Mb in size, in which 98.26% of the assembled contigs were anchored onto 15 pseudochromosomes with the scaffold N50 of 32.97 Mb. Comparative genomic analysis revealed the gene families related to urushiol biosynthesis were expanded, contributing to the ecological fitness and biological adaptability of the lacquer tree. We combined multi-omics data to identify genes that encode key enzymes in the T. vernicifluum urushiol and lignin biosynthetic pathways. Furthermore, the unique active metabolites, such as butin and fisetin, in cultivar lacquers were identified by metabolism profiling. Our work would provide crucial insights into metabolite synthesis such as urushiol and lignin, meanwhile offer a basis for further exploration of the cultivation and breeding of T. vernicifluum and other Anacardiaceae members.

The complete chloroplast (cp) genome of Corydalis fangshanensis W.T. Wang ex S.Y. He, a Chinese endemic plant with limestone-specific distribution was first reported. The cp genome was circular in structure and 192,554 bp in length, consisting of a large single copy region (LSC, 98,393 bp), two inverted repeat regions (IRs, 42,263 bp), and a small single copy region (SSC, 9,635 bp). The overall GC content of the genome was 40.26%. It encoded 112 unique genes, including 78 protein-coding genes, 30 tRNA genes, and 4 rRNA genes. Phylogenetic analysis resolved C. fangshanensis was closely related to C. saxicola G.S. Bunting within Corydalis sect. Thalictrifoliae (Fedde) Lidén, in line with morphological character-based taxonomy. Our result provides informative data for studying the taxonomy, phylogeny and ecology of Corydalis, especially species with specific-limestone distribution and also for studying the adaptive evolution in plants.

Abstract RNA methylation has emerged as a fundamental process in epigenetic regulation. Accumulating evidences indicate that RNA methylation is essential for many biological functions, and its dysregulation is associated with human cancer progression, particularly in gastrointestinal cancers. RNA methylation has a variety of biological properties, including N6-methyladenosine (m6A), 2-O-dimethyladenosine (m6Am), N1-methyladenosine (m1A), 5-methylcytosine (m5C) and 7-methyl guanosine (m7G). Dynamic and reversible methylation on RNA is mediated by RNA modifying proteins called “writers” (methyltransferases) and “erasers” (demethylases). “Readers” (modified RNA binding proteins) recognize and bind to RNA methylation sites, which influence the splicing, stability or translation of modified RNAs. Herein, we summarize the biological functions and mechanisms of these well-known RNA methylations, especially focusing on the roles of m6A in gastrointestinal cancer development.

Patients with metastatic gastric cancer (GC) have a poor prognosis; however, the molecular mechanism of GC metastasis remains unclear. Here, we employed bioinformatics to systematically screen the metastasis‐associated genes and found that the levels of basal cell adhesion molecule (BCAM) were significantly increased in GC tissues from patients with metastasis, as compared to those without metastasis. The upregulation of BCAM was also significantly associated with a shorter survival time. Depletion of BCAM inhibited GC cell migration and invasion. Knockout (KO) of BCAM by the CRISPR/Cas9 system reduced the invasion and metastasis of GC cells. To explore the mechanism of BCAM upregulation, we identified a previously uncharacterized BCAM sense lncRNA that spanned from exon 6 to intron 6 of BCAM, and named it as BCAM‐associated long noncoding RNA (BAN). Knockdown of BAN inhibited BCAM expression at both mRNA and protein levels. Knockdown of BAN suppressed GC cell migration and invasion, which was effectively rescued by ectopic expression of BCAM. Further clinical data showed that BAN upregulation was associated with GC metastasis and poor prognosis. Importantly, BAN expression was also significantly associated with that of BCAM in GC tissues. Taken together, these results indicate that increased expression of BCAM and its sense lncRNA BAN promote GC cell invasion and metastasis, and are associated with poor prognosis of GC patients.

The autophagy receptor p62 mediates the assembly and removal of ubiquitylated protein aggregates by forming p62 bodies. Here, the authors identify an acetylation-dependent mechanism that regulates formation and autophagic clearance of p62 bodies under nutrient-deficient conditions.

Visual recognition and localization of underwater optical beacons is an important step in autonomous underwater vehicle (AUV) docking. The main issues that restrict the use of underwater monocular vision range are the attenuation of light in water, the mirror image between the water surface and the light source, and the small size of the optical beacon. In this study, a fast monocular camera localization method for small 4-light beacons is proposed. A YOLO V5 (You Only Look Once) model with coordinated attention (CA) mechanisms is constructed. Compared with the original model and the model with convolutional block attention mechanisms (CBAM), and our model improves the prediction accuracy to 96.1% and the recall to 95.1%. A sub-pixel light source centroid localization method combining super-resolution generative adversarial networks (SRGAN) image enhancement and Zernike moments is proposed. The detection range of small optical beacons is increased from 7 m to 10 m. In the laboratory self-made pool and anechoic pool experiments, the average relative distance error of our method is 1.04 percent, and the average detection speed is 0.088 s (11.36 FPS). This study offers a solution for the long-distance fast and accurate positioning of underwater small optical beacons due to their fast recognition, accurate ranging, and wide detection range characteristics.

Filamin A, the first discovered non-muscle actin filament cross-linking protein, plays a crucial role in regulating cell migration that participates in diverse cellular and developmental processes. However, the regulatory mechanism of filamin A stability remains unclear. Here, we find that nuclear distribution gene C (NudC), a cochaperone of heat shock protein 90 (Hsp90), is required to stabilize filamin A in mammalian cells. Immunoprecipitation-mass spectrometry and western blotting analyses reveal that NudC interacts with filamin A. Overexpression of human NudC-L279P (an evolutionarily conserved mutation in NudC that impairs its chaperone activity) not only decreases the protein level of filamin A but also results in actin disorganization and the suppression of cell migration. Ectopic expression of filamin A is able to reverse these defects induced by the overexpression of NudC-L279P. Furthermore, Hsp90 forms a complex with filamin A. The inhibition of Hsp90 ATPase activity by either geldanamycin or radicicol decreases the protein stability of filamin A. In addition, ectopic expression of Hsp90 efficiently restores NudC-L279P overexpression-induced protein stability and functional defects of filamin A. Taken together, these data suggest NudC L279P mutation destabilizes filamin A by inhibiting the Hsp90 chaperoning pathway and suppresses cell migration.

While underwater acoustic (UWA) communication offers a practical way to establish a wireless link with underwater vehicles, designing a UWA communication system onboard a small autonomous underwater vehicle (AUV) still poses significant challenges. As the adoption of the low-complexity, robust noncoherent communication technology is limited by low bandwidth efficiency and a low data rate, coherent UWA communication requires Doppler mitigation and channel equalization measures to achieve a relatively high data rate in a moving state. Due to the strict constraints of a small-scale AUV in terms of resources and energy consumption, it is not appropriate to use high-complexity Doppler/multipath compensation technology from the prospect of system implementation. In this paper, an efficient and low-complexity UWA differential binary phase-shift keying (DBPSK) system onboard a small AUV is proposed by simplifying the Doppler and multipath compensation. Specifically, for Doppler, the delay of the adjacent DBPSK symbols is calculated according to the Doppler estimate to facilitate delay-tuning Doppler correction. For multipath, low-complexity LMS channel equalization is incorporated with error correction coding to enable multipath mitigation. With a simple structure and low computational complexity, the proposed scheme facilitates the practical hardware implementation and system integration in the small AUV platform. The numerical simulations are conducted to assess the validity of the proposed scheme under different channel conditions and the effectiveness of the proposed scheme is further verified by two UWA communication field tests, which are performed at a practical shallow water sea and lake, respectively.

The axial compressive performance of steel-reinforced concrete columns with monosymmetric cross-shaped steel (SRCC-MCS) was investigated in this study. Tests were conducted under pure axial compression to determine the effects of cross-shaped steel eccentricity ratio, concrete strength, steel ratio, and stirrup spacing on the resulting failure mode, load-strain curves, and load-displacement curves. The results indicated that increasing the cross-shaped steel eccentricity ratio reduced the axial capacity and ductility, increasing the concrete strength markedly enhanced the axial capacity but reduced the ductility, and increasing the steel ratio and reducing the stirrup spacing increased the axial capacity and ductility. Two calculation methods for determining the axial capacity of an SRCC-MCS under axial compression were proposed considering the effective lateral confinement pressures provided by the stirrups and monosymmetric cross-shaped steel. The proposed equations were compared with those in three extant codes and found to exhibit improved accuracy and consistency.

In this paper, two joints of circular tubed steel-reinforced concrete (CTSRC) column were designed. The load-displacement hysteretic curve and skeleton curve of this new type of joint are obtained by the pseudostatic test under low cycle cyclic load on the top of the column. The results show that this new type of joint has good seismic energy dissipation performance. On the basis of the test, a three-fold skeleton curve model considering three characteristic points of yield, limit, and failure is proposed, and the expression of skeleton curve model is given. The load and unload stiffness degradation law of specimens under reciprocating load is studied, and the expression of stiffness degradation law is given. The hysteresis law of the new type joint specimens is described in detail. The validity of the model is verified by comparing the experimental curve with the model curve. The model can be used in the elastic-plastic seismic time-history analysis on the joint of circular tubed steel-reinforced concrete (CTSRC) column.

A new type joint of Circular Tubed Steel-Reinforced Concrete (CTSRC) columns was designed in this paper. The structural characteristics, manufacturing process, and mechanical properties of raw materials of the new joint were introduced. In order to simulate the earthquake action, two joint specimens were subjected to low-cycle cyclic loading at the end of the column. Based on the in-depth study of the failure characteristics, load-displacement hysteretic curve, skeleton curve, ductility index, load-strain hysteretic curve in the core area of the joint, energy dissipation performance, strength and stiffness degradation performance, and shear deformation in the core area of the joint during the whole loading process, the seismic behavior of this new type of joint was investigated. The results show that the new joint has reasonable failure characteristics, high bearing capacity, good ductility, excellent seismic energy dissipation performance, and strong resistance to strength and stiffness degradation, which meets the seismic design principle of “strong joint and weak component” and is suitable for the results with special requirements for seismic performance. In addition, preliminary design recommendations were put forward. The research results of this paper can provide a theoretical basis for the application of this kind of new structure.

The damage to a concrete wall caused by a strong earthquake is generally concentrated at the bottom of the concrete wall, which seriously threatens the safety of the steel-concrete hybrid structure and is very difficult to repair after an earthquake. In this paper, a steel-concrete hybrid structure with buckling restrained braces at a scale of 1/10 is constructed and tested on a shaking table. First, the mechanical properties of the BRBs are obtained through a static reciprocating loading test. Then, the dynamic properties and seismic response of the steel-concrete hybrid structure with BRBs are obtained through shaking table tests. The results show that (1) the energy dissipation capacity of the BRBs is very good, and none of the BRBs buckle during the shaking table tests; (2) the steel beams and columns are basically in an elastic state; (3) all the cracks on the concrete wall are microcracks, which are widely distributed in floors 1–8 of the concrete walls; (4) the maximum interstory drift angle reaches 1/40, which indicates that the ductility of the steel-concrete hybrid structure is very good. In conclusion, BRBs can significantly improve the seismic performance of the steel-concrete hybrid structures.

In order to ease the traffic congestion near primary and secondary schools during the drop-off and pick-up, traffic behavior was analyzed, and a quantitative allocation method for parking spaces was proposed. The proposed method includes three steps. Firstly, a vehicle queuing model based on G/M/N queue theory was built, and MATLAB was employed to simulate the queuing model to obtain a reasonable parking space for drop-off. Secondly, the reasonable parking space for pick-up is determined based on the cumulative number of vehicles. Finally, an optimization model for the scale of total parking spaces and the short-term parking spaces was proposed to achieve maximum utilization of parking spaces. An empirical analysis and verification were conducted based on actual traffic data of schools. The results show that the proposed model can analyze the overall scale of the parking space for primary and secondary school, as well as the scale of the short-term parking spaces. And the proposed scale of the parking space can well meet the actual parking demand.

Increasing amount of waste tires caused huge environment issues in recent years. Recycling concrete is an effective way. In this paper, waste tires are crushed into particles and incorporated in lightweight aggregate concrete to prepare a special concrete (self-compacting rubber lightweight aggregate concrete (SCRLC)). A detailed experimental research of effects of rubber particles on the properties of SCRLC and corresponding mortar is conducted. The results show that increasing the rubber particles replacement ratio leads to a raising of yield stress and plastic viscosity of mortar pastes. Flowability, filling capacity, and passing ability of SCRLC decline and the segregation resistance property of SCRLC improves as the rubber particles replacement ratio increases. Well, linear correlations between slump flow of SCRLC and shear stress of corresponding mortar pastes and segregation ratio of SCRLC and plastic viscosity of corresponding mortar pastes are obtained. In order to ensure that rubber lightweight aggregate concrete can compact by itself, the upper limit of shear stress of corresponding mortar pastes is 231.7 Pa and the lower limit of plastic viscosity of corresponding mortar pastes is 3.72 Pa·s. Compressive strength, splitting tensile strength, flexural strength, and elastic modulus of SCRLC and compressive strength of corresponding mortar decrease as the rubber particles replacement ratio increases. The 28-day compressive strength of SCRLC can meet the requirements of lightweight aggregate concrete structures until the rubber particles replacement ratio reaches 50%.

In this paper, a new type of buckling-restrained brace characterized by a variable cross-section core (BRB-VCC) is proposed and investigated. The practical design equations of the BRB-VCC are derived based on mechanical and mathematical theories. Six specimens are designed and tested to clarify the mechanical behaviours of the BRB-VCC and to validate the reliability of the proposed equations. The test results show that (1) none of the specimens buckle under compression, as expected, and their ductilities and energy dissipation capacities are satisfactory; (2) the derived formulas are reliable and can be conveniently used in engineering practice; and (3) the yielding displacement of the BRB-VCC is approximately 70% that of the traditional TJ-1 buckling-restrained brace (BRB-TJ-1), which may yield earlier than the BRB-TJ-1 in concrete structures under the action of an earthquake.

MicroRNAs (miRNAs) have been reported to play a critical role in cancer invasion and metastasis. Our previous study showed that miR-375 frequently downregulated in gastric cancer suppresses cell proliferation by targeting Janus kinase 2 (JAK2). Here, we further found that the expression level of miR-375 is significantly decreased in metastatic gastric cancer tissues compared with the non-metastasis controls. Ectopic expression of miR-375 inhibits the migration and invasion of gastric cancer cells partially by targeting JAK2. Furthermore, miR-375 expression is negatively regulated by the metastasis associated transcription factor Snail, which directly binds to the putative promoter of miR-375. Moreover, overexpression of Snail can partially reverse the inhibition of gastric cancer cell migration caused by miR-375. Taken together, these data suggest that miR-375 may be negatively regulated by Snail and involved in gastric cancer cell migration and invasion potentially by targeting JAK2.

Mammalian target of rapamycin (mTOR) is a central regulator for both cell proliferation and cell growth; however, little is known about the regulation of mTOR expression at the transcriptional level. Here, we provide evidences that a conserved human protein TBCK (TBC1 domain containing kinase) is involved in the regulation of mTOR signaling pathway. Depletion of TBCK significantly inhibits cell proliferation, reduces cell size, and disrupts the organization of actin, but not microtubule. Knockdown of TBCK induces a significant decrease in the protein levels of components of mTOR complex (mTORC), and suppresses the activity of mTOR signaling, but not MAPK or PDK1/Akt pathway. Further results show that TBCK influences the expression of mTORC components at the transcriptional level. Thus, these data suggest that TBCK may play an important role in cell proliferation, cell growth and actin organization possibly by modulating mTOR pathway.

BackgroundGastric cancer (GC) is associated with high mortality rates and an unfavorable prognosis at advanced stages. In addition, there are no effective methods for diagnosing gastric cancer at an early stage or for predicting the outcome for the purpose of selecting patient-specific treatment options. Therefore, it is important to investigate new methods for GC diagnosis.Methodology/principal findingsTo facilitate its use in a diagnostic setting, a group of 74 genes with diagnostic and prognostic information was translated into a customized microarray containing a reduced set of 1,042 probes suitable for high throughput processing. In this report, we demonstrate for the first time that the custom mini-array can be used as a reliable diagnostic tool in gastric cancer. With an AUC value of 0.565 (95% CI 0.305-0.825) indicating a perfect test, the sensitivity and specificity of diagnosis from the ROC curve were calculated to be 70% and 80%, respectively.Conclusions/significanceThe data clearly demonstrate the reproducibility and robustness of the small custom-made microarray. The array is an excellent tool for classifying and predicting the outcome of disease in gastric cancer patients.

The transcription factor, Zinc finger of the cerebellum (ZIC1), plays a crucial role in vertebrate development. Recently, ZIC1 has also been found to participate in the progression of human cancers, including medulloblastomas, endometrial cancers, and mesenchymal neoplasms. However, the function of ZIC1 in colon cancer progression has not been defined. In this study, we demonstrate ZIC1 to be silenced or significantly downregulated in colon cancer cell lines. These effects were reversed by demethylation treatment with 5-aza-2'-deoxycytidine (Aza). ZIC1 expression is also significantly downregulated in primary colorectal cancer tissues relative to adjacent non-tumor tissues (p = 0.0001). Furthermore, methylation of ZIC1 gene promoter is frequently detected in primary tumor tissues (85%, 34/40), but not in adjacent non-tumor tissues. Ectopic expression of ZIC1 suppresses cell proliferation and induces apoptosis, which is associated with MAPK and PI(3)K/Akt pathways, as well as the Bcl-xl/Bad/Caspase3 cascade. To identify target candidates of ZIC1, we employed cDNA microarray and found that 337 genes are downregulated and 95 genes upregulated by ectopic expression of ZIC1, which were verified by 10 selected gene expressions by qRT-PCR. Taken together, our results suggest that ZIC1 may potentially function as a tumor suppressor gene, which is downregulated through promoter hypermethylation in colorectal cancers.