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Object detection is a core problem in computer vision and pattern recognition. In this paper, we study the problem of learning an effective object detector using weakly-annotated images (i.e., only the image level annotation is given) and a small proportion of fully-annotated images (i.e., bounding box level annotation is given) with curriculum learning. Our method is built upon Faster R-CNN. Different from previous weakly-supervised object detectors which rely on hand-craft object proposals, the proposed method learns a region proposal network using weakly- and semi-supervised training data. And the weakly-labeled images are fed into the deep network in a meaningful order which illustrates from easy to gradually more complex examples with curriculum learning. We name the Faster R-CNN trained using Weakly- And Semi-Supervised data with Curriculum Learning as WASSCL R-CNN. The WASSCL R-CNN is validated on the PASCAL VOC 2007 benchmark, and obtains 90% of a fully-supervised Faster R-CNN's performance (measured using mAP) with only 15% of fully-supervised annotations together with weak supervision. The results show that the proposed learning framework can significantly reduce the labeling efforts for obtaining reliable object detectors.

The design and fabrication of a self-digitization dielectrophoretic (SD-DEP) chip with simple components for single-cell manipulation and downstream nucleic acid analysis is presented. The device employed the traditional DEP and insulator DEP to create the local electric field that is tailored to approximately the size of single cells, enabling highly efficient single-cell capture. The multistep procedures of cell manipulation, compartmentalization, lysis, and analysis were performed in the integrated microdevice, consuming minimal reagents, minimizing contamination, decreasing lysate dilution, and increasing assay sensitivity. The platform developed here could be a promising and powerful tool in single-cell research for precise medicine.

Metal ions are involved in Aβ aggregate deposition and neurotoxicity via various processes, including acceleration of Aβ aggregation, disruption of normal metal homeostasis, and formation of reactive oxygen species (ROS). Although metal chelation is a promising therapeutic strategy for Alzheimer’s disease (AD), the widespread use of chelation therapy faces a significant problem; namely, it is difficult to differentiate toxic metals associated with Aβ plaques from those required by normal metal homeostasis. Furthermore, the multifactorial nature of AD and the current lack of an accepted unitary theory to account for AD neurodegeneration also restrict AD treatment through a single therapeutic strategy. This paper presents a novel bifunctional platform by integrating nonpharmacological and pharmacological cues into one system for AD treatment. This electrically responsive drug release platform, based on conducting polymer polypyrrole (PPy) incorporated with graphene-mesoporous silica nanohybrids (GSN) nanoreserviors, could realize on-demand controlled drug delivery with spatial and temporal control. Electrochemical stimulation can treat peripheral nerve injury (PNI) to stimulate neurite outgrowth. This novel system can also effectively inhibit Aβ aggregate formation, decrease cellular ROS, and protect cells from Aβ-related toxicity. The purpose of this research is to promote the design of noninvasive remote-controlled multifunctional systems for AD treatment.

It is well-known that aging is the most risk factor for Alzheimer's disease (AD). Recent studies have demonstrated that human telomerase is associated with pathological mechanisms of AD. In view of the central role of telomere and telomerase in the aging process, herein we found that the aggregated form Aβ (Aβ1-40 and Aβ1-42), not Aβ monomer, could inhibit telomerase activity both in vitro and in living cells. The β-sheet structures were essential for Aβ-induced telomerase inhibition. Further studies indicated Aβ oligomers inhibited telomerase activity through binding to DNA·RNA hybrid formed by telomeric DNA and the RNA template of telomerase, then blocking telomerase elongation of telomeric DNA. We also identified that intracellular Aβ localized at telomere, and induced cell senescence and telomere shortening. These results indicate that Aβ oligomers can be potential natural inhibitors of telomerase and that inhibition of telomerase activity may be one of the factors for Aβ-induced cytotoxicity. Our work may offer a new clue to a better understanding of aging and AD.

UAV flight control software is the core of UAV flight control system. Sufficient test of the software is necessary to ensure safety and reliability of flight control system. According to the characteristics of some type of UAV flight control software, this paper proposed a test model based on multiple test environments and types, analyzed and applied test technique of coverage and fault injection, and developed a set of test techniques applicable to UAV flight control software.

Dynamic control of cell-surface interactions with near-infrared (NIR) light is particularly attractive for regeneration medicine and cell-based therapy. Herein we successfully achieve NIR-controlled cell adhesion with upconversion nanoparticles (UCNPs) based programmable substrate. The UCNPs can harvest the biocompatible NIR light and convert it into local UV light, which results in cleavage of the photocaged linkers and on-demand release of adhesive cells. The strategy also enables the feasibility of deep-tissue photocontrol of cell adhesion on substrate. Our work may open a new avenue for design of UCNP-based cell scaffolds to dynamically manipulate cell-matrix and cell-cell interactions.

Being considered a liquid biopsy, circulating tumor cell (CTC) quantification is of great interest for evaluating cancer dissemination, predicting patient prognosis, and also for the evaluation of therapeutic treatments, representing a reliable potential alternative to invasive biopsies and subsequent proteomic and functional genetic analysis. Compared to a biopsy, the gold standard of current cancer diagnosis, an important characteristic of a blood test is that it is safe and can be performed at many points during the disease, allowing the development of appropriate therapy modifications and potentially improving patient's quality of life. In this work, an ultrasensitive electrochemical telomerase activity-sensing strategy is presented that utilizes DNA-templated deposition of silver nanoparticles as electroactive labels through a highly sharp solid-state Ag/AgCl reaction with DNA exonuclease III-assisted background current suppression. This nanoparticle-mediated signal amplification resulted in significantly decreased detection limit, which is better than the vast majority of reported methods and achieves a sensitivity comparable to the conventional telomeric repeat amplification protocol (TRAP). This work may pave a new PCR-free way for the detection of telomerase activity in CTCs via a noninvasive routine blood test for point-of-care diagnosis and individualized treatment of cancer.

Chiral recognition of DNA molecules is important because DNA chiral transition and its different conformations are involved in a series of important life events. Among them, polymorphic human telomere DNA has attracted great interests in recent years because of its important roles in chromosome structural integrity. In this report, we examine the short-term effect of chiral metallo-supramolecular complex enantiomers treatment on tumor cells, and find that a zinc-finger-like alpha helical chiral metallo-supramolecular complex, [Ni2L3]4+-P enantiomer (NiP), can selectively provoke the rapid telomere uncapping, trigger DNA damage responses at telomere and degradation of G-overhang and the delocalization of telomeric protein from telomeres. Further studies indicate that NiP can induce an acute cellular apoptosis and senescence in cancer cells rather than normal cells. These results are further evidenced by the upregulation of p21 and p16 proteins. Moreover, NiP can cause translocation of hTERT from nuclear to cytoplasm through Tyr 707 phosphorylation. While its enantiomer, [Ni2L3]4+-M (NiM), has no such mentioned effects, these results clearly demonstrate the compound’s chiral selectivity in cancer cells. Our work will shed light on design of chiral anticancer drugs targeting G-quadruplex DNA, and developing telomere and telomerase modulation agents.

Manipulation of cell–cell interactions has potential applications in basic research and cell-based therapy. Herein, using a combination of metabolic glycan labelling and bio-orthogonal click reaction, we engineer cell membranes with β-cyclodextrin and subsequently manipulate cell behaviours via photo-responsive host-guest recognition. With this methodology, we demonstrate reversible manipulation of cell assembly and disassembly. The method enables light-controllable reversible assembly of cell–cell adhesion, in contrast with previously reported irreversible effects, in which altered structure could not be reused. We also illustrate the utility of the method by designing a cell-based therapy. Peripheral blood mononuclear cells modified with aptamer are effectively redirected towards target cells, resulting in enhanced cell apoptosis. Our approach allows precise control of reversible cell–cell interactions and we expect that it will promote further developments of cell-based therapy., Reversible manipulation of cell-cell interactions has potential applications in basic research and cell-based therapy. Here the authors control cell-cell adhesion in vitro with light, by modifying the surface sugars of cells to display β-cyclodextrin, which recognises one isoform of light-isomerizable azobenzene linkers.

Background Carcinoembryonic antigen (CEA) as a diagnostic or prognostic marker has been widely studied in patients with lung cancer. However, the relationship between serum CEA and tumor metastasis in lung cancer remains controversial. This study aimed to investigate the ability of serum CEA to assess tumor metastasis in lung cancer patients. Methods We performed a retrospective analysis of 238 patients diagnosed with lung cancer from January to December 2016 at pneumology department of Dazhou Central Hospital (Dazhou, China). Serum CEA levels were quantified in each patient at the time of diagnosis of lung cancer. Metastasis was confirmed by computed tomography (CT), and/or positron emission tomography (PET) and/or surgery or other necessary detecting methods. Results Of the 213 patients eligible for final analysis, 128 were diagnosed with metastasis and 85 were diagnosed without metastasis. Compared to non-metastatic patients, the serum CEA was markedly higher in patients with metastasis (p Conclusion Our study suggested the serum CEA as a valuable marker for tumor metastases assessment in newly diagnosed lung cancer patients, which could have some implications in clinical application.

Artificial hyperthermia is an emerging technique to induce apoptotic cancer cell death. However, achieving effective hyperthermic apoptosis is often difficult, as cells typically acquire resistance to thermal stress. With the aid of sequential irradiation, highly integrated nanoassemblies based on reduced graphene oxide–ZnO nanoparticles–hyaluronic acid (rGo-ZnO-HA) can serve as a multi-synergistic platform for targeted high-performance apoptotic cancer therapy. The surface engineering of ZnO/graphene hybrid with multifunctional HA biomacromolecules simultaneously confers the system colloidal stability, biocompatibility, and a cancer cell targeting ability. After receptor-mediated endocytosis, enzyme-mediated fluorescence activation helps track cellular uptake and provides truly molecular imaging. Furthermore, the reactive oxygen species (ROS) generated by ZnO/rGo under light illumination can effectively sensitize cancer cells to the subsequent NIR laser-induced apoptotic hyperthermia. In particular, photo modulation of cellular ROS to sensitize cells provides a novel approach to increase the efficacy of hyperthermic apoptosis. These findings suggest that a powerful apoptotic therapeutic platform could be achieved based on the multi-synergistic platform.

An active cell scaffold based on a graphene-polymer hydrogel has been successfully fabricated. The macroporous hydrogel can efficiently capture cells not only through the bioadhesive ligand RGD but also through on-demand release of cells with an NIR light stimulus. The latter process shows better dynamic control over cells than traditional passive-hydrogel-based cell depots.

Herein, a pH stimuli-responsive vehicle for intracellular drug delivery using CeO2 capped mesoporous silica nanoparticles (MSN) is reported. β-Cyclodextrin-modified CeO2 nanoparticles could cap onto ferrocene-functionalized mesoporous silica through host-guest interactions. After internalization into A549 cells by a lysosomal pathway, the ferrocenyl moieties are oxidized to ferrocenium ions by CeO2 lids, which could trigger the uncapping of the CeO2 and cause the drugs release. Because of the pH-dependent toxicity, the CeO2 here behaves as a multi-purpose entity that not only acts as a lid but also exhibits a synergistic antitumor effect on cancer cells. Meanwhile, the cell protective effect of CeO2 nanoparticles alone is demonstrated, which ensures that the dissolved CeO2 nanoparticles can be non-toxic to normal cells.

A facile, economic and green one-step hydrothermal synthesis route using dopamine as source towards photoluminescent carbon nanoparticles (CNPs) is proposed. The as-prepared CNPs have an average size about 3.8 nm. The emission spectra of the CNPs are broad, ranging from approximately 380 (purple) to approximately 525 nm (green), depending on the excitation wavelengths. Due to the favorable optical properties, the CNPs can readily enter into A549 cells and has been used for multicolor biolabeling and bioimaging. Most importantly, the as-prepared CNPs contain distinctive catechol groups on their surfaces. Due to the special response of catechol groups to Fe(3+) ions, we further demonstrate that such wholly new CNPs can serve as a very effective fluorescent sensing platform for label-free sensitive and selective detection of Fe(3+) ions and dopamine with a detection limit as low as 0.32 μM and 68 nM, respectively. The new "mix-and-detect" strategy is simple, green, and exhibits high sensitivity and selectivity. The present method was also applied to the determination of Fe(3+) ions in real water samples and dopamine in human urine and serum samples successfully.

Based on domestic embedded multi-core operating system testing, this paper describes the characteristics of the multi-core operating system and existing test contents and gives an effective software function and performance function test method for application focus of the domestic embedded multi-core operating system so as to provide references for testing of domestic embedded software and embedded operating system.

The PLD software design of communication device is taken as application background, under which this paper analyzes four typical issues of software design such as clock design, synchronous design, burr elimination and metastable state, gives solutions based on actual conditions and finally describes characteristics and methods of FPGA software testing. The research can provide references for design and test personnel of the FPGA software.

SCU and its software are widely used in both electrical and electronic devices. It is important and difficult to conduct quantitative analysis, accurate measurement and quality evaluation in SCU circuit design and manufacturing. In order to solve the problem of SCU-based circuit signal testing, this paper mainly studies the FPGA-based SCU output signal testing technology, testing requirement and test case analysis method, etc.

Using porphyrin-functionalized graphene, we construct a PCR-free, low-cost, rapid, and electrochemiluminenscence (ECL) assay for detection of telomerase activity that has been demonstrated in six different cell lines and can be used as initial screening of G-quadruplex DNA binding agents and telomerase inhibitors. This ECL sensor shows highly sensitive for detection of telomerase with the detection limit as low as 10 HeLa cells mL(-1) .

Using a porphyrin-functionalized graphenemodifi ed electrode, an electrochemical impedance peptide sensor for labelfree detection of cyclin A2 has been constructed. This electrochemical sensor can not only detect protein in cancer cells but also differentiate cancer cells from normal ones. Furthermore, the assay provides the potential of using a simple electrochemical technique to estimate the effi ciency of anticancer drugs in cancer therapy.

A dynamic hydrogel was fabricated in which the cell adhesion state could be programmed with signaling molecules in a cellular microenvironment., Design of biological signal-responsive biomaterials is essential for controlling cell–cell and cell–matrix interactions. Herein, we developed a dynamic hydrogel to control cell adhesion with biological signals in a cellular microenvironment. The basic principle was based on using nucleic acid aptamer to recognize cell signalling and control the display of bioligands on the hydrogel. Not only exogenous signalling but also endogenous signalling secreted by surrounding cells could activate the dynamic scaffold and tune the cell adhesion state. Since diverse aptamers have been developed, our design can be extended to multiple biological inputs. The biochemical signal-responsive system will greatly enhance the understanding of complex biological processes as well as the ability to manipulate cellular behaviors.

Herein we report a convenient and sensitive method for the detection of telomerase activity based on upconversion nanoparticle (UCNP) modified cellulose paper. Compared with many solution-phase systems, this paper chip is more stable and easily stores the test results. What's more, the low background fluorescence of the UCNPs increases the sensitivity of this method, and the low telomerase levels in different cell lines can clearly be discriminated by the naked eye.

The non-enzymatic browning, namely Maillard reaction is commonly invoked to account for abiotic chemical transformations of organic matter. Here we report a new reaction pathway via the Maillard reaction to systematically synthesize a series of nitrogen-doped carbon dots (C-dots) with superhigh quantum yield (QY) and tunable multicolor luminescent displayment. The starting materials are glucose and the serial amino acid analogues which allow systemically controlling luminescent and physicochemical properties of C-dots at will. Unexpectedly, the as-prepared C-dots possess bright photoluminescence with QY up to 69.1% which is almost the highest ever reported, favorable biocompatibility, excellent aqueous and nonaqueous dispersibility, ultrahigh photostability, and readily functionalization. We have demonstrated that they are particularly suitable for multicolor luminescent display and long-term and real-time cellular imaging. Furthermore, the methodology is readily scalable to large yield, and can provide sufficient amount of C-dots for practical demands.

The sexual ratio of Gobiocypris rarus exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 17 beta -estradiol from embryo to sexually mature revealed feminization and overdevelopment of connective tissue in male fish gonad in 2-30 pg/L TCDD concentration range. Daphnia magna was not sensitive to the high dose of TCDD (0.1-1000 ng/ml), but the reproduction of D. magna treated with TCDD decreased after the 8th day. 7-Ethoxyresorufin-O-deethylase (EROD) activities in newly fertilized eggs of G. rarus exposed to TCDD dosage groups (1000-100,000 pg/L) were significantly induced and increased with TCDD concentrations at the early life stage, while no difference was found between low TCDD dosage groups (

An electrocatalytic assay was developed for telomerase activity detection by using superior catalytic properties of Pt nanoparticles. This design was PCR-free, and highly sensitive for telomerase with a detection limit of less than 2 cells.

Human telomerase is a specialized ribonucleoprotein polymerase and is used as a clinical cancer marker and special target for chemotherapy. Traditional telomerase detection uses "telomerase repeat amplification protocol" (TRAP) assay. However, TRAP is questioned because it requires use of DNA polymerases, which is susceptible to polymerase chain reaction (PCR)-derived artifacts and time-consuming. Here, a novel PCR-free, electrocatalytic assay for signal-amplified detection of telomerase activity using graphene-mesoporous silica-dispersed palladium nanoparticles-based probe carrier platform to improve probe-target recognition is reported. The low background noise is achieved by using DNA site-specific cleavage endonuclease and the detection signal is amplified by using hemoglobin. As a highly efficient electron sink, hemoglobin does not carry out direct reduction at the surface, minimizing false positives. These merits make this assay highly sensitive, achieving the sensitivity comparable to TRAP. The developed electrocatalysis assay is PCR-free, simple in design, and fast in operation, therefore avoiding PCR amplification-related errors, which make it more reliable to evaluate telomerase activity for clinical use.

Upconversion nanoparticles (UCNPs) have been proposed as a promising new class of biological luminescent labels because of their weak auto-fluorescence background, strong penetration ability under near-infrared (NIR) radiation, resistance to photobleaching, and low toxicity. Although UCNPs hold great promise in nanotechnology and nanomedicine, their applications in ECL fields still remain unexplored. Herein, a label-free, ultra-sensitive and selective electrochemiluminescence (ECL) assay is developed for detection of cyclin A2 by using highly efficient ECL graphene-upconversion hybrid. Being an important member of the cyclin family, cyclin A2 is involved in the initiation of DNA replication, transcription and cell cycle reg-ulation through the association of cyclin-dependent kinases (CDK). Cyclin A2 is a prognostic indicator in early-stage cancers and a target for treatment of different types of cancers. However, the expression level of cyclin A2 is quite low, direct detection of cyclin A2 in crude cancer cell extracts is challenging and important for both clinical diagnosis of cancer in the early stage and the treatment. By chemically grafting cyclin A2 detection specific probe, a PEGlyted hexapeptide, to graphene-upconversion hybrid, the constructed ECL biosensor displays a superior performance for cyclin A2 , which can not only detect cyclin A2 directly in cancer cell extracts, but also discriminate between normal cells and cancer cells. More importantly, the ECL biosensor has different responses between clinical used anticancer drug-treated and non-treated cancer cells, which demonstrates that the sensor can be potentially used for drug screening, and for evaluation of therapeutic treatments in early-stage cancers.

Developing sensitive, rapid, and cost-effective methods for detection of biomolecules is important for both clinical and numerous non-clinical applications. During the last two decades, functional nanomaterials with unique physical and chemical properties have provided significant advantages for biological detection. In this feature article, we introduce recent progress in nanobiosensor development by exploiting the optical, electrical and catalytic properties of a range of nanomaterials, with a focus on gold nanoparticles, carbon nanotubes, graphene and carbon dots. In addition, the perspectives on future opportunities and unsolved challenges are also discussed.

Both human telomeric G-rich and C-rich DNA have been considered as specific drug targets for cancer therapy. However, due to i-motif structure instability and lack of specific binding agents, it remains unclear whether stabilization of telomeric i-motif can inhibit telomerase activity. Single-walled carbon nanotubes (SWNTs) have been reported as the first ligand that can selectively stabilize human telomeric i-motif DNA. Here we report that SWNTs can inhibit telomerase activity through stabilization of i-motif structure. The persistence of i-motif and the concomitant G-quadruplex eventually leads to telomere uncapping and displaces telomere-binding proteins from telomere. The dysfunctional telomere triggers DNA damage response and elicits upregulation of p16 and p21 proteins. This is the first example that SWNTs can inhibit telomerase activity and interfere with the telomere functions in cancer cells. These results provide new insights into understanding the biomedical effects of SWNTs and the biological importance of i-motif DNA.

We report a smart therapeutic nanoplatform based on Fe(3)O(4)@CaP capped gold nanocages, which integrates magnetic targeting, photothermal therapy and chemotherapy for killing cancer cells. Combining photothermal- and chemo-therapy results in a synergistic effect in cancer treatment.

Telomerase is over-expressed in over 85% of all known human tumors. This renders the enzyme a valuable biomarker for cancer diagnosis and an important therapeutic target. The most widely used telomeric repeat amplification protocol (TRAP) assay has been questioned for telomerase detection. It is reported that human telomerase activity can be visualized by using primer-modified Au nanoparticles. The working principle is based on the elongated primers conjugated to the gold nanoparticle (AuNP) surface, which can fold into a G-quadruplex to protect the AuNPs from the aggregation. The developed simple and sensitive colorimetric assay can measure telomerase activity down to 1 HeLa cell µL(-1). More importantly, this assay can be easily extended to high-throughput and automatic format. The AuNP-TS method is PCR-free and therefore avoids the amplification-related errors and becomes more reliable to evaluate telomerase activity. This assay has also been used for initial screening of telomerase inhibitors as anticancer drug agents.

Synthetic siRNAs 21 to 23 nucleotides in length silence gene expression posttranscriptionally, and RNA interference targeting Fas protects mice from fulminant hepatitis. Fas-mediated apoptosis has also been implied in the mechanism of hepatocyte apoptosis upon allogenic hepatocyte transplantation (HTx), and blockade of Fas and Fas ligand interaction successfully promotes the repopulation of allogenic liver cells in recipient spleens. In the present study, we further investigated the protective effects of Fas silencing on allogeneic hepatocytes transplanted into mouse spleens.Hepatocytes were isolated from BALB/c mice and mock transfected or transfected with Fas siRNA or GFP siRNA (n = 8/group). The expression of Fas was examined by RT-PCR and flow cytometric analysis. Forty-eight hours later, the cells were transplanted into spleens of allogenic B6 mice. Spleens were harvested on day 21 after transplantation. Apoptosis was assessed by TUNEL assay, survival of hepatocytes by alanine transaminase (ALT) assay.Fas siRNA transfection reduced Fas expression on hepatocytes at both mRNA and protein levels (P.05). Upon transplanting into recipient spleens, hepatocytes transfected with Fas siRNA demonstrated a lower percentage of apoptosis detected by TUNEL (6 +/- 3% in Fas siRNA group vs 12 +/- 5% in GFP siRNA group and 10 +/- 3% in mock transfected group; P.05), and increased survival as determined by ALT assay (38.2 +/- 10.6 IU/g in Fas siRNA group vs 21.3 +/- 8.4 IU/g in GFP siRNA group and 18.5 +/- 5.9 IU/g in mock-transfected animals).Fas silencing by RNA interference reduces apoptosis and increases survival of allogenic transplanted hepatocytes, and thus holds promise to inhibit acute rejection after hepatocyte transplantation.