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Electronic health record (EHR) or medical claims-based algorithms (i.e., operational definitions) can be used to define safety outcomes using real-world data. However, existing tools do not allow researchers and decision-makers to adequately appraise whether a particular algorithm is fit for purpose (FFP) to support regulatory decisions on drug safety surveillance. Our objective was to develop a tool to enable regulatory decision-makers and other stakeholders to appraise whether a given algorithm is FFP for a specific decision context.We drafted a set of 77 generic items informed by regulatory guidance documents, existing instruments, and publications. The outcome of ischemic stroke served as an exemplar to inform the development of draft items. The items were designed to be outcome independent. We conducted a three-round online Delphi panel to develop and refine the tool and achieve consensus on items ( 70% agreement) among panel participants composed of regulators, researchers from pharmaceutical organizations, academic clinicians, methodologists, pharmacoepidemiologists, and cardiologists. We conducted a qualitative analysis of panel responses. Five pairs of reviewers independently evaluated two ischemic stroke algorithm validation studies to test its application. We developed a user guide, with explanation and elaboration for each item, guidance on essential and additional elements for user responses, and an illustrative example of a complete assessment. Furthermore, we conducted a 2-h online stakeholder panel of 16 participants from regulatory agencies, academic institutions, and industry. We solicited input on key factors for an FFP assessment, their general reaction to the Algorithm CErtaInty Tool (ACE-IT), limitations of the tool, and its potential use.The expert panel reviewed and made changes to the initial list of 77 items. The panel achieved consensus on 38 items, and the final version of the ACE-IT includes 34 items after removal of duplicate items. Applying the tool to two ischemic stroke algorithms demonstrated challenges in its application and identified shared concepts addressed by more than one item. The ACE-IT was viewed positively by the majority of stakeholders. They identified that the tool could serve as an educational resource as well as an information-sharing platform. The time required to complete the assessment was identified as an important limitation. We consolidated items with shared concepts and added a preliminary screen section and a summary assessment box based on their input. The final version of the ACE-IT is a 34-item tool for assessing whether algorithm validation studies on safety outcomes are FFP. It comprises the domains of internal validity (24 items), external validity (seven items), and ethical conduct and reporting of the validation study (three items). The internal validity domain includes sections on objectives, data sources, population, outcomes, design and setting, statistical methods, reference standard, accuracy, and strengths and limitations. The external validity domain includes items that assess the generalizability to a proposed target study. The domain on ethics and transparency includes items on ethical conduct and reporting of the validation study.The ACE-IT supports a structured, transparent, and flexible approach for decision-makers to appraise whether electronic health record or medical claims-based algorithms for safety outcomes are FFP for a specific decision context. Reliability and validity testing using a larger sample of participants in other therapeutic areas and further modifications to reduce the time needed to complete the assessment are needed to fully evaluate its utility for regulatory decision-making.

New construction has resulted in impervious surfaces increasingly replacing natural landscapes, altering surface radiation, thermal properties, and humidity in urban areas. Based on Landsat-8 data, the temporal and spatial impacts of the construction of Dalian Jinzhouwan Airport and Beijing Daxing Airport on the thermal environment were studied. The local thermal gradient (LTG) of the airport before and after construction is compared. The results showed that after the completion of the airport, the LTG value of Daxing Airport increased by 0.033 and that of Jinzhou Bay Airport increased by 0.009. After the airport operation, LTG values increase again. Daxing Airport added another 0.053, and Jinzhou Bay Airport added another 0.127. Two land classification models (land use type, LUT; local climate zone, LCZ) were used to explore the relationship between land use type and LTG. The results show that the increase of alloy buildings after the completion of the airport has a great influence on the thermal environment of the two study areas. The operation of airports will further enhance this effect. Our study can provide a reference for the influence of large-scale traffic construction on the urban thermal environment.

Objective This study evaluated the identification efficiency of contrast-enhanced ultrasound (CEUS) for sentinel lymph nodes (SLN) to accurately represent the axillary node status in early-stage breast cancer. Method In total, 109 consecutive consenting patients with clinically node-negative and T1-2 breast cancer were included in this study. All patients received CEUS to identify SLN before surgery, and a guidewire was deployed to locate SLN in those who were successfully explored by CEUS. The patients underwent sentinel lymph node biopsy (SLNB), and the blue dye was used to trace SLN during the surgery. The decision to perform axillary lymph node dissection (ALND) depended on the intraoperative pathological identification of SLN by CEUS (CE-SLN). The concordance rate of pathological status between CE-SLN and dyed SLN was calculated. Result The CEUS detection rate was 96.3%; CE-SLN failed in 4 patients. Among the remaining 105 successful identifications, 18 were CE-SLN positive by intraoperative frozen section, and one with CE-SLN micrometastasis was diagnosed by paraffin section. No additional lymph node metastases were found in CE-SLN-negative patients. The concordance rate of pathological status between CE-SLN and dyed SLN was 100%. Conclusion CEUS can accurately represent the status of axillary lymph nodes in patients with clinically node-negative and small tumor burden breast cancer. Graphical Abstract

The proppant accumulation form in fractures is related to the formation conductivity after fracture closure, also closely related to the production rate of oil/gas wells. In order to investigate the influence of proppant physical properties on sand accumulation in fractures, a particle–fluid coupling flow model is established based on the Euler two-fluid model. Geometric parameters of a fracture in tight oil wells are approximately scaled in equal proportion as the physical model, which is solved by the finite volume method. And the model accuracy is verified by comparing with the physical experimental simulation in the literature. Results show that the higher proppant concentration corresponds to the faster particle sedimentation rate, and the greater sand embankment accumulation as well. However, the fluid viscosity will increase, inhibiting proppant migration to the deep part of the fracture. Reducing proppant density and particle size will enhance the fluidization ability of particles, which is conducive to the migration to the deep fracture at the initial stage of pumping. But, it is not beneficial to have a desirable accumulation state in the middle and later pumping stage, so it is difficult to obtain a higher comprehensive equilibrium height.

Rose is one of the most important ornamental plants, accounting for one-third of the world’s fresh cut flower market. The vase life refers to the period of a cut flower retaining its appearance in a vase. During this period, the rose was subjected to a variety of abiotic and biotic stresses, resulting in a reduction in the life of cut flowers. Numerous studies have been carried out on cut rose, which proves the effects of various plant hormones on post-harvest dehydration, petal senescence and abscission, disease and vase life of cut rose flowers. In addition, the natural or synthetic hormones or its inhibitor have been successfully used in cut flower preservatives to extend the vase life of rose. However, there is still a lack of systematic and in-depth research on the expression of rose genes related to plant hormone response. Here we analyzed the gene expression changes of the rose flower under treatment of 11 different plant hormones or its inhibitors in order to provide reference for rose studies.

A common way to develop and exploit unconventional tight reservoirs is to use horizontal wells with multiple fractures. It has been postulated that in unconventional tight reservoirs as a result of hydraulic fracturing the stimulated region can be created near the hydraulic fracture. Recently, as practical alternatives to computationally intensive numerical models, analytical multi-linear flow models for unconventional tight reservoirs have been developed. In these models, fluid flow is assumed to obey Darcy's law. However, as unconventional tight gas reservoirs are characterized by widespread micro/nanoscale pores, non-Darcy flow typically occurs in the unstimulated region. In many unconventional tight reservoirs, despite their low permeability and the existence of the stimulated region, unstimulated regions can also affect the production significantly and thus it is necessary to consider the non-Darcy flow in unstimulated regions for modeling the reservoir production. In this paper, an analytical multi-linear flow model considering non-Darcy flow effect for unstimulated regions is proposed. Pseudo-time including pressure-dependent apparent permeability is introduced to derive the model. The pseudo-time is evaluated at the average pressure within the region of influence. The applicability of the model has been discussed. The model was validated by comparison with numerical simulation. It was found that the model’s results are in reasonable agreement with the numerical simulation results and the average relative error is less than 15%. The model can be used to simulate the multistage fractured horizontal well production in unconventional tight gas reservoirs where the non-Darcy flow effect is significant for practical purposes.

Objectives To study the correlations between facial profile markers and crown-lump length (CRL) in a Chinese population, and to evaluate the clinical value of these markers for abnormal fetuses during the first trimester (11 to 13+ 6 gestational weeks) . Methods The facial profile markers were as followings: inferior facial angle (IFA), maxilla-nasion-mandible (MNM) angle, facial maxillary angle (FMA), frontal space (FS) distance and profile line (PL) distance. These markers were measured in facial mid-sagittal section through ViewPoint 6 software. The diagnostic value of these markers for abnormal fetuses was assessed by receiver operating characteristic (ROC) curves. Results According to the ultrasonic examination and follow-up, 31 fetuses were enrolled in the abnormal group, including 14 cases of trisomy 21, 7 cases of trisomy 18, 10 cases with cleft lip and palate (CLP), and 1000 cases were selected to the normal group, during the first trimester,with the CRL from 45mm to 84 mm. In the normal group, the IFA, FS distance and PL distance had negative correlations with CRL during the first trimester (rs=-0.614, p s=-0.42, p s=-0.271, p s=0574, p s=0.451, p p = 0.013; Z=-3.018, p = 0.003). The mean MNM angle of fetuses with trisomy 18 and CLP were 6.98° (SD 2.61) and 9.41° (SD 2.57), respectively, which were significantly greater than the normal group (Z=-2.83, p = 0.005; Z=-5.05, p p p p = 0.56; t=-0.515, p = 0.607; t = 0.613, p = 0.54). Conclusions Fetal facial profile markers had excellent correlations with CRL during the first trimester. IFA had certain clinical significance in detecting trisomy 21. FMA, IFA and MNM angle were reliable indicators for screening trisomy 18. The abnormal MNM angle and FS distance could be used as sensitive indicators for CLP. However, PL distance was not the best markers for trisomy 21, trisomy 18 and CLP during the first trimester.

Wettability plays a vital role in fundamental researches and practical applications. Wettability control and patterning have been widely studied in various fields. Although researches have grown rapidly, the methods are still restricted by limitations including complicated processes, high equipment requirements and shortage of methods to treat complex surfaces. Here we report a simple, low cost, array-based wettability control and patterning method via in-situ modification by flexible plasma stamp. Wettability control and patterning on surfaces of superhydrophobic aluminum, superhydrophobic PDMS and silicon, even plant leaf and fruit are achieved. The relationships between the wettability and the treatment time are investigated. We elucidate that the wetting states can also be reversible. The surface modification mechanism of in-situ plasma treatment is further investigated. Utilizing the step by step treatment, gradient and arbitrary wettability patterning on surfaces have been obtained. Notably, the patterned wettability on the inner surface of a tube has been realized, which has never been reported. Finally, in-situ wettability patterning is applied to achieve microfluidics channels on the inner surface of superhydrophobic tube. This work will bring new insights into the study of wetting field and stimulate more applications on wettability control and patterning.

Extensive efforts have been made to harvest energy from water in the form of raindrops1–6, river and ocean waves7,8, tides9 and others10–17. However, achieving a high density of electrical power generation is challenging. Traditional hydraulic power generation mainly uses electromagnetic generators that are heavy, bulky, and become inefficient with low water supply. An alternative, the water-droplet/solid-based triboelectric nanogenerator, has so far generated peak power densities of less than one watt per square metre, owing to the limitations imposed by interfacial effects—as seen in characterizations of the charge generation and transfer that occur at solid–liquid1–4 or liquid–liquid5,18 interfaces. Here we develop a device to harvest energy from impinging water droplets by using an architecture that comprises a polytetrafluoroethylene film on an indium tin oxide substrate plus an aluminium electrode. We show that spreading of an impinged water droplet on the device bridges the originally disconnected components into a closed-loop electrical system, transforming the conventional interfacial effect into a bulk effect, and so enhancing the instantaneous power density by several orders of magnitude over equivalent devices that are limited by interfacial effects. A device involving a polytetrafluoroethylene film, an indium tin oxide substrate and an aluminium electrode allows improved electricity generation from water droplets, which bridge the previously disconnected circuit components.

Background High temperature seriously limits the annual production of fresh cut lilies, which is one of the four major cut flowers in the global cut flower market. There were few transcriptomes focused on the gene expression of lilies under heat stress. In order to reveal the potential heat response patterns in bulbous plants and provide important genes for further genetic engineering techniques to improve thermotolerance of lily, RNA sequencing of lilies under heat treatments were conducted. Results In this study, seedlings of Lilium longiflorum ‘White Heaven’ were heat-treated at 37 °C for different lengths of time (0 h, 0.5 h, 1 h, 3 h, 6 h, and 12 h with a 12 h-light/12 h-dark cycle). The leaves of these lily seedlings were immediately collected after heat treatments and quickly put into liquid nitrogen for RNA sequencing. 109,364,486–171,487,430 clean reads and 55,044 unigenes including 21,608 differentially expressed genes (DEGs) (fold change ≥2) were obtained after heat treatment. The number of DEGs increased sharply during the heat treatments of 0.5 h–1 h and 1 h–3 h compared to that of other periods. Genes of the heat stress transcription factor (HSF) family and the small heat shock proteins (small HSPs, also known as HSP20) family responded to heat stress early and quickly. Compared to that of the calcium signal and hormone pathways, DEGs of the HSF-HSP pathway and reactive oxygen species (ROS) pathway were significantly and highly induced. Moreover, they had the similar expression pattern in response to heat stress. Small HSPs family genes were the major components in the 50 most highly induced genes at each heat stress treatment and involved in ROS pathway in the rapid response to heat stress. Furthermore, the barley stripe mosaic virus induced gene silencing (BSMV-VIGS) of LlHsfA2 caused a significantly reduced thermotolerance phenotype in Lilium longiflorum ‘White Heaven’, meanwhile decreasing the expression of small HSPs family genes and increasing the ROS scavenging enzyme ascorbate peroxidase (APX) genes, indicating the potential interplay between these two pathways. Conclusions Based on our transcriptomic analysis, we provide a new finding that small HSPs play important roles in crosstalk between HSF-HSP and ROS pathways in heat stress response of lily, which also supply the groundwork for understanding the mechanism of heat stress in bulbous plants.

We present an explicit and recursive representation for high order moments of the first hitting times of single death processes. Based on that, some necessary or sufficient conditions of exponential ergodicity as well as a criterion on l-ergodicity are obtained for single death processes, respectively.

Although a variety of whole-cell biosensors and biosorbents have been developed for detection and removal of heavy metal contaminants, few whole cells can be applied to both monitoring and remediation of copper pollution in water. In this study, a modified plasmid was constructed by incorporating a copper-sensing element and a copper-adsorbing element into a temperature-inducible plasmid, pBV220. This plasmid was subsequently transformed into an engineered Escherichia coli strain lacking copA and cueO. This dual-functional E. coli cell selectively responded to copper ions with a linear detection range of 0.01-25 μM at 37 °C and could express surface-displayed CueR when treated at 42 °C without any costly chemical inducers. The display of CueR on the cell surface specifically enhanced its copper adsorption capacity and rapidly removed copper ions from aqueous solutions. In addition, the CueR surface-displayed cells could be regenerated by adsorption-desorption cycles via pH regulation. Moreover, by simply using two different temperatures, the detection or adsorption of copper using this dual-functional whole cell was achieved without any cross-interference. Most importantly, it provided highly sensitive, accurate quantification, and effective removal of copper in real environmental water samples. Thus, this E. coli cell can be used for large-scale detection and remediation of copper pollutants.

Plants have evolved sophisticated systems in response to environmental changes, and growth arrest is a common strategy used to enhance stress tolerance. Despite the growth–survival trade-off being essential to the shaping of plant productivity, the mechanisms balancing growth and survival remain largely unknown. Aquaporins play a crucial role in growth and stress responses by controlling water transport across membranes. Here, we show that RhPIP2;1, an aquaporin from rose (Rosa sp.), interacts with a membrane-tethered MYB protein, RhPTM. Water deficiency triggers nuclear translocation of the RhPTM C terminus. Silencing of RhPTM causes continuous growth under drought stress and a consequent decrease in survival rate. RNA sequencing (RNA-seq) indicated that RhPTM influences the expression of genes related to carbohydrate metabolism. Water deficiency induces phosphorylation of RhPIP2;1 at Ser 273, which is sufficient to promote nuclear translocation of the RhPTM C terminus. These results indicate that the RhPIP2;1-RhPTM module serves as a key player in orchestrating the trade-off between growth and stress survival in Rosa. Functional interaction between an aquaporin and a membrane-tethered growth suppressor MYB transcription factor leads to activation of the latter, establishing a link between hydraulics and transcriptional control.

Metallic tungsten disulfide (WS2) monolayers have been demonstrated as promising electrocatalysts for hydrogen evolution reaction (HER) induced by the high intrinsic conductivity, however, the key challenges to maximize the catalytic activity are achieving the metallic WS2 with high concentration and increasing the density of the active sites. In this work, single-atom-V catalysts (V SACs) substitutions in 1T-WS2 monolayers (91% phase purity) are fabricated to significantly enhance the HER performance via a one-step chemical vapor deposition strategy. Atomic-resolution scanning transmission electron microscopy (STEM) imaging together with Raman spectroscopy confirm the atomic dispersion of V species on the 1T-WS2 monolayers instead of energetically favorable 2H-WS2 monolayers. The growth mechanism of V SACs@1T-WS2 monolayers is experimentally and theoretically demonstrated. Density functional theory (DFT) calculations demonstrate that the activated V-atom sites play vital important role in enhancing the HER activity. In this work, it opens a novel path to directly synthesize atomically dispersed single-metal catalysts on metastable materials as efficient and robust electrocatalysts. Ru is one of the most active metals for oxygen evolution reaction, but it quickly dissolves in acidic electrolyte particularly in nanosized form. Here the authors show that coral-like solid-solution Ru‒Ir consisting of 3 nm-thick sheets with only 6 at% Ir is a long-lived catalyst with high activity

An interesting subject of non-fuel utilization of coal is the synthesis of high-performance coal-based carbon (CBC) materials to replace expensive Pt counter electrodes (CEs) in dye-sensitized solar cells (DSSCs). Selection of coal source, treatment, and structural optimization of coal should be considered to obtain high-performance CBC CEs. In this study, a coal-based porous carbon material with low cost and high performance was synthesized from three kinds of pulverized coal (collected from different regions of Xinjiang, China) through chemical activation followed by acid washing oxidation treatment. The prepared porous CBC material exhibited higher catalytic activity for the reduction of I−/I3− than Pt. The use of carbon nanotubes (CNTs) plus prepared porous CBC/CNTs composite materials as CEs for DSSCs led to a VOC of 0.62 V, a JSC of 21.92 mA cm−2, an FF of 0.42, and a conversion efficiency of 5.75%, which is higher than those of CEs made of porous CBC, CNTs, or Pt. The improvement in the conversion efficiency could be attributed to the synergistic effect of the good catalytic activity of the prepared CBC materials and the good conductivity of CNTs. Moreover, the double-layer structure played an important role in improving the adhesion and electron transport capacity. Results provide a theoretical basis for the possible use of cheap CBCs as CEs for thin-film solar cells. We use the ZnO as photoanode; the dye is N719.

We find that the DREB subfamily transcription factor, CmERF053, has a novel function to regulate the development of shoot branching and lateral root in addition to affecting abiotic stress. Dehydration-responsive element binding proteins (DREBs) are important plant transcription factors that regulate various abiotic stresses. Here, we isolated an APETALA2/ethylene-responsive factor (AP2/ERF) transcription factor from chrysanthemum (Chrysanthemum morifolium 'Jinba'), CmERF053, the expression of which was rapidly up-regulated by main stem decapitation. Phylogenetic analysis indicated that it belongs to the A-6 group of the DREB subfamily, and the subcellular localization assay confirmed that CmERF053 was a nuclear protein. Overexpression of CmERF053 in Arabidopsis exhibited positive effects of plant lateral organs, which had more shoot branching and lateral roots than did the wild type. We also found that the expression of CmERF053 in axillary buds was induced by exogenous cytokinins. These results suggested that CmERF053 may be involved in cytokinins-related shoot branching pathway. In this study, an altered auxin distribution was observed during root elongation in the seedlings of the overexpression plants. Furthermore, overexpress CmERF053 gene could enhance drought tolerance. Together, these findings indicated that CmERF053 plays crucial roles in regulating shoot branching, lateral root, and drought stress in plant. Moreover, our study provides potential application value for improving plant productivity, ornamental traits, and drought tolerance.

Information exists as unstructured medical text in healthcare databases. Such information is not routinely considered in safety surveillance but typically relies solely on structured (coded) data. Natural language processing (NLP) may allow the capture of concepts from unstructured data and thus enhance safety surveillance capability. We sought to assess the added contribution of unstructured data extracted from medical text by NLP for detecting acute liver dysfunction (ALD) in patients with inflammatory bowel disease (IBD). Using a previously developed rule, we evaluated structured and unstructured NLP-extracted terms from a commercially available electronic medical record (EMR) system. The rule was intended to identify ALD diagnosis and timing of onset and was the result of three iterations of rule development using 150 ALD candidate cases. We evaluated the performance of the rule with or without NLP among all candidate cases and among 50 new cases with clinical adjudication. NLP terms were necessary for the diagnosis of 9% of cases and for ruling out 3% of false-positive cases. Inclusion of NLP terms led to an identification of an additional 9% of ALD-onset dates, with consequent earlier recognition in 5%. NLP-derived terms in one large commercially available EMR system modestly improved the sensitivity and specificity in the identification of ALD and identified earlier onset.

Acute ischemic stroke (AIS), as the third leading cause of death worldwide, is characterized by its high incidence, mortality rate, high incurred disability rate, and frequent reoccurrence. The neuroprotective effects of Ginkgo biloba extract (GBE) against several cerebral diseases have been reported in previous studies, but the underlying mechanisms of action are still unclear. Using a novel in vitro rat cortical capillary endothelial cell-astrocyte-neuron network model, we investigated the neuroprotective effects of GBE and one of its important constituents, Ginkgolide B (GB), against oxygen-glucose deprivation/reoxygenation and glucose (OGD/R) injury. In this model, rat cortical capillary endothelial cells, astrocytes, and neurons were cocultured so that they could be synchronously observed in the same system. Pretreatment with GBE or GB increased the neuron cell viability, ameliorated cell injury, and inhibited the cell apoptotic rate through Bax and Bcl-2 expression regulation after OGD/R injury. Furthermore, GBE or GB pretreatment enhanced the transendothelial electrical resistance of capillary endothelial monolayers, reduced the endothelial permeability coefficients for sodium fluorescein (Na-F), and increased the expression levels of tight junction proteins, namely, ZO-1 and occludin, in endothelial cells. Results demonstrated the preventive effects of GBE on neuronal cell death and enhancement of the function of brain capillary endothelial monolayers after OGD/R injury in vitro; thus, GBE could be used as an effective neuroprotective agent for AIS/reperfusion, with GB as one of its significant constituents.

The ability to control cell patterning on artificial substrates with various physicochemical properties is of essence for important implications in cytology and biomedical fields. Despite extensive progress, the ability to control the cell-surface interaction is complicated by the complexity in the physiochemical features of bioactive surfaces. In particular, the manifestation of special wettability rendered by the combination of surface roughness and surface chemistry further enriches the cell-surface interaction. Herein we investigated the cell adhesion behaviors of Circulating Tumor Cells (CTCs) on topographically patterned but chemically homogeneous surfaces. Harnessing the distinctive cell adhesion on surfaces with different topography, we further explored the feasibility of controlled cell patterning using periodic lattices of alternative topographies. We envision that our method provides a designer's toolbox to manage the extracellular environment.

A comparative study of two methods for the synthesis of hierarchical structural CuBi2O4 particles was performed and the prepared samples were used in ZnO-based dye-sensitized solar cells (DSSCs) as an inorganic photosensitizer and additive for the ZnO anode. The structure, morphology, and light absorption were characterized by X-ray diffraction, scanning electron microscopy, and UV–Visible diffuse reflectance spectra. The photovoltaic performance was also investigated. Results indicate that this new type of thin-film solar cell, namely, ZnO/CuBi2O4/Pt (with CuBi2O4 instead of dye), yielded an overall light conversion efficiency of 0.45%. This result suggests that CuBi2O4 is highly likely to develop into a promising inorganic photosensitizer through further structural optimization and adjustment. By contrast, CuBi2O4 was also added into the ZnO to form a composite photoanode and sensitized by N719 dye thereafter. Results show that the addition of a minimal amount of CuBi2O4 (0.3 wt%) improves the photovoltaic efficiency by 25% compared with that of the pure ZnO-based DSSCs. The reason for such improvement was discussed with an interfacial charge transfer mechanism.

Class cohesion has an immediate impact on maintainability, modifiability and understandability of the software. Here, a new metric of cohesion based on complex networks (CBCN) for measuring connectivity of class members was developed mainly relying on calculating class average clustering coefficient from graphs representing connectivity patterns of the various class members. In addition, the CBCN metric was assessed with theoretical validation according to four properties (nonnegativity and normalization, null and maximum values, monotonicity, cohesive modules) of the class cohesion theory. Based on data comparison with existing seventeen typical class cohesion metrics of class cohesion for a system, the CBCN metric was superior to others. Applying the CBCN metric to three open source software systems to calculate class average clustering coefficients, we found that understanding, modification and maintenance of classes in an open software system could be likely less difficult compared with those of others. Three open software systems have power-law distributions for the class average clustering coefficient, which makes possible the further understanding of the cohesion metric based on complex networks.

This paper deals with the dynamic behavior of the chaotic nonlinear time delay systems of general form $\dot{x}(t)=g(x(t),x(t-\tau ))$ . We carry out stability analysis to identify the parameter zone for which the system shows a stable equilibrium response. Through the bifurcation analysis, we establish that the system shows a stable limit cycle through supercritical Hopf bifurcation beyond certain values of delay and parameters. Next, a numerical simulation of the prototype system is used to show that the system has different behaviors: stability, periodicity and chaos with the variation of delay and other parameters, which demonstrates the validity of our method. We give the single- and two-parameter bifurcation diagrams which are employed to explore the dynamics of the system over the whole parameter space.

High surface area aluminum containing spherical mesocellular silica foams (SMCFs) with ultra-large pore volume and 3D pore size were successfully synthesized through a simple hydrothermal route, and the as-synthesized aluminum containing SMCFs (Al-SMCFs) was applied as the support of NiMo-base catalyst for the hydrodesulfurization (HDS) of fluid catalytic cracking (FCC) diesel. The as-synthesized supports and corresponding catalysts were characterized by powder small X-ray diffraction, nitrogen physisorption, scanning electron microscopy, transmission electron microscopy (TEM), inductively coupled plasma optical emission spectroscopy, and temperature-programmed reduction with H2. The characterization results showed that, compared with other prepared catalysts (NiMo/Al-SBA-15 and NiMo/Al-KIT-6), the NiMo/Al-SMCFs catalyst possessed the most optimal physicochemical parameters, i.e., ultra-large 3D pore size (42.0 nm), high surface area (330.1 m2·g−1), and ultra-large pore volume (1.96 cm3·g−1), resulting in the formation of more homogeneous distribution of octahedral Mo active species and good mass transfer performance. Consequently, the NiMo/Al-SMCFs catalyst displayed the outstanding HDS performance (98.8%) of FCC diesel, confirming that the Al-SMCFs may be a type of promising candidate for oil hydrotreating.

In this paper, we propose a novel classification model for the multiple instance data, which aims to maximize the number of positive instances ranked before the top-ranked negative instances. This method belongs to a recently emerged performance, named as Pos@Top. Our proposed classification model has a convolutional structure that is composed by four layers, i.e., the convolutional layer, the activation layer, the max-pooling layer and the full connection layer. In this paper, we propose an algorithm to learn the convolutional filters and the full connection weights to maximize the Pos@Top measure over the training set. Also, we try to minimize the rank of the filter matrix to explore the low-dimensional space of the instances in conjunction with the classification results. The rank minimization is conducted by the nuclear norm minimization of the filter matrix. In addition, we develop an iterative algorithm to solve the corresponding problem. We test our method on several benchmark datasets. The experimental results show the superiority of our method compared with other state-of-the-art Pos@Top maximization methods.

To meet customers' pressing demands, enterprise database vendors have been pushing advanced analytical techniques into databases. Most major DBMSes use user-defined aggregates (UDAs), a data-driven operator, to implement analytical techniques in parallel. However, UDAs alone are not sufficient to implement statistical algorithms where most of the work is performed by iterative transitions over a large state that cannot be naively partitioned due to data dependency. Typically, this type of statistical algorithm requires pre-processing to set up the large state in the first place and demands post-processing after the statistical inference. This paper presents general iterative state transition (GIST), a new database operator for parallel iterative state transitions over large states. GIST receives a state constructed by a UDA and then performs rounds of transitions on the state until it converges. A final UDA performs post-processing and result extraction. We argue that the combination of UDA and GIST (UDA---GIST) unifies data-parallel and state-parallel processing in a single system, thus significantly extending the analytical capabilities of DBMSes. We exemplify the framework through two high-profile batch applications: cross-document coreference, image denoising and one query-time inference application: marginal inference queries over probabilistic knowledge graphs. The 3 applications use probabilistic graphical models, which encode complex relationships of different variables and are powerful for a wide range of problems. We show that the in-database framework allows us to tackle a 27 times larger problem than a scalable distributed solution for the first application and achieves 43 times speedup over the state-of-the-art for the second application. For the third application, we implement query-time inference using the UDA---GIST framework and apply over a probabilistic knowledge graph, achieving 10 times speedup over sequential inference. To the best of our knowledge, this is the first in-database query-time inference engine over large probabilistic knowledge base. We show that the UDA---GIST framework for data- and graph-parallel computations can support both batch and query-time inference efficiently in databases.

An often key component to coordinating surveillance activities across distributed networks is the design and implementation of a common data model (CDM). The purpose of this study was to evaluate two drug safety surveillance CDMs from an ecosystem perspective to better understand how differences in CDMs and analytic tools affect usability and interpretation of results. Humana claims data from 2007 to 2012 were mapped to Observational Medical Outcomes Partnership (OMOP) and Mini-Sentinel CDMs. Data were described and compared at the patient level by source code and mapped concepts. Study cohort construction and effect estimates were also compared using two different analytical methods—one based on a new user design implementing a high-dimensional propensity score (HDPS) algorithm and the other based on univariate self-controlled case series (SCCS) design—across six established positive drug-outcome pairs to learn how differences in CDMs and analytics influence steps in the database analytic process and results. Claims data for approximately 7.7 million Humana health plan members were transformed into the two CDMs. Three health outcome cohorts and two drug cohorts showed differences in cohort size and constituency between Mini-Sentinel and OMOP CDMs, which was a result of multiple factors. Overall, the implementation of the HDPS procedure on Mini-Sentinel CDM detected more known positive associations than that on OMOP CDM. The SCCS method results were comparable on both CDMs. Differences in the implementation of the HDPS procedure between the two CDMs were identified; analytic model and risk period specification had a significant impact on the performance of the HDPS procedure on OMOP CDM. Differences were observed between OMOP and Mini-Sentinel CDMs. The analysis of both CDMs at the data model level indicated that such conceptual differences had only a slight but not significant impact on identifying known safety associations. Our results show that differences at the ecosystem level of analyses across the CDMs can lead to strikingly different risk estimations, but this can be primarily attributed to the choices of analytic approach and their implementation in the community-developed analytic tools. The opportunities of using CDMs are clear, but our study shows the need for judicious comparison of analyses across the CDMs. Our work emphasizes the need for ongoing efforts to ensure sustainable transparent platforms to maintain and develop CDMs and associated tools for effective safety surveillance.

Resistance has been reported to human epidermal growth factor receptor 2 (HER2)-targeted therapy with the tyrosine kinase inhibitor lapatinib and the antibody trastuzumab in metastatic gastric cancer. An alternative or complement might be to target the extracellular domain of HER2 with therapy-effective radionuclides. The fraction of patients with HER2 expression in primary tumors and major metastatic sites, e.g., lymph nodes and liver, was analyzed to evaluate the potential for such therapy. Samples from primary tumors and lymph node and liver metastases were taken from each patient within a few hours, and to our knowledge, such sampling is unique. The number of analyzed cases was therefore limited, since patients that had received preoperative radiotherapy, chemotherapy, or HER2-targeted therapy were excluded. From a large number of considered patients, only 29 could be included for HER2 analysis. Intracellular mutations were not analyzed since they are assumed to have no or minor effect on the extracellular binding of molecules that deliver radionuclides. HER2 was positive in nearly 52 % of the primary tumors, and these expressed HER2 in corresponding lymph node and liver metastases in 93 and 100 % of the cases, respectively. Similar values for primary tumors and also good concordance with metastases have been indicated in the literature. Thus, relevant radionuclides and targeting molecules for nuclear medicine-based noninvasive, whole-body receptor analysis, dose planning, and therapy can be applied for many patients; see "Discussion" Hopefully, more patients can then be treated with curative instead of palliative intention.

Defects in the DNA damage repair pathway contribute to cancer. The major pathway for oxidative DNA damage repair is base excision repair (BER). Although BER pathway genes (OGG1, APEX1 and XRCC1) have been investigated in a number of cancers, our knowledge on the prognostic significance of these genes and their role in head and neck squamous cell carcinoma is limited. Protein levels of OGG1, APEX1 and XRCC1 and a proliferation marker, Ki-67, were examined by immunohistochemical analysis, in a cohort of 50 HNSCC patients. Significant downregulation of OGG1 (p < 0.04) and XRCC1 (p < 0.05) was observed in poorly differentiated HNSCC compared to mod–well-differentiated cases. Significant upregulation of APEX1 (p < 0.05) and Ki-67 (p < 0.05) was observed in poorly differentiated HNSCC compared to mod-well-differentiated cases. Significant correlation was observed between XRCC1 and OGG1 (r = 0.33, p < 0.02). Inverse correlations were observed between OGG1 and Ki-67 (r = −0.377, p < 0.005), between APEX1 and XRCC1 (r = −0.435,p < 0.002) and between OGG1 and APEX1 (r = −0.34, p < 0.02) in HNSCC. To confirm our observations, we examined BER pathway genes and a proliferation marker, Ki-67, expression at the mRNA level on 50 head and neck squamous cell carcinoma (HNSCC) and 50 normal control samples by quantitative real-time polymerase chain reaction. Significant downregulation was observed in case of OGG1 (p < 0.04) and XRCC1 (p < 0.02), while significant upregulation was observed in case of APEX1 (p < 0.01) and Ki-67 (p < 0.03) in HNSCC tissue samples compared to controls. Our data suggested that deregulation of base excision repair pathway genes, such as OGG1, APEX1 and XRCC1, combined with overexpression of Ki-67, a marker for excessive proliferation, may contribute to progression of HNSCC in Pakistani population.

Chromosome ends are protected by telomeres that prevent DNA damage response and degradation. Telomerase expression extends telomeres and inhibits DNA damage response. Telomeres are also maintained by the recombination-based alternative lengthening pathway. Telomerase is believed to be the sole mechanism for telomere maintenance in the epidermis. We show that basal cells in the epidermis maintain telomeres both by telomerase and alternative lengthening of telomere (ALT) mechanisms in vivo. ALT was detected in epidermal stem cells in Terc(-/-) mice, and normal human epidermal keratinocytes are also ALT-positive. The ALT pathway is suppressed in primary, but not metastatic, epidermal squamous cell carcinomas (SCC) in Terc(+/+) mice. The ALT pathway is expressed in stem cells and basal cells in epidermal SCC in Terc(-/-) mice, and in some telomerase-positive human SCC lines. Telomeres shorten markedly in stem cells and basal cells in epidermal SCC in vivo. Telomere shortening is associated with telomeric DNA damage response and apoptosis in stem cells and basal cells. Stem cells were transformed in both primary and metastatic epidermal SCC. Genetic ablation of this small cell population resulted in significant tumor regression in vivo. We concluded that alternative lengthening of telomeres is important in epidermal homeostasis and tumorigenesis in vivo.

This paper presents a symmetrical double-sided serpentine beam-mass structure design with a convenient and precise process of manufacturing MEMS accelerometers. The symmetrical double-sided serpentine beam-mass structure is fabricated from a single double-device-layer SOI wafer, which has identical buried oxides and device layers on both sides of a thick handle layer. The fabrication process produced proof mass with though wafer thickness (860 μm) to enable formation of a larger proof mass. Two layers of single crystal silicon serpentine beams with highly controllable dimension suspend the proof mass from both sides. A sandwich differential capacitive accelerometer based on symmetrical double-sided serpentine beams-mass structure is fabricated by three layer silicon/silicon wafer direct bonding. The resonance frequency of the accelerometer is measured in open loop system by a network analyzer. The quality factor and the resonant frequency are 14 and 724 Hz, respectively. The differential capacitance sensitivity of the fabricated accelerometer is 15 pF/g. The sensitivity of the device with close loop interface circuit is 2 V/g, and the nonlinearity is 0.6 % over the range of 0–1 g. The measured input referred noise floor of accelerometer with interface circuit is 2 μg/√Hz (0–250 Hz).

There has been increased interest in using multiple observational databases to understand the safety profile of medical products during the postmarketing period. However, it is challenging to perform analyses across these heterogeneous data sources. The Observational Medical Outcome Partnership (OMOP) provides a Common Data Model (CDM) for organizing and standardizing databases. OMOP’s work with the CDM has primarily focused on US databases. As a participant in the OMOP Extended Consortium, we implemented the OMOP CDM on the UK Electronic Healthcare Record database—The Health Improvement Network (THIN). The aim of the study was to evaluate the implementation of the THIN database in the OMOP CDM and explore its use for active drug safety surveillance. Following the OMOP CDM specification, the raw THIN database was mapped into a CDM THIN database. Ten Drugs of Interest (DOI) and nine Health Outcomes of Interest (HOI), defined and focused by the OMOP, were created using the CDM THIN database. Quantitative comparison of raw THIN to CDM THIN was performed by execution and analysis of OMOP standardized reports and additional analyses. The practical value of CDM THIN for drug safety and pharmacoepidemiological research was assessed by implementing three analysis methods: Proportional Reporting Ratio (PRR), Univariate Self-Case Control Series (USCCS) and High-Dimensional Propensity Score (HDPS). A published study using raw THIN data was selected to examine the external validity of CDM THIN. Overall demographic characteristics were the same in both databases. Mapping medical and drug codes into the OMOP terminology dictionary was incomplete: 25 % medical codes and 55 % drug codes in raw THIN were not listed in the OMOP terminology dictionary, representing 6 % condition occurrence counts, 4 % procedure occurrence counts and 7 % drug exposure counts in raw THIN. Seven DOIs had

Background Oral tongue squamous cell carcinoma (OTSCC) is one of the most aggressive forms of head and neck/oral cancer (HNOC), and is a complex disease with extensive genetic and epigenetic defects, including microRNA deregulation. Identifying the deregulation of microRNA-mRNA regulatory modules (MRMs) is crucial for understanding the role of microRNA in OTSCC. Methods A comprehensive bioinformatics analysis was performed to identify MRMs in HNOC by examining the correlation among differentially expressed microRNA and mRNA profiling datasets and integrating with 12 different sequence-based microRNA target prediction algorithms. Confirmation experiments were performed to further assess the correlation among MRMs using OTSCC patient samples and HNOC cell lines. Functional analyses were performed to validate one of the identified MRMs: miR-21-15-Hydroxyprostaglandin Dehydrogenase (HPGD) regulatory module. Results Our bioinformatics analysis revealed 53 MRMs that are deregulated in HNOC. Four high confidence MRMs were further defined by confirmation experiments using OTSCC patient samples and HNOC cell lines, including miR-21-HPGD regulatory module. HPGD is a known anti-tumorigenic effecter, and it regulates the tumorigenic actions of Prostaglandin E2 (PGE2) by converts PGE2 to its biologically inactive metabolite. Ectopic transfection of miR-21 reduced the expression of HPGD in OTSCC cell lines, and the direct targeting of the miR-21 to the HPGD mRNA was confirmed using a luciferase reporter gene assay. The PGE2-mediated upregulation of miR-21 was also confirmed which suggested the existence of a positive feed-forward loop that involves miR-21, HPGD and PGE2 in OTSCC cells that contribute to tumorigenesis. Conclusions We identified a number of high-confidence MRMs in OTSCC, including miR-21-HPGD regulatory module, which may play an important role in the miR-21-HPGD-PGE2 feed-forward loop that contributes to tumorigenesis. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2716-0) contains supplementary material, which is available to authorized users.

The surface of individual, relatively dispersed Fe3O4 nanospheres is coated with a thiol-terminated silane, then the thiol on the Fe3O4 particles’ surfaces treats with nano-Ag colloidal solution to form Ag-modified Fe3O4 nanoparticles. Eventually, a solid shell of Ag is capped onto the Ag-modified Fe3O4 nanoparticles by reducing aliquots of AgNO3 solution using NaBH4 as a reducing agent. The as-prepared Fe3O4-core@Ag-shell nanoeggs, which are uniform in size, highly monodisperse, stable against aggregation and have high magnetization, were depended on thin shell of the attached nano-Ag, the size of Fe3O4 nanoparticles, the volume of thiol-terminated silane as well as the ultrasonication. The Fe3O4-core@Ag-shell nanoeggs are proposed to detect fingermarks on different surface, with which the fingermarks can be viewed directly, due to the clear ridge detail.

This paper discusses the kinetic fractionation, composition and distribution characteristics of carbon and hydrogen isotopes for various alkane gases formed in different environments, by different mechanisms and from different sources in nature. It is demonstrated that the biodegradation or thermodegradation of complex high-molecule sedimentary organic material can form microbial gas or thermogenic gas. The δ13C1 value ranges from −110% to −50% for microbial gases but from −50% to −35% (even heavier) for thermogenic gases. Controlled by the kinetic isotope fractionation, both microbial and thermogenic gases have δ13C and δ D values characterized by normal distribution, i.e. δ13C1 δ 13C2> δ 13C3> δ 13C4 and \( \delta D_{CH_4 } < \delta D_{C_2 H_6 } < \delta D_{C_3 H_8 } < \delta D_{C_4 H_{10} } \). The δ 13C values and δ D values are negatively correlated. Natural gases from 26 commercial gas wells distributed in the Xujiaweizi and Yingshan-Miaotaizi faulted depressions in the Songliao Basin, China, show δ13C1 values ranging from −30.5% to −16.7% with a very narrow δ D range between −203‰−196‰ These gases are characterized by a reverse distribution of δ 13C values but a normal distribution of δ C values, and a negative correlation between their δ 13C and δ C values, indicating an abiological origin. The present study has revealed that abiogenic hydrocarbons not only exist in nature but also can make significant contribution to commercial gas reserviors. It is estimated that the reserve volume of alkane gases with abiogenic characteristics in these 26 gas wells in the Songliao Basin is over 500×108 m3. The prospecting practice in the Songliao Basin has demonstrated that abiogenic alkane gases are of a promising resource, and it provides an example for the investigation of and search for abiogenic commercial natural gases worldwide.

Through the analysis of S-wave particle motion of local events in the shear wave window, the polarization directions of the faster shear wave and the delay times between the faster and the slower shear waves were derived from seismic recordings at the stations near the fault zones. The shear wave splitting results of seven stations in the area of Longmenshan fault zone reveal spatial variation of the polarization directions of the fast shear wave. The directions at stations in the southeastern side of the Longmenshan fault zone (in the Sichuan Basin area) are in the NE direction, whereas the direction at station PWU (in the Plateau), which is in the northwestern side of the faults, is in the EW direction. Systematic changes of the time delays between two split shear waves were also observed. At station L5501 in the southern end of the aftershock zone, the delay times of the slower shear wave decrease systematically after the main shock. After the main shock, the delay times at station PWU were longer than those before the earthquake. Seismic shear wave splitting is caused mostly by stress-aligned microcracks in the rock below the stations. The results demonstrate changes of local stress field during the main-shock and the aftershocks. The stress in the southern part of Wenchuan seismogenic zone was released by the main-shock and the aftershocks. The crustal stresses were transferred to the northeastern part of the zone, resulting in stress increase at station PWU after the main-shock.

Droplet impacting on solid or liquid interfaces is a ubiquitous phenomenon in nature. Although complete rebound of droplets is widely observed on superhydrophobic surfaces, the bouncing of droplets on liquid is usually vulnerable due to easy collapse of entrapped air pocket underneath the impinging droplet. Here, we report a superhydrophobic-like bouncing regime on thin liquid film, characterized by the contact time, the spreading dynamics, and the restitution coefficient independent of underlying liquid film. Through experimental exploration and theoretical analysis, we demonstrate that the manifestation of such a superhydrophobic-like bouncing necessitates an intricate interplay between the Weber number, the thickness and viscosity of liquid film. Such insights allow us to tune the droplet behaviours in a well-controlled fashion. We anticipate that the combination of superhydrophobic-like bouncing with inherent advantages of emerging slippery liquid interfaces will find a wide range of applications., The impact of drops on surfaces is highly relevant to our daily life and many industrial applications, such as self-cleaning and ink printing. Here, Hao et al. show the transition from superhydrophobic-like drop bouncing, due to a trapped air layer, to substrate-dependent bouncing on a liquid thin film.

Background Microtubule-associated tumor suppressor gene (MTUS1) has been identified as tumor suppressor gene in many malignant tumors. In this study, we investigated the role of MTUS1 in the development of salivary adenoid cystic carcinoma (SACC) and its functional effect on the migration and invasion of SACC. Methods Archival clinical samples including 49 primary SACC were examined for MTUS1 expression by immunohistochemistry. Statistical analyses were performed to evaluate the correlation between MTUS1 with histopathological features and survival. The expression of MTUS1/ATIP (AT2 receptor-interacting protein) isoforms was determined in SACC tissue samples and cell lines using quantitative RT-PCR assays. Then we investigated whether the migration and invasion of SACC were mediated by MTUS1/ATIP3a using in vitro cell migration and invasion assay. Results We confirmed that the down-regulation of MTUS1 was a frequent event in SACC, and was correlated with distant metastasis and associated with reduced overall survival and disease free survival. Isoform specific quantitative RT-PCR assays revealed that ATIP1, ATIP3a and ATIP3b were the major isoforms of the MTUS1 gene products in SACC, and were significant down-regulation in SACC as compared to matching normal tissues. For functional analyses, we found that SACC-LM cells (SACC cell line with higher migration and invasion ability) possessed a lower expression level of ATIP3a compared to SACC-83 cells (lower migration and invasion ability). Restoration of ATIP3a expression in SACC-LM cells induced anti-proliferative activity and inhibited the migration and invasion ability. Knockdown of ATIP3a promoted the proliferation, migration and invasion ability of SACC-83 cells. Restoration of ATIP3a inhibited the phosphorylation of ERK (extracellular-regulated kinase) 1/2, the expression of Slug and Vimentin in SACC-LM cells, while knockdown of ATIP3a increased the phosphorylation of ERK1/2, the expression of Slug and Vimentin in SACC-83 cells. Conclusions Our studies confirm that MTUS1 plays an important role in the progression of SACC, and may serve as a biomarker or therapeutic target for patients with SACC. MTUS1/ATIP3a down-regulation contributes to the proliferation, migration and the invasion abilities of SACC. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1209-x) contains supplementary material, which is available to authorized users.

Through its transcriptional activities, the proto-oncoprotein c-jun can regulate cellular proliferation, survival, and differentiation. We have established a novel yeast assay that screens for repressors of c-jun transcriptional activity. This screen led to the identification of a ubiquitously expressed novel RING zinc finger protein, termed Makorin RING zinc finger protein 1 (MKRN1), recently shown to act as an E3 ubiquitin ligase. Overexpression of MKRN1 in mammalian cells inhibited the transcriptional activities of not only c-jun, but also the nuclear receptors, the androgen receptor, and the retinoic acid receptors. Truncation analysis indicates that both the amino and carboxy termini are required for this transrepression activity. Surprisingly, when fused to the heterologous DNA-binding domain of GAL4, MKRN1 activates, rather than inhibits, a GAL4-responsive reporter plasmid. In addition, truncation of either the amino- or carboxy-terminal half of MKRN1 disrupts its transactivation activity, the same observation that was made on its transrepression activity. These results demonstrate that MKRN1 has transcriptional activity and suggest that its transrepression and transactivation functions are mediated by the same mechanism. Interestingly, disruption of MKRN1's ubiquitin ligase activity does not affect its inhibitory transcriptional activity. Thus, MKRN1 may represent a nuclear protein with multiple nuclear functions, including regulating RNA polymerase II-catalyzed transcription.

Multiple displacement-based whole-genome DNA amplification is a promising tool to obtain sufficient DNA from small tissue specimens for various genetic analyses, such as SNP array-based analysis. Using Affymetrix 10 K and 100 K SNP mapping array, we evaluated the performance of the Phi29 DNA polymerase-based genome amplification. Greater than 99% concordance in genotyping calls were achieved between amplified and non-amplified DNAs for both arrays. By utilizing the Affymetrix GeneChip Chromosome Copy Number Tool, the allelic imbalance profiles for the advanced stage oral tongue squamous cell carcinoma (OTSCC) were generated based on 10 K and 100 K SNP mapping array results. The results from these two array platforms agree closely, but more precise allelic imbalance patterns can be revealed from the 100 K SNP mapping array data. Furthermore, our data suggested a frequent loss at 3p11-p12 for advanced stage OTSCC.

We examined the biological role of p12(CDK2-AP1) in cisplatin-mediated responses by using murine ES p12(CDK2-AP1) knockout clones generated by a targeted disruption of murine p12(CDK2-AP1). Homozygous knockout clones showed an increased cellular proliferation along with an increase in S and a decrease in G2/M phase populations. Interestingly, ES p12(CDK2-AP1) knockout clones showed a resistance to cisplatin treatment along with an increased DNA repair activity assessed by host cell reactivation assay using a cisplatin-damaged reporter DNA and a significant reduction of apoptosis upon cisplatin treatment. By using stable p12(CDK2-AP1) short interfering RNA (siRNA) clones from human normal oral keratinocytes, we confirmed that downregulation of p12(CDK2-AP1) resulted in a resistance to cisplatin. More interestingly, cisplatin treatment resulted in a reduction of CDK2 kinase activity in control clones, but p12(CDK2-AP1) knockout clones showed a sustained CDK2 kinase activity. These data suggest that p12(CDK2-AP1) plays a role in cisplatin-mediated cellular responses by modulating CDK2 activity. These data further suggest p12(CDK2-AP1) is a potential gene therapeutic agent for oral/head and neck cancer in conjunction with DNA-damaging agents such as cisplatin.

Gene copy-number abnormalities (CNAs) are characteristic of solid tumors and are found in association with developmental abnormalities and/or mental retardation. The ultimate impact of CNAs is exerted by the altered expression of encoded genes. We have utilized high-density oligonucleotide arrays from Affymetrix to identify DNA CNAs via their impact on mRNA expression levels. In these studies, we have used three different trisomic cell lines (trisomy 9, trisomy 18, trisomy 21) as models of CNAs and have compared mRNA expression in those trisomic cells with that observed in diploid cell lines of matched tissue origin. Our data clearly show that genes from CNA chromosome regions are substantially over-represented ( P0.000001 by chi-square analysis) in the differentially expressed subset from comparisons of all three trisomic cell lines with normal matching cells. In addition, we have been able to detect the origin of the duplication by a statistical scan for over-expressed genes. These data show that microarray detection of differential mRNA expression can be used to identify significant DNA CNAs.

The Drosophila melanogaster broad locus is essential for normal metamorphic development. Broad encodes three genetically distinct functions (rbp, br, and 2Bc) and a family of four zinc-finger DNA-binding proteins (Z1-Z4). The Z1, Z2, and Z3 protein isoforms are primarily associated with the rbp, br, and 2Bc genetic functions respectively. The Z4 protein isoform also provides some rbp genetic function, however an essential function for the Z4 isoform in metamorphosis has not been identified. To determine the degree of conservation of Z4 function between the tobacco hornworm Manduca sexta and Drosophila we generated transgenic Drosophila expressing the Manduca broad Z4 isoform and used this transgene to rescue rbp mutant lethality during Drosophila metamorphosis. We find that the Manduca Z4 protein has significant biological activity in Drosophila with respect to rescue of rbp-associated lethality. There was also some overlap in effects on cuticle gene expression between the Manduca Z4 and Drosophila Z1 isoforms that was not shared with the Drosophila Z4 isoform. Our findings show that Z4 function has been conserved over the 260-million-year period since the divergence of Diptera and Lepidoptera, and are consistent with the hypothesis that the Drosophila Z4 and Manduca Z4 isoforms have essential roles in metamorphosis.

Pharmacovigilance serves to detect previously unrecognised adverse events associated with the use of medicines. The simplest method for detecting signals of such events is crude inspection of lists of spontaneously reported drug-event combinations. Quantitative and automated numerator-based methods such as Bayesian data mining can supplement or supplant these methods. The theoretical basis and limitations of these methods should be understood by drug safety professionals, and automated methods should not be automatically accepted. Published evaluations of these techniques are mainly limited to large regulatory databases, and performance characteristics may differ in smaller safety databases of drug developers. Head-to-head comparisons of the major techniques have not been published. Regardless of previous statistical training, pharmacovigilance practitioners should understand how these methods work. The mathematical basis of these techniques should not obscure the numerous confounders and biases inherent in the data. This article seeks to make automated signal detection methods transparent to drug safety professionals of various backgrounds. This is accomplished by first providing a brief overview of the evolution of signal detection followed by a series of sections devoted to the methods with the greatest utilisation and evidentiary support: proportional reporting rations, the Bayesian Confidence Propagation Neural Network and empirical Bayes screening. Sophisticated yet intuitive explanations are provided for each method, supported by figures in which the underlying statistical concepts are explored. Finally the strengths, limitations, pitfalls and outstanding unresolved issues are discussed. Pharmacovigilance specialists should not be intimidated by the mathematics. Understanding the theoretical basis of these methods should enhance the effective assessment and possible implementation of these techniques by drug safety professionals.

Upon binding retinoic acid (RA), the retinoic acid receptors (RARs) are able to positively and negatively regulate transcription. It has been shown that the DNA-binding domain and carboxy terminus of RARs are necessary for the ligand-dependent ability of the receptor to repress AP-1 transcriptional activity. A fusion of these two regions, shown to constitutively inhibit AP-1 activity, was used in a yeast two-hybrid screen to identify a novel hRARalpha-interacting protein. This protein, hsRPB7, a subunit of RNA polymerase II, interacts with hRARalpha in the absence of RA and addition of RA disrupts the interaction. Truncation analysis indicates that hsRPB7 specifically interacts with the hRARalpha DNA-binding domain. This interaction appears to compromise transcription, since overexpressed hRARalpha, in the absence of RA, is able to repress the activity of several RNA polymerase II-dependent activators, including AP-1 and the glucocorticoid receptor. This repression is relieved by transfected hsRPB7, strongly suggesting that ligand-free hRARalpha can block AP-1 activity by sequestering hsRPB7. The repression is dependent on the integrity of the hRARalpha DBD, since a mutation within the DBD blocks both the hRARalpha-hsRPB7 interaction and ligand-free hRARalpha repression of AP-1. These results provide evidence that non-liganded hRARalpha can regulate transcription by directly interacting with RNA polymerase II, and thus suggest a novel pathway by which hRARalpha can cross-talk with AP-1 and perhaps other families of transcriptional activators.