Double Target Research Articles

MiR-144-3p Inhibits the Invasion and Metastasis of Lung Adenocarcinoma Cells by Targeting IRS1

背景与目的MicroRNAs（miRNAs）是短的非编码RNA，是能够调控基因表达、影响细胞过程、促进疾病发展的重要分子。在许多疾病中可以观察到miRNA表达的变化，包括肝炎、心血管疾病和癌症。本研究旨在探讨miR-144-3p靶向调控胰岛素受体底物1（insulin receptor substrate 1, IRS1）对肺腺癌细胞侵袭和转移的影响。方法通过生物信息学数据库查询miR-144-3p在肺腺癌患者中的表达情况；利用mirTarPathway对miRNA进行KEGG通路富集分析；定量逆转录聚合酶链式反应（quantitative reverse transcription polymerase chain reaction, qRT-PCR）检测miR-144-3p在肺腺癌细胞系中的表达情况与质粒转染效率；Transwell实验检测不同组细胞侵袭迁移能力的变化。生物信息学确定miR-144-3p的关键基因（Hub基因）；双荧光素酶靶标实验检测miR-144和IRS1的相互结合情况；Western blot实验检测IRS1在不同细胞系的表达及过表达miR-144后IRS1的表达情况。结果miR-144-3p在肺腺癌组织中表达降低，qRT-PCR结果提示miR-144-3p在肺腺癌细胞A549中的表达显著降低（P < 0.05）且过表达质粒转染成功（P < 0.05）；过表达miR-144后，细胞的迁移、侵袭和增殖能力下降（P < 0.05）；IRS1在肺腺癌组织中表达上调；生存分析表明高表达IRS1的肺腺癌患者预后不良（P < 0.05）；双荧光素酶实验结果显示，miR-144可特异识别IRS1的3’-UTR抑制报告酶的表达（P < 0.05）；Western blot结果提示IRS1在A549细胞中表达升高（P < 0.05），过表达miR-144后，IRS1蛋白表达水平下降（P < 0.05）；Transwell实验证明，miR-144-3p可通过靶向调控IRS1抑制肺腺癌细胞的侵袭和转移（P < 0.05）。结论miR-144-3p通过靶向调控IRS1抑制A549细胞的侵袭和迁移能力，进而在肿瘤中发挥抑癌作用。

Targeted Drug Delivery System: Advantages, Carriers and Strategies

Abstract: Drug targeting is a new drug delivery system that aims to deliver the drug to the target site of action or site of absorption without releasing the drug at any other non-target site. The delivery system is designed to retain the intact drug without any modification until reaching and releasing at the target site. The targeted drug delivery systems have several advantages over conventional ones as improvement of pharmaceutical activity, low side effects and reduction of the administered dose. The main purpose of the targeted drug delivery system is to obtain the pharmacological action of the therapeutic agent at diseased organs only without affecting the healthy one especially in the case of cancer treatment with chemotherapeutic agents. Drug targeting can be attained using different carriers that maintain and transport the intact drug to preselected organ or tissue. Different types of carriers can be used for drug targeting such as nanotubes and nanowires, nanoshells, quantum dots, nanopores, gold nanoparticles, dendrimers, noisome, ufasomes, virosomes, cubosomes, nanobots and transferosomes. There are different mechanisms of drug targeting such as passive targeting, inverse targeting, active targeting, ligand-mediated targeting, physical targeting, dual targeting and double targeting. The drug targeting is a useful delivery system for delivering the therapeutic agent to a specific site without causing toxicity in other organs. Key words: Drug targeting, Drug delivery system, Pharmacological action, Chemotherapeutic agents, Gold nanoparticles.

Single and double shell ignition targets for the national ignition facility at 527 nm

Converting and using the National Ignition Facility (NIF) to deliver 527 nm light instead of its current 351 nm would allow the laser to deliver more energy and power to ignition targets. We update previous 527 nm target design work to reflect more contemporary target designs using high-density carbon capsules and low density helium gas filled Hohlraums. We extend single shell capsule designs based on current experimental results to higher energy and power and also explore double shell capsules, both driven by green light. These studies were completed using detailed pulse shapes found for targets that converged with acceptable 2D implosion symmetries and then used the Lava Lamp II code to confirm their feasibility at NIF. A 1.2× dimensional scaleup of one tuned NIF target at the limit of its current 351 nm capabilities and shot 170827 uses 3.3 MJ, at the limit of the current NIF's 527 nm capability. With the less-structured pulse of a double shell target, 3.7 MJ could be delivered by the laser. Our LPI calculations do not preclude operation at 527 nm, particularly for low fill Hohlraums, and suggest that the stimulated Raman backscatter may be no worse than the small quantities seen in 170827; stimulated forward Raman scattering may be present. If Stimulated Brillouin Scattering is too great, the much greater laser bandwidth available at 527 nm could be used to decrease backscatter. These larger targets with higher energy and power may offer a better chance of achieving ignition with only modest changes to the NIF laser.

A dual responsive colorimetric sensor based on polyazomethine and ascorbic acid for the detection of Al (III) and Fe (II) ions

In the present paper, a novel double cation target colorimetric sensor was developed for the detection of Al (III), and Fe (II) ions. It was composed of ascorbic acid in a polyazomethine matrix, and polyazomethine was used to form a homogenous matrix for mixing ascorbic acid. The photophysical properties of the colorimetric sensor were clarified by using UV–Vis and fluorescence spectrophotometers. It was found that the developed sensor was exhibited good naked eye selectivity, and sensitivity toward Al (III), and Fe (II) ions with excellent photostability. Furthermore, the detection limit of the sensor was calculated as 0.398 µM (0.096 ppm) and 0.185 µM (0.051 ppm) for Al (III), and Fe (II), respectively. The applicability of the colorimetric sensor in environmental (tap and sea waters) and biological (Bovine serum albumin) solutions was also studied, and the results exhibited that the developed sensor could be successfully applied to monitoring environmental and biological samples.

Constraining computational modeling of indirect drive double shell capsule implosions using experiments

Double shell capsule implosions are an alternative approach to achieving alpha heating on the National Ignition Facility. Current machining techniques construct the outer shell as two hemispheres that are glued together, and the deuterium and tritium (DT) liquid inside the inner shell will be injected by a fill tube. These features introduce asymmetries and jetting that may disrupt the confinement of the DT fuel if not carefully controlled. Simulations indicate that in order to achieve high yields in the laboratory, these features as well as susceptibility to the Rayleigh–Taylor instability (RTI) must be mitigated. Due to uncertainties in computational models and the expense of using the best physics models at adequate resolution in three dimensions, our computational modeling must be constrained by experiments. We report on the results of recent hydrogrowth radiography and dual-axis keyhole experiments with double shell targets that have been used to evaluate our modeling of the outer shell joint as well as the impacts of high-energy x-ray preheat that strongly impacts RTI growth. Our simulations show good agreement with the experimental data and inform several important modeling choices.

Physical Demands and Internal Response in Football Sessions According to Tactical Periodization.

The objectives of the present study were (1)to analyze the internal and external load profile of training and competition carried out by semiprofessional football players during a 27-week period and (2)to examine the possible link between this type of periodization and players' fitness status and their readiness to compete. Training and match data were obtained from 26 semiprofessional football players belonging to the reserve squad of a Spanish La Liga club during the 2018/19 season. For the purpose of this study, the distribution of external and internal load during a typical training microcycle, with 6 or 7 days between matches, was analyzed. Five types of sessions were considered: strength, duration, velocity, preofficial match, and official match. The results showed a different internal and external load profile for each type of session, with the load being consistently higher during matches when compared with training sessions (28.9%-94% higher), showing significant differences in all the variables. There was a clear tapering strategy in the last days of the week to arrive with enough freshness to compete, shown by the decrease of the values in the 2 days before the match (15%-83% reduction, depending on the variable). Furthermore, the horizontal alternation of the load allowed the players to maintain their fitness level during the 27-week period. Our findings suggest that this weekly periodization approach could help achieve a double conditional target, allowing a short tapering strategy to face the match with enough freshness and serving as a strategy for maintaining or optimizing players' physical performance during the season.

Chemoselective ligation assisted DNA walker for analysis of double targets

Chemoselective ligation assisted DNA walker with input and output of double signals, has been constructed through simultaneous assistance of oxime chemistry and alkyne-azide cycloaddition. The constructed DNA walker has been further developed as a biosensor with lipopolysaccharide (LPS) and 5-hydroxymethyl-2-furaldehyde (HMF) as targets. The biosensor owns one-to-one mapping functionality and can sensitively distinguish all cases of two targets through the unique output signal feature. Moreover, the biosensor can simultaneously analyze LPS and HMF. This work provides a new insight for analysis of double targets based on chemoselective ligation assisted DNA walker.

Nonconvex Laplacian Manifold Joint Method for Morphological Reconstruction of Fluorescence Molecular Tomography.

Fluorescence molecular tomography (FMT) is a promising technique for three-dimensional (3D) visualization of biomarkers in small animals. Morphological reconstruction is valuable and necessary for further applications of FMT owing to its innate requirement for knowledge of the molecular probe distributions. In this study, a Laplacian manifold regularization joint ℓ1/2-norm model is proposed for morphological reconstruction and solved by a nonconvex algorithm commonly referred to as the half-threshold algorithm. The model is combined with the structural and sparsity priors to achieve the location and structure of the target. In addition, two improvement forms (truncated and hybrid truncated forms) are proposed for better morphological reconstruction. The truncated form is proposed for balancing the sharpness and smoothness of the boundary of reconstruction. A hybrid truncated form is proposed for more structural priors. To evaluate the proposed methods, three simulation studies (morphological, robust, and double target analyses) and an in vivo experiment were performed. The proposed methods demonstrated morphological accuracy, location accuracy, and reconstruction robustness in glioma simulation studies. An in vivo experiment with an orthotopic glioma mouse model confirmed the advantages of the proposed methods. The proposed methods always yielded the best intersection of union (IoU) in simulations and in vivo experiments (mean of 0.80 IoU). Simulation studies and in vivo experiments demonstrate that the proposed half-threshold hybrid truncated Laplacian algorithm had an improved performance compared with the comparative algorithm in terms of morphology.

Screening of high-efficiency and low-toxicity antitumor active components in Macleaya cordata seeds based on the competitive effect of drugs on double targets by a new laminar flow chip.

It is urgent to obtain targeted drugs that selectively bind to pathological targets rather than physiological targets in the early stage of drug screening. G-Quadruplex has become one of the important targets in the development of anti-tumor drugs. However, drugs that target quadruplexes may also bind to dsDNA, which may lead to adverse reactions. In this study, a new three-phase laminar flow chip was constructed to enable the multi-components of a traditional Chinese medicine extract to dynamically and competitively bind with G-quadruplex DNA (on target) and double-stranded DNA (off target), so as to select high-efficiency and low-toxicity anti-tumor drugs. The results showed that there were five compounds in the extracts of Macleaya cordata seeds that exhibited obvious differences in binding to the two targets. Furthermore, the binding constants and modes of four identified alkaloids as they bound to two DNA targets were verified by fluorescence spectra and molecular docking methods. The toxicity to HepG2 and LO2 cells from the four alkaloids was also compared. The results showed that sanguinarine and chelerythrine could be used as candidate drugs with stronger binding to HT24 than DNA26. The chip can also be used for other types of double-target screening of other traditional Chinese medicine extracts or compound libraries.

Evaluation of prevention of mother-to-child transmission national health information system for HIV/AIDS, in southern region of Mozambique, April to November 2016.

IntroductionMozambique has a generalized HIV epidemic, among pregnant women, HIV prevalence is estimated at 15.8% with a vertical transmission rate of 14%, more than double global targets. We evaluate electronic national health information system (SIS-MA) performance to verify if the data flow procedures met its objectives and evaluated the prevention of mother-to-child transmission (PMTCT) surveillance system to access its attributes and usefulness.Methodswe conducted a descriptive, cross-sectional evaluation of the PMTCT surveillance system in eight facilities in Gaza and Inhambane provinces using the centers for disease control and prevention guidelines (2001). For data quality, we cross-referenced patient registries from health facilities against the SIS-MA. We also interviewed 34 health technicians, using a Likert scale, to assess the following attributes of the PMTCT surveillance system: simplicity, stability, flexibility, acceptability, timeliness and data quality, usefulness of the system and knowledge of PMTCT.Resultsregarding the simplicity measure, we verified that the registry books contain more than 30 variables. The system was 83% flexible in maintaining functionality with the introduction of new health facilities in the system. The completeness of the data was 50% and concordance of data from the register book and monthly reports was 89%.Conclusionthe PMTCT SIS-MA is useful in supporting the collection, analysis, interpretation and continuous and systematic dissemination of health data that are used to define and monitor public health policies in Mozambique. However, continued efforts are needed to improve data quality to ensure that the SIS-MA can adequately monitor the PMTCT program and contribute to reduced vertical transmission.

Study on power load adjustment capacity of a 300MW cogeneration unit in heating season

After the formulation of the "3060" double carbon target, the installed capacity of new energy has increased rapidly and the proportion of power generation has become higher and higher. In the heating season, under the operation mode of "determining electricity by heat" of cogeneration units, in order to meet the consumption of renewable energy and the heating guarantee of people's livelihood, the contradiction with power grid peak shaving is increasing. This paper mainly introduces the load capacity of a 300MW cogeneration unit in the heating season. Through the test method, find out the load capacity of the unit under different heating capacity, which can be used as a reference for power generation enterprises and power grid dispatching.

Gerschgorin disk estimator method for source number estimation based on peak-to-average power ratio

Gerschgorin disk estimator (GDE) method is difficult to detect the number of signal sources effectively under low signal-to-noise ratio (SNR). In view of this situation, we propose GDE method based on peak-to-average power ratio (GDE-PAR) by combining the peak-to-average power ratio (PAR) with the Gerschgorin disk radius. We extract the eigenvectors from the received data and use them as the weights of the data. The PAR is used to modify the corresponding Gerschgorin disk radius, and the number of signal sources is determined by GDE method. This paper adopts Matlab simulation on the Gerschgorin disk radius before and after correction under different SNR conditions. In the case of double target of equal intensity and double target of unequal intensity, three target of equal intensity and three target unequal intensity using Monte Carlo method, we use Akaike information theory criterion (AIC), minimum description length (MDL) criterion, PAR method and GDE-PAR method to estimate the number of signal sources respectively. The results show that under the conditions of low SNR and multi-target of unequal intensity, the probability of successful detection of source by GDE-PAR method is higher than that of AIC, MDL criterion and PAR method.

Ballistic performance of monolithic and double layered thin-metallic hemispherical shells at normal and oblique impact

The present study discusses experimental and numerical investigations on the ballistic performance of aluminum 1100-H12 hemispherical shell targets of 150 mm diameter against 19 mm diameter cylindrical steel projectiles. The influence of nose profile of the projectiles on the impact resistance of the targets, was observed by varying the nose geometry to ogive, blunt, conical and hemispherical shapes. Effect of normal as well as oblique impact on the failure mechanisms and perforation process of shells was studied at 0 (normal), 15 and 30° angle from the normal incidence path. Further, the ballistic performance of two target configurations, viz. 2 mm thick monolithic and double layered in-contact shell targets was investigated and compared within the configurations. The finite element analysis of the ballistic impact on shell targets was done in ABAQUS/Explicit solver by employing the Johnson – Cook constitutive strength and damage model for deformable target material, whereas all the projectiles were assumed as rigid body. The ballistic performance of both shell target configurations against oblique impacts with different projectiles was evaluated and compared in terms of ballistic limit, local and global deformations, failure mechanisms and plastic work done in radial, polar, meridional and shear deformations. The obtained experimental results were then compared with numerical simulations and found in good corroboration. It was observed that both monolithic and layered shell targets showed highest ballistic resistance against hemispherical nosed projectile. For all the projectiles, layered shell targets displayed higher energy dissipation than monolithic targets.

Biological Applications of Short Wavelength Microscopy Based on Compact, Laser-Produced Gas-Puff Plasma Source

Over the last decades, remarkable efforts have been made to improve the resolution in photon-based microscopes. The employment of compact sources based on table-top laser-produced soft X-ray (SXR) in the “water window” spectral range (λ = 2.3–4.4 nm) and extreme ultraviolet (EUV) plasma allowed to overcome the limitations imposed by large facilities, such as synchrotrons and X-ray free electron lasers (XFEL), because of their high complexity, costs, and limited user access. A laser-plasma double stream gas-puff target source represents a powerful tool for microscopy operating in transmission mode, significantly improving the spatial resolution into the nanometric scale, comparing to the traditional visible light (optical) microscopes. Such an approach allows generating the plasma efficiently, without debris, providing a high flux of EUV and SXR photons. In this review, we present the development and optimization of desktop imaging systems: a EUV and an SXR full field microscope, allowing to achieve a sub-50 nm spatial resolution with short exposure time and an SXR contact microscope, capable to resolve internal structures in a thin layer of sensitive photoresist. Details about the source, as well as imaging results for biological applications, will be presented and discussed.

Probing the dual inhibitory mechanisms of novel thiophenecarboxamide derivatives against Mycobacterium tuberculosis PyrG and PanK: an insight from biomolecular modeling study

The growing occurrence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis (Mtb) strains underscores an urgent need for new antibiotics. The development of more bioactive antibiotics against drug-resistant organisms with a different mode of action could be a game-changer for the cure and eradication of tuberculosis (TB). Pantothenate Kinase (PanK) and CTP synthetase (PyrG) are both essential for RNA, DNA, and Lipids biosynthesis pathways. Given the extensive knowledge on these biosynthesis pathways inhibition of Mtb growth and survival, these enzymes present a fascinating opportunity for anti-mycobacterial drug discovery. Recently, it was experimentally established that the active metabolite 11426026 of compound 7947882 (a prodrug activated by EthA monooxygenase, 5-methyl-N-(4-nitrophenyl) thiophene-2-carboxamide) inhibits the activities of PyrG and PanK to indicate novel multitarget therapy aimed at discontinuing Mtb growth. However, the molecular mechanisms of their selective inhibition remain subtle. In this work, molecular dynamics simulations were employed to investigate the inhibitory mechanism as well as the selectivity impact of the active metabolite inhibitor of these enzymes. Computational modeling of the studied protein-ligand systems reveals that the active metabolite can potentially inhibit both PanK and PyrG, thereby creating a pathway as a double target approach in tuberculosis treatment. Communicated by Ramaswamy H. Sarma

MiRNA-191 promotes proliferation, migration and invasion of prostate cancer by targeting PLCD1

Objective: To investigate the effects of miRNA-191 on the proliferation, migration and invasion of prostate cancer, and to explore its mechanism. Methods: The expression levels of miRNA-191 in four human prostate cancer cell lines (PC-3, DU-145, LNCa P, 22RU1) and human normal prostate cell line RWPE-2 were detected, and prostate cancer cell line PC-3 was selected as the experimental object. PC-3 cells were divided into three groups: blank control group (no transfection), miRNA-191 NC group (PC-3 cells transfected with Inhibitor NC) and miRNA-191 Inhibitor group (PC-3 cells transfected with miRNA-191 Inhibitor), and each group was provided with three multiple pores. The expression levels of miRNA-191 and PLCD1 were detected by RT-PCR. The cell proliferation was detected by CCK8 assay. Scratch test and invasive test were used to detect cell migration and invasive ability. Through Targetscan target gene prediction website, PLCD1 was screened as the target protein of miRNA-191, and verified by double luciferase target experiment.Western blot assay was used to detect the expression of PLCD1 in cells of each group. Results: Compared with RWPE-2 cells, the expression level of miRNA-191 in human prostate cancer cells was significantly higher (P ＜0.05), and the expression level of miRNA191 in PC-3 was significantly higher than that in other three cell lines (P＜0.05). After inhibiting the expression of miRNA-191, the expression levels of PLCD1 was significantly higher while PC-3 cells' proliferation ability was inhibited, and their migration and invasion ability were significantly lower than those of blank control group and miRNA-191 NC group (P＜ 0.05). The results of double luciferase reporter gene assay showed that PLCD1 gene was a target gene of miRNA-191. Conclusion: miRNA-191 promote the proliferation, migration and invasion of prostate cancer PC-3 cells by targeting PLCD1.

Evaluation of mechanical properties considering hysteresis characteristic of high damping rubber bearing

Recently, laminated rubber bearings are widely used as seismic isolators for road bridges. Although many studies have been conducted on the dynamic model of High Damping Rubber (HDR) bearings, few models can reflect phenomena such as the dependency of experienced shear strain on initial history. To develop a model that can represent the dependency of the experienced shear strain of HDR and a dynamic loading test was conducted using HDR specimens. The hysteresis characteristics of HDR was measured by applying a horizontal vibration using a hybrid actuator under a constant vertical load. Based on the cyclic shear test, the mechanical properties of HDR were calculated such as absorbed energy, hysteresis loop area, equivalent stiffness, equivalent damping ratio. Dynamic analysis was also performed from the experimental results. The dynamic model applied in program analysis is a bilinear type double-target model. This model can express the nonlinear characteristics related to the initial history of HDR bearings. The parameters required for dynamic analysis were determined from the experimental results. Through this dynamic analysis, the effectiveness of the bilinear type double target model was verified. In this research, a high damping rubber specimen was used.

Take-back regulation policy on closed loop supply chains: Single or double targets?

Many countries have imposed product take-back conditions on their manufacturers, as part of the commitment to the extended product responsibility. This paper explores the feasibility of the take-back regulation operating under a collection target and a reuse target. Two models using different regulation setups are developed to show the effects of a take-back regulation on consumer surplus, the benefits to the supply chain, and social welfare. The results suggest that the optimal strategies of the manufacturer depend on the regulation model applied. Setting higher regulation targets decreases the manufacturer’s profit, but the chain benefits from the reuse target. To achieve a high collection rate and reuse efficiency, policy makers should set a high collection target and a high reuse target. To improve the social welfare, a low collection target and a high reuse target should be set. This study provides some suggestions for the manufacturer to cope with regulation targets and offers some guidelines for policy makers to set and implement the regulation targets.

Physico-Chemical Surface Modifications of Polyetheretherketone (PEEK) Using Extreme Ultraviolet (EUV) Radiation and EUV-Induced Nitrogen Plasma.

In this work, the effect of extreme ultraviolet (EUV) radiation and the combination of EUV radiation and low-temperature nitrogen plasma on the physico-chemical properties of polyetheretherketone (PEEK) surfaces were presented. The laser-plasma EUV source based on a double gas puff target was used in this experiment to irradiate PEEK surfaces with nanosecond pulses of EUV radiation and to produce low-temperature plasma through the photoionization of nitrogen with EUV photons. The changes in surface morphology on irradiated polymer samples were examined using atomic force microscopy (AFM) and scanning electron microscopy (SEM). Chemical changes of the PEEK surfaces were analysed using X-ray photoelectron spectroscopy (XPS). EUV radiation and nitrogen plasma treatment caused significant changes in the topography of modified PEEK’s surfaces and an increase in their average roughness. Strong chemical decomposition, appearance of new functional groups as well as incorporation of nitrogen atoms up to ~17 at.% on the PEEK’s surface were observed.

Wideband spectral emission measurements from laser-produced plasma EUV/SXR source based on a double gas puff target

Wideband spectral emission measurements from laser-produced plasma EUV/SXR source based on a double gas puff target