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Despite the tremendous clinical potential of nucleic acid-based vaccines, their efficacy to induce therapeutic immune response has been limited by the lack of efficient local gene delivery techniques in the human body. In this study, we develop a hydrogel - based organic electronic device ( mu EPO) for both transdermal delivery of nucleic acids and in vivo microarrayed cell electroporation, which is specifically oriented toward one - step transfection of DNAs in subcutaneous antigen - presenting cells (APCs) for cancer immunotherapy. The mu EPO device contains an array of microneedle - shaped electrodes with pre - encapsulated dry DNAs. Upon a pressurized contact with skin tissue, the electrodes are rehydrated, electrically triggered to release DNAs, and then electroporate nearby cells, which can achieve in vivo transfection of more than 50% of the cells in the epidermal and upper dermal layer. As a proof - of - concept, the mu EPO technique is employed to facilitate transdermal delivery of neoantigen genes to activate antigen - specific immune response for enhanced cancer immunotherapy based on a DNA vaccination strategy. In an ovalbumin (OVA) cancer vaccine model, we show that high - efficiency transdermal transfection of APCs with OVA - DNAs induces robust cellular and humoral immune responses, including antigen presentation and generation of IFN -gamma + cytotoxic T lymphocytes with a more than 10 - fold dose sparing over existing intramuscular injection (IM) approach, and effectively inhibits tumor growth in rodent animals.

A simultaneously transmitting and reflecting reconfigurable intelligent surface (STAR-RIS) assisted simultaneous wireless information and power transfer (SWIPT) system is proposed. More particularly, an STAR-RIS is deployed to assist in the information/power transfer from a multi-antenna access point (AP) to multiple single-antenna information users (IUs) and energy users (EUs), where two practical STAR-RIS operating protocols, namely energy splitting (ES) and time switching (TS), are employed. Under the imperfect channel state information (CSI) condition, a multi-objective optimization problem (MOOP) framework, that simultaneously maximizes the minimum data rate and minimum harvested power, is employed to investigate the fundamental rate-energy trade-off between IUs and EUs. To obtain the optimal robust resource allocation strategy, the MOOP is first transformed into a single-objective optimization problem (SOOP) via the {\epsilon}-constraint method, which is then reformulated by approximating semi-infinite inequality constraints with the S-procedure. For ES, an alternating optimization (AO)-based algorithm is proposed to jointly design AP active beamforming and STAR-RIS passive beamforming, where a penalty method is leveraged in STAR-RIS beamforming design. Furthermore, the developed algorithm is extended to optimize the time allocation policy and beamforming vectors in a two-layer iterative manner for TS. Numerical results reveal that: 1) deploying STAR-RISs achieves a significant performance gain over conventional RISs, especially in terms of harvested power for EUs; 2) the ES protocol obtains a better user fairness performance when focusing only on IUs or EUs, while the TS protocol yields a better balance between IUs and EUs; 3) the imperfect CSI affects IUs more significantly than EUs, whereas TS can confer a more robust design to attenuate these effects.

A novel hybrid active-passive reconfigurable intelligent surface (RIS) transmitter enabled downlink multi-user communication system is investigated. Specifically, RISs are exploited to serve as transmitter antennas, where each element can flexibly switch between active and passive modes to deliver information to multiple users. The system energy efficiency (EE) maximization problem is formulated by jointly optimizing the RIS element scheduling and beamforming coefficients, as well as the power allocation coefficients, subject to the user's individual rate requirement and the maximum RIS amplification power constraint. Using the Dinkelbach relaxation, the original mixed-integer nonlinear programming problem is transformed into a nonfractional optimization problem with a two-layer structure, which is solved by the alternating optimization approach. In particular, an exhaustive search method is proposed to determine the optimal operating mode for each RIS element. Then, the RIS beamforming and power allocation coefficients are properly designed in an alternating manner. To overcome the potentially high complexity caused by exhaustive searching, we further develop a joint RIS element mode and beamforming optimization scheme by exploiting the Big-M formulation technique. Numerical results validate that: 1) The proposed hybrid RIS scheme yields higher EE than the baseline multi-antenna schemes employing fully active/passive RIS or conventional radio frequency chains; 2) Both proposed algorithms are effective in improving the system performance, especially the latter can achieve precise design of RIS elements with low complexity; and 3) For a fixed-size hybrid RIS, maximum EE can be reaped by setting only a minority of elements to operate in the active mode.

Federated learning (FL) allows multiple parties (distributed devices) to train a machine learning model without sharing raw data. How to effectively and efficiently utilize the resources on devices and the central server is a highly interesting yet challenging problem. In this paper, we propose an efficient split federated learning algorithm (ESFL) to take full advantage of the powerful computing capabilities at a central server under a split federated learning framework with heterogeneous end devices (EDs). By splitting the model into different submodels between the server and EDs, our approach jointly optimizes user-side workload and server-side computing resource allocation by considering users' heterogeneity. We formulate the whole optimization problem as a mixed-integer non-linear program, which is an NP-hard problem, and develop an iterative approach to obtain an approximate solution efficiently. Extensive simulations have been conducted to validate the significantly increased efficiency of our ESFL approach compared with standard federated learning, split learning, and splitfed learning.

Mobile Virtual Reality (VR) and panoramic video streaming rely on interactive panoramic scene delivery to provide desirable user experiences. However, it is pretty challenging to support multiple users via the wireless network since a panoramic scene typically consumes $4\sim 6\times$ bandwidth compared with a regular video with the same resolution. Motivated by the fact that users only perceive the Field-of-View (FoV), we employ the autoregressive process to predict the user's motion and stream only part of the panoramic content. Notably, we analytically characterize the effect of the delivered portion on the user's successful viewing probability. Then, we formulate an optimization problem to maximize the application-level throughput (which measures the average rate for successful viewing the desired content instead of raw network throughput) while providing a regular service. In addition, we impose three main constraints to our problem: minimum required service rate, maximum allowable energy consumption, and wireless interference. We then propose a novel scheduling algorithm that incorporates users' successful viewing probabilities and asymptotically maximizes application-level throughput while providing service regularity guarantees. We conduct real-trace simulations to evaluate the efficiency of our algorithm.

Truck-involved crashes, especially truck-car crashes, are associated with serious and even fatal injuries, thus necessitating an in-depth analysis. Prior research focused solely on examining the injury severity of truck drivers or developed separate performance models for truck and car drivers. However, the severity of injuries to both drivers in the same truck-car crash may be interrelated, and influencing factors of injury severities sustained by the two parties may differ. To address these concerns, a random parameter bivariate probit model with heterogeneity in means (RPBPHM) is applied to examine factors affecting the injury severity of both drivers in the same truck-car crash and how these factors change over the years. Using truck-car crash data from 2017 to 2019 in the UK, the dependent variable is defined as slight injury and serious injury or fatality. Factors such as driver, vehicle, road, and environmental characteristics are statistically analyzed in this study. According to the findings, the RPBPHM model demonstrated a remarkable statistical fit, and a positive correlation was observed between the two drivers' injury severity in truck-car crashes. More importantly, the effects of the explanatory factors showing relatively temporal stability vary across different types of vehicle crashes. For example, car driver improper actions and lane changing by trucks, have a significant interactive effect on the severity of injuries sustained by drivers involved collisions between trucks and cars. Male truck drivers, young truck drivers, older truck drivers, and truck drivers' improper actions, elevate the estimated odds of only truck drivers; while older car and unsignalized crossing increase the possibility of injury severity of only car drivers. Finally, due to shared unobserved crash-specific factors, the 30-mph speed limit, dark no lights, and head-on collision, significantly affect the severity of injuries sustained by drivers involved in collisions betwe, Green Open Access added to TU Delft Institutional Repository ‘You share, we take care!’ – Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public., Transport and Planning

Benzylic carbocations bearing an ortho- or para-hydroxyl group can be stabilized by forming quinone methides, which have been explored in enantioselective synthesis. However, those with a meta-hydroxyl group have remained almost unexplored in organic synthesis. The lack of resonance stabilization by a typical quinone methide form renders them not only difficult to generate, but also challenging to control for asymmetric bond formation. Here we report an efficient catalytic enantioselective reaction between meta-hydroxyl triarylmethanols and indoles, via triaryl carbocations, for the synthesis of tetraarylmethanes with excellent enantiocontrol. Control experiments reveal that the meta-hydroxyl group is essential for both reactivity and stereocontrol. Ortho-directing groups (alkoxyl, sulfenyl or fluoro) benefit enantiocontrol through secondary hydrogen-bonding interactions, but are not required for reactivity. The resulting tetraarylmethane products show anticancer activities, through a mechanism distinct from that of classical anticancer drugs.

The increasingly deeper neural networks hinder the democratization of privacy-enhancing distributed learning, such as federated learning (FL), to resource-constrained devices. To overcome this challenge, in this paper, we advocate the integration of edge computing paradigm and parallel split learning (PSL), allowing multiple client devices to offload substantial training workloads to an edge server via layer-wise model split. By observing that existing PSL schemes incur excessive training latency and large volume of data transmissions, we propose an innovative PSL framework, namely, efficient parallel split learning (EPSL), to accelerate model training. To be specific, EPSL parallelizes client-side model training and reduces the dimension of local gradients for back propagation (BP) via last-layer gradient aggregation, leading to a significant reduction in server-side training and communication latency. Moreover, by considering the heterogeneous channel conditions and computing capabilities at client devices, we jointly optimize subchannel allocation, power control, and cut layer selection to minimize the per-round latency. Simulation results show that the proposed EPSL framework significantly decreases the training latency needed to achieve a target accuracy compared with the state-of-the-art benchmarks, and the tailored resource management and layer split strategy can considerably reduce latency than the counterpart without optimization., Comment: 15 pages, 13 figures

To address the mechanisms and influential factors of steam explosions which may occur during severe accidents in a nuclear power plant (NPP), the VULCAN apparatus is designed and built to investigate the characteristics of a steam explosion when molten material falls into a water pool. The test facility is composed of a high-speed measurement system and an induction furnace which enables preparation and delivery a small melt jet at temperature up to 1500 degrees C. In the first campaign of tests, tin is employed as the simulant of melt material, and the steam explosion process and pressure signals of a small molten tin jet falling into a deep water pool are recorded by a high-speed camera and a high-frequency pressure sensor, respectively. Debris particles from part test are collected and sieved for analysis of morphology and size distribution of the particles. Multiple occur-rences of steam explosion are observed during the traveling of the melt jet into the water pool, with several cycles of expansion-contraction in each occurrence of steam explosion. The time interval between two occurrences is around 80 ms and between two cycles is around 4 ms. For the melt mass ranging from 20 to 140 g in the present study, it is found that the number of steam explosion occurrences increases with the melt mass. Both the pressure impulse and the conversion ratio of steam explosion increase with melt mass. However, the pressure impulse and conversion ratio do not have a monotonic relation with melt superheat, and the conversion ratio increase with melt superheat when it is below a threshold (370 degrees C), but decrease above the threshold., QC 20220502

We consider the problem of sequential multiple hypothesis testing with nontrivial data collection costs. This problem appears, for example, when conducting biological experiments to identify differentially expressed genes of a disease process. This work builds on the generalized $\alpha$-investing framework which enables control of the false discovery rate in a sequential testing setting. We make a theoretical analysis of the long term asymptotic behavior of $\alpha$-wealth which motivates a consideration of sample size in the $\alpha$-investing decision rule. Posing the testing process as a game with nature, we construct a decision rule that optimizes the expected $\alpha$-wealth reward (ERO) and provides an optimal sample size for each test. Empirical results show that a cost-aware ERO decision rule correctly rejects more false null hypotheses than other methods for $n=1$ where $n$ is the sample size. When the sample size is not fixed cost-aware ERO uses a prior on the null hypothesis to adaptively allocate of the sample budget to each test. We extend cost-aware ERO investing to finite-horizon testing which enables the decision rule to allocate samples in a non-myopic manner. Finally, empirical tests on real data sets from biological experiments show that cost-aware ERO balances the allocation of samples to an individual test against the allocation of samples across multiple tests., Comment: 26 pages, 5 figures, 8 tables

Multi-access edge computing (MEC) is an emerging paradigm that pushes resources for sensing, communications, computing, storage and intelligence (SCCSI) to the premises closer to the end users, i.e., the edge, so that they could leverage the nearby rich resources to improve their quality of experience (QoE). Due to the growing emerging applications targeting at intelligentizing life-sustaining cyber-physical systems, this paradigm has become a hot research topic, particularly when MEC is utilized to provide edge intelligence and real-time processing and control. This article is to elaborate the research issues along this line, including basic concepts and performance metrics, killer applications, architectural design, modeling approaches and solutions, and future research directions. It is hoped that this article provides a quick introduction to this fruitful research area particularly for beginning researchers., Comment: 7 pages, 2 figures, accepted by IEEE Wireless Communications

In 5G and beyond, the newly emerging services, such as edge computing/intelligence services, may demand the provision of heterogeneous communications, computing, and storage (CCS) resources on and across network entities multihop apart. In such cases, traditional resource-oriented auction schemes, where buyers place bids on resources, may not be effective in providing end-to-end (E2E) quality-of-service (QoS) guarantees. To overcome these limitations, in this article, we coin the concept of E2E service auction where the auction commodities are E2E services rather than certain resource. Under this framework, buyers simply bid for services with E2E QoS requirements without having to know the inner working (which resources are behind). To guarantee E2E QoS for winning bids while ensuring essential economic properties, E2E service auction requires addressing the joint problem of network optimization and auction design with both economical and QoS constraints. To substantiate the mechanism design, we illustrate how to devise E2E service auctions for edge computing systems under various scenarios. We also identify the research opportunities on E2E service auction mechanism design for other critical use cases, including edge intelligence., Comment: 7 pages, 3 figures, appeared in IEEE Wireless Communications

The risk for severe illness and mortality from COVID-19 significantly increases with age. As a result, age-stratified modeling for COVID-19 dynamics is the key to study how to reduce hospitalizations and mortality from COVID-19. By taking advantage of network theory, we develop an age-stratified epidemic model for COVID-19 in complex contact networks. Specifically, we present an extension of standard SEIR (susceptible-exposed-infectious-removed) compartmental model, called age-stratified SEAHIR (susceptible-exposedasymptomatic-hospitalized-infectious-removed) model, to capture the spread of COVID-19 over multitype random networks with general degree distributions. We derive several key epidemiological metrics and then propose an age-stratified vaccination strategy to decrease the mortality and hospitalizations. Through extensive study, we discover that the outcome of vaccination prioritization depends on the reproduction number R0. Specifically, the elderly should be prioritized only when R0 is relatively high. If ongoing intervention policies, such as universal masking, could suppress R0 at a relatively low level, prioritizing the high-transmission age group (i.e., adults aged 20-39) is most effective to reduce both mortality and hospitalizations. These conclusions provide useful recommendations for age-based vaccination prioritization for COVID-19., Comment: 11 pages, 9 figures

Feature selection is central to contemporary high-dimensional data analysis. Grouping structure among features arises naturally in various scientific problems. Many methods have been proposed to incorporate the grouping structure information into feature selection. However, these methods are normally restricted to a linear regression setting. To relax the linear constraint, we combine the deep neural networks (DNNs) with the recent Knockoffs technique, which has been successful in an individual feature selection context. We propose Deep-gKnock (Deep group-feature selection using Knockoffs) as a methodology for model interpretation and dimension reduction. Deep-gKnock performs model-free group-feature selection by controlling group-wise False Discovery Rate (gFDR). Our method improves the interpretability and reproducibility of DNNs. Experimental results on both synthetic and real data demonstrate that our method achieves superior power and accurate gFDR control compared with state-of-the-art methods.

A new organocatalytic transfer hydrogenation strategy for the asymmetric synthesis of 1,1-diarylethanes is described. Under mild conditions, a range of 1,1-diarylethanes substituted with an o-hydroxyphenyl or indole unit could be obtained with excellent efficiency and enantioselectivity. We also extended the protocol to an unprecedented asymmetric hydroarylation of 1,1-diarylalkenes with indoles for the synthesis of a range of highly enantioenriched 1,1,1-triarylethanes bearing acyclic all-carbon quaternary stereocenters. These diaryl- and triarylethanes exhibit impressive cytotoxicity against a number of human cancer cell lines. Preliminary mechanistic studies combined with DFT calculations provided important insight into the reaction mechanism.

A new organocatalytic transfer hydrogenation strategy for the asymmetric synthesis of 1,1-diarylethanes is described. Under mild conditions, a range of 1,1-diarylethanes substituted with an o-hydroxyphenyl or indole unit could be obtained with excellent efficiency and enantioselectivity. We also extended the protocol to an unprecedented asymmetric hydroarylation of 1,1-diarylalkenes with indoles for the synthesis of a range of highly enantioenriched 1,1,1-triarylethanes bearing acyclic all-carbon quaternary stereocenters. These diaryl- and triarylethanes exhibit impressive cytotoxicity against a number of human cancer cell lines. Preliminary mechanistic studies combined with DFT calculations provided important insight into the reaction mechanism.

A new organocatalytic transfer hydrogenation strategy for the asymmetric synthesis of 1,1-diarylethanes is described. Under mild conditions, a range of 1,1-diarylethanes substituted with an o-hydroxyphenyl or indole unit could be obtained with excellent efficiency and enantioselectivity. We also extended the protocol to an unprecedented asymmetric hydroarylation of 1,1-diarylalkenes with indoles for the synthesis of a range of highly enantioenriched 1,1,1-triarylethanes bearing acyclic all-carbon quaternary stereocenters. These diaryl- and triarylethanes exhibit impressive cytotoxicity against a number of human cancer cell lines. Preliminary mechanistic studies combined with DFT calculations provided important insight into the reaction mechanism.

Inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1) have shown to be promising in clinical trials against cancer and other diseases, and lots of efforts have been put into the development of organic compounds as more potent PARP-1 inhibitors. Here we describe a strategy to conveniently obtain metal-based PARP-1 inhibitors with enhanced biological activities by conjugating platinum moiety with an original inhibitor, e.g., benzonaphthyridone. Based on the structure activity relationship analysis of PARP-1 inhibitors, three platinated PARP-1 inhibitors were designed, and the complexes were synthesized and characterized. Complex 3 presented significantly enhanced cytotoxicity against a panel of human cancer cells and a 10-fold increased inhibitory effect against recombinant PARP-1 compared with the original PARP-1 inhibitor. Complex 3 was as cytotoxic as cisplatin and its spectrum of anticancer activity was identical to that of cisplatin. The complex was able to enter into cancer cells efficiently, bind to DNA well, and block cell cycle at G(2)/M phase, indicating that complex 3 is an effective anticancer agent with a distinct mechanism of action. Our study implies that the conjugation of platinum with PARP-1 inhibitors could be a valid strategy to obtain more potent anticancer agents with improved biological activities. (C) 2013 Elsevier Masson SAS. All rights reserved.

Small-molecule inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1) have currently drawn much attention as promising chemotherapeutic drug candidates, and there is a need to develop more potent PARP inhibitors with improved bioavailability. Here we report a strategy to improve the cytotoxicity of PARP inhibitors by conjugation with organometallic ruthenium(II)-arene compounds. We also report a systematic study to reveal the mechanism of action of these ruthenium-PARP inhibitor conjugates. The complexes have been synthesized and characterized spectroscopically. The improved antiproliferative activity from the as-prepared complexes in four human cancer cell lines has indicated their potential for further development as antitumor drugs. Cellular uptake study reveals that the most active complex 3 easily entered into cells. Target validation assays show that the complexes inhibited PARP-1 slightly better than the original PARP inhibitors, that complex 3 strongly bound to DNA and inhibited transcription, and that this complex arrested the cell cycle at the G(0)/G(1) stage. This type of information could shed light on the design of the next generation of more active ruthenium-PARP inhibitor conjugates. (C) 2013 Elsevier Inc. All rights reserved.

Cisplatin is a widely used anticancer drug that acts by binding DNA and causing the formation of intrastrand and interstrand (ICL) crosslinks, but the precise downstream effects of the latter damage are not well understood. In this study, we investigated the influence of cisplatin ICLs on synthetic nucleosomes that were platinated in a site-specific manner in vitro and on gene transcription in live mammalian cells. Nucleosome core particles that we constructed contained site-specific cisplatin 5′-d(G*pC)/5′-d(G*pC) ICLs, where the asterisk denotes the platinated nucleoside, to examine the influence of platinum lesions on the dynamic behavior of nucleosomes in solution. A cisplatin ICL, but not a 1,2-d(GpG) crosslink, significantly inhibited ATP-independent histone octamer-DNA sliding. We also used a novel linearization-recircularization strategy described here to synthesize mammalian expression vectors containing site-specific cisplatin ICLs. Plasmid vectors were tested in live mammalian cells to study the transcription inhibition effects of cisplatin ICLs in the context of two different repair backgrounds. Cisplatin ICLs inhibit transcription as effectively as 1,2-d(GpG) crosslinks. We determined that nucleotide excision repair plays a key role in the removal of cisplatin ICLs, acting in a replication-independent fashion. We also found that loss of mismatch repair function dramatically attenuates the transcription inhibition effects by cisplatin ICLs but not 1,2-d(GpG) intrastrand crosslinks. Our results revealed the unique properties of cisplatin ICLs on nucleosome mobility and on transcription, and they defined how these adducts act in a manner completely different from that used for cisplatin 1,2-d(GpG) crosslinks. These new findings provide direct support for a role of ICLs in the pharmacologic activities of cisplatin, despite the lower frequency of their formation., National Cancer Institute (U.S.) (Grant CA034992)

Inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1) have shown to be promising in clinical trials against cancer and other diseases, and lots of efforts have been put into the development of organic compounds as more potent PARP-1 inhibitors. Here we describe a strategy to conveniently obtain metal-based PARP-1 inhibitors with enhanced biological activities by conjugating platinum moiety with an original inhibitor, e.g., benzonaphthyridone. Based on the structure activity relationship analysis of PARP-1 inhibitors, three platinated PARP-1 inhibitors were designed, and the complexes were synthesized and characterized. Complex 3 presented significantly enhanced cytotoxicity against a panel of human cancer cells and a 10-fold increased inhibitory effect against recombinant PARP-1 compared with the original PARP-1 inhibitor. Complex 3 was as cytotoxic as cisplatin and its spectrum of anticancer activity was identical to that of cisplatin. The complex was able to enter into cancer cells efficiently, bind to DNA well, and block cell cycle at G(2)/M phase, indicating that complex 3 is an effective anticancer agent with a distinct mechanism of action. Our study implies that the conjugation of platinum with PARP-1 inhibitors could be a valid strategy to obtain more potent anticancer agents with improved biological activities. (C) 2013 Elsevier Masson SAS. All rights reserved.

Small-molecule inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1) have currently drawn much attention as promising chemotherapeutic drug candidates, and there is a need to develop more potent PARP inhibitors with improved bioavailability. Here we report a strategy to improve the cytotoxicity of PARP inhibitors by conjugation with organometallic ruthenium(II)-arene compounds. We also report a systematic study to reveal the mechanism of action of these ruthenium-PARP inhibitor conjugates. The complexes have been synthesized and characterized spectroscopically. The improved antiproliferative activity from the as-prepared complexes in four human cancer cell lines has indicated their potential for further development as antitumor drugs. Cellular uptake study reveals that the most active complex 3 easily entered into cells. Target validation assays show that the complexes inhibited PARP-1 slightly better than the original PARP inhibitors, that complex 3 strongly bound to DNA and inhibited transcription, and that this complex arrested the cell cycle at the G(0)/G(1) stage. This type of information could shed light on the design of the next generation of more active ruthenium-PARP inhibitor conjugates. (C) 2013 Elsevier Inc. All rights reserved.

Inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1) have shown to be promising in clinical trials against cancer and other diseases, and lots of efforts have been put into the development of organic compounds as more potent PARP-1 inhibitors. Here we describe a strategy to conveniently obtain metal-based PARP-1 inhibitors with enhanced biological activities by conjugating platinum moiety with an original inhibitor, e.g., benzonaphthyridone. Based on the structure activity relationship analysis of PARP-1 inhibitors, three platinated PARP-1 inhibitors were designed, and the complexes were synthesized and characterized. Complex 3 presented significantly enhanced cytotoxicity against a panel of human cancer cells and a 10-fold increased inhibitory effect against recombinant PARP-1 compared with the original PARP-1 inhibitor. Complex 3 was as cytotoxic as cisplatin and its spectrum of anticancer activity was identical to that of cisplatin. The complex was able to enter into cancer cells efficiently, bind to DNA well, and block cell cycle at G(2)/M phase, indicating that complex 3 is an effective anticancer agent with a distinct mechanism of action. Our study implies that the conjugation of platinum with PARP-1 inhibitors could be a valid strategy to obtain more potent anticancer agents with improved biological activities. (C) 2013 Elsevier Masson SAS. All rights reserved.

Cisplatin is a widely used anticancer drug that acts by binding DNA and causing the formation of intrastrand and interstrand (ICL) crosslinks, but the precise downstream effects of the latter damage are not well understood. In this study, we investigated the influence of cisplatin ICLs on synthetic nucleosomes that were platinated in a site-specific manner in vitro and on gene transcription in live mammalian cells. Nucleosome core particles that we constructed contained site-specific cisplatin 5′-d(G*pC)/5′-d(G*pC) ICLs, where the asterisk denotes the platinated nucleoside, to examine the influence of platinum lesions on the dynamic behavior of nucleosomes in solution. A cisplatin ICL, but not a 1,2-d(GpG) crosslink, significantly inhibited ATP-independent histone octamer-DNA sliding. We also used a novel linearization-recircularization strategy described here to synthesize mammalian expression vectors containing site-specific cisplatin ICLs. Plasmid vectors were tested in live mammalian cells to study the transcription inhibition effects of cisplatin ICLs in the context of two different repair backgrounds. Cisplatin ICLs inhibit transcription as effectively as 1,2-d(GpG) crosslinks. We determined that nucleotide excision repair plays a key role in the removal of cisplatin ICLs, acting in a replication-independent fashion. We also found that loss of mismatch repair function dramatically attenuates the transcription inhibition effects by cisplatin ICLs but not 1,2-d(GpG) intrastrand crosslinks. Our results revealed the unique properties of cisplatin ICLs on nucleosome mobility and on transcription, and they defined how these adducts act in a manner completely different from that used for cisplatin 1,2-d(GpG) crosslinks. These new findings provide direct support for a role of ICLs in the pharmacologic activities of cisplatin, despite the lower frequency of their formation., National Cancer Institute (U.S.) (Grant CA034992)

Starting from three achiral compounds, the title reaction provides rapid access to a variety of molecules that contain indoline, tetrahydroquinoline, and tetrahydroisoquinoline moieties (see scheme). The process features the efficient formation of multiple new bonds and chiral centers, excellent stereoselectivity, oxetane desymmetrization, and easy product purification through filtration. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Starting from three achiral compounds, the title reaction provides rapid access to a variety of molecules that contain indoline, tetrahydroquinoline, and tetrahydroisoquinoline moieties (see scheme). The process features the efficient formation of multiple new bonds and chiral centers, excellent stereoselectivity, oxetane desymmetrization, and easy product purification through filtration. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

DNA is a major target of anticancer drugs. The resulting adducts interfere with key cellular processes, such as transcription, to trigger downstream events responsible for drug activity. cis-Diammine(pyridine)chloroplatinum(II), cDPCP or pyriplatin, is a monofunctional platinum(II) analogue of the widely used anticancer drug cisplatin having significant anticancer properties with a different spectrum of activity. Its novel structure-activity properties hold promise for overcoming drug resistance and improving the spectrum of treatable cancers over those responsive to cisplatin. However, the detailed molecular mechanism by which cells process DNA modified by pyriplatin and related monofunctional complexes is not at all understood. Here we report the structure of a transcribing RNA polymerase II (pol II) complex stalled at a site-specific monofunctional pyriplatin-DNA adduct in the active site. The results reveal a molecular mechanism of pol II transcription inhibition and drug action that is dramatically different from transcription inhibition by cisplatin and UV-induced 1,2-intrastrand cross-links. Our findings provide insight into structure-activity relationships that may apply to the entire family of monofunctional DNA-damaging agents and pave the way for rational improvement of monofunctional platinum anticancer drugs., National Cancer Institute (U.S.) (Grant CA034992)

Resistance of tumor cells to platinum anticancer agents poses a major problem in cancer chemotherapy. One of the mechanisms associated with platinum-based drug resistance is the enhanced capacity of the cell to carry out nucleotide excision repair (NER) on platinum-damaged DNA. Endonucleases XPF and XPG are critical components of NER, responsible for excising the damaged DNA strand to remove the DNA lesion. Here, we investigated possible consequences of down-regulation of XPF and XPG gene expression in osteosarcoma cancer cells (U2OS) and the impact on cellular transcription and DNA repair. We further evaluated the sensitivity of such cells toward the platinum anticancer drugs cisplatin and oxaliplatin., National Cancer Institute (U.S.) (Grant Number CA034992.), National University of Singapore., German Academic Exchange Service (DAAD)

To overcome drug resistance and reduce the side effects of cisplatin, a widely used antineoplastic agent, major efforts have been made to develop next generation platinum-based anticancer drugs. Because cisplatin–DNA adducts block RNA polymerase II unless removed by transcription-coupled excision repair, compounds that react similarly but elude repair are desirable. The monofunctional platinum agent pyriplatin displays antitumor activity in mice, a cytotoxicity profile in cell cultures distinct from that of cisplatin, and a unique in vitro transcription inhibition mechanism. In this study, we incorporated pyriplatin globally or site specifically into luciferase reporter vectors to examine its transcription inhibition profiles in live mammalian cells. Monofunctional pyriplatin reacted with plasmid DNA as efficiently as bifunctional cisplatin and inhibited transcription as strongly as cisplatin in various mammalian cells. Using repair-defective nucleotide excision repair (NER)-, mismatch repair-, and single-strand break repair–deficient cells, we show that NER is mainly responsible for removal of pyriplatin–DNA adducts. These findings reveal that the mechanism by which pyriplatin generates its antitumor activity is very similar to that of cisplatin, despite the chemically different nature of their DNA adducts, further supporting a role for monofunctional platinum anticancer agents in human cancer therapy. This information also provides support for the validity of the proposed mechanism of action of cisplatin and provides a rational basis for the design of more potent platinum anticancer drug candidates using a monofunctional DNA-damaging strategy., National Cancer Institute (U.S.) (Grant Number CA034992)

Poly(ADP-ribose) polymerase-1 (PARP-1) was recently identified as a platinum−DNA damage response protein. To investigate the properties of binding of PARP-1 to different platinum−DNA adducts in greater detail, biotinylated DNA probes containing a site-specific cisplatin 1,2-d(GpG) or 1,3-d(GpTpG) intrastrand cross-link or a cisplatin 5′-GC/5′-GC interstrand cross-link (ICL) were utilized in binding assays with cell-free extracts (CFEs) in vitro. The activated state of PARP-1 was generated by treatment of cells with a DNA-damaging agent or by addition of NAD+ to CFEs. PARP-1 binds with a higher affinity to cisplatin-damaged DNA than to undamaged DNA, and the amount of protein that binds to the most common cisplatin−DNA cross-link, 1,2-d(GpG), is greater than the amount that binds to other types of cisplatin−DNA cross-links. Both DNA damage-activated PARP-1 and unactivated PARP-1 bind to cisplatin-damaged DNA, and both automodified PARP-1 and cleaved PARP-1 bind to cisplatin−DNA lesions. The role of poly(ADP-ribose) (pADPr) in mediating binding of PARP-1 to platinum damage was further investigated. The extent of binding of PARP-1 to the cisplatin 1,2-d(GpG) cross-link decreases upon automodification, and overactivated PARP-1 loses its affinity for the cross-link. Elimination of pADPr facilitates binding of PARP-1 to the cisplatin 1,2-d(GpG) cross-link. PARP-1 also binds to DNA damaged by other platinum compounds, including oxaliplatin and pyriplatin, indicating protein affinity for the damage in an adduct-specific manner rather than recognition of distorted DNA. Our results reveal the unique binding properties for binding of PARP-1 to platinum−DNA damage, providing insights into, and a better understanding of, the cellular response to platinum-based anticancer drugs., Rita Allen Foundation, National Cancer Institute (U.S.) (CA034992)

Poly(ADP-ribose) polymerase-1 (PARP-1) was recently identified as a platinum−DNA damage response protein. To investigate the properties of binding of PARP-1 to different platinum−DNA adducts in greater detail, biotinylated DNA probes containing a site-specific cisplatin 1,2-d(GpG) or 1,3-d(GpTpG) intrastrand cross-link or a cisplatin 5′-GC/5′-GC interstrand cross-link (ICL) were utilized in binding assays with cell-free extracts (CFEs) in vitro. The activated state of PARP-1 was generated by treatment of cells with a DNA-damaging agent or by addition of NAD+ to CFEs. PARP-1 binds with a higher affinity to cisplatin-damaged DNA than to undamaged DNA, and the amount of protein that binds to the most common cisplatin−DNA cross-link, 1,2-d(GpG), is greater than the amount that binds to other types of cisplatin−DNA cross-links. Both DNA damage-activated PARP-1 and unactivated PARP-1 bind to cisplatin-damaged DNA, and both automodified PARP-1 and cleaved PARP-1 bind to cisplatin−DNA lesions. The role of poly(ADP-ribose) (pADPr) in mediating binding of PARP-1 to platinum damage was further investigated. The extent of binding of PARP-1 to the cisplatin 1,2-d(GpG) cross-link decreases upon automodification, and overactivated PARP-1 loses its affinity for the cross-link. Elimination of pADPr facilitates binding of PARP-1 to the cisplatin 1,2-d(GpG) cross-link. PARP-1 also binds to DNA damaged by other platinum compounds, including oxaliplatin and pyriplatin, indicating protein affinity for the damage in an adduct-specific manner rather than recognition of distorted DNA. Our results reveal the unique binding properties for binding of PARP-1 to platinum−DNA damage, providing insights into, and a better understanding of, the cellular response to platinum-based anticancer drugs., Rita Allen Foundation, National Cancer Institute (U.S.) (CA034992)

DNA is a major target of anticancer drugs. The resulting adducts interfere with key cellular processes, such as transcription, to trigger downstream events responsible for drug activity. cis-Diammine(pyridine)chloroplatinum(II), cDPCP or pyriplatin, is a monofunctional platinum(II) analogue of the widely used anticancer drug cisplatin having significant anticancer properties with a different spectrum of activity. Its novel structure-activity properties hold promise for overcoming drug resistance and improving the spectrum of treatable cancers over those responsive to cisplatin. However, the detailed molecular mechanism by which cells process DNA modified by pyriplatin and related monofunctional complexes is not at all understood. Here we report the structure of a transcribing RNA polymerase II (pol II) complex stalled at a site-specific monofunctional pyriplatin-DNA adduct in the active site. The results reveal a molecular mechanism of pol II transcription inhibition and drug action that is dramatically different from transcription inhibition by cisplatin and UV-induced 1,2-intrastrand cross-links. Our findings provide insight into structure-activity relationships that may apply to the entire family of monofunctional DNA-damaging agents and pave the way for rational improvement of monofunctional platinum anticancer drugs.

DNA is a major target of anticancer drugs. The resulting adducts interfere with key cellular processes, such as transcription, to trigger downstream events responsible for drug activity. cis-Diammine(pyridine)chloroplatinum(II), cDPCP or pyriplatin, is a monofunctional platinum(II) analogue of the widely used anticancer drug cisplatin having significant anticancer properties with a different spectrum of activity. Its novel structure-activity properties hold promise for overcoming drug resistance and improving the spectrum of treatable cancers over those responsive to cisplatin. However, the detailed molecular mechanism by which cells process DNA modified by pyriplatin and related monofunctional complexes is not at all understood. Here we report the structure of a transcribing RNA polymerase II (pol II) complex stalled at a site-specific monofunctional pyriplatin-DNA adduct in the active site. The results reveal a molecular mechanism of pol II transcription inhibition and drug action that is dramatically different from transcription inhibition by cisplatin and UV-induced 1,2-intrastrand cross-links. Our findings provide insight into structure-activity relationships that may apply to the entire family of monofunctional DNA-damaging agents and pave the way for rational improvement of monofunctional platinum anticancer drugs.

DNA is a major target of anticancer drugs. The resulting adducts interfere with key cellular processes, such as transcription, to trigger downstream events responsible for drug activity. cis-Diammine(pyridine)chloroplatinum(II), cDPCP or pyriplatin, is a monofunctional platinum(II) analogue of the widely used anticancer drug cisplatin having significant anticancer properties with a different spectrum of activity. Its novel structure-activity properties hold promise for overcoming drug resistance and improving the spectrum of treatable cancers over those responsive to cisplatin. However, the detailed molecular mechanism by which cells process DNA modified by pyriplatin and related monofunctional complexes is not at all understood. Here we report the structure of a transcribing RNA polymerase II (pol II) complex stalled at a site-specific monofunctional pyriplatin-DNA adduct in the active site. The results reveal a molecular mechanism of pol II transcription inhibition and drug action that is dramatically different from transcription inhibition by cisplatin and UV-induced 1,2-intrastrand cross-links. Our findings provide insight into structure-activity relationships that may apply to the entire family of monofunctional DNA-damaging agents and pave the way for rational improvement of monofunctional platinum anticancer drugs.

The nature and scope of available documents are changing significantly in many areas of document analysis and retrieval as complex, heterogeneous collections become accessible to virtually everyone via the web. The increasing level of diversity presents a great challenge for document image content categorization, indexing, and retrieval. Meanwhile, the processing of documents with unconstrained layouts and complex formatting often requires effective leveraging of broad contextual knowledge. In this dissertation, we first present a novel approach for document image content categorization, using a lexicon of shape features. Each lexical word corresponds to a scale and rotation invariant local shape feature that is generic enough to be detected repeatably and is segmentation free. A concise, structurally indexed shape lexicon is learned by clustering and partitioning feature types through graph cuts. Our idea finds successful application in several challenging tasks, including content recognition of diverse web images and language identification on documents composed of mixed machine printed text and handwriting. Second, we address two fundamental problems in signature-based document image retrieval. Facing continually increasing volumes of documents, detecting and recognizing unique, evidentiary visual entities (\eg, signatures and logos) provides a practical and reliable supplement to the OCR recognition of printed text. We propose a novel multi-scale framework to detect and segment signatures jointly from document images, based on the structural saliency under a signature production model. We formulate the problem of signature retrieval in the unconstrained setting of geometry-invariant deformable shape matching and demonstrate state-of-the-art performance in signature matching and verification. Third, we present a model-based approach for extracting relevant named entities from unstructured documents. In a wide range of applications that require structured informat

Dyneins are protein motor complexes that generate force towards the minus ends of microtubules, and cytoplasmic dynein plays a variety of important roles in cell. A small library of synthetic chemicals based on the nature product purealin was first examined for inhibition of cytoplasmic dynein heavy chain and cell growth. The compounds showed effective antiproliferative activity against a mouse leukemia cell line, but selective activities against a small panel of human carcinoma cell lines. Purealin and some of its analogues showed concentration dependent inhibitory effects against the microtubule-stimulated ATPase activity of both bovine cytoplasmic dynein heavy chain as well as the recombinant motor domain of human cytoplasmic dynein in an uncompetitive pattern, indicating that they do not compete with the binding of ATP. Purealin also weakly inhibited p53 nuclear accumulation after DNA damage. Treatment of cells with small interfering RNAs of cytoplasmic dynein heavy chain were also used as a positive control in this assay, although the lifetime of the protein turned out to be too long for the siRNA approach to be useful in a screening protocol.A strategy was built to screen for dynein inhibitors based on a GFP-GR nuclear translocation assay by using a mouse mammary adenocarcinoma cell line (3617.4) stably expressing the fluorescent protein. A small library of synthetic compounds was screened for inhibition of hormone-stimulated GFP-GR nuclear translocation. Several compounds was found to elicit the desired phenotype, and these compounds inhibited the ATPase activity of cytoplasmic dynein heavy chain motor domain without competing for the hydrolyzable ATP-binding site. Biochemical specificity tests showed that the compounds did not compete for GR binding nor inhibit the ATPase activities of Hsp70, Hsp90 or myosin. Libraries of compounds designed to be Hsp70-perturbing agents were also evaluated. Previous data showed that the Hsp70 chaperone class is induced in ce

Dyneins are protein motor complexes that generate force towards the minus ends of microtubules, and cytoplasmic dynein plays a variety of important roles in cell. A small library of synthetic chemicals based on the nature product purealin was first examined for inhibition of cytoplasmic dynein heavy chain and cell growth. The compounds showed effective antiproliferative activity against a mouse leukemia cell line, but selective activities against a small panel of human carcinoma cell lines. Purealin and some of its analogues showed concentration dependent inhibitory effects against the microtubule-stimulated ATPase activity of both bovine cytoplasmic dynein heavy chain as well as the recombinant motor domain of human cytoplasmic dynein in an uncompetitive pattern, indicating that they do not compete with the binding of ATP. Purealin also weakly inhibited p53 nuclear accumulation after DNA damage. Treatment of cells with small interfering RNAs of cytoplasmic dynein heavy chain were also used as a positive control in this assay, although the lifetime of the protein turned out to be too long for the siRNA approach to be useful in a screening protocol.A strategy was built to screen for dynein inhibitors based on a GFP-GR nuclear translocation assay by using a mouse mammary adenocarcinoma cell line (3617.4) stably expressing the fluorescent protein. A small library of synthetic compounds was screened for inhibition of hormone-stimulated GFP-GR nuclear translocation. Several compounds was found to elicit the desired phenotype, and these compounds inhibited the ATPase activity of cytoplasmic dynein heavy chain motor domain without competing for the hydrolyzable ATP-binding site. Biochemical specificity tests showed that the compounds did not compete for GR binding nor inhibit the ATPase activities of Hsp70, Hsp90 or myosin. Libraries of compounds designed to be Hsp70-perturbing agents were also evaluated. Previous data showed that the Hsp70 chaperone class is induced in ce

By means of effective load, Pe, and effective impulse, Ie, a characteristic curve for the response of structures subjected to general pulse loading is obtained. The structural response to an arbitrary impact can be estimated from this curve. Alternatively, a characteristic curve by means of total effective load, P′e, and total impulse, I, is also deduced so as to simplify the computation, while its validity is discussed

By means of effective load, Pe, and effective impulse, Ie, a characteristic curve for the response of structures subjected to general pulse loading is obtained. The structural response to an arbitrary impact can be estimated from this curve. Alternatively, a characteristic curve by means of total effective load, P′e, and total impulse, I, is also deduced so as to simplify the computation, while its validity is discussed

By means of effective load, Pe, and effective impulse, Ie, a characteristic curve for the response of structures subjected to general pulse loading is obtained. The structural response to an arbitrary impact can be estimated from this curve. Alternatively, a characteristic curve by means of total effective load, P′e, and total impulse, I, is also deduced so as to simplify the computation, while its validity is discussed