bluuebunny/crossref_metadata_2025 huggingface dataset:
Estimating multilevel regional variation in excess mortality of cancer patients using integrated nested Laplace approximation
Authors: Seppä Karri , Rue Håvard , Hakulinen Timo , Läärä Esa , Sillanpää Mikko J. , Pitkäniemi Janne
Published: October 2018

Models of excess mortality with random effects were used to estimate regional variation in relative or net survival of cancer patients. Statistical inference for these models based on the Markov chain Monte Carlo (MCMC) methods is computationally intensive and, therefore, not feasible for routine analyses of cancer register data. This study assessed the performance of the integrated nested Laplace approximation (INLA) in monitoring regional variation in cancer survival. Poisson regression model of excess mortality including both spatially correlated and unstructured random effects was fitted to the data of patients diagnosed with ovarian and breast cancer in Finland during 1955‐2014 with follow up from 1960 through 2014 by using the period approach with five‐year calendar time windows. We estimated standard deviations associated with variation (i) between hospital districts and (ii) between municipalities within hospital districts. Posterior estimates based on the INLA approach were compared to those based on the MCMC simulation. The estimates of the variation parameters were similar between the two approaches. Variation within hospital districts dominated in the total variation between municipalities. In 2000‐2014, the proportion of the average variation within hospital districts was 68% (95% posterior interval: 35%‐93%) and 82% (60%‐98%) out of the total variation in ovarian and breast cancer, respectively. In the estimation of regional variation, the INLA approach was accurate, fast, and easy to implement by using the R‐INLA package.
Coffee Ring–Inspired Approach toward Oriented Self‐Assembly of Biomimetic Murray MOFs as Sweat Biosensor
Authors: Wang Zhengyun , Liu Ting , Yu Yang , Asif Muhammad , Xu Ning , Xiao Fei , Liu Hongfang
Published: October 2018

The emergence of metal–organic frameworks (MOFs) has sparked intensive attention and opened up the possibility of “crystal engineering.” However, low conductivity, slow diffusion of guest molecules, as well as powder forms always hinder the development of MOF application, especially for biosensors and bioelectronics. Herein, a coffee ring–inspired strategy toward oriented self‐assembly of a biomimetic MOF film following Murray's law is proposed, which can effectively reduce the transfer resistance. The approach includes two types of self‐assembly, evaporation‐driven and heteroepitaxy self‐assembly, and endows the centimeter‐expanded MOF film with oriented macropores, mesopores, and micropores. The Murray MOF network enables greatly enhanced electrons and mass transfer efficiency for electrochemical sensing. Also, the newly discovered lactate and glucose sensing abilities in a wide pH hold striking potential in new generation of wearable sweat biosensors, miniature bioelectronics, and lab‐on‐a‐chip devices.
Serpentine Ni3Ge2O5(OH)4 Nanosheets with Tailored Layers and Size for Efficient Oxygen Evolution Reactions
Authors: Zhang Ning , Yang Baopeng , He Yuanqing , He Yulu , Liu Xiaohe , Liu Min , Song Guoyong , Chen Gen , Pan Anqiang , Liang Shuquan , Ma Renzhi , Venkatesh Shishir , Roy Vellaisamy A. L.
Published: October 2018

Layered serpentine Ni3Ge2O5(OH)4 is compositionally active and structurally favorable for adsorption and diffusion of reactants in oxygen evolution reactions (OER). However, one of the major problems for these materials is limited active sites and low efficiency for OER. In this regard, a new catalyst consisting of layered serpentine Ni3Ge2O5(OH)4 nanosheets is introduced via a controlled one‐step synthetic process where the morphology, size, and layers are well tailored. The theoretical calculations indicate that decreased layers and increased exposure of (100) facets in serpentine Ni3Ge2O5(OH)4 lead to much lower Gibbs free energy in adsorption of reactive intermediates. Experimentally, it is found that the reduction in number of layers with minimized particle size exhibits plenty of highly surface‐active sites of (100) facets and demonstrates a much enhanced performance in OER than the corresponding multilayered nanosheets. Such a strategy of tailoring active sites of serpentine Ni3Ge2O5(OH)4 nanosheets offers an effective method to design highly efficient electrocatalysts.
High‐Performance Wafer‐Scale MoS2 Transistors toward Practical Application
Authors: Xu Hu , Zhang Haima , Guo Zhongxun , Shan Yuwei , Wu Shiwei , Wang Jianlu , Hu Weida , Liu Hanqi , Sun Zhengzong , Luo Chen , Wu Xing , Xu Zihan , Zhang David Wei , Bao Wenzhong , Zhou Peng
Published: October 2018

Atomic thin transition‐metal dichalcogenides (TMDs) are considered as an emerging platform to build next‐generation semiconductor devices. However, to date most devices are still based on exfoliated TMD sheets on a micrometer scale. Here, a novel chemical vapor deposition synthesis strategy by introducing multilayer (ML) MoS2 islands to improve device performance is proposed. A four‐probe method is applied to confirm that the contact resistance decreases by one order of magnitude, which can be attributed to a conformal contact by the extra amount of exposed edges from the ML‐MoS2 islands. Based on such continuous MoS2 films synthesized on a 2 in. insulating substrate, a top‐gated field effect transistor (FET) array is fabricated to explore key metrics such as threshold voltage (V
T) and field effect mobility (μFE) for hundreds of MoS2 FETs. The statistical results exhibit a surprisingly low variability of these parameters. An average effective μFE of 70 cm2 V−1 s−1 and subthreshold swing of about 150 mV dec−1 are extracted from these MoS2 FETs, which are comparable to the best top‐gated MoS2 FETs achieved by mechanical exfoliation. The result is a key step toward scaling 2D‐TMDs into functional systems and paves the way for the future development of 2D‐TMDs integrated circuits.
Teleology as a tacit dimension of teaching and learning evolution: A sociological approach to classroom interaction in science education
Authors: Gresch Helge , Martens Matthias
Published: October 2018

Teleology has been described as an intuitive cognitive bias and as a major type of student conception. There is controversy regarding whether teleological explanations are a central obstacle to, are legitimate in, or are even supportive of science learning. However, interaction in science classrooms has not yet been investigated with regard to teleology. Consequently, this study addresses the question of how teleological explanations emerge in science classroom interactions about evolution and how teachers and students address emerging teleology. In this article, we introduce a theoretical and methodological framework drawing from the sociology of knowledge and systems theory, suggesting that this framework may enrich the understanding of knowledge construction and of social practices in the science classroom because it enables distinguishing between explicit and tacit knowledge. We investigated seven secondary school units about evolution and present data from four grade‐12 classes in Germany, a country with very few creationists, to contrast two ways in which teleology is addressed. In the first type, the teachers combine intentional and need‐based teleological explanations with aspects of scientific theories in an ambiguous way. Contrastingly, in the second type, the teachers construct a duality between correct mechanistic and incorrect teleological explanations by discrediting preceding scientific theories. In the discussion, we argue that the presented sociological approach can also be valuable in other science education contexts, such as creationism, the nature of science and socio‐scientific issues, because classroom interaction involves tacit communication, such as a tacit epistemology, which are essential grounds for the students' knowledge construction.
Green power allocation for cognitive radio networks with spectrum sensing
Authors: Yadav Ramnaresh , Kumar Ashwani , Singh Keshav
Published: October 2018

Green wireless communication has drawn ample interest in the 5G cellular networks. In this article, we investigate an energy‐efficient power allocation with spectrum sensing for cognitive radio (CR) networks. The optimization problem is formulated as a ratio of the sum rate (SR) to the total power consumption in the signal transmission and spectrum sensing subject to the total power constraint. Because the original optimization problem is nonconvex, we adopt Dinkelback's method and propose an optimal energy‐efficient power allocation scheme that iteratively improves the energy efficiency (EE) performance of the CR network and finally gives an optimal solution. In addition, an expression for the optimal solution is derived through the dual‐decomposition method, and its performance is validated through simulation results. The impact of the probability of detection (PD) and the probability of PU activeness (PA) on the achievable average EE and SR is demonstrated when the CR network is designed from the energy‐efficient perspective. © 2018 Institute of Electrical Engineers of Japan. Published by John Wiley & Sons, Inc.
Preparation and properties of poly(vinyl alcohol) films using carbohydrates as plasticizers
Authors: Dai Hongguang , Wang Juan , Liu Naren
Published: October 2018

Three nontoxic carbohydrates (ribose, xylose, fructose) were used as poly(vinyl alcohol) (PVA) plasticizers to prepare PVA films using a casting method. Fourier transform infrared spectra demonstrated that hydrogen bonds formed between the carbohydrate and PVA. The crystallinity of raw PVA and PVA film plasticized by carbohydrate was characterized by X‐ray diffraction. Differential scanning calorimetry showed that carbohydrate decreased the melting point (Tm) of PVA. The decomposition temperature of PVA increased with addition of carbohydrate. The thermal stability of PVA film plasticized by carbohydrate (CAPF) was higher than that of PVA film plasticized by glycerol (GLPF). The thermal processing window of CAPF was broader than that of GLPF. The water vapor resistance of CAPF was better than that of GLPF. The mechanical properties of PVA films stored at different relative humidity were studied. Generally, the tensile strength of CAPF was larger than that of GLPF, while the elongation at break of CAPF was close to that of GLPF. Our experimental results indicate that carbohydrates are effective plasticizers for PVA. J. VINYL ADDIT. TECHNOL., 25:E181–E187, 2019. © 2018 Society of Plastics Engineers
Boosting $$ H\to b\overline{b} $$ with machine learning
Authors: Lin Joshua , Freytsis Marat , Moult Ian , Nachman Benjamin
Published: October 2018

Abstract

High-p

T
Higgs production at hadron colliders provides a direct probe of the internal structure of the gg → H loop with the

$$ H\to b\overline{b} $$

H
→
b

b
¯

decay offering the most statistics due to the large branching ratio. Despite the overwhelming QCD background, recent advances in jet substructure have put the observation of the

$$ gg\to H\to b\overline{b} $$

gg
→
H
→
b

b
¯

channel at the LHC within the realm of possibility. In order to enhance the sensitivity to this process, we develop a two-stream convolutional neural network, with one stream acting on jet information and one using global event properties. The neural network significantly increases the discovery potential of a Higgs signal, both for high-p

T
Standard Model production as well for possible beyond the Standard Model contributions. Unlike most studies for boosted hadronically decaying massive particles, the boosted Higgs search is unique because double b-tagging rejects nearly all background processes that do not have two hard prongs. In this context — which goes beyond state-of-the-art two-prong tagging — the network is studied to identify the origin of the additional information leading to the increased significance. The procedures described here are also applicable to related final states where they can be used to identify additional sources of discrimination power that are not being exploited by current techniques.
Lepto-quark portal dark matter
Authors: Choi Soo-Min , Kang Yoo-Jin , Lee Hyun Min , Ro Tae-Gyu
Published: October 2018

Abstract

We consider the extension of the Standard Model with scalar leptoquarks as a portal to dark matter (DM), motivated by the recent anomalies in semi-leptonic B-meson decays. Taking singlet and triplet scalar leptoquarks as the best scenarios for explaining B-meson anomalies, we discuss the phenomenological constraints from rare meson decays, muon (g − 2)
μ
, and leptoquark searches at the Large Hadron Collider (LHC). Introducing leptoquark couplings to scalar dark matter, we find that the DM annihilations into a pair of leptoquarks open a wide parameter space, being compatible with XENON1T bound, and show that there is an interesting interplay between LHC leptoquark searches and distinct signatures from cascade annihilations of dark matter.
Solving and classifying the solutions of the Yang-Baxter equation through a differential approach. Two-state systems
Authors: Vieira R. S.
Published: October 2018

Abstract

The formal derivatives of the Yang-Baxter equation with respect to its spectral parameters, evaluated at some fixed point of these parameters, provide us with two systems of differential equations. The derivatives of the R matrix elements, however, can be regarded as independent variables and eliminated from the systems, after which two systems of polynomial equations are obtained in place. In general, these polynomial systems have a non-zero Hilbert dimension, which means that not all elements of the R matrix can be fixed through them. Nonetheless, the remaining unknowns can be found by solving a few number of simple differential equations that arise as consistency conditions of the method. The branches of the solutions can also be easily analyzed by this method, which ensures the uniqueness and generality of the solutions. In this work we considered the Yang-Baxter equation for two-state systems, up to the eight-vertex model. This differential approach allowed us to solve the Yang-Baxter equation in a systematic way and also to completely classify its regular solutions.
Formation of subsurface cracks in silicon wafers by grinding
Authors: Yin Jingfei , Bai Qian , Li Yinnan , Zhang Bi
Published: October 2018

Single-crystal silicon is an important material in the semiconductor and optical industries. However, being hard and brittle, a silicon wafer is vulnerable to subsurface cracks (SSCs) during grinding, which is detrimental to the performance and lifetime of a wafer product. Therefore, studying the formation of SSCs is important for optimizing SSC-removal processes and thus improving surface integrity. In this study, a statistical method is used to study the formation of SSCs induced during grinding of silicon wafers. The statistical results show that grinding-induced SSCs are not stochastic but anisotropic in their distributions. Generally, when grinding with coarse abrasive grains, SSCs form along the cleavage planes, primarily the {111} planes. However, when grinding with finer abrasive grains, SSCs tend to form along planes with a fracture-surface energy higher than that of the cleavage planes. These findings provide a guidance for the accurate detection of SSCs in ground silicon wafers.
The Role of High-Throughput Laboratories in Homeland Security
Authors: Beugelsdijk Tony J. , Layne Scott P.
Published: October 2018

Infectious diseases pose threats from natural and manmade sources, and arguably the situation is getting worse. The outbreak of the coronavirus causing the severe acute respiratory syndrome (SARS) shows that the world is linked by thousands of people traveling millions of miles every single day who can spread SARS or new strains of influenza with pandemic potential. 1 The world is also becoming a more dangerous place, with rogue nations and terrorist networks aggressively seeking nuclear, chemical, and biological weapons. Of these, biological weapons are the cheapest to produce and likely the most attractive because they can be used anonymously.
Two-Dimensional Parallel Dispenser for Microarray Printing
Authors: Kuoni Andreas , Boillat Marc , de Rooij Nico F.
Published: October 2018

Parallel printing in a microarray format is becoming increasingly important. This paper presents a 2-D multi-channel dispenser with a spotting spacing of 500 μm. The dispenser is continuously loaded from a 384-well plate format and shoots upward. New technologies using polyimide substrate was developed, and the flexibility of the polyimide sheets allows scaling the dispenser up to an array format of 24 × 16. Drop formation is analyzed by stroboscopic illumination and by spotting onto glass slides. Droplets of 65 pL are dispensed in parallel up to 5 kHz at a droplet speed of 2 m/s.
Automation and ISO 17025 Test Validation of a Toxoplasma Gondii Antibodies Enzyme-Linked Immunosorbent Assay
Authors: Wu John T. Y. , Wong Lester S. Y. , Chow Eva Y. W. , Bowlby Evelyn E.
Published: October 2018

The authors automated an enzyme-linked immunosorbent assay to detect porcine serum antibodies to Toxoplasma gondii. Two thousand swine sera can be assayed in two eight-hour shifts using a robotic workstation. The automated-ELISA programming is not complex and the test configuration is flexible. This high-throughput screening (HTS) a-ELISA can achieve a 10-fold increase (100→ 1000 tests) in test capacity over the manual method. The assay has been validated according to the requirements of the ISO/IEC 17025 standard. These include repeatability, reproducibility, and optimal threshold value studies. Other requirements are proficiency panel testing, analyst training, standard operation procedure, and equipment certifications.
Transfer of Low Nanoliter Volumes between Microplates Using Focused Acoustics—Automation Considerations
Authors: Ellson Richard , Mutz Mitchell , Browning Brent , Lee Lawrence , Miller Michael F. , Papen Roeland
Published: October 2018

Acoustic droplet ejection (ADE) gently and precisely aliquots nanoliter and picoliter liquid volumes without any physical contact with the solution being transferred. The technology is very automation-friendly, as it is compatible with conventional microplates. Focused energy from an acoustic transducer induces droplet ejection into an inverted standard microplate. The commercial system transfers low-nanoliter volumes of dimethyl sulfoxide–dissolved compound libraries and thereby enables cell-based assays to be performed in 1536-well plates.
Conceptual Design for an Automated High-Throughput Magnetic Protein Complex Purification Workcell
Authors: Najmabadi Peyman , Goldenberg Andrew A. , Emili Andrew
Published: October 2018

One of the major challenges facing the emerging field of proteomics research is related to the technical difficulties in analyzing protein structure and function on a genomic scale. The routine purification of protein complexes as a means to investigate protein–protein interaction networks is of particularly high interest because of its significant potential to improve overall understanding of protein function and to improve ongoing drug discovery efforts. Automation of currently practiced laboratory procedures has the potential to markedly improve protein purification throughput, but important technical issues remain to be addressed. This paper investigates key bottlenecks in the automation of standard affinity-based procedures for protein complex purification and introduces a promising conceptual design for an automated workcell that would allow for rapid and efficient magnetic bead-based purification of protein complexes from model organisms suitable for a medium-sized research laboratory setting. The design specifications are based on a modular and flexible design that will permit routine, unattended batch isolation and processing of protein complexes from microbes. (JALA 2003;8:101–6)
Improving Sample Analysis Throughput and Quality with a .NET™-based, Real-Time QC Decision Support System
Authors: Staab Torsten , Shiina Toshiyuki , Miller Derek
Published: October 2018

This report describes an integrated, software-based quality control system designed to significantly improve the sample analysis throughput and quality of beryllium analysis laboratories throughout the U.S. Department of Energy complex. Originally, this system was developed to minimize the downtimes of expensive instrumentation (here: Perkin Elmer® 4300™ DV Inductively Coupled Plasma Optical Emission Spectrometers) and to automate the sample analysis quality control process. This automated software system was also expected to eliminate time-consuming and error-prone result data interpretation, which previously was done manually. To achieve these goals, Los Alamos National Laboratory recently implemented a rule-based decision support system in the C#.NET™ that continuously extracts and analyzes data from the instrument's result database as the data is being generated. Using a customer-specific expert rule base, the system is capable of detecting abnormal operating situations fully autonomously in real time. This also enables the system to perform on-the-fly quality control and automatic, electronic event notification of lab personnel via e-mail and pager. (JALA 2003;8:107–12)
Sample Processing with Hydrophobic Microfluidics
Authors: McNeely Michael R. , Sputea Mark K. , Tusneem Nadeem A. , Oliphant Arnold R
Published: October 2018

Hydrophobic microfluidics is a method for controlling fluid flow in microfluidic systems using short restrictions in channel diameter that act as passive valves. Systems designed using hydrophobic microfluidics have the advantage of easily interfacing with external hardware and integrating with external analysis equipment. This allows it to take advantage of both the micro and macro realms, whichever is most suited for the application, as well as allowing for an inexpensive integration of microfluidics into a company's sample analysis protocols. This method of fluid control is excellent for highly parallel sample analysis, such as DNA processing.
Laboratory Accreditation the Next Generation of Quality Improvement in Thailand
Authors: Promptmas C. , Prijavudhi A.
Published: October 2018

A Thailand quality assessment program called ìThe External Quality Assessment in Clinical Chemistry, EQAC” was found in 1986. A blind lyophilized control serum is monthly-cycle distributed to the participants and the returned test-report values are evaluated by a computed program. Evaluated report Mean Variance Index Scores (MVIS) and mean score of all tests are posted back to the participants.

In 1999 the program was applied by 324 laboratory participants of which 59% of general hospital and community health hospital laboratory, 29% of private hospital laboratory including polyclinics, and 12% of the others. By now as many as 144 trials of 23 biochemistry tests at different methods were assessed from the EQAC program. Participant communication, knowledge update and enhanced quality encouragement have been managed by mean of participants' VIS from 120 to 93 during 1987–1998.

For the next millennium, the implementation of ISO/IEC Guide 25 for quality system in clinical laboratory will be a promising strategy of quality improvement in Thailand. The Ministry of Public Health is step forward to adopt this guide for certifying standard laboratories. These efforts will be a first step towards the next generation of quality improvement for clinical laboratory in Thailand.
Simultaneous Fluorescent Detection of Two mRNA Targets by High Performance Signal Amplification
Authors: Gonzales Frank R.
Published: October 2018

Development of drug candidates, which modulate cytokine responses or metabolic pathways by targeting gene expression, requires analytical systems that measure specific messenger RNAs rapidly and accurately and that can be adapted to high throughput screening operations. Chromagen's High Performance Signal Amplification (HPSA), system, a DNA probe hybridization method, has been enhanced to measure two different mRNA targets simultaneously in the same micro-plate well. Multi-target testing using HPSA takes advantage of a family of low molecular weight fluorescent dyes with large quantum yields, which exhibit distinct excitation and emission wavelengths. A two-target model system using cultured human THP-1 cells examined IL-1β mRNA induction in response to bacterial lipopolysaccharide (LPS) exposure and also monitored intrinsic β-actin mRNA as a housekeeping gene transcript. An oligonucleotide DNA probe complementary to IL-1β RNA was labeled with a reporter ligand while a β-actin DNA probe was linked directly to an enzyme. Sample mRNA was captured onto the surface of micro-plate wells and hybridized to both DNA probes. After removing non-hybridized probe, a second enzyme conjugate that specifically recognizes the IL-1β DNA probe reporter ligand was allowed to bind. The two enzyme systems were distinguished by using substrates labeled with different fluorescent tags (one for IL-1β and the other for β-actin). Resolution of the two fluorescent products was carried out with Chromagen's high-sensitivity, photon-counting fluorometer. This system was capable of detecting synthetic RNA targets for IL-1β and β-actin in the attomole range. Authentic β-actin mRNA was measured in 50,000 uninduced cells and this signal could be specifically competed away by addition of excess unlabeled β-actin probe during hybridization. A time course of IL-1β mRNA induction in THP-1 cells by LPS revealed that peak induction occurred after 2–3 hours. The β-actin mRNA level showed an initial decrease, but remained relatively constant throughout the remaining time points. Results obtained with the dual detection format paralleled those generated when each target was measured separately in its single-target gene expression assay. Chromagen's HPSA two-target system not only augments screening information, but also saves testing time and conserves reagents. The potential of this system is being explored with different gene targets of therapeutic value and other housekeeping genes.
Cleavage Automated: A New Combinatorial Chemistry Tool
Authors: Cook N.J. , Young K. , Stanley A.L.
Published: October 2018

Liquid handling systems are in common use throughout the research chemistry industry, for a variety of fluid dispensing applications. However, few manual or automatic systems have been specifically designed for dosing highly corrosive acid/solvent mixes. Even fewer can withstand 60% Trifluoroacetic acid mixes — a standard mixture for cleavage of compound from polystyrene beads. A design is presented of such an automated dosing system. The requirements are to reduce human exposure to chemicals, remove potential for repetitive strain injury, and increase reaction plate throughput. Material choice, the use of process valves, equipment protection, and a novel plate detection system are discussed. Modifications resulting from the prototype test are discussed, along with additional improvements to the system and further research.
Manufacture Automation: Model and Object Recognition by Using Object Position Auto Locating Algorithm and Object Comparison Model
Authors: Su Ching-Liang
Published: October 2018

This research uses the geometry matching technique to identify the different objects. The object is extracted from the background. The second moment 6 is used to find the orientation and the center point of the extracted object. Since the second moment can find the orientations and the center point of the object, the perfect object and the test object can be aligned to the same orientation. Furthermore, these two images can be shifted to the same centroid. After this, the perfect object can be subtracted from the test face. By using the subtracted result, the objects can be classified. The techniques used in this research can very accurately classify different objects.
Flexible, Parameter-Controlled Nanoliter Pipetting on a Tecan xyz Platform
Authors: Schlegel Joerg
Published: October 2018

Cost pressure and rising throughput requirements are important drivers for assay miniaturization. Typical examples for the trend “smaller is better” are found in BioChip applications and in High Throughput Screening (HTS), which is evolving from the 96-well standard to high-density microplates with 384, 864, 1536 or more wells. These applications require the automated pipetting of liquids in the submicroliter volume range, a difficult task for traditional automated liquid handling systems based on syringe pumps.

Tecan developed a new device for the accurate pipetting of volumes in the nanoliter range. Based on ink-jet printer technology, this device allows the exact control of the volume of the ejected droplets via a set of parameters. The integration of this new technology into Tecan's flexible xyz-platforms allows an easy use of this powerful technology for several applications. Results such as volume range, accuracy and precision are discussed.
Managing Laboratory Automation: Integration and Informatics in Drug Discovery
Authors: Manley Charles
Published: October 2018

Drug discovery today requires the focused use of lab automation and other resources in Combinatorial Chemistry and High-Throughput Screening (HTS). The ultimate value of both Combinatorial Chemistry and High-Throughput Screening technologies and the lasting impact they will have on the drug discovery process is a chapter that remains to be written. Central to their success and impact is how well they are integrated with each other and with the rest of Drug Discovery — and Informatics is key to this success. This presentation will focus on Informatics and the integration of the disciplines of combinatorial chemistry and HTS in modern drug discovery. Examples from experiences at Neurogen from the last five years will be described.
Data Management and Integration of Clinical Laboratory Information: Current Status and Future Perspectives of Physiological Function Examination Systems in Japan
Authors: Nagata Tatsuo Kuroki Shirou , Nakano Kazushi , Maruyama Ikuro
Published: October 2018

The roles of the clinical laboratory department in each hospital are becoming more important than before. On the other hand, there have been endeavors to seek a way to integrate and systemize examinationsand testing and to add values to the results. The role of the laboratory department in the medical field is significant in making decisions on diagnosis and treatment. Increasingly, laboratory information of value is being more heavily demanded from the out-patient and in-patient clinics.

Our department has been responsive to the current needs of those workplaces, and over the past 5 years has developed an examination system using computers. Currently this system is operating in the blood examination and physiological examination branches. Furthermore, we are developing a new system with the aim of establishing “electronic medical records.”

At first, we explain in this paper the background and reason why we intend to manage and integrate the data of clinical laboratory information. Then we provide an overview of the present status and perspective of the physiological examination system in Japan.
High-Speed Flow Sensing as a Diagnostic Tool in the Development of Microfluidic Systems
Authors: Boillat Marc , Tinguely Xavier , Droz Bastien , van der Schoot Bart
Published: October 2018

Seyonic is developing a family of high-speed micro flow sensors with full-scale sensitivities between 0.25 and 10 microliter per second. The flow rate is determined by the measurement of a pressure difference across a fluidic restriction, using two integrated piezo-resistive pressure sensors. Main applications are in sub-microliter dispensing systems, where both sensor accuracy and speed provide real-time validation of the requested liquid volumes. The very fast response of the sensor, less than 2 ms, allows for measurement of liquid volumes down to the nL range. The sensor is able to measure not only the flow, but also the instantaneous pressure in the systems under evaluation. It is therefore possible to obtain valuable information on the system's operation for the characterization of fluidic components such as micromachined pumps, solenoid valves and jet dispensers
Fully Automated Anti-Varicella Zoster Enzyme-Linked Immunosorbent Assays Supporting Manufacture of a Novel Intravenous Therapeutic for Treatment of Ailments Caused by the Varicella Zoster Virus
Authors: Lee Macaulay Anne , Masi Andrea , Soluk Lori , Morier Jeff , Kierek-Jaszczuk Danuta
Published: October 2018

Two non-competitive, antibody-capture enzyme-linked immunosorbent assays, a commercial Kit VZIG ELISA and an in-house developed, amplified VZIG ELISA were automated by using the liquid handling and plate processing abilities of the Microlab AT plus 2 and Microlab F.A.M.E. instruments, respectively. The evaluation of the experimental data has also been automated by using the F.A.M.E.-specific data import converter and PLA software program for data capture / uploading and analysis. The automation increased the economy of analytical operations and traceability of the experimental data thus better supporting the production and clinical studies on a therapeutic Varicella Zoster Immune Globulin manufactured at Cangene.
Assay Development in High Density MicroWell® Plates: Use of Well Geometries, Format, Surface Modification and Optical Properties to Achieve Optimal Assay Performance
Authors: Sullivan Barbara M. , Simon Kathryn D. , Nanda Susan K. W. , Pocius Judy , Scholz Wendy K.
Published: October 2018

While high density MicroWell plates, including 384 well and 1536 well plates, offer advantages of low volume reaction or growth vessels in a standardized footprint allowing robotic manipulation, the greatest benefits lie in the increased well surface area to reaction volume ratios. This surface area to volume benefit can be utilized to optimize assay development by utilizing the molecular surface as a reactant. The well geometry and optical properties are also enhanced in high-density plates, allowing microscopic imaging and increased signal detection for fluorescence and luminescence.

The molecular characteristics of high density MicroWell plates were examined in regard to base materials and induced surface modification. Various modification methods including injection-molding parameters, exposure to high and low energy sources and exposure to specific physical conditions were studied. The surfaces were molecularly characterized and then utilized as reactants in high throughput and low volume in vitro assays. Polystyrene plates exhibited a natural relatively hydrophobic surface due to the hydrocarbon backbone of the polystyrene along with the repeating benzene ring. Exposure to direct electrical discharge, and several forms of irradiation in the presence of air and oxygenated atmosphere resulted in surfaces exhibiting various levels of oxidation. These levels were measured and the molecular species were calculated.

These specific surfaces were utilized as reactants in solid phase, cell based and cell culture assays. Specific surfaces demonstrated specific efficacy in regard to particular applications. For example, a highly charged surface exhibiting hydroxyl, carbonyl, and some carboxyl moieties was best for adherent cell culture. Utilizing passive adsorption procedures, a variant surface exhibiting more hydroxyl and carbonyl groups did not bind IgG well but did bind phospholipids, providing a surface “high-binding” for lipids while maintaining low background due to non-specific adsorption. A surface, commonly referred to as “high binding,” having slightly lower surface energy than the other two studied and characterized by aromatic hydrocarbons, hydroxyl and some few carbonyl groups did not bind hydrophobic antigens, but did bind glycoproteins such as IgG very well under slightly basic, passive conditions.

The geometries of wells were also examined. Well geometries contributed significantly by eliminating reagent wicking or creeping, enhancing detection of signals, and increasing the active surface area to reagent volume, allowing the utilization of decreased substrate concentrations along with low reagent volumes without loss of sensitivity.
Solving the MALDI-TOF-MS Automation Puzzle
Authors: Köster Claus , Hufnagel Peter , Schürenberg Martin
Published: October 2018

In recent years Matrix-Assisted Laser Desorption/Ionization Time-Of-Flight Mass Spectrometry (MALDI-TOF-MS) 1 has grown rapidly in its importance in the areas of Genome and Proteome research. The received mass spectra have high information content and can be acquired in a few seconds. Another reason for doing MALDI-TOF-MS is the possibility of fully automated processing.
Automation for Contract Laboratories — Benefits from a Customer Perspective
Authors: North Nigel
Published: October 2018

Automation requires significant capital investment and for contract laboratories this funding may be difficult to justify. However, with increasing commitment to the automation of dosage form analysis by pharmaceutical companies and the adoption of automation earlier in the development process, outsourcing of automated methods will be an important requirement in the future. Contract laboratories that do not have automation equipment will not be able to compete as effectively for business as those that have this capability. The benefits to the customer of outsourcing automated methods will be discussed together with the potential problems for the contract laboratory in forming a strategy to meet this need. The adoption of new technology in other development functions (e.g., bioanalysis), by pharmaceutical companies and contract facilities has been very successful. The learnings from this situation will also be briefly outlined to provide some perspective around the implementation of automated methods.
Multiplex SNP Genotyping Using Locked Nucleic Acid and Microfluidics
Authors: Choleva Yoanna , Nørholm Mikkel , Pedersen Susanne , Mouritzen Peter , Høiby Poul E. , Nielsen Alex. T. , Møller Søren , Jakobsen Mogens H. , Kongsbak Lars
Published: October 2018

Locked Nucleic Acid's or LNA are a new class of bicyclic DNA analogues that have a high affinity and specificity towards complementary nucleic acids. LNA containing oligonucleotides were used to develop a multiplex SNP genotyping assay based entirely on hybridization between capture probe and target. The approach incorporates a polymer microarray platform, photochemistry for immobilization of oligonucleotides onto microarrays, and a dedicated software tool to aid primer and capture probe design for highly multiplex genotyping. Furthermore, these technologies are combined in an integrated microfluidics platform for simple, highly multiplex and robust SNP genotyping.
Collecting Sample Weight Data on Various Liquid Handling Robots
Authors: Bruner Jimmy , Birkemo Larry , Jordan Kelly , Smith Glenn , Ormand James
Published: October 2018

Liquid-handling platforms often do not provide a mechanism for collecting weight data needed for instrument qualification and sample transfer confirmation. This paper discusses the development, implementation, and application of a system that facilitates liquid-handling confirmation required for Good Laboratory Practice (GLP) compliance and provides an avenue to track the amount of sample transferred for extraction.

The Balance Data Collector (BDC) system was designed as a flexible generic balance tool to be used with Tecan Gemini© and Packard WinPrep® software. The BDC system provides a user interface for balance configuration, a pointer to a file for storing weight data, and an external interface through command-line arguments.

BDC is currently used for instrument qualification and sample collection in bioanalytical applications. Instrument qualification includes refining instrument liquid classes and verifying pipetting accuracy and precision. For bioanalytical applications using 96-well plates, BDC collects individual aliquot weights of samples transferred during an assay.

The BDC system provides the user with the capability to control a balance via liquid-handling programming platforms such as Tecan Gemini© and Packard WinPrep®. Integration of liquid-handling platforms and BDC reduces the time the scientist must spend recording weight data needed for GLP compliance and can be used to increase accuracy of calculated sample concentrations.
A Fully Automated High-Throughput Nucleic Acid Purification System Using Silica Coated Magnetic Bead Technology
Authors: Schade Carola , Lubenow Helge , Weierstall Thomas , Wehren Achim , Haab Jean-Marc , Paras Brian
Published: October 2018

The design of a fully automated high-throughput system for the purification of sequencing templates is described. Hardware, software, and chemistries have been optimized to suit the needs of high-throughput laboratories involved in genome sequencing projects. Using this system, up to 5760 samples (60 times 96-well plates) can be purified in less than 16 hours during a single unattended run. The system can also be configured to perform sequencing reaction setup for all 60 plates following template purification, extending total run times to < 24 hours. Final sequencing reactions are prepared in 384-well microplates.
Gene Expression Microarrays: Improvements and Applications towards Agricultural Gene Discovery
Authors: Zhu Tong , Chang Hur-Song , Schmeits James , Gil Pedro , Shi Liang , Budworth Paul , Zou Guangzhou , Chen Xi , Wang Xun
Published: October 2018

In agriculture, the associations between genes and resulting traits revealed by high throughput approaches such as transcription profiling could be used to select more environmentally friendly chemicals for plant protection and to develop plants with increased grain yields and better nutrition value, with more resistance to diseases and tolerance to abiotic stress. However, one of the major challenges to apply such approaches is the limited genomic information for most of the very diversified crop species. We developed multiple strategies and platform technologies to address this issue. Here we report our improvements of these technologies towards large-scale transcription profiling and their applications in agricultural gene discovery.
MagneSil™ Paramagnetic Particles: Magnetics for DNA Purification
Authors: Otto Paul
Published: October 2018

MagneSil™ Paramagnetic Particles are silica-paramagnetic particles with an affinity for nucleic acids under defined conditions. Particle structure and solution composition can be altered to selectively adsorb nucleic acids based upon type and size. These properties have been used to develop purification methods based on a three-step bind, wash, and elute process. The MagneSil™ technology is readily adaptable to robotic platforms, allowing complete automation of the purification process in either 96- or 384- well plate formats. This article introduces the basic physical and performance characteristics of the MagneSil™ Paramagnetic Particles.
High Throughput Mapping of Protein-Protein Interactions: Automation of the Yeast Two-Hybrid System
Authors: Richmond Steve A. , Gregan Kelly , Burke Julian F.
Published: October 2018

Protein-protein interactions are a vital component in both the function and regulation of virtually all biological processes. In the yeast two-hybrid system, one of the most commonly-used methods for studying protein-protein interactions, protein-protein interactions are detected by expression of a reporter gene driven by the interaction between bait and prey proteins. We report here the development of an automated system, the MegaMate, for carrying out high throughput (over 100,000 clones per day) yeast two-hybrid screens with full data tracking.
The μFill: A New 96-/384- Well Microplate Reagent Dispenser for HTS and Drug Discovery
Authors: Held Paul , Greene Jason
Published: October 2018

Today's biomedical research requires instrumentation that is both functional and versatile. While high throughput screening (HTS) and drug discovery laboratories require instrumentation that can be automated, pilot assay laboratories may not necessarily need total automation. Towards that end, Bio-Tek has developed the μFill, a 96-/384-well microplate reagent dispenser capable of running stand-alone or computer-controlled as part of a robotics system. The μFill is compatible with both 96- and 384-well microplates, and using a specially designed adaptor can also dispense to deep-well microplates. It is capable of dispensing from 10–3000 μl for 96-well plates and 5–1500 μl for 384-well plates in 1-μl increments. The μFill can dispense 20 μl into a 96-well plate in four seconds and into a 384-well microplate in 12 seconds. The microprocessor-controlled syringe pump is based on a tested, low-maintenance design that requires no calibration, yet provides a high degree of accuracy and precision. The accuracy with an 80 μl dispense is within 1 μl with a percentage CV of less than 2%, and with a dispense volume of 20 μl, the percentage CV is still less than 5%. For those needing to dispense organic solvents or sterile aqueous solutions, a model that is autoclavable and has increased solvent resistance is also available. The programming allows for the control of flow rates from 225 μl/well/sec, for dispensing to cell cultures, and to 1000 μl/well/sec for rapid and vigorous reagent dispensing. The flexible software provides complete programming capabilities from the keypad. For more complete automation, robotics interfaces can be developed using ActiveX® software commands. The μFill's size, with a 14 times 14-inch footprint and a height of seven inches, allows it to be used almost anywhere.
A Simple Filter Algorithm for Gene Expression Profiling Data
Authors: Hoffmann Georg
Published: October 2018

Gene expression profiling with microarrays is a promising method to identify groups of genes, which are likely to differentiate between complex diseases, such as severe malignancies. 1 , 2 One problem, besides the well-known sample preparation and hybridization challenge 3 is the abundance of experimental results (typically thousands of oligonucleotide probes) for a small number of clinical samples (typically 10 to 100). Since traditional statistics require large data sets and are often tedious, I looked for a simpler and widely applicable filtering approach.

The method is based on observations obtained with artificial neural nets (ANN), which we are using for the classification of tumor genes in a similar way as described by Khan, et al. 2 An ANN in its simplest structure calculates the relationships between input patterns and their respective output classes using weight factors ( Fig. 1 ). The higher the weight, the higher is the contribution of an input signal to the observed output pattern.