A versatile maskless microscope projection photolithography system and its application in light-directed fabrication of DNA microarrays

We present a maskless microscope projection lithography system (MPLS), in which photomasks have been replaced by a Digital Micromirror Device type spatial light modulator (DMD, Texas Instruments). Employing video projector technology high resolution patterns, designed as bitmap images on the computer, are displayed using a micromirror array consisting of about 786000 tiny individually addressable tilting mirrors. The DMD, which is located in the image plane of an infinity corrected microscope, is projected onto a substrate placed in the focal plane of the microscope objective. With a 5x(0.25 NA) Fluar microscope objective, a fivefold reduction of the image to a total size of 9 mm2 and a minimum feature size of 3.5 microns is achieved. Our system can be used in the visible range as well as in the near UV (with a light intensity of up to 76 mW/cm2 around the 365 nm Hg-line). We developed an inexpensive and simple method to enable exact focusing and controlling of the image quality of the projected patterns. Our MPLS has originally been designed for the light-directed in situ synthesis of DNA microarrays. One requirement is a high UV intensity to keep the fabrication process reasonably short. Another demand is a sufficient contrast ratio over small distances (of about 5 microns). This is necessary to achieve a high density of features (i.e. separated sites on the substrate at which different DNA sequences are synthesized in parallel fashion) while at the same time the number of stray light induced DNA sequence errors is kept reasonably small. We demonstrate the performance of the apparatus in light-directed DNA chip synthesis and discuss its advantages and limitations.Comment: 12 pages, 9 figures, journal articl

A Low-Power RRAM Memory Block for Embedded, Multi-Level Weight and Bias Storage in Artificial Neural Networks

Pattern recognition as a computing task is very well suited for machine learning algorithms utilizing artificial neural networks (ANNs). Computing systems using ANNs usually require some sort of data storage to store the weights and bias values for the processing elements of the individual neurons. This paper introduces a memory block using resistive memory cells (RRAM) to realize this weight and bias storage in an embedded and distributed way while also offering programming and multi-level ability. By implementing power gating, overall power consumption is decreased significantly without data loss by taking advantage of the non-volatility of the RRAM technology. Due to the versatility of the peripheral circuitry, the presented memory concept can be adapted to different applications and RRAM technologies

A Versatile, Voltage-Pulse Based Read and Programming Circuit for Multi-Level RRAM Cells

In this work, we present an integrated read and programming circuit for Resistive Random Access Memory (RRAM) cells. Since there are a lot of different RRAM technologies in research and the process variations of this new memory technology often spread over a wide range of electrical properties, the proposed circuit focuses on versatility in order to be adaptable to different cell properties. The circuit is suitable for both read and programming operations based on voltage pulses of flexible length and height. The implemented read method is based on evaluating the voltage drop over a measurement resistor and can distinguish up to eight different states, which are coded in binary, thereby realizing a digitization of the analog memory value. The circuit was fabricated in the 130 nm CMOS process line of IHP. The simulations were done using a physics-based, multi-level RRAM model. The measurement results prove the functionality of the read circuit and the programming system and demonstrate that the read system can distinguish up to eight different states with an overall resistance ratio of 7.9

Normal stroma suppresses cancer cell proliferation via mechanosensitive regulation of JMJD1a-mediated transcription

Tissue homeostasis is dependent on the controlled localization of specific cell types and the correct composition of the extracellular stroma. While the role of the cancer stroma in tumour progression has been well characterized, the specific contribution of the matrix itself is unknown. Furthermore, the mechanisms enabling normal-not cancer-stroma to provide tumour-suppressive signals and act as an antitumorigenic barrier are poorly understood. Here we show that extracellular matrix (ECM) generated by normal fibroblasts (NFs) is softer than the CAF matrix, and its physical and structural features regulate cancer cell proliferation. We find that normal ECM triggers downregulation and nuclear exit of the histone demethylase JMJD1a resulting in the epigenetic growth restriction of carcinoma cells. Interestingly, JMJD1a positively regulates transcription of many target genes, including YAP/ TAZ (WWTR1), and therefore gene expression in a stiffness-dependent manner. Thus, normal stromal restricts cancer cell proliferation through JMJD1a-dependent modulation of gene expression.Peer reviewe

Position dependent mismatch discrimination on DNA microarrays – experiments and model

<p>Abstract</p> <p>Background</p> <p>The propensity of oligonucleotide strands to form stable duplexes with complementary sequences is fundamental to a variety of biological and biotechnological processes as various as microRNA signalling, microarray hybridization and PCR. Yet our understanding of oligonucleotide hybridization, in particular in presence of surfaces, is rather limited. Here we use oligonucleotide microarrays made in-house by optically controlled DNA synthesis to produce probe sets comprising all possible single base mismatches and base bulges for each of 20 sequence motifs under study.</p> <p>Results</p> <p>We observe that mismatch discrimination is mostly determined by the defect position (relative to the duplex ends) as well as by the sequence context. We investigate the thermodynamics of the oligonucleotide duplexes on the basis of double-ended molecular zipper. Theoretical predictions of defect positional influence as well as long range sequence influence agree well with the experimental results.</p> <p>Conclusion</p> <p>Molecular zipping at thermodynamic equilibrium explains the binding affinity of mismatched DNA duplexes on microarrays well. The position dependent nearest neighbor model (PDNN) can be inferred from it. Quantitative understanding of microarray experiments from first principles is in reach.</p

European fitness landscape for children and adolescents: updated reference values, fitness maps and country rankings based on nearly 8 million test results from 34 countries gathered by the FitBack network

Objectives (1) To develop reference values for health-related fitness in European children and adolescents aged 6–18 years that are the foundation for the web-based, open-access and multilanguage fitness platform (FitBack); (2) to provide comparisons across European countries. Methods This study builds on a previous large fitness reference study in European youth by (1) widening the age demographic, (2) identifying the most recent and representative country-level data and (3) including national data from existing fitness surveillance and monitoring systems. We used the Assessing Levels of PHysical Activity and fitness at population level (ALPHA) test battery as it comprises tests with the highest test–retest reliability, criterion/construct validity and health-related predictive validity: the 20 m shuttle run (cardiorespiratory fitness); handgrip strength and standing long jump (muscular strength); and body height, body mass, body mass index and waist circumference (anthropometry). Percentile values were obtained using the generalised additive models for location, scale and shape method. Results A total of 7 966 693 test results from 34 countries (106 datasets) were used to develop sex-specific and age-specific percentile values. In addition, country-level rankings based on mean percentiles are provided for each fitness test, as well as an overall fitness ranking. Finally, an interactive fitness platform, including individual and group reporting and European fitness maps, is provided and freely available online (www.fitbackeurope.eu). Conclusion This study discusses the major implications of fitness assessment in youth from health, educational and sport perspectives, and how the FitBack reference values and interactive web-based platform contribute to it. Fitness testing can be conducted in school and/or sport settings, and the interpreted results be integrated in the healthcare systems across Europe