Combinatorial CRISPR-Cas9 screens for de novo mapping of genetic interactions.

We developed a systematic approach to map human genetic networks by combinatorial CRISPR-Cas9 perturbations coupled to robust analysis of growth kinetics. We targeted all pairs of 73 cancer genes with dual guide RNAs in three cell lines, comprising 141,912 tests of interaction. Numerous therapeutically relevant interactions were identified, and these patterns replicated with combinatorial drugs at 75% precision. From these results, we anticipate that cellular context will be critical to synthetic-lethal therapies

dRail: a novel physical layout methodology for power gated circuits

In this paper we present a physical layout methodology, called dRail, to allow power gated and non-power gated cells to be placed next to each other. This is unlike traditional voltage area layout which separates cells to prevent shorting of power supplies leading to impact on area, routing and power. To implement dRail, a modified standard cell architecture and physical layout is proposed. The methodology is validated by implementing power gating on the data engine in an ARM Cortex-A5 processor using a 65nm library, and shows up to 38% reduction in area cost when compared to traditional voltage area layou

Single-Flux-Quantum Bipolar Digital-to-Analog Converter Comprising Polarity-Switchable Double-Flux-Quantum Amplifier

We present a single-flux-quantum (SFQ)-based digital-to-analog converter (DAC) generating bipolar output voltages, in which the key component is a polarity-switchable double-flux-quantum amplifier (PS-DFQA). The DAC comprised a dc/SFQ converter, an 8-bit variable pulse-number-multiplier (PNM), and a 8-fold PS-DFQA integrated on a single chip. SFQ pulse-frequency modulation was employed to realize variable output voltage amplitude, for which the multiplication factor of the variable-PNM was controlled by a commercial data generator situated at room temperature. The variable-PNM realized 8-bit resolution with a multiplication factor between 0 and 255. Bias currents fed to the 8-fold PS-DFQA were polarity-switched in synchronization with the digital code for the variable-PNM. The whole circuits including I/O elements were designed using SFQ cell libraries, and fabricated using a niobium integration process. Sinusoidal bipolar voltage waveform of 0.38 mVpp was demonstrated using a reference signal source of 43.94 MHz

Design of a ROIC for scanning type HgCdTe LWIR focal plane arrays

Design of a silicon readout integrated circuit (ROIC) for LWIR HgCdTe Focal Plane is presented. ROIC incorporates time delay integration (TDI) functionality over seven elements with a supersampling rate of three, increasing SNR and the spatial resolution. Novelty of this topology is inside TDI stage; integration of charges in TDI stage implemented in current domain by using switched current structures that reduces required area for chip and improves linearity performance. ROIC, in terms of functionality, is capable of bidirectional scan, programmable integration time and 5 gain settings at the input. Programming can be done parallel or serially with digital interface. ROIC can handle up to 3.5V dynamic range with the input stage to be direct injection (DI) type. With the load being 10pF capacitive in parallel with 1MΩ resistance, output settling time is less than 250nsec enabling the clock frequency up to 4MHz. The manufacturing technology is 0.35μm, double poly-Si, four-metal (3 metals and 1 top metal) 5V CMOS process

ImageJ2: ImageJ for the next generation of scientific image data

ImageJ is an image analysis program extensively used in the biological sciences and beyond. Due to its ease of use, recordable macro language, and extensible plug-in architecture, ImageJ enjoys contributions from non-programmers, amateur programmers, and professional developers alike. Enabling such a diversity of contributors has resulted in a large community that spans the biological and physical sciences. However, a rapidly growing user base, diverging plugin suites, and technical limitations have revealed a clear need for a concerted software engineering effort to support emerging imaging paradigms, to ensure the software's ability to handle the requirements of modern science. Due to these new and emerging challenges in scientific imaging, ImageJ is at a critical development crossroads. We present ImageJ2, a total redesign of ImageJ offering a host of new functionality. It separates concerns, fully decoupling the data model from the user interface. It emphasizes integration with external applications to maximize interoperability. Its robust new plugin framework allows everything from image formats, to scripting languages, to visualization to be extended by the community. The redesigned data model supports arbitrarily large, N-dimensional datasets, which are increasingly common in modern image acquisition. Despite the scope of these changes, backwards compatibility is maintained such that this new functionality can be seamlessly integrated with the classic ImageJ interface, allowing users and developers to migrate to these new methods at their own pace. ImageJ2 provides a framework engineered for flexibility, intended to support these requirements as well as accommodate future needs

Cell replication and redundancy elimination during placement for cycle time optimization

This paper presents a new timing driven approach for cell replication tailored to the practical needs of standard cell layout design. Cell replication methods have been studied extensively in the context of generic partitioning problems. However, until now it has remained unclear what practical benefit can be obtained from this concept in a realistic environment for timing driven layout synthesis. Therefore, this paper presents a timing driven cell replication procedure, demonstrates its incorporation into a standard cell placement and routing tool and examines its benefit on the final circuit performance in comparison with conventional gate or transistor sizing techniques. Furthermore, we demonstrate that cell replication can deteriorate the stuck-at fault testability of circuits and show that stuck-at redundancy elimination must be integrated into the placement procedure. Experimental results demonstrate the usefulness of the proposed methodology and suggest that cell replication should be an integral part of the physical design flow complementing traditional gate sizing techniques

Chaste: a test-driven approach to software development for biological modelling

Chaste (‘Cancer, heart and soft-tissue environment’) is a software library and a set of test suites for computational simulations in the domain of biology. Current functionality has arisen from modelling in the fields of cancer, cardiac physiology and soft-tissue mechanics. It is released under the LGPL 2.1 licence.\ud \ud Chaste has been developed using agile programming methods. The project began in 2005 when it was reasoned that the modelling of a variety of physiological phenomena required both a generic mathematical modelling framework, and a generic computational/simulation framework. The Chaste project evolved from the Integrative Biology (IB) e-Science Project, an inter-institutional project aimed at developing a suitable IT infrastructure to support physiome-level computational modelling, with a primary focus on cardiac and cancer modelling

An enhanced CRISPR repressor for targeted mammalian gene regulation.

The RNA-guided endonuclease Cas9 can be converted into a programmable transcriptional repressor, but inefficiencies in target-gene silencing have limited its utility. Here we describe an improved Cas9 repressor based on the C-terminal fusion of a rationally designed bipartite repressor domain, KRAB-MeCP2, to nuclease-dead Cas9. We demonstrate the system's superiority in silencing coding and noncoding genes, simultaneously repressing a series of target genes, improving the results of single and dual guide RNA library screens, and enabling new architectures of synthetic genetic circuits