Desynchronization: Synthesis of asynchronous circuits from synchronous specifications

Asynchronous implementation techniques, which measure logic delays at run time and activate registers accordingly, are inherently more robust than their synchronous counterparts, which estimate worst-case delays at design time, and constrain the clock cycle accordingly. De-synchronization is a new paradigm to automate the design of asynchronous circuits from synchronous specifications, thus permitting widespread adoption of asynchronicity, without requiring special design skills or tools. In this paper, we first of all study different protocols for de-synchronization and formally prove their correctness, using techniques originally developed for distributed deployment of synchronous language specifications. We also provide a taxonomy of existing protocols for asynchronous latch controllers, covering in particular the four-phase handshake protocols devised in the literature for micro-pipelines. We then propose a new controller which exhibits provably maximal concurrency, and analyze the performance of desynchronized circuits with respect to the original synchronous optimized implementation. We finally prove the feasibility and effectiveness of our approach, by showing its application to a set of real designs, including a complete implementation of the DLX microprocessor architectur

Developing a collaborative project on higher education pedagogy: The institutional, organizational, and community identity dimensions of student staff partnerships

This case study presents an ambitious student-staff partnership project at University College London (UCL) to publish a collaborative book on higher education pedagogy. Over two-and-a-half years, a total of 86 students and staff contributed to the project, which sought to provide educators with a new type of scholarly material under the unifying theme of connecting research and teaching. Multiple layers of student-staff partnership were interwoven throughout the project; this case study contextualizes these layers against three dimensions: institutional, organizational, and community identity. Central to the project was our distinctive approach to engaging with Graduate Teaching Assistants (GTAs) and their crucial role in bringing the three dimensions together. As such, the project represents a model of enhanced student-staff partnership that has the capacity to empower students and break down educational silos to form new, multi-specialty learning communities.</jats:p

CircumMed+Euro pine forest database: an electronic archive for Mediterranean and European forests

Large thematic databases of vegetation-plots are increasingly needed for vegetation studies and biodiversity research. In this paper, we present the CircumMed+Euro Pine Forest Database (GIVD ID: EU-00-026), which in September 2018 encompassed 5590 records from pine-dominated vegetation plots (relevés) and associated vegetation types from 23 countries of temperate Europe, Eastern Mediterranean and North Africa. These vegetation plots were collected through a detailed literature search for plots not included in the European Vegetation Archive (EVA). The database includes plots from 192 bibliographic references and unpublished vegetation plots by different authors. All vegetation plots are georeferenced, and coordinates are available with different accuracy as reported by the authors. The database is managed by the Vegetation Science Group, Department of Botany and Zoology of the Masaryk University in Brno (Czech Republic). It is registered in the Global Index of Vegetation-Plot Databases (GIVD) with the code EU-00-026 and is accessible through the European Vegetation Archive (EVA) or by asking the Custodian. The CircumMed+Euro Pine Forest Database is an important resource for conducting different types of broad-scale studies in the fields of vegetation classification, plant invasion ecology, macroecology and biological conservationN/

Processed pseudogenes acquired somatically during cancer development

Cancer evolves by mutation, with somatic reactivation of retrotransposons being one such mutational process. Germline retrotransposition can cause processed pseudogenes, but whether this occurs somatically has not been evaluated. Here we screen sequencing data from 660 cancer samples for somatically acquired pseudogenes. We find 42 events in 17 samples, especially non-small cell lung cancer (5/27) and colorectal cancer (2/11). Genomic features mirror those of germline LINE element retrotranspositions, with frequent target-site duplications (67%), consensus TTTTAA sites at insertion points, inverted rearrangements (21%), 5′ truncation (74%) and polyA tails (88%). Transcriptional consequences include expression of pseudogenes from UTRs or introns of target genes. In addition, a somatic pseudogene that integrated into the promoter and first exon of the tumour suppressor gene, MGA, abrogated expression from that allele. Thus, formation of processed pseudogenes represents a new class of mutation occurring during cancer development, with potentially diverse functional consequences depending on genomic context

Pitfalls in assessing stromal tumor infiltrating lymphocytes (sTILs) in breast cancer

Abstract: Stromal tumor-infiltrating lymphocytes (sTILs) are important prognostic and predictive biomarkers in triple-negative (TNBC) and HER2-positive breast cancer. Incorporating sTILs into clinical practice necessitates reproducible assessment. Previously developed standardized scoring guidelines have been widely embraced by the clinical and research communities. We evaluated sources of variability in sTIL assessment by pathologists in three previous sTIL ring studies. We identify common challenges and evaluate impact of discrepancies on outcome estimates in early TNBC using a newly-developed prognostic tool. Discordant sTIL assessment is driven by heterogeneity in lymphocyte distribution. Additional factors include: technical slide-related issues; scoring outside the tumor boundary; tumors with minimal assessable stroma; including lymphocytes associated with other structures; and including other inflammatory cells. Small variations in sTIL assessment modestly alter risk estimation in early TNBC but have the potential to affect treatment selection if cutpoints are employed. Scoring and averaging multiple areas, as well as use of reference images, improve consistency of sTIL evaluation. Moreover, to assist in avoiding the pitfalls identified in this analysis, we developed an educational resource available at www.tilsinbreastcancer.org/pitfalls

Report on computational assessment of Tumor Infiltrating Lymphocytes from the International Immuno-Oncology Biomarker Working Group

Funder: U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)Funder: National Center for Research Resources under award number 1 C06 RR12463-01, VA Merit Review Award IBX004121A from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service, the DOD Prostate Cancer Idea Development Award (W81XWH-15-1-0558), the DOD Lung Cancer Investigator-Initiated Translational Research Award (W81XWH-18-1-0440), the DOD Peer Reviewed Cancer Research Program (W81XWH-16-1-0329), the Ohio Third Frontier Technology Validation Fund, the Wallace H. Coulter Foundation Program in the Department of Biomedical Engineering and the Clinical and Translational Science Award Program (CTSA) at Case Western Reserve University.Funder: Susan G Komen Foundation (CCR CCR18547966) and a Young Investigator Grant from the Breast Cancer Alliance.Funder: The Canadian Cancer SocietyFunder: Breast Cancer Research Foundation (BCRF), Grant No. 17-194Abstract: Assessment of tumor-infiltrating lymphocytes (TILs) is increasingly recognized as an integral part of the prognostic workflow in triple-negative (TNBC) and HER2-positive breast cancer, as well as many other solid tumors. This recognition has come about thanks to standardized visual reporting guidelines, which helped to reduce inter-reader variability. Now, there are ripe opportunities to employ computational methods that extract spatio-morphologic predictive features, enabling computer-aided diagnostics. We detail the benefits of computational TILs assessment, the readiness of TILs scoring for computational assessment, and outline considerations for overcoming key barriers to clinical translation in this arena. Specifically, we discuss: 1. ensuring computational workflows closely capture visual guidelines and standards; 2. challenges and thoughts standards for assessment of algorithms including training, preanalytical, analytical, and clinical validation; 3. perspectives on how to realize the potential of machine learning models and to overcome the perceptual and practical limits of visual scoring

Application of a risk-management framework for integration of stromal tumor-infiltrating lymphocytes in clinical trials

Funder: Breast Cancer Research Foundation (BCRF); doi: https://doi.org/10.13039/100001006Abstract: Stromal tumor-infiltrating lymphocytes (sTILs) are a potential predictive biomarker for immunotherapy response in metastatic triple-negative breast cancer (TNBC). To incorporate sTILs into clinical trials and diagnostics, reliable assessment is essential. In this review, we propose a new concept, namely the implementation of a risk-management framework that enables the use of sTILs as a stratification factor in clinical trials. We present the design of a biomarker risk-mitigation workflow that can be applied to any biomarker incorporation in clinical trials. We demonstrate the implementation of this concept using sTILs as an integral biomarker in a single-center phase II immunotherapy trial for metastatic TNBC (TONIC trial, NCT02499367), using this workflow to mitigate risks of suboptimal inclusion of sTILs in this specific trial. In this review, we demonstrate that a web-based scoring platform can mitigate potential risk factors when including sTILs in clinical trials, and we argue that this framework can be applied for any future biomarker-driven clinical trial setting

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Coping with the variability of combinational logic delays

This paper proposes a technique for creating a combinational logic network with an output that signals when all other outputs have stabilized. The method is based on dual-rail encoding, and guarantees low timing overhead and reasonable area and power overhead. We discuss various scenarios in which completion detection can be used to measure the delay of a synchronous circuit at fabrication time or at run time, and of an asynchronous circuit at run time. We conclude by showing, on a large set of benchmarks, the effectiveness of the proposed technique.Peer Reviewe

From synchronous to asynchronous: an automatic approach

This paper presents a methodology to derive asynchronous circuits from optimized synchronous circuits by replacing the clock distribution tree by a handshaking network. A case study shows the applicability of the method and the potential benefits of de-synchronizing synchronous circuits.Peer Reviewe