The new all-silicon Inner Tracker (ITk) is being constructed by the ATLAS collaboration to track charged particles produced at the High-Luminosity LHC. The outer portion of the ITk detector will ...include nearly 18,000 highly segmented and radiation hard silicon strip sensors (ATLAS18 design). Throughout the production of 22,000 sensors, the strip sensors are subjected to a comprehensive suite of mechanical and electrical tests as part of the Quality Control (QC) program. In a large fraction of the batches delivered to date, high surface electrostatic charge has been measured on both the sensors and the plastic sheets between which the sensors are packaged for shipping and handling rigidity. Aggregate data from across QC sites indicate a correlation between observed electrical failures and the sensor/plastic sheet charge build up. To mitigate these issues, the QC testing sites introduced recovery techniques involving UV light or flows of ionizing gas. Significant modifications to sensor handling procedures were made to prevent subsequent build up of static charge. This publication details a precise description of the issue, a variety of sensor recovery techniques, and trend analyses of sensors initially failing electrical tests (IV, strip scan, etc.).
The ATLAS experiment will replace its existing Inner Detector with the new all-silicon Inner Tracker (ITk) to cope with the operating conditions of the forthcoming high-luminosity phase of the LHC ...(HL-LHC). The outer regions of the ITk will be instrumented with ∼18000 ATLAS18 strip sensors fabricated by Hamamatsu Photonics K.K. (HPK). With the launch of full-scale sensor production in 2021, the ITk strip sensor community has undertaken quality control (QC) testing of these sensors to ensure compliance with mechanical and electrical specifications agreed with HPK. The testing is conducted at seven QC sites on each of the monthly deliveries of ∼500 sensors.
This contribution will give an overview of the QC procedures and analysis; the tests most likely to determine pass/fail for a sensor are IV, long-term leakage current stability, full strip test and visual inspection. The contribution will then present trends in the results and properties following completion of ∼60% of production testing. It will also mention challenges overcome through collaborative efforts with HPK during the early phases of production. With less than 5% of sensors rejected by QC testing, the overall production quality has been very good.
Multi‐omics studies promise the improved characterization of biological processes across molecular layers. However, methods for the unsupervised integration of the resulting heterogeneous data sets ...are lacking. We present Multi‐Omics Factor Analysis (MOFA), a computational method for discovering the principal sources of variation in multi‐omics data sets. MOFA infers a set of (hidden) factors that capture biological and technical sources of variability. It disentangles axes of heterogeneity that are shared across multiple modalities and those specific to individual data modalities. The learnt factors enable a variety of downstream analyses, including identification of sample subgroups, data imputation and the detection of outlier samples. We applied MOFA to a cohort of 200 patient samples of chronic lymphocytic leukaemia, profiled for somatic mutations, RNA expression, DNA methylation and ex vivo drug responses. MOFA identified major dimensions of disease heterogeneity, including immunoglobulin heavy‐chain variable region status, trisomy of chromosome 12 and previously underappreciated drivers, such as response to oxidative stress. In a second application, we used MOFA to analyse single‐cell multi‐omics data, identifying coordinated transcriptional and epigenetic changes along cell differentiation.
Synopsis
Multi‐Omics Factor Analysis (MOFA) is a computational framework for unsupervised discovery of the principal axes of biological and technical variation when multiple omics assays are applied to the same samples. MOFA is a broadly applicable approach for multi‐omics data integration.
The inferred latent factors represent the underlying principal axes of heterogeneity across the samples. Factors can be shared by multiple data modalities or can be data‐type specific.
The model flexibly handles missing values and different data types.
In an application to Chronic Lymphocytic Leukaemia, MOFA discovers a low dimensional space spanned by known clinical markers and underappreciated axes of variation such as oxidative stress.
In an application to multi‐omics profiles from single‐cells, MOFA recovers differentiation trajectories and identifies coordinated variation between the transcriptome and the epigenome.
Multi‐Omics Factor Analysis (MOFA) is a computational framework for unsupervised discovery of the principal axes of biological and technical variation when multiple omics assays are applied to the same samples. MOFA is a broadly applicable approach for multi‐omics data integration.
Cancer development is an evolutionary genomic process with parallels to Darwinian selection. It requires acquisition of multiple somatic mutations that collectively cause a malignant phenotype and ...continuous clonal evolution is often linked to tumor progression. Here, we show the clonal evolution structure in 15 myelofibrosis (MF) patients while receiving treatment with JAK inhibitors (mean follow-up 3.9 years). Whole-exome sequencing at multiple time points reveal acquisition of somatic mutations and copy number aberrations over time. While JAK inhibition therapy does not seem to create a clear evolutionary bottleneck, we observe a more complex clonal architecture over time, and appearance of unrelated clones. Disease progression associates with increased genetic heterogeneity and gain of RAS/RTK pathway mutations. Clonal diversity results in clone-specific expansion within different myeloid cell lineages. Single-cell genotyping of circulating CD34 + progenitor cells allows the reconstruction of MF phylogeny demonstrating loss of heterozygosity and parallel evolution as recurrent events.
Construction of the new all-silicon Inner Tracker (ITk), developed by the ATLAS collaboration for the High Luminosity LHC, started in 2020 and is expected to continue till 2028. The ITk detector will ...include 18,000 highly segmented and radiation hard n+-in-p silicon strip sensors (ATLAS18), which are being manufactured by Hamamatsu Photonics. Mechanical and electrical characteristics of produced sensors are measured upon their delivery at several institutes participating in a complex Quality Control (QC) program. The QC tests performed on each individual sensor check the overall integrity and quality of the sensor. During the QC testing of production ATLAS18 strip sensors, an increased number of sensors that failed the electrical tests was observed. In particular, IV measurements indicated an early breakdown, while large areas containing several tens or hundreds of neighbouring strips with low interstrip isolation were identified by the Full strip tests, and leakage current instabilities were measured in a long-term leakage current stability setup. Moreover, a high surface electrostatic charge reaching a level of several hundreds of volts per inch was measured on a large number of sensors and on the plastic sheets, which mechanically protect these sensors in their paper envelopes. Accumulated data indicates a clear correlation between observed electrical failures and the sensor charge-up. To mitigate the above-described issues, the QC testing sites significantly modified the sensor handling procedures and introduced sensor recovery techniques based on irradiation of the sensor surface with UV light or application of intensive flows of ionized gas. In this presentation, we will describe the setups implemented by the QC testing sites to treat silicon strip sensors affected by static charge and evaluate the effectiveness of these setups in terms of improvement of the sensor performance.
The tumor microenvironment is the cellular and molecular environment in which the tumor exists and with which it continuously interacts. In B-cell lymphomas, this microenvironment is intriguing in ...that it plays critical roles in the regulation of tumor cell survival and proliferation, fostering immune escape as well as the development of treatment resistance. The purpose of this review is to summarize the proceedings of the Second Annual Summit on the Immune Microenvironment in Hematologic Malignancies that took place on September 11-12, 2014 in Dublin, Ireland. We provide a timely overview of the composition and biological relevance of the cellular and molecular microenvironment interface and discuss the role of interactions between the microenvironment and neoplastic cells in a variety of B-cell lymphomas. In addition, we focus on various novel therapeutic strategies that target the tumor microenvironment, including agents that modulate B-cell receptor pathways and immune-checkpoints, chimeric antigen receptor T cells and immunomodulatory agents.
Capturing carbon dioxide from the atmosphere ("air capture") in an industrial process has been proposed as an option for stabilizing global CO2 concentrations. Published analyses suggest these air ...capture systems may cost a few hundred dollars per tonne of CO2, making it cost competitive with mainstream CO2 mitigation options like renewable energy, nuclear power, and carbon dioxide capture and storage from large CO2 emitting point sources. We investigate the thermodynamic efficiencies of commercial separation systems as well as trace gas removal systems to better understand and constrain the energy requirements and costs of these air capture systems. Our empirical analyses of operating commercial processes suggest that the energetic and financial costs of capturing CO2 from the air are likely to have been underestimated. Specifically, our analysis of existing gas separation systems suggests that, unless air capture significantly outperforms these systems, it is likely to require more than 400 kJ of work per mole of CO2, requiring it to be powered by CO2-neutral power sources in order to be CO2 negative. We estimate that total system costs of an air capture system will be on the order of $1,000 per tonne of CO2, based on experience with as-built large-scale trace gas removal systems.
Charting differences between tumors and normal tissue is a mainstay of cancer research. However, clonal tumor expansion from complex normal tissue architectures potentially obscures cancer-specific ...events, including divergent epigenetic patterns. Using whole-genome bisulfite sequencing of normal B cell subsets, we observed broad epigenetic programming of selective transcription factor binding sites coincident with the degree of B cell maturation. By comparing normal B cells to malignant B cells from 268 patients with chronic lymphocytic leukemia (CLL), we showed that tumors derive largely from a continuum of maturation states reflected in normal developmental stages. Epigenetic maturation in CLL was associated with an indolent gene expression pattern and increasingly favorable clinical outcomes. We further uncovered that most previously reported tumor-specific methylation events are normally present in non-malignant B cells. Instead, we identified a potential pathogenic role for transcription factor dysregulation in CLL, where excess programming by EGR and NFAT with reduced EBF and AP-1 programming imbalances the normal B cell epigenetic program.
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