Resolution studies and performance evaluation of the LHCb VELO upgrade

The LHCb detector at CERN is scheduled to undergo an upgrade during the second long shutdown of the LHC. As part of this upgrade, the vertex detector (VELO) will be replaced with a new hybrid pixel detector, based on an evolution of the Timepix ASIC. The performance of this detector should improve upon that achieved by the current VELO, in addition to facilitating the complete detector readout at 40 MHz. As part of the preparation for this upgrade, this thesis presents the results of studies carried out on the single hit resolution of silicon hybrid pixel detectors. The development of a particle beam telescope has been carried out to allow these studies, shown to operate with track rates in excess of 45 kHz and with a pointing resolution at the device under test of less than 2 μm. A wide range of sensor types, thicknesses and resistivities have then been tested under different operating conditions and the results presented, with single hit resolutions varying between 4 μm and 12 μm depending on the conditions and incident angle. The resistivity of the devices is observed to have a significant effect on the single hit resolution, with high resistivity substrates allowing operation at lower bias voltages. This facilitates increased charge sharing, and the corresponding improvement in resolution. At sufficiently large incident angles however, the resolution becomes independent of the electric field, being instead dominated by the sensor geometry and variations in the charge deposited along the track length. No significant differences were found between the various detector technologies (n-on-n, n-on-p and p-on-n) though a difference in performance is expected for low-voltage operation of higher resistivity samples. A simplified model of the physical processes contributing to the detector resolution has been constructed, shown to reasonably reproduce the observed resolution as a function of angle and bias voltage. This model is extrapolated to potential future directions in the design of pixel sensors, highlighting the differences between various technology choices. The integration of the ATLAS FE-I4 ASIC into the telescope has been carried out, and the performance of an unirradiated planar silicon sensor was shown in order to verify this. Efficiency measurements show that the device is fully efficient in the angular range measured. The tracking performance of two irradiated sensors mounted on FE-I4 ASICs has been investigated, in addition to the mapping of collected charge over the pixel unit cell under various biasing conditions and at varying incident angles with respect to the incoming particles. For the sample irradiated to 2e15 1 MeV neq /cm2 the single hit resolution was 12.5 μm at perpendicular incidence, dropping to 8 μm at 22 degrees. The sample irradiated to 4e15 1 MeV neq /cm2 was found to have a resolution of around 13.5 μm, which remained relatively insensitive to the incident track angle. The conclusions drawn suggest that the upgraded VELO detector will be able to overcome the difficult radiation environment if it is able to reach the high voltage operation required. The implementation of these observations in the LHCb simulation environment has allowed some initial studies on the likely degradation of the detector performance to take place, showing that the high tracking efficiency (99.4 % for Long tracks) is likely to be maintained throughout the full lifetime of the upgrade. The impact parameter resolution was not observed to vary significantly. These studies have been carried out alongside simulations to gauge the expected compression that can be achieved in the data transmission of the VELOPix ASIC. Different designs of the front-end have been implemented, leading to the adoption of binary readout for the upgraded VELO. The uniformity of the pixel pitch across the detector has additionally been used to show the sensitivity of the system to multiple scattering, shown to be a credible tool with which to control the event reconstruction in the online LHCb trigger. A reduction of the number of VELO tracks passed to the forward reconstruction of almost 50 % has been shown, for the loss of only 5 % of tracks with momentum above 20 GeV/c. This could potentially replace the lifetime biasing cuts currently envisaged in the trigger

Combining TCAD and Monte Carlo Methods to Simulate CMOS Pixel Sensors with a Small Collection Electrode using the Allpix Squared Framework

Combining electrostatic field simulations with Monte Carlo methods enables realistic modeling of the detector response for novel monolithic silicon detectors with strongly non-linear electric fields. Both the precise field description and the inclusion of Landau fluctuations and production of secondary particles in the sensor are crucial ingredients for the understanding and reproduction of detector characteristics. In this paper, a CMOS pixel sensor with small collection electrode design, implemented in a high-resistivity epitaxial layer, is simulated by integrating a detailed electric field model from finite element TCAD into a Monte Carlo based simulation with the Allpix$^2$ framework. The simulation results are compared to data recorded in test-beam measurements and very good agreement is found for various quantities such as cluster size, spatial resolution and efficiency. Furthermore, the observables are studied as a function of the intra-pixel incidence position to enable a detailed comparison with the detector behavior observed in data. The validation of such simulations is fundamental for modeling the detector response and for predicting the performance of future prototype designs. Moreover, visualization plots extracted from the charge carrier drift model of the framework can aid in understanding the charge propagation behavior in different regions of the sensor.Comment: 15 pages, 18 figure

Comparison of small collection electrode CMOS pixel sensors with partial and full lateral depletion of the high-resistivity epitaxial layer

Large area silicon pixel trackers are currently under development for the High Luminosity upgrade of the LHC detectors. They are also foreseen for the detectors proposed for the future high energy Compact Linear Collider CLIC. For the CLIC tracker a single hit resolution of 7 μm, a timing resolution of a few nanoseconds and a material budget of 1–2 % of radiation length per detection layer are required. Integrated CMOS technologies are promising candidates to reduce the cost, facilitate the production and to achieve a low material budget. CMOS sensors with a small size of the collection electrode benefit from a small sensor capacitance, resulting in a large signal to noise ratio and a low power consumption. The Investigator is a test-chip developed for the ALICE Inner Tracking System upgrade, implemented in a 180 nm CMOS process with a small collection electrode on a high resistivity epitaxial layer. The Investigator has been produced in different process variants: the standard process and a modified process, where an additional N-layer has been inserted to obtain full lateral depletion. This paper presents a comparison of test-beam results for both process variants, focuses on spatial and timing resolution as well as efficiency measurements

Time Resolution Studies with Timepix3 Assemblies with Thin Silicon Pixel Sensors

Timepix3 is a multi-purpose readout ASIC for hybrid pixel detectors. It can measure time and energy simultaneously by employing time-of-arrival (ToA) and time-over-threshold (ToT) techniques. Both methods are systematically affected by timewalk. In this paper, a method for pixel-by-pixel calibration of the time response is presented. Assemblies of Timepix3 ASICs bump-bonded to thin planar silicon pixel sensors of different thicknesses between 50 um and 150 um are calibrated and characterised in particle beams. For minimum ionising particles, time resolutions down to 0.72 $\pm$ 0.04 ns are achieved.Comment: preprint submitted to JINST, revision

An HLA-G/SPAG9/STAT3 axis promotes brain metastases

Brain metastases (BM) are the most common brain neoplasm in adults. Current BM therapies still offer limited efficacy and reduced survival outcomes, emphasizing the need for a better understanding of the disease. Herein, we analyzed the transcriptional profile of brain metastasis initiating cells (BMICs) at two distinct stages of the brain metastatic cascade-the "premetastatic" or early stage when they first colonize the brain and the established macrometastatic stage. RNA sequencing was used to obtain the transcriptional profiles of premetastatic and macrometastatic (non-premetastatic) lung, breast, and melanoma BMICs. We identified that lung, breast, and melanoma premetastatic BMICs share a common transcriptomic signature that is distinct from their non-premetastatic counterparts. Importantly, we show that premetastatic BMICs exhibit increased expression of HLA-G, which we further demonstrate functions in an HLA-G/SPAG9/STAT3 axis to promote the establishment of brain metastatic lesions. Our findings suggest that unraveling the molecular landscape of premetastatic BMICs allows for the identification of clinically relevant targets that can possibly inform the development of preventive and/or more efficacious BM therapies

Stem Cells, Cell Therapies, and Bioengineering in Lung Biology and Disease 2021

The 9th biennial conference titled “Stem Cells, Cell Therapies, and Bioengineering in Lung Biology and Diseases” was hosted virtually, due to the ongoing COVID-19 pandemic, in collaboration with the University of Vermont Larner College of Medicine, the National Heart, Lung, and Blood Institute, the Alpha-1 Foundation, the Cystic Fibrosis Foundation, and the International Society for Cell & Gene Therapy. The event was held from July 12th through 15th, 2021 with a pre-conference workshop held on July 9th. As in previous years, the objectives remained to review and discuss the status of active research areas involving stem cells (SCs), cellular therapeutics, and bioengineering as they relate to the human lung. Topics included 1) technological advancements in the in situ analysis of lung tissues, 2) new insights into stem cell signaling and plasticity in lung remodeling and regeneration, 3) the impact of extracellular matrix in stem cell regulation and airway engineering in lung regeneration, 4) differentiating and delivering stem cell therapeutics to the lung, 5) regeneration in response to viral infection, and 6) ethical development of cell-based treatments for lung diseases. This selection of topics represents some of the most dynamic and current research areas in lung biology

AMBRA1 regulates cyclin D to guard S-phase entry and genomic integrity

Mammalian development, adult tissue homeostasis and the avoidance of severe diseases including cancer require a properly orchestrated cell cycle, as well as error-free genome maintenance. The key cell-fate decision to replicate the genome is controlled by two major signalling pathways that act in parallel-the MYC pathway and the cyclin D-cyclin-dependent kinase (CDK)-retinoblastoma protein (RB) pathway(1,2). Both MYC and the cyclin D-CDK-RB axis are commonly deregulated in cancer, and this is associated with increased genomic instability. The autophagic tumour-suppressor protein AMBRA1 has been linked to the control of cell proliferation, but the underlying molecular mechanisms remain poorly understood. Here we show that AMBRA1 is an upstream master regulator of the transition from G1 to S phase and thereby prevents replication stress. Using a combination of cell and molecular approaches and in vivo models, we reveal that AMBRA1 regulates the abundance of D-type cyclins by mediating their degradation. Furthermore, by controlling the transition from G1 to S phase, AMBRA1 helps to maintain genomic integrity during DNA replication, which counteracts developmental abnormalities and tumour growth. Finally, we identify the CHK1 kinase as a potential therapeutic target in AMBRA1-deficient tumours. These results advance our understanding of the control of replication-phase entry and genomic integrity, and identify the AMBRA1-cyclin D pathway as a crucial cell-cycle-regulatory mechanism that is deeply interconnected with genomic stability in embryonic development and tumorigenesis

Microchannel cooling for the LHCb VELO Upgrade I

The LHCb VELO Upgrade I, currently being installed for the 2022 start of LHC Run 3, uses silicon microchannel coolers with internally circulating bi-phase \cotwo for thermal control of hybrid pixel modules operating in vacuum. This is the largest scale application of this technology to date. Production of the microchannel coolers was completed in July 2019 and the assembly into cooling structures was completed in September 2021. This paper describes the R\&D path supporting the microchannel production and assembly and the motivation for the design choices. The microchannel coolers have excellent thermal peformance, low and uniform mass, no thermal expansion mismatch with the ASICs and are radiation hard. The fluidic and thermal performance is presented.Comment: 31 pages, 27 figure

Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies