Cosmological Simulations of Galaxy Groups and Clusters-III: Constraining Quasar Feedback Models with the Atacama Large Millimeter Array

The thermal Sunyaev-Zeldovich (SZ) effect serves as a direct potential probe of the energetic outflows from quasars that are responsible for heating the intergalactic medium. In this work, we use the GIZMO meshless finite mass hydrodynamic cosmological simulation SIMBA (Dave et al. 2019), which includes different prescriptions for quasar feedback, to compute the SZ effect arising from different feedback modes. From these theoretical simulations, we perform mock observations of the Atacama Large Millimeter Array (ALMA) in four bands (320 GHz, 135 GHZ, 100 GHz and 42 GHz) to characterize the feasibility of direct detection of the quasar SZ signal. Our results show that for all the systems we get an enhancement of the SZ signal, when there is radiative feedback, while the signal gets suppressed when the jet mode of feedback is introduced in the simulations. Our mock ALMA maps reveal that, with the current prescription of jet feedback, the signal goes below the detection threshold of ALMA. We also find that the signal is higher for high redshift systems, making it possible for ALMA and cross SZ-X-ray studies to disentangle the varying modes of quasar feedback and their relative importance in the cosmological context.Comment: Accepted for publication in Ap

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Development of experimental techniques for the analysis of instabilities in GaN devices

reservedThe thesis is composed of a brief portrayal of the experimental results obtained by analysis of wide bandgap material devices, specifically Gallium Nitride (GaN) ones. In addition to that, an innovative measurement technique to measure the instabilities of certain device parameters in different stress conditions is explored. The devices are tested in the Advanced Characterization and Modelling of Electronics [ACME] lab in the Department of Information Engineering [DEI] of the University of Padua, whereas the test structures are manufactured by Ferdinand-Braun-Institut [FBH],Berlin. In the first part of the thesis, p-n diodes are analyzed by performing IV and temperature-dependent IV to investigate the leakage current and on-resistancce of the devices. Further, the breakdown mechanism of the devices are investigated by performing breakdown tests and temperature-dependent breakdown tests to study the avalanche mechanism. In the second part, GaN vertical trench MOSFETs are analyzed by performing DC characterization tests like IDVG, IDVD, IGVG, and IGVD tests investigating device performance, leakage, and instabilities in threshold voltage. In the final part of the thesis, a new approach to measure threshold voltage instabilities is explored and a measurement setup is devised that can measure threshold voltage with a measurement time as low as 1us and can apply pulsed gate stress up to 25 V. Tests are performed on different devices like packaged Si power MOSFETs, SiC, Gan-Hemts, and Gan vertical trench MOSFETs [by FBH] to analyze the transient in threshold voltage hence gaining a better understanding of the charge trappings in the devices.The thesis is composed of a brief portrayal of the experimental results obtained by analysis of wide bandgap material devices, specifically Gallium Nitride (GaN) ones. In addition to that, an innovative measurement technique to measure the instabilities of certain device parameters in different stress conditions is explored. The devices are tested in the Advanced Characterization and Modelling of Electronics [ACME] lab in the Department of Information Engineering [DEI] of the University of Padua, whereas the test structures are manufactured by Ferdinand-Braun-Institut [FBH],Berlin. In the first part of the thesis, p-n diodes are analyzed by performing IV and temperature-dependent IV to investigate the leakage current and on-resistancce of the devices. Further, the breakdown mechanism of the devices are investigated by performing breakdown tests and temperature-dependent breakdown tests to study the avalanche mechanism. In the second part, GaN vertical trench MOSFETs are analyzed by performing DC characterization tests like IDVG, IDVD, IGVG, and IGVD tests investigating device performance, leakage, and instabilities in threshold voltage. In the final part of the thesis, a new approach to measure threshold voltage instabilities is explored and a measurement setup is devised that can measure threshold voltage with a measurement time as low as 1us and can apply pulsed gate stress up to 25 V. Tests are performed on different devices like packaged Si power MOSFETs, SiC, Gan-Hemts, and Gan vertical trench MOSFETs [by FBH] to analyze the transient in threshold voltage hence gaining a better understanding of the charge trappings in the devices

Abstract 2868: A cell based phenotypic assay platform for cancer metastasis drug discovery and diagnostics

Abstract Metastatic cancers are difficult to treat and are the cause of about 90% of cancer related deaths. Furthermore, predictive diagnostics are not readily available, and lack of good translational assays has impaired drug discovery. Mestastop has developed a platform of cell based functional assays that aims to address these drug discovery and diagnostic gaps. The platform is comprised of a set of 14 cell based phenotypic assays that capture multiple aspects of the complex process of metastasis, including characterization of the plasticity ratios (EMT, MET) and stemness of cells, invasion, intravasation, circulation, extravasation, and survival in secondary tissues (e.g metabolic shift, exosome secretion). Wild type tumor cells (initially a set of colon tumor cell lines) are utilized in the platform. Non-metastatic wild type cells (e.g. HT-29) that have been engineered into metastatic cells are also utilized to further elucidate metastatic processes, thereby creating two baseline data sets for each assay; one for the normal growing tumor and the other for the select metastatic population. Patient derived tumors are now being analyzed in the platform to help build a translational model. Preclinical animal models are being jointly developed with Immunobiome Inc. (South Korea). As the data from all these assays present a multivariate problem, we are developing a machine learning algorithm, METSCANTM, to analyze the results. The platform will be applied to the screening of novel compounds for drug discovery and of approved drugs for repurposing. Analysis of patient derived tumors may allow for the early detection of patients with high metastatic potential. Four colon cancer cell lines and several standard chemotherapy drugs have been used to validate the platform. A group of triple negative breast cancer cell lines is now being tested. Preliminary data for a set of approved, marketed drugs has further validated the potential of the platform for drug discovery and repurposing. The Mestastop proprietary assay platform will empower biopharma in the discovery of novel drug candidates and repurposing of approved drugs for the treatment of metastasis, and the early diagnosis of cancers with high metastatic potential, thereby addressing the unmet need in the area of cancer metastasis. Citation Format: Arnab Roy Chowdhury, Debabani Roy Chowdhury, Manoj Pandre, Samrat Roy, Sundarajan Kannan, John W. Ellingboe. A cell based phenotypic assay platform for cancer metastasis drug discovery and diagnostics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2868.</jats:p

Abstract 2841: Dissecting tumorigenesis and metastatic properties of cell lines by phenotypic functional assays and plasticity ratio (PR)

Abstract Cancer cell plasticity plays a defining role in initial tumorigenesis and secondary metastasis. The epithelial to mesenchymal transition (EMT) is critical for the primary tumor cell population to promote metastasis, whereas the reverse mesenchymal to epithelial transition (MET) is important for tumorigenesis in secondary organs post seeding. To understand the contribution of such plasticity in colorectal cancer, we have assessed the functional properties of four colorectal cancer cell lines (HT29, HCT 116, SW 480, Colo 205) in our comprehensive phenotypic metastasis assay platform and mapped their respective plasticity ratios (PR, total vimentin/total E cadherin). Next, we took cells with a low PR (HT 29) and engineered them (using plasmid vectors containing gene of interest, in both constitutive and inducible strategies) to have a high PR, thus changing their functional behavior (e.g. extravasation, platelet binding) to more closely resemble wild type cells having a high PR (SW 480). Interestingly, when we engineered SW 480 to increase its PR, we did not see a concomitant change in functional behavior. There was a decrease in extravasation and platelet binding suggesting a PR threshold and maxima exists for cellular behavior. Successful conversion of cells from low to high PR and vice versa helped us establish EMT and MET screening platforms in a 2D format; cells with high PR taking more time to go through MET. Variation in glutamine addiction, ROS formation, exosome secretion and stemness (CD44+ CD133-) was also observed in cells with low and high PR. No significant increase in either doubling time or chemoresistance was observed with increase in PR (20% only). Early in vivo experimental data with HT 29 engineered cells and a higher PR clone shows a marked difference in tumorigenesis; the former with lower PR showing high growth but the latter with higher PR forming only small tumors. Our data suggests that irrespective of the genetic signatures of driver genes and mutational profile of cell lines, tumorigenesis and metastatic potential depends on the plasticity of the cell, which can be quantitated by measuring the PR and subsequently mapping to the various cellular functions of the tumor cells. We are currently evaluating patient tumor samples and correlating the tumor PR with our functional assay platform to create a proprietary algorithm METSCAN™ that will help address both drug discovery needs and predictive assessment of primary tumor metastasis. Citation Format: Samrat Roy, Debabani Roy Chowdhury, Manoj Pandre, Sundarajan Kannan, Rajesh Kumar RK, Amit K. Sharma, John W. Ellingboe, Arnab Roy Chowdhury. Dissecting tumorigenesis and metastatic properties of cell lines by phenotypic functional assays and plasticity ratio (PR) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2841.</jats:p

Autonomous self-healing organic crystals for nonlinear optics.

Non-centrosymmetric molecular crystals have a plethora of applications, such as piezoelectric transducers, energy storage and nonlinear optical materials owing to their unique structural order which is absent in other synthetic materials. As most crystals are brittle, their efficiency declines upon prolonged usage due to fatigue or catastrophic failure, limiting their utilities. Some natural substances, like bone, enamel, leaf and skin, function efficiently, last a life-time, thanks to their inherent self-healing nature. Therefore, incorporating self-healing ability in crystalline materials will greatly broaden their scope. Here, we report single crystals of a dibenzoate derivative, capable of self-healing within milliseconds via autonomous actuation. Systematic quantitative experiments reveal the limit of mechanical forces that the self-healing crystals can withstand. As a proof-of-concept, we also demonstrate that our self-healed crystals can retain their second harmonic generation (SHG) with high efficiency. Kinematic analysis of the actuation in our system also revealed its impressive performance parameters, and shows actuation response times in the millisecond range

The hypomethylating agent Decitabine causes a paradoxical increase in 5-hydroxymethylcytosine in human leukemia cells

The USFDA approved "epigenetic drug", Decitabine, exerts its effect by hypomethylating DNA, demonstrating the pivotal role aberrant genome-wide DNA methylation patterns play in cancer ontology. Using sensitive technologies in a cellular model of Acute Myeloid Leukemia, we demonstrate that while Decitabine reduces the global levels of 5-methylcytosine (5mC), it results in paradoxical increase of 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) levels. Hitherto, the only biological mechanism known to generate 5hmC, 5fC and 5caC, involving oxidation of 5mC by members of Ten-Eleven-Translocation (TET) dioxygenase family, was not observed to undergo any alteration during DAC treatment. Using a multi-compartmental model of DNA methylation, we show that partial selectivity of TET enzymes for hemi-methylated CpG dinucleotides could lead to such alterations in 5hmC content. Furthermore, we investigated the binding of TET1-catalytic domain (CD)-GFP to DNA by Fluorescent Correlation Spectroscopy in live cells and detected the gradual increase of the DNA bound fraction of TET1-CD-GFP after treatment with Decitabine. Our study provides novel insights on the therapeutic activity of DAC in the backdrop of the newly discovered derivatives of 5mC and suggests that 5hmC has the potential to serve as a biomarker for monitoring the clinical success of patients receiving DAC