DEVELOPMENT OF ADVANCED GERMANIUM DETECTORS FOR RARE EVENT PHYSICS

High Purity Germanium (HPGe) detectors are widely used in rare-event physics searches for dark matter, neutrinoless double-beta decay, and solar neutrinos. This dissertation fo- cuses on improving crystal quality by controlling the impurity concentration, dislocation density, and growth environment as well as developing advanced Ge detectors for various physics applications. The dissertation presents experimental investigations of electrical conduction mechanisms in p-type amorphous germanium (a-Ge), which is used as an elec- trical contact material in HPGe detectors. By measuring the surface leakage current from three high-purity planar Ge detectors, we determine the localization length and hopping parameters in a-Ge. The dissertation also explores the possibility of using advanced Ge de- tectors to detect solar neutrinos. We investigate the potential of achieving internal charge amplification at cryogenic temperature, which could significantly reduce the energy reso- lution and energy threshold of Ge detectors. Finally, this dissertation discusses the charge trapping phenomenon of an n-type HPGe detector operated at 5.2 K. We investigate the trapping cross-section and binding energy of cluster dipole states in an HPGe detector, finding that the binding energy of cluster dipole states at 5.2 K is approximately 5 8 meV. This low energy level makes the detector ideal for detecting low-mass dark matter and solar neutrinos

Synthesis and structure-activity relationships of α,β-methylene-ADP derivatives: potent and selective ecto-5-nucleotidase inhibitors

Ecto-5'-nucleotidase (ecto-5'-NT, eN, CD73, EC 3.1.3.5) is a member of the group of ecto-nucleotidases which dephosphorylate extracellular nucleotides. eN catalyzes the dephosphorylation of nucleoside monophosphates and its main substrate is AMP. Further members of the membrane-bound group of ecto-nucleotidases include nucleoside triphosphate diphosphohydrolases (NTPDases; subtypes 1, 2, 3 and 8), nucleotide pyrophosphatase/phosphodiesterases (NPPs 1-4) and alkaline phosphatases (APs; tissue non-specific, intestinal, placental and germ cell APs). NTPDase and NPPs are ATP- and ADP-hydrolyzing ecto-nucleotidases, which prevent ATP, ADP and other nucleotides from acting on purinergic P2X and P2Y receptors. They produce AMP which is further hydrolyzed by eN thereby elevating extracellular concentrations of adenosine which activates adenosine receptors. Recently it was shown that inhibition of eN with monoclonal antibodies, siRNA, or drug-like inhibitors delays tumor growth and metastasis. Thus, eN inhibitors have potential as novel therapeutics, e.g. for melanomas, lung, prostate and breast cancers. Only very few, moderately potent eN inhibitors are currently known. In the present study we used the ADP analog α,β-methylene-ADP (AOPCP, adenosine-5-O'-[(phosphonomethyl)phosphonic acid]) as a lead structure for the development of potent, selective and metabolically stable eN inhibitors. Derivatives substituted at the N6-, C-8- or C-2-positions and/or at the methylene diphosphonate-side chain were synthesized to improve potency and metabolic stability. All new compounds were tested for inhibition of rat recombinant eN. For the preparation of the target compounds with 2-, 6- or 8-substitution and for 2,6-disubstituted derivatives, a convergent synthetic strategy was applied which involves the initial preparation of the intermediate nucleosides followed by phosphorylation with methylenebis(phosphonic dichloride) to provide the desired AOPCP derivatives. For side-chain-modified analogs of AOPCP commercially available substituted bis(phosphonic acid) derivatives were employed for 5 phosphorylation. Altogether 60 AOPCP derivatives and analogs were obtained in good yields and high purity by an optimized method for their preparation. 6 (Ar)alkylamino-substitution, 2-amino-, 2-halo-, and 2-thioalkyl-substitution significantly improved potency. The most potent nucleotides were 2-chloro-N6-(2 chlorobenzyl)¬purine riboside-5-O-[(phosphonomethyl)¬phosphonic acid] (144, Ki= 0.34 nM), and 2-chloro-N6-benzyl--N6-methylpurine riboside-5-O'-[(phosphonomethyl)phosphonic acid] (149, Ki= 0.88 nM). The compounds displayed high selectivity versus other ecto-nucleotidases and ADP-activated P2Y receptors. They also showed high metabolic stability upon incubation with liver microsomes and blood plasma. These compounds are the most potent eN inhibitors known to date and may serve as valuable pharmacological tools to further elucidate the enzyme’s (patho)physiological roles

Data Augmentation through Pseudolabels in Automatic Region Based Coronary Artery Segmentation for Disease Diagnosis

Coronary Artery Diseases(CADs) though preventable are one of the leading causes of death and disability. Diagnosis of these diseases is often difficult and resource intensive. Segmentation of arteries in angiographic images has evolved as a tool for assistance, helping clinicians in making accurate diagnosis. However, due to the limited amount of data and the difficulty in curating a dataset, the task of segmentation has proven challenging. In this study, we introduce the idea of using pseudolabels as a data augmentation technique to improve the performance of the baseline Yolo model. This method increases the F1 score of the baseline by 9% in the validation dataset and by 3% in the test dataset.Comment: arXiv admin note: text overlap with arXiv:2310.0474

Development of Low-Threshold Detectors for Low-Mass Dark Matter Searches Using an N-Type Germanium Detector at 5.2 K

We investigated charge transport in an n-type germanium detector at 5.2 K to explore new technology for enhancing low-mass dark matter detection sensitivity. Calculations of dipole and cluster dipole state binding energies and electric field-dependent trapping cross-sections are critical to developing low-threshold detectors. The detector operates in two modes: depleting at 77K before cooling, or directly cooling to 5.2 K and applying different bias voltages. Results indicated lower binding energy of charge states in the second mode, at zero field and under an electric field, suggesting different charge states formed under different operating modes. Measured cluster dipole and dipole state binding energies at zero field were 7.884$\pm$0.644 meV and 8.369$\pm$0.748 meV, respectively, signifying high low-threshold potential for low-mass dark matter searches in the future.Comment: 7 pages, 8 figure

Development of low-threshold detectors for low-mass dark matter searches with a p-type germanium detector operated at cryogenic temperature

This study investigates new technology for enhancing the sensitivity of low-mass dark matter detection by analyzing charge transport in a p-type germanium detector at 5.2 K. To achieve low-threshold detectors, precise calculations of the binding energies of dipole and cluster dipole states, as well as the cross-sections of trapping affected by the electric field, are essential. The detector was operated in two modes: depleted at 77 K before cooling to 5.2 K and cooled directly to 5.2 K with various bias voltages. Our results indicate that the second mode produces lower binding energies and suggests different charge states under varying operating modes. Notably, our measurements of the dipole and cluster dipole state binding energies at zero fields were $8.716\pm 0.435$ meV and $6.138\pm 0.308$ meV, respectively. These findings have strong implications for the development of low-threshold detectors for detecting low-mass dark matter in the future.Comment: 7 pages, 8 figures. arXiv admin note: substantial text overlap with arXiv:2302.0841

Design of Substrate Transmembrane Mimetics as Structural Probes for γ-Secretase

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of the American Chemical Society (JACS), copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/jacs.9b13405.γ-Secretase is a membrane-embedded aspartyl protease complex central in biology and medicine. How this enzyme recognizes transmembrane substrates and catalyzes hydrolysis in the lipid bilayer is unclear. Inhibitors that mimic the entire substrate transmembrane domain and engage the active site should provide important tools for structural biology, yielding insight into substrate gating and trapping the protease in the active state. Here we report transmembrane peptidomimetic inhibitors of the γ-secretase complex that contain an N-terminal helical peptide region that engages a substrate docking exosite and a C-terminal transition-state analog moiety targeted to the active site. Both regions are required for stoichiometric inhibition of γ-secretase. Moreover, enzyme inhibition kinetics and photoaffinity probe displacement experiments demonstrate that both the docking exosite and the active site are engaged by the bipartite inhibitors. The solution conformations of these potent transmembranemimetic inhibitors are similar to those of bound natural substrates, suggesting these probes are preorganized for high-affinity binding and should allow visualization of the active γ-secretase complex, poised for intramembrane proteolysis, by cryo-electron microscopy.NIH R01 grant GM 122894NIH grant P30GM110761NIH grant P41GM11113

CMOS Approach to Compressed-domain Image Acquisition

A hardware implementation of a real-time compressed-domain image acquisition system is demonstrated. The system performs front-end computational imaging, whereby the inner product between an image and an arbitrarily-specified mask is implemented in silicon. The acquisition system is based on an intelligent readout integrated circuit (iROIC) that is capable of providing independent bias voltages to individual detectors, which enables implementation of spatial multiplication with any prescribed mask through a bias-controlled response-modulation mechanism. The modulated pixels are summed up in the image grabber to generate the compressed samples, namely aperture-coded coefficients, of an image. A rigorous bias-selection algorithm is presented to the readout circuit, which exploits the bias-dependent nature of the imager’s responsivity. Proven functionality of the hardware in transform coding compressed image acquisition, silicon-level compressive sampling, in pixel nonuniformity correction and hardware-level implementation of region-based enhancement is demonstrated

X-Ray Co-Crystal Structure Guides the Way to Subnanomolar Competitive Ecto-5 '-Nucleotidase (CD73) Inhibitors for Cancer Immunotherapy

Ecto-5'-nucleotidase (CD73, EC 3.1.3.5) catalyzes the extracellular hydrolysis of AMP yielding adenosine, which induces immunosuppression, angiogenesis, metastasis, and proliferation of cancer cells. CD73 inhibition is therefore proposed as a novel strategy for cancer (immuno)therapy, and CD73 antibodies are currently undergoing clinical trials. Despite considerable efforts, the development of small molecule CD73 inhibitors has met with limited success. To develop a suitable drug candidate, a high resolution (2.05 degrees A) co-crystal structure of the CD73 inhibitor PSB-12379, a nucleotide analogue, in complex with human CD73 is determined. This allows the rational design and development of a novel inhibitor (PSB-12489) with subnanomolar inhibitory potency toward human and rat CD73, high selectivity, as well as high metabolic stability. A co-crystal structure of PSB-12489 with CD73 (1.85 degrees A) reveals the interactions responsible for increased potency. PSB-12489 is the most potent CD73 inhibitor to date representing a powerful tool compound and novel lead structure

Mapping 123 million neonatal, infant and child deaths between 2000 and 2017

Since 2000, many countries have achieved considerable success in improving child survival, but localized progress remains unclear. To inform efforts towards United Nations Sustainable Development Goal 3.2—to end preventable child deaths by 2030—we need consistently estimated data at the subnational level regarding child mortality rates and trends. Here we quantified, for the period 2000–2017, the subnational variation in mortality rates and number of deaths of neonates, infants and children under 5 years of age within 99 low- and middle-income countries using a geostatistical survival model. We estimated that 32% of children under 5 in these countries lived in districts that had attained rates of 25 or fewer child deaths per 1,000 live births by 2017, and that 58% of child deaths between 2000 and 2017 in these countries could have been averted in the absence of geographical inequality. This study enables the identification of high-mortality clusters, patterns of progress and geographical inequalities to inform appropriate investments and implementations that will help to improve the health of all populations

Population and fertility by age and sex for 195 countries and territories, 1950–2017: a systematic analysis for the Global Burden of Disease Study 2017

Background: Population estimates underpin demographic and epidemiological research and are used to track progress on numerous international indicators of health and development. To date, internationally available estimates of population and fertility, although useful, have not been produced with transparent and replicable methods and do not use standardised estimates of mortality. We present single-calendar year and single-year of age estimates of fertility and population by sex with standardised and replicable methods. Methods: We estimated population in 195 locations by single year of age and single calendar year from 1950 to 2017 with standardised and replicable methods. We based the estimates on the demographic balancing equation, with inputs of fertility, mortality, population, and migration data. Fertility data came from 7817 location-years of vital registration data, 429 surveys reporting complete birth histories, and 977 surveys and censuses reporting summary birth histories. We estimated age-specific fertility rates (ASFRs; the annual number of livebirths to women of a specified age group per 1000 women in that age group) by use of spatiotemporal Gaussian process regression and used the ASFRs to estimate total fertility rates (TFRs; the average number of children a woman would bear if she survived through the end of the reproductive age span [age 10–54 years] and experienced at each age a particular set of ASFRs observed in the year of interest). Because of sparse data, fertility at ages 10–14 years and 50–54 years was estimated from data on fertility in women aged 15–19 years and 45–49 years, through use of linear regression. Age-specific mortality data came from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 estimates. Data on population came from 1257 censuses and 761 population registry location-years and were adjusted for underenumeration and age misreporting with standard demographic methods. Migration was estimated with the GBD Bayesian demographic balancing model, after incorporating information about refugee migration into the model prior. Final population estimates used the cohort-component method of population projection, with inputs of fertility, mortality, and migration data. Population uncertainty was estimated by use of out-of-sample predictive validity testing. With these data, we estimated the trends in population by age and sex and in fertility by age between 1950 and 2017 in 195 countries and territories. Findings: From 1950 to 2017, TFRs decreased by 49\ub74% (95% uncertainty interval [UI] 46\ub74–52\ub70). The TFR decreased from 4\ub77 livebirths (4\ub75–4\ub79) to 2\ub74 livebirths (2\ub72–2\ub75), and the ASFR of mothers aged 10–19 years decreased from 37 livebirths (34–40) to 22 livebirths (19–24) per 1000 women. Despite reductions in the TFR, the global population has been increasing by an average of 83\ub78 million people per year since 1985. The global population increased by 197\ub72% (193\ub73–200\ub78) since 1950, from 2\ub76 billion (2\ub75–2\ub76) to 7\ub76 billion (7\ub74–7\ub79) people in 2017; much of this increase was in the proportion of the global population in south Asia and sub-Saharan Africa. The global annual rate of population growth increased between 1950 and 1964, when it peaked at 2\ub70%; this rate then remained nearly constant until 1970 and then decreased to 1\ub71% in 2017. Population growth rates in the southeast Asia, east Asia, and Oceania GBD super-region decreased from 2\ub75% in 1963 to 0\ub77% in 2017, whereas in sub-Saharan Africa, population growth rates were almost at the highest reported levels ever in 2017, when they were at 2\ub77%. The global average age increased from 26\ub76 years in 1950 to 32\ub71 years in 2017, and the proportion of the population that is of working age (age 15–64 years) increased from 59\ub79% to 65\ub73%. At the national level, the TFR decreased in all countries and territories between 1950 and 2017; in 2017, TFRs ranged from a low of 1\ub70 livebirths (95% UI 0\ub79–1\ub72) in Cyprus to a high of 7\ub71 livebirths (6\ub78–7\ub74) in Niger. The TFR under age 25 years (TFU25; number of livebirths expected by age 25 years for a hypothetical woman who survived the age group and was exposed to current ASFRs) in 2017 ranged from 0\ub708 livebirths (0\ub707–0\ub709) in South Korea to 2\ub74 livebirths (2\ub72–2\ub76) in Niger, and the TFR over age 30 years (TFO30; number of livebirths expected for a hypothetical woman ageing from 30 to 54 years who survived the age group and was exposed to current ASFRs) ranged from a low of 0\ub73 livebirths (0\ub73–0\ub74) in Puerto Rico to a high of 3\ub71 livebirths (3\ub70–3\ub72) in Niger. TFO30 was higher than TFU25 in 145 countries and territories in 2017. 33 countries had a negative population growth rate from 2010 to 2017, most of which were located in central, eastern, and western Europe, whereas population growth rates of more than 2\ub70% were seen in 33 of 46 countries in sub-Saharan Africa. In 2017, less than 65% of the national population was of working age in 12 of 34 high-income countries, and less than 50% of the national population was of working age in Mali, Chad, and Niger. Interpretation: Population trends create demographic dividends and headwinds (ie, economic benefits and detriments) that affect national economies and determine national planning needs. Although TFRs are decreasing, the global population continues to grow as mortality declines, with diverse patterns at the national level and across age groups. To our knowledge, this is the first study to provide transparent and replicable estimates of population and fertility, which can be used to inform decision making and to monitor progress. Funding: Bill & Melinda Gates Foundation