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An abundance of evidence from a wide range of astrophysical and cosmological observations suggests the existence of nonluminous cold dark matter, which makes up about 83% of the matter and 27% of the mass-energy of the Universe. Weakly Interacting Massive Particles (WIMPs) have been one of the most promising dark matter candidates. Various detection techniques have been used to directly search for the interaction in terrestrial detectors where WIMP particles are expected to scatter off target nuclei. Over the last fifteen years, dual-phase time projection chambers (TPCs) with liquid xenon (LXe) as target and detection medium have led the WIMP dark matter search. The XENON dark matter search project is a phased program focused on the direct detection of WIMPs through a series of experiments employing dual-phase xenon TPCs with increasing target mass operated at the Gran Sasso underground laboratory (LNGS) in Italy. The XENON1T experiment is the most recent generation, completed at the end of 2018. The XENON1T dark matter search results from the one ton-year exposure have set the most stringent limit on the WIMP-nucleon spin-independent elastic scatter cross-section over a wide range of masses, with a minimum upper limit of 4.1 x 10⁻⁴⁷ cm² at 30 GeV · c⁻² and a 90% confidence level. XENON1T is the first WIMP dark matter experiment which has deployed a dual-phase xenon TPC at the multi-ton scale, with 3.2 t of LXe used. The large xenon mass posed new challenges in reliable and stable xenon cooling, in achieving and maintaining ultra-high purity as well as in efficient and safe xenon storage, transfer and recovery. The Cryogenic Infrastructure was designed and constructed to solve these challenges. It consists of four highly interconnected systems --- the Cryogenic System, the Purification System, the Cryostat and Cryogenic Pipe, and the ReStoX System. The XENON1T Cryogenic Infrastructure has performed successfully and will continue to serve the next generation experiment, called XENONnT, with a new Cryostat containing a total of 8.4 tons of xenon. I first give an instrument overview of the systems in XENON1T. I then review the cooling methods in LXe detectors which led to the design of the cooling system implemented in the XENON1T experiment, and suggest a design of the cooling system for future LXe dark matter experiments at the 50 tons scale. I describe and discuss in detail the design and the performance of the XENON1T Cryogenic Infrastructure. Finally, I describe the detector stability and the corresponding data selection in all three XENON1T science runs, and describe the dark matter search results from the one ton-year exposure.

Emerging infectious diseases remain persistent threats that are challenging to predict. Humanity has faced many terrible pandemics and will face more, but to pinpoint the specific time and place of an outbreak, the type of pathogen, and the consequences is effectively impossible. This point was recently highlighted by the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) viral pandemic, which led to global clinical and socioeconomic damage. When confronted by such a viral threat, the biomedical research community fervently responded with unprecedented haste to reveal SARS-CoV-2 clinical information, genome sequences, spike fusion protein structures, antigenic properties, antiviral therapeutics, and new vaccine platforms all within a year. As a small part of the tremendous collaborative research response, I used structural methods to study the SARS-CoV-2 spike fusion protein, specifically mechanisms of antibody-mediated viral neutralization. Viral fusion proteins are key components of virus particles that enable a virus to enter an animal host cell. Fusion proteins are the most common targets for neutralizing antibodies and serve a vital role as vaccine immunogens to elicit a protective immune response. To develop an understanding of SARS-CoV-2 antibody-mediated neutralization, one of my primary research interests was solving antibody structures in complex with the spike fusion protein using cryo-EM (cryogenic electron microscopy). With antibody structures I helped characterize spike epitopes, rationalize antigenic properties of emerging variants, and hypothesize viral neutralization mechanisms. I discovered antibody structures with multiple neutralization mechanisms including receptor blocking, conformational “locking” of the RBD (receptor binding domain), and spike disassembly. Viruses are evolving pathogens, and the Omicron sub-lineages are some of the most antibody-resistant SARS-CoV-2 variants to date. I studied mechanisms of Omicron antibody neutralization, which included traditional mechanism such as receptor blocking, as well as new mechanisms involving spike disassembly and conformational locking at SD1 (subdomain 1) epitopes. I also investigated broad antibody recognition at a conserved RBD epitope which neutralized not only SARS-CoV-2 but also SARS-CoV and other sarbecoviruses. Lastly, I had the opportunity to study other classes of viral fusion proteins, including those of alphaviruses and rabies virus, which serve as representative class members of the other varieties of viral fusion proteins, broadening my research for any type of known viral pathogen. Structural studies of antibodies highlight vulnerabilities of the spike protein when targeting SARS-CoV-2 and other fusion proteins in future vaccine design. The trials and tribulations of SARS-CoV-2 and the wealth of new research on coronaviruses offer hope of future pandemic preparedness. Understanding the structural mechanisms of viral fusion proteins and antibody neutralization gives hope of developing further therapeutic interventions. The work described in this thesis on fusion proteins SARS-CoV-2 spike (S), alphavirus envelope (E), and rabies virus glycoprotein (G) have prepared me to combat other infectious viral agents, including those already infecting humans and those at risk of spilling over into humans. When posed with such unpredictable emerging threats, we can learn from the past and position ourselves to be ready for the future.

Thesis (MScEng (Electical and Electronic Engineering))--University of Stellenbosch, 2008. / A Cryogenic CMOS-based Control System for Testing Superconductor Electronics P.C. van Niekerk Department of Electrical and Electronic Engineering University of Stellenbosch Private Bag X1, 7602 Matieland, South Africa Thesis: M.Sc.Eng. (E&E) March 2008 A complete control system, with accompanying software, is designed to interface superconductive digital and sensory circuits for use in cryogenic vacuumed environments. It acts as an inter-mediator between superconductor electronics and room temperature electronics for research purposes. In order to facilitate low bit-error rate communications with superconductive electronics, the system is designed to have ultra low-noise current and voltage sources for transmitting data to superconductor electronics. Very high sensitivity voltage inputs are also implemented for data extraction from superconductor electronics. It implements both digital as well as analog design components, including ADC and DAC devices. The data is transmitted via a USB cable connection at 1Mbaud to a computer where the data is processed by specially designed software and graphically displayed for user interfaced research. Extensive research is done on the electronic components, such as CMOS devices, for functioning in an average temperature of 70 Kelvin inside cryogenic environments. This is done to reduce the thermal noise and heat transfer to superconductor electronics. An integrated temperature control system also ensures a stable environment for the electronics to operate at 70 K.

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The purpose of this study was to determine whether deep-cryogenic freezing produces a change in the timbre or playing characteristics of brass trumpets. The experimental procedure consisted of two parts: quantitative analysis and qualitative analysis. For qualitative analysis a panel of four professional trumpet players evaluated five trumpets: four were frozen and re-evaluated, and one served as the experimental control. Analysis of the harmonic spectra of tones from each instrument provided quantitative data. Since previous studies requiring the analysis of musical instrument tones have suffered from a high degree of variation among tones played by human performers, I constructed a mechanical device that could play tones on the test instruments with greater consistency than is possible with live performers.The changes observed in the qualitative and quantitative analyses are very small, and possibly contradictory. The test panel rated all of the instruments higher after they had been frozen, and any actual improvement in the playing characteristics is suspect because the control instrument received the second highest improvement of the five instruments in the study. In the quantitative analysis, I observed some slight changes in the amplitudes of some of the harmonics in the spectral graphs, but I also observed slight variations in some of the harmonics of the control instrument. Inconsistencies in the performance of the electronic equipment used in the study could account for some of the variation. The instrument that showed the most statistically significant improvements was rated significantly higher in intonation after cryogenic processing, but I was unable to measure any frequency changes in the tones the mechanical embouchure played on the test instruments.Although one may not actually be able to measure differences reported in the qualitative analysis, it is not possible to rule out any acoustical change from cryogenic freezing. In fact, in the quantitative measurements, three of the instruments showed changes greater (some positive and some negative) than the "experimental error" seen in the control instrument's measurements. Additionally, one member of the test panel is convinced that cryogenic freezing has improved his instrument significantly, but the other three trumpeters are ambivalent. / School of Music

A high resolution pressure gauge has been developed for use in thermodynamic measurements along the lambda line in liquid helium. The gauge was designed to operate at cryogenic temperatures and provide pressure measurements up to 30bar, with an accuracy of 3 × 10¯¹ºbar in a 1Hz bandwidth. Experiments reported here show the gauge to have met these specifications; at least for measurements close to zero pressure, at temperatures close to 4.5K. It is expected that operation at higher pressures, and at temperatures closer to the lambda transition, will result in similar or even improved performance. The gauge consists of a titanium-alloy diaphragm with a superconducting position transducer read-out. Compensation techniques internal to the superconducting circuit were used to eliminate any significant sensitivity to temperature fluctuations and in-line acceleration. For high values of common-mode rejection, thermal compensation revealed a non-linear temperature characteristic which was exploited to provide a further reduction in the temperature sensitivity. Acceleration compensation was achieved up to a common-mode rejection of more than 78dB. Present performance appears to be limited by thermal gradient fluctuations at low frequencies and at higher frequencies by a noise source which appears to originate beyond the superconducting transducer. It is expected that some further improvement may be gained in this higher frequency band simply by trapping a larger persistent current in the superconducting circuit. In the course of development and characterization of the gauge several anomalous effects were discovered and investigated. In response to changes in temperature, the gauge was found to exhibit irreversible behaviour in a variety of ways. These phenomena were fully investigated and found to be complex in nature. A critical state model was employed which was successful in explaining many of the observed effects. Other authors have observed apparently related behaviour in samples of niobium and some have developed similar critical state models which give results generally consistent with those reported here. However, these latter works have not investigated the presence of such effects within superconducting wires; neither have they considered the implications for devices based upon superconducting wire circuits. It appears this anomalous behaviour may be relevant to a broad range of instruments employing superconducting wire circuits similar to that used here. If this is the case, the results presented here have significant consequences for the performance of such devices

Thesis (Ph. D.)--Electrical and Computer Engineering, Georgia Institute of Technology, 2007. / Cressler, John, Committee Chair ; Laskar, Joy, Committee Member ; Papapolymerou, Ioannis, Committee Member ; Zhou, Haomin, Committee Member ; Milor, Linda, Committee Member.

Termination of translation in eukaryotes occurs when a translating ribosome encounters a stop codon (UAA, UAG, or UGA) in its A site. This triggers the recruitment of translation termination factors eRF1, a tRNA-mimicking protein responsible for decoding the stop codon and catalyzing peptide release, and eRF3, a translational GTPase that stimulates peptide release in a GTP-hydrolysis-dependent manner. Upon successful stop codon decoding by eRF1, eRF3 carries out GTP hydrolysis and dissociates from the ribosome. eRF1 subsequently gets accommodated into the peptidyl transferase center (PTC) and catalyzes the release of the nascent peptide. The structures for the pre-accommodated eRF1 with eRF3 trapped on ribosome using non-hydrolysable GTP analogs as well as for the PTC-accommodated eRF1 have been solved using cryogenic electron-microscopy (cryo-EM). The structures reveal the binding mode and interactions between the release factors and the pre-termination complex. However, the mechanism of eRF3 GTPase activation and subsequent eRF1 accommodation into the PTC remains poorly understood. To address this knowledge gap, we used single-particle time-resolved cryo-EM (TRCEM) to capture the structures of intermediates formed during the termination process. For our TRCEM experiments, we first developed a Polydimethylsiloxane (PDMS)-based modular microfluidic mixing-spraying device with a SiO₂ internal coating. The device has a SiO₂-coated PDMS-based 3D splitting-and-recombination (SAR) micro-mixer capable of mixing two fluids within 0.5 ms with more than 90% efficiency. The SiO₂coating strengthens the PDMS channels and acts as a hydrophilic barrier preventing sample adsorption to the PDMS surface. The micro-mixer is connected to a glass microcapillary that acts as the reaction channel. Channels of different lengths can be used to vary the overall reaction time between 10 ms and 1000 ms. The microcapillary is connected to a 3D micro-sprayer for generating a 3D plume of sprayed droplets. A cryo-EM grid is passed through the spray cone to collect droplets and is rapidly plunged into liquid cryogen for vitrification. By using TRCEM as well as the conventional blotting method for cryo-EM sample preparation, we captured the reaction between a pre-termination (pre-TC) mimic and the ternary complex of eRF1, eRF3, and GTP at reaction times of 450 ms, 900 ms, 15 s, and 10 min. Classification of the cryo-EM data resulted in maps for five distinct factor-bound classes. Four maps belonged to intermediates with densities for eRF1 and eRF3 bound to the pre-TC in varying conformations. The fifth map had a density matching the PTC-accommodated eRF1. Population analysis allowed us to arrange the classes chronologically and track the events leading to GTPase activation during the termination process. Atomic model building and refinement allowed us to determine the hydrolysis state of the eRF3-bound GTP and revealed the catalytic mechanism for GTP-hydrolysis. The models revealed a potential mechanism for GDP dissociation post-GTP-hydrolysis.