Structure and Mechanics of Proteins from Single Molecules to Cells

Physical factors drive evolution and play important roles in motility and attachment as well as in differentiation. As animal cells adhere to survive, they generate force and “feel” various mechanical features of their surroundings and respond to externally applied forces. This mechanosensitivity requires a substrate for cells to adhere to and a mechanism for cells to apply force, followed by a cellular response to the mechanical properties of the substrate. We have taken an outside-in approach to characterize several aspects of cellular mechanosensitivity. First, we used single molecule force spectroscopy to measure how fibrinogen, an extracellular matrix protein that forms the scaffold of blood clots, responds to applied force and found that it rapidly unfolds in 23 nm steps at forces around 100 pN. Second, we used tensile testing to measure the force-extension behavior of fibrin gels and found that they behave almost linearly to strains of over 100%, have extensibilities of 170 ± 15 %, and undergo a large volume decrease that corresponds to a large and negative peak in compressibility at low strain, which indicates a structural transition. Using electron microscopy and X-ray scattering we concluded that these properties are likely due to coiled-coil unfolding, as observed at the single molecule level in fibrinogen. Moving inside cells, we used total internal reflection fluorescence and atomic force microscopy to image self-assembled myosin filaments. These filaments of motor proteins that are responsible for cell and muscle contractility were found to be asymmetric, with an average of 32% more force generating heads on one half than the other. This could imply a force imbalance, so that rather than being simply contractile, myosin filaments may also be motile in cells

Discrimination, Coping, and Depression among Black Men Who Have Sex with Men

Black men who have sex with men (BMSM) have elevated risk for depression compared to the general population. BMSM’s capacity to cope with these experiences is not well understood. Increased understanding of how multiple forms of discrimination contribute to depression and how BMSM cope with discrimination can better inform interventions. Data come from 3,510 BMSM who attended Black Pride events in six U.S. cities from 2015-2017. Participants completed a health survey that ascertained their psychosocial health and resiliency profiles. Using multivariable logistic regression models, we tested the associations between type-specific discrimination (race, sexuality, HIV status) and depression. We then conducted sub-analyses to determine if coping attenuated the association between type-specific discrimination and depression. Our findings indicated that increased odds of depression among BMSM were associated with discrimination based on race (aOR=1.38, 95% CI = 1.08-1.76), sexual orientation (aOR=1.32, 95% CI = 1.01-1.72), and HIV status (aOR=1.53, 95% CI = 1.08-2.17). Sub-analyses indicated coping had inconsistent moderation effects between type-specific discrimination and depression. Our findings demonstrate that impact of various forms of discrimination on BMSM’s mental health and the mitigating role of coping. Interventions should seek to address depression by reducing experiences of discrimination and building coping resiliency

OPPORTUNITY MATTERS: A MIXED-METHODS STUDY OF SOCIOECONOMIC STANDING, MASCULINITY, AND CONCURRENCY AMONG BLACK MEN

Background: Black men’s (BM) increased HIV risk is not fully explained by individual-level risk factors such as no condom use during sex. Their sexual networks--featuring high concentrations of concurrency--have been identified as social structural pathways to HIV disparities. Sociodemographics, like socioeconomic standing (SS) and sexual orientation, and masculinities have previously been identified as drivers of BM’s concurrency. Conscious of these factors, this dissertation used quantitative data from the National Survey of Family Growth (NSFG) (n=1709) to explore the direct and moderated relationship between BM's concurrency and their levels of respectability masculinity (SS and sexual orientation) and traditional masculinity ideologies. The dissertation also used qualitative (focus group) data from the Sexual Concurrency Media Study (N=3) to explore the influence of masculinities and personal values on BM’s relationship satisfaction, stress-coping behaviors, and concurrency; and the underlying cognitions and affective experiences shaping BM’s concurrency. Methods: An SS-index was created using financial-based measures in the NSFG. Exploratory Factor Analysis was used to derive a measure reflecting men’s level of traditional masculinity ideologies. Multiple logistic regression was used to model men’s odds of concurrency. Directed content analysis was used to analyze focus group transcripts. Results: Direct effects analyses revealed that greater odds of concurrency was significantly associated with: lower SS; traditional gender conforming (TGC) orientation; and higher endorsement of heteronormative traditional masculinity ideologies. Moderated effects analyses revealed: SS moderated the association between sexual orientation and concurrency resulting in greater odds of concurrency for TGC and traditional gender non-conforming (TGNC) BM and heteronormative traditional masculinity ideologies moderated the association between sexual orientation and concurrency resulting in greater odds of concurrency for TGC and TGNC BM. Qualitative analyses results revealed that relationship dissatisfaction; supportive community norms; sociodemographics; and cognitions, despite affective experiences all impact BM’s concurrency. Conclusions/Implications: BM’s concurrency and HIV risk are impacted by masculinities and socioeconomic factors, albeit in unexpected ways. Addressing these in future research and interventions might enhance existing efforts designed to reduce BM’s disproportionate HIV burden.Doctor of Philosoph

Interpreting and exploiting narrative as a sketch design generator for application in VE

The research in this paper focusses on how a narrative text can be the generator of an architectural drawing, or other architectural representation, such as an Architectural Virtual Environment. The drawn physical sketch has traditionally played that role. A particular approach to narrative has been important for some notable architects and their architecture. Ian Ritchie (2014), for instance, celebrates the use of poetry to describe the essential spirit of a scheme before any drawing is done. The work in the paper here describes the proposition to capture such narrative text in a systematic and structured way. We describe foundational work on how the captured narrative text has been translated into a contemporary, computer-mediated, design development environment. Different narrative accounts recalling a now demolished house form the focus case study. This case study is the vehicle through which the initial principles establishing how best to move from narrative to virtual representation are established and tested

Molecular Dipolar Crystals as High Fidelity Quantum Memory for Hybrid Quantum Computing

We study collective excitations of rotational and spin states of an ensemble of polar molecules, which are prepared in a dipolar crystalline phase, as a candidate for a high fidelity quantum memory. While dipolar crystals are formed in the high density limit of cold clouds of polar molecules under 1D and 2D trapping conditions, the crystalline structure protects the molecular qubits from detrimental effects of short range collisions. We calculate the lifetime of the quantum memory by identifying the dominant decoherence mechanisms, and estimate their effects on gate operations, when a molecular ensemble qubit is transferred to a superconducting strip line cavity (circuit QED). In the case rotational excitations coupled by dipole-dipole interactions we identify phonons as the main limitation of the life time of qubits. We study specific setups and conditions, where the coupling to the phonon modes is minimized. Detailed results are presented for a 1D dipolar chain

Network analyses of Oppositional Defiant Disorder (ODD) symptoms in children

Based on parent and teacher ratings of their children, this study used regularized partial correlation network analysis (EBIC glasso) to examine the structure of DSM-5 Oppositional Defiant Disorder (ODD) symptoms. Parent and teachers (N = 934) from the general community in Malaysia completed questionnaires covering DSM-5 ODD symptoms. The most central ODD symptom for parent ratings was anger, followed by argue. For teacher ratings, it was anger, followed by defy. For both parent and teacher ratings, the networks revealed at least medium effect size connections for temper and argue, defy, and argue, blames others, and annoy, and spiteful and angry. Overall, the findings were highly comparable across parent and teacher ratings, and they showed a novel understanding of the structure of the ODD symptoms. The clinical implications of the findings for assessment and treatment of ODD are discussed