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The design and synthesis of cell-penetrant autophagy-inducing peptides and the development of a novel assay for measuring cell penetration
No full textAbstract: Biotherapeutics are gaining popularity as efficient modulators of protein-protein interactions. However, accessing intracellular targets remains a significant hurdle for developing them into drugs. Cell-penetrating peptides (CPP) have been studied extensively for their penetration properties and have been used as carriers for small and large biotherapeutics. Though they have been employed in numerous clinical applications, their immunogenicity and poor systemic distribution, has prevented them from advancing in the drug development pipeline. Strategies have been emerging to render bioactive peptides intrinsically cell-penetrant. One of the most successful approaches has been peptide stapling, which locks a peptide into a specific conformation and can yield high binding affinity, resistance to proteolytic degradation, and improved biological activity. But it is still not well understood what biochemical and structural modifications specifically affect cell penetration. This dissertation describes the use of a diversity-oriented stapling approach to generate intrinsically cell-penetrant, autophagy-inducing peptides. In addition, to investigate the cell penetration of these peptides, a novel quantitative assay was developed which can report on penetration with subcellular resolution. Chapter 1 describes the design and synthesis of autophagy-inducing peptides derived from the autophagy regulator Beclin 1. Diversity-oriented bis-alkylation was applied to optimize intrinsically cell-penetrant autophagy inducers. The most potent stapled peptide, DD5-o, was shown to be active in vivo and in a cellular model of Huntington's disease. Chapter 2 highlights further structure-activity relationship studies conducted on DD5-o, as well as structural determination. The solution structure of DD5-o in methanol revealed α-helical conformation stabilized by an unusual (i,i+3) staple, cross-linking two D-cysteines. iv In producing the autophagy inducer DD5-o, the diversity-oriented bis-alkylation strategy was shown to be a promising avenue for rendering peptides more cellpenetrant. The mechanism and limitations of this reaction were studied, and methods for monitoring progression of the reaction were developed. These details are described in Chapter 3. Chapter 4 provides an overview of current methods used for measuring cell penetration, as well as the design and setup of the chloroalkane penetration assay (CAPA). This assay was benchmarked to known CPPs and the data demonstrated that CAPA can accurately report on cytosolic penetration in a quantitative manner. Chapter 5 shows different applications of CAPA. Due to its flexibility and high throughput, it was used for cell penetration profiling of different peptides. Temperature, serum content, and time are factors that can affect the extent of cell penetration, and we showed that the effects of each can be quantified using CAPA. CAPA was also applied to investigate the structure-penetration relationships of bioactive peptides. It was further applied to measure the uptake of nanoparticles, as well as to measure nuclear penetration using a different cell line. Our data to date show that CAPA is an exciting tool for measuring and profiling the cell penetration of biotherapeutics.Thesis (Ph.D.)--Tufts University, 2018.Submitted to the Dept. of Chemistry.Advisor: Joshua Kritzer.Committee: Charles Mace, David Walt, and Loren Walensky.Keyword: Chemistry
Who do Multiracials consider part of their racial ingroup?
No full textAbstract: This paper tests who Multiracials consider as part of their racial ingroup. A Multiracial's racial ingroup is flexible, or has multiple ingroup member possibilities. Blacks, Asians, and/or Whites who share a Multiracial's component racial group, Multiracials with different racial backgrounds (different-race Multiracials), and Multiracials with the same racial backgrounds (same-race Multiracials) can potentially be considered ingroup members by Asian/Whites and Black/Whites. Across two studies, I used an anticipated online interaction paradigm to determine if Multiracials consider Monoracials (Study 1) and different-race Multiracials (Study 2) as ingroup members to the same extent as same-race Multiracials. Study 1 revealed that a Minority individual is an ingroup member more than a White individual while Study 2 revealed that different-race Multiracials are considered ingroup members, but more so the different-race Multiracial with a shared Minority racial background. Implications of these findings for intra- versus inter-group interactions and mental and physical health are discussed.Thesis (M.S.)--Tufts University, 2018.Submitted to the Dept. of Psychology.Advisor: Jessica Remedios.Committee: Courtney Bonam, and Keith Maddox.Keyword: Social psychology
Research supporting nutrition-sensitive programming.
No full textThis presentation was given at Innovaiton Lab Director's meeting - Kampala Uganda.Keywords: FTFNIL, Aflatoxins, Nutrition, Nepal, Uganda, Bangladesh
Effect of Silver Diamine Fluoride on Shear Bonding Strength to Dentin for Different Restorative Materials on Primary Molars
No full textAbstract: Aim and Hypothesis: This In vitro study was conducted to investigate the effect of silver diamine fluoride (SDF) on shear bond strength (SBS) of three different restorative materials after SDF treatment on primary dentin. Materials and Methods: Glass ionomer cement (GIC), resin-modified bioactive resin (ACTIVA), and composite resin (CR) were tested. Thirty teeth were randomized into three groups of 10 teeth. Each tooth was split mesiodistally and randomized into test (artificial caries + SDF) and control (sound dentine + no SDF). The restorative material was placed, then tested for SBS, and type of failure was recorded. Results: All the test groups exhibited significantly lower mean SBS compared to the control groups (CR: p = 0.001; ACTIVA: p = 0.001; GIC: p = 0.004). For the SDF group, the comparison of materials was significant (p = 0.006), with significance between CR and ACTIVA (p = 0.009) and ACTIVA and GIC (p = 0.020), but not CR and GIC (p = 0.950). For the control group, Welch's F test was statistically significant (p = 0.044), but all post-hoc tests were not. The control CR group had only mixed failures, with a significantly greater percentage of mixed failures than the test group (p = 0.023). The test ACTIVA group showed only adhesive failures, with a significantly greater percentage of adhesive failures than the control group (p=0.041). The test GIC group had only mixed failures with no significant difference between test and control groups (p = 1.00). For the SDF group, ACTIVA only exhibited adhesive failures, and only mixed in GIC; the difference between groups was significant (p < 0.001). For the type of failure in the test group, CR had adhesive failures in 70% of samples with a significant difference between CR and GIC (p = 0.002), but not between CR and ACTIVA (p = 0.105). For the control group, there was no significant difference in type of failure (p=0.094). Conclusion: SDF significantly reduced the SBS when compared to the control. For the test group, mean SBS was highest for CR, GIC and then ACTIVA; differences between ACTIVA and the other groups were significant. For the control group, SBS was again highest for CR, then GIC and then ACTIVA, but all post-hoc tests were not significant. For type of failure, SDF exhibited a greater percentage of adhesive failures with ACTIVA and CR than with GIC. In the control group, a mixed type of failure was more dominant than the adhesive with no significant differences between materials. We recommend considering using CR or GIC after applying SDF on carious primary dentin.Thesis (M.S.)--Tufts University, 2018.Submitted to the Dept. of Pediatric Dentistry.Advisor: Cheen Loo.Committee: Gerard Kugel, Yoon Kang, and Matthew Finkelman.Keyword: Dentistry
Why Children Fail to Learn to Read: Identifying the Cognitive, Neural, and Environmental Precursors
No full textAbstract: Reading development utilizes and repurposes multiple cognitive and neural systems that support innate functions such as vision, hearing, language, and learning. In most children, these systems become seamlessly integrated through the experience of reading to form a reading circuit. In a subset of children with developmental dyslexia, however, neural specialization for reading proceeds atypically and reading impairment ensues. Because of the complexity of this circuit and the heterogeneity of dyslexia-related deficits, forming a cohesive theory of dyslexia etiology has been challenging and multiple hypotheses have been proposed. To establish the etiological causes of dyslexia, it is important to demonstrate that a particular mechanism of deficit precedes reading impairment and is present in pre-reading children. This dissertation reports findings from four studies that investigated the cognitive, neural and environmental substrates of reading failure in pre-reading children. Specifically, Study 1 applied latent profile analysis to identify heterogeneous profiles of dyslexia risk in 1,215 kindergarten students and to demonstrate the high longitudinal stability of these profiles. Using voxel based morphometry and diffusion weighted imaging, Study 2 demonstrated the grey matter and white matter characteristics of each of the risk profiles identified in Study 1 in a subset of the children (n=100). The study also showed that some neuroanatomical substrates of risk predict longitudinal reading outcomes above behavioral measures. In support of the regularity extraction deficit in dyslexia, Study 3 demonstrated unique association between the processing of temporal regularity in musical rhythm and reading development in 74 kindergarten children. Furthermore, a mediation analysis revealed a causal path from rhythm performance to phonological awareness skills and to reading skills. Finally, using diffusion methods, Study 4 demonstrated links between socioeconomic status (SES) and the coherence of white matter tracts important for reading development. Additionally, SES modulated the relationship between dyslexia risk and longitudinal reading outcomes. The findings in these studies may contribute to a better theoretical understanding of the etiology of dyslexia and in addition, highlight the importance of early identification and individualized remediation.Thesis (Ph.D.)--Tufts University, 2018.Submitted to the Dept. of Child Development.Advisor: Maryanne Wolf.Committee: Aniruddh Patel, Calvin Gidney, and Nadine Gaab.Keywords: Developmental psychology, Cognitive psychology, and Language
Capacity of health facilities for diagnosis and treatment of HIV/AIDS in Ethiopia.
No full textBackground: There are dearth of literature on the capacity of the health system to diagnose and treat HIV/AIDS in Ethiopia. In this study we evaluated the capacity of health facilities for HIV/AIDS care, its spatial distribution and variations by regions and zones in Ethiopia.Keywords: Capacity, Health facilities, HIV/AIDS, Ethiopia.Springer Open
Dietary intakes of flavan-3-ols and cardiovascular health: a field synopsis using evidence mapping of randomized trials and prospective cohort studies.
No full textBackground: There is considerable interest in the impact of increased flavan-3-ol intake on cardiovascular disease (CVD) and diabetes outcomes. Through evidence mapping, we determined the extent of the evidence base to initiate a future systematic review investigating the impact of flavan-3-ol intake on CVD and diabetes outcomes.Keywords: Cardiovascular disease, Diabetes, Lipids, Flavan-3-ols, Evidence mapping, Cocoa, Tea, Berries, Cinnamon, Red wine.Springer Open
All Manner of Torment: The Intersection of Social Justice and Social Control in Early Conceptions of Hell.
No full textA comparative analysis of Plato, the Apocalypse of Peter, and Augustine's conceptions of hell, and how each reveals its respective author's ideas about justice and social control
Children’s Ability to Causally Reason About Emotions Across Development.
No full textThis study investigated the development of children’s understanding of the causes of emotions. Prior research demonstrates that children are capable of differentiating between various emotions and can recognize emotions in others. The present study extends these findings to explore whether or not young children can recognize and understand that emotions can be caused by something external (i.e., in the surrounding environment). Ninety-six participants comprised six 6-month age groups from 12-48 months old. Participants watched two types of puppet shows: Causal and Non Causal. In the Causal shows, a target toy scared the puppet, and in the Non Causal shows, a target toy did not scare the puppet. The experimenter then presented the participants with four toys (including the target toy) and asked participants to play with the toys, determine how to make the puppet feel better when it is scared, and identify which toy made the puppet scared. We assessed participants’ causal reasoning based on their predictive looking, play, and interventions. The results of this study suggested that children as young as 1-3 years old are not fully capable of causally reasoning about emotions and only exhibit mastery of components skills of causal reasoning about emotions. Further research should be conducted to better understand how young children use causal reasoning with emotions
Dark Rooms / Daniel Corral.
No full textDark Rooms is an examination of queer folks and how identity and intimacy are formed in private settings. Utilizing the camera obscura method by extinguishing all available light of an enclosed space, I proceed to illuminate my subjects with a pinhole size opening in the room that projects an image of their outside environments. The camera obscura here acts as a portal to their surroundings and serves as an analogy for queer folks to authorize their own identity in private while simultaneously having access to public spaces. This series invites viewers to peek into the world that is camera obscura and queer intimacy.Keywords: Camera obscura, queer community, queer spaces, digital photography