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Mechanisms of Transcriptional Regulation in the Drosophila Female Germline
No full textSexual reproduction is the union of two haploid genomes that reside in sex-specific gametes. Sex-specific gamete production results from the differentiation of germline stem cells within the gonads of males and females. In Drosophila, XX germline stem cells are female and differentiate into an egg. Single X germline stem cells are male and develop into sperm. Sperm contain little genetic information besides the necessary haploid genome for the zygote's development, while eggs contain maternally provided instructions to ensure early embryonic development. These developmental instructions, in the form of RNAs and proteins, are provided to the developing oocyte throughout the differentiation process of oogenesis. A significant amount of research has elucidated how maternally provided RNAs and proteins are regulated and control embryonic development, however, there is little known about how these essential maternal processes are controlled at the transcriptional level. Herein, we define the function of two genes, sov and ovo, and how they both contribute to oocyte development to derive a functional egg. sov was a previously unmapped locus that we were able to attribute to the gene CG14438. We show that sov is required for oocyte specification and maturation and it accomplishes this through the regulation and stabilization of heterochromatin in female germ cells. ovo is required for female germ cell survival and we found that OVO exists eternally in the female germline. We show that OVO is involved in positively regulating the transcription of numerous maternal pathways essential for oocyte maturation and embryonic development. This altogether posits sov and ovo as key regulators of female germline transcription that is required for germ cell viability and the continual reproductive success of females generationally
Mitotic Safeguards and Vulnerabilities: Timing of the Mitotic Surveillance Pathway & the Basis of KIF18A Addiction in Cancer
No full textSuccessful replication and segregation of the genome is critical for faithful cell division. As such, cells have evolved redundant safeguards to prevent errors in these processes. Delays in mitosis lead to an increased frequency of DNA damage and aneuploidy, both drivers of tumorigenesis. Consequently, the Mitotic Surveillance Pathway (MSP), discovered in our and other labs, compensates for this defect by triggering cell death or a cell cycle arrest in daughter cells whose parent mitosis exceed a characteristic threshold of mitotic duration. This pathway, unlike the Spindle Assembly Checkpoint (SAC) which monitors chromosome attachment to the mitotic spindle, is highly dysregulated in most cancer cell lines, strongly suggesting a tumor suppressive role. Previous work identified central components of this biological clock including the proteins USP28, 53BP1, p53 and p21. However, how cells measure mitotic duration to make this cell fate decision remains unknown. This thesis proposes a mechanistic model in which the protein 53BP1 is modified at kinetochores by the kinase PLK1, priming it for pathway activation. Eventually, 53BP1 falls off kinetochores to form a multimeric complex with de-ubiquitylating enzyme USP28 and p53. We speculate that formation of this complex is one step of a multi-arm activation pathway required for p53-dependent cell cycle arrest.
In addition to studying the Mitotic Surveillance Pathway, we also investigated how genetic and phenotypic changes that arise during tumorigenesis generate a druggable vulnerability to KIF18A inhibition in cancer cell division. The efficacy of current antimitotic cancer drugs is limited by toxicity in highly proliferative healthy tissues. A cancer-specific dependency on the microtubule motor protein KIF18A therefore makes it an attractive therapeutic target. Not all cancers require KIF18A however, and the determinants underlying this distinction remain unclear. Here we show that KIF18A inhibition drives a modest increase in SAC signaling which can result in lethal mitotic delays. Whether cells arrest during division depends on a balance between SAC signal strength and anaphase promoting complex/cyclosome (APC/C) activity. Increased chromosome number and low basal APC/C activity dysregulate this balance and cooperatively increase KIF18A dependency. KIF18A dependent cancer cells exhibit hallmarks of this imbalance, including high ploidy, a long metaphase to anaphase transition, and slow mitosis overall. Together, our data reveal vulnerabilities in the cell division apparatus of cancer cells that can be exploited for therapeutic benefit
GENETIC AND ENVIRONMENTAL INFLUENCES ON AUTISM SPECTRUM DISORDER AND RELATED QUANTITATIVE BEHAVIORAL TRAITS
No full textAutism is a heritable neurodevelopmental disorder that presents heterogeneously across the life course. Increasing prevalence, high co-occurrence with psychiatric and medical conditions, and health disparities underscore the need for prevention and tailored interventions. Past research has demonstrated genetic and environmental factors impact both likelihood of diagnosis and severity of related symptoms. However, only a handful of studies have investigated joint contributions of genetics and the environment to these outcomes.
We undertook three complementary studies to address this gap in research. For the first two, we recruited mothers and their children with autism from the Simons Powering Autism Research for Knowledge study and collected autism-related behavioral outcomes, genetic data, and pregnancy exposure histories. We tested for gene-environment interaction effects using both categorical diagnosis of autism and quantitative traits as outcomes. In Aim 1, we measured genetic burden using traditional polygenic scores for autism (PGS-ASD) and in Aim 2 we developed complementary, functionally informed gene expression risk scores (GeRS-ASD). We found interactions between GeRS-ASD and eclampsia, but not PGS-ASD or other exposures, significantly increased odds of ASD among children. Joint effects on quantitative traits were generally widespread, both increasing and decreasing severity though some exposures were associated with specific traits. In Aim 3, our goal was to characterize joint and individual genetic and environmental influences on transcriptional variation, towards improving detection of specific effects. We used genetic and pregnancy exposure data from a prospective birth cohort, Markers of Autism Risk in Babies, to characterize effects of genetically regulated expression (GReX) on exposure-specific transcriptional variation. Differential expression in response to gestational diabetes mellitus during pregnancy was altered greatly after controlling for effects of GReX. These changes were pronounced for a subset of genes with stronger associations between GReX and assayed expression.
We detected and characterized joint effects of common genetic influences and pregnancy exposures on autism and related outcomes, demonstrating a need and setting a foundation for larger scale research of this nature. Future work should also further examine joint and independent contributions to exposure-dependent transcriptional variation, with potential implications for understanding etiologic mechanisms
UNDERGRADUATE INTRODUCTORY BIOLOGY FACULTY’S INFLUENCE ON STUDENT PERSISTENCE IN STEM
No full textPersistence in Science, Technology, Engineering and Mathematics (STEM) undergraduate programs is low in most demographic groups and is significantly lower for students from marginalized groups (Eagan et al., 2015). Classroom climate and interaction with faculty are two of the reasons studies cite for students leaving the STEM major (Geisinger & Raman, 2013; Seymour & Hewitt, 1997; Suresh, 2006). However, undergraduate biology faculty often have limited training in pedagogy and may lack the expertise to create a classroom environment that fosters learning and belonging. A mixed methods study of Introductory Biology faculty who interact with BioInteractive examined faculty’s beliefs about the nature of intelligence, current knowledge and use of research-based instructional strategies (RBIS), and faculty’s needs and desire for professional development (PD) to embed inclusive instructional practices effectively in their courses. The study included survey data from 1,439 participants (N = 1,439; 2-year n = 622; 4-year n = 817) and an analysis of 151 syllabi. The study also sought to identify differences in beliefs and behaviors pertaining to a growth mindset, RBIS use, and PD needs between faculty at 2-year and 4-year institutions. These findings were used to inform BioInteractive’s online PD initiatives and directly impact the design of a free 20+ hour online course on inclusive teaching
MATERNAL AND PERINATAL DEATH SURVEILLANCE AND RESPONSE IN HUMANITARIAN SETTINGS: UNPACKING IMPLEMENTATION COMPLEXITIES AND PROGRAMMATIC ADAPTATIONS
No full textBackground: Global movements have advocated for Maternal and Perinatal Death Surveillance and Response (MPDSR) as a strategy to reduce global maternal and perinatal mortality. A growing evidence base documents many implementation challenges and best practices in low- and middle-income countries. Nonetheless, little is known about MPDSR implementation in humanitarian settings.
Methods: Paper 1 systematically reviews peer-reviewed and grey literature to
synthesize learning and evidence on MPDSR within the gamut of mortality surveillance and quality improvement initiatives in humanitarian settings. Paper 2 analyzes 66 key informant interviews conducted December 2021-July 2022 with stakeholders supporting or directly implementing MPDSR interventions in Cox’s Bazar (CXB) refugee camps, refugee settlements in Uganda, South Sudan, the occupied Palestinian Territories (oPT), and Yemen to understand the complexities of MPDSR implementation in diverse humanitarian settings. Paper 3 assesses implementation of community-based MPDSR (CB-MPDSR) approaches using a sub-set of the key informant interviews to examine contextual factors that influence implementation.
Results: Paper 1 unveils a vast landscape of MPDSR and related death review interventions within humanitarian settings in 26 countries, albeit with significant gaps in the documentation of their implementation. Paper 2 contributed to the identified gaps by providing thorough insights of the implementation of MPDSR in CXB, Uganda, South Sudan, oPT, and Yemen and illustrated the importance of considerations related to the complex health system dynamics when implementing MPDSR. Successful implementation in these contexts was driven by best practices bolstering an enabling implementation climate, improving community involvement, and adapting programming fit-for-context. Paper 3 depicted varied CB-MPDSR approaches including both active and passive surveillance systems and suggested that strategic engagement of diverse community stakeholders may improve participation, trust, and transparency between communities, humanitarian actors, and health systems.
Conclusions:
The three papers in this dissertation depict a varied implementation landscape of MPDSR and related death review interventions in humanitarian settings. Given the unique contextual considerations of conflict-affected contexts, the results call for a customized approach to implementing MPDSR interventions. Improved coordination and alignment of MPDSR programming across humanitarian partners and government actors and continued research to refine approaches that bolster community involvement are crucial for scale-up within LMICs
Proceedings of Summer Symposium for Students 2023
No full textCold-Formed Steel Research Consortium (CFSRC) hosted the fourth edition of Summer Symposium for Students on May 23, 2022. 13 CFSRC student researchers from 6 different universities shared their work with their colleagues including the CFSRC investigator team. In addition, industry groups affiliated with CFSRC attended the symposium and hear directly from the students performing the research.The cold-formed steel and related research focusing on from reliability to OPENFAST, seismic design to imperfection analysis and fasteners to system design was presented.
Editors: Benjamin W. Schafer and Deniz Ayhan Moe
COACHING DISCIPLINARY LITERACY PRACTICES: A CASE STUDY ON SCIENCE INSTRUCTION AND LEARNING
No full textInstruction in areas like mathematics, science, and social studies focuses solely on teaching the content. However, to deeply understand the content, literacy skills must be incorporated. Disciplinary literacy instruction emphasizes that each discipline has a set of unique and specialized literacy skills that students must learn to understand the content of that discipline. A mixed-methods needs assessment revealed that elementary teachers have knowledge of basic and intermediate literacy skills, and they prioritize encouraging a love of reading. Also, the teachers reported not knowing how to support students with literacy strategies in the content areas. The second phase of the study was an intervention designed to examine the impact of literacy coaching on the implementation of disciplinary literacy practices in an elementary classroom and on teacher knowledge of disciplinary literacy practices. A case study design was used to incorporate qualitative data to best understand the target population and develop a rich description of how participants understand and incorporate disciplinary literacy practices in a science classroom. An inquiry approach enabled incorporation of the voices, opinions, and beliefs of the teachers. Participants included two elementary teachers who took part in one pre- intervention observation, six literacy coaching sessions, three post-intervention observations, and one interview over the course of 3–4 weeks. Findings include that the mandated curriculum had a major impact on the teaching of science. After the coaching sessions, the teachers incorporated the literacy practices that scientists use by implementing student collaboration, student talk, and inquiry. The teachers found the literacy coaching sessions to be helpful and valuable toward their understandings of the science discipline
Exploring strategies and evaluating systems: insights to inform primary health care strengthening in India
No full textIntroduction: Through its three objectives, this dissertation aims to derive policy lessons for strengthening primary health care (PHC) in India. Objective one explores reform strategies undertaken by high performing PHC systems in select middle-income countries. Objective two determines effect of structural and clinical quality of care on public sector PHC facility bypassing in Bihar and reconciles system and community perceptions of quality of care. Objective three evaluates equality of quality-weighted utilization incidence and quality-weighted benefit incidence of PHC facility services in Bihar.
Methods: Objective one is a scoping literature review. Objectives two and three utilized secondary data from a facility and household survey in Bihar. In objective two, four multi-level logistic regression models were fitted to determine association between public sector PHC facility bypassing and facility level quality; the third objective used the benefits incidence analysis tool to estimate incidence of un-weighted and quality weighted utilization, out-of-pocket expenditure (OOPE) and benefits of PHC facility services by socioeconomic status.
Results: Despite variations in PHC reform strategies examined in objective one, few common characteristics existed, e.g., increased public financing for PHC, delivery of PHC services by multi-disciplinary teams, community empanelment and gatekeeping. In Bihar, compared to private, public sector PHC facilities had better average structural and clinical quality; neither was associated with bypassing. Greater drugs availability was associated with reduced bypassing. On average, utilization of public sector PHC facilities was similar across socioeconomic quintiles though wealthiest utilized care the most and paid highest OOPE on average. Median quality weights of PHC facilities were statistically significantly different across socioeconomic quintiles. Quality-weighted concentration indices for public sector PHC facility utilization, OOPE and total and net benefits were more pro-rich than the un-weighted, but not statistically significant.
Conclusion: Despite variations in PHC reform strategies across study countries, some common characteristics emerge, many of which also find mention in India’s current PHC reforms. Enhancing structural and clinical quality of public sector PHC facilities in Bihar is unlikely to reduce bypassing; though availability of drugs is imperative to increase utilization. There is a need to monitor equality of quality of care available to the community
Academic Performance Among First-Generation Students In Occupational Therapy
No full textFirst-generation students at U.S. universities have lower academic performance than their continuing-generation counterparts. Low academic performance among students in allied health programs places students at high risk for attrition, leaving the healthcare community with a shortage of healthcare professionals, which has negative repercussions on the community. This study examined the factors contributing to low academic performance among first-generation students in higher education. A mixed-methods needs assessment revealed that first-generation students in occupational therapy had low academic engagement, social integration, and academic self-efficacy as it pertained to their self-regulatory processes. The intervention focused on improving the use of academic self-regulatory strategies and confidence using those strategies for first-generation students in occupational therapy. The program encompassed components of Zimmerman’s self-regulated learning model: forethought (task analysis and setting goals), performance (self-monitoring performance), and self-reflection (evaluating one’s progress and adjusting one’s strategies). Ten students participated in the academic self-regulation program. A mixed methods study examined the process and outcome evaluations using a qualitative open- ended questionnaire and quantitative survey. Quantitatively, a one-group pretest-posttest quasi- experimental design was used to examine any changes in the participants’ use of the academic self-regulatory strategies and level of confidence in using those strategies via quantitative surveys. The program improved the participants' use of academic self-regulatory strategies and confidence using those strategies. Findings from this study can inform occupational therapy programs about the benefits of an academic self-regulation program on the students’ learning, which has implications for their academic performance and overall success in the program
ETHNIC AND RACIAL DISPARITIES IN PEDIATRIC MENTAL HEALTH ACCESS AND ADEQUACY OF HEALTH INSURANCE
No full textBackground: The U.S. mental health care system is challenged by the need to be responsive to the ethnic and cultural diversity of families and the desire to combat the persistence of ethnic/racial disparities. Consequently, racial/ethnic minority children in the United States are more likely than non-Hispanic White children to have severe and persistent mental, emotional, developmental or behavioral disorders and less likely to access mental health services. This dissertation examines racial/ethnic differences in access to mental health services for children with mental, emotional, behavioral, or developmental disorders and the adequacy of health insurance coverage to meet their needs. Methods: This dissertation begins with a chapter on the background and significance of this topic. The first manuscript discusses the current state of pediatric mental health care, underlining the challenges and potential obstacles for racial/ethnic minority families to access care. The second manuscript examines racial/ethnic disparities in children receiving any mental health services and difficulties in obtaining mental health care. The third manuscript focused on perceived adequacy of health insurance coverage to meet their child’s needs. Results: This study found that being a racial/ethnic minority increases the likelihood of parents reporting difficulty obtaining mental health services and having inadequate insurance coverage. Conclusion: Disparities in mental health care for racial/ethnic minorities represents a serious public health concern. Initiatives to improve access to mental health care for racial/ethnic minorities should recognize these disparities and address the lack of culturally appropriate services within the health care system and health insurance policies