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The Role Of Adolescent Dating Aggression In The Longitudinal Associations Between Girls’ Exposure To Interpersonal Violence And Subsequent Appraisals Of Romantic Conflict
No full textRomantic relationships are a central arena of adolescent development, providing intimacy and requiring adolescents to learn how to manage conflict. Adolescents\u27 conflict management reflects their interpersonal competencies and mental representations of relationships which are often shaped by interpersonal histories, including adverse experiences. For instance, childhood interpersonal violence exposure (IVE) and adolescent dating aggression are linked to how adolescents’ think about and behave during romantic conflict. The current study examined how childhood IVE and adolescent dating aggression influence how adolescent girls (N=67) think about romantic conflict. Using a virtual reality task, real-time responses to age-typical romantic conflict were assessed. It was hypothesized that adolescent dating aggression victimization would mediate the relationship between childhood IVE and threat appraisals or anticipated aggression during romantic conflict. However, results of the current study did not support these hypotheses. The current study findings go against prior literature that supports relations among these constructs. I discuss potential explanations for the nonsignificant results, including methodological differences between the current study and the broader body of literature and explore alternative models. Additionally, strengths and limitations of the virtual reality procedure are discussed. Overall, the current study is a call for additional work aimed toward identifying the individual difference factors that lead some adolescents to make threat appraisals during romantic conflict
A Two-Pronged Approach To Improving Hydrocephalus Treatment: Utilizing A Multicenter Pediatric Shunt Biobank And Building A Choroid Plexus-On-A-Chip
No full textHydrocephalus is a neurological condition characterized by the buildup of cerebrospinal fluid (CSF) in the ventricles of the brain, causing increased intracranial pressure (ICP) and dilatation of the ventricles. The estimated incidence of hydrocephalus in the United States is 1 per 1100 people. The current gold-standard of treatment is ventricular shunting. Patients have a severely diminished quality of life and suffer from long-term neurologic deficits because of the high failure rate of ventricular shunts; of the 30,000 shunts placed annually in the United States, 98% fail within ten years. A major cause of failure is the obstruction of ventricular catheters (VC) by tissue, restricting its drainage of CSF. Although multiple studies have tried to identify factors that cause VC failure, the mechanisms by which tissue obstructs the holes of the VC are not completely understood. Additionally, no successful non-surgical or pharmacological treatment strategies exist, primarily because we do not understand how CSF secretion is modulated by the choroid plexus (CP). Specifically, we need to understand the role of the CP’s ion and water transporters in CSF secretion, and their dysregulation by hydrocephalus-induced inflammation. To address these issues, we chose a two-pronged approach to the problem of hydrocephalus treatment: reforming the current gold standard of treatment (shunts), and revolutionizing treatment strategies by building a model to understand CSF secretion.
In the first prong of this work, we characterized VC obstructions and identified links to clinical factors. 343 VCs and their associated clinical data were collected from five hospital centers. Each hole on the VCs was classified by degree of tissue obstruction and subjected to microscopic analysis. Univariate, multivariate, and binned analyses were conducted to test for associations between clinical data and degree of VC obstruction. Our data show that the age of the patient at their first surgery, entry site of the VC, contact of the VC with the ventricular wall and length of time a VC is implanted are factors that influence the degree of VC obstruction. Number of lifetime revisions and duration of implantation are correlated with the degree of VC obstruction, but do not predict it. We also explored the relationship between ventricular obstruction and ventricular dilation and flow through the holes of the catheter. The tissue aggregates obstructing VCs are composed predominantly of astrocytes and macrophages.
In the second prong of this work, we developed a “CP-on-a-chip”, a microfluidic, 2-compartment model of the blood-cerebrospinal fluid barrier. The model provides the mechanical cue of physiological shear in the luminal and abluminal compartments, maintains physiologically accurate tissue-fluid ratios and allows us to track and manipulate secretion and barrier function of the CP. Immunofluorescent labeling has confirmed that CP epithelial cells grown inside the abluminal compartment orient themselves correctly and express critical tight junction components, establishing a low permeability, monolayer. We have also successfully simulated secretion of fluid across compartments. Future work involves studying inflammation mediated barrier integrity loss and subsequent CSF dysregulation as it pertains to hydrocephalus
There Is No Transformation Without Trust: A Qualitative Study Examining The Relationship Between State Education Agents And School Leaders
No full textThe economic vitality of our nation is intricately linked to the strength of our educational system. High performing schools ensure that students transition into the workforce, reinforcing the economic fabric of our country. On the contrary, low performing schools pose a threat to our economic wellbeing, undermining the very threads that hold our nation together. Since the Lyndon B. Johnson administration, significant efforts have been made at both national and state levels to combat the educational and economic challenges stemming from low performance. In Michigan, where charter schools represent a substantial portion of low performing schools, the state government has implemented a partnership model under the Every Student Succeeds Act (ESSA) to support struggling schools. However, challenges persist, particularly in fostering trust and collaboration between state education agents (SAs) and school leaders (SLs). This qualitative study examines the historical context of state takeovers in Michigan, exploring policies, strategies, and the role of trust in stakeholder relationships. Using the Relational Trust Theory (RTT) as a framework\, the research identifies best practices for cultivating trust in partnership agreements. The study presents findings from semi-structured interviews with ten participants, including SAs and SLs, alongside a comprehensive document review of the Partnership Agreement to provide insights into the challenges and opportunities within the model’s implementation. The study concludes that fostering trust through transparency, sustained support, and mutual accountability is crucial for the long-term success of the Partnership Agreements. These findings add to the discourse on educational policy effectiveness and provide recommendations for enhancing collaborative partnerships in school reform initiatives
Risk Appraisal: An Investigation Of Personality Traits And Prior Injury On Thrill And Adventure Seeking Behavior In A High-Risk Modern Circus Performance Art Task
No full textIntroduction. Individuals make decisions every day that involve some assessment of risk.. Relevant psychological factors that require a deeper investigation include sensation seeking (SS), personality traits, anxiety, and self-efficacy (SE). The theoretical framework for the study is the biopsychosocial model of challenge and threat (BPSCT). Much of risk appraisal research has been done in a lab or on a computer, while this study presented a relevant, novel, and innovative physical task that incorporated risk in an ecologically valid setting. Purpose. The purpose of this research study was to examine participants\u27 willingness to participate in a high-risk modern circus performance art task by investigating SS, extraversion, openness, neuroticism, conscientiousness, agreeableness, previous injury, HR, and BP as mediated by anticipatory anxiety, SE, and intention willingness. Methods. Participants completed multiple questionnaires including demographics, SSS V, Big Five Inventory, previous injury, STAI, a SE scale, and intention willingness, and had their HR and BP monitored. Behavior willingness was observed and grabbing the trapeze bar was viewed as someone believing they had the resources to complete the task (challenge state). Statistical analysis was a serial mediation model using the computational tool PROCESS. Results. There were 3 significant chains of mediation, two started with neuroticism and one with SBP. The indirect effect of neuroticism to anxiety to intention willingness to behavior willingness was significant (LLCI of -.1058 to a ULCI of -.0067). The indirect effect of neuroticism to SE to intention willingness to behavior willingness was also significant (LLCI of -.1633 to a ULCI of -.0008). The indirect effect of SBP change to intention willingness to behavior willingness was significant (LLCI of -.2109 to a ULCI of -.0351). Evaluating the specific frequencies revealed 21 participants (18.3%) scored 0 or remained seated, 2 participants (1.7%) stood up but did not take any steps toward the rig, and 92 participants (80%) grabbed the trapeze bar. Conclusion. Results reflected that both the psychological and physiological variables were both valuable. There was moderate support for the proposed serial mediation model and the study was able to narrow the gap between intention and behavior when it comes to risk-taking
Integrative Analysis Of Mettl And Cmtr1 Methyltransferases In Cancer
No full textHuman methyltransferase-like (METTL) proteins transfer methyl groups to nucleic acids, proteins, lipids, and other small molecules, subsequently playing important roles in various cellular processes. In Aim 1, we performed integrated genomic, transcriptomic, proteomic, and clinicopathological analyses of 34 METTLs in a cohort of primary tumor and cell line data. We identified a subset of METTL genes, notably METTL1, TMT1B, and NTMT1, with high frequencies of genomic amplification and/or up-regulation at the mRNA and protein levels in multiple human cancers. Higher METTL1 expression was associated with high-grade tumors and poor disease prognosis. Loss-of-function analysis in tumor cell lines indicated METTL1’s biological importance in cancer cell growth and survival. Functional annotation and pathway analysis of METTL1-associated proteins revealed that, in addition to the cofactor WDR4, RNA regulators and DNA packaging complexes may be functionally interconnected with METTL1 in human cancer. Our results provide new information for functional study of METTL alterations in human cancer and may lead to inhibitors that target cancer-promoting METTLs.
mRNA cap formation is a critical element in regulating mRNA function both in the nucleus and cytoplasm, and multiple mRNA capping genes have been associated with cancer. However, the role of the cap 2-O-metylation enzyme CMTR1 in cancer has not been significantly investigated. In Aim 2, we investigated CMTR1, finding that it is overexpressed at the RNA and protein level in multiple cancer types, as well as having significant survival effects. Using integrated genomic, transcriptomic, proteomic, and clinicopathological analyses, we find that CMTR1’s expression differs based on clinical subtype in multiple cancer types, and CMTR1’s post-translational modifications are also increased in tumor tissues. Using knockout and knockdown in vitro models, CMTR1 loss results in reduced 2-dimensional and anchorage-independent growth. RNA-seq showed that CMTR1 loss results in reduced expression of ribosomal protein and snoRNA host genes across multiple cell types. Since many of the downregulated genes are snoRNA hosts, we investigated if CMTR1 loss affects snoRNA levels; we find that CMTR1 loss reduced levels of selected snoRNAs. Together, these results suggest that CMTR1 is dysregulated in cancer and that further investigation of its suitability for targeting may be warranted
In Vitro Investigation Of Shunt Catheter Failure In Hydrocephalus Treatment
No full textHydrocephalus is a neurological condition precipitated by an abnormal buildup of cerebrospinalfluid (CSF) that may lead to neurologic injury or death if left untreated. It is estimated that hydrocephalus impacts between 1-2 out of 1000 infants in the United States alone, contributing to $2 billion in healthcare costs annually. The most common method of hydrocephalus management is the surgical insertion of a shunt system to redirect the extra CSF into the peritoneum. However, these interventions have high failure rates with 98% of surgical treatments failing after 10 years. Despite 70 years of continued efforts, shunts still fail at a shocking rate necessitating medical intervention and revision surgeries. To date, only a few studies investigated shunt failure in in-vitro or in-vivo models. There is a critical need for a highly reproducible, physiologically relevant in vitro model for hydrocephalus. This investigation directly addresses the need for a cost-effective high-throughput in-vitro model for hydrocephalus. Furthermore, the architecture of commercially available catheters is restricted by the limitations of manufacturing processes. Our investigation also addresses the critical need for an improved method to produce ventricular catheters. Utilizing the in-vitro model and ventricular catheter manufacturing process we investigated the hypothesis that shunt obstruction rate is reduced in ventricular catheters with lower inherent resistance. We also systematically investigated the impact of catheter architecture on the resistance of catheters. Our results demonstrated a statistically significant inverse correlation between survival time and relative resistance (R=-0.495, P=0.027). Furthermore, the presented results provided preliminary evidence of a hypothesis-driven approach to ventricular catheter architecture optimization. The Experimental catheter with reduced relative resistance had a longer survival time compared to commercially available ventricular catheters. These results also provide proof of principle for our fully integrated catheter production and testing setup that could be utilized in future investigations to further improve the survival of ventricular catheters
Biochemical, Structural, And Drug Design Studies Of Sars-Cov-2 3cl Protease
No full textPublic health responses to COVID-19 have taken a two-pronged approach, utilizing both prophylactic vaccines for prevention and therapeutic antivirals for intervention. Targeting the SARS-CoV-2 main protease (3CLpro/Mpro), a protein essential for viral polyprotein processing and, thus, replication and propagation, presents a promising avenue for antiviral drug development. Our research focuses on the design of second-generation direct-acting antiviral agents that inhibit this protease. Employing a combination of X-ray crystallography, computational techniques, and biochemical assays, we have identified potent lead molecules targeting the SARS-CoV-2 3CLpro, expanding the battery of inhibitors available to treat coronavirus infection. We report the design of inhibitors with nanomolar potency against SARS-CoV-2 3CLpro, supported by high-resolution co-crystal structures of the inhibitor-enzyme complexes, in silico docking analysis, in vitro biochemical data. We also report the development of in silico screens that have successfully identified potent SARS-CoV-2 3CLpro inhibitors and the development of compounds that inhibit SARS-CoV-2 3CLpro nirmatrelvir and ensitrelvir-resistant mutants. These findings pave the way to position our inhibitors as strong candidates for further development in the fight against COVID-19
Environmental Pollution And Early-Life Metabolic Programming
No full textSubstantial evidence demonstrates that parental pollutant exposures can induce harmful health effects in the offspring, including the predisposition to Type II Diabetes. As rates of Type II Diabetes continue to rise in younger populations, a crucial gap lies in understanding the role of parental influence in the etiology of later-life metabolic disease. Therefore, the central goal of this work was to determine how early life exposure to smoking level benzene, an endocrine-disrupting air pollutant, affects the metabolic health of offspring, and to identify potential developmental mechanisms involved in disease susceptibility. This goal was achieved using two models of early life air pollution exposure in mice, the first during pregnancy to represent maternal in utero pollutant exposure, the second in adult male mice representing pre-conceptional pollutant exposure. First, we assessed the effects of gestational benzene exposure on offspring in early postnatal life and adulthood. In offspring of benzene-exposed dams, we identified sex-specific developmental impairments in the neural circuitry central to metabolic control, associated with a neuroinflammatory response. In adulthood, offspring exhibited whole-body metabolic dysfunction, further apparent at the transcriptional level. To gain a deeper understanding of the effects of gestational benzene on microglial developmental programming, we then examined the transcriptional profiles of microglia from postnatal-aged offspring. Transcriptomic analyses revealed that gestational benzene exposure modulated IGF-1-related inflammatory, myelination, and glucose homeostatic processes in both sexes, with further sex-specific developmental effects. Finally, we sought to determine the contribution of the father to pollutant-induced metabolic dysfunction in offspring. We found that male offspring of benzene-exposed fathers showed a predisposition to metabolic imbalance when challenged with poor diet in adulthood, through the inheritance of pollutant-altered transcriptional signatures passed through the germline. In summary, our findings reveal that parental exposure to the pollutant benzene predisposes offspring to the development of Type II Diabetes through early-life metabolic reprogramming. This work calls for efforts to reduce environmental pollution levels and prevent the negative impact of pollution on the health of future generations
