Browsing by Subject "Development"
Now showing 1 - 10 of 80
Results Per Page
Sort Options
Item A Conserved Female-Specific Requirement for the GGT Gene in Mosquito Larvae Facilitates RNAi-Mediated Sex Separation in Multiple Species of Disease Vector Mosquitoes(MDPI, 2022-01-27) Mysore, Keshava; Sun, Longhua; Li, Ping; Roethele, Joseph B.; Misenti, Joi K.; Kosmach, John; Igiede, Jessica; Duman-Scheel, Molly; Medical and Molecular Genetics, School of MedicineAlthough several emerging mosquito control technologies are dependent on mass releases of adult males, methods of sex-sorting that can be implemented globally have not yet been established. RNAi screens led to the discovery of siRNA, which targets gamma-glutamyl transpeptidase (GGT), a gene which is well conserved in multiple species of mosquitoes and located at the sex-determining M locus region in Aedes aegypti. Silencing the A. aegypti, Aedes albopictus, Anopheles gambiae, Culex pipiens, and Culex quinquefasciatus GGT genes resulted in female larval death, with no significant impact on male survival. Generation of yeast strains that permitted affordable expression and oral delivery of shRNA corresponding to mosquito GGT genes facilitated larval target gene silencing and generated significantly increased 5 males:1 female adult ratios in each species. Yeast targeting a conserved sequence in Culex GGT genes was incorporated into a larval mass-rearing diet, permitting the generation of fit adult male C. pipiens and C. quinquefasciatus, two species for which labor-intensive manual sex separation had previously been utilized. The results of this study indicate that female-specific yeast-based RNAi larvicides may facilitate global implementation of population-based control strategies that require releases of sterile or genetically modified adult males, and that yeast RNAi strategies can be utilized in various species of mosquitoes that have progressed to different stages of sex chromosome evolution.Item A Developmentally-Informative Genome-wide Association Study of Alcohol Use Frequency(Springer, 2024) Thomas, Nathaniel S.; Gillespie, Nathan A.; Chan, Grace; Edenberg, Howard J.; Kamarajan, Chella; I-Chun Kuo, Sally; Miller, Alex P.; Nurnberger, John I., Jr.; Tischfield, Jay; Dick, Danielle M.; Salvatore, Jessica E.; Medical and Molecular Genetics, School of MedicineContemporary genome-wide association study (GWAS) methods typically do not account for variability in genetic effects throughout development. We applied genomic structural equation modeling to combine developmentally-informative phenotype data and GWAS to create polygenic scores (PGS) for alcohol use frequency that are specific to developmental stage. Longitudinal cohort studies targeted for gene-identification analyses include the Collaborative Study on the Genetics of Alcoholism (adolescence n = 1,118, early adulthood n = 2,762, adulthood n = 5,255), the National Longitudinal Study of Adolescent to Adult Health (adolescence n = 3,089, early adulthood n = 3,993, adulthood n = 5,149), and the Avon Longitudinal Study of Parents and Children (ALSPAC; adolescence n = 5,382, early adulthood n = 3,613). PGS validation analyses were conducted in the COGA sample using an alternate version of the discovery analysis with COGA removed. Results suggest that genetic liability for alcohol use frequency in adolescence may be distinct from genetic liability for alcohol use frequency later in developmental periods. The age-specific PGS predicts an increase of 4 drinking days per year per PGS standard deviation when modeled separately from the common factor PGS in adulthood. The current work was underpowered at all steps of the analysis plan. Though small sample sizes and low statistical power limit the substantive conclusions that can be drawn regarding these research questions, this work provides a foundation for future genetic studies of developmental variability in the genetic underpinnings of alcohol use behaviors and genetically-informed, age-matched phenotype prediction.Item A framework for translating tauopathy therapeutics: Drug discovery to clinical trials(Wiley, 2024) Feldman, Howard H.; Cummings, Jeffrey L.; Boxer, Adam L.; Staffaroni, Adam M.; Knopman, David S.; Sukoff Rizzo, Stacey J.; Territo, Paul R.; Arnold, Steven E.; Ballard, Clive; Beher, Dirk; Boeve, Bradley F.; Dacks, Penny A.; Diaz, Kristophe; Ewen, Colin; Fiske, Brian; Gonzalez, M. Isabel; Harris, Glenn A.; Hoffman, Beth J.; Martinez, Terina N.; McDade, Eric; Nisenbaum, Laura K.; Palma, Jose-Alberto; Quintana, Melanie; Rabinovici, Gil D.; Rohrer, Jonathan D.; Rosen, Howard J.; Troyer, Matthew D.; Kim, Doo Yeon; Tanzi, Rudolph E.; Zetterberg, Henrik; Ziogas, Nick K.; May, Patrick C.; Rommel, Amy; Medicine, School of MedicineThe tauopathies are defined by pathological tau protein aggregates within a spectrum of clinically heterogeneous neurodegenerative diseases. The primary tauopathies meet the definition of rare diseases in the United States. There is no approved treatment for primary tauopathies. In this context, designing the most efficient development programs to translate promising targets and treatments from preclinical studies to early-phase clinical trials is vital. In September 2022, the Rainwater Charitable Foundation convened an international expert workshop focused on the translation of tauopathy therapeutics through early-phase trials. Our report on the workshop recommends a framework for principled drug development and a companion lexicon to facilitate communication focusing on reproducibility and achieving common elements. Topics include the selection of targets, drugs, biomarkers, participants, and study designs. The maturation of pharmacodynamic biomarkers to demonstrate target engagement and surrogate disease biomarkers is a crucial unmet need. HIGHLIGHTS: Experts provided a framework to translate therapeutics (discovery to clinical trials). Experts focused on the "5 Rights" (target, drug, biomarker, participants, trial). Current research on frontotemporal degeneration, progressive supranuclear palsy, and corticobasal syndrome therapeutics includes 32 trials (37% on biologics) Tau therapeutics are being tested in Alzheimer's disease; primary tauopathies have a large unmet need.Item A pilot study of the utility of a hospital-based school program for pediatric patients with cardiac diagnoses(Frontiers Media, 2024-12-11) Thibodaux, Lia K.; Orr, Ashley L.; Reisinger, Debra L.; Fodstad, Jill; Xu, Guang; Wikel, Kristin; Curtin, Michelle; Psychiatry, School of MedicineIntroduction: Pediatric patients with complex cardiac diagnoses are at increased risk for physical, cognitive, and developmental complications. Formalized school support [i.e., individualized education programs (IEPs), Section 504 Accommodation Plans (Section 504 Plans)] that addresses the needs of these patients is necessary, and hospital-based school programs (HBSPs) have the potential to bolster the acquisition of academic support. In this pilot study, we look at the impact of one such HBSP. Methods: Retrospective demographic and school support data for pediatric cardiac patients were analyzed. Results: Our sample included 29 pediatric cardiac patients spanning two academic years. These patients had 100 HBSP encounters and 82 inpatient and 12 outpatient encounters, with 68.9% of patients having multiple encounters in a single year and 44.8% of patients being seen in both years. The HBSP made recommendations for patients to receive IEPs (N = 8) and Section 504 Plans (N = 13). The patients also submitted requests for medical homebound(N = 27), obtaining releases of information (N = 39), submitting medical reports (N = 10), and completing certificates of incapacity (N = 7). Statistical analyses revealed no significant relationships with patients entering or receiving a recommendation for an IEP or Section 504 Plan in any of their encounters with the HBSP on the basis of sex, race/ethnicity, school level, or rates of encounters in this sample. Discussion: Similar to previous studies, these patients had high rates of IEPs/Section 504 Plans in place and continued to receive school recommendations through the HBSP. A high use of the HBSP was seen in the total number of encounters and communications (i.e., submitting to the school of record requests for classroom placement changes via medical homebound). Working with the HBSP provided access to information, formal support recommendations, and communication between medical and school settings in the form of changes in school status.Item Access to Knowledge in Brazil: New Research on Intellectual Property, Innovation and Development(Bloomsbury Academic, 2010) Shaver, LeaAccess to knowledge is a demand for democratic participation, for global inclusion and for economic justice. It is a reaction to the excessively restrictive international IP regime put in place over the last two decades, which seeks to reassert the public interest in a more balanced information policy. With sponsorship from the Ford Foundation, the Information Society Project at Yale Law School has embarked on a new series of access to knowledge research, in partnership with colleagues in Brazil, China, Egypt, Ethiopia, India, Russia and South Africa. The first book in this series, Access to Knowledge in Brazil, focuses on current issues in intellectual property, innovation and development policy from a Brazilian perspective. Each chapter is authored by scholars from the Fundação Getulio Vargas law schools in São Paolo and Rio de Janeiro and examines a policy area that significantly impacts access to knowledge in the country. These include: exceptions and limitations to copyright, free software and open business models, patent reform and access to medicines, and open innovation in the biotechnology sector.Item Access to Knowledge in Egypt: New Research on Intellectual Property, Innovation and Development(Bloomsbury Academic, 2010) Shaver, Lea; Rizk, NaglaThe conventional wisdom in Egypt examines the issue of intellectual property solely as a question of policing and enforcement. The high levels of protection indicated by the WTO Agreement on Trade Related Aspects of Intellectual Property Rights are unquestioningly assumed to be desirable. Policy debates - and all too often academic ones as well - focus only on the questions of how to more efficiently tighten IP protection and crack down on piracy. Yet a more critical examination is urgently needed, whereby IP law, policy, and practice are viewed from a development perspective, rather than from an enforcement perspective. This volume takes on this endeavor. It offers the first examination of IP issues in Egypt adopting a multidisciplinary bottom-up approach that aims at maximizing access and contribution to knowledge, and in turn, promoting development. Bringing rigorous empirical research to bear on unquestioned ideologies, the collaborating authors question the conventional wisdom that more IP protection is necessarily better for innovation and development.Item Advances in pediatric acute kidney injury pharmacology and nutrition: a report from the 26th Acute Disease Quality Initiative (ADQI) consensus conference(Springer, 2024) Wong Vega, Molly; Starr, Michelle C.; Brophy, Patrick D.; Devarajan, Prasad; Soranno, Danielle E.; Akcan‑Arikan, Ayse; Basu, Rajit; Goldstein, Stuart L.; Charlton, Jennifer R.; Barreto, Erin; Pediatrics, School of MedicineBackground: In the past decade, there have been substantial advances in our understanding of pediatric AKI. Despite this progress, large gaps remain in our understanding of pharmacology and nutritional therapy in pediatric AKI. Methods: During the 26th Acute Disease Quality Initiative (ADQI) Consensus Conference, a multidisciplinary group of experts reviewed the evidence and used a modified Delphi process to achieve consensus on recommendations for gaps and advances in care for pharmacologic and nutritional management of pediatric AKI. The current evidence as well as gaps and opportunities were discussed, and recommendations were summarized. Results: Two consensus statements were developed. (1) High-value, kidney-eliminated medications should be selected for a detailed characterization of their pharmacokinetics, pharmacodynamics, and pharmaco-"omics" in sick children across the developmental continuum. This will allow for the optimization of real-time modeling with the goal of improving patient care. Nephrotoxin stewardship will be identified as an organizational priority and supported with necessary resources and infrastructure. (2) Patient-centered outcomes (functional status, quality of life, and optimal growth and development) must drive targeted nutritional interventions to optimize short- and long-term nutrition. Measures of acute and chronic changes of anthropometrics, body composition, physical function, and metabolic control should be incorporated into nutritional assessments. Conclusions: Neonates and children have unique metabolic and growth parameters compared to adult patients. Strategic investments in multidisciplinary translational research efforts are required to fill the knowledge gaps in nutritional requirements and pharmacological best practices for children with or at risk for AKI.Item Age-Related Changes in MicroRNA Expression and Pharmacogenes in Human Liver(Wiley, 2015-08) Burgess, Kimberly S.; Philips, Santosh; Benson, Eric A.; Desta, Zeruesenay; Gaedigk, Andrea; Gaedigk, Roger; Segar, Matthew W.; Liu, Yunlong; Skaar, Todd C.; Department of Pharmacology and Toxicology, IU School of MedicineDevelopmental changes in the liver can significantly impact drug disposition. Due to the emergence of microRNAs (miRNAs) as important regulators of drug disposition gene expression, we studied age-dependent changes in miRNA expression. Expression of 533 miRNAs was measured in 90 human liver tissues (fetal, pediatric [1-17 years], and adult [28-80 years]; n = 30 each). In all, 114 miRNAs were upregulated and 72 were downregulated from fetal to pediatric, and 2 and 3, respectively, from pediatric to adult. Among the developmentally changing miRNAs, 99 miRNA-mRNA interactions were predicted or experimentally validated (e.g., hsa-miR-125b-5p-CYP1A1; hsa-miR-34a-5p-HNF4A). In human liver samples (n = 10 each), analyzed by RNA-sequencing, significant negative correlations were observed between the expression of >1,000 miRNAs and mRNAs of drug disposition and regulatory genes. Our data suggest a mechanism for the marked changes in hepatic gene expression between the fetal and pediatric developmental periods, and support a role for these age-dependent miRNAs in regulating drug disposition.Item Astrocyte Ensheathment of Calyx-Forming Axons of the Auditory Brainstem Precedes Accelerated Expression of Myelin Genes and Myelination by Oligodendrocytes(Wiley, 2024) Heller, Daniel T.; Kolson, Douglas R.; Brandebura, Ashley N.; Amick, Emily M.; Wan, Jun; Ramadan, Jad; Holcomb, Paul S.; Liu, Sheng; Deerinck, Thomas J.; Ellisman, Mark H.; Qian, Jiang; Mathers, Peter H.; Spirou, George A.; Medical and Molecular Genetics, School of MedicineEarly postnatal brain development involves complex interactions among maturing neurons and glial cells that drive tissue organization. We previously analyzed gene expression in tissue from the mouse medial nucleus of the trapezoid body (MNTB) during the first postnatal week to study changes that surround rapid growth of the large calyx of Held (CH) nerve terminal. Here, we present genes that show significant changes in gene expression level during the second postnatal week, a developmental timeframe that brackets the onset of airborne sound stimulation and the early stages of myelination. Gene Ontology analysis revealed that many of these genes are related to the myelination process. Further investigation of these genes using a previously published cell type-specific bulk RNA-Seq data set in cortex and our own single-cell RNA-Seq data set in the MNTB revealed enrichment of these genes in the oligodendrocyte lineage (OL) cells. Combining the postnatal day (P)6-P14 microarray gene expression data with the previously published P0-P6 data provided fine temporal resolution to investigate the initiation and subsequent waves of gene expression related to OL cell maturation and the process of myelination. Many genes showed increasing expression levels between P2 and P6 in patterns that reflect OL cell maturation. Correspondingly, the first myelin proteins were detected by P4. Using a complementary, developmental series of electron microscopy 3D image volumes, we analyzed the temporal progression of axon wrapping and myelination in the MNTB. By employing a combination of established ultrastructural criteria to classify reconstructed early postnatal glial cells in the 3D volumes, we demonstrated for the first time that astrocytes within the mouse MNTB extensively wrap the axons of the growing CH terminal prior to OL cell wrapping and compaction of myelin. Our data revealed significant expression of several myelin genes and enrichment of multiple genes associated with lipid metabolism in astrocytes, which may subserve axon wrapping in addition to myelin formation. The transition from axon wrapping by astrocytes to OL cells occurs rapidly between P4 and P9 and identifies a potential new role of astrocytes in priming calyceal axons for subsequent myelination.Item Astrocytes Regulate the Development and Maturation of Retinal Ganglion Cells Derived from Human Pluripotent Stem Cells(Elsevier, 2019-02-12) VanderWall, Kirstin B.; Vij, Ridhima; Ohlemacher, Sarah K.; Sridhar, Akshayalakshmi; Fligor, Clarisse M.; Feder, Elyse M.; Edler, Michael C.; Baucum, Anthony J.; Cummins, Theodore R.; Meyer, Jason S.; Biology, School of ScienceRetinal ganglion cells (RGCs) form the connection between the eye and the brain, with this connectivity disrupted in numerous blinding disorders. Previous studies have demonstrated the ability to derive RGCs from human pluripotent stem cells (hPSCs); however, these cells exhibited some characteristics that indicated a limited state of maturation. Among the many factors known to influence RGC development in the retina, astrocytes are known to play a significant role in their functional maturation. Thus, efforts of the current study examined the functional maturation of hPSC-derived RGCs, including the ability of astrocytes to modulate this developmental timeline. Morphological and functional properties of RGCs were found to increase over time, with astrocytes significantly accelerating the functional maturation of hPSC-derived RGCs. The results of this study clearly demonstrate the functional and morphological maturation of RGCs in vitro, including the effects of astrocytes on the maturation of hPSC-derived RGCs.