Selective and specific activation of Rab5 during endocytosis of receptor tyrosine kinases

The Rab family of proteins are low molecular weight GTPases that have the ability to switch between GTP- (active) and GDP- (inactive) bound form, and in that sense act as molecular switches. Through distinct localization on various vesicles and organelles and by cycling through GTP/GDP bound forms, Rabs are able to recruit and activate numerous effector proteins, both spatially and temporally, and hence behave as key regulators of trafficking in both endocytic and biosynhtetic pathways. The Rab5 protein has been shown to regulate transport from plasma membrane to the early endosome as well as activate signaling pathways from the early endosome. This dissertation focused on understanding Rab5 activation via endocytosis of receptor tyrosine kinases (RTKs). First, tyrosine kinase activity of RTKs was linked to endosome fusion by demonstrating that tyrosine kinase inhibitors block endosome fusion and activation of Rab5, and a constitutively active form of Rab5 is able to rescue endosome fusion. However, depending on how much ligand is available at the cell surface, the receptor-ligand complexes can be internalized via a number of distinct pathways. Similarly, Rab5 was activated in a ligand-dependent concentration dependent manner via clathrin- and caveolin-mediated pathways, as well as a pathway independent of both. However, overexpression Rabex-5, a nucleotide exchange factor for Rab5, is able to rescue activation even when all of the pathways of EGF-receptor internalization were blocked. Next, the three naturally occurring splice variants of Rabex-5 selectively activated Rab5. Lastly, Rabex-5 inhibits differentiation of 3T3-L1 and PC12 cells through 1) degradation of signaling endosome via Rab5-dependent fusion with the early endosome, 2) and inhibition of signaling cascade via ubiquitination of Ras through the ZnF domain at the N-terminus of Rabex-5. In conclusion, these data shed light on complexity of the endosomal trafficking system where tyrosine kinase activity of the receptor is able to affect endosome fusion; how different endocytic pathways affect activation of one of the key regulators of early endocytic events; and how selective activation of Rab5 via Rabex-5 can control adipogenesis and neurogenesis.

The Effect of Mobile Technology as an Active Student Response System on the Acquisition of U.S. History Content of Secondary Students with Specific Learning Disabilities

Students with specific learning disabilities (SLD) typically learn less history content than their peers without disabilities and show fewer learning gains. Even when they are provided with the same instructional strategies, many students with SLD struggle to grasp complex historical concepts and content area vocabulary. Many strategies involving technology have been used in the past to enhance learning for students with SLD in history classrooms. However, very few studies have explored the effectiveness of emerging mobile technology in K-12 history classrooms. This study investigated the effects of mobile devices (iPads) as an active student response (ASR) system on the acquisition of U.S. history content of middle school students with SLD. An alternating treatments single subject design was used to compare the effects of two interventions. There were two conditions and a series of pretest probesin this study. The conditions were: (a) direct instruction and studying from handwritten notes using the interactive notebook strategy and (b) direct instruction and studying using the Quizlet App on the iPad. There were three dependent variables in this study: (a) percent correct on tests, (b) rate of correct responses per minute, and (c) rate of errors per minute. A comparative analysis suggested that both interventions (studying from interactive notes and studying using Quizlet on the iPad) had varying degrees of effectiveness in increasing the learning gains of students with SLD. In most cases, both interventions were equally effective. During both interventions, all of the participants increased their percentage correct and increased their rate of correct responses. Most of the participants decreased their rate of errors. The results of this study suggest that teachers of students with SLD should consider a post lesson review in the form of mobile devices as an ASR system or studying from handwritten notes paired with existing evidence-based practices to facilitate students’ knowledge in U.S. history. Future research should focus on the use of other interactive applications on various mobile operating platforms, on other social studies subjects, and should explore various testing formats such as oral question-answer and multiple choice.

Effects of Repeated Readings on Reading Abilities of English Language Learners with Specific Learning Disabilities

This study investigated the effects of repeated readings on the reading abilities of 4, third-, fourth-, and fifth-grade English language learners (ELLs) with specific learning disabilities (SLD). A multiple baseline probe design across subjects was used to explore the effects of repeated readings on four dependent variables: reading fluency (words read correctly per minute; wpm), number of errors per minute (epm), types of errors per minute, and answer to literal comprehension questions. Data were collected and analyzed during baseline, intervention, generalization probes, and maintenance probes. Throughout the baseline and intervention phases, participants read a passage aloud and received error correction feedback. During baseline, this was followed by fluency and literal comprehension question assessments. During intervention, this was followed by two oral repeated readings of the passage. Then the fluency and literal comprehension question assessments were administered. Generalization probes followed approximately 25% of all sessions and consisted of a single reading of a new passage at the same readability level. Maintenance sessions occurred 2-, 4-, and 6-weeks after the intervention ended. The results of this study indicated that repeated readings had a positive effect on the reading abilities of ELLs with SLD. Participants read more wpm, made fewer epm, and answered more literal comprehension questions correctly. Additionally, on average, generalization scores were higher in intervention than in baseline. Maintenance scores were varied when compared to the last day of intervention, however, with the exception of the number of hesitations committed per minute maintenance scores were higher than baseline means. This study demonstrated that repeated readings improved the reading abilities of ELLs with SLD and that gains were generalized to untaught passages. Maintenance probes 2-, 4-, and 6- weeks following intervention indicated that mean reading fluency, errors per minute, and correct answers to literal comprehensive questions remained above baseline levels. Future research should investigate the use of repeated readings in ELLs with SLD at various stages of reading acquisition. Further, future investigations may examine how repeated readings can be integrated into classroom instruction and assessments.