Region-specific tauopathy and synucleinopathy in brain of the alpha-synuclein overexpressing mouse model of Parkinson's disease

<p>Abstract</p> <p>Background</p> <p>α-synuclein [α-Syn]-mediated activation of GSK-3β leading to increases in hyperphosphorylated Tau has been shown by us to occur in striata of Parkinson's diseased [PD] patients and in animal models of PD. In Alzheimer's disease, tauopathy exists in several brain regions; however, the pattern of distribution of tauopathy in other brain regions of PD or in animal models of PD is not known. The current studies were undertaken to analyze the distribution of tauopathy in different brain regions in a widely used mouse model of PD, the α-Syn overexpressing mouse.</p> <p>Results</p> <p>High levels of α-Syn levels were seen in the brain stem, with a much smaller increase in the frontal cortex; neither cerebellum nor hippocampus showed any overexpression of α-Syn. Elevated levels of p-Tau, hyperphosphorylated at Ser202, Ser262 and Ser396/404, were seen in brain stem, with lower levels seen in hippocampus. In both frontal cortex and cerebellum, increases were seen only in p-Ser396/404 Tau, but not in p-Ser202 and p-Ser262. p-GSK-3β levels were not elevated in any of the brain regions, although total GSK-3β was elevated in brain stem. p-p38MAPK levels were unchanged in all brain regions examined, while p-ERK levels were elevated in brain stem, hippocampus and cerebellum, but not the frontal cortex. p-JNK levels were increased in brain stem and cerebellum but not in the frontal cortex or hippocampus. Elevated levels of free tubulin, indicating microtubule destabilization, were seen only in the brain stem.</p> <p>Conclusion</p> <p>Our combined data suggest that in this animal model of PD, tauopathy, along with microtubule destabilization, exists primarily in the brain stem and striatum, which are also the two major brain regions known to express high levels of α-Syn and undergo the highest levels of degeneration in human PD. Thus, tauopathy in PD may have a very restricted pattern of distribution.</p

Inclusive leadership in early childhood education: practices and perspectives of program administrators

There is an overwhelming amount of evidence to support the inclusion of children with disabilities as best practice in early childhood education (ECE) programs (Council for Exceptional Children, Division of Early Childhood (DEC)/National Association for the Education of Young Children (NAEYC), 2009; Green, Terry, &amp; Gallagher, 2014; Strain &amp; Bovey, 2011; Rafferty, Piscitelli, &amp; Boettcher, 2003). Unfortunately, data indicates that a majority of preschool children with disabilities receive special education services in separate settings (U.S. Department of Education, 2013). While a wealth of research provides evidence of how teachers can support inclusion in their classrooms, there is very little research exploring how leaders in the field promote inclusion within their programs. The purpose of this phenomenological case study was to gain insight into the perspectives of early childhood leaders about practices that facilitate inclusion. Leadership theory was used as a framework to explore data collected in the form of interviews, observations, and documents that revealed descriptions of contexts in which participants led as well as emerging structural and textural themes for and across participants to capture the essence of leadership practices in inclusive ECE programs. Implications for practice and directions for future research are discussed

External Device to Incrementally Skid the Habitat (E-DISH)

A Mars habitat transport system was designed as part of the NASA Mars exploration program. The transport system, the External Device to Incrementally Skid the Habitat (E - DISH), will be used to transport Mars habitats from their landing sites to the colony base and will be detached after unloading. The system requirements for Mars were calculated and scaled for model purposes. Specific model materials are commonly found and recommendations for materials for the Mars design are included

Noncanonical binding of BiP ATPase domain to Ire1 and Perk is dissociated by unfolded protein CH1 to initiate ER stress signaling

The unfolded protein response (UPR) is an essential cell signaling system that detects the accumulation of misfolded proteins within the endoplasmic reticulum (ER) and initiates a cellular response in order to maintain homeostasis. How cells detect the accumulation of misfolded proteins remains unclear. In this study, we identify a noncanonical interaction between the ATPase domain of the ER chaperone BiP and the luminal domains of the UPR sensors Ire1 and Perk that dissociates when authentic ER unfolded protein CH1 binds to the canonical substrate binding domain of BiP. Unlike the interaction between chaperone and substrates, we found that the interaction between BiP and UPR sensors was unaffected by nucleotides. Thus, we discover that BiP is dual functional UPR sensor, sensing unfolded proteins by canonical binding to substrates and transducing this event to noncanonical, signaling interaction to Ire1 and Perk. Our observations implicate BiP as the key component for detecting ER stress and suggest an allosteric mechanism for UPR induction.</jats:p

Large conformational changes in MutS during DNA scanning, mismatch recognition and repair signalling: Conformations of MutS during DNA MMR activation

MutS protein recognizes mispaired bases in DNA and targets them for mismatch repair. Little is known about the transient conformations of MutS as it signals initiation of repair. We have used single-molecule fluorescence resonance energy transfer (FRET) measurements to report the conformational dynamics of MutS during this process. We find that the DNA-binding domains of MutS dynamically interconvert among multiple conformations when the protein is free and while it scans homoduplex DNA. Mismatch recognition restricts MutS conformation to a single state. Steady-state measurements in the presence of nucleotides suggest that both ATP and ADP must be bound to MutS during its conversion to a sliding clamp form that signals repair. The transition from mismatch recognition to the sliding clamp occurs via two sequential conformational changes. These intermediate conformations of the MutS:DNA complex persist for seconds, providing ample opportunity for interaction with downstream proteins required for repair