Microtubule Modification Influences Cellular Response to amyloid-β Exposure

During the normal aging process, cytoskeletal changes such as a reduction in density or disruption of cytoskeletal components occur that can affect neuronal function. As aging is the biggest risk factor for Alzheimer\u27s disease (AD), this study sought to determine how microtubule (MT) modification influences cellular response upon exposure to β-amyloid1-42 (Aβ1-42), which is implicated in AD. The MT networks of hypothalamic GT1-7 neurons were modified by common disrupting or stabilizing drugs, and then the physical and mechanical properties of the modified neurons were determined. The MT modified neurons were then exposed to Aβ1-42 and the ability of the neurons to cope with this exposure was determined by a variety of biochemical assays. Flow cytometry studies indicated that MT disruption reduced the binding of Aβ1-42 to the plasma membrane by 45% per cell compared to neurons with stabilized or unaltered MTs. Although the cells with disrupted MTs experienced less peptide-membrane binding, they experienced similar or increased levels of cytotoxicity caused by the Aβ1-42 exposure. In contrast, MT stabilization delayed toxicity caused by Aβ1-42. These results demonstrate that MT modification significantly influences the ability of neurons to cope with toxicity induced by Aβ1-42

Pediatric diabetes consortium T1D New Onset ( NeOn ) study: clinical outcomes during the first year following diagnosis

Objective There have been few prospective, multicenter studies investigating the natural history of type 1 diabetes ( T1D ) from the time of diagnosis. The objective of this report from the Pediatric Diabetes Consortium ( PDC ) T1D New Onset ( NeOn ) study was to assess the natural history and clinical outcomes in children during the first year after diagnosis of T1D . Research design and methods: Clinical measures from the first year following diagnosis were analyzed for 857 participants (mean age 9.1 yr, 51% female, 66% non‐Hispanic White) not participating in an intervention study who had a HbA1c result at 12 months. Results Mean HbA1c ± SD was 102 ± 25 mmol/mol (11.4 ± 2.3%) at diagnosis, 55 ± 12 mmol/mol (7.2 ± 1.1%) at 3 months, 56 ± 15 mmol/mol (7.3 ± 1.3%) at 6 months and 62 ± 16 mmol/mol (7.8 ± 1.5%) at 12 months from diagnosis. A severe hypoglycemic ( SH ) event occurred in 31 (4%) participants (44 events, 5.2 events per 100 person‐years). Diabetic ketoacidosis ( DKA ) not including diagnosis occurred in 10 (1%) participants (13 events, 1.5 events per 100 person‐years). Conclusions After onset of T1D , mean HbA1c reaches its nadir at 3–6 months with a gradual increase through 12 months. SH and DKA are uncommon but still occur during the first year with T1D . Data from large cohorts, such as the PDC T1D NeOn study, provide important insights into the course of T1D during the first year following diagnosis, which will help to inform the development of models to target future interventions.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/107374/1/pedi12068.pd

Clinical outcomes in youth beyond the first year of type 1 diabetes: Results of the Pediatric Diabetes Consortium (PDC) type 1 diabetes new onset (NeOn) study

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138914/1/pedi12459.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138914/2/pedi12459_am.pd

Vitamin D status in youth with type 1 and type 2 diabetes enrolled in the Pediatric Diabetes Consortium (PDC) is not worse than in youth without diabetes

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134500/1/pedi12340.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134500/2/pedi12340_am.pd

A cross‐sectional view of the current state of treatment of youth with type 2 diabetes in the USA: enrollment data from the Pediatric Diabetes Consortium Type 2 Diabetes Registry

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136377/1/pedi12377_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136377/2/pedi12377.pd

Etiological Approach to Characterization of Diabetes Type: The SEARCH for Diabetes in Youth Study

OBJECTIVE To describe an etiologic approach to classification of diabetes types in youth based on the 1997 American Diabetes Association (ADA) framework, using data from the SEARCH for Diabetes in Youth Study

Development, validation and use of an insulin sensitivity score in youths with diabetes: the SEARCH for Diabetes in Youth study

The ability to measure insulin sensitivity across the phenotypic spectrum of diabetes may contribute to a more accurate characterisation of diabetes type. Our goal was to develop and validate an insulin sensitivity (IS) score using the euglycaemic–hyperinsulinaemic clamp in a subset (n=85) of 12– to 19-year-old youths with diabetes participating in the SEARCH study in Colorado, USA

Distinct Molecular Evolutionary Mechanisms Underlie the Functional Diversification of the Wnt and TGFβ Signaling Pathways

The canonical Wnt pathway is one of the oldest and most functionally diverse of animal intercellular signaling pathways. Though much is known about loss-of-function phenotypes for Wnt pathway components in several model organisms, the question of how this pathway achieved its current repertoire of functions has not been addressed. Our phylogenetic analyses of 11 multigene families from five species belonging to distinct phyla, as well as additional analyses employing the 12 Drosophila genomes, suggest frequent gene duplications affecting ligands and receptors as well as co-evolution of new ligand–receptor pairs likely facilitated the expansion of this pathway’s capabilities. Further, several examples of recent gene loss are visible in Drosophila when compared to family members in other phyla. By comparison the TGFβ signaling pathway is characterized by ancient gene duplications of ligands, receptors, and signal transducers with recent duplication events restricted to the vertebrate lineage. Overall, the data suggest that two distinct molecular evolutionary mechanisms can create a functionally diverse developmental signaling pathway. These are the recent dynamic generation of new genes and ligand–receptor interactions as seen in the Wnt pathway and the conservative adaptation of ancient pre-existing genes to new roles as seen in the TGFβ pathway. From a practical perspective, the former mechanism limits the investigator’s ability to transfer knowledge of specific pathway functions across species while the latter facilitates knowledge transfer