Medicaid caseload for pediatric oral health care

Background

The authors’ aims were to compare, according to strata, dentists’ participation in Medicaid and Medicaid provider-level caseload measured as the number of patients or visits for preventive or restorative care for 2 comparison years.

cAMP stimulates the ubiquitin/proteasome pathway in rat spinal cord neurons

Proteasome impairment and accumulation of ubiquitinated proteins are implicated in neurodegeneration associated with different forms of spinal cord injury. We show herein that elevating cAMP in rat spinal cord neurons increases 26S proteasome activity in a protein kinase A-dependent manner. Treating spinal cord neurons with dibutyryl-cAMP (db-cAMP) also raised the levels of various components of the UPP including proteasome subunits Rpt6 and β5, polyubiquitin shuttling factor p62/sequestosome1, E3 ligase CHIP, AAA-ATPase p97 and the ubiquitin gene ubB. Finally, db-cAMP reduced the accumulation of ubiquitinated proteins, proteasome inhibition, and neurotoxicity triggered by the endogenous product of inflammation prostaglandin J2. We propose that optimizing the effects of cAMP/PKA-signaling on the UPP could offer an effective therapeutic approach to prevent UPP-related proteotoxicity in spinal cord neurons.     

Emerging role of p62/sequestosome-1 in the pathogenesis of Alzheimer's disease

The p62/sequestosome-1 is a multifunctional protein containing several protein-protein interaction domains. Through these interactions p62 is involved in the regulation of cellular signaling and protein trafficking, aggregation and degradation. p62 protein can bind through its UBA motif to ubiquitinated proteins and control their aggregation and degradation via either autophagy or proteasomes. p62 protein has been reported to be seen in association with the intracellular inclusions in primary and secondary tauopathies, α-synucleinopathies and other neurodegenerative brain disorders displaying inclusions with misfolded proteins. In Alzheimer's disease (AD), p62 protein is associated with neurofibrillary tangles composed primarily of hyperphosphorylated tau protein and ubiquitin. Increasing evidence indicates that p62 has an important role in the degradation of tau protein. The lack of p62 protein expression provokes the tau pathology in mice. Recent studies have demonstrated that the p62 gene expression and cytoplasmic p62 protein levels are significantly reduced in the frontal cortex of AD patients. Decline in the level of p62 protein can disturb the signaling pathways of Nrf2, cyclic AMP and NF-κB and in that way increase oxidative stress and impair neuronal survival. We will review here the molecular and functional characteristics of p62 protein and outline its potential role in the regulation of Alzheimer's pathogenesis.     

Hsp90 regulates tau pathology through co-chaperone complexes in Alzheimer's disease

Alzheimer's disease is a tauopathy which involves the deposition of microtubule-associated tau proteins into neurofibrillary tangles. Post-translational modifications, in particular site-specific phosphorylations, affect the conformation of tau protein which is an intrinsically disordered protein. These structural changes significantly increase the affinity of tau protein for certain molecular chaperones. Hsp90 is a major cellular chaperone which assembles large complexes with a variety of co-chaperones. The main function of Hsp90 complexes is to maintain protein quality control and assist in protein degradation via proteasomal and autophagic-lysosomal pathways. Tau protein is a client protein for these Hsp90 complexes. If the tau protein is in an abnormal or modified form, then it can trigger the recruitment of CHIP protein, a co-chaperone with E3 activity, to the complex which induces the ubiquitination of tau protein and activates its downstream degradation processes. Large immunophilins, FKBP51 and FKBP52 are also co-chaperones of Hsp90-tau complexes. These proteins contain peptidylprolyl cis/trans isomerase activity which catalyzes phosphorylation-dependent rotation in pSer/Thr-Pro peptide bond. The proline switch in the tau conformation triggers dephosphorylation of Ser/Thr residues phosphorylated, e.g. by two well-known tau kinases Cdk5 and GSK-3β. Binding of PP5 protein phosphatase to Hsp90 complex, can also dephosphorylate tau protein. Subsequently, dephosphorylated tau protein can be shuttled back to the microtubules. It seems that high-affinity binding of abnormal tau to Hsp90 complexes may have some counteracting effects on the aggregation process, since Hsp90 inhibitors can ameliorate the aggregation process in several neurodegenerative diseases. We will review the role of Hsp90 chaperone network in the regulation of tau biology and pathology in Alzheimer's disease.     

Evolutionary landscape of clonal hematopoiesis in 3,359 individuals from the general population

1. Download : Download high-res image (155KB)
2. Download : Download full-size image