CREB inactivation by HDAC1/PP1γ contributes to dopaminergic neurodegeneration in Parkinson's disease.

Understanding the pathogenesis of nigral dopaminergic neurodegeneration is critical for developing mechanism-based treatments for Parkinson's disease (PD). In the nigral dopaminergic neurons of postmortem human PD brains, we found that CREB, a well-recognized pro-survival transcription factor in neurons, was inactivated by dephosphorylation at Ser133. CREB dephosphorylation correlated with decreased expression of NURR1, one of its target genes crucial for dopaminergic neuron survival, confirming that CREB function was impaired in nigral dopaminergic neurons in PD. An MPTP mouse model was used to further elucidate the mechanism underlying CREB dephosphorylation. Protein phosphatase 1γ (PP1γ), which dephosphorylates CREB, was constitutively associated with histone deacetylase 1 (HDAC1). HDAC1 promotes CREB Ser133 dephosphorylation via a stable interaction with PP1γ. We found that CREB interacted with the HDAC1/PP1γ complex during dopaminergic neurodegeneration. Importantly, increased CREB/HDAC1 interaction occurred in the nigral dopaminergic neurons of PD patients as demonstrated using a proximity ligation assay. Disrupting CREB/HDAC1 interaction via either overexpression of GAL4 M1, a CREB mutant, or administration of trichostatin A, a pan-HDAC inhibitor, restored the expression levels of phospho-CREB (Ser133) and NURR1, and protected nigral dopaminergic neurons in the MPTP-treated mice brain. Collectively, our results demonstrated that HDAC1/PP1γ-mediated CREB inactivation contributed to dopaminergic neuronal degeneration. Disruption of CREB/HDAC1 interaction has the potential as a new approach for PD therapy.Significance StatementPD is the most common movement disorder attributed to the progressive loss of dopaminergic neurons in the substantia nigra. Understanding the pathogenesis of nigral dopaminergic neurodegeneration is critical for developing mechanism-based treatments for PD. We found in nigral dopaminergic neurons of postmortem human PD brains that CREB, a well-recognized pro-survival transcription factor in neurons, was inactivated by dephosphorylation at Ser133. HDAC1, constitutively associated with PP1γ, interacted with CREB to mediate its dephosphorylation during dopaminergic degeneration. Disrupting CREB/HDAC1 interaction restored CREB activity and protected nigral dopaminergic neurons in the MPTP mouse brains. This work suggests that disruption of the CREB/HDAC1 interaction to restore CREB activity may be a potential therapeutic approach in PD.

A Complex Fluviolacustrine Environment on Early Mars and Its Astrobiological Potentials.

Chloride-bearing deposits and phyllosilicates-bearing units are widely distributed in the southern highlands of Mars, but these phases are rarely found together in fluviolacustrine environments. The study of the coexistence of these minerals can provide important insights into geochemistry, water activity, and ultimately the climate and habitability of early Mars. Here we use high-resolution compositional and morphological orbiter data to identify and characterize the context of diverse minerals in a Noachian fluviolacustrine environment west of Knobel crater (6.7°S, 226.8°W). The chlorides in this region are likely formed through the evaporation of brines in a closed topographic basin. The formation age of chlorides is older than 3.7 Ga, based on stratigraphic relationships identified and previously obtained crater retention ages. The timing of the alteration of basaltic materials to iron-magnesium smectites in relation to the chloride formation in this location is enigmatic and is unable to be resolved with currently available remote sensing data. Importantly, we find that this close relationship between these key minerals revealed by the currently available data details a complex and intimate history of aqueous activity in the region. Of critical importance are the evaporitic deposits as analogous terrestrial deposits have been shown to preserve ancient biosignatures and possibly even sustain microbial communities for hundreds of millions of years. These salts could have protected organic matter from ultraviolet radiation, or even allow modern habitable microenvironments in the shallow subsurface through periodic deliquescence. The high astrobiology potential of this site makes it a good candidate for future landed and sample return missions (e.g., the Chinese 2020 Mars mission).

The impact of publishing medical specialty society guidelines on subsequent adoption of best practices: a case study with type 2 diabetes.

AIMS: Our goal was to determine the effect of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) consensus algorithm for the initiation and adjustment of type 2 diabetes (T2D) therapy, published in 2006, on the incidence of early metformin monotherapy (EMM), defined as the prescription of metformin and no other antidiabetic medications within 30 days of initial T2D diagnosis. METHODS: The incidence of EMM in the United States (US) from January 2005 to December 2007 was estimated using data from the i3 InVision Data Mart, an integrated database of enrollment dates, inpatient and outpatient medical claims, pharmaceutical claims, and laboratory results from a diverse group of US health plans. The trend in the incidence of EMM was analysed using joinpoint regression modelling. RESULTS: A statistically significant joinpoint was found in July 2006 (p < 0.05). From January 2005 to July 2006, EMM increased at an annualised rate of 15.6%. From July 2006 to December 2007, EMM increased at an annualised rate of 66.0%. CONCLUSIONS: Our findings suggest that publication of the ADA/EASD algorithm caused a significant acceleration in the incidence of EMM.

Applications of capillary electrochromatography analysis for formulated pesticide products.

The feasibility of using capillary electrochromatography (CEC) as a high-efficiency reversed-phase separation technique has been demonstrated for the analysis of some pesticide formulation products. Some operating parameters of CEC analysis (organic modifier content, pH of the buffer, and sample diluent) were studied using commercially available capillaries packed with Hypersil (Phenomenex, Torrance, CA, U.S.A.) octadecylsilic (ODS) particles. It was found that the resolution decreases in linear fashion with the increase in percent acetonitrile in the sample diluent for neutral components if a combination of electrokinetic injection and pressure injection is used. Several practical applications of the CEC technique in the analysis of pesticide formulation products are described in detail. The results indicate that CEC, compared with HPLC, not only has higher efficiency, but is also practical, precise, and accurate in terms of simplicity, efficiency, recovery, and linearity.