Dickkopf-1 Overexpression in vitro Nominates Candidate Blood Biomarkers Relating to Alzheimer's Disease Pathology

BACKGROUND: Previous studies suggest that Dickkopf-1 (DKK1), an inhibitor of Wnt signaling, plays a role in amyloid-induced toxicity and hence Alzheimer's disease (AD). However, the effect of DKK1 expression on protein expression, and whether such proteins are altered in disease, is unknown. OBJECTIVE: We aim to test whether DKK1 induced protein signature obtained in vitro were associated with markers of AD pathology as used in the amyloid/tau/neurodegeneration (ATN) framework as well as with clinical outcomes. METHODS: We first overexpressed DKK1 in HEK293A cells and quantified 1,128 proteins in cell lysates using aptamer capture arrays (SomaScan) to obtain a protein signature induced by DKK1. We then used the same assay to measure the DKK1-signature proteins in human plasma in two large cohorts, EMIF (n = 785) and ANM (n = 677). RESULTS: We identified a 100-protein signature induced by DKK1 in vitro. Subsets of proteins, along with age and apolipoprotein E ɛ4 genotype distinguished amyloid pathology (A + T-N-, A+T+N-, A+T-N+, and A+T+N+) from no AD pathology (A-T-N-) with an area under the curve of 0.72, 0.81, 0.88, and 0.85, respectively. Furthermore, we found that some signature proteins (e.g., Complement C3 and albumin) were associated with cognitive score and AD diagnosis in both cohorts. CONCLUSIONS: Our results add further evidence for a role of DKK regulation of Wnt signaling in AD and suggest that DKK1 induced signature proteins obtained in vitro could reflect theATNframework as well as predict disease severity and progression in vivo

Breast cancer in young women

Although uncommon, breast cancer in young women is worthy of special attention due to the unique and complex issues that are raised. This article reviews specific challenges associated with the care of younger breast cancer patients, which include fertility preservation, management of inherited breast cancer syndromes, maintenance of bone health, secondary prevention, and attention to psychosocial issues

Tests of Lorentz invariance at the Sudbury Neutrino Observatory

Experimental tests of Lorentz symmetry in systems of all types are critical for ensuring that the basic assumptions of physics are well-founded. Data from all phases of the Sudbury Neutrino Observatory, a kiloton-scale heavy water Cherenkov detector, are analyzed for possible violations of Lorentz symmetry in the neutrino sector. Such violations would appear as one of eight possible signal types in the detector: six seasonal variations in the solar electron neutrino survival probability differing in energy and time dependence, and two shape changes to the oscillated solar neutrino energy spectrum. No evidence for such signals is observed, and limits on the size of such effects are established in the framework of the Standard Model Extension, including 40 limits on perviously unconstrained operators and improved limits on 15 additional operators. This makes limits on all minimal, Dirac-type Lorentz violating operators in the neutrino sector available for the first time

Search for hep solar neutrinos and the diffuse supernova neutrino background using all three phases of the Sudbury Neutrino Observatory

A search has been performed for neutrinos from two sources, the hep reaction in the solar pp fusion chain and the νe component of the diffuse supernova neutrino background (DSNB), using the full dataset of the Sudbury Neutrino Observatory with a total exposure of 2.47 kton-years after fiducialization. The hep search is performed using both a single-bin counting analysis and a likelihood fit. We find a best-fit flux that is compatible with solar model predictions while remaining consistent with zero flux, and set a one-sided upper limit of φhep<30×103 cm-2 s-1 [90% credible interval (CI)]. No events are observed in the DSNB search region, and we set an improved upper bound on the νe component of the DSNB flux of φνeDSNB<19 cm-2 s-1 (90% CI) in the energy range 22.9<Eν<36.9 MeV

DETECTION OF CYSTIC-FIBROSIS HOMOZYGOTES AND HETEROZYGOTES WITH PLASMA

4 years data for reproductive success analysis (binomial fledged response

Exclusion of late infantile neuronal ceroid lipofuscinosis (LINCL) in a fetus by assay of tripeptidyl peptidase I in chorionic villi

We report the exclusion of late infantile neuronal ceroid lipofuscinosis in a fetus by assay of tripeptidyl peptidase I activity and by mutational analysis in chorionic villi. This is the first pregnancy at risk for LINCL to be monitored by enzyme assay. No morphological abnormalities were detecte

6C-butylglucoses from glucuronolactone: Suppression of silyl migration during borohydride reduction of lactols by cerium (III) chloride: Inhibition of phosphoglucomutase

The synthesis of the epimeric 6C-butylglucoses from D-glucuronolactone is reported. The sodium borohydride reduction of two fully protected lactols is highly stereoselective but is accompanied by migration of a silyl protecting group; in the presence of cerium(III) chloride, there is little change in the stereoselectivity but the migration of the silyl group is suppressed. 6R-6C-Methylglucose and 6R-6C-butlylglucose are both better inhibitors of phosphoglucomutase than their 6S epimers

Tetrazoles of manno- and rhamno-pyranoses: Contrasting inhibition of mannosidases by [4.3.0] but of rhamnosidase by [3.3.0] bicyclic tetrazoles

The synthesis of tetrazoles derived from D-manno and D- rhamnopyranose from L-gulonolactone and of L-rhamnopyranose from D-gulonolactone is described. These and other materials are assessed as inhibitors of glycosidases. The [4.3.0] tetrazoles of D-manno- and D-rhamnopyranose are inhibitors of human liver α-mannosidase. In contrast the D-furanose analogues show no inhibitory activity whilst the [3.3.0] L-rhamno furanotetrazole is a potent rhamnosidase inhibitor, a potential inhibitor of mycobacterial cell wall biosynthesis and as such may provide a strategy for the treatment of tuberculosis

6R- and 6S-6C-Methylmannose from D-mannuronolactone. Inhibition of phosphoglucomutase and phosphomannomutase: agents for the study of the primary metabolism of mannose

The syntheses of 6S-3 and 6R-6 6C-methylmannoses rely on opposite and highly stereoselective reductions of fully and partially protected ketones derived from D-mannuronolactone, respectively. Reduction of the silylated ketone 2 by sodium borohydride was accompanied by complete migration of the silyl protecting group to the new stereogenic centre; the silyl migration was suppressed when the reduction was conducted in the presence of cerium(III) chloride. Both epimers were good inhibitors of phosphoglucomutase and phosphomannomutase, and are specific inhibitors of phosphohexomutases. This work confirms that 6C-alkylhexoses provide a valuable set of compounds with good bioavailability for the study of enzymes involved in the primary metabolism of sugar phosphates. The X-ray crystallographic analysis of 7- deoxy-2,3:5,6-di-O-isopropylidene-α-L-glycero-D-manno-heptofuranose 16 is reported