BackgroundThe study aimed to validate previously discovered plasma biomarkers associated with AD, using a design based on imaging measures as surrogate for disease severity and assess their prognostic value in predicting conversion to dementia.MethodsThree multicenter cohorts of cognitively healthy elderly, mild cognitive impairment (MCI), and AD participants with standardized clinical assessments and structural neuroimaging measures were used. Twenty-six candidate proteins were quantified in 1148 subjects using multiplex (xMAP) assays.ResultsSixteen proteins correlated with disease severity and cognitive decline. Strongest associations were in the MCI group with a panel of 10 proteins predicting progression to AD (accuracy 87%, sensitivity 85%, and specificity 88%).ConclusionsWe have identified 10 plasma proteins strongly associated with disease severity and disease progression. Such markers may be useful for patient selection for clinical trials and assessment of patients with predisease subjective memory complaints.
scFOSs do not modify intestinal calcium absorption in postmenopausal women who do not receive hormonal replacement therapy. The results from a subgroup of women who had been going through menopause for >6 y (n = 6) suggest that scFOSs may influence calcium absorption in the late postmenopausal phase. The small number of subjects and the related P value warrant verification and further investigation with women in late menopause only.
Fermentable carbohydrates have been shown to be nondigestible by human enzymes in the small intestine but are fermented extensively in the large bowel to short-chain fatty acids (SCFAs), which can increase mineral absorption. It has been shown that feeding such carbohydrates including short-chain fructo-oligosaccharides
The rhamnogalacturonan-II dimer (dRG-II) forms strong complexes in vitro with lead (Pb) and other selected cations. We examined the in vivo bioavailability of Pb complexed with dRG-II and the effect of unleaded dRG-II on the intestinal absorption and tissue retention of Pb in rats. Forty male Wistar rats were divided into four groups. Each group consumed a purified control diet for 3 wk or the same diet supplemented with: i) 3 mg of Pb/kg, ii) 0.5 g of leaded dRG-II/kg, or iii) 0.5 g of leaded dRG-II/kg and 4.5 g of unleaded dRG-II/kg. The leaded dRG-II provided approximately 3 mg of Pb/kg of diet. A chemical balance study was conducted during the last 5 d of the 3-wk study, and blood and organs were sampled for Pb and mineral analyses. The apparent intestinal absorptions of Pb were 62.3, 15.2, 11.8 and -0.1%, and Pb balances were 1.9, 9.6, 5.6 and -0.2 microg/d for the control and the three experimental groups, respectively. The Pb complexed with dRG-II was less available than Pb acetate, as reflected by significantly lower blood and tissue Pb levels. The addition of unleaded dRG-II decreased the intestinal absorption and the tissue retention of Pb significantly. We further found that the apparent absorption and status of magnesium, zinc and iron were unaffected by Pb treatment or dRG-II addition. We conclude that dRG-II may be useful in decreasing toxicity related to chronic Pb exposure. Human studies will be necessary however, to further evaluate the clinical utility of this beneficial effect.
The LIN-1 ETS transcription factor plays a pivotal role in controlling cell fate decisions during development of the Caenorhabditis elegans vulva. Prior to activation of the RTK/Ras/ERK-signaling pathway, LIN-1 functions as a SUMOylated transcriptional repressor that inhibits vulval cell fate. Here we demonstrate using the yeast two-hybrid system that SUMOylation of LIN-1 mediates interactions with a protein predicted to be involved in transcriptional repression: the RAD-26 Mi-2β/CHD4 component of the nucleosome remodeling and histone deacetylation (NuRD) transcriptional repression complex. Genetic studies indicated that rad-26 functions to inhibit vulval cell fates in worms. Using the yeast two-hybrid system, we showed that the EGL-27/MTA1 component of the NuRD complex binds the carboxy-terminus of LIN-1 independently of LIN-1 SUMOylation. EGL-27 also binds UBC-9, an enzyme involved in SUMOylation, and MEP-1, a zinc-finger protein previously shown to bind LIN-1. Genetic studies indicate that egl-27 inhibits vulval cell fates in worms. These results suggest that LIN-1 recruits multiple proteins that repress transcription via both the SUMOylated amino-terminus and the unSUMOylated carboxy-terminus. Assays in cultured cells showed that the carboxy-terminus of LIN-1 was converted to a potent transcriptional activator in response to active ERK. We propose a model in which LIN-1 recruits multiple transcriptional repressors to inhibit the 1° vulval cell fate, and phosphorylation by ERK converts LIN-1 to a transcriptional activator that promotes the 1° vulval cell fate.
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