Background: Meprin β cleaves the amyloid precursor protein. Results: Meprin β-mediated cleavage of the amyloid precursor protein leads to an increase of amyloid β production and to the generation of an N-terminal truncated amyloid β variant. Conclusion: Meprin β can generate N-terminal truncated amyloid β peptides. Significance: Our data indicate that meprin β is a novel protease in amyloid β generation. The amyloid β (Aβ) peptide, which is abundantly found in the brains of patients suffering from Alzheimer disease, is central in the pathogenesis of this disease. Therefore, to understand the processing of the amyloid precursor protein (APP) is of critical importance. Recently, we demonstrated that the metalloprotease meprin β cleaves APP and liberates soluble N-terminal APP (N-APP) fragments. In this work, we present evidence that meprin β can also process APP in a manner reminiscent of β-secretase. We identified cleavage sites of meprin β in the amyloid β sequence of the wild type and Swedish mutant of APP at positions p1 and p2, thereby generating Aβ variants starting at the first or second amino acid residue. We observed even higher kinetic values for meprin β than BACE1 for both the wild type and the Swedish mutant APP form. This enzymatic activity of meprin β on APP and Aβ generation was also observed in the absence of BACE1/2 activity using a β-secretase inhibitor and BACE knock-out cells, indicating that meprin β acts independently of β-secretase.

A bstractWe consider the impact of colored scalars that can couple directly to matter fields on the recently measured h → γγ excess. Among all possible candidates only scalar states transforming as (8, 2, 1/2) and ($ \overline{\mathbf{6}} $, 3, −1/3) under the Standard Model gauge group can individually accommodate the excess and remain in agreement with all available data. Current experimental constraints require such colored states to have an order one coupling to the Standard Model Higgs and a mass below 300 GeV. We use the best fit values to predict the correlated effect in h → Zγ and di-Higgs production. We furthermore discuss where and how these states appear in extensions of the Standard Model with primary focus on scenarios of matter unification. We revisit two simple SU(5) setups to show that these two full-fledged models not only accommodate a light color octet state but correlate its mass with observable partial proton decay lifetimes.

We hypothesised that breast cancer risk for relatives of women with early-onset breast cancer could be predicted by tumour morphological features. We studied female first-degree relatives of a population-based sample of 452 index cases with a first primary invasive breast cancer diagnosed before the age of 40 years. For the index cases, a standardised tumour morphology review had been conducted for all; estrogen (ER) and progesterone receptor (PR) status was available for 401 (89%), and 77 (17%) had a high-risk mutation in a breast cancer susceptibility gene or methylation of the BRCA1 promoter region in peripheral blood DNA. We calculated standardised incidence ratios (SIR) by comparing the number of mothers and sisters with breast cancer with the number expected based on Australian incidence rates specific for age and year of birth. Using Cox proportional hazards modelling, absence of extensive sclerosis, extensive intraductal carcinoma, absence of acinar and glandular growth patterns, and the presence of trabecular and lobular growth patterns were independent predictors with between a 1.8- and 3.1-fold increased risk for relatives (all P <0.02). Excluding index cases with known genetic predisposition or BRCA1 promoter methylation, absence of extensive sclerosis, circumscribed growth, extensive intraductal carcinoma and lobular growth pattern were independent predictors with between a 2.0- and 3.3-fold increased risk for relatives (all P <0.02). Relatives of the 128 (34%) index cases with none of these four features were at population risk (SIR = 1.03, 95% CI = 0.57 to 1.85) while relatives of the 37 (10%) index cases with two or more features were at high risk (SIR = 5.18, 95% CI = 3.22 to 8.33). This wide variation in risks for relatives based on tumour characteristics could be of clinical value, help discover new breast cancer susceptibility genes and be an advance on the current clinical practice of using ER and PR as pathology-based predictors of familial and possibly genetic risks.