Alpha-protein kinase 3 (ALPK3)-truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy.

AIMS: The aim of this study was to determine the frequency of heterozygous truncating ALPK3 variants (ALPK3tv) in patients with hypertrophic cardiomyopathy (HCM) and confirm their pathogenicity using burden testing in independent cohorts and family co-segregation studies. METHODS AND RESULTS : In a discovery cohort of 770 index patients with HCM, 12 (1.56%) were heterozygous for ALPK3tv [odds ratio(OR) 16.01, 95% confidence interval (CI) 7.89-29.74, P < 8.36e-11] compared to the Genome Aggregation Database (gnomAD) population. In a validation cohort of 2047 HCM probands, 32 (1.56%) carried heterozygous ALPK3tv (OR 16.17, 95% CI 10.31-24.87, P < 2.2e-16, compared to gnomAD). Combined logarithm of odds score in seven families with ALPK3tv was 2.99. In comparison with a cohort of genotyped patients with HCM (n = 1679) with and without pathogenic sarcomere gene variants (SP+ and SP-), ALPK3tv carriers had a higher prevalence of apical/concentric patterns of hypertrophy (60%, P < 0.001) and of a short PR interval (10%, P = 0.009). Age at diagnosis and maximum left ventricular wall thickness were similar to SP- and left ventricular systolic impairment (6%) and non-sustained ventricular tachycardia (31%) at baseline similar to SP+. After 5.3 ± 5.7 years, 4 (9%) patients with ALPK3tv died of heart failure or had cardiac transplantation (log-rank P = 0.012 vs. SP- and P = 0.425 vs. SP+). Imaging and histopathology showed extensive myocardial fibrosis and myocyte vacuolation. CONCLUSIONS : Heterozygous ALPK3tv are pathogenic and segregate with a characteristic HCM phenotype

The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients

The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophagy-related gene ATG7, a key component of the autophagy pathway that plays an important role in HD pathogenesis, to be associated with the age at onset in a large group of European Huntington disease patients. To confirm this association in a second independent patient cohort, we analysed the ATG7 V471A polymorphism in additional 1,464 European HD patients of the “REGISTRY” cohort from the European Huntington Disease Network (EHDN). In the entire REGISTRY cohort we could not confirm a modifying effect of the ATG7 V471A polymorphism. However, analysing a modifying effect of ATG7 in these REGISTRY patients and in patients of our previous HD cohort according to their ethnic origin, we identified a significant effect of the ATG7 V471A polymorphism on the HD age at onset only in the Italian population (327 patients). In these Italian patients, the polymorphism is associated with a 6-years earlier disease onset and thus seems to have an aggravating effect. We could specify the role of ATG7 as a genetic modifier for HD particularly in the Italian population. This result affirms the modifying influence of the autophagic pathway on the course of HD, but also suggests population-specific modifying mechanisms in HD pathogenesis

Mineralogical effects on the detectability of the postperovskite boundary

The discovery of a phase transition in Mg-silicate perovskite (Pv) to postperovskite (pPv) at lowermost mantle pressure-temperature (P - T) conditions may provide an explanation for the discontinuous increase in shear wave velocity found in some regions at a depth range of 200 to 400 km above the core-mantle boundary, hereafter the D′′ discontinuity. However, recent studies on binary and ternary systems showed that reasonable contents of Fe[superscript 2+] and Al for pyrolite increase the thickness (width of the mixed phase region) of the Pv - pPv boundary (400–600 km) to much larger than the D′′ discontinuity (≤ 70 km). These results challenge the assignment of the D′′ discontinuity to the Pv - pPv boundary in pyrolite (homogenized mantle composition). Furthermore, the mineralogy and composition of rocks that can host a detectable Pv → pPv boundary are still unknown. Here we report in situ measurements of the depths and thicknesses of the Pv → pPv transition in multiphase systems (San Carlos olivine, pyrolitic, and midocean ridge basaltic compositions) at the P - T conditions of the lowermost mantle, searching for candidate rocks with a sharp Pv - pPv discontinuity. Whereas the pyrolitic mantle may not have a seismologically detectable Pv → pPv transition due to the effect of Al, harzburgitic compositions have detectable transitions due to low Al content. In contrast, Al-rich basaltic compositions may have a detectable Pv - pPv boundary due to their distinct mineralogy. Therefore, the observation of the D′′ discontinuity may be related to the Pv → pPv transition in the differentiated oceanic lithosphere materials transported to the lowermost mantle by subducting slabs.National Science Foundation (U.S.). (Grant number EAR0738655)National Science Foundation (U.S.). (Grant number EAR1045673)United States. (DOE) National Nuclear Security Administration Stewardship Science Graduate Fellowshi

American cranberry (Vaccinium macrocarpon) extract affects human prostate cancer cell growth via cell cycle arrest by modulating expression of cell cycle regulators

Prostate cancer is one of the most common cancers in the world, and its prevalence is expected to increase appreciably in the coming decades. As such, more research is necessary to understand the etiology, progression and possible preventative measures to delay or to stop the development of this disease. Recently, there has been interest in examining the effects of whole extracts from commonly harvested crops on the behaviour and progression of cancer. Here, we describe the effects of whole cranberry extract (WCE) on the behaviour of DU145 human prostate cancer cells in vitro. Following treatment of DU145 human prostate cancer cells with 10, 25 and 50 μg ml⁻¹ of WCE, respectively for 6 h, WCE significantly decreased the cellular viability of DU145 cells. WCE also decreased the proportion of cells in the G2-M phase of the cell cycle and increased the proportion of cells in the G1 phase of the cell cycle following treatment of cells with 25 and 50 μg ml⁻¹ treatment of WCE for 6 h. These alterations in cell cycle were associated with changes in cell cycle regulatory proteins and other cell cycle associated proteins. WCE decreased the expression of CDK4, cyclin A, cyclin B1, cyclin D1 and cyclin E, and increased the expression of p27. Changes in p16(INK4a) and pRBp107 protein expression levels also were evident, however, the changes noted in p16(INK4a) and pRBp107 protein expression levels were not statistically significant. These findings demonstrate that phytochemical extracts from the American cranberry (Vaccinium macrocarpon) can affect the behaviour of human prostate cancer cells in vitro and further support the potential health benefits associated with cranberries

Electronic and magnetic structures of the postperovskite-type Fe[subscript 2]O[subscript 3] and implications for planetary magnetic records and deep interiors

Recent studies have shown that high pressure (P) induces the metallization of the Fe[superscript 2+]–O bonding, the destruction of magnetic ordering in Fe, and the high-spin (HS) to low-spin (LS) transition of Fe in silicate and oxide phases at the deep planetary interiors. Hematite (Fe[subscript 2]O[subscript 3]) is an important magnetic carrier mineral for deciphering planetary magnetism and a proxy for Fe in the planetary interiors. Here, we present synchrotron Mössbauer spectroscopy and X-ray diffraction combined with ab initio calculations for Fe[subscript 2]O[subscript 3] revealing the destruction of magnetic ordering at the hematite → Rh[subscript 2]O[subscript 3]-II type (RhII) transition at 70 GPa and 300 K, and then the revival of magnetic ordering at the RhII → postperovskite (PPv) transition after laser heating at 73 GPa. At the latter transition, at least half of Fe[subscript 3+] ions transform from LS to HS and Fe[subscript 2]O[subscript 3] changes from a semiconductor to a metal. This result demonstrates that some magnetic carrier minerals may experience a complex sequence of magnetic ordering changes during impact rather than a monotonic demagnetization. Also local Fe enrichment at Earth's core-mantle boundary will lead to changes in the electronic structure and spin state of Fe in silicate PPv. If the ultra-low-velocity zones are composed of Fe-enriched silicate PPv and/or the basaltic materials are accumulated at the lowermost mantle, high electrical conductivity of these regions will play an important role for the electromagnetic coupling between the mantle and the core.Department of Energy National Nuclear Security Administration Stewardship Science Graduate FellowshipNational Science Foundatio