Angiotensin-converting enzyme 2 is reduced in Alzheimer's disease in association with increasing amyloid-β and tau pathology

BACKGROUND: Hyperactivity of the classical axis of the renin-angiotensin system (RAS), mediated by angiotensin II (Ang II) activation of the angiotensin II type 1 receptor (AT1R), is implicated in the pathogenesis of Alzheimer’s disease (AD). Angiotensin-converting enzyme-2 (ACE-2) degrades Ang II to angiotensin 1–7 (Ang (1-7)) and counter-regulates the classical axis of RAS. We have investigated the expression and distribution of ACE-2 in post-mortem human brain tissue in relation to AD pathology and classical RAS axis activity. METHODS: We measured ACE-2 activity by fluorogenic peptide substrate assay in mid-frontal cortex (Brodmann area 9) in a cohort of AD (n = 90) and age-matched non-demented controls (n = 59) for which we have previous data on ACE-1 activity, amyloid β (Aβ) level and tau pathology, as well as known ACE1 (rs1799752) indel polymorphism, apolipoprotein E (APOE) genotype, and cerebral amyloid angiopathy severity scores. RESULTS: ACE-2 activity was significantly reduced in AD compared with age-matched controls (P < 0.0001) and correlated inversely with levels of Aβ (r = −0.267, P < 0.001) and phosphorylated tau (p-tau) pathology (r = −0.327, P < 0.01). ACE-2 was reduced in individuals possessing an APOE ε4 allele (P < 0.05) and was associated with ACE1 indel polymorphism (P < 0.05), with lower ACE-2 activity in individuals homozygous for the ACE1 insertion AD risk allele. ACE-2 activity correlated inversely with ACE-1 activity (r = −0.453, P < 0.0001), and the ratio of ACE-1 to ACE-2 was significantly elevated in AD (P < 0.0001). Finally, we show that the ratio of Ang II to Ang (1–7) (a proxy measure of ACE-2 activity indicating  conversion of Ang II to Ang (1–7)) is reduced in AD. CONCLUSIONS: Together, our findings indicate that ACE-2 activity is reduced in AD and is an important regulator of the central classical ACE-1/Ang II/AT1R axis of RAS, and also that dysregulation of this pathway likely plays a significant role in the pathogenesis of AD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13195-016-0217-7) contains supplementary material, which is available to authorized users

Full-scale fatigue testing of a wind turbine blade in flapwise direction and examining the effect of crack propagation on the blade performance

In this paper, the sensitivity of the structural integrity of wind turbine blades to debonding of the shear web from the spar cap was investigated. In this regard, modal analysis, static and fatigue testing were performed on a 45.7 m blade for three states of the blade: (i) as received blade (ii) when a crack of 200 mm was introduced between the web and the spar cap and (iii) when the crack was extended to 1000 mm. Calibration pull-tests for all three states of the blade were performed to obtain the strain-bending moment relationship of the blade according to the estimated target bending moment (BM) which the blade is expected to experience in its service life. The resultant data was used to apply appropriate load in the fatigue tests. The blade natural frequencies in flapwise and edgewise directions over a range of frequency domain were found by modal testing for all three states of the blade. The blade first natural frequency for each state was used for the flapwise fatigue tests. These were performed in accordance with technical specification IEC TS 61400-23. The fatigue results showed that, for a 200 mm crack between the web and spar cap at 9 m from the blade root, the crack did not propagate at 50% of the target BM up to 62,110 cycles. However, when the load was increased to 70% of target BM, some damages were detected on the pressure side of the blade. When the 200 mm crack was extended to 1000 mm, the crack began to propagate when the applied load exceeded 100% of target BM and the blade experienced delaminations, adhesive joint failure, compression failure and sandwich core failure

Composition profiles of InAs–GaAs quantum dots determined by medium-energy ion scattering

The composition profile along the [001] growth direction of low-growth-rate InAs–GaAs quantum dots (QDs) has been determined using medium-energy ion scattering (MEIS). A linear profile of In concentration from 100% In at the top of the QDs to 20% at their base provides the best fit to MEIS energy spectra

Neuroprotection in a Novel Mouse Model of Multiple Sclerosis

The authors acknowledge the support of the Barts and the London Charity, the Multiple Sclerosis Society of Great Britain and Northern Ireland, the National Multiple Sclerosis Society, USA, notably the National Centre for the Replacement, Refinement & Reduction of Animals in Research, and the Wellcome Trust (grant no. 092539 to ZA). The siRNA was provided by Quark Pharmaceuticals. The funders and Quark Pharmaceuticals had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Looking For Disoriented Chiral Condensates From Pion Distributions

We suggest two methods for the detection of the formation of disoriented chiral condensates in heavy ion collisions. We show that the variance in the number of charged pions (in a suitable range of momentum space) provides a signature for the observation of a disoriented chiral condensate. The signal should be observable even if multiple domains of D$\chi$C form provided the average number of pions per domain is significantly larger than unity. The variance of the number charged pions alone provides a signal which can be used even if the number of neutral pions cannot be measured in a given detector. On the other hand, the probability distribution in $R$, the proportion of neutral pions to all pions emitted in heavy ion collisions in certain kinematic regions, has been suggested as a signal of a disoriented chiral condensate. Here we note that the signature can be greatly enhanced by making suitable cuts in the data. In particular, we consider reducing the data set such that the $k$ pions with lowest $p_T$ are all neutral. We find that, given such cuts, can be substantially different from 1/3. For example, for a single D$\chi$C domain without contamination due to incoherently emitted pions, is 3/5 given the pion with lowest $p_T$ is neutral, and 5/7 given the two pions with lowest $p_T$ are both neutral, {\it etc.}. The effects of multi-domain D$\chi$C formation and noise due to incoherent pion emission can be systematically incorporated. Potential applications to experiments and their limitations are briefly discussed.Comment: 16 pages in REVTeX, 7 figures. Combined and updated version of nucl-th/9903029 and nucl-th/9904074. Accepted by Phys. Rev.

Oral rehydration versus intravenous therapy for treating dehydration due to gastroenteritis in children: a meta-analysis of randomised controlled trials

BACKGROUND: Despite treatment recommendations from various organizations, oral rehydration therapy (ORT) continues to be underused, particularly by physicians in high-income countries. We conducted a systematic review of randomised controlled trials (RCTs) to compare ORT and intravenous therapy (IVT) for the treatment of dehydration secondary to acute gastroenteritis in children. METHODS: RCTs were identified through MEDLINE, EMBASE, CENTRAL, authors and references of included trials, pharmaceutical companies, and relevant organizations. Screening and inclusion were performed independently by two reviewers in order to identify randomised or quasi-randomised controlled trials comparing ORT and IVT in children with acute diarrhea and dehydration. Two reviewers independently assessed study quality using the Jadad scale and allocation concealment. Data were extracted by one reviewer and checked by a second. The primary outcome measure was failure of rehydration. We analyzed data using standard meta-analytic techniques. RESULTS: The quality of the 14 included trials ranged from 0 to 3 (Jadad score); allocation concealment was unclear in all but one study. Using a random effects model, there was no significant difference in treatment failures (risk difference [RD] 3%; 95% confidence intervals [CI]: 0, 6). The Mantel-Haenzsel fixed effects model gave a significant difference between treatment groups (RD 4%; 95% CI: 2, 5) favoring IVT. Based on the four studies that reported deaths, there were six in the IVT groups and two in ORT. There were no significant differences in total fluid intake at six and 24 hours, weight gain, duration of diarrhea, or hypo/hypernatremia. Length of stay was significantly shorter for the ORT group (weighted mean difference [WMD] -1.2 days; 95% CI: -2.4,-0.02). Phlebitis occurred significantly more often with IVT (number needed to treat [NNT] 33; 95% CI: 25,100); paralytic ileus occurred more often with ORT (NNT 33; 95% CI: 20,100). These results may not be generalizable to children with persistent vomiting. CONCLUSION: There were no clinically important differences between ORT and IVT in terms of efficacy and safety. For every 25 children (95% CI: 20, 50) treated with ORT, one would fail and require IVT. The results support existing practice guidelines recommending ORT as the first course of treatment in appropriate children with dehydration secondary to gastroenteritis

Network Archaeology: Uncovering Ancient Networks from Present-day Interactions

Often questions arise about old or extinct networks. What proteins interacted in a long-extinct ancestor species of yeast? Who were the central players in the Last.fm social network 3 years ago? Our ability to answer such questions has been limited by the unavailability of past versions of networks. To overcome these limitations, we propose several algorithms for reconstructing a network's history of growth given only the network as it exists today and a generative model by which the network is believed to have evolved. Our likelihood-based method finds a probable previous state of the network by reversing the forward growth model. This approach retains node identities so that the history of individual nodes can be tracked. We apply these algorithms to uncover older, non-extant biological and social networks believed to have grown via several models, including duplication-mutation with complementarity, forest fire, and preferential attachment. Through experiments on both synthetic and real-world data, we find that our algorithms can estimate node arrival times, identify anchor nodes from which new nodes copy links, and can reveal significant features of networks that have long since disappeared.Comment: 16 pages, 10 figure