Comparison of BMD changes and bone formation marker levels 3 years after bisphosphonate discontinuation: FLEX and HORIZON-PFT Extension I trials

An ASBMR task force recommends a drug holiday for certain women treated for ≥5 years with oral alendronate or ≥3 years with intravenous zoledronic acid, with reassessment 2-3 years later. It is not known whether changes in BMD or bone turnover markers differ after oral or intravenous therapy. Our goal was to compare changes in BMD and procollagen type I N propeptide, PINP, after oral or intravenous bisphosphonate use. In the Fracture Intervention Trial Long-term Extension (FLEX), women who received a mean 5 years of alendronate were randomized to placebo or continued treatment. In the Health Outcomes and Reduced Incidence with Zoledronic acid Once Yearly-Pivotal Fracture Trial Extension I (HORIZON-PFT E1), women who received 3 years of zoledronic acid were randomized to placebo or continued treatment. We examined the proportion of participants with BMD loss or PINP gain ≥least significant change (LSC), and those whose values exceeded a threshold (T score ≤-2.5 or PINP ≥36.0 ng/mL, a premenopausal median value). After 3 years of placebo, the FLEX group had greater mean total hip BMD decreases (-2.3% versus -1.2% in the HORIZON-PFT E1 group, p < 0.01), and greater rises in PINP (+11.6 ng/mL versus +6.7 ng/mL, p < 0.01). There was a greater proportion of individuals in FLEX with total hip BMD loss and PINP increases that exceeded LSC, and PINP values ≥36.0 ng/mL. In contrast, there were small changes in the proportion of women with femoral neck T scores ≤-2.5 in both groups. In conclusion, 3 years after bisphosphonate discontinuation, a considerable proportion of former alendronate and zoledronic acid users had meaningful declines in total hip BMD and elevations in PINP. Despite a longer treatment course, alendronate may have a more rapid offset of drug effect than zoledronic acid

Strategies for Managing Soil Fertility and Health in Organic Orchards - A Fact Sheet

This fact sheet is a report of research to provide fruit growers with locally adapted advice and solutions for managing soil fertility in certified organic stone-fruits.It includes information of transitioning to organic management; building soil organic matter and providing appropriate nutrients, including phosphorus, potassium, seconary nutrients and trace elements; soil testing; cover crops; mulches; and possible organic management systems

Electron Dephasing in Mesoscopic Metal Wires

The low-temperature behavior of the electron phase coherence time, $\tau_{\phi}$, in mesoscopic metal wires has been a subject of controversy recently. Whereas theory predicts that $\tau_{\phi}(T)$ in narrow wires should increase as $T^{-2/3}$ as the temperature $T$ is lowered, many samples exhibit a saturation of $\tau_{\phi}$ below about 1 K. We review here the experiments we have performed recently to address this issue. In particular we emphasize that in sufficiently pure Ag and Au samples we observe no saturation of $\tau_{\phi}$ down to our base temperature of 40 mK. In addition, the measured magnitude of $\tau_{\phi}$ is in excellent quantitative agreement with the prediction of the perturbative theory of Altshuler, Aronov and Khmelnitskii. We discuss possible explanations why saturation of $\tau_{\phi}$ is observed in many other samples measured in our laboratory and elsewhere, and answer the criticisms raised recently by Mohanty and Webb regarding our work.Comment: 14 pages, 3 figures; to appear in proceedings of conference "Fundamental Problems of Mesoscopic Physics", Granada, Spain, 6-11 September, 200

The Intentional Use of Service Recovery Strategies to Influence Consumer Emotion, Cognition and Behaviour

Service recovery strategies have been identified as a critical factor in the success of. service organizations. This study develops a conceptual frame work to investigate how specific service recovery strategies influence the emotional, cognitive and negative behavioural responses of . consumers., as well as how emotion and cognition influence negative behavior. Understanding the impact of specific service recovery strategies will allow service providers' to more deliberately and intentionally engage in strategies that result in positive organizational outcomes. This study was conducted using a 2 x 2 between-subjects quasi-experimental design. The results suggest that service recovery has a significant impact on emotion, cognition and negative behavior. Similarly, satisfaction, negative emotion and positive emotion all influence negative behavior but distributive justice has no effect

A cellular chemical probe targeting the chromodomains of Polycomb repressive complex 1

We report the design and characterization of UNC3866, a potent antagonist of the methyllysine (Kme) reading function of the Polycomb CBX and CDY families of chromodomains. Polycomb CBX proteins regulate gene expression by targeting Polycomb repressive complex 1 (PRC1) to sites of H3K27me3 via their chromodomains. UNC3866 binds the chromodomains of CBX4 and CBX7 most potently, with a K d of â ∼1/4100 nM for each, and is 6-to 18-fold selective as compared to seven other CBX and CDY chromodomains while being highly selective over >250 other protein targets. X-ray crystallography revealed that UNC3866's interactions with the CBX chromodomains closely mimic those of the methylated H3 tail. UNC4195, a biotinylated derivative of UNC3866, was used to demonstrate that UNC3866 engages intact PRC1 and that EED incorporation into PRC1 is isoform dependent in PC3 prostate cancer cells. Finally, UNC3866 inhibits PC3 cell proliferation, consistent with the known ability of CBX7 overexpression to confer a growth advantage, whereas UNC4219, a methylated negative control compound, has negligible effects

Erratum: Addendum: A cellular chemical probe targeting the chromodomains of Polycomb repressive complex 1 (Nature chemical biology (2016) 12 3 (180-187))

[No abstract available

Comprehensive analysis of epigenetic clocks reveals associations between disproportionate biological ageing and hippocampal volume

The concept of age acceleration, the difference between biological age and chronological age, is of growing interest, particularly with respect to age-related disorders, such as Alzheimer’s Disease (AD). Whilst studies have reported associations with AD risk and related phenotypes, there remains a lack of consensus on these associations. Here we aimed to comprehensively investigate the relationship between five recognised measures of age acceleration, based on DNA methylation patterns (DNAm age), and cross-sectional and longitudinal cognition and AD-related neuroimaging phenotypes (volumetric MRI and Amyloid-β PET) in the Australian Imaging, Biomarkers and Lifestyle (AIBL) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Significant associations were observed between age acceleration using the Hannum epigenetic clock and cross-sectional hippocampal volume in AIBL and replicated in ADNI. In AIBL, several other findings were observed cross-sectionally, including a significant association between hippocampal volume and the Hannum and Phenoage epigenetic clocks. Further, significant associations were also observed between hippocampal volume and the Zhang and Phenoage epigenetic clocks within Amyloid-β positive individuals. However, these were not validated within the ADNI cohort. No associations between age acceleration and other Alzheimer’s disease-related phenotypes, including measures of cognition or brain Amyloid-β burden, were observed, and there was no association with longitudinal change in any phenotype. This study presents a link between age acceleration, as determined using DNA methylation, and hippocampal volume that was statistically significant across two highly characterised cohorts. The results presented in this study contribute to a growing literature that supports the role of epigenetic modifications in ageing and AD-related phenotypes