Objectively measured physical activity and sedentary behaviour and ankle brachial index: Cross-sectional and longitudinal associations in older men

AbstractBackgroundAssociations between bouts of physical activity (PA), sedentary behaviour (SB) and cardiovascular disease, and their mutual independence are not well defined. A low ankle brachial index (ABI ≤0.9) indicates peripheral arterial disease (PAD) and is predictive of cardiovascular events and functional impairment. We investigated the independence of PA and SB and the importance of bout duration in relation to ABI using objective measures.Methods945 men from the British Regional Heart Study, mean age 78.4 y, had concurrent measurements of ABI (Vicorder) and physical activity (Actigraph GT3X accelerometer); 427 men also had accelerometer measurements one year previously and contributed data to longitudinal analyses.Results and conclusionIn cross-sectional analyses, after adjusting for covariates each extra 10 min of moderate and vigorous PA per day was associated with an OR of 0.81 (95% CI 0.72, 0.91) for a low ABI, a stronger association than for light PA (OR 0.85, 95% CI 0.75, 0.98). Each extra 30 min of SB was associated with an OR of 1.19 (95% CI 1.07, 1.33) for a low ABI. Associations between moderate and vigorous PA and ABI persisted after adjustment for light PA or SB. Bout lengths for PA and SB were not associated with a low ABI. One year changes in PA or SB were not associated with low ABI.All physical activity and lower levels of SB, regardless of bout duration were inversely associated with ABI; more intense PA showed a stronger association. No associations between changes in PA and ABI were observed, but power may have been limited

Mutations in the LRRK2 Roc-COR tandem domain link Parkinson's disease to Wnt signalling pathways

Mutations in PARK8, encoding LRRK2, are the most common known cause of Parkinson's disease. The LRRK2 Roc-COR tandem domain exhibits GTPase activity controlling LRRK2 kinase activity via an intramolecular process. We report the interaction of LRRK2 with the dishevelled family of phosphoproteins (DVL1-3), key regulators of Wnt (Wingless/Int) signalling pathways important for axon guidance, synapse formation and neuronal maintenance. Interestingly, DVLs can interact with and mediate the activation of small GTPases with structural similarity to the LRRK2 Roc domain. The LRRK2 Roc-COR domain and the DVL1 DEP domain were necessary and sufficient for LRRK2–DVL1 interaction. Co-expression of DVL1 increased LRRK2 steady-state protein levels, an effect that was dependent on the DEP domain. Strikingly, LRRK2–DVL1-3 interactions were disrupted by the familial PARK8 mutation Y1699C, whereas pathogenic mutations at residues R1441 and R1728 strengthened LRRK2–DVL1 interactions. Co-expression of DVL1 with LRRK2 in mammalian cells resulted in the redistribution of LRRK2 to typical cytoplasmic DVL1 aggregates in HEK293 and SH-SY5Y cells and co-localization in neurites and growth cones of differentiated dopaminergic SH-SY5Y cells. This is the first report of the modulation of a key LRRK2-accessory protein interaction by PARK8 Roc-COR domain mutations segregating with Parkinson's disease. Since the DVL1 DEP domain is known to be involved in the regulation of small GTPases, we propose that: (i) DVLs may influence LRRK2 GTPase activity, and (ii) Roc-COR domain mutations modulating LRRK2–DVL interactions indirectly influence kinase activity. Our findings also link LRRK2 to Wnt signalling pathways, suggesting novel pathogenic mechanisms and new targets for genetic analysis in Parkinson's disease

Objectively measured physical activity, sedentary time and subclinical vascular disease: Cross-sectional study in older British men.

Low physical activity (PA) and high levels of sedentary time (ST) are associated with higher cardiovascular disease (CVD) risk among older people. However, their independent contribution and importance of duration of PA and ST bouts remain unclear. We investigated associations between objectively measured PA, ST and non-invasive vascular measures, markers of CVD risk. Cross-sectional study of 1216 men from the British Regional Heart Study, mean age 78.5years, measured in 2010-2012. Carotid intima thickness (CIMT), distensibility coefficient (DC) and plaque presence were measured using ultrasound; pulse wave velocity (cfPWV) and augmentation index (AIx) using a Vicorder. PA and ST were measured using hip-worn ActiGraph GT3X accelerometers. After adjusting for covariates, each additional 1000 steps per day was associated with a 0.038m/s lower cfPWV (95% CI=-0.076, 0.0003), 0.095 10(-3) kPa(-1) higher DC (95% CI=0.006, 0.185), 0.26% lower AIx (95% CI=-0.40, -0.12) and a 0.005mm lower CIMT (95% CI=-0.008, -0.001). Moderate and vigorous PA (MVPA) was associated with lower AIx and CIMT, light PA (LPA) with lower cfPWV and CIMT and ST with higher cfPWV, AIx and CIMT and lower DC. LPA and ST were highly correlated (r=-0.62). The independence of MVPA and ST or MVPA and LPA was inconsistent across vascular measures. Bout lengths for both PA and ST were not associated with vascular measures. In our cross-sectional study of older men, all PA regardless of intensity or bout duration was beneficially associated with vascular measures, as was lower ST. LPA was particularly relevant for cfPWV and CIMT

Humanizing sociotechnical transitions through energy justice: an ethical framework for global transformative change

Poverty, climate change and energy security demand awareness about the interlinkages between energy systems and social justice. Amidst these challenges, energy justice has emerged to conceptualize a world where all individuals, across all areas, have safe, affordable and sustainable energy that is, essentially, socially just. Simultaneously, new social and technological solutions to energy problems continually evolve, and interest in the concept of sociotechnical transitions has grown. However, an element often missing from such transitions frameworks is explicit engagement with energy justice frameworks. Despite the development of an embryonic set of literature around these themes, an obvious research gap has emerged: can energy justice and transitions frameworks be combined? This paper argues that they can. It does so through an exploration of the multi-level perspective on sociotechnical systems and an integration of energy justice at the model’s niche, regime and landscape level. It presents the argument that it is within the overarching process of sociotechnical change that issues of energy justice emerge. Here, inattention to social justice issues can cause injustices, whereas attention to them can provide a means to examine and potential resolve them

AD51B in Familial Breast Cancer

Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11–1.19, P = 8.88 x 10−16) and among familial cases (OR: 1.24, 95% CI: 1.16–1.32, P = 6.19 x 10−11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk

The Atacama Cosmology Telescope: DR6 Gravitational Lensing Map and Cosmological Parameters

We present cosmological constraints from a gravitational lensing mass map covering 9400 sq. deg. reconstructed from CMB measurements made by the Atacama Cosmology Telescope (ACT) from 2017 to 2021. In combination with BAO measurements (from SDSS and 6dF), we obtain the amplitude of matter fluctuations $\sigma_8 = 0.819 \pm 0.015$ at 1.8% precision, $S_8\equiv\sigma_8({\Omega_{\rm m}}/0.3)^{0.5}=0.840\pm0.028$ and the Hubble constant $H_0= (68.3 \pm 1.1)\, \text{km}\,\text{s}^{-1}\,\text{Mpc}^{-1}$ at 1.6% precision. A joint constraint with CMB lensing measured by the Planck satellite yields even more precise values: $\sigma_8 = 0.812 \pm 0.013$, $S_8\equiv\sigma_8({\Omega_{\rm m}}/0.3)^{0.5}=0.831\pm0.023$ and $H_0= (68.1 \pm 1.0)\, \text{km}\,\text{s}^{-1}\,\text{Mpc}^{-1}$. These measurements agree well with $\Lambda$CDM-model extrapolations from the CMB anisotropies measured by Planck. To compare these constraints to those from the KiDS, DES, and HSC galaxy surveys, we revisit those data sets with a uniform set of assumptions, and find $S_8$ from all three surveys are lower than that from ACT+Planck lensing by varying levels ranging from 1.7-2.1$\sigma$. These results motivate further measurements and comparison, not just between the CMB anisotropies and galaxy lensing, but also between CMB lensing probing $z\sim 0.5-5$ on mostly-linear scales and galaxy lensing at $z\sim 0.5$ on smaller scales. We combine our CMB lensing measurements with CMB anisotropies to constrain extensions of $\Lambda$CDM, limiting the sum of the neutrino masses to $\sum m_{\nu} < 0.12$ eV (95% c.l.), for example. Our results provide independent confirmation that the universe is spatially flat, conforms with general relativity, and is described remarkably well by the $\Lambda$CDM model, while paving a promising path for neutrino physics with gravitational lensing from upcoming ground-based CMB surveys.Comment: 30 pages, 16 figures, prepared for submission to ApJ. Cosmological likelihood data is here: https://lambda.gsfc.nasa.gov/product/act/actadv_prod_table.html ; likelihood software is here: https://github.com/ACTCollaboration/act_dr6_lenslike . Also see companion papers Qu et al and MacCrann et al. Mass maps will be released when papers are publishe

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

The Atacama Cosmology Telescope: DR6 gravitational lensing map and cosmological parameters

We present cosmological constraints from a gravitational lensing mass map covering 9400 deg2 reconstructed from measurements of the cosmic microwave background (CMB) made by the Atacama Cosmology Telescope (ACT) from 2017 to 2021. In combination with measurements of baryon acoustic oscillations and big bang nucleosynthesis, we obtain the clustering amplitude σ 8 = 0.819 ± 0.015 at 1.8% precision, S8≡σ8(Ωm/0.3)0.5=0.840±0.028 , and the Hubble constant H 0 = (68.3 ± 1.1) km s−1 Mpc−1 at 1.6% precision. A joint constraint with Planck CMB lensing yields σ 8 = 0.812 ± 0.013, S8≡σ8(Ωm/0.3)0.5=0.831±0.023 , and H 0 = (68.1 ± 1.0) km s−1 Mpc−1. These measurements agree with ΛCDM extrapolations from the CMB anisotropies measured by Planck. We revisit constraints from the KiDS, DES, and HSC galaxy surveys with a uniform set of assumptions and find that S 8 from all three are lower than that from ACT+Planck lensing by levels ranging from 1.7σ to 2.1σ. This motivates further measurements and comparison, not just between the CMB anisotropies and galaxy lensing but also between CMB lensing probing z ∼ 0.5–5 on mostly linear scales and galaxy lensing at z ∼ 0.5 on smaller scales. We combine with CMB anisotropies to constrain extensions of ΛCDM, limiting neutrino masses to ∑m ν < 0.13 eV (95% c.l.), for example. We describe the mass map and related data products that will enable a wide array of cross-correlation science. Our results provide independent confirmation that the universe is spatially flat, conforms with general relativity, and is described remarkably well by the ΛCDM model, while paving a promising path for neutrino physics with lensing from upcoming ground-based CMB surveys