Are buffers around home representative of physical activity spaces among adults?

Residential buffers are frequently used to assess built environment characteristics relevant to physical activity (PA), yet little is known about how well they represent the spatial areas in which individuals undertake PA. We used System for Observing Play and Recreation in Communities data for 217 adults from five US states who wore an accelerometer and a GPS for three weeks to create newly defined PA-specific activity spaces. These PA spaces were based on PA occurring in bouts of ≥10min and were defined as 1) the single minimum convex polygon (MCP) containing all of a participant's PA bout minutes and 2) the combination of many MCPs constructed using each PA bout independently. Participants spent a large proportion of their PA bout time outside of 0.5, 1, and 5 mile residential buffers, and these residential buffers were a poor approximation of the spatial areas in which PA bouts occurred. The newly proposed GPS-based PA spaces can be used in future studies in place of the more general concept of activity space to better approximate built environments experienced during PA

Where Are Adults Active? An Examination of Physical Activity Locations Using GPS in Five US Cities

Increasing physical activity (PA) at the population level requires appropriately targeting intervention development. Identifying the locations in which participants with various sociodemographic, body weight, and geographic characteristics tend to engage in varying intensities of PA as well as locations these populations underutilize for PA may facilitate this process. A visual location-coding protocol was developed and implemented in Google Fusion Tables and Maps using data from participants (N = 223, age 18–85) in five states. Participants concurrently wore ActiGraph GT1M accelerometers and Qstarz BT-Q1000X GPS units for 3 weeks to identify locations of moderate-to-vigorous (MVPA) or vigorous (VPA) bouts. Cochran-Mantel-Haenzel general association tests examined usage differences by participant characteristics (sex, age, race/ethnicity, education, body mass index (BMI), and recruitment city). Homes and roads encompassed >40% of bout-based PA minutes regardless of PA intensity. Fitness facilities and schools were important for VPA (19 and 12% of bout minutes). Parks were used for 13% of MVPA bout minutes but only 4% of VPA bout minutes. Hispanics, those without a college degree, and overweight/obese participants frequently completed MVPA bouts at home. Older adults often used roads for MVPA bouts. Hispanics, those with ≤high school education, and healthy/overweight participants frequently had MVPA bouts in parks. Applying a new location-coding protocol in a diverse population showed that adult PA locations varied by PA intensity, sociodemographic characteristics, BMI, and geographic location. Although homes, roads, and parks remain important locations for demographically targeted PA interventions, observed usage patterns by participant characteristics may facilitate development of more appropriately targeted interventions

RAN Translation at \u3cem\u3eC9orf72\u3c/em\u3e-Associated Repeat Expansions is Selectively Enhanced by the Integrated Stress Response

Repeat-associated non-AUG (RAN) translation allows for unconventional initiation at disease-causing repeat expansions. As RAN translation contributes to pathogenesis in multiple neurodegenerative disorders, determining its mechanistic underpinnings may inform therapeutic development. Here we analyze RAN translation at G4C2 repeat expansions that cause C9orf72-associated amyotrophic lateral sclerosis and frontotemporal dementia (C9RAN) and at CGG repeats that cause fragile X-associated tremor/ataxia syndrome. We find that C9RAN translation initiates through a cap- and eIF4A-dependent mechanism that utilizes a CUG start codon. C9RAN and CGG RAN are both selectively enhanced by integrated stress response (ISR) activation. ISR-enhanced RAN translation requires an eIF2α phosphorylation-dependent alteration in start codon fidelity. In parallel, both CGG and G4C2 repeats trigger phosphorylated-eIF2α-dependent stress granule formation and global translational suppression. These findings support a model whereby repeat expansions elicit cellular stress conditions that favor RAN translation of toxic proteins, creating a potential feed-forward loop that contributes to neurodegeneration

DDX3X and specific initiation factors modulate FMR1 repeat‐associated non‐AUG‐initiated translation

A CGG trinucleotide repeat expansion in the 5′ UTR of FMR1 causes the neurodegenerative disorder Fragile X‐associated tremor/ataxia syndrome (FXTAS). This repeat supports a non‐canonical mode of protein synthesis known as repeat‐associated, non‐AUG (RAN) translation. The mechanism underlying RAN translation at CGG repeats remains unclear. To identify modifiers of RAN translation and potential therapeutic targets, we performed a candidate‐based screen of eukaryotic initiation factors and RNA helicases in cell‐based assays and a Drosophila melanogaster model of FXTAS. We identified multiple modifiers of toxicity and RAN translation from an expanded CGG repeat in the context of the FMR1 5′UTR. These include the DEAD‐box RNA helicase belle/DDX3X, the helicase accessory factors EIF4B/4H, and the start codon selectivity factors EIF1 and EIF5. Disrupting belle/DDX3X selectively inhibited FMR1 RAN translation in Drosophila in vivo and cultured human cells, and mitigated repeat‐induced toxicity in Drosophila and primary rodent neurons. These findings implicate RNA secondary structure and start codon fidelity as critical elements mediating FMR1 RAN translation and identify potential targets for treating repeat‐associated neurodegeneration.SynopsisFragile X‐associated tremor/ataxia syndrome is caused by CGG repeat‐associated non‐AUG (RAN) translation that initiates within the 5′UTR of FMR1. A candidate‐based screen identified several initiation factors—DDX3X/Belle, eIF4B, eIF4H, eIF1, and eIF5—critical for FMR1 RAN translation.Knockdown of the RNA helicase DDX3X selectively suppresses FMR1 RAN translation in Drosophila melanogaster, cultured HeLa cells, and in vitro translation assays.DDX3X knockdown reduces CGG repeat‐associated toxicity in Drosophila and mammalian neurons.Eukaryotic initiation factors that modulate RNA‐RNA secondary structure (DDX3X, EIF4B, EIF4H) or start codon fidelity (EIF1, EIF5) impact FMR1 RAN translation.FXTAS is caused by CGG repeat‐associated non‐AUG (RAN) translation that initiates within the 5′UTR of FMR1. A candidate‐based screen identified several initiation factors—DDX3X/Belle, eIF4B, eIF4H, eIF1, and eIF5—critical for FMR1 RAN translation.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151325/1/embr201847498.reviewer_comments.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151325/2/embr201847498-sup-0001-Appendix.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151325/3/embr201847498_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151325/4/embr201847498.pd

The Hawaii Infrared Parallax Program. III. 2MASS J0249-0557 c:A Wide Planetary-mass Companion to a Low-mass Binary in the β Pic Moving Group

We have discovered a wide planetary-mass companion to the $\beta$ Pic moving group member 2MASSJ02495639-0557352 (M6 VL-G) using CFHT/WIRCam astrometry from the Hawaii Infrared Parallax Program. In addition, Keck laser guide star adaptive optics aperture-masking interferometry shows that the host is itself a tight binary. Altogether, 2MASSJ0249-0557ABc is a bound triple system with an $11.6^{+1.0}_{-1.3}$ $M_{\rm Jup}$ object separated by $1950\pm200$ AU (40") from a relatively close ($2.17\pm0.22$ AU, 0.04") pair of $48^{+12}_{-13}$ $M_{\rm Jup}$ and $44^{+11}_{-14}$ $M_{\rm Jup}$ objects. 2MASSJ0249-0557AB is one of the few ultracool binaries to be discovered in a young moving group and the first confirmed in the $\beta$ Pic moving group ($22\pm6$ Myr). The mass, absolute magnitudes, and spectral type of 2MASSJ0249-0557 c (L2 VL-G) are remarkably similar to those of the planet $\beta$ Pic b (L2, $13.0^{+0.4}_{-0.3}$ $M_{\rm Jup}$). We also find that the free-floating object 2MASSJ2208+2921 (L3 VL-G) is another possible $\beta$ Pic moving group member with colors and absolute magnitudes similar to $\beta$ Pic b and 2MASSJ0249-0557 c. $\beta$ Pic b is the first directly imaged planet to have a "twin," namely an object of comparable properties in the same stellar association. Such directly imaged objects provide a unique opportunity to measure atmospheric composition, variability, and rotation across different pathways of assembling planetary-mass objects from the same natal material.Comment: Accepted to AJ, only change is color scheme of figure

Search for eccentric black hole coalescences during the third observing run of LIGO and Virgo

Despite the growing number of confident binary black hole coalescences observed through gravitational waves so far, the astrophysical origin of these binaries remains uncertain. Orbital eccentricity is one of the clearest tracers of binary formation channels. Identifying binary eccentricity, however, remains challenging due to the limited availability of gravitational waveforms that include effects of eccentricity. Here, we present observational results for a waveform-independent search sensitive to eccentric black hole coalescences, covering the third observing run (O3) of the LIGO and Virgo detectors. We identified no new high-significance candidates beyond those that were already identified with searches focusing on quasi-circular binaries. We determine the sensitivity of our search to high-mass (total mass M>70 M⊙) binaries covering eccentricities up to 0.3 at 15 Hz orbital frequency, and use this to compare model predictions to search results. Assuming all detections are indeed quasi-circular, for our fiducial population model, we place an upper limit for the merger rate density of high-mass binaries with eccentricities 0<e≤0.3 at 0.33 Gpc−3 yr−1 at 90\% confidence level

Search for gravitational-lensing signatures in the full third observing run of the LIGO-Virgo network

Gravitational lensing by massive objects along the line of sight to the source causes distortions of gravitational wave-signals; such distortions may reveal information about fundamental physics, cosmology and astrophysics. In this work, we have extended the search for lensing signatures to all binary black hole events from the third observing run of the LIGO--Virgo network. We search for repeated signals from strong lensing by 1) performing targeted searches for subthreshold signals, 2) calculating the degree of overlap amongst the intrinsic parameters and sky location of pairs of signals, 3) comparing the similarities of the spectrograms amongst pairs of signals, and 4) performing dual-signal Bayesian analysis that takes into account selection effects and astrophysical knowledge. We also search for distortions to the gravitational waveform caused by 1) frequency-independent phase shifts in strongly lensed images, and 2) frequency-dependent modulation of the amplitude and phase due to point masses. None of these searches yields significant evidence for lensing. Finally, we use the non-detection of gravitational-wave lensing to constrain the lensing rate based on the latest merger-rate estimates and the fraction of dark matter composed of compact objects

Ultralight vector dark matter search using data from the KAGRA O3GK run

Among the various candidates for dark matter (DM), ultralight vector DM can be probed by laser interferometric gravitational wave detectors through the measurement of oscillating length changes in the arm cavities. In this context, KAGRA has a unique feature due to differing compositions of its mirrors, enhancing the signal of vector DM in the length change in the auxiliary channels. Here we present the result of a search for U(1)B−L gauge boson DM using the KAGRA data from auxiliary length channels during the first joint observation run together with GEO600. By applying our search pipeline, which takes into account the stochastic nature of ultralight DM, upper bounds on the coupling strength between the U(1)B−L gauge boson and ordinary matter are obtained for a range of DM masses. While our constraints are less stringent than those derived from previous experiments, this study demonstrates the applicability of our method to the lower-mass vector DM search, which is made difficult in this measurement by the short observation time compared to the auto-correlation time scale of DM

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570