Cardiac dysfunction is a hallmark of aging in humans and mice. Here we report that a two-week treatment to restore youthful Bridging Integrator 1 (BIN1) levels in the hearts of 24-month-old mice ...rejuvenates cardiac function and substantially reverses the aging phenotype. Our data indicate that age-associated overexpression of BIN1 occurs alongside dysregulated endosomal recycling and disrupted trafficking of cardiac Ca
1.2 and type 2 ryanodine receptors. These deficiencies affect channel function at rest and their upregulation during acute stress. In vivo echocardiography reveals reduced systolic function in old mice. BIN1 knockdown using an adeno-associated virus serotype 9 packaged shRNA-mBIN1 restores the nanoscale distribution and clustering plasticity of ryanodine receptors and recovers Ca
transient amplitudes and cardiac systolic function toward youthful levels. Enhanced systolic function correlates with increased phosphorylation of the myofilament protein cardiac myosin binding protein-C. These results reveal BIN1 knockdown as a novel therapeutic strategy to rejuvenate the aging myocardium.
Abstract
Active Pixel sensors play a crucial role in enabling successful low-light scientific experiments due to their inherent advantages and capabilities. Such devices not only offer high spatial ...resolution but also feature individual pixels with integrated amplifiers, allowing for direct signal amplification at the pixel level. This results in reduced readout noise and improved signal-to-noise ratio (SNR), which are particularly vital when dealing with limited photon counts in low-light environments. This holds particularly true for scientific CMOS (sCMOS) sensors, acknowledged as an advanced evolution of Active Pixel sensors. However, despite their advantages, such sensors can still exhibit limitations such as higher cost and presence of noise artifacts that should be closely investigated. In particular, CYGNO project fits in a global effort aimed at direct detection of Dark Matter particles. CYGNO collaboration intends to build a detector based on a Time Projection Chamber making use of Gas Electron Multipliers for the amplification of ionization electrons. The GEM multiplication process produces photons that can be readout by a high-resolution sCMOS sensor. Such detection system is being designed to have enough sensitivity to detect low-energy particles and to measure released energy with enough granularity so to reconstruct direction and energy profile along their trajectories. The image sensor has an important role in the detector performance, having a direct impact on the SNR of the experiment. This work proposes a study on the performance of three different sCMOS sensors with respect to their sensitivity to low-energy particles and their intrinsic noise, which are of the utmost importance for various scientific experiments.
LIVE:LIFE is a multi-centre, open-label, prospective observational cohort study assessing health-related quality of life (HRQoL) in older patients with chronic heart failure (CHF) following ...initiation of ivabradine. The primary endpoint is change in Minnesota Living with Heart Failure Questionnaire (MLWHFQ) total score after 6months.
Consenting patients aged ≥70years with CHF, in whom ivabradine was initiated within its licensed indication, were enrolled. Demographic, clinical and HRQoL (MLWHFQ, SF-12) data were collected at baseline (V1), 2 (V2) and 6months (V3). Over 14months, 240 patients were recruited from 44 UK centres. Ninety-nine (41%) were female and 28% aged ≥80years. Aetiology was ischaemic in 152 (63%) and 59% had been diagnosed with CHF for ≤2yrs. 52% of patients were New York Heart Association (NYHA) Class III and 57% had left ventricular ejection fraction <35%. 57% received beta-blockers. Patients had multiple comorbidities (144 (60%) hypertension, 105 (44%) asthma/COPD, 80 (33%) diabetes) and were prescribed a mean of 9±3 daily medications. Resting heart rate was 83bpm at baseline and fell 13bpm by V3. In patients completing both visits (n=187), comparing V3 to baseline: MLWHFQ total score improved by 9 points (p<0.0001, 95% CI: 7–12); 30% of patients improved ≥1 NYHA class and global assessment improved from patient (59%) and physician (60%) perspectives. 88% of patients completing V3 were still taking ivabradine.
These contemporary prospective UK data demonstrate improvements in HRQoL and functional status with ivabradine therapy in typical older CHF patients. Despite comorbidities and polypharmacy, ivabradine was well tolerated.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Low-pressure gas Time Projection Chambers being developed for directional dark matter searches offer a technology with strong particle identification capability combined with the potential to produce ...a definitive detection of Galactic Weakly Interacting Massive Particle (WIMP) dark matter. A source of events able to mimic genuine WIMP-induced nuclear recoil tracks arises in such experiments from the decay of radon gas inside the vacuum vessel. The recoils that result from associated daughter nuclei are termed Radon Progeny Recoils (RPRs). We present here experimental data from a long-term study using the DRIFT-II directional dark matter experiment at the Boulby Underground Laboratory of the RPRs, and other backgrounds that are revealed by relaxing the normal cuts that are applied to WIMP search data. By detailed examination of event classes in both spatial and time coordinates using 3.5 years of data, we demonstrate the ability to determine the origin of 4 specific background populations and describe development of new technology and mitigation strategies to suppress them.
We present the first search for a dark matter annual modulation signal in the Southern Hemisphere conducted with NaI(Tl) detectors, performed by the DM-Ice17 experiment. Nuclear recoils from dark ...matter interactions are expected to yield an annually modulated signal independent of location within the Earth’s hemispheres. DM-Ice17, the first step in the DM-Ice experimental program, consists of 17 kg of NaI(Tl) located at the South Pole under 2200 m.w.e. overburden of Antarctic glacial ice. Taken over 3.6 years for a total exposure of 60.8 kg yr, DM-Ice17 data are consistent with no modulation in the energy range of 4–20 keV, providing the strongest limits on weakly interacting massive particle dark matter from a direct detection experiment located in the Southern Hemisphere. The successful deployment and stable long-term operation of DM-Ice17 establishes the South Pole ice as a viable location for future dark matter searches and in particular for a high-sensitivity NaI(Tl) dark matter experiment to directly test the DAMA/LIBRA claim of the observation of dark matter.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UM
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