We present the first limits on inelastic electron-scattering dark matter and dark photon absorption using a prototype SuperCDMS detector having a charge resolution of 0.1 electron-hole pairs (CDMS ...HVeV, a 0.93 g CDMS high-voltage device). These electron-recoil limits significantly improve experimental constraints on dark matter particles with masses as low as 1 MeV/c^{2}. We demonstrate a sensitivity to dark photons competitive with other leading approaches but using substantially less exposure (0.49 g d). These results demonstrate the scientific potential of phonon-mediated semiconductor detectors that are sensitive to single electronic excitations.
This article presents an analysis and the resulting limits on light dark matter inelastically scattering off of electrons, and on dark photon and axionlike particle absorption, using a ...second-generation SuperCDMS high-voltage eV-resolution detector. The 0.93 g Si detector achieved a 3 eV phonon energy resolution; for a detector bias of 100 V, this corresponds to a charge resolution of 3% of a single electron-hole pair. The energy spectrum is reported from a blind analysis with 1.2 g-days of exposure acquired in an above-ground laboratory. With charge carrier trapping and impact ionization effects incorporated into the dark matter signal models, the dark matter-electron cross section σe is constrained for dark matter masses from 0.5 to 104 MeV / c2; in the mass range from 1.2 to 50 eV / c2 the dark photon kinetic mixing parameter ϵ and the axioelectric coupling constant gae are constrained. The minimum 90% confidence-level upper limits within the above-mentioned mass ranges are σe = 8.7 × 10−34 cm2, ϵ = 3.3 × 10−14, and gae = 1.0 × 10−9.
RATIONALE:Loss-of-function studies in cardiac myocytes (CMs) are currently limited by the need for appropriate conditional knockout alleles. The factors that regulate CM maturation are poorly ...understood. Previous studies on CM maturation have been confounded by heart dysfunction caused by whole organ gene inactivation.
OBJECTIVE:To develop a new technical platform to rapidly characterize cell-autonomous gene function in postnatal murine CMs and apply it to identify genes that regulate transverse tubules (T-tubules), a hallmark of mature CMs.
METHODS AND RESULTS:We developed CRISPR/Cas9/AAV9-based somatic mutagenesis, a platform in which AAV9 delivers tandem guide RNAs targeting a gene of interest and cardiac troponin-T promoter–driven Cre to Rosa neonatal mice. When directed against junctophilin-2 (Jph2), a gene previously implicated in T-tubule maturation, we achieved efficient, rapid, and CM-specific JPH2 depletion. High-dose AAV9 ablated JPH2 in 64% CMs and caused lethal heart failure, whereas low-dose AAV9 ablated JPH2 in 22% CMs and preserved normal heart function. In the context of preserved heart function, CMs lacking JPH2 developed T-tubules that were nearly morphologically normal, indicating that JPH2 does not have a major, cell-autonomous role in T-tubule maturation. However, in hearts with severe dysfunction, both adeno-associated virus–transduced and nontransduced CMs exhibited T-tubule disruption, which was more severe in the transduced subset. These data indicate that cardiac dysfunction disrupts T-tubule structure and that JPH2 protects T-tubules in this context. We then used CRISPR/Cas9/AAV9-based somatic mutagenesis to screen 8 additional genes for required, cell-autonomous roles in T-tubule formation. We identified RYR2 (Ryanodine Receptor-2) as a novel, cell-autonomously required T-tubule maturation factor.
CONCLUSIONS:CRISPR/Cas9/AAV9-based somatic mutagenesis is a powerful tool to study cell-autonomous gene functions. Genetic mosaics are invaluable to accurately define cell-autonomous gene function. JPH2 has a minor role in normal T-tubule maturation but is required to stabilize T-tubules in the failing heart. RYR2 is a novel T-tubule maturation factor.
We report the result of a blinded search for weakly interacting massive particles (WIMPs) using the majority of the SuperCDMS Soudan data set. With an exposure of 1690 kg d, a single candidate event ...is observed, consistent with expected backgrounds. This analysis (combined with previous Ge results) sets an upper limit on the spin-independent WIMP-nucleon cross section of 1.4×10^{-44} (1.0×10^{-44}) cm^{2} at 46 GeV/c^{2}. These results set the strongest limits for WIMP-germanium-nucleus interactions for masses >12 GeV/c^{2}.
The paucity of knowledge about cardiomyocyte maturation is a major bottleneck in cardiac regenerative medicine. In development, cardiomyocyte maturation is characterized by orchestrated structural, ...transcriptional, and functional specializations that occur mainly at the perinatal stage. Sarcomeres are the key cytoskeletal structures that regulate the ultrastructural maturation of other organelles, but whether sarcomeres modulate the signal transduction pathways that are essential for cardiomyocyte maturation remains unclear. To address this question, here we generated mice with cardiomyocyte-specific, mosaic, and hypomorphic mutations of α-actinin-2 (
) to study the cell-autonomous roles of sarcomeres in postnatal cardiomyocyte maturation.
mutation resulted in defective structural maturation of transverse-tubules and mitochondria. In addition,
mutation triggered transcriptional dysregulation, including abnormal expression of key sarcomeric and mitochondrial genes, and profound impairment of the normal progression of maturational gene expression. Mechanistically, the transcriptional changes in
mutant cardiomyocytes strongly correlated with those in cardiomyocytes deleted of serum response factor (SRF), a critical transcription factor that regulates cardiomyocyte maturation.
mutation increased the monomeric form of cardiac α-actin, which interacted with the SRF cofactor MRTFA and perturbed its nuclear localization. Overexpression of a dominant-negative MRTFA mutant was sufficient to recapitulate the morphological and transcriptional defects in
and
mutant cardiomyocytes. Together, these data indicate that
-based sarcomere organization regulates structural and transcriptional maturation of cardiomyocytes through MRTF-SRF signaling.
We present an analysis of electron recoils in cryogenic germanium detectors operated during the SuperCDMS Soudan experiment. The data are used to set new constraints on the axioelectric coupling of ...axionlike particles and the kinetic mixing parameter of dark photons, assuming the respective species constitutes all of the galactic dark matter. This study covers the mass range from 40 eV/c2to 500 keV/c2for both candidates, excluding previously untested parameter space for masses below ∼ 1 keV/c2. For the kinetic mixing of dark photons, values below 10−15 are reached for particle masses around 100 eV/c2; for the axioelectric coupling of axionlike particles, values below 10−12 are reached for particles with masses in the range of a few-hundred eV/c2.
After birth, cardiomyocytes (CM) acquire numerous adaptations in order to efficiently pump blood throughout an animal's lifespan. How this maturation process is regulated and coordinated is poorly ...understood. Here, we perform a CRISPR/Cas9 screen in mice and identify serum response factor (SRF) as a key regulator of CM maturation. Mosaic SRF depletion in neonatal CMs disrupts many aspects of their maturation, including sarcomere expansion, mitochondrial biogenesis, transverse-tubule formation, and cellular hypertrophy. Maintenance of maturity in adult CMs is less dependent on SRF. This stage-specific activity is associated with developmentally regulated SRF chromatin occupancy and transcriptional regulation. SRF directly activates genes that regulate sarcomere assembly and mitochondrial dynamics. Perturbation of sarcomere assembly but not mitochondrial dynamics recapitulates SRF knockout phenotypes. SRF overexpression also perturbs CM maturation. Together, these data indicate that carefully balanced SRF activity is essential to promote CM maturation through a hierarchy of cellular processes orchestrated by sarcomere assembly.
Cardiac excitation-contraction coupling requires dyads, the nanoscopic microdomains formed adjacent to Z-lines by apposition of transverse tubules and junctional sarcoplasmic reticulum. Disruption of ...dyad architecture and function are common features of diseased cardiomyocytes. However, little is known about the mechanisms that modulate dyad organization during cardiac development, homeostasis, and disease. Here, we use proximity proteomics in intact, living hearts to identify proteins enriched near dyads. Among these proteins is CMYA5, an under-studied striated muscle protein that co-localizes with Z-lines, junctional sarcoplasmic reticulum proteins, and transverse tubules in mature cardiomyocytes. During cardiac development, CMYA5 positioning adjacent to Z-lines precedes junctional sarcoplasmic reticulum positioning or transverse tubule formation. CMYA5 ablation disrupts dyad architecture, dyad positioning at Z-lines, and junctional sarcoplasmic reticulum Ca
release, leading to cardiac dysfunction and inability to tolerate pressure overload. These data provide mechanistic insights into cardiomyopathy pathogenesis by demonstrating that CMYA5 anchors junctional sarcoplasmic reticulum to Z-lines, establishes dyad architecture, and regulates dyad Ca
release.
Recent breakthroughs in cryogenic silicon detector technology allow for the observation of single electron-hole pairs released via particle interactions within the target material. This implies ...sensitivity to energy depositions as low as the smallest band gap, which is ∼ 1.2 eV for silicon, and therefore sensitivity to eV / c2-scale bosonic dark matter and to thermal dark matter at masses below 100 MeV / c2. Various interaction channels that can probe the lowest currently accessible masses in direct searches are related to standard photoelectric absorption. In any of these respective dark matter signal models any uncertainty on the photoelectric absorption cross section is propagated into the resulting exclusion limit or into the significance of a potential observation. Using first-time precision measurements of the photoelectric absorption cross section in silicon recently performed at Stanford University, this article examines the importance having accurate knowledge of this parameter at low energies and cryogenic temperatures for these dark matter searches.
PDF
