The electronics of the LZ experiment, the 7-tonne dark matter detector to be installed at the Sanford Underground Research Facility (SURF), is designed to permit studies of physics where the energies deposited range from 1 keV of nuclear-recoil energy up to 3,000 keV of electron-recoil energy. The system is designed to provide a 70% efficiency for events that produce three photoelectrons in the photomultiplier tubes (PMTs). This corresponds approximately to the lowest energy threshold achievable in multi-tonne time-projection chambers, and drives the noise specifications for the front end. The upper limit of the LZ dynamic range is defined to accommodate the electroluminescence (S2) signals. The low-energy channels of the LZ amplifiers provide the dynamic range required for the tritium and krypton calibrations. The high-energy channels provide the dynamic range required to measure the activated Xe lines.

Abstract: Background: After initial treatment for ductal carcinoma in situ (DCIS), a subsequent clinically significant event (SCSE) such as another diagnosis of DCIS, atypia or invasive breast cancer (IBC), will likely lead to further surgical/medical therapy. Pathologically, DCIS is treated on the basis of estrogen (ER) and progesterone receptor (PR) status with hormonal therapy (HT), ie, tamoxifen (TMX) or aromatase inhibitor, regardless of human epidermal growth factor receptor (HER2) overexpression. Although HER2 is a well-established prognostic marker for IBC, the role of HER2 in DCIS is less appreciated. Recent studies have documented the prognostic value of p16, COX-2 and Ki67 as prognostic biomarkers for locoregional invasive recurrences due to abrogated response to cellular stress (ARCS). Notably, a high-risk population of DCIS patients lacking ER expression but over-expressing HER2, p16 and COX-2 has been recently identified. In the present study, we compared expression levels of HER2 and the 3 ARCS markers in a large cohort of DCIS patients treated with contemporary standard of care and with >5-year follow-up to assess their association with cancer progression and predictive value for developing a SCSE. Methods: Formalin-fixed paraffin-embedded tissue sections from 99 patients diagnosed with primary DCIS(1999-2013) were stained forER, PR and HER2 expression by immunohistochemistry (IHC).If equivocal, HER2 amplification was assessed by Silver In Situ Hybridization. An additional slide was stained forp16, Ki67 and COX-2 using a novel multiplex IHC strategy. Quantification of the 3 ARCS markers' expression in both epithelial and stromal compartments was carried out using a software (InformTM)-guided approach. For expression level comparison of the three markers between HER2+ and HER2- DCIS, Wilcoxon-Mann-Whitney test was used. Fisher's exact or Chi-square test was used for other data analysis. Results: Simultaneous increase in epithelial p16, COX-2 and Ki67 expression in DCIS lesions was associated with subsequent IBC progression. HER2+ DCIS was significantly associated with high grade (p=0.0014), comedo-necrosis subtype (p=0.0022) compared to HER2- lesions. Upregulation of stromal COX-2 and p16 was significantly (p=0.008) associated with progression to SCSE in HER2- DCIS. The majority (5/6, 83%) of HER2+ DCIS patients treated with HT developed a SCSE, while only 22% (6/27) of HER2- DCIS patients treated with HT developed a SCSE. COX-2 upregulation was significantly associated with resistance to HT in HER2+ DCIS patients. Conclusion: High expression of p16, COX-2 and Ki67 in DCIS lesions can serve as powerful predictive biomarkers for DCIS progression to IBC. Our preliminary data suggest that overexpression of stromal p16 and COX-2 may help predict SCSEs in HER2- DCIS. Additionally, assessment of HER2 expression in DCIS may allow identification of patients who would not benefit from traditional HT as HER2 overexpression may predict TMX resistance. Since our data suggest that TMX resistance in HER2+ DCIS may be linked to upregulation of COX-2, one may propose that COX-2 inhibitors in conjunction with TMX may minimize TMX resistance in HER2+ DCIS. These preliminary data will need to be reproduced in a larger cohort to solidify their significance. Citation Format: Yin J, Gascard P, Last B, Singh M, Tlsty T, Tjoe JA. HER2 overexpression in ductal carcinoma in situ: A biomarker for risk stratification and therapeutic implication [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-18-04.

Herein, we report a new approach to bio-inspired catalyst design. The molecular catalyst employed in these studies is based on the robust and selective Re(bpy)(CO)₃Cl-type (bpy = 2,2'-bipyridine) homogeneous catalysts, which have been extensively studied for their ability to reduce CO₂ electrochemically or photochemically in the presence of a photosensitizer. These catalysts can be highly active photocatalysts in their own right. In this work, the bipyridine ligand was modified with amino acids and synthetic peptides. These results build on earlier findings wherein the bipyridine ligand was functionalized with amide groups to promote dimer formation and CO₂ reduction by an alternate bimolecular mechanism at lower overpotential (ca. 250 mV) than the more commonly observed unimolecular process. The bio-inspired catalysts were designed to allow for the incorporation of proton relays to support reduction of CO₂ to CO and H₂O. The coupling of amino acids tyrosine and phenylalanine led to the formation of two structurally similar Re catalyst/peptide catalysts for comparison of proton transport during catalysis. This article reports the synthesis and characterization of novel catalyst/peptide hybrids by molecular dynamics (MD simulations of structural dynamics), NMR studies of solution phase structures, and electrochemical studies to measure the activities of new bio-inspired catalysts in the reduction of CO_2.

© 2015 Macmillan Publishers Limited.Recent studies implicate chromatin modifiers in autism spectrum disorder (ASD) through the identification of recurrent de novo loss of function mutations in affected individuals. ASD risk genes are co-expressed in human

The poly-ADP-ribosylation (PARsylation) activity of tankyrase (TNKS) regulates diverse physiological processes including energy metabolism and wnt/β-catenin signaling. This TNKS activity uses NAD+ as a co-substrate to post-translationally modify various acceptor proteins including TNKS itself. PARsylation by TNKS often tags the acceptors for ubiquitination and proteasomal degradation. Whether this TNKS activity is regulated by physiological changes in NAD+ levels or, more broadly, in cellular energy charge has not been investigated. Because the NAD+ biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT) in vitro is robustly potentiated by ATP, we hypothesized that nutritional energy might stimulate cellular NAMPT to produce NAD+ and thereby augment TNKS catalysis. Using insulin-secreting cells as a model, we showed that glucose indeed stimulates the autoPARsylation of TNKS and consequently its turnover by the ubiquitin-proteasomal system. This glucose effect on TNKS is mediated primarily by NAD+ since it is mirrored by the NAD+ precursor nicotinamide mononucleotide (NMN), and is blunted by the NAMPT inhibitor FK866. The TNKS-destabilizing effect of glucose is shared by other metabolic fuels including pyruvate and amino acids. NAD+ flux analysis showed that glucose and nutrients, by increasing ATP, stimulate NAMPT-mediated NAD+ production to expand NAD+ stores. Collectively our data uncover a metabolic pathway whereby nutritional energy augments NAD+ production to drive the PARsylating activity of TNKS, leading to autoPARsylation-dependent degradation of the TNKS protein. The modulation of TNKS catalytic activity and protein abundance by cellular energy charge could potentially impose a nutritional control on the many processes that TNKS regulates through PARsylation. More broadly, the stimulation of NAD+ production by ATP suggests that nutritional energy may enhance the functions of other NAD+-driven enzymes including sirtuins.

We report muon spin rotation (μSR) experiments together with first-principles calculations on microscopic properties of superconductivity in the kagome superconductor LaRu3Si2 with Tc≃ 7K. Below Tc, μSR reveals type-II superconductivity with a single s-wave gap, which is robust against hydrostatic pressure up to 2 GPa. We find that the calculated normal state band structure features a kagome flat band, and Dirac as well as van Hove points formed by the Ru-dz2 orbitals near the Fermi level. We also find that electron-phonon coupling alone can only reproduce a small fraction of Tc from calculations, which suggests other factors in enhancing Tc such as the correlation effect from the kagome flat band, the van Hove point on the kagome lattice, and the high density of states from narrow kagome bands. Our experiments and calculations taken together point to nodeless moderate coupling kagome superconductivity in LaRu3Si2.

Unconventional superconductors often feature competing orders, small superfluid density, and nodal electronic pairing. While unusual superconductivity has been proposed in the kagome metals AV₃Sb₅, key spectroscopic evidence has remained elusive. Here we utilize pressure-tuned and ultra-low temperature muon spin spectroscopy to uncover the unconventional nature of superconductivity in RbV₃Sb₅ and KV₃Sb₅. At ambient pressure, we observed time-reversal symmetry breaking charge order below [Formula: see text] 110 K in RbV₃Sb₅ with an additional transition at [Formula: see text] 50 K. Remarkably, the superconducting state displays a nodal energy gap and a reduced superfluid density, which can be attributed to the competition with the charge order. Upon applying pressure, the charge-order transitions are suppressed, the superfluid density increases, and the superconducting state progressively evolves from nodal to nodeless. Once optimal superconductivity is achieved, we find a superconducting pairing state that is not only fully gapped, but also spontaneously breaks time-reversal symmetry. Our results point to unprecedented tunable nodal kagome superconductivity competing with time-reversal symmetry-breaking charge order and offer unique insights into the nature of the pairing state.

Magnetic topological phases of quantum matter are an emerging frontier in physics and materials science, of which kagome magnets appear as a highly promising platform. Here, we explore magnetic correlations in the recently identified topological kagome system TbMn6Sn6 using muon spin rotation, combined with local field analysis and neutron diffraction. Our studies identify an out-of-plane ferrimagnetic structure with slow magnetic fluctuations which exhibit a critical slowing down below TC1* ≃ 120 K and finally freeze into static patches with ideal out-of-plane order below TC1 ≃ 20 K. We further show that hydrostatic pressure of 2.1 GPa stabilises the static out-of-plane topological ferrimagnetic ground state in the whole volume of the sample. Therefore the exciting perspective arises of a magnetically-induced topological system whose magnetism can be controlled through external parameters. The present results will stimulate theoretical investigations to obtain a microscopic understanding of the relation between the low-temperature volume-wise magnetic evolution of the static c-axis ferrimagnetic patches and the topological electronic properties in TbMn6Sn6.

Magnetic topological phases of quantum matter are an emerging frontier in physics and material science. Along these lines, several kagome magnets have appeared as the most promising platforms. Here, we explore magnetic correlations in the kagome magnet Co₃Sn₂S₂. Using muon spin-rotation, we present evidence for competing magnetic orders in the kagome lattice of this compound. Our results show that while the sample exhibits an out-of-plane ferromagnetic ground state, an in-plane antiferromagnetic state appears at temperatures above 90 K, eventually attaining a volume fraction of 80% around 170 K, before reaching a non-magnetic state. Strikingly, the reduction of the anomalous Hall conductivity (AHC) above 90 K linearly follows the disappearance of the volume fraction of the ferromagnetic state. We further show that the competition of these magnetic phases is tunable through applying either an external magnetic field or hydrostatic pressure. Our results taken together suggest the thermal and quantum tuning of Berry curvature induced AHC via external tuning of magnetic order.