Sarcospan Regulates Cardiac Isoproterenol Response and Prevents Duchenne Muscular Dystrophy-Associated Cardiomyopathy.

BackgroundDuchenne muscular dystrophy is a fatal cardiac and skeletal muscle disease resulting from mutations in the dystrophin gene. We have previously demonstrated that a dystrophin-associated protein, sarcospan (SSPN), ameliorated Duchenne muscular dystrophy skeletal muscle degeneration by activating compensatory pathways that regulate muscle cell adhesion (laminin-binding) to the extracellular matrix. Conversely, loss of SSPN destabilized skeletal muscle adhesion, hampered muscle regeneration, and reduced force properties. Given the importance of SSPN to skeletal muscle, we investigated the consequences of SSPN ablation in cardiac muscle and determined whether overexpression of SSPN into mdx mice ameliorates cardiac disease symptoms associated with Duchenne muscular dystrophy cardiomyopathy.Methods and resultsSSPN-null mice exhibited cardiac enlargement, exacerbated cardiomyocyte hypertrophy, and increased fibrosis in response to β-adrenergic challenge (isoproterenol; 0.8 mg/day per 2 weeks). Biochemical analysis of SSPN-null cardiac muscle revealed reduced sarcolemma localization of many proteins with a known role in cardiomyopathy pathogenesis: dystrophin, the sarcoglycans (α-, δ-, and γ-subunits), and β1D integrin. Transgenic overexpression of SSPN in Duchenne muscular dystrophy mice (mdx(TG)) improved cardiomyofiber cell adhesion, sarcolemma integrity, cardiac functional parameters, as well as increased expression of compensatory transmembrane proteins that mediate attachment to the extracellular matrix.ConclusionsSSPN regulates sarcolemmal expression of laminin-binding complexes that are critical to cardiac muscle function and protects against transient and chronic injury, including inherited cardiomyopathy

Field-Induced Xy And Ising Ground States In A Quasi-Two-Dimensional S=1/2 Heisenberg Antiferromagnet

High field specific heat up to 35 T, C-p, and magnetic susceptibility, chi, measurements were performed on the quasi-two-dimensional (2D) Heisenberg antiferromagnet [Cu(pyz)(2)(pyO)(2)](PF6)(2). While no C-p anomaly is observed down to 0.5 K in zero magnetic field, the application of field parallel to the crystallographic ab-plane induces a lambda-like anomaly in C-p, suggesting Ising-type magnetic order. On the other hand when the field is parallel to the c-axis, C-p and chi show evidence of XY-type antiferromagnetism. This dependence upon the field orientation occurs because the extreme two-dimensionality allows the intrinsic (zero field) spin anisotropy to dominate the interlayer coupling, which has hitherto masked such effects in other materials

Experimental realization of field-induced XY and Ising ground states in a quasi-2D S=1/2 Heisenberg antiferromagnet

High field specific heat, Cp, and magnetic susceptibility, \c{hi}, measurements were performed on the quasi-two dimensional Heisenberg antiferromagnet [Cu(pyz)2(pyO)2](PF6)2. While no Cp anomaly is observed down to 0.5 K in zero magnetic field, the application of field parallel to the crystallographic ab-plane induces a lambda-like anomaly in Cp, consistent with Ising-type magnetic order. On the other hand, when the field is parallel to the c-axis, Cp and \c{hi} show evidence of XY-type antiferromagnetism. We argue that it is a small but finite easy-plane anisotropy in quasi-two dimensional [Cu(pyz)2(pyO)2](PF6)2 that allows the unusual observation of field induced XY and Ising-type magnetic states.Comment: 4 figure

Preclinical development of G1T38: A novel, potent and selective inhibitor of cyclin dependent kinases 4/6 for use as an oral antineoplastic in patients with CDK4/6 sensitive tumors

Inhibition of the p16INK4a/cyclin D/CDK4/6/RB pathway is an effective therapeutic strategy for the treatment of estrogen receptor positive (ER+) breast cancer. Although efficacious, current treatment regimens require a dosing holiday due to severe neutropenia potentially leading to an increased risk of infections, as well as tumor regrowth and emergence of drug resistance. Therefore, a next generation CDK4/6 inhibitor that can inhibit proliferation of CDK4/6-dependent tumors while minimizing neutropenia could reduce both the need for treatment holidays and the risk of inducing drug resistance

Buffalo Reading List

This reading list gathers together literature focused on buffalo (also known as bison) to support ongoing efforts to restore this iconic species to its keystone cultural and ecological role. The books and articles compiled here are grounded in a wide range of academic disciplines and approaches, representing many distinct ways of thinking about buffalo within the realm of Western sciences. This is not intended to be an exhaustive account of what is known about buffalo, much of which is held in Indigenous knowledge systems and communities. This academic list is designed as a resource for those working towards buffalo restoration, including conservation practitioners, researchers, parks and government officials, and Tribal communities. It is divided into categories according to either discipline or thematic focus, each containing a subset of pertinent literature. Topics include the paleobiology of bison, histories of buffalo loss, relationships between Indigenous Peoples and buffalo, buffalo restoration and reintroduction, buffalo ecology, buffalo and climate change, governance and human dimensions of buffalo, bison and cattle, bison as livestock, and the genetics of bison. This list is intended as a living document to grow with the increasingly rich scholarship on buffalo, and will be updated regularly

FASER: ForwArd Search ExpeRiment at the LHC

FASER, the ForwArd Search ExpeRiment, is a proposed experiment dedicated to searching for light, extremely weakly-interacting particles at the LHC. Such particles may be produced in the LHC's high-energy collisions in large numbers in the far-forward region and then travel long distances through concrete and rock without interacting. They may then decay to visible particles in FASER, which is placed 480 m downstream of the ATLAS interaction point. In this work, we describe the FASER program. In its first stage, FASER is an extremely compact and inexpensive detector, sensitive to decays in a cylindrical region of radius R = 10 cm and length L = 1.5 m. FASER is planned to be constructed and installed in Long Shutdown 2 and will collect data during Run 3 of the 14 TeV LHC from 2021-23. If FASER is successful, FASER 2, a much larger successor with roughly R ~ 1 m and L ~ 5 m, could be constructed in Long Shutdown 3 and collect data during the HL-LHC era from 2026-35. FASER and FASER 2 have the potential to discover dark photons, dark Higgs bosons, heavy neutral leptons, axion-like particles, and many other long-lived particles, as well as provide new information about neutrinos, with potentially far-ranging implications for particle physics and cosmology. We describe the current status, anticipated challenges, and discovery prospects of the FASER program.Comment: 13 pages, 4 figures, submitted as Input to the European Particle Physics Strategy Update 2018-2020 and draws on FASER's Letter of Intent, Technical Proposal, and physics case documents (arXiv:1811.10243, arXiv:1812.09139, and arXiv:1811.12522

Metadata Framework to Support Deployment of Digital Health Technologies in Clinical Trials in Parkinson’s Disease

Sensor data from digital health technologies (DHTs) used in clinical trials provides a valuable source of information, because of the possibility to combine datasets from different studies, to combine it with other data types, and to reuse it multiple times for various purposes. To date, there exist no standards for capturing or storing DHT biosensor data applicable across modalities and disease areas, and which can also capture the clinical trial and environment-specific aspects, so-called metadata. In this perspectives paper, we propose a metadata framework that divides the DHT metadata into metadata that is independent of the therapeutic area or clinical trial design (concept of interest and context of use), and metadata that is dependent on these factors. We demonstrate how this framework can be applied to data collected with different types of DHTs deployed in the WATCH-PD clinical study of Parkinson’s disease. This framework provides a means to pre-specify and therefore standardize aspects of the use of DHTs, promoting comparability of DHTs across future studies

Technical Proposal for FASER: ForwArd Search ExpeRiment at the LHC

FASER is a proposed small and inexpensive experiment designed to search for light, weakly-interacting particles during Run 3 of the LHC from 2021-23. Such particles may be produced in large numbers along the beam collision axis, travel for hundreds of meters without interacting, and then decay to standard model particles. To search for such events, FASER will be located 480 m downstream of the ATLAS IP in the unused service tunnel TI12 and be sensitive to particles that decay in a cylindrical volume with radius R=10 cm and length L=1.5 m. FASER will complement the LHC's existing physics program, extending its discovery potential to a host of new, light particles, with potentially far-reaching implications for particle physics and cosmology. This document describes the technical details of the FASER detector components: the magnets, the tracker, the scintillator system, and the calorimeter, as well as the trigger and readout system. The preparatory work that is needed to install and operate the detector, including civil engineering, transport, and integration with various services is also presented. The information presented includes preliminary cost estimates for the detector components and the infrastructure work, as well as a timeline for the design, construction, and installation of the experiment.Comment: 82 pages, 62 figures; submitted to the CERN LHCC on 7 November 201

The forgotten drought of 1765–1768: Reconstructing and re-evaluating historical droughts in the British and Irish Isles

Historical precipitation records are fundamental for the management of water resources, yet rainfall observations typically span 100–15 0 years at most, with considerable uncertainties surrounding earlier records. Here, we analyse some of the longest a vailabl e precipitation records globally, for England and Wales, Scotland and Ireland. To assess the credibility of these records and extend them further back in time, we statistically reconstruct (using independent predictors) monthly precipitation series representing these regions for the period 1748–2000. By applying the Standardized Precipi- tation Index at 12-month accumulations (SPI-12) to the observed and our reconstructed series we re-evaluate historical meteorological droughts. We find strong agreement between observed and reconstructed drought chronol- ogies in post-1870 records, but divergence in e arlier series due to biases in early precipitation observations. Hence, the 1800s decade was less drought prone in our reconstructions relative to observations. Overall, the drought of 1834–1836 was the most intense SPI-12 event in our reconstruction for England and Wales. Newspaper accounts and documentary sources confirm the extent of impacts across England in particular. We also identify a major, “forgotten” drought in 1765–1768 that affected the British-Irish Isles. This was the most intense event in our reconstructions for Ireland and Scotland, and ranks first for accumulated deficits a cross all three regional series. Moreover, the 1765–1768 event was also the most extreme multi-year drought across all regional series when considering 36-month a ccumulations (SPI-36). Newspaper and other sources confirm the occurrence and major socio- economic impact of this drought, such as major rivers like the Shannon being fordable by foot. Our results provide new insights into historical droughts across the British Irish Isles. Given the importance of historical droughts for stress-testing the resilience of water resources, drought plans and supply sys- tems, the forgotten drought of 1765–1 768 offers perhaps the most extreme benchmark scenario in more than 250-years