Notch Signaling Regulates Bile Duct Morphogenesis in Mice

BACKGROUND: Alagille syndrome is a developmental disorder caused predominantly by mutations in the Jagged1 (JAG1) gene, which encodes a ligand for Notch family receptors. A characteristic feature of Alagille syndrome is intrahepatic bile duct paucity. We described previously that mice doubly heterozygous for Jag1 and Notch2 mutations are an excellent model for Alagille syndrome. However, our previous study did not establish whether bile duct paucity in Jag1/Notch2 double heterozygous mice resulted from impaired differentiation of bile duct precursor cells, or from defects in bile duct morphogenesis. METHODOLOGY/PRINCIPAL FINDINGS: Here we characterize embryonic biliary tract formation in our previously described Jag1/Notch2 double heterozygous Alagille syndrome model, and describe another mouse model of bile duct paucity resulting from liver-specific deletion of the Notch2 gene. CONCLUSIONS/SIGNIFICANCE: Our data support a model in which bile duct paucity in Notch pathway loss of function mutant mice results from defects in bile duct morphogenesis rather than cell fate specification

Inhibiting IL-1beta-mediated inflammation in pediatric and young adult patients with sickle cell anemia: a randomized, placebo-controlled, double-blind trial with canakinumab (ACZ885)

Excessive intravascular release of lysed cellular contents from damaged red blood cells (RBCs) in patients with sickle cell anemia (SCA) can activate the inflammasome, a multiprotein oligomer promoting maturation and secretion of pro-inflammatory cytokines, including interleukin 1-beta (IL-1). We hypothesized that IL-1 blockade by canakinumab in patients with SCA would reduce markers of inflammation and clinical disease activity. In this randomized, double-blind, multi-center phase 2a study, patients aged 8-20 years old with SCA (HbSS or HbS0thalassemia), history of acute pain episodes and elevated hsCRP >1.0 mg/L at screening were randomized 1:1 to received 6 monthly treatments with 300 mg s.c. canakinumab or placebo. Measured outcomes at baseline and weeks 4, 8, 12, 16, 20 and 24 included electronic patient-reported outcomes, hospitalization rate and adverse events (AEs) and serious AEs (SAEs). All but one of the 49 enrolled patients received background hydroxyurea therapy. Although the primary objective (pre-specified reduction of pain) was not met, compared to placebo-arm patients, canakinumab-treated patients had reductions in markers of inflammation, incidence of SCA-related AE and SAE, and number and duration of hospitalizations, as well as trends for improvement in pain intensity, fatigue and absences from school or work. Post-hoc analysis revealed treatment effects on weight gain in, restricted to pediatric patients. Canakinumab was well tolerated with no treatment-related SAEs and no new safety finding. These findings demonstrate that the inflammation associated with SCA can be reduced by selective IL-1b blockade by canakinumab with potential for therapeutic benefits. This trial was registered at www.clinicaltrials.gov as NCT02961218

A Scalable Cryo-CMOS Controller for the Wideband Frequency-Multiplexed Control of Spin Qubits and Transmons

Building a large-scale quantum computer requires the co-optimization of both the quantum bits (qubits) and their control electronics. By operating the CMOS control circuits at cryogenic temperatures (cryo-CMOS), and hence in close proximity to the cryogenic solid-state qubits, a compact quantum-computing system can be achieved, thus promising scalability to the large number of qubits required in a practical application. This work presents a cryo-CMOS microwave signal generator for frequency-multiplexed control of 4 x 32 qubits (32 qubits per RF output). A digitally intensive architecture offering full programmability of phase, amplitude, and frequency of the output microwave pulses and a wideband RF front end operating from 2 to 20 GHz allow targeting both spin qubits and transmons. The controller comprises a qubit-phase-tracking direct digital synthesis (DDS) back end for coherent qubit control and a single-sideband (SSB) RF front end optimized for minimum leakage between the qubit channels. Fabricated in Intel 22-nm FinFET technology, it achieves a 48-dB SNR and 45-dB spurious-free dynamic range (SFDR) in a 1-GHz data bandwidth when operating at 3 K, thus enabling high-fidelity qubit control. By exploiting the on-chip 4096-instruction memory, the capability to translate quantum algorithms to microwave signals has been demonstrated by coherently controlling a spin qubit at both 14 and 18 GHz

Susan Lynn Williams: The Life of an Exceptional Scholar, Leader, and Friend (1951–2018)

Susan Lynn Williams (1951–2018) was an exceptional marine ecologist whose research focused broadly on the ecology of benthic nearshore environments dominated by seagrasses, seaweeds, and coral reefs. She took an empirical approach founded in techniques of physiological ecology. Susan was committed to applying her research results to ocean management through outreach to decision-makers and resource managers. Susan’s career included research throughout the USA in tropical, temperate, and polar regions, but she specialized in tropical marine ecology. Susan’s scholarship, leadership, and friendship touched many people, leading to this multi-authored paper. Susan’s scholarship was multi-faceted, and she excelled in scientific discovery, integration of scientific results, application of science for conservation, and teaching, especially as a mentor to undergraduate and graduate students and postdoctoral scholars. Susan served in a variety of leadership positions throughout her career. She embodied all facets of leadership; leading by example, listening to others, committing to the “long haul,” maintaining trust, and creating a platform for all to shine. Susan was an important role model for women in science. Susan was also a loyal friend, maintaining friendships for many decades. Susan loved cooking and entertaining with friends. This paper provides an overview of the accomplishments of Susan in the broad categories of scholarship, leadership, and friendship

Data set for analyses

Includes study area, site, year, and species information as well as covariates used in the analyses. Exact location information is not included for sites due to the sensitive nature of many of the species. Please contact authors directly to request this information