Impacts of projected climate change over the Lake Champlain basin in Vermont

The Lake Champlain basin is a critical ecological and socioeconomic resource of the northeastern United States and southern Quebec, Canada. While general circulation models (GCMs) provide an overview of climate change in the region, they lack the spatial and temporal resolution necessary to fully anticipate the effects of rising global temperatures associated with increasing greenhouse gas concentrations. Observed trends in precipitation and temperature were assessed across the Lake Champlain basin to bridge the gap between global climate change and local impacts. Future shifts in precipitation and temperature were evaluated as well as derived indices, including maple syrup production, days above 32.2°C (90°F), and snowfall, relevant to managing the natural and human environments in the region. Four statistically downscaled, biascorrected GCM simulations were evaluated from the Coupled Model Intercomparison Project phase 5 (CMIP5) forced by two representative concentration pathways (RCPs) to sample the uncertainty in future climate simulations. Precipitation is projected to increase by between 9.1 and 12.8mmyr-1 decade-1 during the twenty-first century while daily temperatures are projected to increase between 0.43° and 0.49°C decade-1. Annual snowfall at six major ski resorts in the region is projected to decrease between 46.9%and 52.4%by the late twenty-first century. In the month of July, the number of days above 32.2°C in Burlington, Vermont, is projected to increase by over 10 days during the twenty-first century. © 2014 American Meteorological Society

Approximating (k,ℓ)(k,\ell)-center clustering for curves

The Euclidean $k$-center problem is a classical problem that has been extensively studied in computer science. Given a set $\mathcal{G}$ of $n$ points in Euclidean space, the problem is to determine a set $\mathcal{C}$ of $k$ centers (not necessarily part of $\mathcal{G}$) such that the maximum distance between a point in $\mathcal{G}$ and its nearest neighbor in $\mathcal{C}$ is minimized. In this paper we study the corresponding $(k,\ell)$-center problem for polygonal curves under the Fr\'echet distance, that is, given a set $\mathcal{G}$ of $n$ polygonal curves in $\mathbb{R}^d$, each of complexity $m$, determine a set $\mathcal{C}$ of $k$ polygonal curves in $\mathbb{R}^d$, each of complexity $\ell$, such that the maximum Fr\'echet distance of a curve in $\mathcal{G}$ to its closest curve in $\mathcal{C}$ is minimized. In this paper, we substantially extend and improve the known approximation bounds for curves in dimension $2$ and higher. We show that, if $\ell$ is part of the input, then there is no polynomial-time approximation scheme unless $\mathsf{P}=\mathsf{NP}$. Our constructions yield different bounds for one and two-dimensional curves and the discrete and continuous Fr\'echet distance. In the case of the discrete Fr\'echet distance on two-dimensional curves, we show hardness of approximation within a factor close to $2.598$. This result also holds when $k=1$, and the $\mathsf{NP}$-hardness extends to the case that $\ell=\infty$, i.e., for the problem of computing the minimum-enclosing ball under the Fr\'echet distance. Finally, we observe that a careful adaptation of Gonzalez' algorithm in combination with a curve simplification yields a $3$-approximation in any dimension, provided that an optimal simplification can be computed exactly. We conclude that our approximation bounds are close to being tight.Comment: 24 pages; results on minimum-enclosing ball added, additional author added, general revisio

A cardinal role for cathepsin D in co-ordinating the host-mediated apoptosis of macrophages and killing of pneumococci

The bactericidal function of macrophages against pneumococci is enhanced by their apoptotic demise, which is controlled by the anti-apoptotic protein Mcl-1. Here, we show that lysosomal membrane permeabilization (LMP) and cytosolic translocation of activated cathepsin D occur prior to activation of a mitochondrial pathway of macrophage apoptosis. Pharmacological inhibition or knockout of cathepsin D during pneumococcal infection blocked macrophage apoptosis. As a result of cathepsin D activation, Mcl-1 interacted with its ubiquitin ligase Mule and expression declined. Inhibition of cathepsin D had no effect on early bacterial killing but inhibited the late phase of apoptosis-associated killing of pneumococci in vitro. Mice bearing a cathepsin D-/- hematopoietic system demonstrated reduced macrophage apoptosis in vivo, with decreased clearance of pneumococci and enhanced recruitment of neutrophils to control pulmonary infection. These findings establish an unexpected role for a cathepsin D-mediated lysosomal pathway of apoptosis in pulmonary host defense and underscore the importance of apoptosis-associated microbial killing to macrophage function

The vulnerability, impacts, adaptation and climate services advisory board (VIACS AB v1.0) contribution to CMIP6

This paper describes the motivation for the creation of the Vulnerability, Impacts, Adaptation and Climate Services (VIACS) Advisory Board for the Sixth Phase of the Coupled Model Intercomparison Project (CMIP6), its initial activities, and its plans to serve as a bridge between climate change applications experts and climate modelers. The climate change application community comprises researchers and other specialists who use climate information (alongside socioeconomic and other environmental information) to analyze vulnerability, impacts and adaptation of natural systems and society in relation to past, ongoing and projected future climate change. Much of this activity is directed toward the co-development of information needed by decision-makers for managing projected risks. CMIP6 provides a unique opportunity to facilitate a two-way dialogue between climate modelers and VIACS experts who are looking to apply CMIP6 results for a wide array of research and climate services objectives. The VIACS Advisory Board convenes leaders of major impact sectors, international programs, and climate services to solicit community feedback that increases applications relevance of the CMIP6-Endorsed Model Intercomparison Projects (MIPs). As an illustration of its potential, the VIACS community provided CMIP6 leadership with a list of prioritized climate model variables and MIP experiments of greatest interest to the climate model applications community, indicating the applicability and societal relevance of climate model simulation outputs. The VIACS Advisory Board also recommended an impacts version of Obs4MIPs, and indicated user needs for the gridding and processing of model output

Case report: response to the ERK1/2 inhibitor ulixertinib in BRAF D594G cutaneous melanoma.

Melanoma is characterized by oncogenic mutations in pathways regulating cell growth, proliferation, and metabolism. Greater than 80% of primary melanoma cases harbor aberrant activation of the mitogen-activated protein kinase kinase/extracellular-signal-regulated kinase (MEK/ERK) pathway, with oncogenic mutations in BRAF, most notably BRAF V600E, being the most common. Significant progress has been made in BRAF-mutant melanoma using BRAF and MEK inhibitors; however, non-V600 BRAF mutations remain a challenge with limited treatment options. We report the case of an individual diagnosed with stage III BRAF D594G-mutant melanoma who experienced an extraordinary response to the ERK1/2 inhibitor ulixertinib as fourth-line therapy. Ulixertinib was obtained via an intermediate expanded access protocol with unique flexibility to permit both single-agent and combination treatments, dose adjustments, breaks in treatment to undergo surgery, and long-term preventive treatment following surgical resection offering this patient the potential for curative treatment

First observation of low energy electron neutrinos in a liquid argon time projection chamber

Citation: Acciarri, R., Adams, C., Asaadi, J., Baller, B., Bolton, T., Bromberg, C., . . . ArgoNeu, T. C. (2017). First observation of low energy electron neutrinos in a liquid argon time projection chamber. Physical Review D, 95(7), 15. doi:10.1103/PhysRevD.95.072005The capabilities of liquid argon time projection chambers (LArTPCs) to reconstruct the spatial and calorimetric information of neutrino events have made them the detectors of choice in a number of experiments, specifically those looking to observe electron neutrino (nu(e)) appearance. The LArTPC promises excellent background rejection capabilities, especially in this "golden" channel for both short and long baseline neutrino oscillation experiments. We present the first experimental observation of electron neutrinos and antineutrinos in the ArgoNeut LArTPC, in the energy range relevant to DUNE and the Fermilab Short Baseline Neutrino Program. We have selected 37 electron candidate events and 274 gamma candidate events, and measured an 80% purity of electrons based on a topological selection. Additionally, we present a separation of electrons from gammas using calorimetric energy deposition, demonstrating further separation of electrons from background gammas

Engineering the Petawatt Laser into Nova

The engineering process of integrating the Petawatt (10{sup 15} watts) laser system into the existing 30 kJ (UV) Nova laser at Lawrence Livermore National Laboratory (LLNL) is described in detail. The nanosecond-long, chirped Petawatt laser pulse is initially generated in a separate master oscillator room and then injected into one of Nova`s 10 beamlines. There, the pulse is further amplified and enlarged to {approximately}{phi}60 cm, temporally compressed under vacuum to <500 fs using large diameter diffraction gratings, and then finally focused onto targets using a parabolic mirror. The major Petawatt components are physically large which created many significant engineering challenges in design, installation and implementation. These include the diffraction gratings and mirrors, vacuum compressor chamber, target chamber, and parabolic focusing mirror. Other Petawatt system components were also technically challenging and include: an injection beamline, transport spatial filters, laser diagnostics, alignment components, motor controls, interlocks, timing and synchronization systems, support structures, and vacuum systems. The entire Petawatt laser system was designed, fabricated, installed, and activated while the Nova laser continued its normal two-shift operation. This process required careful engineering and detailed planning to prevent experimental downtime and to complete the project on schedule

Evidence for Updating the Core Domain Set of Outcome Measures for Juvenile Idiopathic Arthritis: Report from a Special Interest Group at OMERACT 2016

Objective. The current Juvenile Idiopathic Arthritis (JIA) Core Set was developed in 1997 to identify the outcome measures to be used in JIA clinical trials using statistical and consensus-based techniques, but without patient involvement. The importance of patient/parent input into the research process has increasingly been recognized over the years. An Outcome Measures in Rheumatology (OMERACT) JIA Core Set Working Group was formed to determine whether the outcome domains of the current core set are relevant to those involved or whether the core set domains should be revised.Methods. Twenty-four people from the United States, Canada, Australia, and Europe, including patient partners, formed the working group. Guided by the OMERACT Filter 2.0 process, we performed (1) a systematic literature review of outcome domains, (2) a Web-based survey (142 patients, 343 parents), (3) an idea-generation study (120 parents), (4) 4 online discussion boards (24 patients, 20 parents), and (5) a Special Interest Group (SIG) activity at the OMERACT 13 (2016) meeting.Results. A MEDLINE search of outcome domains used in studies of JIA yielded 5956 citations, of which 729 citations underwent full-text review, and identified additional domains to those included in the current JIA Core Set. Qualitative studies on the effect of JIA identified multiple additional domains, including pain and participation. Twenty-one participants in the SIG achieved consensus on the need to revise the entire JIA Core Set.Conclusion. The results of qualitative studies and literature review support the need to expand the JIA Core Set, considering, among other things, additional patient/parent-centered outcomes, clinical data, and imaging data

Evaluation and Recommendations on Good Clinical Laboratory Practice Guidelines for Phase I–III Clinical Trials

Marcella Sarzotti-Kelsoe and colleagues harmonize various approaches to Good Clinical Laboratory Practice for clinical trials into a single set of recommendations