Lab Retriever: a software tool for calculating likelihood ratios incorporating a probability of drop-out for forensic DNA profiles.

BackgroundTechnological advances have enabled the analysis of very small amounts of DNA in forensic cases. However, the DNA profiles from such evidence are frequently incomplete and can contain contributions from multiple individuals. The complexity of such samples confounds the assessment of the statistical weight of such evidence. One approach to account for this uncertainty is to use a likelihood ratio framework to compare the probability of the evidence profile under different scenarios. While researchers favor the likelihood ratio framework, few open-source software solutions with a graphical user interface implementing these calculations are available for practicing forensic scientists.ResultsTo address this need, we developed Lab Retriever, an open-source, freely available program that forensic scientists can use to calculate likelihood ratios for complex DNA profiles. Lab Retriever adds a graphical user interface, written primarily in JavaScript, on top of a C++ implementation of the previously published R code of Balding. We redesigned parts of the original Balding algorithm to improve computational speed. In addition to incorporating a probability of allelic drop-out and other critical parameters, Lab Retriever computes likelihood ratios for hypotheses that can include up to four unknown contributors to a mixed sample. These computations are completed nearly instantaneously on a modern PC or Mac computer.ConclusionsLab Retriever provides a practical software solution to forensic scientists who wish to assess the statistical weight of evidence for complex DNA profiles. Executable versions of the program are freely available for Mac OSX and Windows operating systems

Parton Distributions in the Virtual Photon Target and Factorization Scheme Dependence

We investigate parton distributions in the virtual photon target, both polarized and unpolarized, up to the next-leading order (NLO) in QCD. Parton distributions can be predicted completely up to NLO, but they are factorization-scheme-dependent. We analyze parton distributions in several factorization schemes and discuss their scheme dependence. Particular attentions are paid to the axial anomaly effect on the first moments of the polarized quark parton distributions, and also to the large-$x$ behaviors of polarized and unpolarized parton distributions.Comment: 6 pages, LaTeX, 3 ps figures, uses npb.sty, Contribution to the Zeuthen Workshop on Elementary Particle Theory: Loops and Legs in Quantum Field Theory, Koenigstein-Weissig, Germany, April 200

Behavioral ecology of odometric memories in desert ants: acquisition, retention, and integration

Assuming that the acquisition and retention of memories have costs, properties of memories should fit the functional requirements for the system of memory. Based on a functional analysis of what path integration is meant to do, we predicted that odometric memories in desert ants should show (1) little improvement with repeated training: performance should be as good after one training trial as after six training trials, (2) decay of memory after 24 h, and (3) performance based solely on the most recent outbound trip, with no integration over multiple memories. Desert ants (Cataglyphis fortis) traveled in narrow straight plastic channels to forage for cookie crumbs in a feeder at 6- or 12-m distance. Each ant was tested once by being taken from the feeder and released 2 m from the end of a 32-m channel to run home. The distance at which the ant first turned back (first turn) constituted the data. In acquisition, groups trained one or six times before being tested had unsystematic scatter that did not differ significantly. In retention, ants tested after a 24-h delay showed larger unsystematic scatter than control animals tested after no delay. In integration, ants were trained five times at 6 or 12 m and then tested at 12 or 6 m, respectively. No evidence of integration of multiple odometric memories was found. The results show that the properties of odometric memories are indeed tailored to what the memory system is used fo

Co-targeting HGF/cMET Signaling with MEK Inhibitors in Metastatic Uveal Melanoma.

Patients with metastatic uveal melanoma usually die within 1 year of diagnosis, emphasizing an urgent need to develop new treatment strategies. The liver is the most common site of metastasis. Mitogen-activated protein kinase kinase (MEK) inhibitors improve survival in V600 BRAF-mutated cutaneous melanoma patients but have limited efficacy in patients with uveal melanoma. Our previous work showed that hepatocyte growth factor (HGF) signaling elicits resistance to MEK inhibitors in metastatic uveal melanoma. In this study, we demonstrate that expression of two BH3-only family proteins, Bim-EL and Bmf, contributes to HGF-mediated resistance to MEK inhibitors. Targeting HGF/cMET signaling with LY2875358, a neutralizing and internalizing anti-cMET bivalent antibody, and LY2801653, a dual cMET/RON inhibitor, overcomes resistance to trametinib provided by exogenous HGF and by conditioned medium from primary hepatic stellate cells. We further determined that activation of PI3Kα/γ/δ isoforms mediates the resistance to MEK inhibitors by HGF. Combination of LY2801653 with trametinib decreases AKT phosphorylation and promotes proapoptotic PARP cleavage in metastatic uveal melanoma explants. Together, our data support the notion that selectively blocking cMET signaling or PI3K isoforms in metastatic uveal melanoma may break the intrinsic resistance to MEK inhibitors provided by factors from stromal cells in the liver

Simulating the weak death of the neutron in a femtoscale universe with near-Exascale computing

The fundamental particle theory called Quantum Chromodynamics (QCD) dictates everything about protons and neutrons, from their intrinsic properties to interactions that bind them into atomic nuclei. Quantities that cannot be fully resolved through experiment, such as the neutron lifetime (whose precise value is important for the existence of light-atomic elements that make the sun shine and life possible), may be understood through numerical solutions to QCD. We directly solve QCD using Lattice Gauge Theory and calculate nuclear observables such as neutron lifetime. We have developed an improved algorithm that exponentially decreases the time-to solution and applied it on the new CORAL supercomputers, Sierra and Summit. We use run-time autotuning to distribute GPU resources, achieving 20% performance at low node count. We also developed optimal application mapping through a job manager, which allows CPU and GPU jobs to be interleaved, yielding 15% of peak performance when deployed across large fractions of CORAL.Comment: 2018 Gordon Bell Finalist: 9 pages, 9 figures; v2: fixed 2 typos and appended acknowledgement

Paracrine Effect of NRG1 and HGF Drives Resistance to MEK Inhibitors in Metastatic Uveal Melanoma.

Uveal melanoma patients with metastatic disease usually die within one year, emphasizing an urgent need to develop new treatment strategies for this cancer. MEK inhibitors improve survival in cutaneous melanoma patients but show only modest efficacy in metastatic uveal melanoma patients. In this study, we screened for growth factors that elicited resistance in newly characterized metastatic uveal melanoma cell lines to clinical-grade MEK inhibitors, trametinib and selumetinib. We show that neuregulin 1 (NRG1) and hepatocyte growth factor (HGF) provide resistance to MEK inhibition. Mechanistically, trametinib enhances the responsiveness to NRG1 and sustained HGF-mediated activation of AKT. Individually targeting ERBB3 and cMET, the receptors for NRG1 and HGF, respectively, overcome resistance to trametinib provided by these growth factors and by conditioned medium from fibroblasts that produce NRG1 and HGF. Inhibition of AKT also effectively reverses the protective effect of NRG1 and HGF in trametinib-treated cells. Uveal melanoma xenografts growing in the liver in vivo and a subset of liver metastases of uveal melanoma patients express activated forms of ERBB2 (the coreceptor for ERBB3) and cMET. Together, these results provide preclinical evidence for the use of MEK inhibitors in combination with clinical-grade anti-ERBB3 or anti-cMET monoclonal antibodies in metastatic uveal melanoma

Cholinergic Mesopontine Signals Govern Locomotion and Reward through Dissociable Midbrain Pathways

The mesopontine tegmentum, including the pedunculopontine and laterodorsal tegmental nuclei (PPN and LDT), provides major cholinergic inputs to midbrain and regulates locomotion and reward. To delineate the underlying projection-specific circuit mechanisms, we employed optogenetics to control mesopontine cholinergic neurons at somata and at divergent projections within distinct midbrain areas. Bidirectional manipulation of PPN cholinergic cell bodies exerted opposing effects on locomotor behavior and reinforcement learning. These motor and reward effects were separable via limiting photostimulation to PPN cholinergic terminals in the ventral substantia nigra pars compacta (vSNc) or to the ventral tegmental area (VTA), respectively. LDT cholinergic neurons also form connections with vSNc and VTA neurons; however, although photo-excitation of LDT cholinergic terminals in the VTA caused positive reinforcement, LDT-to-vSNc modulation did not alter locomotion or reward. Therefore, the selective targeting of projection-specific mesopontine cholinergic pathways may offer increased benefit in treating movement and addiction disorders

Optical gradation for crushed limestone aggregates

The strength and durability of asphalt pavement is directly affected by the characteristics of its main ingredient, mineral aggregate. Besides material strength, research has shown that mixture properties such as particle shape and mixture gradation have a significant affect on the quality of the asphalt concrete. A standard called Superpave has been developed which sets forth specifications for material selection and methods for measurement of aggregate properties. These standards require monitoring of aggregate properties, particularly gradation. In this dissertation, the feasibility of developing an optically based method for determining aggregate gradation was explored. The physical system primarily consists of a standard monochrome CCD video camera and a computer with a frame grabber board. Software was developed to separate touching or overlapping particles in the image, and to detect the size and shape of each particle. Correlation to estimate each particle\u27s mass and to predict the sieving behavior for crushed limestone aggregates was developed and tested. Laboratory testing demonstrated the ability to measure gradation over a range of particle sizes from 4.75 mm to 25 mm with an accuracy of +/-3 in terms of percent-passing residual when compared with mechanical sieving