An improved synthesis of the HDAC inhibitor trichostatin A

Histone deacetylase inhibitors (HDIs) have found a wide variety of medicinal uses and are most noted for their specific apoptotic action towards cancer cells. Several hydroxamate HDIs have since been moved on to phase 1 and 2 clinical drug trials, with one having already been approved for treatment of advanced cutaneous T-cell lymphoma. Trichostatin A is one of the most potent known naturally-occurring inhibitors of histone deacetylase. Unfortunately for researchers, the syntheses that have been reported are both long and difficult, which leads to a low overall yield and therefore to a prohibitively expensive product, limiting its medicinal potential. This work builds on several previously published syntheses and shows a more efficient synthesis of Trichostatin A, which will make it more available for use in a variety of treatments

Approximate inference in related multi-output Gaussian Process Regression

In Gaussian Processes a multi-output kernel is a covariance function over correlated outputs. Using a prior known relation between outputs, joint auto- and cross-covariance functions can be constructed. Realizations from these joint-covariance functions give outputs that are consistent with the prior relation. One issue with gaussian process regression is efficient inference when scaling upto large datasets. In this paper we use approximate inference techniques upon multi-output kernels enforcing relationships between outputs. Results of the proposed methodology for theoretical data and real world applications are presented. The main contribution of this paper is the application and validation of our methodology on a dataset of real aircraft fight tests, while imposing knowledge of aircraft physics into the model

Identification of Physical Parameters Using Change-Point Kernels

Engineering design is a costly exercise, primarily because gathering data for various design cases requires constructing and experimenting on that design point. Hence engineers learn basic principles of the system and construct more detailed models based on the initial principles and simplifying assumptions. Eg. FEM in structural design or CFD in fluid simulations. We estimate the physical parameters, experimental data for tensile test of AL6061 and lift diagrams for XFLR5 airfoil using change-point kernels

Adding Flight Mechanics to Flight Loads Surrogate Model using Multi-Output Gaussian Processes

In this paper analytical methods to formally incorporate knowledge of physics-based equations between multiple outputs in a Gaussian Process (GP) model are presented. In Gaussian Processes a multi-output kernel is a covariance function over correlated outputs. Using a general framework for constructing auto- and cross-covariance functions that are consistent with the physical laws, physics-based relationships among several outputs can be imposed. Results of the proposed methodology for simulated data and measurement from flight tests are presented. The main contribution of this paper is the application and validation of our methodology on a dataset of flight tests, while imposing knowledge of flight mechanics into the model

Structure and functional analysis of a tilapia (Oreochromis mossambicus) growth hormone gene: activation and repression by pituitary transcription factor Pit-1

A gene encoding the Tilapia mossambica (Oreochromis mossambicus) growth hormone (tiGH) was isolated and sequenced. The gene spans 5.6 kb, including 3.7 kb of 5' and 0.2 kb of 3' flanking sequences and a 1.7-kb transcription unit comprised of six exons and five introns. The gene and the 5' flanking region contain several potential binding sites for Pit-1, a key transcription activator of mammalian GH genes. One of these (-57/-42) is highly conserved in fish GH genes. It activates transcription in pituitary cells and binds Pit-1. Transfection of luciferase reporter plasmids containing either the -3602/+19 tiGH sequence or one of its 5' deletion mutants (-2863/, -1292/, and -463/+19) resulted in strong activity in Pit-1-producing rat pituitary GC cells. A dose-dependent activation of the tiGH promoter was achieved in nonpituitary fish EPC and monkey COS cells cotransfected with a rat Pit-1 expression vector, demonstrating the crucial role played by Pit-1 as an activator of the tiGH gene. Fusion of the tiGH promoter with the beta-galactosidase gene led to transient expression specifically in the nervous system of microinjected zebrafish embryos. The activity of the tiGH promoter in GC and EPC cells was strongly repressed by extending its 3' end from +19 to +40, a sequence in which a Pit-1-binding site was identified using gel retardation assays. Point mutations of the site that suppressed Pit-1 binding in vitro restored full tiGH promoter activity. Thus, a Pit-1-binding site located in the 5' untranslated region mediates Pit-1-dependent repression of the tiGH gene

Experimental Investigation into the Influence of Backfill Types on the Vibro-acoustic Characteristics of Leaks in MDPE Pipe

Pipe leak location estimates are commonly conducted using Vibro-Acoustic Emission (VAE) based methods, usually using accelerometers or hydrophones. Successful estimation of a leak's location is dependent on a number of factors, including the speed of sound, resonance, backfill, reflections from other sources, leak shape and size. However, despite some investigation into some of the aforementioned factors, the influence of backfill type on a leak's VAE signal has still not been experimentally quantified. A limited number of studies have attempted to quantify the effects of backfill. However, all of these studies couple other variables which could be equally responsible for their observed changes in leak signal. There have been no controlled studies where one variable can be directly compared to one another (i.e. all variables remain constant, only changing backfill type). The aim of this paper is to better characterise the influence of backfill on a leak's VAE signal by individually isolating all variables. For the first time, this paper demonstrates the influence of backfill on leak VAE signal by keeping all other variables consistent. It was found that the backfill type had a strong influence on the frequency and amplitude of leak signals, which is likely to have a significant impact on the accuracy of leak location estimates

PHANGS CO kinematics: disk orientations and rotation curves at 150 pc resolution

We present kinematic orientations and high resolution (150 pc) rotation curves for 67 main sequence star-forming galaxies surveyed in CO (2-1) emission by PHANGS-ALMA. Our measurements are based on the application of a new fitting method tailored to CO velocity fields. Our approach identifies an optimal global orientation as a way to reduce the impact of non-axisymmetric (bar and spiral) features and the uneven spatial sampling characteristic of CO emission in the inner regions of nearby galaxies. The method performs especially well when applied to the large number of independent lines-of-sight contained in the PHANGS CO velocity fields mapped at 1'' resolution. The high resolution rotation curves fitted to these data are sensitive probes of mass distribution in the inner regions of these galaxies. We use the inner slope as well as the amplitude of our fitted rotation curves to demonstrate that CO is a reliable global dynamical mass tracer. From the consistency between photometric orientations from the literature and kinematic orientations determined with our method, we infer that the shapes of stellar disks in the mass range of log($\rm M_{\star}(M_{\odot})$)=9.0-10.9 probed by our sample are very close to circular and have uniform thickness.Comment: 19 figures, 36 pages, accepted for publication in ApJ. Table of PHANGS rotation curves available from http://phangs.org/dat

Cloning and functional expression of intracellular loop variants of the honey bee (Apis mellifera) RDL GABA receptor

The insect GABA receptor, RDL (resistance to dieldrin), plays central roles in neuronal signalling and is the target of several classes of insecticides. To study the GABA receptor from an important pollinator species, we cloned Rdl cDNA from the honey bee, Apis mellifera. Three Rdl variants were identified, arising from differential use of splice acceptor sites in the large intracellular loop between transmembrane regions 3 and 4. These variants were renamed from previously, as Amel_RDLvar1, Amel_RDLvar2 and Amel_RDLvar3. When expressed in Xenopus laevis oocytes, the three variants showed no difference in sensitivity to the agonist, GABA, with EC50s of 29 μM, 20 μM and 29 μM respectively. Also, the potencies of the antagonists, fipronil and imidacloprid, were similar on all three variants. Fipronil IC50 values were 0.18 μM, 0.31 μM and 0.20 μM whereas 100 μM imidacloprid reduced the GABA response by 17%, 24% and 31%. The possibility that differential splicing of the RDL intracellular loop may represent a species-specific mechanism leading to insensitivity to insecticides is discussed

Time resolved speckle contrast optical spectroscopy at quasi-null source-detector separation for non-invasive measurement of microvascular blood flow

Time (or path length) resolved speckle contrast optical spectroscopy (TD-SCOS) at quasi-null (2.85 mm) source-detector separation was developed and demonstrated. The method was illustrated by in vivo studies on the forearm muscle of an adult subject. The results have shown that selecting longer photon path lengths results in higher hyperemic blood flow change and a faster return to baseline by a factor of two after arterial cuff occlusion when compared to SCOS without time resolution. This indicates higher sensitivity to the deeper muscle tissue. In the long run, this approach may allow the use of simpler and cheaper detector arrays compared to time resolved diffuse correlation spectroscopy that are based on readily available technologies. Hence, TD-SCOS may increase the performance and decrease cost of devices for continuous non-invasive, deep tissue blood flow monitoring