Aptamer therapeutics: the 21st century\u27s magic bullet of nanomedicine

Aptamers, also known as chemical antibodies, are short single-stranded DNA, RNA or peptide molecules. These molecules can fold into complex three-dimensional structures and bind to target molecules with high affinity and specificity. The nucleic acid aptamers are selected from combinatorial libraries by an iterative in vitro selection procedure known as systematic evolution of ligands by exponential enrichment (SELEX). As a new class of therapeutics and drug targeting entities, bivalent and multivalent aptamer-based molecules are emerging as highly attractive alternatives to monoclonal antibodies as targeted therapeutics.Aptamers have several advantages, offering the possibility of overcoming limitations of antibodies: 1) they can be selected against toxic or non-immunogenic targets; 2) aptamers can be chemically modified by using modified nucleotides to enhance their stability in biological fluids or via incorporating reporter molecules, radioisotopes and functional groups for their detection and immobilization; 3) they have very low immunogenicity; 4) they display high stability at room temperature, in extreme pH, or solvent; 5) once selected, they can be chemically synthesized free from cell- culturederived contaminants, and they can be manufactured at any time, in large amounts, at relatively low cost and reproducibly; 6) they are smaller and thus can diffuse more rapidly into tissues and organs, leading to faster targeting in drug delivery; 7) they have lower molecular weight that can lead to faster body clearance, resulting in a low background noise for imaging and minimizing the radiation dose to the patient in diagnostic imaging. Thus, the high selectivity and sensitivity, ease of screening and production, chemical versatility as well as stability make aptamers a class of highly attractive agents for the development of novel therapeutics, targeted drug delivery vehicles and molecular imaging.In the review, we will discuss the latest technological advances in developing aptamers, its application as a novel class of drug on its own, as well as in surface functionalization of both polymer nanoparticles or nanoliposomes in the treatment of cancer, viral and autoimmune diseases

The Spectral Energy Distribution of Powerful Starburst Galaxies I : Modelling the Radio Continuum

This article has been accepted for publication in Monthly Notices of the Royal Astronomical Society. © 2018 The Author(s). Published by Oxford University Press on behalf of the Royal Astronomical Society. All rights reserved.We have acquired radio-continuum data between 70MHz and 48 GHz for a sample of 19 southern starburst galaxies at moderate redshifts (0.067 < z < 0.227) with the aim of separating synchrotron and free-free emission components. Using a Bayesian framework, we find the radio continuum is rarely characterized well by a single power law, instead often exhibiting lowfrequency turnovers below 500 MHz, steepening at mid to high frequencies, and a flattening at high frequencies where free-free emission begins to dominate over the synchrotron emission. These higher order curvature components may be attributed to free-free absorption across multiple regions of star formation with varying optical depths. The decomposed synchrotron and free-free emission components in our sample of galaxies form strong correlations with the total-infrared bolometric luminosities. Finally, we find that without accounting for free-free absorption with turnovers between 90 and 500MHz the radio continuum at low frequency (v < 200 MHz) could be overestimated by upwards of a factor of 12 if a simple power-law extrapolation is used from higher frequencies. The mean synchrotron spectral index of our sample is constrained to be α = -1.06, which is steeper than the canonical value of -0.8 for normal galaxies. We suggest this may be caused by an intrinsically steeper cosmic ray distribution.Peer reviewe

Decoherence Bounds on Quantum Computation with Trapped Ions

Using simple physical arguments we investigate the capabilities of a quantum computer based on cold trapped ions. From the limitations imposed on such a device by spontaneous decay, laser phase coherence, ion heating and other sources of error, we derive a bound between the number of laser interactions and the number of ions that may be used. The largest number which may be factored using a variety of species of ion is determined.Comment: 5 pages in RevTex, 2 figures, the paper is also avalaible at http://qso.lanl.gov/qc

How spiking neurons give rise to a temporal-feature map

A temporal-feature map is a topographic neuronal representation of temporal attributes of phenomena or objects that occur in the outside world. We explain the evolution of such maps by means of a spike-based Hebbian learning rule in conjunction with a presynaptically unspecific contribution in that, if a synapse changes, then all other synapses connected to the same axon change by a small fraction as well. The learning equation is solved for the case of an array of Poisson neurons. We discuss the evolution of a temporal-feature map and the synchronization of the single cells’ synaptic structures, in dependence upon the strength of presynaptic unspecific learning. We also give an upper bound for the magnitude of the presynaptic interaction by estimating its impact on the noise level of synaptic growth. Finally, we compare the results with those obtained from a learning equation for nonlinear neurons and show that synaptic structure formation may profit from the nonlinearity

Strong suppression of heat conduction in a laboratory replica of galaxy-cluster turbulent plasmas

In conventional gases and plasmas, it is known that heat fluxes are proportional to temperature gradients, with collisions between particles mediating energy flow from hotter to colder regions and the coefficient of thermal conduction given by Spitzer's theory. However, this theory breaks down in magnetized, turbulent, weakly collisional plasmas, although modifications are difficult to predict from first principles due to the complex, multiscale nature of the problem. Understanding heat transport is important in astrophysical plasmas such as those in galaxy clusters, where observed temperature profiles are explicable only in the presence of a strong suppression of heat conduction compared to Spitzer's theory. To address this problem, we have created a replica of such a system in a laser laboratory experiment. Our data show a reduction of heat transport by two orders of magnitude or more, leading to large temperature variations on small spatial scales (as is seen in cluster plasmas)

Multi-site investigation of strategies for the clinical implementation of CYP2D6 genotyping to guide drug prescribing

PURPOSE: A number of institutions have clinically implemented CYP2D6 genotyping to guide drug prescribing. We compared implementation strategies of early adopters of CYP2D6 testing, barriers faced by both early adopters and institutions in the process of implementing CYP2D6 testing, and approaches taken to overcome these barriers. METHODS: We surveyed eight early adopters of CYP2D6 genotyping and eight institutions in the process of adoption. Data were collected on testing approaches, return of results procedures, applications of genotype results, challenges faced, and lessons learned. RESULTS: Among early adopters, CYP2D6 testing was most commonly ordered to assist with opioid and antidepressant prescribing. Key differences among programs included test ordering and genotyping approaches, result reporting, and clinical decision support. However, all sites tested for copy-number variation and nine common variants, and reported results in the medical record. Most sites provided automatic consultation and had designated personnel to assist with genotype-informed therapy recommendations. Primary challenges were related to stakeholder support, CYP2D6 gene complexity, phenotype assignment, and sustainability. CONCLUSION: There are specific challenges unique to CYP2D6 testing given the complexity of the gene and its relevance to multiple medications. Consensus lessons learned may guide those interested in pursuing similar clinical pharmacogenetic programs

An Evolutionarily Conserved Function of Polycomb Silences the MHC Class I Antigen Presentation Pathway and Enables Immune Evasion in Cancer.

Loss of MHC class I (MHC-I) antigen presentation in cancer cells can elicit immunotherapy resistance. A genome-wide CRISPR/Cas9 screen identified an evolutionarily conserved function of polycomb repressive complex 2 (PRC2) that mediates coordinated transcriptional silencing of the MHC-I antigen processing pathway (MHC-I APP), promoting evasion of T cell-mediated immunity. MHC-I APP gene promoters in MHC-I low cancers harbor bivalent activating H3K4me3 and repressive H3K27me3 histone modifications, silencing basal MHC-I expression and restricting cytokine-induced upregulation. Bivalent chromatin at MHC-I APP genes is a normal developmental process active in embryonic stem cells and maintained during neural progenitor differentiation. This physiological MHC-I silencing highlights a conserved mechanism by which cancers arising from these primitive tissues exploit PRC2 activity to enable immune evasion.Cancer Research UK Clinician Scientist Fellowship C53779/A20097 (M.L.B), Leukaemia Foundation Australia Senior Fellowship and Howard Hughes Medical Institute International Research Scholarship 55008729 (M.A.D), Peter and Julie Alston Centenary fellowship (K.D.S.), Wellcome Trust Principal Research Fellowship 101835/Z/13/Z (P.J.L), Peter MacCallum Postgraduate Scholarship (C.E.S), NHMRC Postgraduate Scholarship (K.L.C.), Maddie Riewoldt's Vision 064728 (Y-C.C), Victorian Cancer Agency (E.Y.N.L), CSL Centenary fellowship (S-J.D), National Breast Cancer Foundation Fellowship ECF-17-005 (P.A.B.), Addenbrooke’s Charitable Trust and NIHR Cambridge BRC (M.L.B., P.J.L), NHMRC grant 1085015, 1106444 (M.A.D) and 1128984 (M.A.D, S-J.D)

Implementation and evaluation of various demons deformable image registration algorithms on GPU

Online adaptive radiation therapy (ART) promises the ability to deliver an optimal treatment in response to daily patient anatomic variation. A major technical barrier for the clinical implementation of online ART is the requirement of rapid image segmentation. Deformable image registration (DIR) has been used as an automated segmentation method to transfer tumor/organ contours from the planning image to daily images. However, the current computational time of DIR is insufficient for online ART. In this work, this issue is addressed by using computer graphics processing units (GPUs). A grey-scale based DIR algorithm called demons and five of its variants were implemented on GPUs using the Compute Unified Device Architecture (CUDA) programming environment. The spatial accuracy of these algorithms was evaluated over five sets of pulmonary 4DCT images with an average size of 256x256x100 and more than 1,100 expert-determined landmark point pairs each. For all the testing scenarios presented in this paper, the GPU-based DIR computation required around 7 to 11 seconds to yield an average 3D error ranging from 1.5 to 1.8 mm. It is interesting to find out that the original passive force demons algorithms outperform subsequently proposed variants based on the combination of accuracy, efficiency, and ease of implementation.Comment: Submitted to Physics in Medicine and Biolog

First narrow-band search for continuous gravitational waves from known pulsars in advanced detector data

Spinning neutron stars asymmetric with respect to their rotation axis are potential sources of continuous gravitational waves for ground-based interferometric detectors. In the case of known pulsars a fully coherent search, based on matched filtering, which uses the position and rotational parameters obtained from electromagnetic observations, can be carried out. Matched filtering maximizes the signalto- noise (SNR) ratio, but a large sensitivity loss is expected in case of even a very small mismatch between the assumed and the true signal parameters. For this reason, narrow-band analysis methods have been developed, allowing a fully coherent search for gravitational waves from known pulsars over a fraction of a hertz and several spin-down values. In this paper we describe a narrow-band search of 11 pulsars using data from Advanced LIGO’s first observing run. Although we have found several initial outliers, further studies show no significant evidence for the presence of a gravitational wave signal. Finally, we have placed upper limits on the signal strain amplitude lower than the spin-down limit for 5 of the 11 targets over the bands searched; in the case of J1813-1749 the spin-down limit has been beaten for the first time. For an additional 3 targets, the median upper limit across the search bands is below the spin-down limit. This is the most sensitive narrow-band search for continuous gravitational waves carried out so far