249 research outputs found
Translational and Regulatory Challenges for Exon Skipping Therapies
Several translational challenges are currently impeding the therapeutic development of antisense-mediated exon skipping approaches for rare diseases. Some of these are inherent to developing therapies for rare diseases, such as small patient numbers and limited information on natural history and interpretation of appropriate clinical outcome measures. Others are inherent to the antisense oligonucleotide (AON)-mediated exon skipping approach, which employs small modified DNA or RNA molecules to manipulate the splicing process. This is a new approach and only limited information is available on long-term safety and toxicity for most AON chemistries. Furthermore, AONs often act in a mutation-specific manner, in which case multiple AONs have to be developed for a single disease. A workshop focusing on preclinical development, trial design, outcome measures, and different forms of marketing authorization was organized by the regulatory models and biochemical outcome measures working groups of Cooperation of Science and Technology Action: "Networking towards clinical application of antisense-mediated exon skipping for rare diseases." The workshop included participants from patient organizations, academia, and members of staff from the European Medicine Agency and Medicine Evaluation Board (the Netherlands). This statement article contains the key outcomes of this meeting.status: publishe
Incremental QBF Solving
We consider the problem of incrementally solving a sequence of quantified
Boolean formulae (QBF). Incremental solving aims at using information learned
from one formula in the process of solving the next formulae in the sequence.
Based on a general overview of the problem and related challenges, we present
an approach to incremental QBF solving which is application-independent and
hence applicable to QBF encodings of arbitrary problems. We implemented this
approach in our incremental search-based QBF solver DepQBF and report on
implementation details. Experimental results illustrate the potential benefits
of incremental solving in QBF-based workflows.Comment: revision (camera-ready, to appear in the proceedings of CP 2014,
LNCS, Springer
QRAT+: Generalizing QRAT by a More Powerful QBF Redundancy Property
The QRAT (quantified resolution asymmetric tautology) proof system simulates
virtually all inference rules applied in state of the art quantified Boolean
formula (QBF) reasoning tools. It consists of rules to rewrite a QBF by adding
and deleting clauses and universal literals that have a certain redundancy
property. To check for this redundancy property in QRAT, propositional unit
propagation (UP) is applied to the quantifier free, i.e., propositional part of
the QBF. We generalize the redundancy property in the QRAT system by QBF
specific UP (QUP). QUP extends UP by the universal reduction operation to
eliminate universal literals from clauses. We apply QUP to an abstraction of
the QBF where certain universal quantifiers are converted into existential
ones. This way, we obtain a generalization of QRAT we call QRAT+. The
redundancy property in QRAT+ based on QUP is more powerful than the one in QRAT
based on UP. We report on proof theoretical improvements and experimental
results to illustrate the benefits of QRAT+ for QBF preprocessing.Comment: preprint of a paper to be published at IJCAR 2018, LNCS, Springer,
including appendi
Population of isomers in decay of the giant dipole resonance
The value of an isomeric ratio (IR) in N=81 isotones (Ba, Ce,
Nd and Sm) is studied by means of the ( reaction.
This quantity measures a probability to populate the isomeric state in respect
to the ground state population. In ( reactions, the giant dipole
resonance (GDR) is excited and after its decay by a neutron emission, the
nucleus has an excitation energy of a few MeV. The forthcoming decay
by direct or cascade transitions deexcites the nucleus into an isomeric or
ground state. It has been observed experimentally that the IR for Ba
and Ce equals about 0.13 while in two heavier isotones it is even less
than half the size. To explain this effect, the structure of the excited states
in the energy region up to 6.5 MeV has been calculated within the Quasiparticle
Phonon Model. Many states are found connected to the ground and isomeric states
by , and transitions. The single-particle component of the wave
function is responsible for the large values of the transitions. The calculated
value of the isomeric ratio is in very good agreement with the experimental
data for all isotones. A slightly different value of maximum energy with which
the nuclei rest after neutron decay of the GDR is responsible for the reported
effect of the A-dependence of the IR.Comment: 16 pages, 4 Fig
Entanglement Measures for Single- and Multi-Reference Correlation Effects
Electron correlation effects are essential for an accurate ab initio
description of molecules. A quantitative a priori knowledge of the single- or
multi-reference nature of electronic structures as well as of the dominant
contributions to the correlation energy can facilitate the decision regarding
the optimum quantum chemical method of choice. We propose concepts from quantum
information theory as orbital entanglement measures that allow us to evaluate
the single- and multi-reference character of any molecular structure in a given
orbital basis set. By studying these measures we can detect possible artifacts
of small active spaces.Comment: 14 pages, 4 figure
Accurate ab initio spin densities
We present an approach for the calculation of spin density distributions for
molecules that require very large active spaces for a qualitatively correct
description of their electronic structure. Our approach is based on the
density-matrix renormalization group (DMRG) algorithm to calculate the spin
density matrix elements as basic quantity for the spatially resolved spin
density distribution. The spin density matrix elements are directly determined
from the second-quantized elementary operators optimized by the DMRG algorithm.
As an analytic convergence criterion for the spin density distribution, we
employ our recently developed sampling-reconstruction scheme [J. Chem. Phys.
2011, 134, 224101] to build an accurate complete-active-space
configuration-interaction (CASCI) wave function from the optimized matrix
product states. The spin density matrix elements can then also be determined as
an expectation value employing the reconstructed wave function expansion.
Furthermore, the explicit reconstruction of a CASCI-type wave function provides
insights into chemically interesting features of the molecule under study such
as the distribution of - and -electrons in terms of Slater
determinants, CI coefficients, and natural orbitals. The methodology is applied
to an iron nitrosyl complex which we have identified as a challenging system
for standard approaches [J. Chem. Theory Comput. 2011, 7, 2740].Comment: 37 pages, 13 figure
The prognostic value of the suPARnostic® ELISA in HIV-1 infected individuals is not affected by uPAR promoter polymorphisms
<p>Abstract</p> <p>Background</p> <p>High blood levels of soluble urokinase Plasminogen Activator Receptor (suPAR) are associated with poor outcomes in human immunodeficiency-1 (HIV-1) infected individuals. Research on the clinical value of suPAR in HIV-1 infection led to the development of the suPARnostic<sup>® </sup>assay for commercial use in 2006. The aim of this study was to: 1) Evaluate the prognostic value of the new suPARnostic<sup>® </sup>assay and 2) Determine whether polymorphisms in the active promoter of uPAR influences survival and/or suPAR values in HIV-1 patients who are antiretroviral therapy (ART) naive.</p> <p>Methods</p> <p>DNA samples were collected retrospectively from 145 Danes infected with HIV-1 with known seroconversion times. In addition, plasma was collected retrospectively from 81 of these participants for use in the suPAR analysis. Survival was analysed using Kaplan Meier analysis.</p> <p>Results</p> <p>Survival was strongly correlated to suPAR levels (p < 0.001). Levels at or above 6 ng/ml were associated with death in 13 of 27 patients within a two-years period; whereas only one of 54 patients with suPAR levels below 6 ng/ml died during this period. We identified two common uPAR promoter polymorphisms: a G to A transition at -118 and an A to G transition at -465 comparative to the transcription start site. These promoter transitions influenced neither suPAR levels nor patient survival.</p> <p>Conclusion</p> <p>Plasma suPAR levels, as measured by the suPARnostic<sup>® </sup>assay, were strongly predictive of survival in ART-naïve HIV-1 infected patients. Furthermore, plasma suPAR levels were not influenced by uPAR promoter polymorphisms.</p
CXCR2 Signaling Protects Oligodendrocytes and Restricts Demyelination in a Mouse Model of Viral-Induced Demyelination
BACKGROUND: The functional role of ELR-positive CXC chemokines during viral-induced demyelination was assessed. Inoculation of the neuroattenuated JHM strain of mouse hepatitis virus (JHMV) into the CNS of susceptible mice results in an acute encephalomyelitis that evolves into a chronic demyelinating disease, modeling white matter pathology observed in the human demyelinating disease Multiple Sclerosis. METHODOLOGY/PRINCIPAL FINDINGS: JHMV infection induced the rapid and sustained expression of transcripts specific for the ELR+ chemokine ligands CXCL1 and CXCL2, as well as their binding receptor CXCR2, which was enriched within the spinal cord during chronic infection. Inhibiting CXCR2 signaling with neutralizing antiserum significantly (p<0.03) delayed clinical recovery. Moreover, CXCR2 neutralization was associated with an increase in the severity of demyelination that was independent of viral recrudescence or modulation of neuroinflammation. Rather, blocking CXCR2 was associated with increased numbers of apoptotic cells primarily within white matter tracts, suggesting that oligodendrocytes were affected. JHMV infection of enriched oligodendrocyte progenitor cell (OPC) cultures revealed that apoptosis was associated with elevated expression of cleaved caspase 3 and muted Bcl-2 expression. Inclusion of CXCL1 within JHMV infected cultures restricted caspase 3 cleavage and increased Bcl-2 expression that was associated with a significant (p<0.001) decrease in apoptosis. CXCR2 deficient oligodendrocytes were refractory to CXCL1 mediated protection from JHMV-induced apoptosis, readily activating caspase 3 and down regulating Bcl-2. CONCLUSION/SIGNIFICANCE: These findings highlight a previously unappreciated role for CXCR2 signaling in protecting oligodendrocyte lineage cells from apoptosis during inflammatory demyelination initiated by viral infection of the CNS
Stereotypical Chronic Lymphocytic Leukemia B-Cell Receptors Recognize Survival Promoting Antigens on Stromal Cells
Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world. Survival of CLL cells depends on their close contact with stromal cells in lymphatic tissues, bone marrow and blood. This microenvironmental regulation of CLL cell survival involves the stromal secretion of chemo- and cytokines as well as the expression of adhesion molecules. Since CLL survival may also be driven by antigenic stimulation through the B-cell antigen receptor (BCR), we explored the hypothesis that these processes may be linked to each other. We tested if stromal cells could serve as an antigen reservoir for CLL cells, thus promoting CLL cell survival by stimulation through the BCR. As a proof of principle, we found that two CLL BCRs with a common stereotyped heavy chain complementarity-determining region 3 (previously characterized as “subset 1”) recognize antigens highly expressed in stromal cells – vimentin and calreticulin. Both antigens are well-documented targets of autoantibodies in autoimmune disorders. We demonstrated that vimentin is displayed on the surface of viable stromal cells and that it is present and bound by the stereotyped CLL BCR in CLL-stroma co-culture supernatant. Blocking the vimentin antigen by recombinant soluble CLL BCR under CLL-stromal cell co-culture conditions reduces stroma-mediated anti-apoptotic effects by 20–45%. We therefore conclude that CLL BCR stimulation by stroma-derived antigens can contribute to the protective effect that the stroma exerts on CLL cells. This finding sheds a new light on the understanding of the pathobiology of this so far mostly incurable disease
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