308 research outputs found
Asymptotic Expansions for Stationary Distributions of Perturbed Semi-Markov Processes
New algorithms for computing of asymptotic expansions for stationary
distributions of nonlinearly perturbed semi-Markov processes are presented. The
algorithms are based on special techniques of sequential phase space reduction,
which can be applied to processes with asymptotically coupled and uncoupled
finite phase spaces.Comment: 83 page
Future directions for the management of pain in osteoarthritis.
Osteoarthritis (OA) is the predominant form of arthritis worldwide, resulting in a high degree of functional impairment and reduced quality of life owing to chronic pain. To date, there are no treatments that are known to modify disease progression of OA in the long term. Current treatments are largely based on the modulation of pain, including NSAIDs, opiates and, more recently, centrally acting pharmacotherapies to avert pain. This review will focus on the rationale for new avenues in pain modulation, including inhibition with anti-NGF antibodies and centrally acting analgesics. The authors also consider the potential for structure modification in cartilage/bone using growth factors and stem cell therapies. The possible mismatch between structural change and pain perception will also be discussed, introducing recent techniques that may assist in improved patient phenotyping of pain subsets in OA. Such developments could help further stratify subgroups and treatments for people with OA in future
The problem of equilibration and the computation of correlation functions on a quantum computer
We address the question of how a quantum computer can be used to simulate
experiments on quantum systems in thermal equilibrium. We present two
approaches for the preparation of the equilibrium state on a quantum computer.
For both approaches, we show that the output state of the algorithm, after long
enough time, is the desired equilibrium. We present a numerical analysis of one
of these approaches for small systems. We show how equilibrium
(time)-correlation functions can be efficiently estimated on a quantum
computer, given a preparation of the equilibrium state. The quantum algorithms
that we present are hard to simulate on a classical computer. This indicates
that they could provide an exponential speedup over what can be achieved with a
classical device.Comment: 25 pages LaTex + 8 figures; various additional comments, results and
correction
Circumventing antivector immunity: potential use of nonhuman adenoviral vectors
Adenoviruses are efficient gene delivery vectors based on their ability to transduce a wide variety of cell types and drive high-level transient transgene expression. While there have been advances in modifying human adenoviral (HAdV) vectors to increase their safety profile, there are still pitfalls that need to be further addressed. Preexisting humoral and cellular immunity against common HAdV serotypes limits the efficacy of gene transfer and duration of transgene expression. As an alternative, nonhuman AdV (NHAdV) vectors can circumvent neutralizing antibodies against HAdVs in immunized mice and monkeys and in human sera, suggesting that NHAdV vectors could circumvent preexisting humoral immunity against HAdVs in a clinical setting. Consequently, there has been an increased interest in developing NHAdV vectors for gene delivery in humans. In this review, we outline the recent advances and limitations of HAdV vectors for gene therapy and describe examples of NHAdV vectors focusing on their immunogenicity, tropism, and potential as effective gene therapy vehicles
Cortical Factor Feedback Model for Cellular Locomotion and Cytofission
Eukaryotic cells can move spontaneously without being guided by external
cues. For such spontaneous movements, a variety of different modes have been
observed, including the amoeboid-like locomotion with protrusion of multiple
pseudopods, the keratocyte-like locomotion with a widely spread lamellipodium,
cell division with two daughter cells crawling in opposite directions, and
fragmentations of a cell to multiple pieces. Mutagenesis studies have revealed
that cells exhibit these modes depending on which genes are deficient,
suggesting that seemingly different modes are the manifestation of a common
mechanism to regulate cell motion. In this paper, we propose a hypothesis that
the positive feedback mechanism working through the inhomogeneous distribution
of regulatory proteins underlies this variety of cell locomotion and
cytofission. In this hypothesis, a set of regulatory proteins, which we call
cortical factors, suppress actin polymerization. These suppressing factors are
diluted at the extending front and accumulated at the retracting rear of cell,
which establishes a cellular polarity and enhances the cell motility, leading
to the further accumulation of cortical factors at the rear. Stochastic
simulation of cell movement shows that the positive feedback mechanism of
cortical factors stabilizes or destabilizes modes of movement and determines
the cell migration pattern. The model predicts that the pattern is selected by
changing the rate of formation of the actin-filament network or the threshold
to initiate the network formation
Caspase-2 is upregulated after sciatic nerve transection and its inhibition protects dorsal root ganglion neurons from Apoptosis after serum withdrawal
Sciatic nerve (SN) transection-induced apoptosis of dorsal root ganglion neurons (DRGN) is one factor determining the efficacy of peripheral axonal regeneration and the return of sensation. Here, we tested the hypothesis that caspase-2(CASP2) orchestrates apoptosis of axotomised DRGN both in vivo and in vitro by disrupting the local neurotrophic supply to DRGN. We observed significantly elevated levels of cleaved CASP2 (C-CASP2), compared to cleaved caspase-3 (C-CASP3), within TUNEL+DRGN and DRG glia (satellite and Schwann cells) after SN transection. A serum withdrawal cell culture model, which induced 40% apoptotic death in DRGN and 60% in glia, was used to model DRGN loss after neurotrophic factor withdrawal. Elevated C-CASP2 and TUNEL were observed in both DRGN and DRG glia, with C-CASP2 localisation shifting from the cytosol to the nucleus, a required step for induction of direct CASP2-mediated apoptosis. Furthermore, siRNAmediated downregulation of CASP2 protected 50% of DRGN from apoptosis after serum withdrawal, while downregulation of CASP3 had no effect on DRGN or DRG glia survival. We conclude that CASP2 orchestrates the death of SN-axotomised DRGN directly and also indirectly through loss of DRG glia and their local neurotrophic factor support. Accordingly, inhibiting CASP2 expression is a potential therapy for improving both the SN regeneration response and peripheral sensory recovery
Molecular motors robustly drive active gels to a critically connected state
Living systems often exhibit internal driving: active, molecular processes
drive nonequilibrium phenomena such as metabolism or migration. Active gels
constitute a fascinating class of internally driven matter, where molecular
motors exert localized stresses inside polymer networks. There is evidence that
network crosslinking is required to allow motors to induce macroscopic
contraction. Yet a quantitative understanding of how network connectivity
enables contraction is lacking. Here we show experimentally that myosin motors
contract crosslinked actin polymer networks to clusters with a scale-free size
distribution. This critical behavior occurs over an unexpectedly broad range of
crosslink concentrations. To understand this robustness, we develop a
quantitative model of contractile networks that takes into account network
restructuring: motors reduce connectivity by forcing crosslinks to unbind.
Paradoxically, to coordinate global contractions, motor activity should be low.
Otherwise, motors drive initially well-connected networks to a critical state
where ruptures form across the entire network.Comment: Main text: 21 pages, 5 figures. Supplementary Information: 13 pages,
8 figure
Oral octreotide capsules for the treatment of acromegaly: comparison of 2 phase 3 trial results
Purpose Results are presented from 2 to 3 trials investigating oral octreotide capsules (OOC) as an alternative to injectable somatostatin receptor ligands (iSRLs) in the treatment of acromegaly. Methods CH-ACM-01 was an open-label trial (N = 155) and CHIASMA OPTIMAL was a double-blind placebo-controlled (DPC) trial (N = 56), both investigating OOC as maintenance therapy for patients with acromegaly who were biochemical responders receiving iSRLs. Results Baseline characteristics in both trials reflected those expected of patients with acromegaly responding to treatment and were similar between trials, despite differences in inclusion criteria. OOC demonstrated a consistent degree of biochemical response across trials, with 65% of patients in CH-ACM-01 maintaining response during the core period and 64% of patients in CHIASMA OPTIMAL at the end of the DPC. Mean insulin-like growth factor I (IGF-I) levels remained within inclusion criteria at the end of treatment in both trials. Of 110 patients entering the fixed-dose phase in CH-ACM-01, 80% maintained or improved acromegaly symptoms from baseline to the end of treatment. Over 85% of patients in both trials elected to continue into the extension phases. OOC were found to be well tolerated across both trials, and no dose-related adverse events were observed. Conclusions OOC demonstrated remarkably consistent results for biochemical response, durability of response, and preference to continue with oral treatment across these 2 complementary landmark phase 3 trials, despite differences in the design of each.Diabetes mellitus: pathophysiological changes and therap
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