431 research outputs found
Algorithm for Adapting Cases Represented in a Tractable Description Logic
Case-based reasoning (CBR) based on description logics (DLs) has gained a lot
of attention lately. Adaptation is a basic task in the CBR inference that can
be modeled as the knowledge base revision problem and solved in propositional
logic. However, in DLs, it is still a challenge problem since existing revision
operators only work well for strictly restricted DLs of the \emph{DL-Lite}
family, and it is difficult to design a revision algorithm which is
syntax-independent and fine-grained. In this paper, we present a new method for
adaptation based on the DL . Following the idea of
adaptation as revision, we firstly extend the logical basis for describing
cases from propositional logic to the DL , and present a
formalism for adaptation based on . Then we present an
adaptation algorithm for this formalism and demonstrate that our algorithm is
syntax-independent and fine-grained. Our work provides a logical basis for
adaptation in CBR systems where cases and domain knowledge are described by the
tractable DL .Comment: 21 pages. ICCBR 201
TSUNAMI: an antisense method to phenocopy splicing-associated diseases in animals
Antisense oligonucleotides (ASOs) are versatile molecules that can be designed to specifically alter splicing patterns of target pre-mRNAs. Here we exploit this feature to phenocopy a genetic disease. Spinal muscular atrophy (SMA) is a motor neuron disease caused by loss-of-function mutations in the SMN1 gene. The related SMN2 gene expresses suboptimal levels of functional SMN protein due to alternative splicing that skips exon 7; correcting this defect-e.g., with ASOs-is a promising therapeutic approach. We describe the use of ASOs that exacerbate SMN2 missplicing and phenocopy SMA in a dose-dependent manner when administered to transgenic Smn(-/-) mice. Intracerebroventricular ASO injection in neonatal mice recapitulates SMA-like progressive motor dysfunction, growth impairment, and shortened life span, with alpha-motor neuron loss and abnormal neuromuscular junctions. These SMA-like phenotypes are prevented by a therapeutic ASO that restores correct SMN2 splicing. We uncovered starvation-induced splicing changes, particularly in SMN2, which likely accelerate disease progression. These results constitute proof of principle that ASOs designed to cause sustained splicing defects can be used to induce pathogenesis and rapidly and accurately model splicing-associated diseases in animals. This approach allows the dissection of pathogenesis mechanisms, including spatial and temporal features of disease onset and progression, as well as testing of candidate therapeutics
Can follow-up procalcitonin measurements shorten the periods of antibiotic administrations for septic patients?
Simple excision and closure of a distal limb of loop colostomy prolapse by stapler device
Stomal prolapse is one of the common complications in transverse colostomy and can be managed conservatively in most cases; however, laparotomy and reconstruction of the stoma may sometimes be required, especially in case of irreducible colostomy prolapse. We have reported a simple local repair with reconstruction of the loop colostomy. We herein report a new more simple technique to avoid laparotomy and allow excision of the irreducible colostomy prolapse and complete closure of the distal limb of loop colostomy when no decompression is required in the distal limb of the stoma. In this procedure, the number of stapler and the time with blood loss for the operation can be saved
Clinical features of spinal and bulbar muscular atrophy
Spinal and bulbar muscular atrophy is an X-linked motor neuron disease caused by a CAG repeat expansion in the androgen receptor gene. To characterize the natural history and define outcome measures for clinical trials, we assessed the clinical history, laboratory findings and muscle strength and function in 57 patients with genetically confirmed disease. We also administered self-assessment questionnaires for activities of daily living, quality of life and erectile function. We found an average delay of over 5 years from onset of weakness to diagnosis. Muscle strength and function correlated directly with serum testosterone levels and inversely with CAG repeat length, age and duration of weakness. Motor unit number estimation was decreased by about half compared to healthy controls. Sensory nerve action potentials were reduced in nearly all subjects. Quantitative muscle assessment and timed 2 min walk may be useful as meaningful indicators of disease status. The direct correlation of testosterone levels with muscle strength indicates that androgens may have a positive effect on muscle function in spinal and bulbar muscular atrophy patients, in addition to the toxic effects described in animal models
Propositional update operators based on formula/literal dependence
International audienceWe present and study a general family of belief update operators in a propositional setting. Its operators are based on formula/literal dependence, which is more fine-grained than the notion of formula/variable dependence that was proposed in the literature: formula/variable dependence is a particular case of formula/literal dependence. Our update operators are defined according to the "forget-then-conjoin" scheme: updating a belief base by an input formula consists in first forgetting in the base every literal on which the input formula has a negative influence, and then conjoining the resulting base with the input formula. The operators of our family differ by the underlying notion of formula/literal dependence, which may be defined syntactically or semantically, and which may or may not exploit further information like known persistent literals and pre-set dependencies. We argue that this allows to handle the frame problem and the ramification problem in a more appropriate way. We evaluate the update operators of our family w.r.t. two important dimensions: the logical dimension, by checking the status of the Katsuno-Mendelzon postulates for update, and the computational dimension, by identifying the complexity of a number of decision problems (including model checking, consistency and inference), both in the general case and in some restricted cases, as well as by studying compactability issues. It follows that several operators of our family are interesting alternatives to previous belief update operators
Ablation of Proliferating Cells in the CNS Exacerbates Motor Neuron Disease Caused by Mutant Superoxide Dismutase
Proliferation of glia and immune cells is a common pathological feature of many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Here, to investigate the role of proliferating cells in motor neuron disease, SOD1G93A transgenic mice were treated intracerebroventicularly (ICV) with the anti-mitotic drug cytosine arabinoside (Ara-C). ICV delivery of Ara-C accelerated disease progression in SOD1G93A mouse model of ALS. Ara-C treatment caused substantial decreases in the number of microglia, NG2+ progenitors, Olig2+ cells and CD3+ T cells in the lumbar spinal cord of symptomatic SOD1G93A transgenic mice. Exacerbation of disease was also associated with significant alterations in the expression inflammatory molecules IL-1β, IL-6, TGF-β and the growth factor IGF-1
Simulating the carbon balance of a temperate larch forest under various meteorological conditions
<p>Abstract</p> <p>Background</p> <p>Changes in the timing of phenological events may cause the annual carbon budget of deciduous forests to change. Therefore, one should take such events into account when evaluating the effects of global warming on deciduous forests. In this article, we report on the results of numerical experiments done with a model that includes a phenological module simulating the timing of bud burst and other phenological events and estimating maximum leaf area index.</p> <p>Results</p> <p>This study suggests that the negative effects of warming on tree productivity (net primary production) outweigh the positive effects of a prolonged growing season. An increase in air temperature by 3°C (5°C) reduces cumulative net primary production by 21.3% (34.2%). Similarly, cumulative net ecosystem production (the difference between cumulative net primary production and heterotrophic respiration) decreases by 43.5% (64.5%) when temperatures are increased by 3°C (5°C). However, the positive effects of CO<sub>2 </sub>enrichment (2 × CO<sub>2</sub>) outweigh the negative effects of warming (<5°C).</p> <p>Conclusion</p> <p>Although the model was calibrated and validated for a specific forest ecosystem, the implications of the study may be extrapolated to deciduous forests in cool-temperate zones. These forests share common features, and it can be conjectured that carbon stocks would increase in such forests in the face of doubled CO<sub>2 </sub>and increased temperatures as long as the increase in temperature does not exceed 5°C.</p
Protective Effect of Geranylgeranylacetone via Enhancement of HSPB8 Induction in Desmin-Related Cardiomyopathy
An arg120gly (R120G) missense mutation in HSPB5 (alpha-beta-crystallin ), which belongs to the small heat shock protein (HSP) family, causes desmin-related cardiomyopathy (DRM), a muscle disease that is characterized by the formation of inclusion bodies, which can contain pre-amyloid oligomer intermediates (amyloid oligomer). While we have shown that small HSPs can directly interrupt amyloid oligomer formation, the in vivo protective effects of the small HSPs on the development of DRM is still uncertain.In order to extend the previous in vitro findings to in vivo, we used geranylgeranylacetone (GGA), a potent HSP inducer. Oral administration of GGA resulted not only in up-regulation of the expression level of HSPB8 and HSPB1 in the heart of HSPB5 R120G transgenic (R120G TG) mice, but also reduced amyloid oligomer levels and aggregates. Furthermore, R120G TG mice treated with GGA exhibited decreased heart size and less interstitial fibrosis, as well as improved cardiac function and survival compared to untreated R120G TG mice. To address possible mechanism(s) for these beneficial effects, cardiac-specific transgenic mice expressing HSPB8 were generated. Overexpression of HSPB8 led to a reduction in amyloid oligomer and aggregate formation, resulting in improved cardiac function and survival. Treatment with GGA as well as the overexpression of HSPB8 also inhibited cytochrome c release from mitochondria, activation of caspase-3 and TUNEL-positive cardiomyocyte death in the R120G TG mice.Expression of small HSPs such as HSPB8 and HSPB1 by GGA may be a new therapeutic strategy for patients with DRM
Targeting the Neurokinin Receptor 1 with Aprepitant: A Novel Antipruritic Strategy
Chronic pruritus is a global clinical problem with a high impact on the quality of life and lack of specific therapies. It is an excruciating and frequent symptom of e.g. uncurable renal, liver and skin diseases which often does not respond to conventional treatment with e.g. antihistamines. Therefore antipruritic therapies which target physiological mechanisms of pruritus need to be developed. Substance P (SP) is a major mediator of pruritus. As it binds to the neurokinin receptor 1 (NKR1), we evaluated if the application of a NKR1 antagonist would significantly decrease chronic pruritus.Twenty hitherto untreatable patients with chronic pruritus (12 female, 8 male; mean age, 66.7 years) were treated with the NKR1 antagonist aprepitant 80 mg for one week. 16 of 20 patients (80%) experienced a considerable reduction of itch intensity, as assessed by the visual analog scale (VAS, range 0 to 10). Considering all patients, the mean value of pruritus intensity was significantly reduced from 8.4 VAS points (SD +/-1.7) before treatment to 4.9 VAS points (SD +/-3.2) (p<0.001, CI 1.913-5.187). Patients with dermatological diseases (e.g. atopic diathesis, prurigo nodularis) had the best profit from the treatment. Side-effects were mild (nausea, vertigo, and drowsiness) and only occurred in three patients.The high response rate in patients with therapy refractory pruritus suggests that the NKR1 antagonist aprepitant may indeed exhibit antipruritic effects and may present a novel, effective treatment strategy based on pathophysiology of chronic pruritus. The results are promising enough to warrant confirming the efficacy of NKR1 antagonists in a randomized, controlled clinical trial
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