7,281 research outputs found
Desynchronizing effect of high-frequency stimulation in a generic cortical network model
Transcranial Electrical Stimulation (TCES) and Deep Brain Stimulation (DBS)
are two different applications of electrical current to the brain used in
different areas of medicine. Both have a similar frequency dependence of their
efficiency, with the most pronounced effects around 100Hz. We apply
superthreshold electrical stimulation, specifically depolarizing DC current,
interrupted at different frequencies, to a simple model of a population of
cortical neurons which uses phenomenological descriptions of neurons by
Izhikevich and synaptic connections on a similar level of sophistication. With
this model, we are able to reproduce the optimal desynchronization around
100Hz, as well as to predict the full frequency dependence of the efficiency of
desynchronization, and thereby to give a possible explanation for the action
mechanism of TCES.Comment: 9 pages, figs included. Accepted for publication in Cognitive
Neurodynamic
Probabilistic Guarantees for Safe Deep Reinforcement Learning
Deep reinforcement learning has been successfully applied to many control
tasks, but the application of such agents in safety-critical scenarios has been
limited due to safety concerns. Rigorous testing of these controllers is
challenging, particularly when they operate in probabilistic environments due
to, for example, hardware faults or noisy sensors. We propose MOSAIC, an
algorithm for measuring the safety of deep reinforcement learning agents in
stochastic settings. Our approach is based on the iterative construction of a
formal abstraction of a controller's execution in an environment, and leverages
probabilistic model checking of Markov decision processes to produce
probabilistic guarantees on safe behaviour over a finite time horizon. It
produces bounds on the probability of safe operation of the controller for
different initial configurations and identifies regions where correct behaviour
can be guaranteed. We implement and evaluate our approach on agents trained for
several benchmark control problems
Survivin as a therapeutic target in Sonic hedgehog-driven medulloblastoma.
Medulloblastoma (MB) is a highly malignant brain tumor that occurs primarily in children. Although surgery, radiation and high-dose chemotherapy have led to increased survival, many MB patients still die from their disease, and patients who survive suffer severe long-term side effects as a consequence of treatment. Thus, more effective and less toxic therapies for MB are critically important. Development of such therapies depends in part on identification of genes that are necessary for growth and survival of tumor cells. Survivin is an inhibitor of apoptosis protein that regulates cell cycle progression and resistance to apoptosis, is frequently expressed in human MB and when expressed at high levels predicts poor clinical outcome. Therefore, we hypothesized that Survivin may have a critical role in growth and survival of MB cells and that targeting it may enhance MB therapy. Here we show that Survivin is overexpressed in tumors from patched (Ptch) mutant mice, a model of Sonic hedgehog (SHH)-driven MB. Genetic deletion of survivin in Ptch mutant tumor cells significantly inhibits proliferation and causes cell cycle arrest. Treatment with small-molecule antagonists of Survivin impairs proliferation and survival of both murine and human MB cells. Finally, Survivin antagonists impede growth of MB cells in vivo. These studies highlight the importance of Survivin in SHH-driven MB, and suggest that it may represent a novel therapeutic target in patients with this disease
Bladder cancer, a unique model to understand cancer immunity and develop immunotherapy approaches
International audienceWith the mechanistic understanding of immune checkpoints and success in checkpoint blockade using antibodies for the treatment of certain cancers, immunotherapy has become one of the hottest areas in cancer research, with promise of long-lasting therapeutic effect. Currently, however, only a proportion of cancers have a good response to checkpoint inhibition immunotherapy. Better understanding of the cancer response and resistance mechanisms is essential to fully explore the potential of immunotherapy to cure the majority of cancers. Bladder cancer, one of the most common and aggressive malignant diseases, has been successfully treated both at early and advanced stages by different immunotherapeutic approaches, bacillus Calmette-Guérin (BCG) intravesical instillation and anti-PD-1/PD-L1 immune checkpoint blockade, respectively. Therefore, it provides a good model to investigate cancer immune response mechanisms and to improve the efficiency of immunotherapy. Here, we review bladder cancer immunotherapy with equal weight on BCG and anti-PD-1/PD-L1 therapies and demonstrate why and how bladder cancer can be used as a model to study the predictors and mechanisms of cancer immune response and shine light on further development of immunotherapy approaches and response predictive biomarkers to improve immunotherapy of bladder cancer and other malignancies. We review the success of BCG and anti-PD-1/PD-L1 treatment of bladder cancer, the underlying mechanisms and the therapeutic response predictors, including the limits to our knowledge. We then highlight briefly the adaptation of immunotherapy approaches and predictors developed in other cancers for bladder cancer therapy. Finally, we explore the potential of using bladder cancer as a model to investigate cancer immune response mechanisms and new therapeutic approaches, which may be translated into immunotherapy of other human cancers
Tuning of Human Modulation Filters Is Carrier-Frequency Dependent
Licensed under the Creative Commons Attribution License
Complete larval development of the hermit crabs Clibanarius aequabilis and Clibanarius erythropus (Decapoda : Anomura : Diogenidae), under laboratory conditions, with a revision of the larval features of genus Clibanarius
The complete larval development (four zoeae and one megalopa) of Clibanarius aequabilis and C. erythropus, reared under laboratory conditions, is described and illustrated. The larval stages of the two northeastern Atlantic Clibanarius species cannot be easily differentiated. Their morphological characters are compared with those of other known Clibanarius larvae. The genus Clibanarius is very homogeneous with respect to larval characters. All Clibanarius zoeae display a broad and blunt rostrum, smooth abdominal segments and an antennal scale without a terminal spine. Beyond the second zoeal stage, the fourth telson process is present as a fused spine, and the uropods are biramous. In the fourth larval stage all species display a mandibular palp. The Clibanarius megalopa presents weakly developed or no ocular scales, symmetrical chelipeds, apically curved corneous dactylus in the second and third pereiopods, and 5-11 setae on the posterior margin of the telson. Apart from the number of zoeal stages, Clibanarius species may be separated, beyond the second zoeal stage, by the telson formula and the morphology of the fourth telson process.info:eu-repo/semantics/publishedVersio
Funding models in palliative care: lessons from international experience
Background:Funding models influence provision and development of palliative care services. As palliative care integrates into mainstream health care provision, opportunities to develop funding mechanisms arise. However, little has been reported on what funding models exist or how we can learn from them.Aim:To assess national models and methods for financing and reimbursing palliative care.Design:Initial literature scoping yielded limited evidence on the subject as national policy documents are difficult to identify, access and interpret. We undertook expert consultations to appraise national models of palliative care financing in England, Germany, Hungary, Republic of Ireland, New Zealand, The Netherlands, Norway, Poland, Spain, Sweden, Switzerland, the United States and Wales. These represent different levels of service development and a variety of funding mechanisms.Results:Funding mechanisms reflect country-specific context and local variations in care provision. Patterns emerging include the following:Provider payment is rarely linked to population need and often perpetuates existing inequitable patterns in service provision.Funding is frequently characterised as a mixed system of charitable, public and private payers.The basis on which providers are paid for services rarely reflects individual care input or patient needs.Conclusion:Funding mechanisms need to be well understood and used with caution to ensure best practice and minimise perverse incentives. Before we can conduct cross-national comparisons of costs and impact of palliative care, we need to understand the funding and policy context for palliative care in each country of interest
Obstetric anal sphincter injury: a systematic review of information available on the internet.
OBJECTIVE: There is no systematic evaluation of online health information pertaining to obstetric anal sphincter injury. Therefore, we evaluated the accuracy, credibility, reliability, and readability of online information concerning obstetric anal sphincter injury. MATERIALS AND METHODS: Multiple search engines were searched. The first 30 webpages were identified for each keyword and considered eligible if they provided information regarding obstetric anal sphincter injury. Eligible webpages were assessed by two independent researchers for accuracy (prioritised criteria based upon the RCOG Third and Fourth Degree Tear guideline); credibility; reliability; and readability. RESULTS: Fifty-eight webpages were included. Seventeen webpages (30%) had obtained Health On the Net certification, or Information Standard approval and performed better than those without such approvals (pâ=â0.039). The best overall performing website was http://www.pat.nhs.uk (score of 146.7). A single webpage (1%) fulfilled the entire criteria for accuracy with a score of 18: www.tamesidehospital.nhs.uk . Twenty-nine webpages (50%) were assessed as credible (scores â„7). A single webpage achieved a maximum credibility score of 10: www.meht.nhs.uk . Over a third (21 out of 58) were rated as poor or very poor. The highest scoring webpage was http://www.royalsurrey.nhs.uk (score 62). No webpage met the recommended Flesch Reading Ease Score above 70. The intra-class coefficient between researchers was 0.98 (95% CI 0.96-0.99) and 0.94 (95% CI 0.89-0.96) for accuracy and reliability assessments. CONCLUSION: Online information concerning obstetric anal sphincter injury often uses language that is inappropriate for a lay audience and lacks sufficient accuracy, credibility, and reliability
MCT Expression and Lactate Influx/Efflux in Tanycytes Involved in Glia-Neuron Metabolic Interaction
Metabolic interaction via lactate between glial cells and neurons has been proposed as one of the mechanisms involved in hypothalamic glucosensing. We have postulated that hypothalamic glial cells, also known as tanycytes, produce lactate by glycolytic metabolism of glucose. Transfer of lactate to neighboring neurons stimulates ATP synthesis and thus contributes to their activation. Because destruction of third ventricle (III-V) tanycytes is sufficient to alter blood glucose levels and food intake in rats, it is hypothesized that tanycytes are involved in the hypothalamic glucose sensing mechanism. Here, we demonstrate the presence and function of monocarboxylate transporters (MCTs) in tanycytes. Specifically, MCT1 and MCT4 expression as well as their distribution were analyzed in Sprague Dawley rat brain, and we demonstrate that both transporters are expressed in tanycytes. Using primary tanycyte cultures, kinetic analyses and sensitivity to inhibitors were undertaken to confirm that MCT1 and MCT4 were functional for lactate influx. Additionally, physiological concentrations of glucose induced lactate efflux in cultured tanycytes, which was inhibited by classical MCT inhibitors. Because the expression of both MCT1 and MCT4 has been linked to lactate efflux, we propose that tanycytes participate in glucose sensing based on a metabolic interaction with neurons of the arcuate nucleus, which are stimulated by lactate released from MCT1 and MCT4-expressing tanycytes
Who is in the driver's seat in 8p12 amplifications? ZNF703 in luminal B breast tumors
Two recent reports identify ZNF703 as an oncogene driving selection of frequent chromosome 8p12 amplifications in luminal B breast tumors. The estrogen-responsive ZNF703 gene encodes a transcriptional cofactor that, when overexpressed, induces cell proliferation and interferes with transforming growth factor beta signaling. In MCF7 cells, increased ZNF703 expression results in activation of genes involved in stem cell self-renewal - while in primary human mammary epithelial cells, ZNF703 increases the ratio of luminal to basal progenitors. Expression of the murine homolog of ZNF703 reduces cell adhesion and promotes metastasis. ZNF703 overexpression thus alters regulation of proliferation and differentiation in luminal B tumors
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