Summary Neuropathic pain develops as a result of lesions or disease affecting the somatosensory nervous system either in the periphery or centrally. Examples of neuropathic pain include painful ...polyneuropathy, postherpetic neuralgia, trigeminal neuralgia, and post-stroke pain. Clinically, neuropathic pain is characterised by spontaneous ongoing or shooting pain and evoked amplified pain responses after noxious or non-noxious stimuli. Methods such as questionnaires for screening and assessment focus on the presence and quality of neuropathic pain. Basic research is enabling the identification of different pathophysiological mechanisms, and clinical assessment of symptoms and signs can help to determine which mechanisms are involved in specific neuropathic pain disorders. Management of neuropathic pain requires an interdisciplinary approach, centred around pharmacological treatment. A better understanding of neuropathic pain and, in particular, of the translation of pathophysiological mechanisms into sensory signs will lead to a more effective and specific mechanism-based treatment approach.
Summary Background Patients with neuropathic pain present with various pain-related sensory abnormalities. These sensory features form different patterns or mosaics—the sensory profile—in individual ...patients. One hypothesis for the development of sensory profiles is that distinct pathophysiological mechanisms of pain generation produce specific sensory abnormalities. Several controlled trials of promising new drugs have produced negative results, but these findings could have been a result of heterogeneity in the patient population. Subgrouping patients on the basis of individual sensory profiles could reduce this heterogeneity and improve trial design. Recent developments A statistical categorisation of patients with neuropathic pain showed that subgroups of patients with distinct sensory profiles who perceive their pain differently do exist across a range of neuropathic disorders, although some distinct disorder-specific profiles were also detected. Results of the first clinical trials to use the subgroup approach at baseline could show a superior effect of the study drugs in specific subgroups, rather than in the entire cohort of patients. Where next? A new classification of neuropathic pain should take into account subgroups of patients with different sensory profiles. Sensory phenotyping has the potential to improve clinical trial design by enriching the study population with potential treatment responders, and might lead to a stratified treatment approach and ultimately to personalised treatment.
Complex regional pain syndromes (CRPS) are multifactorial disorders with complex aetiology and pathogenesis. Management of CRPS is challenging, partly because of a lack of clinical data regarding the ...efficacy of the various therapies, and partly because successful treatment of CRPS requires a multidisciplinary, patient-tailored approach. The pain in CRPS is often described as typical 'burning' neuropathic pain, and is accompanied by a variety of sensory, motor and autonomic signs and symptoms. Because research into therapies specifically in CRPS has been scarce, treatment for these syndromes has been largely based on therapeutic strategies adapted from neuropathic pain states; however, increased understanding of the pathogenesis of CRPS has provided the opportunity to develop mechanism-based treatments. The interactions between the multiple pathophysiological mechanisms that contribute to the development, progression and maintenance of CRPS remain poorly understood. This Review describes the challenges in linking the current theories and knowledge of pathophysiological mechanisms to the mode of actions of the different treatment approaches. We discuss the current treatment strategies for CRPS, including pharmacotherapy, sympathetic ganglion block interventions, psychological support, physiotherapy and occupational therapy, and establish the concept of mechanism-based treatment for CRPS.
Temporally and spatially defined calcium signatures are integral parts of numerous signalling pathways. Monitoring calcium dynamics with high spatial and temporal resolution is therefore critically ...important to understand how this ubiquitous second messenger can control diverse cellular responses. Yellow cameleons (YCs) are fluorescence resonance energy transfer (FRET)‐based genetically encoded Ca2+ ‐sensors that provide a powerful tool to monitor the spatio‐temporal dynamics of Ca2+ fluxes. Here we present an advanced set of vectors and transgenic lines for live cell Ca2+ imaging in plants. Transgene silencing mediated by the cauliflower mosaic virus (CaMV) 35S promoter has severely limited the application of nanosensors for ions and metabolites and we have thus used the UBQ10 promoter from Arabidopsis and show here that this results in constitutive and stable expression of YCs in transgenic plants. To improve the spatial resolution, our vector repertoire includes versions of YCs that can be targeted to defined locations. Using this toolkit, we identified temporally distinct responses to external ATP at the plasma membrane, in the cytosol and in the nucleus of neighbouring root cells. Moreover analysis of Ca2+ dynamics in Lotus japonicus revealed distinct Nod factor induced Ca2+ spiking patterns in the nucleus and the cytosol. Consequently, the constructs and transgenic lines introduced here enable a detailed analysis of Ca2+ dynamics in different cellular compartments and in different plant species and will foster novel approaches to decipher the temporal and spatial characteristics of calcium signatures.
Plant receptor-like kinases (RLKs) function in diverse signaling pathways, including the responses to microbial signals in symbiosis and defense. This versatility is achieved with a common overall ...structure: an extracytoplasmic domain (ectodomain) and an intracellular protein kinase domain involved in downstream signal transduction. Various surfaces of the leucine-rich repeat (LRR) ectodomain superstructure are utilized for interaction with the cognate ligand in both plant and animal receptors. RLKs with lysin-motif (LysM) ectodomains confer recognitional specificity toward N-acetylglucosamine-containing signaling molecules, such as chitin, peptidoglycan (PGN), and rhizobial nodulation factor (NF), that induce immune or symbiotic responses. Signaling downstream of RLKs does not follow a single pattern; instead, the detailed analysis of brassinosteroid (BR) signaling, innate immunity, and symbiosis revealed at least three largely nonoverlapping pathways. In this review, we focus on RLKs involved in plant-microbe interactions and contrast the signaling pathways leading to symbiosis and defense.
Summary
Whether rice, yeast or fly there is barely a model organism not yet reached by transcription activator‐like effectors (TALEs) and their derivative fusion proteins. Insights into fundamental ...biology are now arriving on the back of work in recent years to develop these proteins as tools for molecular biology. This began with the publication of the simple cipher determining base‐specific DNA recognition by TALEs in 2009, and now encompasses a huge variety of established fusion proteins mediating targeted modifications to transcriptome, genome and, recently, epigenome. Straightforward design and exquisite specificity, allowing unique sites to be targeted even within complex eukaryote genomes, are key to the popularity of this system. Synthetic biology is one field that is just beginning to make use of these properties, with a number of recent publications demonstrating TALE‐mediated regulation of synthetic genetic circuits. Intense interest has surrounded the CRISPR/Cas9 system within the last 12 months, and it is already proving its mettle as a tool for targeted gene modifications and transcriptional regulation. However, questions over off‐target activity and means for independent regulation of multiple Cas9‐guide RNA pairs must be resolved before this method can be included in the synthetic biology toolbox. TALEs are already showing promise as regulators of synthetic biological systems, a role that is likely to be developed further in the coming years.
The Golden Gate (GG) modular assembly approach offers a standardized, inexpensive and reliable way to ligate multiple DNA fragments in a pre-defined order in a single-tube reaction. We developed a GG ...based toolkit for the flexible construction of binary plasmids for transgene expression in plants. Starting from a common set of modules, such as promoters, protein tags and transcribed regions of interest, synthetic genes are assembled, which can be further combined to multigene constructs. As an example, we created T-DNA constructs encoding multiple fluorescent proteins targeted to distinct cellular compartments (nucleus, cytosol, plastids) and demonstrated simultaneous expression of all genes in Nicotiana benthamiana, Lotus japonicus and Arabidopsis thaliana. We assembled an RNA interference (RNAi) module for the construction of intron-spliced hairpin RNA constructs and demonstrated silencing of GFP in N. benthamiana. By combination of the silencing construct together with a codon adapted rescue construct into one vector, our system facilitates genetic complementation and thus confirmation of the causative gene responsible for a given RNAi phenotype. As proof of principle, we silenced a destabilized GFP gene (dGFP) and restored GFP fluorescence by expression of a recoded version of dGFP, which was not targeted by the silencing construct.
As an indirect approach to relate previously identified sensory phenotypes of patients suffering from peripheral neuropathic pain to underlying mechanisms, we used a published sorting algorithm to ...estimate the prevalence of denervation, peripheral and central sensitization in 657 healthy subjects undergoing experimental models of nerve block (NB) (compression block and topical lidocaine), primary hyperalgesia (PH) (sunburn and topical capsaicin), or secondary hyperalgesia (intradermal capsaicin and electrical high-frequency stimulation), and in 902 patients suffering from neuropathic pain. Some of the data have been previously published. Randomized split-half analysis verified a good concordance with a priori mechanistic sensory profile assignment in the training (79%, Cohen κ = 0.54, n = 265) and the test set (81%, Cohen κ = 0.56, n = 279). Nerve blocks were characterized by pronounced thermal and mechanical sensory loss, but also mild pinprick hyperalgesia and paradoxical heat sensations. Primary hyperalgesia was characterized by pronounced gain for heat, pressure and pinprick pain, and mild thermal sensory loss. Secondary hyperalgesia was characterized by pronounced pinprick hyperalgesia and mild thermal sensory loss. Topical lidocaine plus topical capsaicin induced a combined phenotype of NB plus PH. Topical menthol was the only model with significant cold hyperalgesia. Sorting of the 902 patients into these mechanistic phenotypes led to a similar distribution as the original heuristic clustering (65% identity, Cohen κ = 0.44), but the denervation phenotype was more frequent than in heuristic clustering. These data suggest that sorting according to human surrogate models may be useful for mechanism-based stratification of neuropathic pain patients for future clinical trials, as encouraged by the European Medicines Agency.
This paper presents a model order reduction approach for large scale high dimensional parametric models arising in the analysis of financial risk. To understand the risks associated with a financial ...product, one has to perform several thousand computationally demanding simulations of the model which require efficient algorithms. We establish a model reduction approach based on a variant of the proper orthogonal decomposition method to generate small model approximations for the high dimensional parametric convection-diffusion-reaction partial differential equations. This approach requires to solve the full model at some selected parameter values to generate a reduced basis. We propose an adaptive greedy sampling technique based on surrogate modeling for the selection of the sample parameter set. The new technique is analyzed, implemented, and tested on industrial data of a floater with cap and floor under the Hull–White model. The results illustrate that the reduced model approach works well for short-rate models.
The effect of variable DC bearing current amplitude, bearing current polarity, mechanical force, rotation speed, bearing temperature, and number of the balls on the fluting in an axial ball bearing ...type 51208 is investigated under DC currents. The results are obtained from two different test setups with two different lubricants (mineral-oil-based grease and polyglycol oil). The speed varies between 100 rpm and 2000 rpm, the axial bearing force between 200 N and 2400 N, the DC current amplitude between 0.5 A and 20 A, the bearing temperature between 29 °C and 80 °C, the number of steel balls per bearing between 3 and 15, and the test duration between 6 h and 168 h. The results show that with a higher bearing current density and/or a higher bearing speed, a lower bearing force and/or a lower bearing temperature, a bigger number of roller elements, but also at a negative polarity of a DC electric bearing current, the occurring of fluting is more probable and occurs at an earlier stage of operation.
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