TRPV4 is necessary for trigeminal irritant pain and functions as a cellular formalin receptor.

Detection of external irritants by head nociceptor neurons has deep evolutionary roots. Irritant-induced aversive behavior is a popular pain model in laboratory animals. It is used widely in the formalin model, where formaldehyde is injected into the rodent paw, eliciting quantifiable nocifensive behavior that has a direct, tissue-injury-evoked phase, and a subsequent tonic phase caused by neural maladaptation. The formalin model has elucidated many antipain compounds and pain-modulating signaling pathways. We have adopted this model to trigeminally innervated territories in mice. In addition, we examined the involvement of TRPV4 channels in formalin-evoked trigeminal pain behavior because TRPV4 is abundantly expressed in trigeminal ganglion (TG) sensory neurons, and because we have recently defined TRPV4's role in response to airborne irritants and in a model for temporomandibular joint pain. We found TRPV4 to be important for trigeminal nocifensive behavior evoked by formalin whisker pad injections. This conclusion is supported by studies with Trpv4(-/-) mice and TRPV4-specific antagonists. Our results imply TRPV4 in MEK-ERK activation in TG sensory neurons. Furthermore, cellular studies in primary TG neurons and in heterologous TRPV4-expressing cells suggest that TRPV4 can be activated directly by formalin to gate Ca(2+). Using TRPA1-blocker and Trpa1(-/-) mice, we found that both TRP channels co-contribute to the formalin trigeminal pain response. These results imply TRPV4 as an important signaling molecule in irritation-evoked trigeminal pain. TRPV4-antagonistic therapies can therefore be envisioned as novel analgesics, possibly for specific targeting of trigeminal pain disorders, such as migraine, headaches, temporomandibular joint, facial, and dental pain, and irritation of trigeminally innervated surface epithelia.

Nme Gene Family Evolutionary History Reveals Pre-Metazoan Origins and High Conservation between Humans and the Sea Anemone, Nematostella vectensis

Background: The Nme gene family is involved in multiple physiological and pathological processes such as cellular differentiation, development, metastatic dissemination, and cilia functions. Despite the known importance of Nme genes and their use as clinical markers of tumor aggressiveness, the associated cellular mechanisms remain poorly understood. Over the last 20 years, several non-vertebrate model species have been used to investigate Nme functions. However, the evolutionary history of the family remains poorly understood outside the vertebrate lineage. The aim of the study was thus to elucidate the evolutionary history of the Nme gene family in Metazoans. Methodology/Principal Findings: Using a total of 21 eukaryote species including 14 metazoans, the evolutionary history of Nme genes was reconstructed in the metazoan lineage. We demonstrated that the complexity of the Nme gene family, initially thought to be restricted to chordates, was also shared by the metazoan ancestor. We also provide evidence suggesting that the complexity of the family is mainly a eukaryotic innovation, with the exception of Nme8 that is likely to be a choanoflagellate/metazoan innovation. Highly conserved gene structure, genomic linkage, and protein domains were identified among metazoans, some features being also conserved in eukaryotes. When considering the entire Nme family, the starlet sea anemone is the studied metazoan species exhibiting the most conserved gene and protein sequence features with humans. In addition, we were able to show that most of the proteins known to interact with human NME proteins were also found in starlet sea anemone. Conclusion/Significance: Together, our observations further support the association of Nme genes with key cellular functions that have been conserved throughout metazoan evolution. Future investigations of evolutionarily conserved Nme gene functions using the starlet sea anemone could shed new light on a wide variety of key developmental and cellular processes.

Off-diagonal ekpyrotic scenarios and equivalence of modified, massive and/or Einstein gravity

Using our anholonomic frame deformation method, we show how generic off-diagonal cosmological solutions depending, in general, on all spacetime coordinates and undergoing a phase of ultra-slow contraction can be constructed in massive gravity. In this paper, there are found and studied new classes of locally anisotropic and (in)homogeneous cosmological metrics with open and closed spatial geometries. The late time acceleration is present due to effective cosmological terms induced by nonlinear off-diagonal interactions and graviton mass. The off-diagonal cosmological metrics and related Stückelberg fields are constructed in explicit form up to nonholonomic frame transforms of the Friedmann–Lamaître–Robertson–Walker (FLRW) coordinates. We show that the solutions include matter, graviton mass and other effective sources modeling nonlinear gravitational and matter fields interactions in modified and/or massive gravity, with polarization of physical constants and deformations of metrics, which may explain certain dark energy and dark matter effects. There are stated and analyzed the conditions when such configurations mimic interesting solutions in general relativity and modifications and recast the general Painlevé–Gullstrand and FLRW metrics. Finally, we elaborate on a reconstruction procedure for a subclass of off-diagonal cosmological solutions which describe cyclic and ekpyrotic universes, with an emphasis on open issues and observable signatures.

Evaluating Invariances in Document Layout Functions

With the development of variable-data-driven digital presses - where each document printed is potentially unique - there is a need for pre-press optimization to identify material that is invariant from document to document. In this way rasterisation can be confined solely to those areas which change between successive documents thereby alleviating a potential performance bottleneck. Given a template document specified in terms of layout functions, where actual data is bound at the last possible moment before printing, we look at deriving and exploiting the invariant properties of layout functions from their formal specifications. We propose future work on generic extraction of invariance from such properties for certain classes of layout functions.

Complex functions with Geogebra

Complex functions, generally feature some interesting peculiarities, seen as extensions real functions, complementing the study of real analysis. However, the visualization of some complex functions properties requires the simultaneous visualization of two-dimensional spaces. The multiple Windows of GeoGebra, combined with its ability of algebraic computation with complex numbers, allow the study of the functions defined from ℂ to ℂ through traditional techniques and by the use of Domain Colouring. Here, we will show how we can use GeoGebra for the study of complex functions, using several representations and creating tools which complement the tools already provided by the software. Our proposals designed for students of the first year of engineering and science courses can and should be used as an educational tool in collaborative learning environments. The main advantage in its use in individual terms is the promotion of the deductive reasoning (conjecture / proof). In performed the literature review few references were found involving this educational topic and by the use of a single software.

An updated evolutionary classification of CRISPR–Cas systems

The evolution of CRISPR–cas loci, which encode adaptive immune systems in archaea and bacteria, involves rapid changes, in particular numerous rearrangements of the locus architecture and horizontal transfer of complete loci or individual modules. These dynamics complicate straightforward phylogenetic classification, but here we present an approach combining the analysis of signature protein families and features of the architecture of cas loci that unambiguously partitions most CRISPR–cas loci into distinct classes, types and subtypes. The new classification retains the overall structure of the previous version but is expanded to now encompass two classes, five types and 16 subtypes. The relative stability of the classification suggests that the most prevalent variants of CRISPR–Cas systems are already known. However, the existence of rare, currently unclassifiable variants implies that additional types and subtypes remain to be characterized.

Towards a logical foundation of randomized computation

This dissertation investigates the relations between logic and TCS in the probabilistic setting. It is motivated by two main considerations. On the one hand, since their appearance in the 1960s-1970s, probabilistic models have become increasingly pervasive in several fast-growing areas of CS. On the other, the study and development of (deterministic) computational models has considerably benefitted from the mutual interchanges between logic and CS. Nevertheless, probabilistic computation was only marginally touched by such fruitful interactions. The goal of this thesis is precisely to (start) bring(ing) this gap, by developing logical systems corresponding to specific aspects of randomized computation and, therefore, by generalizing standard achievements to the probabilistic realm. To do so, our key ingredient is the introduction of new, measure-sensitive quantifiers associated with quantitative interpretations. The dissertation is tripartite. In the first part, we focus on the relation between logic and counting complexity classes. We show that, due to our classical counting propositional logic, it is possible to generalize to counting classes, the standard results by Cook and Meyer and Stockmeyer linking propositional logic and the polynomial hierarchy. Indeed, we show that the validity problem for counting-quantified formulae captures the corresponding level in Wagner's hierarchy. In the second part, we consider programming language theory. Type systems for randomized \lambda-calculi, also guaranteeing various forms of termination properties, were introduced in the last decades, but these are not "logically oriented" and no Curry-Howard correspondence is known for them. Following intuitions coming from counting logics, we define the first probabilistic version of the correspondence. Finally, we consider the relationship between arithmetic and computation. We present a quantitative extension of the language of arithmetic able to formalize basic results from probability theory. This language is also our starting point to define randomized bounded theories and, so, to generalize canonical results by Buss.

Variational Quantum Splines: Moving Beyond Linearity for Quantum Activation Functions

Activation functions within neural networks play a crucial role in Deep Learning since they allow to learn complex and non-trivial patterns in the data. However, the ability to approximate non-linear functions is a significant limitation when implementing neural networks in a quantum computer to solve typical machine learning tasks. The main burden lies in the unitarity constraint of quantum operators, which forbids non-linearity and poses a considerable obstacle to developing such non-linear functions in a quantum setting. Nevertheless, several attempts have been made to tackle the realization of the quantum activation function in the literature. Recently, the idea of the QSplines has been proposed to approximate a non-linear activation function by implementing the quantum version of the spline functions. Yet, QSplines suffers from various drawbacks. Firstly, the final function estimation requires a post-processing step; thus, the value of the activation function is not available directly as a quantum state. Secondly, QSplines need many error-corrected qubits and a very long quantum circuits to be executed. These constraints do not allow the adoption of the QSplines on near-term quantum devices and limit their generalization capabilities. This thesis aims to overcome these limitations by leveraging hybrid quantum-classical computation. In particular, a few different methods for Variational Quantum Splines are proposed and implemented, to pave the way for the development of complete quantum activation functions and unlock the full potential of quantum neural networks in the field of quantum machine learning.

Mechanisms Predisposing Penile Fracture And Long-term Outcomes On Erectile And Voiding Functions.

Purpose. To determine the mechanisms predisposing penile fracture as well as the rate of long-term penile deformity and erectile and voiding functions. Methods. All fractures were repaired on an emergency basis via subcoronal incision and absorbable suture with simultaneous repair of eventual urethral lesion. Patients' status before fracture and voiding and erectile functions at long term were assessed by periodic follow-up and phone call. Detailed history included cause, symptoms, and single-question self-report of erectile and voiding functions. Results. Among the 44 suspicious cases, 42 (95.4%) were confirmed, mean age was 34.5 years (range: 18-60), mean follow-up 59.3 months (range 9-155). Half presented the classical triad of audible crack, detumescence, and pain. Heterosexual intercourse was the most common cause (28 patients, 66.7%), followed by penile manipulation (6 patients, 14.3%), and homosexual intercourse (4 patients, 9.5%). Woman on top was the most common heterosexual position (n = 14, 50%), followed by doggy style (n = 8, 28.6%). Four patients (9.5%) maintained the cause unclear. Six (14.3%) patients had urethral injury and two (4.8%) had erectile dysfunction, treated by penile prosthesis and PDE-5i. No patient showed urethral fistula, voiding deterioration, penile nodule/curve or pain. Conclusions. Woman on top was the potentially riskiest sexual position (50%). Immediate surgical treatment warrants long-term very low morbidity.

An Integrated Framework To Improve The Concept Of Resource Specialisation.

Resource specialisation, although a fundamental component of ecological theory, is employed in disparate ways. Most definitions derive from simple counts of resource species. We build on recent advances in ecophylogenetics and null model analysis to propose a concept of specialisation that comprises affinities among resources as well as their co-occurrence with consumers. In the distance-based specialisation index (DSI), specialisation is measured as relatedness (phylogenetic or otherwise) of resources, scaled by the null expectation of random use of locally available resources. Thus, specialists use significantly clustered sets of resources, whereas generalists use over-dispersed resources. Intermediate species are classed as indiscriminate consumers. The effectiveness of this approach was assessed with differentially restricted null models, applied to a data set of 168 herbivorous insect species and their hosts. Incorporation of plant relatedness and relative abundance greatly improved specialisation measures compared to taxon counts or simpler null models, which overestimate the fraction of specialists, a problem compounded by insufficient sampling effort. This framework disambiguates the concept of specialisation with an explicit measure applicable to any mode of affinity among resource classes, and is also linked to ecological and evolutionary processes. This will enable a more rigorous deployment of ecological specialisation in empirical and theoretical studies.

Two-component System Vicrk Regulates Functions Associated With Establishment Of Streptococcus Sanguinis In Biofilms.

Streptococcus sanguinis is a commensal pioneer colonizer of teeth and an opportunistic pathogen of infectious endocarditis. The establishment of S. sanguinis in host sites likely requires dynamic fitting of the cell wall in response to local stimuli. In this study, we investigated the two-component system (TCS) VicRK in S. sanguinis (VicRKSs), which regulates genes of cell wall biogenesis, biofilm formation, and virulence in opportunistic pathogens. A vicK knockout mutant obtained from strain SK36 (SKvic) showed slight reductions in aerobic growth and resistance to oxidative stress but an impaired ability to form biofilms, a phenotype restored in the complemented mutant. The biofilm-defective phenotype was associated with reduced amounts of extracellular DNA during aerobic growth, with reduced production of H2O2, a metabolic product associated with DNA release, and with inhibitory capacity of S. sanguinis competitor species. No changes in autolysis or cell surface hydrophobicity were detected in SKvic. Reverse transcription-quantitative PCR (RT-qPCR), electrophoretic mobility shift assays (EMSA), and promoter sequence analyses revealed that VicR directly regulates genes encoding murein hydrolases (SSA_0094, cwdP, and gbpB) and spxB, which encodes pyruvate oxidase for H2O2 production. Genes previously associated with spxB expression (spxR, ccpA, ackA, and tpK) were not transcriptionally affected in SKvic. RT-qPCR analyses of S. sanguinis biofilm cells further showed upregulation of VicRK targets (spxB, gbpB, and SSA_0094) and other genes for biofilm formation (gtfP and comE) compared to expression in planktonic cells. This study provides evidence that VicRKSs regulates functions crucial for S. sanguinis establishment in biofilms and identifies novel VicRK targets potentially involved in hydrolytic activities of the cell wall required for these functions.

Monte Carlo Simulation Of The Response Functions Of Cdte Detectors To Be Applied In X-ray Spectroscopy.

In this work, the energy response functions of a CdTe detector were obtained by Monte Carlo (MC) simulation in the energy range from 5 to 160keV, using the PENELOPE code. In the response calculations the carrier transport features and the detector resolution were included. The computed energy response function was validated through comparison with experimental results obtained with (241)Am and (152)Eu sources. In order to investigate the influence of the correction by the detector response at diagnostic energy range, x-ray spectra were measured using a CdTe detector (model XR-100T, Amptek), and then corrected by the energy response of the detector using the stripping procedure. Results showed that the CdTe exhibits good energy response at low energies (below 40keV), showing only small distortions on the measured spectra. For energies below about 80keV, the contribution of the escape of Cd- and Te-K x-rays produce significant distortions on the measured x-ray spectra. For higher energies, the most important correction is the detector efficiency and the carrier trapping effects. The results showed that, after correction by the energy response, the measured spectra are in good agreement with those provided by a theoretical model of the literature. Finally, our results showed that the detailed knowledge of the response function and a proper correction procedure are fundamental for achieving more accurate spectra from which quality parameters (i.e., half-value layer and homogeneity coefficient) can be determined.

O esporte paraolímpico no Brasil : abordagem da sociologia do esporte de Pierre Bourdieu

Universidade Estadual de Campinas . Faculdade de Educação Física

Proposta de ensino de polybat para pessoas com paralisia cerebral

Universidade Estadual de Campinas . Faculdade de Educação Física