Identification of Molecular Pathologies Sufficient to Cause Neuropathic Excitability in Primary Somatosensory Afferents Using Dynamical Systems Theory

Pain caused by nerve injury (i.e. neuropathic pain) is associated with development of neuronal hyperexcitability at several points along the pain pathway. Within primary afferents, numerous injury-induced changes have been identified but it remains unclear which molecular changes are necessary and sufficient to explain cellular hyperexcitability. To investigate this, we built computational models that reproduce the switch from a normal spiking pattern characterized by a single spike at the onset of depolarization to a neuropathic one characterized by repetitive spiking throughout depolarization. Parameter changes that were sufficient to switch the spiking pattern also enabled membrane potential oscillations and bursting, suggesting that all three pathological changes are mechanistically linked. Dynamical analysis confirmed this prediction by showing that excitability changes co-develop when the nonlinear mechanism responsible for spike initiation switches from a quasi-separatrix-crossing to a subcritical Hopf bifurcation. This switch stems from biophysical changes that bias competition between oppositely directed fast- and slow-activating conductances operating at subthreshold potentials. Competition between activation and inactivation of a single conductance can be similarly biased with equivalent consequences for excitability. “Bias” can arise from a multitude of molecular changes occurring alone or in combination; in the latter case, changes can add or offset one another. Thus, our results identify pathological change in the nonlinear interaction between processes affecting spike initiation as the critical determinant of how simple injury-induced changes at the molecular level manifest complex excitability changes at the cellular level. We demonstrate that multiple distinct molecular changes are sufficient to produce neuropathic changes in excitability; however, given that nerve injury elicits numerous molecular changes that may be individually sufficient to alter spike initiation, our results argue that no single molecular change is necessary to produce neuropathic excitability. This deeper understanding of degenerate causal relationships has important implications for how we understand and treat neuropathic pain

Environmental Factors Influence Language Development in Children with Autism Spectrum Disorders

International audienc

DNA Methylation Changes in Atypical Adenomatous Hyperplasia, Adenocarcinoma In Situ, and Lung Adenocarcinoma

BACKGROUND:Aberrant DNA methylation is common in lung adenocarcinoma, but its timing in the phases of tumor development is largely unknown. Delineating when abnormal DNA methylation arises may provide insight into the natural history of lung adenocarcinoma and the role that DNA methylation alterations play in tumor formation. METHODOLOGY/PRINCIPAL FINDINGS:We used MethyLight, a sensitive real-time PCR-based quantitative method, to analyze DNA methylation levels at 15 CpG islands that are frequently methylated in lung adenocarcinoma and that we had flagged as potential markers for non-invasive detection. We also used two repeat probes as indicators of global DNA hypomethylation. We examined DNA methylation in 249 tissue samples from 93 subjects, spanning the putative spectrum of peripheral lung adenocarcinoma development: histologically normal adjacent non-tumor lung, atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS, formerly known as bronchioloalveolar carcinoma), and invasive lung adenocarcinoma. Comparison of DNA methylation levels between the lesion types suggests that DNA hypermethylation of distinct loci occurs at different time points during the development of lung adenocarcinoma. DNA methylation at CDKN2A ex2 and PTPRN2 is already significantly elevated in AAH, while CpG islands at 2C35, EYA4, HOXA1, HOXA11, NEUROD1, NEUROD2 and TMEFF2 are significantly hypermethylated in AIS. In contrast, hypermethylation at CDH13, CDX2, OPCML, RASSF1, SFRP1 and TWIST1 and global DNA hypomethylation appear to be present predominantly in invasive cancer. CONCLUSIONS/SIGNIFICANCE:The gradual increase in DNA methylation seen for numerous loci in progressively more transformed lesions supports the model in which AAH and AIS are sequential stages in the development of lung adenocarcinoma. The demarcation of DNA methylation changes characteristic for AAH, AIS and adenocarcinoma begins to lay out a possible roadmap for aberrant DNA methylation events in tumor development. In addition, it identifies which DNA methylation changes might be used as molecular markers for the detection of preinvasive lesions

Cognitive Behavior Therapy for Anxious Adolescents: Developmental Influences on Treatment Design and Delivery

Anxiety disorders in adolescence are common and disruptive, pointing to a need for effective treatments for this age group. Cognitive behavior therapy (CBT) is one of the most popular interventions for adolescent anxiety, and there is empirical support for its application. However, a significant proportion of adolescent clients continue to report anxiety symptoms post-treatment. This paper underscores the need to attend to the unique developmental characteristics of the adolescent period when designing and delivering treatment, in an effort to enhance treatment effectiveness. Informed by the literature from developmental psychology, developmental psychopathology, and clinical child and adolescent psychology, we review the ‘why’ and the ‘how’ of developmentally appropriate CBT for anxious adolescents. ‘Why’ it is important to consider developmental factors in designing and delivering CBT for anxious adolescents is addressed by examining the age-related findings of treatment outcome studies and exploring the influence of developmental factors, including cognitive capacities, on engagement in CBT. ‘How’ clinicians can developmentally tailor CBT for anxious adolescents in six key domains of treatment design and delivery is illustrated with suggestions drawn from both clinically and research-oriented literature. Finally, recommendations are made for research into developmentally appropriate CBT for anxious adolescents

Aptamers for pharmaceuticals and their application in environmental analytics

Aptamers are single-stranded DNA or RNA oligonucleotides, which are able to bind with high affinity and specificity to their target. This property is used for a multitude of applications, for instance as molecular recognition elements in biosensors and other assays. Biosensor application of aptamers offers the possibility for fast and easy detection of environmental relevant substances. Pharmaceutical residues, deriving from human or animal medical treatment, are found in surface, ground, and drinking water. At least the whole range of frequently administered drugs can be detected in noticeable concentrations. Biosensors and assays based on aptamers as specific recognition elements are very convenient for this application because aptamer development is possible for toxic targets. Commonly used biological receptors for biosensors like enzymes or antibodies are mostly unavailable for the detection of pharmaceuticals. This review describes the research activities of aptamer and sensor developments for pharmaceutical detection, with focus on environmental applications

European consensus statement on diagnosis and treatment of adult ADHD: The European Network Adult ADHD.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is among the most common psychiatric disorders of childhood that persists into adulthood in the majority of cases. The evidence on persistence poses several difficulties for adult psychiatry considering the lack of expertise for diagnostic assessment, limited treatment options and patient facilities across Europe. METHODS: The European Network Adult ADHD, founded in 2003, aims to increase awareness of this disorder and improve knowledge and patient care for adults with ADHD across Europe. This Consensus Statement is one of the actions taken by the European Network Adult ADHD in order to support the clinician with research evidence and clinical experience from 18 European countries in which ADHD in adults is recognised and treated. RESULTS: Besides information on the genetics and neurobiology of ADHD, three major questions are addressed in this statement: (1) What is the clinical picture of ADHD in adults? (2) How can ADHD in adults be properly diagnosed? (3) How should ADHD in adults be effectively treated? CONCLUSIONS: ADHD often presents as an impairing lifelong condition in adults, yet it is currently underdiagnosed and treated in many European countries, leading to ineffective treatment and higher costs of illness. Expertise in diagnostic assessment and treatment of ADHD in adults must increase in psychiatry. Instruments for screening and diagnosis of ADHD in adults are available and appropriate treatments exist, although more research is needed in this age group

Molecular gated nanoporous anodic alumina for the detection of cocaine

[EN] We present herein the use of nanoporous anodic alumina (NAA) as a suitable support to implement molecular gates for sensing applications. In our design, a NAA support is loaded with a fluorescent reporter (rhodamine B) and functionalized with a short single-stranded DNA. Then pores are blocked by the subsequent hybridisation of a specific cocaine aptamer. The response of the gated material was studied in aqueous solution. In a typical experiment, the support was immersed in hybridisation buffer solution in the absence or presence of cocaine. At certain times, the release of rhodamine B from pore voids was measured by fluorescence spectroscopy. The capped NAA support showed poor cargo delivery, but presence of cocaine in the solution selectively induced rhodamine B release. By this simple procedure a limit of detection as low as 5 × 10−7 M was calculated for cocaine. The gated NAA was successfully applied to detect cocaine in saliva samples and the possible re-use of the nanostructures was assessed. Based on these results, we believe that NAA could be a suitable support to prepare optical gated probes with a synergic combination of the favourable features of selected gated sensing systems and NAA.We thank Projects MAT2015-64139-C4-1-R and TEC2015-71324-R (MINECO/FEDER), the Catalan Government (Project 2014 SGR 1344), the ICREA (ICREA2014 Academia Award) and the Generalitat Valenciana (Project PROMETEOII/2014/047) for support. We also thank to the Agencia Espanola del Medicamento y Productos Sanitarios for its concessions. A.R. thanks the UPV for her predoctoral fellowship. The authors also thank the Electron Microscopy Service at UPV for support.Ribes, À.; Xifre Perez, E.; Aznar, E.; Sancenón Galarza, F.; Pardo Vicente, MT.; Marsal, LF.; Martínez-Máñez, R. (2016). Molecular gated nanoporous anodic alumina for the detection of cocaine. Scientific Reports. 6. https://doi.org/10.1038/srep38649S386496Nadrah, P., Planinšek, O. & Gaberšček, M. Stimulus-responsive Mesoporous Silica Particles. J. Mater. Sci. 49, 481–495 (2014).Baeza, A., Colilla, M. & Vallet-Regí, M. Advances in Mesoporous Silica Nanoparticles for Targeted Stimuli-Responsive Drug Delivery. Expert Opin. Drug Deliv. 12, 319–337 (2015).Karimi, M., Mirshekari, H., Aliakbari, M., Zangabad, P. S. & Hamblin, M. R. Smart Mesoporous Silica Nanoparticles for Controlled-Release Drug Delivery. Nanotech. Rev. 5, 195–207 (2016).Aznar, E. et al. Gated Materials for On-Command Release of Guest Molecules. Chem. Rev. 116, 561−718 (2016).Sancenón, F., Pascual, Ll., Oroval, M., Aznar, E. & Martínez-Máñez, R. Gated Silica Mesoporous Materials in Sensing Applications. Chemistry Open. 4, 418–437 (2015).Lu, C.-H., Willner, B. & Willner, I. DNA nanotechnology: From sensing and DNA machines to drug-delivery systems. ACSNano 7, 8320–8332 (2013).Klajn, R., Stoddart, J. F. & Grzybowski, B. A. Nanoparticles Functionalized With Reversible Molecular And Supramolecular Switches. Chem. Soc. Rev. 39, 2203–2237 (2010).Wei, R., Martin, T. G., Rant, U. & Dietz, H. DNA Origami Gatekeepers for Solid-State Nanopores. Angew. Chem. Int. Ed. 51, 4864 4867 (2012).Zhu, C. L., Lu, C. H., Song, X. Y., Yang, H. H. & Wang, X. R. Bioresponsive Controlled Release Using Mesoporous Silica Nanoparticles Capped with Aptamer-Based Molecular Gate. J. Am. Chem. Soc. 133, 1278–1281 (2011).Özalp, V. C., Pinto, A., Nikulina, E., Chulivin, A. & Schäfer, T. In Situ Monitoring of DNA-Aptavalve Gating Function on Mesoporous Silica Nanoparticles. Part. Part. Sys. Charact. 31, 161–167 (2014).Choi, Y. L., Jaworski, J., Seo, M. L., Lee, S. J. & Jung, J. H. Controlled release using mesoporous silica nanoparticles functionalized with 18-crown-6 derivative. J. Mater. Chem. 21, 7882–7885 (2011).Zhang, Z., Wang, F., Balogh, D. & Willner, I. pH-controlled release of substrates from mesoporous SiO2 nanoparticles gated by metal ion-dependent DNAzymes. J. Mater. Chem. B. 2, 4449–4455 (2014).Fu, L. et al. Portable and Quantitative Monitoring of Heavy Metal Ions Using Dnazyme-Capped Mesoporous Silica Nanoparticles with a Glucometer Readout. J. Mater. Chem. B. 1, 6123–6128 (2013).Díez, P. et al. Toward the Design of Smart Delivery Systems Controlled by Integrated Enzyme-Based Biocomputing Ensembles. J. Am. Chem. Soc. 136, 9116–9123 (2014).Tang, D. et al. Low-Cost and Highly Sensitive lmmunosensing Platform for Aflatoxins Using One-Step Competitive Displacement Reaction Mode and Portable Glucometer-Based Detection. Anal. Chem. 86, 11451–11458 (2014).Hou, L., Zhu, C., Wu, X., Chen, G. & Tang, D. Bioresponsive Controlled Release from Mesoporous Silica Nanocontainers with Glucometer Readout. Chem. Commun. 50, 1441–1443 (2014).Chen, Z. et al. Stimulus-response mesoporous silica nanoparticle-based chemiluminescence biosensor for cocaine determination. Biosens. Bioelectro. 75, 8–14 (2016).Pascual, L. L. et al. Oligonucleotide-Capped Mesoporous Silica Nanoparticles as DNA-Responsive Dye Delivery Systems for Genomic DNA Detection. Chem. Commun. 51, 1414–1416 (2015).Qian, R., Ding, I. & Ju, H. Switchable Fluorescent Imaging of Intracellular Telomerase Activity Using Telomerase-Responsive Mesoporous Silica Nanoparticle. J. Am. Chem. Soc. 135, 13282–13285 (2013).Ren, K., Wu, J., Zhang, Y., Yan, F. & Ju, H. Proximity Hybridization Regulated DNA Biogate for Sensitive Electrochemical Immunoassay. Anal. Chem. 86, 7494–7499 (2014).Chen, Y., Santos, A., Wang, Y., Wang, C. & Losic, D. Biomimetic Nanoporous Anodic Alumina Distributed Bragg Reflectors in the Form of Films and Microsized Particles for Sensing Applications. ACS Appl Mater Interfaces. 7, 19816–19824 (2015).Aw, M. S., Bariana, M. & Losic, D. In Nanoporous Alumina. Fabrication, Structure, Properties and Applications (ed. Losic, D., Santos, A. ) 319–354 (Springer International Publishing, 2015).Urteaga, R. & Berli, C. L. In Nanoporous Alumina. Fabrication, Structure, Properties and Applications (ed. Losic, D., Santos, A. ) 249–269 (Springer International Publishing, 2015).Vojkuvka, L., Marsal, L. F., Ferré-Borrull, J., Formentin, P. & Pallarés, J. Self-Ordered Porous Alumina Membranes with Large Lattice Constant Fabricated by Hard Anodization. Superlattices Microstruct. 44, 577–582 (2008).De la Escosura-Muñiz, A. & Merkoçi, A. Nanochannels Preparation and Application in Biosensing. ACS Nano. 6, 7556–7583 (2012).Kumeria, T. et al. Nanoporous Anodic Alumina Rugate Filters for Sensing of Ionic Mercury: Toward Environmental Point-of-Analysis Systems. ACS Appl. Mater. Interfaces. 6, 12971−12978 (2014).Santos, A., Kumeria, T. & Losic, D. Nanoporous Anodic Alumina: A Versatile Platform for Optical Biosensors. Materials. 7, 4297–4320 (2014).Ferré-Borrull, J., Pallarès, J., Macías, G. & Marsal, L. F. Nanostructural Engineering of Nanoporous Anodic Alumina for Biosensing Applications. Materials. 7, 5225–5253 (2014).Gong, D., Yadavalli, V., Paulose, M., Pishko, M. & Grimes, C. A. Controlled Molecular Release Using Nanoporous Alumina Capsules. Biomed Microdevices. 5, 75–80 (2003).Alvarez, S. D., Li, C.-P., Chiang, C. E., Schuller, I. K. & Sailor, M. J. A Label-Free Porous Alumina Interferometric Immunosensor. ACSNano. 3, 3301–3307 (2009).Krismastuti, F. S. H., Bayat, H., Voelcker, N. H. & Schönherr, H. Real Time Monitoring of Layer-by-Layer Polyelectrolyte Deposition and Bacterial Enzyme Detection in Nanoporous Anodized Aluminum Oxide Anal. Chem. 87, 3856–3863 (2015).Ma, D.-L. et al. A Luminescent Cocaine Detection Platform Using a Split G-Quadruplex-Selective Iridium (III) Complex and a Three-Way DNA Junction Architecture. ACS Appl. Mater. Interfaces. 7, 19060−19067 (2015).Kohli, P. et al. DNA-Functionalized Nanotube Membranes with Single-Base Mismatch Selectivity. Science 305, 984–986 (2004).Abelow, A. E. et al. Biomimetic glass nanopores employing aptamer gates responsive to a small molecule. Chem. Commun. 46, 7984–7986 (2010).Ma, D.-L., Chan, D. S.-H. & Leung, C.-H. Group 9 Organometallic Compounds for Therapeutic and Bioanalytical Applications. Acc. Chem. Res. 47, 3614–3631 (2014).Wanga, G., Zhua, Y., Chena, L. & Zhanga, X. Photoinduced electron transfer (PET) based label-free aptasensor for platelet-derived growth factor-BB and its logic gate application. Biosens. Bioelectron. 63, 552–557 (2015).Laptenko, O. et al. The p53 C Terminus Controls Site-Specific DNA Binding and Promotes Structural Changes within the Central DNA Binding Domain. Molec. Cell. 57, 1034–1046 (2015).McKeague, M. & DeRosa, M. C. Challenges and Opportunities for Small Molecule Aptamer Development. J. Nucleic Acids. 2012, 1–20 (2012).McKeague, M. et al. Analysis of In Vitro Aptamer Selection Parameters, J. Mol. Evol. 81, 150–161 (2015).Ellington, A. D. & Szostak, J. W. In vitro selection of RNA molecules that bind specific ligands. Nature. 346, 818–822 (1990).Wochner, A. et al. A DNA aptamer with high affinity and specificity for therapeutic anthracyclines. Anal Biochem. 373, 34–42 (2008).Song, K. M., Jeong, E., Jeon, W., Cho, M. & Ban, C. Aptasensor for ampicillin using gold nanoparticle based dual fluorescence-colorimetric methods. Anal. Bioanal. Chem. 402, 2153–2161 (2012).Özalp, V. C. & Schäfer, T. Aptamer-Based Switchable Nanovalves for Stimuli-Responsive Drug Delivery. Chem. Eur. J. 17, 9893–9896 (2011).Stojanovic, M. N., de Prada, P. & Landry, D. W. Aptamer-Based Folding Fluorescent Sensor for Cocaine. J. Am. Chem Soc. 123, 4928–4931 (2001).Wen, Y. et al. DNA-based intelligent logic controlled release systems. Chem. Commun. 48, 8410–8412 (2012).Chen, L. et al. Programmable DNA switch for bioresponsive controlled release. J. Mater. Chem. 21, 13811–13816 (2011).Oroval, M. et al. An aptamer-gated silica mesoporous material for thrombin detection. Chem. Commun. 49, 5480–5482 (2013).Barroso, M., Gallardo, E. & Queiroz, J. A. Bioanalytical methods for the determination of cocaine and metabolites in human biological samples. Bioanalysis. 1, 977–1000 (2009).Phan, H. M., Yoshizuka, K., Murry, D. J. & Perry, P. J. Drug testing in the workplace. Pharmacotherapy. 32, 649–656 (2012).Kidwell, D. A., Blanco, M. A. & P. Smith, F. P. Cocaine detection in a university population by hair analysis and skin swab testing. Forensic Sci. Int. 84, 75–86 (1997).Swensen, J. S. et al. Continuous, Real-Time Monitoring of Cocaine in Undiluted Blood Serum via a Microfluidic, Electrochemical Aptamer-Based Sensor. J. Am. Chem. Soc. 131, 4262–4266 (2009).Cai, Q. et al. Determination of cocaine on banknotes through an aptamer-based electrochemiluminescence biosensor. Anal. Bioanal. Chem. 400, 289–294 (2011).Zou, R. et al. Highly specific triple-fragment aptamer for optical detection of cocaine. RSC Adv. 2, 4636–4638 (2012).Qiu, L. et al. A novel label-free fluorescence aptamer-based sensor method for cocaine detection based on isothermal circular strand-displacement amplification and graphene oxide absorption. New J. Chem. 37, 3998 (2013).Marsal, L. F., Vojkuvka, L., Formentin, P., Pallarés, J. & Ferré-Borrull, J. Fabrication and Optical Characterization of Nanoporous Alumina Films Annealed at Different Temperatures. Optical Mater. 31, 860–864 (2009).Bosker, W. M. & Huestis, M. A. Oral Fluid Testing for Drugs of Abuse. Clinical Chem. 55, 1910–1931 (2009).Kolbrich, E. A. et al. Cozart® RapiScan Oral Fluid Drug Testing System: An Evaluation of Sensitivity, Specificity, and Efficiency for Cocaine Detection Compared with ELISA and GC-MS Following Controlled Cocaine Administration. J. Anal Toxicol. 27, 407–411 (2003).Cooper, G., Wilson, L., Reid, C., Main, L. & Hand, C. Evaluation of the Cozart® RapiScan drug test system for opiates and cocaine in oral fluid. Forensic Sci. Int. 150, 239–243 (2005).Chang, Y. H. et al. Cocaine detection by a mid-infrared waveguide integrated with a microfluidic chip. Lab Chip. 12, 3020–3023 (2012).Walczak, R. et al. Toward Portable Instrumentation for Quantitative Cocaine Detection with Lab-on-a-Paper and Hybrid Optical Readout. Procedia Chem. 1, 999–1002 (2009).Qiu, L. et al. A novel label-free fluorescence aptamer-based sensor method for cocaine detection based on isothermal circular strand-displacement amplification and graphene oxide absorption. New J. Chem. 37, 3998–4003 (2013)

Are Children with Autism Spectrum Disorder Initially Attuned to Object Function Rather Than Shape for Word Learning?

We investigate the function bias-generalising words to objects with the same function-in typically developing (TD) children, children with autism spectrum disorder (ASD) and children with other developmental disorders. Across four trials, a novel object was named and its function was described and demonstrated. Children then selected the other referent from a shape match (same shape, different function) and function match (same function, different shape) object. TD children and children with ASD were 'function biased', although further investigation established that having a higher VMA facilitated function bias understanding in TD children, but having a lower VMA facilitated function bias understanding in children with ASD. This suggests that children with ASD are initially attuned to object function, not shape