Discrete Breathers in a Realistic Coarse-Grained Model of Proteins

We report the results of molecular dynamics simulations of an off-lattice protein model featuring a physical force-field and amino-acid sequence. We show that localized modes of nonlinear origin (discrete breathers) emerge naturally as continuations of a subset of high-frequency normal modes residing at specific sites dictated by the native fold. In the case of the small $\beta$-barrel structure that we consider, localization occurs on the turns connecting the strands. At high energies, discrete breathers stabilize the structure by concentrating energy on few sites, while their collapse marks the onset of large-amplitude fluctuations of the protein. Furthermore, we show how breathers develop as energy-accumulating centres following perturbations even at distant locations, thus mediating efficient and irreversible energy transfers. Remarkably, due to the presence of angular potentials, the breather induces a local static distortion of the native fold. Altogether, the combination of this two nonlinear effects may provide a ready means for remotely controlling local conformational changes in proteins.Comment: Submitted to Physical Biolog

Dynamical response of the Hodgkin-Huxley model in the high-input regime

The response of the Hodgkin-Huxley neuronal model subjected to stochastic uncorrelated spike trains originating from a large number of inhibitory and excitatory post-synaptic potentials is analyzed in detail. The model is examined in its three fundamental dynamical regimes: silence, bistability and repetitive firing. Its response is characterized in terms of statistical indicators (interspike-interval distributions and their first moments) as well as of dynamical indicators (autocorrelation functions and conditional entropies). In the silent regime, the coexistence of two different coherence resonances is revealed: one occurs at quite low noise and is related to the stimulation of subthreshold oscillations around the rest state; the second one (at intermediate noise variance) is associated with the regularization of the sequence of spikes emitted by the neuron. Bistability in the low noise limit can be interpreted in terms of jumping processes across barriers activated by stochastic fluctuations. In the repetitive firing regime a maximization of incoherence is observed at finite noise variance. Finally, the mechanisms responsible for spike triggering in the various regimes are clearly identified.Comment: 14 pages, 24 figures in eps, submitted to Physical Review

Ultrasonography of salivary glands in primary Sjögren's syndrome: A comparison with contrast sialography and scintigraphy

Objective. To compare ultrasonography (US) of salivary glands with contrast sialography and scintigraphy, in order to evaluate the diagnostic value of this method in primary SS (pSS). Methods. The diagnostic value of parotid gland US was studied in 77 patients with pSS (male/female ratio 3/74; mean age 54 yrs) and in 79 with sicca symptoms but without SS. The two groups were matched for sex and age. Imaging findings of US were graded using an ultrasonographic score ranging from 0 to 16, which was obtained by the sum of the scores for each parotid and submandibular gland. The sialographic and scintigraphic patterns were classified in four different stages. The area under receiver operating characteristic curve (AUC-ROC) was employed to evaluate the screening methods performance. Results. Of the 77 patients with pSS, 66 had abnormal US findings. Mean US score in pSS patients was 9.0 (range from 3 to 16). Subjects without confirmed pSS had the mean US score 3.9 (range from 0 to 9) (P < 0.0001). Results of sialography showed that 59 pSS patients had abnormal findings at Stage 1 (n = 4), Stage 2 (n = 8), Stage 3 (n = 33) or Stage 4 (n = 14), and 58 patients had abnormal scintigraphic findings at Stage 1 (n = 11), Stage 2 (n = 18), Stage 3 (n = 25) or Stage 4 (n = 4). Through ROC curves US arose as the best performer (AUC = 0.863 +/- 0.030), followed by sialography (AUC = 0.804 +/- 0.035) and by salivary gland scintigraphy (AUC = 0.783 +/- 0.037). The difference between AUC-ROC curve of salivary gland US and scintigraphy was significant (P = 0.034). Setting the cut-off score 6 US resulted in the best ratio of sensitivity (75.3%) to specificity (83.5%), with a likelihood ratio of 4.58. If a threshold 8.0 was applied the test gained specificity, at the cost of a serious loss of sensitivity (sensitivity 54.5%, specificity 97.5%, likelihood ratio 21.5). Conclusions. Salivary gland US is a useful method in visualizing glandular structural changes in patients suspected of having pSS and it may represent a good option as a first-line imaging tool in the diagnostics of the disease

Extra-articular rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease that mainly affects the joints, though a consistent proportion of patients may also display extra articular manifestations (EAMs). From rheumatoid nodules to interstitial lung disease, from cardiovascular events to vasculitis, the spectrum of EAMs encompasses various conditions with different prognoses. EAMs may also occur as first RA manifestation, therefore the coordination with other health professionals, including general practitioners, is needed. The aim of this article is to provide an overview on EAMs in RA with particular focus on the recognised risk factors and the available recommendations for managing them, as well as comorbidities in RA patients

Ad hoc Joint FAO/WHO Expert Consultation on Risk Assessment of Food Allergens Part 2: Review and establish threshold levels in foods of the priority allergens

The main purpose of this second meeting was to establish threshold levels in foods of the priority allergens. Based on the defined approach, the Expert Committee discussed and agreed on the safety objective, which could be described as “to minimise, to a point where further refinement does not meaningfully reduce health impact, the probability of any clinically relevant objective allergic response, as defined by dose distribution modelling of minimum eliciting doses (MEDs) and supported by data regarding severity of symptoms in the likely range of envisioned Reference Doses (RfD)”. The Committee further identified several important considerations to guide decision-making. These included a clear definition of criteria to be met by quantitative data on which reference doses (RfD) are based, supporting data on health manifestations (severity) at the proposed RfD, quality, quantity, availability and accessibility of data (for priority allergens), as well as how to deal with priority allergens for which information supporting one or more of those considerations was lacking.El objetivo principal de esta segunda reunión fue establecer niveles umbral en los alimentos de los alérgenos prioritarios. Sobre la base del enfoque definido, el Comité de Expertos discutió y acordó el objetivo de seguridad, que podría describirse como “minimizar, hasta un punto en el que un mayor refinamiento no reduzca significativamente el impacto en la salud, la probabilidad de cualquier respuesta alérgica objetiva clínicamente relevante, como definido por el modelo de distribución de dosis de dosis mínimas provocadoras (MED) y respaldado por datos sobre la gravedad de los síntomas en el rango probable de dosis de referencia previstas (RfD) ”. El Comité identificó además varias consideraciones importantes para orientar la toma de decisiones. Estos incluyeron una definición clara de los criterios que deben cumplir los datos cuantitativos en los que se basan las dosis de referencia (RfD), datos de apoyo sobre manifestaciones de salud (gravedad) en la RfD propuesta, calidad, cantidad, disponibilidad y accesibilidad de los datos (para alérgenos prioritarios). , así como cómo tratar los alérgenos prioritarios para los que faltaba información que respaldara una o más de esas consideraciones.Instituto de Investigación de Tecnología de AlimentosFil: Baumert, Joseph. Universidad de Nebraska-Lincoln. Departamento de Ciencia y Tecnología de Alimentos; Estados UnidosFil: Brooke-Taylor, Simon. Brooke-Taylor & Co. Consultor australiano de regulación alimentaria y análisis de riesgos (Pty Ltd); Australia.Fil: Crevel, René W.R. René Crevel Consulting Limited; Reino Unido.Fil: Houben, Geert F. Imperial College London. Instituto Nacional del Corazón y los Pulmones; Reino Unido.Fil: Jackson, Lauren. Administración de Alimentos y Medicamentos de los Estados Unidos. División de Ciencia y Tecnología del Procesamiento de Alimentos. Ingeniería de Procesos; Estados UnidosFil: Kyriakidis, Symeon. Laboratorio Estatal de Química General (GCSL).Autoridad Independiente de Ingresos Públicos (IAPR); Grecia.Fil: La Vieille, Sébastien. Universidad Laval. Departamento de Ciencias de los Alimentos; Canadá.Fil: Lee, N Alice. Universidad de Nueva Gales del Sur. Escuela de Química e Ingeniería. Ciencia e ingeniería de los alimentos; Australia.Fil: López, María Cristina. Universidad Nacional de San Martín. Ingeniería de Alimentos; Argentina.Fil: Luccioli, Stefano. Administración de Alimentos y Medicamentos de los Estados Unidos. Centro de Seguridad Alimentaria y Nutrición Aplicada; Estados UnidosFil: O’Mahony, Patrick. Autoridad de Seguridad Alimentaria de Irlanda; Irlanda.Fil: O’Mahony, Patrick. Universidad College Dublin; Irlanda.Fil: Polenta, Gustavo Alberto. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Investigación Tecnología de Alimentos; Argentina.Fil: Polenta, Gustavo Alberto. Instituto de Ciencia y Tecnología de los Sistemas Alimentarios Sustentables (ICyTeSAS) UEDD INTA-CONICET; Argentina.Fil: Pöpping, Bert. Food Consulting Strategically (FOCO); Alemania.Fil: Pöpping, Bert. Comités de Normalización ISO - CEN. Grupo de trabajo CEN Alérgenos Alimentarios (CEN TC 275 WG 12).); Alemania.Fil: Remington, Benjamin C. Remington Consulting Group B.V.; Holanda.Fil: Remington, Benjamin C. Universidad de Nebraska–Lincoln. Programa de Recursos e Investigación de Alergias Alimentarias. Estados UnidosFil: Srikulnath, Sirinrat. Universidad de Kasetsart (UKaset). Instituto de Investigación y Desarrollo de Productos Alimentarios. Centro de Servicio de Aseguramiento de la Calidad de los Alimentos. Unidad de Alérgenos Alimentarios; Tailandia.Fil: Taylor, Stephen L. Universidad de Nebraska-Lincoln. Departamento de Ciencia y Tecnología de Alimentos; Estados UnidosFil: Turner, Paul J. Colegio Imperial de Ciencia, Tecnología y Medicina. Alergia e Inmunología Pediátricas; Inglaterra

Relationship between the prevalence of subclinical tenosynovitis and treatment in patients with RA in clinical remission: STARTER study

Objective: This study is a sub-analysis from the patient cohort of the STARTER (Sonographic Tenosynovitis Assessment in RheumaToid arthritis patiEnts in Remission) study. The aim was to evaluate differences in ultrasound-detected joint and/or tendon involvement between patients receiving therapies based on a combination of conventional synthetic DMARDs (csDMARDs) and biologic DMARDs (bDMARDs) and those who were treated with either csDMARDs or bDMARDs in monotherapy. Material and methods: Four hundred and twenty-seven consecutive patients with a diagnosis of RA were recruited between October 2013 and June 2014. They were divided into three subgroups based on their therapy at baseline: patients with bDMARD in monotherapy, patients with csDMARD in monotherapy and patients in combination therapy (csDMARD + bDMARD). At baseline, 6 months and 12 months, a clinical examination (28 joint count) and an ultrasound evaluation were performed in each patient. A score of grey-scale (GS) and power Doppler (PD) synovitis and tenosynovitis was calculated based on the OMERACT scoring systems. Results: Two hundred and fifty-six patients completed the observation period: 48 patients from the bDMARD group (18.75%), 152 patients from the csDMARD group (59.38%) and 56 patients from csDMARD + bDMARD group (21.88%). The analysis showed that GS tenosynovitis and PD tenosynovitis are better controlled in combination therapy than they are ith csDMARD alone (P=0.025 and P=0.047, respectively); for PD synovitis, there was a better response in those who were treated with the combination therapy when compared with the patients receiving csDMARD (P=0.01) or bDMARD (P=0.02) alone. Conclusions: The analysis showed a lower prevalence of subclinical inflammatory manifestations detected with ultrasound imaging in those patients treated with the combination therapy than in those in monotherapy

Nigella sativa (Black Cumin) Seed Extract Alleviates Symptoms of Allergic Diarrhea in Mice, Involving Opioid Receptors

The incidence of food hypersensitivity and food allergies is on the rise and new treatment approaches are needed. We investigated whether N. sativa, one of its components, thymoquinone, or synthetic opioid receptor (OR)-agonists can alleviate food allergy. Hence, ovalbumin (OVA) -sensitized BALB/c-mice were pre-treated either with a hexanic N. sativa seed extract, thymoquinone, kappa- (U50'4889) or mu-OR-agonists (DAMGO) and subsequently challenged intra-gastrically with OVA. All 4 treatments significantly decreased clinical scores of OVA-induced diarrhea. N. sativa seed extract, thymoquinone, and U50'488 also decreased intestinal mast cell numbers and plasma mouse mast cell protease-1 (MMCP-1). DAMGO, in contrast, had no effect on mast cell parameters but decreased IFNγ, IL-4, IL-5, and IL-10 concentration after ex vivo re-stimulation of mesenteric lymphocytes. The effects on allergy symptoms were reversible by OR-antagonist pre-treatment, whereas most of the effects on immunological parameter were not. We demonstrate that N. sativa seed extract significantly improves symptoms and immune parameters in murine OVA-induced allergic diarrhea; this effect is at least partially mediated by thymoquinone. ORs may also be involved and could be a new target for intestinal allergy symptom alleviation. N. sativa seed extract seems to be a promising candidate for nutritional interventions in humans with food allergy

Probing Molecular Mechanisms of the Hsp90 Chaperone: Biophysical Modeling Identifies Key Regulators of Functional Dynamics

Deciphering functional mechanisms of the Hsp90 chaperone machinery is an important objective in cancer biology aiming to facilitate discovery of targeted anti-cancer therapies. Despite significant advances in understanding structure and function of molecular chaperones, organizing molecular principles that control the relationship between conformational diversity and functional mechanisms of the Hsp90 activity lack a sufficient quantitative characterization. We combined molecular dynamics simulations, principal component analysis, the energy landscape model and structure-functional analysis of Hsp90 regulatory interactions to systematically investigate functional dynamics of the molecular chaperone. This approach has identified a network of conserved regions common to the Hsp90 chaperones that could play a universal role in coordinating functional dynamics, principal collective motions and allosteric signaling of Hsp90. We have found that these functional motifs may be utilized by the molecular chaperone machinery to act collectively as central regulators of Hsp90 dynamics and activity, including the inter-domain communications, control of ATP hydrolysis, and protein client binding. These findings have provided support to a long-standing assertion that allosteric regulation and catalysis may have emerged via common evolutionary routes. The interaction networks regulating functional motions of Hsp90 may be determined by the inherent structural architecture of the molecular chaperone. At the same time, the thermodynamics-based “conformational selection” of functional states is likely to be activated based on the nature of the binding partner. This mechanistic model of Hsp90 dynamics and function is consistent with the notion that allosteric networks orchestrating cooperative protein motions can be formed by evolutionary conserved and sparsely connected residue clusters. Hence, allosteric signaling through a small network of distantly connected residue clusters may be a rather general functional requirement encoded across molecular chaperones. The obtained insights may be useful in guiding discovery of allosteric Hsp90 inhibitors targeting protein interfaces with co-chaperones and protein binding clients

Astrocyte networks and intercellular calcium propagation

International audienceAstrocytes organize in complex networks through connections by gap junction channels that are regulated by extra-and intracellular signals. Calcium signals generated in individual cells, can propagate across these networks in the form of intercellular calcium waves, mediated by diffusion of second messengers molecules such as inositol 1,4,5-trisphosphate. The mechanisms underpinning the large variety of spatiotemporal patterns of propagation of astrocytic calcium waves however remain a matter of investigation. In the last decade, awareness has grown on the morphological diversity of astrocytes as well as their connections in networks, which seem dependent on the brain area, developmental stage, and the ultra-structure of the associated neuropile. It is speculated that this diversity underpins an equal functional variety but the current experimental techniques are limited in supporting this hypothesis because they do not allow to resolve the exact connectivity of astrocyte networks in the brain. With this aim we present a general framework to model intercellular calcium wave propagation in astrocyte networks and use it to specifically investigate how different network topologies could influence shape, frequency and propagation of these waves