A flavin-dependent monooxygenase produces nitrogenous tomato aroma volatiles using cysteine as a nitrogen source.

Tomato (Solanum lycopersicum) produces a wide range of volatile chemicals during fruit ripening, generating a distinct aroma and contributing to the overall flavor. Among these volatiles are several aromatic and aliphatic nitrogen-containing compounds for which the biosynthetic pathways are not known. While nitrogenous volatiles are abundant in tomato fruit, their content in fruits of the closely related species of the tomato clade is highly variable. For example, the green-fruited species Solanum pennellii are nearly devoid, while the red-fruited species S. lycopersicum and Solanum pimpinellifolium accumulate high amounts. Using an introgression population derived from S. pennellii, we identified a locus essential for the production of all the detectable nitrogenous volatiles in tomato fruit. Silencing of the underlying gene (SlTNH1;Solyc12g013690) in transgenic plants abolished production of aliphatic and aromatic nitrogenous volatiles in ripe fruit, and metabolomic analysis of these fruit revealed the accumulation of 2-isobutyl-tetrahydrothiazolidine-4-carboxylic acid, a known conjugate of cysteine and 3-methylbutanal. Biosynthetic incorporation of stable isotope-labeled precursors into 2-isobutylthiazole and 2-phenylacetonitrile confirmed that cysteine provides the nitrogen atom for all nitrogenous volatiles in tomato fruit. Nicotiana benthamiana plants expressing SlTNH1 readily transformed synthetic 2-substituted tetrahydrothiazolidine-4-carboxylic acid substrates into a mixture of the corresponding 2-substituted oxime, nitro, and nitrile volatiles. Distinct from other known flavin-dependent monooxygenase enzymes in plants, this tetrahydrothiazolidine-4-carboxylic acid N-hydroxylase catalyzes sequential hydroxylations. Elucidation of this pathway is a major step forward in understanding and ultimately improving tomato flavor quality.

Periodicity Disruption of a Model Quasibiennial Oscillation of Equatorial Winds.

The quasibiennial oscillation (QBO) of equatorial winds on Earth is the clearest example of the spontaneous emergence of a periodic phenomenon in geophysical fluids. In recent years, observations have revealed intriguing disruptions of this regular behavior, and different QBO-like regimes have been reported in a variety of systems. Here, we show that part of the variability in mean-flow reversals can be attributed to the intrinsic dynamics of wave-mean-flow interactions in stratified fluids. Using a constant-in-time monochromatic wave forcing, bifurcation diagrams are mapped for a hierarchy of simplified models of the QBO, ranging from a quasilinear model to fully nonlinear simulations. The existence of new bifurcations associated with faster and shallower flow reversals, as well as a quasiperiodic route to chaos are reported in these models. The possibility for periodicity disruptions is investigated by probing the resilience of regular wind reversals to external perturbations.

[Can medical oncologists talk about cure to their patient after localized breast cancer treatment?] / Pouvons-nous à l'heure actuelle parler de guérison après le traitement d'un cancer du sein localisé ?

INTRODUCTION: Despite ongoing therapeutic advances in oncology, the use of the term cure in front of patients remains controversial. The word remission is often preferred in clinical practice. The purpose of this research is to explore how oncologists vary in their usage and definition of the word cure when talking to patients. METHODS: Qualitative and exploratory pilot study conducted by semi structured interviews with a group of French oncologists about a clinical vignette of localized breast cancer treated by surgery and complete adjuvant treatment. RESULTS: Thirteen oncologists participated in this study between January and March 2016. They were divided into two groups according to whether or not they use the term cure in their clinical practice. A first group of five doctors define the word cure as the lasting absence of relapse of the disease. Because of their duty of transparency and the uncertainty of post-therapeutic relapse, these five doctors tend to never use the word cure. The analysis of the second group of eight doctors, who do use of the word cure in their practice, highlighted an absence of consensus on its definition. However, all of them justify their use of it with the importance of expressing positive emotions such as hope to patients. DISCUSSION: Our findings confirm that there are divergent understandings of the concept of cure between oncologists and how they manage prognosis uncertainty. Medical language is thus influenced by scientific knowledge, but also by doctors' personal values and ways of thinking, perhaps influencing the doctor-patient relationship in turn. This exploratory study will be extended on a wider scale to explore the coexistence of other elements of diversity.

Quantitative prediction of vasopressin secretion using a computational population model of rat magnocellular neurons.

The goal of this study was to create a realistic and quantitative simulation of vasopressin (AVP) secretion under iso-osmotic and short-term challenged plasma osmolality. The relationship between AVP concentration ([AVP]) and plasma osmolality was computed using a sophisticated and integrated model that chronologically simulates (1) the overall firing rate of the hypothalamus' magnocellular neuronal (MCN) population, (2) the propagation of the spike activity down the axons, (3) the fatigue and facilitation mechanisms of AVP release at the axon terminals and (4) the [AVP] pharmacodynamics based on the trains of AVP release. This global simulation predicted that the differential MCN sensitivity to dynorphin would be the most critical mechanism underlying the individual variability of MCN firing behaviors (silence, irregular, phasic and continuous firing patterns). However, at the level of the MCN population, the simulation predicted that the dynorphin factor must be combined with the distribution of the resting membrane potentials among the MCNs to obtain a realistic overall firing rate in response to a change in osmolality. Moreover, taking advantage of the integrated model, the simulation predicted that the selective removal of the frequency-dependent facilitation of AVP secretion has a major impact on the overall [AVP]-to-osmolality relationship (mean absolute change of 2.59 pg/ml); the action potential propagation failure, while critical, has a smaller quantitative impact on the overall [AVP] (0.58 pg/ml). The present integrated model (from a single MCN to a quantitative plasma [AVP]) improves our knowledge of the mechanisms underlying overall MCN firing and AVP excitation-secretion coupling.

New determinants of firing rates and patterns of vasopressinergic magnocellular neurons: predictions using a mathematical model of osmodetection.

Arginine vasopressin (AVP), one of the most important hormones involved in hydromineral homeostasis, is secreted by hypothalamic magnocellular neurons (MCNs). Here, we implemented two critical parameters for MCN physiology into a Hodgkin-Huxley simulation of the MCN. By incorporating the mechanosensitive channel (MSC) responsible for osmodetection and the synaptic inputs whose frequencies are modulated by changes in ambient osmolality into our model, we were able to develop an improved model with increased physiological relevance and gain new insight into the determinants of the firing patterns of AVP magnocellular neurons. Our results with this MCN model predict that 1) a single MCN is able to display all the firing patterns experimentally observed: silent, irregular, phasic and continuous firing patterns; 2) under conditions of hyperosmolality, burst durations are regulated by the frequency-dependent fatigue of dynorphin secretion; and 3) the transitions between firing patterns are controlled by EPSP and IPSP frequencies (0, 2, 4, 8, 16, 32, 64 and 128 Hz). Moreover, this simulation predicts that EPSPs and IPSPs do not modify the spiking frequency (SF) of phasic firing patterns (0.0034 Hz/Hz [EPSP]; 0.0012 Hz/Hz [IPSP]). Rather, these afferents strongly regulate SF during irregular and continuous firing patterns (0.075 Hz/Hz [EPSP]; 0.027 Hz/Hz [IPSP]). The use of the realistic MCN model developed here allows for an improved understanding of the determinants driving the firing patterns and spiking frequencies of vasopressinergic magnocellular neurons.

Neuronal sodium leak channel is responsible for the detection of sodium in the rat median preoptic nucleus.

Sodium (Na(+)) ions are of primary importance for hydromineral and cardiovascular homeostasis, and the level of Na(+) in the body fluid compartments [plasma and cerebrospinal fluid (CSF)] is precisely monitored in the hypothalamus. Glial cells seem to play a critical role in the mechanism of Na(+) detection. However, the precise role of neurons in the detection of extracellular Na(+) concentration ([Na(+)](out)) remains unclear. Here we demonstrate that neurons of the median preoptic nucleus (MnPO), a structure in close contact with the CSF, are specific Na(+) sensors. Electrophysiological recordings were performed on dissociated rat MnPO neurons under isotonic [Na(+)] (100 mM NaCl) with local application of hypernatriuric (150, 180 mM NaCl) or hyponatriuric (50 mM NaCl) external solution. The hyper- and hyponatriuric conditions triggered an in- and an outward current, respectively. The reversal potential of the current matched the equilibrium potential of Na(+), indicating that a change in [Na(+)](out) modified the influx of Na(+) in the MnPO neurons. The conductance of the Na(+) current was not affected by either the membrane potential or the [Na(+)](out). Moreover, the channel was highly selective for lithium over guanidinium. Together, these data identified the channel as a Na(+) leak channel. A high correlation between the electrophysiological recordings and immunofluorescent labeling for the Na(X) channel in dissociated MnPO neurons strongly supports this channel as a candidate for the Na(+) leak channel responsible for the Na(+)-sensing ability of rat MnPO neurons. The absence of Na(X) labeling and of a specific current evoked by a change in [Na(+)](out) in mouse MnPO neurons suggests species specificity in the hypothalamus structures participating in central Na(+) detection.

Computational simulation of vasopressin secretion using a rat model of the water and electrolyte homeostasis.

BACKGROUND: In mammals, vasopressin (AVP) is released from magnocellular neurons of the hypothalamus when osmotic pressure exceeds a fixed set-point. AVP participates to the hydromineral homeostasis (HH) by controlling water excretion at the level of the kidneys. Our current understanding of the HH and AVP secretion is the result of a vast amount of data collected over the five past decades. This experimental data was collected using a number of systems under different conditions, giving a fragmented view of the components involved in HH. RESULTS: Here, we present a high-level model of the rat HH based on selected published results to predict short-term (hours) to long-term (days) variation of six major homeostatic parameters: (1) the extracellular sodium concentration, (2) the AVP concentration, (3) the intracellular volume, (4) the extracellular volume, (5) the urine volume and (6) the water intake. The simulation generates quantitative predictions like the daily mean of the extracellular sodium concentration (142.2 mmol/L), the AVP concentration, (1.7 pg/ml), the intracellular volume (45.3 ml/100 g body weight--bw), the extracellular volume (22.6 ml/100 g bw), the urine volume (11.8 ml/100 g bw) and the cumulative water intake (18 ml/100 g bw). The simulation also computes the dynamics of all these parameters with a high temporal resolution of one minute. This high resolution predicts the circadian fluctuation of the AVP secretion (5 ± 2 pg/ml) and defines the limits of a restoration and a maintenance phase in the HH (2.1 pg/ml). Moreover, the simulation can predict the action of pharmacological compounds that disrupt the HH. As an example, we tested the action of a diuretic (furosemide) combined with a sodium deficient diet to generate quantitative prediction on the extracellular sodium concentration (134 mmol/L) and the need-induced water intake (20.3 ml/100 g bw). These simulated data are compatible with experimental data (136 ± 3 mmol/L and 17.5 ± 3.5 ml/100 g bw, respectively). CONCLUSION: The quantitative agreement of the predictions with published experimental data indicates that our simplified model of the HH integrates most of the essential systems to predict realistic physiological values and dynamics under a set of normal and perturbed hydromineral conditions.