The spiking and secretory activity of oxytocin neurones in response to osmotic stimulation: a computational model.

KEY POINTS: A quantitative model of oxytocin neurones that combines a spiking model, a model of stimulus-secretion coupling and a model of plasma clearance of oxytocin was tested. To test the model, a variety of sources of published data were used that relate either the electrical activity of oxytocin cells or the secretion of oxytocin to experimentally induced changes in plasma osmotic pressure. To use these data to test the model, the experimental challenges involved were computationally simulated. The model predictions closely matched the reported outcomes of the different experiments. ABSTRACT: Magnocellular vasopressin and oxytocin neurones in the rat hypothalamus project to the posterior pituitary, where they secrete their products into the bloodstream. In rodents, both vasopressin and oxytocin magnocellular neurones are osmoresponsive, and their increased spiking activity is mainly a consequence of an increased synaptic input from osmoresponsive neurons in regions adjacent to the anterior wall of the third ventricle. Osmotically stimulated vasopressin secretion promotes antidiuresis while oxytocin secretion promotes natriuresis. In this work we tested a previously published computational model of the spiking and secretion activity of oxytocin cells against published evidence of changes in spiking activity and plasma oxytocin concentration in response to different osmotic challenges. We show that integrating this oxytocin model with a simple model of the osmoresponsive inputs to oxytocin cells achieves a strikingly close match to diverse sources of data. Comparing model predictions with published data using bicuculline to block inhibitory GABA inputs supports the conclusion that inhibitory inputs and excitatory inputs are co-activated by osmotic stimuli. Finally, we studied how the gain of osmotically stimulated oxytocin release changes in the presence of a hypovolaemic stimulus, showing that this is best explained by an inhibition of an osmotically regulated inhibitory drive to the magnocellular neurones.

Abnormal brain state distribution and network connectivity in a SYNGAP1 rat model.

Mutations in the SYNGAP1 gene are one of the common predictors of neurodevelopmental disorders, commonly resulting in individuals developing autism, intellectual disability, epilepsy, and sleep deficits. EEG recordings in neurodevelopmental disorders show potential to identify clinically translatable biomarkers to both diagnose and track the progress of novel therapeutic strategies, as well as providing insight into underlying pathological mechanisms. In a rat model of SYNGAP1 haploinsufficiency in which the exons encoding the calcium/lipid binding and GTPase-activating protein domains have been deleted (Syngap+/Δ-GAP ), we analysed the duration and occurrence of wake, non-rapid eye movement and rapid eye movement brain states during 6 h multi-electrode EEG recordings. We find that although Syngap+/Δ-GAP animals spend an equivalent percent time in wake and sleep states, they have an abnormal brain state distribution as the number of wake and non-rapid eye movement bouts are reduced and there is an increase in the average duration of both wake and non-rapid eye movement epochs. We perform connectivity analysis by calculating the average imaginary coherence between electrode pairs at varying distance thresholds during these states. In group averages from pairs of electrodes at short distances from each other, a clear reduction in connectivity during non-rapid eye movement is present between 11.5 Hz and 29.5 Hz, a frequency range that overlaps with sleep spindles, oscillatory phenomena thought to be important for normal brain function and memory consolidation. Sleep abnormalities were mostly uncorrelated to the electrophysiological signature of absence seizures, spike and wave discharges, as was the imaginary coherence deficit. Sleep spindles occurrence, amplitude, power and spread across multiple electrodes were not reduced in Syngap+/Δ-GAP rats, with only a small decrease in duration detected. Nonetheless, by analysing the dynamic imaginary coherence during sleep spindles, we found a reduction in high-connectivity instances between short-distance electrode pairs. Finally comparing the dynamic imaginary coherence during sleep spindles between individual electrode pairs, we identified a group of channels over the right somatosensory, association and visual cortices that have a significant reduction in connectivity during sleep spindles in mutant animals. This matched a significant reduction in connectivity during spindles when averaged regional comparisons were made. These data suggest that Syngap+/Δ-GAP rats have altered brain state dynamics and EEG connectivity, which may have clinical relevance for SYNGAP1 haploinsufficiency in humans.

Sequential Multimaterial Additive Manufacturing of Functionally Graded Biopolymer Composites.

Cellulose, chitin, and pectin are three of the most abundant natural materials on Earth. Despite this, large-scale additive manufacturing with these biopolymers is used only in limited applications and frequently relies on extensive refinement processes or plastic additives. We present novel developments in a digital fabrication and design approach for multimaterial three-dimensional printing of biopolymers. Specifically, our computational and digital fabrication workflow-sequential multimaterial additive manufacturing-enables the construction of biopolymer composites with continuously graded transitional zones using only a single extruder. We apply this method to fabricate structures on length scales ranging from millimeters to meters. Transitional regions between materials created using these methods demonstrated comparable mechanical properties with homogenous mixtures of the same composition. We present a computational workflow and physical system support a novel and flexible form of multimaterial additive manufacturing with a diverse array of potential applications.

Effects of nettle slurry (Urtica dioica L.) used as foliar fertilizer on potato (Solanum tuberosum L.) yield and plant growth.

Organic agriculture is becoming increasingly important, and many natural products are now available for organic farmers to manage and improve their crops. Several ethnobotanical studies have indicated that the use of nettle slurry as fertilizer in organic farming for horticultural crops is spreading. Sometimes, however, the consequences of using these natural products have been poorly evaluated, and there is very little scientific evidence for the effects of using these slurries. In this study, we aimed to analyze the possible effect of nettle slurry on potato yields produced by organic farming. To achieve this main objective, we assessed the effect of nettle slurry on potato yields, plant size and growth parameters, chlorophyll content, and the presence of pests and diseases. Different slurry doses were assessed in 36 plots and nine variables were measured during the crop cycle. Under these field experimental conditions, nettle slurry (including one treatment with Urtica in combination with Equisetum) had no significant effects on yield, chlorophyll content, or the presence of pests and diseases in organic potato crops. The highest chlorophyll content was found in the double dose treatment, but the difference was not significant. This result, together with a small improvement in plant height with the double dose treatment, might indicate very slight crop enhancement which, under our experimental conditions, was not enough to improve yield. The Urtica and Equisetum slurry chemical analyses showed very low levels of nitrogen, phosphorus, and potassium.

A Predictive, Quantitative Model of Spiking Activity and Stimulus-Secretion Coupling in Oxytocin Neurons.

Oxytocin neurons of the rat hypothalamus project to the posterior pituitary, where they secrete their products into the bloodstream. The pattern and quantity of that release depends on the afferent inputs to the neurons, on their intrinsic membrane properties, and on nonlinear interactions between spiking activity and exocytosis: A given number of spikes will trigger more secretion when they arrive close together. Here we present a quantitative computational model of oxytocin neurons that can replicate the results of a wide variety of published experiments. The spiking model mimics electrophysiological data of oxytocin cells responding to cholecystokinin (CCK), a peptide produced in the gut after food intake. The secretion model matches results from in vitro experiments on stimulus-secretion coupling in the posterior pituitary. We mimic the plasma clearance of oxytocin with a two-compartment model, replicating the dynamics observed experimentally after infusion and injection of oxytocin. Combining these models allows us to infer, from measurements of oxytocin in plasma, the spiking activity of the oxytocin neurons that produced that secretion. We have tested these inferences with experimental data on oxytocin secretion and spiking activity in response to intravenous injections of CCK. We show how intrinsic mechanisms of the oxytocin neurons determine this relationship: In particular, we show that the presence of an afterhyperpolarization (AHP) in oxytocin neurons dramatically reduces the variability of their spiking activity and even more markedly reduces the variability of oxytocin secretion. The AHP thus acts as a filter, protecting the final product of oxytocin cells from noisy fluctuations.

Oxygenation of alkane C-H bonds with methyl(trifluoromethyl)dioxirane: effect of the substituents and the solvent on the reaction rate.

[Chemical reaction: See text] The mechanism of the oxygenation of alkane C-H bonds with methyl(trifluoromethyl)dioxirane (1a) is studied through the effect of the substituent and solvent on the rate of oxygenation of 2-substituted adamantanes (2). The results suggest a remarkable electron deficiency at the reacting carbon atom in the transition state leading to the regular oxygenation products. The linearity of the Hammett plot reveals that the reaction mechanism does not change within a range of 0.15-0.67 units of sigma(I). A change in the solvent does not affect the distribution of the products, indicating a through-bond transmission of the substituent effect as the origin of the deactivation of the substrate.

Conformational mobility of thianthrene-5-oxide.

[reaction: see text] Data on the apparent dipole moment of thianthrene-5-oxide (1) and (1)H NMR spectra in different solvents support the conformational mobility of 1, which flaps between two limit boat conformations with the sulfinyl group in pseudoequatorial and pseudoaxial positions, respectively. The conformational equilibrium of 1 occurs too fast for the (1)H NMR (500 MHz) time-scale even at -130 degrees C, and the equilibrium constant has not been determined. The apparent dipole moments of 1 in n-hexane and 1,4-dioxane and the (1)H NMR spectra of 1 and the model compounds cis- and trans-thianthrene-5,10-dioxides (2) and thianthrene (5) in different solvents and at various temperatures confirm that the relative position of the conformational equilibrium of 1 is solvent-dependent, and more polar solvents favor the conformation with the sulfoxide group in the pseudoaxial position (1(')(ax)). Variable-temperature (1)H NMR spectra have established the interconversion barrier of trans-2 and confirmed that the conformational equilibrium of cis-2 is strongly displaced toward the conformation with both sulfinyl groups in the pseudoequatorial position. The (1)H NMR data support the transannular interaction of the functional groups in 1 and trans-2.

Mechanism of the oxidation of sulfides by dioxiranes. 1. Intermediacy of a 10-S-4 hypervalent sulfur adduct.

Earlier studies established that dimethyldioxirane (1a) reacts with sulfides 2 in two consecutive concerted electrophilic oxygen-transfer steps to give first sulfoxides 3 and then sulfones 4. The same sequential electrophilic oxidation model was assumed for the reaction of sulfides 2 with the strongly electrophilic methyl(trifluoromethyl)dioxirane (1b). In this paper we report on a systematic and general study on the mechanism of the reaction of simple sulfides 2 with DMDO (1a) and TFDO (1b) which provides clear evidence for the involvement of hypervalent sulfur species in the oxidation process. In the oxidation of sulfides 2a-c, diphenyl sulfide (2d), para-substituted aryl methyl sulfides 2e-i, and phenothiazine 2k with 1b, the major product was the corresponding sulfone 4, even when a 10-fold excess of sulfide relative to 1b was used. The sulfone:sulfoxide 4:3 ratio depends among other factors on the dioxirane 1a or 1b used, the sulfide substitution pattern, the polar, protic, or aprotic character of the solvent, and the temperature. The influence of these factors and also deuterium and (18)O tracer experiments performed allow a general mechanism to be depicted for these oxidations in which the key step is the reversible cyclization of a zwitterionic intermediate, 6, to form a hypervalent sulfur species, 7. The classical sequential mechanism which establishes that sulfides are oxidized first to sulfides and then to sulfones can be enclosed in our general picture of the process and represents just those particular cases in which the zwitterionic intermediate 6 decomposes prior to undergoing ring closure to afford the hypervalent sulfurane intermediate 7.

Mechanism of the oxidation of sulfides by dioxiranes: conformational mobility and transannular interaction in the oxidation of thianthrene 5-oxide.

The detailed study of the oxidation of thianthrene 5-oxide (1) with methyl(trifluoromethyl)dioxirane (5b) in different solvents and in the presence of (18)O isotopic tracers is reported. Thianthrene 5-oxide (1) is a flexible molecule in solution, and this property allows for transannular interaction of the sulfoxide group with the expected zwitterionic 7 and hypervalent 10-S-4 sulfurane 9 intermediates formed in the oxidation and biases the course of the reaction toward the monooxygenation pathway.