Are there sex differences in oxytocin and vasopressin V1a receptors ligand binding affinities?

BACKGROUND: There is substantial evidence for sex differences in the functioning of one of the most common receptor systems; G protein-coupled receptors (GPCRs). There are many points along the GPCR-mediated molecular signaling pathway at which males and females may differ, one of the first of which, chronologically, is in the stability of the interaction between the ligand and the receptor, or its binding affinity. Here we investigate the binding affinities of oxytocin (OT) and vasopressin (AVP) at the oxytocin receptor (OTR) and the vasopressin V1a receptor (V1aR), both of which are present in numerous in brain regions associated with social behavior. METHOD: In order to investigate sex- and estrous cycle-dependent differences in ligand-receptor binding affinity, male (n = 6) Syrian hamsters (Mesocricetus auratus), females on the day of estrus (E females, n = 6), and females on the second day of diestrus (D2 females n = 6) were chosen for study. Brains from hamsters were mounted on slides and competition and saturation binding assays were conducted. RESULTS: We report a remarkable similarity in the binding affinities of OT and AVP in males and females. Small differences were detected, however, in receptor and ligand specificity in females depending on whether they were in the estrous or diestrous stage of their ovulatory cycle. CONCLUSION: These data suggest that sex differences in binding affinity are not a likely source of the many sex differences that have been observed in the effects of OT and AVP in hamsters and other species.

Prolactin and oxytocin: potential targets for migraine treatment.

Migraine is a severe neurovascular disorder of which the pathophysiology is not yet fully understood. Besides the role of inflammatory mediators that interact with the trigeminovascular system, cyclic fluctuations in sex steroid hormones are involved in the sex dimorphism of migraine attacks. In addition, the pituitary-derived hormone prolactin and the hypothalamic neuropeptide oxytocin have been reported to play a modulating role in migraine and contribute to its sex-dependent differences. The current narrative review explores the relationship between these two hormones and the pathophysiology of migraine. We describe the physiological role of prolactin and oxytocin, its relationship to migraine and pain, and potential therapies targeting these hormones or their receptors.In summary, oxytocin and prolactin are involved in nociception in opposite ways. Both operate at peripheral and central levels, however, prolactin has a pronociceptive effect, while oxytocin appears to have an antinociceptive effect. Therefore, migraine treatment targeting prolactin should aim to block its effects using prolactin receptor antagonists or monoclonal antibodies specifically acting at migraine-pain related structures. This action should be local in order to avoid a decrease in prolactin levels throughout the body and associated adverse effects. In contrast, treatment targeting oxytocin should enhance its signalling and antinociceptive effects, for example using intranasal administration of oxytocin, or possibly other oxytocin receptor agonists. Interestingly, the prolactin receptor and oxytocin receptor are co-localized with estrogen receptors as well as calcitonin gene-related peptide and its receptor, providing a positive perspective on the possibilities for an adequate pharmacological treatment of these nociceptive pathways. Nevertheless, many questions remain to be answered. More particularly, there is insufficient data on the role of sex hormones in men and the correct dosing according to sex differences, hormonal changes and comorbidities. The above remains a major challenge for future development.

Spotting priming-active compounds using parsley cell cultures in microtiter plates.

BACKGROUND: Conventional crop protection has major drawbacks, such as developing pest and pathogen insensitivity to pesticides and low environmental compatibility. Therefore, alternative crop protection strategies are needed. One promising approach treats crops with chemical compounds that induce the primed state of enhanced defense. However, identifying priming compounds is often tedious as it requires offline sampling and analysis. High throughput screening methods for the analysis of priming-active compounds have great potential to simplify the search for such compounds. One established method to identify priming makes use of parsley cell cultures. This method relies on measurement of fluorescence of furanocoumarins in the final sample. This study demonstrates for the first time the online measurement of furanocoumarins in microtiter plates. As not all plants produce fluorescence molecules as immune response, a signal, which is not restricted to a specific plant is required, to extend online screening methods to other plant cell cultures. It was shown that the breathing activity of primed parsley cell cultures increases, compared to unprimed parsley cell cultures. The breathing activity can by monitored online. Therefore, online identification of priming-inducing compounds by recording breathing activity represents a promising, straight-forward and highly informative approach. However, so far breathing has been recorded in shake flasks which suffer from low throughput. For industrial application we here report a high-throughput, online identification method for identifying priming-inducing chemistry. RESULTS: This study describes the development of a high-throughput screening system that enables identifying and analyzing the impact of defense priming-inducing compounds in microtiter plates. This screening system relies on the breathing activity of parsley cell cultures. The validity of measuring the breathing activity in microtiter plates to drawing conclusions regarding priming-inducing activity was demonstrated. Furthermore, for the first time, the fluorescence of the priming-active reference compound salicylic acid and of furanocoumarins were simultaneously monitored online. Dose and time studies with salicylic acid-treated parsley cell suspensions revealed a wide range of possible addition times and concentrations that cause priming. The online fluorescence measuring method was further confirmed with three additional compounds with known priming-causing activity. CONCLUSIONS: Determining the OTR, fluorescence of the priming-active chemical compound SA and of furanocoumarins in parsley suspension cultures in MTPs by online measurement is a powerful and high-throughput tool to study possible priming compounds. It allows an in-depth screening for priming compounds and a better understanding of the priming process induced by a given substance. Evaluation of priming phenomena via OTR should also be applicable to cell suspensions of other plant species and varieties and allow screening for priming-inducing chemical compounds in intact plants. These online fluorescence methods to measure the breathing activity, furanocoumarin and SA have the potential to accelerate the search for new priming compounds and promote priming as a promising, eco-friendly crop protection strategy.

Neuromodulatory functions exerted by oxytocin on different populations of hippocampal neurons in rodents.

Oxytocin (OT) is a neuropeptide widely known for its peripheral hormonal effects (i.e., parturition and lactation) and central neuromodulatory functions, related especially to social behavior and social, spatial, and episodic memory. The hippocampus is a key structure for these functions, it is innervated by oxytocinergic fibers, and contains OT receptors (OTRs). The hippocampal OTR distribution is not homogeneous among its subregions and types of neuronal cells, reflecting the specificity of oxytocin's modulatory action. In this review, we describe the most recent discoveries in OT/OTR signaling in the hippocampus, focusing primarily on the electrophysiological oxytocinergic modulation of the OTR-expressing hippocampal neurons. We then look at the effect this modulation has on the balance of excitation/inhibition and synaptic plasticity in each hippocampal subregion. Additionally, we review OTR downstream signaling, which underlies the OT effects observed in different types of hippocampal neuron. Overall, this review comprehensively summarizes the advancements in unraveling the neuromodulatory functions exerted by OT on specific hippocampal networks.

The modulation of emotional and social behaviors by oxytocin signaling in limbic network.

Neuropeptides can exert volume modulation in neuronal networks, which account for a well-calibrated and fine-tuned regulation that depends on the sensory and behavioral contexts. For example, oxytocin (OT) and oxytocin receptor (OTR) trigger a signaling pattern encompassing intracellular cascades, synaptic plasticity, gene expression, and network regulation, that together function to increase the signal-to-noise ratio for sensory-dependent stress/threat and social responses. Activation of OTRs in emotional circuits within the limbic forebrain is necessary to acquire stress/threat responses. When emotional memories are retrieved, OTR-expressing cells act as gatekeepers of the threat response choice/discrimination. OT signaling has also been implicated in modulating social-exposure elicited responses in the neural circuits within the limbic forebrain. In this review, we describe the cellular and molecular mechanisms that underlie the neuromodulation by OT, and how OT signaling in specific neural circuits and cell populations mediate stress/threat and social behaviors. OT and downstream signaling cascades are heavily implicated in neuropsychiatric disorders characterized by emotional and social dysregulation. Thus, a mechanistic understanding of downstream cellular effects of OT in relevant cell types and neural circuits can help design effective intervention techniques for a variety of neuropsychiatric disorders.

Impact of the Closure Oxygen Transfer Rate on Volatile Compound Composition and Oxidation Aroma Intensity of Merlot and Cabernet Sauvignon Blend: A 10 Year Study.

This study evaluated the impact of closure type on unoaked 100 %-Merlot, oak-aged 70%-Merlot/30%-Cabernet Sauvignon, and 30%-Merlot/70%-Cabernet Sauvignon during a 10 year period. Closures were microagglomerate corks, screw caps, and synthetics with the known oxygen transfer rate (OTR), ranging from 0.1 to 4.6 mg/y, including natural corks. Oxidation intensity perception, dissolved oxygen, sulfite, and 3-methyl-2,4-nonanedione (MND) were monitored on a regular basis. After 10 years of aging, additional aroma impact markers were evaluated (3-sulfanylhexan-1-ol, H2S, DMS, methional, and phenylacetaldehyde). Low OTR levels (≤0.3 mg/y) delayed the oxidation of red wines in this long-term experiment. In addition, our results led us to hypothesize that the MND concentration in young wines might be linked with their ability to produce it during bottle aging that is with their aging potential. Finally, we found that the kinetic accumulation of MND in wines was first strongly impacted by its intrinsic composition and thereafter by the OTRT0 of the stopper.

Cutaneous Squamous Cell Carcinoma Arising in Immunosuppressed Patients: A Systematic Review of Tumor Profiling Studies.

As solid organ transplantation becomes more prevalent, more individuals are living as members of the immunosuppressed population with an elevated risk for cutaneous squamous cell carcinoma (cSCC). Although great progress has been made in understanding the pathogenesis of cSCC in general, little is known about the drivers of tumorigenesis in immunosuppressed patients and organ-transplant recipients, specifically. This systematic review sought to synthesize information regarding the genetic and epigenetic alterations as well as changes in protein and mRNA expression that place this growing population at risk for cSCC, influence treatment response, and promote tumor aggressiveness. This review will provide investigators with a framework to identify future areas of investigation and clinicians with additional insight into how to best manage these patients.

Transition of fouling characteristics after development of membrane wetting in membrane-aerated biofilm reactors (MABRs).

The practical applications of water treatment techniques based on hydrophobic aeration membrane are limited due to membrane pores blocking. Various studies have revealed that both biofilm and microbial secretion can exacerbate membrane fouling. Recently, we constructed a membrane-aerated biofilm reactor (MABR) system for treating micro-polluted surface water in order to identify the primary cause for oxygen transfer rate (OTR) decline. It was found that microbial secretion had a more prominent negative effect than that caused by biofilm, as manifested by the fact the effect of microbial secretion (66.49%) was greater than the resistance of biofilm (38.83%). Fouling decreased the total pore volume of all membrane. The peak location of adsorption capacity was more likely to occur at smaller pore sizes with longer running time. Notably, continuous fluorescence distribution between the separating layer and pores like finger in MABR system exhibited an increasing trend with the operation time, indicating a gradual increase of microbial viability. Core protein structure was revealed by different bond peaks (0-90 d). Specifically, for different organic components of EPS, the hydrophilic HIS was the main content, while the mass transfer resistance caused by the gel increased, which reduced the contact angle and increased the bubble point pressure. Therefore, effects of EPS content and composition should be considered during the application of water treatment techniques based on MABR.

Protective Effects of a synthetic glycosaminoglycan mimetic (OTR4132) in a rat immunotoxic lesion model of septohippocampal cholinergic degeneration.

Using a partial hippocampal cholinergic denervation model, we assessed the effects of the RGTA® named OTR4132, a synthetic heparan-mimetic biopolymer with neuroprotective/neurotrophic properties. Long-Evans male rats were injected with the cholinergic immunotoxin 192 IgG-saporin into the medial septum/diagonal band of Broca (0.37 µg); vehicle injections served as controls. Immediately after surgery, OTR4132 was injected into the lateral ventricles (0.25 µg/5 µl/rat) or intramuscularly (1.5 mg/kg). To determine whether OTR4132 reached the lesion site, some rats received intracerebroventricular (ICV) or intramuscular (I.M.) injections of fluorescent OTR4132. Rats were sacrificed at 4, 10, 20, or 60 days post-lesion (DPL). Fluorescein-labeled OTR4132 injected ICV or I.M. was found in the lesion from 4 to 20 DPL. Rats with partial hippocampal cholinergic denervation showed decreases in hippocampal acetylcholinesterase reaction products and in choline acetyltransferase-positive neurons in the medial septum. These lesions were the largest at 10 DPL and then remained stable until 60 DPL. Both hippocampal acetylcholinesterase reaction products and choline acetyltransferase-positive neurons in the medial septum effects were significantly attenuated in OTR4132-treated rats. These effects were not related to competition between OTR4132 and 192 IgG-saporin for the neurotrophin receptor P75 (p75NTR), as OTR4132 treatment did not alter the internalization of Cy3-labelled 192 IgG. OTR4132 was more efficient at reducing the acetylcholinesterase reaction products and choline acetyltransferase-positive neurons than a comparable heparin dose used as a comparator. Using the slice superfusion technique, we found that the lesion-induced decrease in muscarinic autoreceptor sensitivity was abolished by intramuscular OTR4132. After partial cholinergic damage, OTR4132 was able to concentrate at the brain lesion site possibly due to the disruption of the blood-brain barrier and to exert structural and functional effects that hold promises for neuroprotection/neurotrophism.

Preoperative Predictors of Optimal Tumor Resectability in Patients With Epithelial Ovarian Cancer.

Background Several studies have shown that whether complete tumor resection can be achieved during debulking surgery depends on various patient-related factors. However, none of these studies was conducted among patients with epithelial ovarian cancer (EOC) in sub-Saharan Africa. In this study, we aimed to determine the preoperative predictors of optimal tumor resectability (OTR) during primary debulking surgery (PDS) in patients with EOC. Methodology In this study, we reviewed all patients with histologically diagnosed EOC who underwent PDS between January 2011 and December 2020. We included 83 patients with complete clinical records for subsequent data analysis. Descriptive statistics were computed for patients' data, and binary logistic regression analysis was used to assess the strength of associations between patients' preoperative characteristics and OTR. Results The overall rate of OTR was 53.0%, while the rate in advanced EOC patients was 36.1%. In the univariate analyses, pleural effusion, ascites, tumor bilaterality, size of the largest tumor, retroperitoneal lymph nodes, omental caking, peritoneal thickening, significant extrapelvic tumor, serum cancer antigen-125 (CA-125) levels, and hemoglobin levels were recorded as the predictors of OTR. However, after adjusting for covariates in the final multivariate models, we found that the absence of moderate-to-large pleural effusion (odds ratio (OR) = 5.60; 95% confidence interval (CI) = 1.32, 23.71) and having serum CA-125 levels of ≤370 U/mL (OR = 6.80; 95% CI = 1.19, 38.79) were the overall independent predictors of OTR while not having any preexisting comorbidity (OR = 18.21; 95% CI = 2.40, 38.10), and the absence of pleural effusions (OR = 13.75; 95% CI = 1.80, 24.85) or enlarged retroperitoneal lymph nodes (OR = 11.95; 95% CI = 1.35, 16.07) were predictors of OTR in advanced EOC patients. Conclusions We demonstrated that the radiological absence of pleural effusions and enlarged retroperitoneal lymph nodes and having no preexisting medical morbidity and serum CA-125 levels of ≤370 U/mL were the independent predictors of OTR during PDS. The preliminary data generated from this study can be used to develop variables for a prediction model in a future validation study.

Skin cancer biology and barriers to treatment: Recent applications of polymeric micro/nanostructures.

Background: Skin cancer has been the leading type of cancer worldwide. Melanoma and non-melanoma skin cancers are now the most common types of skin cancer that have been reached to epidemic proportion. Based on the rapid prevalence of skin cancers, and lack of efficient drug delivery systems, it is essential to surge the possible ways to prevent or cure the disease. Aim of review: Although surgical modalities and therapies have been made great progress in recent years, however, there is still an urgent need to alleviate its increased burden. Hence, understanding the precise pathophysiological signaling mechanisms and all other factors of such skin insults will be beneficial for the development of more efficient therapies. Key scientific concepts of review: In this review, we explained new understandings about onset and development of skin cancer and described its management via polymeric micro/nano carriers-based therapies, highlighting the current key bottlenecks and future prospective in this field. In therapeutic drug/gene delivery approaches, polymeric carriers-based system is the most promising strategy. This review discusses that how polymers have successfully been exploited for development of micro/nanosized systems for efficient delivery of anticancer genes and drugs overcoming all the barriers and limitations associated with available conventional therapies. In addition to drug/gene delivery, intelligent polymeric nanocarriers platforms have also been established for combination anticancer therapies including photodynamic and photothermal, and for theranostic applications. This portfolio of latest approaches could promote the blooming growth of research and their clinical availability.

Device for respiration activity measurement enables the determination of oxygen transfer rates of microbial cultures in shaken 96-deepwell microtiter plates.

Mini-bioreactors with integrated online monitoring capabilities are well established in the early stages of process development. Mini-bioreactors fulfil the demand for high-throughput-applications and a simultaneous reduction of material costs and total experimental time. One of the most essential online monitored parameters is the oxygen transfer rate (OTR). OTR-monitoring allows fast characterization of bioprocesses and process transfer to larger scales. Currently, OTR-monitoring on a small-scale is limited to shake flasks and 48-well microtiter plates (MTP). Especially, 96-deepwell MTP are used for high-throughput-experiments during early-stage bioprocess development. However, a device for OTR monitoring in 96-deepwell MTP is still not available. To determine OTR values, the measurement of the gas composition in each well of a MTP is necessary. Therefore, a new micro(µ)-scale Transfer rate Online Measurement device (µTOM) was developed. The µTOM includes 96 parallel oxygen-sensitive sensors and a single robust sealing mechanism. Different organisms (Escherichia coli, Hansenula polymorpha, and Ustilago maydis) were cultivated in the µTOM. The measurement precision for 96 parallel cultivations was 0.21 mmol·L-1 ·h-1 (pooled standard deviation). In total, a more than 15-fold increase in throughput and an up to a 50-fold decrease in media consumption, compared with the shake flask RAMOS-technology, was achieved using the µTOM for OTR-monitoring.

The role of vasopressin V1A and oxytocin OTR receptors in protective effects of arginine vasopressin against H2O2-induced oxidative stress in H9C2 cells.

BACKGROUND: Oxidative stress, has been shown to play an important role in the pathophysiology of cardiac remodelling and heart failure. The aim of study is effect of arginine vasopressin (AVP) on apoptosis of cardiomyocyte via its receptors. MATERIALS AND METHODS: The cell viability effect of AVP in H9C2 cardiomyocytes was assayed using the MTT method. The transcription and translation level of apoptosis genes (Bax, Bcl-2, caspase-3) were discovered with qRT-PCR and western blotting. RESULTS: The results showed that vasopressin could reduce apoptosis in cardiomyocytes cell line through downregulation of caspase-3, BAX and upregulation of Bcl-2 (p < .001). Also, there was a decrease in anti-apoptosis effect of vasopressin when V1A and OTR receptors were blocked with their antagonists. DISCUSSION: These results suggest that activation of V1A and OTR receptors in H9C2 cells mediate protective effect of vasopressin via regulating apoptosis marker that lead to cell survival under conditions of stress oxidative.Key pointAVP may contribute to the improvement of heart ischaemia through its actions on V1A and OTR receptors.

Employing the Operational Model to Measure System-Independent OTR Efficacy.

Ideally, pharmacological analysis is based on quantitative measurements applied toward unveiling biological mechanisms and guiding medicinal chemistry efforts in drug discovery and basic research. The most robust analysis frameworks generate findings which can be dissociated from the specific experimental setting to provide insights of a broader scope. With insufficient efficacy being the leading cause of drug failures in late-stage clinical trials, more rigorous preclinical definitions might assist in better translation. This chapter details a new method for accessing the Black and Leff operational model of agonism using a stable Flp-In™ T-REx™ HEK293 cell line under tetracycline-dependent control of OTR expression. We cover steps for performing the Gq-coupled HTRF® IP-One assay, curve-fitting data, calculating and statistically representing system-independent drug activity, predicting responses in different sensitivities, and plotting of multivariate analyses.

Prolonged efavirenz exposure reduces peripheral oxytocin and vasopressin comparable to known drugs of addiction in male Sprague Dawley rats.

INTRODUCTION: Several drugs of abuse (DOA) are capable of modulating neurohypophysial hormones, such as oxytocin (OT) and vasopressin (VP), potentially resulting in the development of psychological abnormalities, such as cognitive dysfunction, psychoses, and affective disorders. Efavirenz (EFV), widely used in Africa and globally to treat HIV, induces diverse neuropsychiatric side effects while its abuse has become a global concern. The actions of EFV may involve neurohypophysial system (NS) disruption like that of known DOA. This study investigated whether sub-chronic EFV exposure, at a previously-determined rewarding dose, alters peripheral OT and VP levels versus that of a control, ∆9-tetrahydrocannabinol (∆9-THC), methamphetamine (MA) and cocaine. MATERIALS AND METHODS: To simulate the conditions under which reward-driven behavior had previously been established for EFV, male Sprague Dawley rats (n = 16/exposure) received intraperitoneal vehicle (control) or drug administration across an alternating sixteen-day dosing protocol. Control administration (saline/olive oil; 0.2 ml) occurred on odd-numbered and drug administration (EFV: 5 mg/kg, ∆9-THC: 0.75 mg/kg, MA: 1 mg/kg, or cocaine: 20 mg/kg) on even-numbered days followed by euthanasia, trunk blood collection and plasma extraction for neuropeptide assay. Effect of drug exposure on peripheral OT and VP levels was assessed versus controls and quantified using specific ELISA kits. Statistical significance was determined by Kruskal-Wallis ANOVA, with p < 0.05. Ethics approval: NWU-00291-17-A5. RESULTS: Delta-9-THC reduced OT and VP plasma levels (p < 0.0001, p = 0.0141; respectively), cocaine reduced plasma OT (p = 0.0023), while MA reduced plasma VP levels (p = 0.0001), all versus control. EFV reduced OT and VP plasma levels (p < 0.0001; OT and VP) versus control, and similar to ∆9-THC. CONCLUSION: EFV markedly affects the NS in significantly reducing both plasma OT and VP equivalent to DOA. Importantly, EFV has distinct effects on peripheral OT and VP levels when assessed within the context of drug dependence. The data highlights a possible new mechanism underlying previously documented EFV-induced effects in rats, and whereby EFV may induce neuropsychiatric adverse effects clinically; also providing a deeper understanding of the suggested abuse-potential of EFV.

Targeted T cell receptor gene editing provides predictable T cell product function for immunotherapy.

Adoptive transfer of T cells expressing a transgenic T cell receptor (TCR) has the potential to revolutionize immunotherapy of infectious diseases and cancer. However, the generation of defined TCR-transgenic T cell medicinal products with predictable in vivo function still poses a major challenge and limits broader and more successful application of this "living drug." Here, by studying 51 different TCRs, we show that conventional genetic engineering by viral transduction leads to variable TCR expression and functionality as a result of variable transgene copy numbers and untargeted transgene integration. In contrast, CRISPR/Cas9-mediated TCR replacement enables defined, targeted TCR transgene insertion into the TCR gene locus. Thereby, T cell products display more homogeneous TCR expression similar to physiological T cells. Importantly, increased T cell product homogeneity after targeted TCR gene editing correlates with predictable in vivo T cell responses, which represents a crucial aspect for clinical application in adoptive T cell immunotherapy.

Impact of Closure OTR on the Volatile Compound Composition and Oxidation Aroma Intensity of Sauvignon Blanc Wines during and after 10 Years of Bottle Storage.

The oxygen transfer rate (OTR) of closures is a well-known parameter impacting the quality of Sauvignon blanc wines (SBw) within the first years of storage, but little research has been published on its long-term effects. The chemical changes in oxidation odor intensity in three SBw sealed with natural cork and other closures that had different known OTRs, ranging from <0.1 to 4.6 mg/year, were monitored over a 10 year period. During aging, free SO2 and 3-sulfanylhexanol loss, concomitant with increases in dissolved O2, OD420, and sotolon, were correlated with closure OTR levels. After 10 years of aging, sensory analysis was conducted, supported by additional chemical analysis of aroma impact markers, including methional, phenylacetaldehyde, 2-furanmethanthiol, 4-methyl-4-sulfanylpentan-2-one, ethyl-2-sulfanylacetate, and hydrogen sulfide, as well as total SO2 and dissolved CO2. These analyses revealed that selected SBw were protected from oxidation over a 10 year aging period, provided that the closure OTR did not exceed 0.3 mg/year.

Oxytocinergic Feedback Circuitries: An Anatomical Basis for Neuromodulation of Social Behaviors.

Oxytocin (OT) is a neuropeptide produced by hypothalamic neurons and is known to modulate social behavior among other functions. Several experiments have shown that OT modulates neuronal activity in many brain areas, including sensory cortices. OT neurons thus project axons to various cortical and subcortical structures and activate neuronal subpopulations to increase the signal-to-noise ratio, and in turn, increases the saliency of social stimuli. Less is known about the origin of inputs to OT neurons, but recent studies show that cells projecting to OT neurons are often located in regions where the OT receptor (OTR) is expressed. Thus, we propose the existence of reciprocal connectivity between OT neurons and extrahypothalamic OTR neurons to tune OT neuron activity depending on the behavioral context. Furthermore, the latest studies have shown that OTR-expressing neurons located in social brain regions also project to other social brain regions containing OTR-expressing neurons. We hypothesize that OTR-expressing neurons across the brain constitute a common network coordinated by OT.

Molecular, biochemical and behavioural evidence for a novel oxytocin receptor and serotonin 2C receptor heterocomplex.

The complexity of oxytocin-mediated functions is strongly associated with its modulatory effects on other neurotransmission systems, including the serotonin (5-hydroxytryptamine, 5-HT) system. Signalling between oxytocin (OT) and 5-HT has been demonstrated during neurodevelopment and in the regulation of specific emotion-based behaviours. It is suggested that crosstalk between neurotransmitters is driven by interaction between their specific receptors, particularly the oxytocin receptor (OTR) and the 5-hydroxytryptamine 2C receptor (5-HTR2C), but evidence for this and the downstream signalling consequences that follow are lacking. Considering the overlapping central expression profiles and shared involvement of OTR and 5-HTR2C in certain endocrine functions and behaviours, including eating behaviour, social interaction and locomotor activity, we investigated the existence of functionally active OTR/5-HTR2C heterocomplexes. Here, we demonstrate evidence for a potential physical interaction between OTR and 5-HTR2Cin vitro in a cellular expression system using flow cytometry-based FRET (fcFRET). We could recapitulate this finding under endogenous expression levels of both receptors via in silico analysis of single cell transcriptomic data and ex vivo proximity ligation assay (PLA). Next, we show that co-expression of the OTR/5-HTR2C pair resulted in a significant depletion of OTR-mediated Gαq-signalling and significant changes in receptor trafficking. Of note, attenuation of OTR-mediated downstream signalling was restored following pharmacological blockade of the 5-HTR2C. Finally, we demonstrated a functional relevance of this novel heterocomplex, in vivo, as 5-HTR2C antagonism increased OT-mediated hypoactivity in mice. Overall, we provide compelling evidence for the formation of functionally active OTR/5-HTR2C heterocomplexes, adding another level of complexity to OTR and 5-HTR2C signalling functionality. This article is part of the special issue on Neuropeptides.

Study of the role of oxygen in the evolution of red wine colour under different ageing conditions in barrels and bottles.

Wine ageing in barrels is conditioned, among other factors, by the amount of oxygen received during this process, which thus impacts its final properties. The aim of this study was to evaluate the effect of oxygen on wine colour during ageing in barrels and bottles during different times. The use of barrels with different and known rates of oxygenation allows the effect of different oxygenation conditions throughout the process in barrels and its later evolution in bottles. A simulation process of ageing in bottles was used to study the impact of bottling in wines after differing ageing periods in barrels. The study of winés oxygen consumption capacity has been tied to colour modifications during ageing in barrels and bottles. Wines aged in barrels with a high oxygenation rate showed greater avidity to consume oxygen taking less time to consume that available, which is reflected in a greater increase in colour intensity.