Tibia Valga Correction by Extraperiosteal Fibular Release in Multiple Exostosis Disease.

Genu valgum is a frequent deformity encountered in Multiple Hereditary Exostosis (MHE) patients. If left untreated, lower limb deformity leads to poor functional outcomes in adulthood. Our hypothesis was that in some cases, fibular shortening would lead to a lateral epiphysiodesis-like effect on the tibia. We herein report the case of a 6-year-old child with MHE who underwent extraperiosteal resection of the fibula for tibia valga correction. To obtain the lateral release of the calf skeleton, resection included inter-tibio-fibular exostosis along with proximal fibular metaphysis and diaphysis without any osseous procedure on the tibia. Gradual improvement of the valgus deformity occurred during follow-up (HKA from 165° preop to 178° at 27-month follow-up). Lateral release of the fibula led to an increase in the fibula/tibia index (from 93% preop to 96% at follow-up). Studying fibular growth in MHE patients could help understand how valgus deformity occurs in these patients. Even if encouraging, this result is just the report of a unique case. Further research and a larger series of patients are required to assess fibular release as a valuable option to treat valgus deformity in MHE.

Information Complexity Ranking: A New Method of Ranking Images by Algorithmic Complexity.

Predicting how an individual will perceive the visual complexity of a piece of information is still a relatively unexplored domain, although it can be useful in many contexts such as for the design of human-computer interfaces. We propose here a new method, called Information Complexity Ranking (ICR) to rank objects from the simplest to the most complex. It takes into account both their intrinsic complexity (in the algorithmic sense) with the Kolmogorov complexity and their similarity to other objects using the work of Cilibrasi and Vitanyi on the normalized compression distance (NCD). We first validated the properties of our ranking method on a reference experiment composed of 7200 randomly generated images divided into 3 types of pictorial elements (text, digits, and colored dots). In the second step, we tested our complexity calculation on a reference dataset composed of 1400 images divided into 7 categories. We compared our results to the ground-truth values of five state-of-the-art complexity algorithms. The results show that our method achieved the best performance for some categories and outperformed the majority of the state-of-the-art algorithms for other categories. For images with many semantic elements, our method was not as efficient as some of the state-of-the-art algorithms.

Essential Oil Trunk Injection Into Orchard Trees: Consequences on the Performance and Preference of Hemipteran Pests.

Apples and pears are among the most widely cultivated fruit species in the world. Pesticides are commonly applied using ground sprayers in conventional orchards; however, most of it will not reach the target plant, increasing the contamination of nontarget organisms such as natural predators, pollinators, and decomposers. Trunk injection is an alternative method of pesticide application that could reduce risks to beneficials and workers. Essential oils represent a 'green' alternative to pesticides due to their reported insecticidal, antimicrobial, antiviral, nematicidal, and antifungal properties. The aim of this study was, therefore, to evaluate the impact that the injection of a cinnamon essential oil solution into the trunk of apple and pear trees could have on their respective pests, Dysaphis plantaginea and Cacopsylla pyri, respectively. The feeding behavior (preference), the life history traits (performance), and the timing of this effect were measured. The injection of an essential oil emulsion in trees impacted hemipteran host-plant colonization, as for both species a modification of their preference and of their performance was observed. The feeding behavior of D. plantaginea was altered as a significantly lower proportion of aphids ingested phloem sap on injected trees, suggesting that the aphids starved to death. On the contrary, the feeding behavior of the psyllids was little changed compared to the control condition, implying that the observed mortality was due to intoxication. The results presented here could theoretically be used to control these two orchard hemipteran pests, although the effectiveness in real conditions still has to be demonstrated.

Athletic children: Guidelines and monitoring in pediatric orthopedic surgery.

In day-to-day practice pediatric orthopedic surgeons often come up against the question of sport. The aim of the present study was to analyze the relationship between sport and childhood, with 3 questions: (1) What are the benefits of sport for children? (2) How to manage high-level child athletes? And (3) What sports are possible after major orthopedic surgery? Sports provide many benefits for children, and are to be encouraged. Sixty minutes' moderate to intense physical activity per day benefits motor development and bone mineralization and reduces the risk of obesity. On the other hand, excessive sports activity, as encountered in high-level sport, can be harmful for the child's development. The amount of training should not exceed a certain threshold in terms of hours per week according to age. Surgical treatment of sport-related traumatic lesions does not necessarily accelerate return to sport: indications need to be reasonable, despite pressure from the patient's circle. Sports are possible after major orthopedic surgery, although return to sport tends to be delayed and the level is lower than preoperatively.

Functional Investigation of Melatonin Receptor Activation by Homogenous cAMP Assay.

Cyclic adenosine monophosphate (cAMP) is an important ubiquitous second messenger and one of the major pathways transducing the activation of G protein-coupled receptors (GPCRs). Quantifying intracellular levels of cAMP in an accurate and high-throughput manner is, therefore, of high interest to access functional responses of GPCRs. The neurohormone melatonin is selectively recognized by two GPCRs in mammals, named MT1 and MT2. Both have an inhibitory action on intracellular cAMP levels. Here, we describe a homogeneous high-throughput-compatible methodology routinely used in our laboratory to measure cAMP levels following activation of melatonin receptors.

Structural Elements Directing G Proteins and ß-Arrestin Interactions with the Human Melatonin Type 2 Receptor Revealed by Natural Variants.

G protein-coupled receptors (GPCRs) can engage distinct subsets of signaling pathways, but the structural determinants of this functional selectivity remain elusive. The naturally occurring genetic variants of GPCRs, selectively affecting different pathways, offer an opportunity to explore this phenomenon. We previously identified 40 coding variants of the MTNR1B gene encoding the melatonin MT2 receptor (MT2). These mutations differently impact the ß-arrestin 2 recruitment, ERK activation, cAMP production, and Gαi1 and Gαz activation. In this study, we combined functional clustering and structural modeling to delineate the molecular features controlling the MT2 functional selectivity. Using non-negative matrix factorization, we analyzed the signaling signatures of the 40 MT2 variants yielding eight clusters defined by unique signaling features and localized in distinct domains of MT2. Using computational homology modeling, we describe how specific mutations can selectively affect the subsets of signaling pathways and offer a proof of principle that natural variants can be used to explore and understand the GPCR functional selectivity.

Current status and impending progress for cassava structural genomics.

KEY MESSAGE: We demystify recent advances in genome assemblies for the heterozygous staple crop cassava (Manihot esculenta), and highlight key cassava genomic resources. Cassava, Manihot esculenta Crantz, is a crop of societal and agricultural importance in tropical regions around the world. Genomics provides a platform for accelerated improvement of cassava's nutritional and agronomic traits, as well as for illuminating aspects of cassava's history including its path towards domestication. The highly heterozygous nature of the cassava genome is widely recognized. However, the full extent and context of this heterozygosity has been difficult to reveal because of technological limitations within genome sequencing. Only recently, with several new long-read sequencing technologies coming online, has the genomics community been able to tackle some similarly difficult genomes. In light of these recent advances, we provide this review to document the current status of the cassava genome and genomic resources and provide a perspective on what to look forward to in the coming years.

Biopesticide Trunk Injection Into Apple Trees: A Proof of Concept for the Systemic Movement of Mint and Cinnamon Essential Oils.

The use of conventional pesticides is debated because of their multiple potential adverse effects on non-target organisms, human health, pest resistance development and environmental contaminations. In this setting, this study focused on developing alternatives, such as trunk-injected essential oil (EO)-based biopesticides. We analysed the ecophysiology of apple trees (Malus domestica) following the injection of Cinnamomum cassia and Mentha spicata nanoemulsions in the tree's vascular system. Targeted and untargeted volatile organic compounds (VOCs) analyses were performed on leaf-contained and leaf-emitted VOCs and analysed through dynamic headspace-gas chromatography-mass spectrometry (DHS-GC-MS) and thermal desorption unit (TDU)-GC-MS. Our results showed that carvone, as a major constituent of the M. spicata EO, was contained in the leaves (mean concentrations ranging from 3.39 to 19.7 ng gDW -1) and emitted at a constant rate of approximately 0.2 ng gDW -1 h-1. Trans-cinnamaldehyde, C. cassia's major component, accumulated in the leaves (mean concentrations of 83.46 and 350.54 ng gDW -1) without being emitted. Furthermore, our results highlighted the increase in various VOCs following EO injection, both in terms of leaf-contained VOCs, such as methyl salicylate, and in terms of leaf-emitted VOCs, such as caryophyllene. Principal component analysis (PCA) highlighted differences in terms of VOC profiles. In addition, an analysis of similarity (ANOSIM) and permutational multivariate analysis of variance (PERMANOVA) revealed that the VOC profiles were significantly impacted by the treatment. Maximum yields of photosystem II (Fv/Fm) were within the range of 0.80-0.85, indicating that the trees remained healthy throughout the experiment. Our targeted analysis demonstrated the systemic translocation of EOs through the plant's vascular system. The untargeted analysis, on the other hand, highlighted the potential systemic acquired resistance (SAR) induction by these EOs. Lastly, C. cassia and M. spicata EOs did not appear phytotoxic to the treated trees, as demonstrated through chlorophyll fluorescence measurements. Hence, this work can be seen as a proof of concept for the use of trunk-injected EOs given the systemic translocation, increased production and release of biogenic VOCs (BVOCs) and absence of phytotoxicity. Further works should focus on the ecological impact of such treatments in orchards, as well as apple quality and production yields.

MiBiOmics: an interactive web application for multi-omics data exploration and integration.

BACKGROUND: Multi-omics experimental approaches are becoming common practice in biological and medical sciences underlining the need to design new integrative techniques and applications to enable the multi-scale characterization of biological systems. The integrative analysis of heterogeneous datasets generally allows to acquire additional insights and generate novel hypotheses about a given biological system. However, it can become challenging given the often-large size of omics datasets and the diversity of existing techniques. Moreover, visualization tools for interpretation are usually non-accessible to biologists without programming skills. RESULTS: Here, we present MiBiOmics, a web-based and standalone application that facilitates multi-omics data visualization, exploration, integration, and analysis by providing easy access to dedicated and interactive protocols. It implements classical ordination techniques and the inference of omics-based (multilayer) networks to mine complex biological systems, and identify robust biomarkers linked to specific contextual parameters or biological states. CONCLUSIONS: MiBiOmics provides easy-access to exploratory ordination techniques and to a network-based approach for integrative multi-omics analyses through an intuitive and interactive interface. MiBiOmics is currently available as a Shiny app at https://shiny-bird.univ-nantes.fr/app/Mibiomics and as a standalone application at https://gitlab.univ-nantes.fr/combi-ls2n/mibiomics .

Transgenerational phenotypic plasticity of diapause induction and related fitness cost in a commercial strain of the parasitoid Aphidius ervi Haliday.

Diapause is an adaptation that insects have evolved to synchronize their life cycle with that of seasonal climatic changes and resources availability. However, cues for its induction are not always clear and, in some cases, a maternal effect may be involved. At the population level, just a part of the individuals may exhibit diapause with important consequences in terms of winter survival. Moreover, clear indicators of diapause state are difficult to identify. Diapause induction was thus investigated in the aphid parasitoid species Aphidius ervi Haliday (Hymenoptera: Braconidae) developing in the aphid Sitobion avenae (Hemiptera: Aphididae) at four crossed photothermal regimes (16 °C and 8 °C, 16:8 h L:D and 8:16 h L:D), and during 2 successive generations. We analyzed the reliability of changes in mummy color to assess for the diapausing state compared to dissections, and we measured parasitoid morphological and physiological traits. We observed that the proportion of dark brown mummies increased after one generation under low photothermal regime compared to other regimes. No diapause was recorded at 16 °C, 16:8 h L:D, while we observed 16.2% and 67.5% diapause incidence at 8 °C, 8:16 h L:D, at 1st and 2nd generation, respectively. Diapause induction is thus increased by short day-length conditions and low temperatures as well as by maternal effects. All parasitoid life-history traits (weight, size, fat content, water content, egg-load, and longevity) were affected by the photothermal regime and/or the generation. These results raise new questions on the environmental thresholds needed to induce diapause and on survival and adaptation potential of commercially available parasitoid strains in different environments.

The effect of protein-enriched snacks on serum albumin concentration in non-selected haemodialysis patients.

OBJECTIVE: Serum albumin level is not only one of the protein-energy wasting criteria but also a powerful marker of mortality in patients on haemodialysis (HD) treatment. The study aimed to assess the effect of a protein-enriched snack given during HD treatment on serum albumin level. DESIGN AND METHODS: This prospective, single-centre, observational, non-randomized 16-month study was sub-divided into four 4-month periods. Patients on hemodialysis for more than three months and receiving a regular standard snack (8.8 g of protein) during the HD session were included and assigned during four four-month periods to receive either the standard snack or a protein-enriched snack (28.7 g). Patients were not selected based on nutritional criteria. RESULTS: Sixty-six patients completed the study. Serum albumin levels significantly increased, from 3.43 ± 0.28 g/dl in the first period (standard snack) to 3.62 ± 0.32 g/dl (p < 0.0001) in the second period (enriched snack). In the third period (standard snack), albumin levels remained stable (3.61 ± 0.35 g/dl). After the fourth period (enriched snack), serum albumin levels further increased significantly (3.69 ± 0.30 g/dl; p = 0.05 and p = 0.007, respectively). Weight and normalized protein nitrogen appearance remained stable during the 16-month study period. CONCLUSIONS: This study suggests that the intake of a protein-enriched snack during HD treatment, independently from baseline serum albumin level, could significantly increase their serum albumin levels. Serum albumin level is a powerful predictor of mortality; therefore, this simple and effective action could be of real interest to improve patients' outcomes.

Long-term mortality risk associated with citric acid- and acetic acid-based bicarbonate haemodialysis: a historical cohort propensity score-matched study in a large, multicentre, population-based study.

BACKGROUND: Citric acid-based bicarbonate dialysate (CiD) is increasingly used in haemodialysis (HD) to improve haemodynamic tolerance and haemocompatibility associated with acetic acid-based bicarbonate dialysate. Safety concerns over CiD have been raised recently after a French ecological study reported higher mortality hazard in HD clinics with high CiD consumption. Therefore, we evaluated the mortality risk associated with various acidifiers (AcD, CiD) of bicarbonate dialysate. METHODS: In this multicentre, historical cohort study, we included adult incident HD patients (European, Middle-East and Africa Fresenius Medical Care network; 1 January 2014 to 31 October 2018). We recorded acidifiers of bicarbonate dialysis and dialysate composition for each dialysis session. In the primary intention-to-treat analysis, patients were assigned to the exposed group if they received CiD in >70% of sessions during the first 3 months (CiD70%), whereas the non-exposed group received no CiD at all. In the secondary analysis, exposure was assessed on a monthly basis for the whole duration of the follow-up. RESULTS: We enrolled 10 121 incident patients during the study period. Of them, 371 met the criteria for inclusion in CiD70%. After propensity score matching, mortality was 11.43 [95% confidence interval (CI) 8.86-14.75] and 12.04 (95% CI 9.44-15.35) deaths/100 person-years in the CiD0% and CiD70% groups, respectively (P = 0.80). A similar association trend was observed in the secondary analysis. CONCLUSIONS: We did not observe evidence of increased mortality among patients exposed to CiD in a large European cohort of dialysis patients despite the fact that physicians were more inclined to prescribe CiD to subjects with worse medical conditions.

GPR50-Ctail cleavage and nuclear translocation: a new signal transduction mode for G protein-coupled receptors.

Transmission of extracellular signals by G protein-coupled receptors typically relies on a cascade of intracellular events initiated by the activation of heterotrimeric G proteins or ß-arrestins followed by effector activation/inhibition. Here, we report an alternative signal transduction mode used by the orphan GPR50 that relies on the nuclear translocation of its carboxyl-terminal domain (CTD). Activation of the calcium-dependent calpain protease cleaves off the CTD from the transmembrane-bound GPR50 core domain between Phe-408 and Ser-409 as determined by MALDI-TOF-mass spectrometry. The cytosolic CTD then translocates into the nucleus assisted by its 'DPD' motif, where it interacts with the general transcription factor TFII-I to regulate c-fos gene transcription. RNA-Seq analysis indicates a broad role of the CTD in modulating gene transcription with ~ 8000 differentially expressed genes. Our study describes a non-canonical, direct signaling mode of GPCRs to the nucleus with similarities to other receptor families such as the NOTCH receptor.

Pelvic fractures in children (pelvic ring and acetabulum).

Pelvic fractures in children are rare and often the result of high-energy trauma. The possibility of associated lesions cannot be ignored. Treatment at a specialized children's hospital is a must. The multidisciplinary care team must include a paediatric orthopaedic surgeon. In the emergency room, the surgeon contributes to haemodynamic stabilization of the child by reducing and stabilizing posterior arch fractures and restoring the skeletal cohesion to make it easier to move the child and allow other examinations to be performed. Imaging modalities are used to determine the stability of the pelvic ring fracture, the risk of epiphysiodesis of an acetabulum fracture if the triradiate cartilage is open and the joint congruency if the triradiate cartilage is closed. Internal fixation can be used if surgery is being performed for associated non-orthopaedic injuries. Most vertically stable fractures are treated non-surgically. Fractures that are unstable vertically will require surgical treatment. Treatment of acetabulum fractures depends on the status of the triradiate cartilage. In older children, it is similar to the treatments used in adults. In children with open growth plates, the goal is to make sure the acetabulum continues growing. In all cases, the patients must be instructed to start physical therapy as soon as possible. Full recovery can be expected after stable pelvic fractures. Unstable pelvic fractures can lead to sequelae, the severity of which depend on the residual pelvic displacement and involvement of the growth plates that can cause epiphysiodesis. Surgery to correct these deformities is challenging. The most serious occur when the vertical displacement of the hemipelvis must be corrected. After an acetabulum fracture, removal of the growth blocker can be done in children under 10 years of age. In older children, acetabular dysplasia requires periacetabular osteotomy.

Intraoperative ketorolac in high-risk breast cancer patients. A prospective, randomized, placebo-controlled clinical trial.

BACKGROUND: Ketorolac has been associated with a lower risk of recurrence in retrospective studies, especially in patients with positive inflammatory markers. It is still unknown whether a single dose of pre-incisional ketorolac can prolong recurrence-free survival. METHODS: The KBC trial is a multicenter, placebo-controlled, randomized phase III trial in high-risk breast cancer patients powered for 33% reduction in recurrence rate (from 60 to 40%). Patients received one dose of ketorolac tromethamine or a placebo before surgery. Eligible patients were breast cancer patients, planned for curative surgery, and with a Neutrophil-to-Lymphocyte Ratio≥4, node-positive disease or a triple-negative phenotype. The primary endpoint was Disease-Free Survival (DFS) at two years. Secondary endpoints included safety, pain assessment and overall survival. FINDINGS: Between February 2013 and July 2015, 203 patients were assigned to ketorolac (n = 96) or placebo (n = 107). Baseline characteristics were similar between arms. Patients had a mean age of 55.7 (SD14) years. At two years, 83.1% of the patients were alive and disease free in the ketorolac vs. 89.7% in the placebo arm (HR: 1.23; 95%CI: 0.65-2.31) and, respectively, 96.8% vs. 98.1% were alive (HR: 1.09; 95%CI: 0.34-3.51). CONCLUSIONS: A single administration of 30 mg of ketorolac tromethamine before surgery does not increase disease-free survival in high risk breast cancer patients. Overall survival difference between ketorolac tromethamine group and placebo group was not statistically significant. The study was however underpowered because of lower recurrence rates than initially anticipated. No safety concerns were observed. TRIAL REGISTRATION: ClinicalTrials.gov NCT01806259.

Detection of recombinant and endogenous mouse melatonin receptors by monoclonal antibodies targeting the C-terminal domain.

Melatonin receptors play important roles in the regulation of circadian and seasonal rhythms, sleep, retinal functions, the immune system, depression, and type 2 diabetes development. Melatonin receptors are approved drug targets for insomnia, non-24-hour sleep-wake disorders, and major depressive disorders. In mammals, two melatonin receptors (MTRs) exist, MT1 and MT2 , belonging to the G protein-coupled receptor (GPCR) superfamily. Similar to most other GPCRs, reliable antibodies recognizing melatonin receptors proved to be difficult to obtain. Here, we describe the development of the first monoclonal antibodies (mABs) for mouse MT1 and MT2 . Purified antibodies were extensively characterized for specific reactivity with mouse, rat, and human MT1 and MT2 by Western blot, immunoprecipitation, immunofluorescence, and proximity ligation assay. Several mABs were specific for either mouse MT1 or MT2 . None of the mABs cross-reacted with rat MTRs, and some were able to react with human MTRs. The specificity of the selected mABs was validated by immunofluorescence microscopy in three established locations (retina, suprachiasmatic nuclei, pituitary gland) for MTR expression in mice using MTR-KO mice as control. MT2 expression was not detected in mouse insulinoma MIN6 cells or pancreatic beta-cells. Collectively, we report the first monoclonal antibodies recognizing recombinant and native mouse melatonin receptors that will be valuable tools for future studies.

Type 2 diabetes-associated variants of the MT2 melatonin receptor affect distinct modes of signaling.

Melatonin is produced during the night and regulates sleep and circadian rhythms. Loss-of-function variants in MTNR1B, which encodes the melatonin receptor MT2, a G protein-coupled receptor (GPCR), are associated with an increased risk of type 2 diabetes (T2D). To identify specific T2D-associated signaling pathway(s), we profiled the signaling output of 40 MT2 variants by monitoring spontaneous (ligand-independent) and melatonin-induced activation of multiple signaling effectors. Genetic association analysis showed that defects in the melatonin-induced activation of Gαi1 and Gαz proteins and in spontaneous ß-arrestin2 recruitment to MT2 were the most statistically significantly associated with an increased T2D risk. Computational variant impact prediction by in silico evolutionary lineage analysis strongly correlated with the measured phenotypic effect of each variant, providing a predictive tool for future studies on GPCR variants. Together, this large-scale functional study provides an operational framework for the postgenomic analysis of the multiple GPCR variants present in the human population. The association of T2D risk with signaling pathway-specific defects opens avenues for pathway-specific personalized therapeutic intervention and reveals the potential relevance of MT2 function during the day, when melatonin is undetectable, but spontaneous activity of the receptor occurs.

The orphan GPR50 receptor promotes constitutive TGFß receptor signaling and protects against cancer development.

Transforming growth factor-ß (TGFß) signaling is initiated by the type I, II TGFß receptor (TßRI/TßRII) complex. Here we report the formation of an alternative complex between TßRI and the orphan GPR50, belonging to the G protein-coupled receptor super-family. The interaction of GPR50 with TßRI induces spontaneous TßRI-dependent Smad and non-Smad signaling by stabilizing the active TßRI conformation and competing for the binding of the negative regulator FKBP12 to TßRI. GPR50 overexpression in MDA-MB-231 cells mimics the anti-proliferative effect of TßRI and decreases tumor growth in a xenograft mouse model. Inversely, targeted deletion of GPR50 in the MMTV/Neu spontaneous mammary cancer model shows decreased survival after tumor onset and increased tumor growth. Low GPR50 expression is associated with poor survival prognosis in human breast cancer irrespective of the breast cancer subtype. This describes a previously unappreciated spontaneous TGFß-independent activation mode of TßRI and identifies GPR50 as a TßRI co-receptor with potential impact on cancer development.

Importance of the second extracellular loop for melatonin MT1 receptor function and absence of melatonin binding in GPR50.

BACKGROUND AND PURPOSE: Recent crystal structures of GPCRs have emphasized the previously unappreciated role of the second extracellular (E2) loop in ligand binding and gating and receptor activation. Here, we have assessed the role of the E2 loop in the activation of the melatonin MT1 receptor and in the inactivation of the closely related orphan receptor GPR50. EXPERIMENTAL APPROACH: Chimeric MT1 -GPR50 receptors were generated and functionally analysed in terms of 2-[125 I]iodomelatonin binding, Gi /cAMP signalling and ß-arrestin2 recruitment. We also used computational molecular dynamics (MD) simulations. KEY RESULTS: MD simulations of 300 ns revealed (i) the tight hairpin structure of the E2 loop of the MT1 receptor (ii) the most suitable features for melatonin binding in MT1 receptors and (iii) major predicted rearrangements upon MT1 receptor activation, stabilizing interaction networks between Phe179 or Gln181 in the E2 loop and transmembrane helixes 5 and 6. Functional assays confirmed these predictions, because reciprocal replacement of MT1 and GPR50 residues/domains led to the predicted loss- and gain-of-melatonin action of MT1 receptors and GPR50 respectively. CONCLUSIONS AND IMPLICATIONS: Our work demonstrated the crucial role of the E2 loop for MT1 receptor and GPR50 function by proposing a model in which the E2 loop is important in stabilizing active MT1 receptor conformations and by showing how evolutionary processes appear to have selected for modifications in the E2 loop in order to make GPR50 unresponsive to melatonin. LINKED ARTICLES: This article is part of a themed section on Recent Developments in Research of Melatonin and its Potential Therapeutic Applications. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.16/issuetoc.