Mining genomic regions associated with agronomic and biochemical traits in quinoa through GWAS.

Quinoa (Chenopodium quinoa Willd.), an Andean crop, is a facultative halophyte food crop recognized globally for its high nutritional value and plasticity to adapt to harsh conditions. We conducted a genome-wide association study on a diverse set of quinoa germplasm accessions. These accessions were evaluated for the following agronomic and biochemical traits: days to 50% flowering (DTF), plant height (PH), panicle length (PL), stem diameter (SD), seed yield (SY), grain diameter (GD), and thousand-grain weight (TGW). These accessions underwent genotyping-by-sequencing using the DNBSeq-G400R platform. Among all evaluated traits, TGW represented maximum broad-sense heritability. Our study revealed average SNP density of ≈ 3.11 SNPs/10 kb for the whole genome, with the lowest and highest on chromosomes Cq1B and Cq9A, respectively. Principal component analysis clustered the quinoa population in three main clusters, one clearly representing lowland Chilean accessions, whereas the other two groups corresponded to germplasm from the highlands of Peru and Bolivia. In our germplasm set, we estimated linkage disequilibrium decay to be ≈ 118.5 kb. Marker-trait analyses revealed major and consistent effect associations for DTF on chromosomes 3A, 4B, 5B, 6A, 7A, 7B and 8B, with phenotypic variance explained (PVE) as high as 19.15%. Nine associations across eight chromosomes were also found for saponin content with 20% PVE by qSPN5A.1. More QTLs were identified for PL and TGW on multiple chromosomal locations. We identified putative candidate genes in the genomic regions associated with DTF and saponin content. The consistent and major-effect genomic associations can be used in fast-tracking quinoa breeding for wider adaptation across marginal environments.

An Audit of Orthopaedic Discharge Summaries Comparing Electronic With Handwritten Summaries: A Quality Improvement Project.

Introduction Discharge summaries (DS), which are sent from inpatient to outpatient settings, transmit critical clinical information. DS play a crucial role in the discharge process since they provide critical information about the patients that is simple to remember and help with patient follow-up in the community. This audit sought to determine if a quality improvement (QI) program may have an influence on the severity of mistakes at the moment of discharge and to assess the existing degree of inconsistencies on handwritten DS for orthopaedic patients. Methodology From the orthopaedics department at a tertiary care facility in south India, 100 handwritten DS and 100 electronic DS over six months were randomly chosen, and they were retrospectively audited against a predetermined set of criteria. The errors were compiled and compared by three reviewers. Results Some of the criteria, such as the doctor's signature, the speciality of admission, procedural therapy at the hospital, and the date of admission, were contained in all handwritten and electronic DS. Some of the metrics showed that electronic DS performed better than handwritten DS in areas such as hospital complications, which increased from 50% to 100%, contact information, which increased from 34% to 95%, and condition at discharge, which increased from 66% to 96%. Also, understandability increased from 58% to 100%, prognostic details increased from 70% to 96%, allergies increased from 66% to 100%, physical examination findings increased from 88% to 100%, admission diagnosis increased from 80% to 100%, patient/physician details increased from 92% to 100%, the information given to patient increased from 88% to 100%, problem list/issue pending increased from 35% to 92%, investigation increased from 80% to 100%, discharge medications increased from 88% to 100%, follow-up plan increased from 80% to 100%, discharge diagnosis increased from 94% to 100%, International Classification of Diseases, Tenth Revision (ICD-10) code increased from 93% to 100%, and days of admission increased from 92% to 100%. Conclusion Following the deployment of electronic DS, we were able to better care for patients and lessen their discomfort. We advise converting to electronic DS to enhance patient care and better record-keeping since this will become a significant problem if all notes are not accurately filled and are not readable.

Multidrug-Resistant Staphylococcus aureus Isolates in a Tertiary Care Hospital, Kingdom of Bahrain.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is a ubiquitous pathogen associated with a wide spectrum of human infections. In recent decades, MRSA infections have been increasingly reported in individuals without established risk factors, infecting immunocompetent members of the community. This emergence is attributed to the production of various virulence factors, notably Panton-Valentine leukocidin (PVL). OBJECTIVE: The aim of this study was to better understand the prevalence, antibiotic resistance profiles, and molecular characteristics of S. aureus and MRSA in a tertiary care hospital in the Kingdom of Bahrain. MATERIALS AND METHODS: This cross-sectional study was carried out in a tertiary hospital for a one-year period, from December 2020 to December 2021. A total of 161 consecutive S. aureus isolates were collected. Antibiotic susceptibility was tested using BD Phoenix™ automated identification and susceptibility testing system. Molecular analysis was conducted via conventional PCR and conventional multiplex PCR for SCCmec typing. RESULTS: In this study, 161 S. aureus isolates were investigated, 60% (n=97) were characterized as MRSA, of which, 12% (n=12) were healthcare-associated methicillin-resistant Staphylococcus aureus (HA-MRSA) while 88% (n=85) were community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA). No statistically significant difference (P>0.05) in antibiotic resistance trends between HA-MRSA and CA-MRSA was detected. Multidrug resistance (MDR) amounted to 19% (n=30) of all S. aureus isolates, 14% (n=9) of methicillin-susceptible Staphylococcus aureus (MSSA) isolates, and 22% (n=21) of MRSA isolates. SCCmec typing demonstrated a high prevalence of type IV (61%, n=59), followed by type V (32%, n=31), then type II (4%, n=4), and type III (3%, n=3). The PVL prevalence was 39% (n=25) in MSSA and 62% (n=60) in MRSA, 33% (n=4) in HA-MRSA, and 66% (n=56) in CA-MRSA. CONCLUSION: This study demonstrated the emergence of PVL-producing CA-MRSA in a tertiary care hospital, as well as the detection of PVL-producing MDR strains. This development prompts serious measures to be taken in order to sustain a healthy clinical environment.

Complications Following Breast Augmentation In Transfeminine Individuals: A Systemic Review And Meta-Analysis.

BACKGROUND: Breast augmentation is the most commonly performed procedure for gender affirmation in transfeminine individuals. While adverse events among breast augmentation in cis-gender females were well-described, their relative incidence in transfeminine individuals patients is less elucidated. AIM: This study aims to compare complication rates after breast augmentation between cisgender females and transfeminine patients and to evaluate the safety and efficacy of breast augmentation in transfeminine individuals. METHODS: PubMed, the Cochrane Library, and other resources were queried for studies published up to Jan 2022. A total of 1864 transfeminine patients from 14 studies were included in this project. Primary outcomes including complications (capsular contracture, hematoma or seroma, infection, implant asymmetry/malposition, hemorrhage, skin or systemic complications), patient satisfaction, and reoperation rates were pooled. A direct comparison of these rates was performed against historical rates in cisgender females. RESULTS: Within the transfeminine group, pooled rate of capsular contracture was 3.62% ((95% CI, 0.0038-0.0908); hematoma/seroma was 0.63% ((95% CI: 0.0014-0.0134); infection incidence was 0.08% (95% CI, 0.0000-0.0054); implant asymmetry was 3.89% (95% CI, 0.0149-0.0714). There was no statistical difference between rates of capsular contracture (p=0.41) and infection (p=0.71) between the transfeminine vs cis-gender groups, while there were higher rates of hematoma/seroma (p=0.0095) and implant asymmetry/malposition (p<0.00001) in the transfeminine group. CONCLUSION: Breast augmentation is an important procedure for gender affirmation, and in transfeminine individuals carries relatively higher rates of post-operative hematoma and implant malposition relative to cisgender females.

Synergistic antimicrobial effect of ascorbic acid and nicotinamide with rifampicin and vancomycin against SCCmec type IV methicillin-resistant Staphylococcus aureus (MRSA).

Background. Methicillin-resistant Staphylococcus aureus (MRSA) is a pathogenic bacteria involved in a wide spectrum of human diseases. Many virulence factors promote this widespread propagation. One important factor is acquiring antibiotic resistance genes, which leads to a reduction in the availability and efficacy of therapy options. Recently, research has suggested that the remarkable antimicrobial effect of antioxidants against superbugs such as MRSA shows synergistic effects when accompanied by antimicrobial therapy. This paper aims to examine the synergistic effects of ascorbic acid and nicotinamide with a panel of antibiotics used in antimicrobial therapy against MRSA. Material and Methods. Two SCCmec type IV MRSA reference strains (EMRSA-15 and USA300) and 10 MRSA clinical isolates feature in this paper. SCCmec typing was conducted on the 10 clinical isolates via multiplex PCR after identification. Synergy experiments on antioxidants and antibiotics were evaluated via checkerboard assay. The minimum inhibitory concentration (MIC) of each agent was determined in accordance with the Clinical and Laboratory Standards Institute (CLSI) M100 guidelines through twofold microdilution assay. Results and Discussion. Synergy (FIC <0.5) was demonstrated for ascorbic acid (1/2 to 1/4 MIC) with rifampicin (1/2 to 1/8 MIC), and also ascorbic acid (1/2 to 1/16 MIC) when associated with vancomycin (1/2 MIC). Similarly, nicotinamide (1/2 to 1/16 MIC) showed a synergistic effect when paired with low concentrations of rifampicin (1/2 to 1/16 MIC), and also (at 1/4 to 1/16 MIC) with vancomycin (1/2 MIC). All reduced MICs due to synergistic combinations demonstrated statistical significance (P<0.05). Conclusion. The synergistic activity demonstrated in associating antioxidants with antibiotics shows promise in managing superbugs. However, more research is required to better understand the mechanism of the synergy and for utilization in clinical care.

The Effect of Ascorbic Acid and Nicotinamide on Panton-Valentine Leukocidin Cytotoxicity: An Ex Vivo Study.

Background: Panton−Valentine Leukocidin sustains a strong cytotoxic activity, targeting immune cells and, consequently, perforating the plasma membrane and inducing cell death. The present study is aimed to examine the individual effect of ascorbic acid and nicotinamide on PVL cytotoxicity ex vivo, as well as their effect on granulocytes viability when treated with PVL. Materials and Methods: The PVL cytotoxicity assay was performed in triplicates using the commercial Cytotoxicity Detection Kit PLUS (LDH). LDH release was measured to determine cell damage and cell viability was measured via flow cytometry. Results and discussion: A clear reduction in PVL cytotoxicity was demonstrated (p < 0.001). Treatment with ascorbic acid at 5 mg/mL has shown a 3-fold reduction in PVL cytotoxicity; likewise, nicotinamide illustrated a 4-fold reduction in PVL cytotoxicity. Moreover, granulocytes' viability after PVL treatment was maintained when incubated with 5 mg/mL of ascorbic acid and nicotinamide. Conclusions: our findings illustrated that ascorbic acid and nicotinamide exhibit an inhibitory effect on PVL cytotoxicity and promote cell viability, as the cytotoxic effect of the toxin is postulated to be neutralized by antioxidant incubation. Further investigations are needed to assess whether these antioxidants may be viable options in PVL cytotoxicity attenuation in PVL-associated diseases.

Expression of syndecan-1 in different grades of oral squamous cell carcinoma: An immunohistochemical study.

Background: Syndecans are a family of transmembrane proteins, belonging to heparin sulphate proteoglycan family and are localized entirely to the epithelial cells with the stratified squamous epithelia. They are involved in cell-cell adhesion and interaction with the extracellular matrix and play a critical role in cell growth, differentiation, cell morphology, and migration. The down regulation of syndecan-1 indicates loss of cellular adhesion and possibility of invasion. The present study is aimed to evaluate the difference in immunohistochemical expression of syndecan-1 in different grades of oral squamous cell carcinoma (OSCC) patients and control group. Methods: The present study consists of 42 cases of paraffin-embedded tissue sections of OSCC; 14 well differentiated, 14 moderately differentiated, and 14 poorly differentiated. As a control, 10 paraffin-embedded tissue sections of unaffected oral mucosa were used. The sections were stained for immunohistochemical expression of syndecan -1. The intensity of staining was scored. The immunohistochemistry scores for each sample were obtained by Tissue Quant software. Results: Statistical analysis revealed that there was a significant decrease in intensity of staining between normal and different grades of OSCC. Conclusion: This study shows that as cellular differentiation was lost, syndecan-1 expression was less. This provides an insight and understanding of the pathophysiology of the invasive process of OSCC and helps in establishing the prognostic link.

Genetic networks underlying salinity tolerance in wheat uncovered with genome-wide analyses and selective sweeps.

KEY MESSAGE: A genetic framework underpinning salinity tolerance at reproductive stage was revealed by genome-wide SNP markers and major adaptability genes in synthetic-derived wheats, and trait-associated loci were used to predict phenotypes. Using wild relatives of crops to identify genes related to improved productivity and resilience to climate extremes is a prioritized area of crop genetic improvement. High salinity is a widespread crop production constraint, and development of salt-tolerant cultivars is a sustainable solution. We evaluated a panel of 294 wheat accessions comprising synthetic-derived wheat lines (SYN-DERs) and modern bread wheat advanced lines under control and high salinity conditions at two locations. The GWAS analysis revealed a quantitative genetic framework of more than 200 loci with minor effect underlying salinity tolerance at reproductive stage. The significant trait-associated SNPs were used to predict phenotypes using a GBLUP model, and the prediction accuracy (r2) ranged between 0.57 and 0.74. The r2 values for flag leaf weight, days to flowering, biomass, and number of spikes per plant were all above 0.70, validating the phenotypic effects of the loci discovered in this study. Furthermore, the germplasm sets were compared to identify selection sweeps associated with salt tolerance loci in SYN-DERs. Six loci associated with salinity tolerance were found to be differentially selected in the SYN-DERs (12.4 Mb on chromosome (chr)1B, 7.1 Mb on chr2A, 11.2 Mb on chr2D, 200 Mb on chr3D, 600 Mb on chr6B, and 700.9 Mb on chr7B). A total of 228 reported markers and genes, including 17 well-characterized genes, were uncovered using GWAS and EigenGWAS. A linkage disequilibrium (LD) block on chr5A, including the Vrn-A1 gene at 575 Mb and its homeologs on chr5D, were strongly associated with multiple yield-related traits and flowering time under salinity stress conditions. The diversity panel was screened with more than 68 kompetitive allele-specific PCR (KASP) markers of functional genes in wheat, and the pleiotropic effects of superior alleles of Rht-1, TaGASR-A1, and TaCwi-A1 were revealed under salinity stress. To effectively utilize the extensive genetic information obtained from the GWAS analysis, a genetic interaction network was constructed to reveal correlations among the investigated traits. The genetic network data combined with GWAS, selective sweeps, and the functional gene survey provided a quantitative genetic framework for identifying differentially retained loci associated with salinity tolerance in wheat.

Genomic Regions Associated With Salinity Stress Tolerance in Tropical Maize (Zea Mays L.).

Being a widely cultivated crop globally under diverse climatic conditions and soil types, maize is often exposed to an array of biotic and abiotic stresses. Soil salinity is one of the challenges for maize cultivation in many parts of lowland tropics that significantly affects crop growth and reduces economic yields. Breeding strategies integrated with molecular approach might accelerate the process of identifying and developing salinity-tolerant maize cultivars. In this study, an association mapping panel consisting of 305 diverse maize inbred lines was phenotyped in a managed salinity stress phenotyping facility at International Center for Biosaline Agriculture (ICBA), Dubai, United Arab Emirates (UAE). Wide genotypic variability was observed in the panel under salinity stress for key phenotypic traits viz., grain yield, days to anthesis, anthesis-silking interval, plant height, cob length, cob girth, and kernel number. The panel was genotyped following the genome-based sequencing approach to generate 955,690 SNPs. Total SNPs were filtered to 213,043 at a call rate of 0.85 and minor allele frequency of 0.05 for association analysis. A total of 259 highly significant (P ≤ 1 × 10-5) marker-trait associations (MTAs) were identified for seven phenotypic traits. The phenotypic variance for MTAs ranged between 5.2 and 9%. A total of 64 associations were found in 19 unique putative gene expression regions. Among them, 12 associations were found in gene models with stress-related biological functions.

Orphan Crops: A Best Fit for Dietary Enrichment and Diversification in Highly Deteriorated Marginal Environments.

Orphan crops are indigenous and invariably grown by small and marginal farmers under subsistence farming systems. These crops, which are common and widely accepted by local farmers, are highly rich in nutritional profile, good for medicinal purposes, and well adapted to suboptimal growing conditions. However, these crops have suffered neglect and abandonment from the scientific community because of very low or no investments in research and genetic improvement. A plausible reason for this is that these crops are not traded internationally at a rate comparable to that of the major food crops such as wheat, rice, and maize. Furthermore, marginal environments have poor soils and are characterized by extreme weather conditions such as heat, erratic rainfall, water deficit, and soil and water salinity, among others. With more frequent extreme climatic events and continued land degradation, orphan crops are beginning to receive renewed attention as alternative crops for dietary diversification in marginal environments and, by extension, across the globe. Increased awareness of good health is also a major contributor to the revived attention accorded to orphan crops. Thus, the introduction, evaluation, and adaptation of outstanding varieties of orphan crops for dietary diversification will contribute not only to sustained food production but also to improved nutrition in marginal environments. In this review article, the concept of orphan crops vis-à-vis marginality and food and nutritional security is defined for a few orphan crops. We also examined recent advances in research involving orphan crops and the potential of these crops for dietary diversification within the context of harsh marginal environments. Recent advances in genomics coupled with molecular breeding will play a pivotal role in improving the genetic potential of orphan crops and help in developing sustainable food systems. We concluded by presenting a potential roadmap to future research engagement and a policy framework with recommendations aimed at facilitating and enhancing the adoption and sustainable production of orphan crops under agriculturally marginal conditions.

Probiotics: Potential novel therapeutics for microbiota-gut-brain axis dysfunction across gender and lifespan.

Probiotics are live microorganisms, which when administered in adequate amounts, present a health benefit for the host. While the beneficial effects of probiotics on gastrointestinal function are generally well recognized, new animal research and clinical studies have found that alterations in gut microbial communities can have a broad range of effects throughout the body. Non-intestinal sites impacted include the immune, endocrine, cardiovascular and the central nervous system (CNS). In particular, there has been a growing interest and appreciation about the role that gut microbiota may play in affecting CNS-related function through the 'microbiota-gut-brain axis'. Emerging evidence suggests potential therapeutic benefits of probiotics in several CNS conditions, such as anxiety, depression, autism spectrum disorders and Parkinson's disease. There may also be some gender-specific variances in terms of probiotic mediated effects, with the gut microbiota shaping and being concurrently molded by the hormonal environment governing differences between the sexes. Probiotics may influence the ability of the gut microbiome to affect a variety of biological processes in the host, including neurotransmitter activity, vagal neurotransmission, generation of neuroactive metabolites and inflammatory response mediators. Some of these may engage in cross talk with host sex hormones, such as estrogens, which could be of relevance in relation to their effects on stress response and cognitive health. This raises the possibility of gender-specific variation with regards to the biological action of probiotics, including that on the endocrine and central nervous systems. In this review we aim to describe the current understanding in relation to the role and use of probiotics in microbiota-gut-brain axis-related dysfunction. Furthermore, we will address the conceptualization and classification of probiotics in the context of gender and lifespan as well as how restoring gut microbiota composition by clinical or dietary intervention can help in supporting health outcomes other than those related to the gastrointestinal tract. We also evaluate how these new learnings may impact industrial effort in probiotic research and the discovery and development of novel and more personalized, condition-specific, beneficial probiotic therapeutic agents.

Plasma-Initiated Graft Polymerization of Acrylic Acid onto Fluorine-Doped Tin Oxide as a Platform for Immobilization of Water-Oxidation Catalysts.

The discovery of new and versatile strategies for the immobilization of molecular water-oxidation catalysts (WOCs) is crucial for developing clean energy conversion devices [e.g., (photo)electrocatalytic cells for water splitting]. The traditional approach for surface attachment to transparent conductive oxides [e.g., fluorine doped tin oxide (FTO)] is via synthetic modification of the ligand architecture to incorporate functional groups such as carboxylic acids (-COOH) or phosphonates (-PO3H2) prior to immobilization. However, challenges arising from desorption and the cumbersome derivatizations steps have limited the scope and applications of surface-bound WOCs. Herein, we report the successful immobilization of underivatized Ru(II)-based WOCs (Ru-Cat1 = [Ru(tpy) (bpy) (H2O)]2+ (tpy = 2,2':6'2″-terpyridine and bpy = 2,2'-bipyridine) and Ru-Cat2 = [Ru(Mebimpy) (bpy) (H2O)]2+ (Mebimpy = 2,6-bis(1-methylbenzimidazol-2-yl) pyridine)) and the Ru(II) polypyridyl chromophore Ru-C3 = [Ru(bpy)3]2+ onto a FTO plasma-grafted poly(acrylic acid) surface (PAA|FTO). Various characterization techniques such as attenuated total reflectance Fourier transform infrared spectroscopy, scanning electron microscopy, atomic force microscopy, and cyclic voltammetry measurements provide evidence for the plasma-induced grafted PAA|FTO film and immobilization. Surface stability and electrocatalytic properties of these new hybrid composite films upon cycling were investigated at different pH values. Immobilized Ru-Cat1 and Ru-Cat2 onto PAA|FTO displayed pH-dependent (RuIII/RuII) couples and onset potentials indicative of PCET (proton-coupled electron transfer) reactions. Based on cyclic voltammetry results and spectroscopic monitoring, the immobilized WOCs Ru-Cat1 and Ru-Cat2 exhibited a higher surface stability in neutral aqueous solutions relative to Ru-C3 upon electrochemical oxidation. We attribute the surface PCET and stability to the presence of a water ligand in the coordination sphere of immobilized Ru-Cat1 and Ru-Cat2 which can H-bond with negatively charged carboxylate groups of the cross-linked PAA brushes. Our findings demonstrate that the plasma-grafted polymeric network onto FTO offers a versatile platform to directly anchor unmodified homogeneous WOCs or chromophores for potential applications in solar-to-fuel energy conversion.

Hippocampal monoamine changes in the Flinders sensitive line rat: A case for the possible use of selective α2C-AR-antagonists in stress and anxiety disorders in companion animals.

Non-selective α2-adrenoreceptor (AR) stimulation delivers favourable sedative, analgesic, muscle relaxant and anxiolytic actions in companion animals, but is associated with cardiovascular and respiratory side effects. Anxiety conditions underscore monoamine disturbances amenable to α2-AR modulation. We investigated sub-chronic (14 day s.c.) treatment with the selective α2C-AR antagonist, ORM-10921 (0.03, 0.1, 0.3 mg/kg/d) on hippocampal noradrenaline (NA), dopamine (DA), serotonin (5-HT) and their turnover levels in stress sensitive Flinders Sensitive Line (FSL) rats versus Flinders Resistant Line (FRL) controls, using high performance liquid chromatography. The effects of ORM-10921 were compared to the non-selective α2-AR antagonist, idazoxan (IDAZ; 3 mg/kg/d), and to imipramine (IMI; 15 mg/kg/d), a reference antidepressant in this model. FSL rats displayed significantly reduced 5-HT (p = 0.03) and DA (p = 0.02) levels vs. FRL controls, while NA levels showed a similar trend. ORM-10921 significantly increased NA (all doses p ≤ 0.02), 5-HT (0.1 and 0.3 mg/kg p ≤ 0.03) and DA levels (all doses p ≤ 0.03), which correlated with decreased monoamine turnover. In contrast, IDAZ significantly elevated NA (p < 0.005) and DA (p < 0.004) but not 5-HT levels. IMI also significantly increased 5-HT (p < 0.009), with a tendency to increase NA (p = 0.09) but not DA. ORM-10921 exerts similar albeit broader effects on hippocampal monoamines than IDAZ, explaining earlier established efficacy associated with α2C-AR antagonism in animal models of depression and cognitive dysfunction. These and the current studies encourage application of ORM-10921 in depression in humans, as well as raise the intriguing possibility that selective α2C-AR antagonists may be beneficial in anxiety and stress-related disorders in companion animals. Both warrant further study.

Application of the PET ligand [11C]ORM-13070 to examine receptor occupancy by the α2C-adrenoceptor antagonist ORM-12741: translational validation of target engagement in rat and human brain.

BACKGROUND: Availability of the α2C-adrenoceptor (α2C-AR) positron emission tomography (PET) tracer, [11C]ORM-13070, and the α2C-AR antagonist ORM-12741 allows probing of the roles of this G-protein coupled receptor subtype in brain function, both in healthy humans and in patients with various brain disorders. This translational study employed [11C]ORM-13070 autoradiography and PET to determine α2C-AR occupancy by ORM-12741 in rat and human brain, respectively. RESULTS: ORM-12741 has high affinity (Ki: 0.08 nM) and potent antagonist activity (Kb: 0.04 nM) as well as selectivity (Ki estimates for the human α2A-AR and α2B-AR were 8.3 nM and 0.8 nM, respectively) for the human α2C-AR subtype. [11C]ORM-13070 had highest uptake in the basal ganglia of rat and human brain. Pretreatment with ORM-12741 inhibited [11C]ORM-13070 binding in rat striatum in a time- and dose-dependent manner at 10 and 50 µg/kg (s.c.) with an EC50 estimate of 1.42 ng/mL in rat plasma, corresponding to protein-free drug concentration of 0.23 nM. In the living human brain, time- and dose-related α2C-AR occupancy was detected with EC50 estimates of 24 ng/mL and 31 ng/mL for the caudate nucleus and putamen, respectively, corresponding to protein-free concentrations in plasma of 0.07 nM and 0.1 nM. Modelling-based maximum α2C-AR occupancy estimates were 63% and 52% in the caudate nucleus and the putamen, respectively. CONCLUSIONS: ORM-12741 is a selective α2C-AR antagonist which penetrates the rat and human brain to occupy α2C-ARs in a manner consistent with its receptor pharmacology. Trial registration number and date of registration: ClinicalTrial.cov NCT00829907. Registered 11 December 2008. https://clinicaltrials.gov/ .

Barley yield formation under abiotic stress depends on the interplay between flowering time genes and environmental cues.

Since the dawn of agriculture, crop yield has always been impaired through abiotic stresses. In a field trial across five locations worldwide, we tested three abiotic stresses, nitrogen deficiency, drought and salinity, using HEB-YIELD, a selected subset of the wild barley nested association mapping population HEB-25. We show that barley flowering time genes Ppd-H1, Sdw1, Vrn-H1 and Vrn-H3 exert pleiotropic effects on plant development and grain yield. Under field conditions, these effects are strongly influenced by environmental cues like day length and temperature. For example, in Al-Karak, Jordan, the day length-sensitive wild barley allele of Ppd-H1 was associated with an increase of grain yield by up to 30% compared to the insensitive elite barley allele. The observed yield increase is accompanied by pleiotropic effects of Ppd-H1 resulting in shorter life cycle, extended grain filling period and increased grain size. Our study indicates that the adequate timing of plant development is crucial to maximize yield formation under harsh environmental conditions. We provide evidence that wild barley alleles, introgressed into elite barley cultivars, can be utilized to support grain yield formation. The presented knowledge may be transferred to related crop species like wheat and rice securing the rising global food demand for cereals.

The Genome Sequence of the Wild Tomato Solanum pimpinellifolium Provides Insights Into Salinity Tolerance.

Solanum pimpinellifolium, a wild relative of cultivated tomato, offers a wealth of breeding potential for desirable traits such as tolerance to abiotic and biotic stresses. Here, we report the genome assembly and annotation of S. pimpinellifolium 'LA0480.' Moreover, we present phenotypic data from one field experiment that demonstrate a greater salinity tolerance for fruit- and yield-related traits in S. pimpinellifolium compared with cultivated tomato. The 'LA0480' genome assembly size (811 Mb) and the number of annotated genes (25,970) are within the range observed for other sequenced tomato species. We developed and utilized the Dragon Eukaryotic Analyses Platform (DEAP) to functionally annotate the 'LA0480' protein-coding genes. Additionally, we used DEAP to compare protein function between S. pimpinellifolium and cultivated tomato. Our data suggest enrichment in genes involved in biotic and abiotic stress responses. To understand the genomic basis for these differences in S. pimpinellifolium and S. lycopersicum, we analyzed 15 genes that have previously been shown to mediate salinity tolerance in plants. We show that S. pimpinellifolium has a higher copy number of the inositol-3-phosphate synthase and phosphatase genes, which are both key enzymes in the production of inositol and its derivatives. Moreover, our analysis indicates that changes occurring in the inositol phosphate pathway may contribute to the observed higher salinity tolerance in 'LA0480.' Altogether, our work provides essential resources to understand and unlock the genetic and breeding potential of S. pimpinellifolium, and to discover the genomic basis underlying its environmental robustness.

Biochemical and Functional Characterization of the Trace Amine-Associated Receptor 1 (TAAR1) Agonist RO5263397.

Trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor, which signals through elevating intracellular cAMP levels, and expressed in most vertebrates, including rodents and humans. In recent years, several lines of evidence indicated the role of TAAR1 in the regulation of dopaminergic system and its importance in physiological processes such as locomotion, control of emotional states and cognition. In our study, we used RO5263397, a selective TAAR1 agonist, as a tool and characterized its pharmacology in vitro in HEK293 cells and its effects in vivo in tests assessing potential antidepressant and antipsychotic actions. We found that RO5263397 not only increases cAMP levels at very low concentrations but also can induce the phosphorylation of ERK and CREB in a concentration- and time-dependent manner. Like other TAAR1 agonists, RO5263397 potently suppressed high dopamine-dependent hyperactivity in mice lacking the dopamine transporter. Moreover, RO5263397 produced a strong antidepressant-like effect in the forced swim test comparable to fluoxetine. Furthermore, the antidepressant-like activity was blocked by pretreatment with SCH23390 (dopamine D1 receptor antagonist) or NBQX (glutamate AMPA receptor antagonist) but only in part by WAY100635 (serotonin 5HT1A receptor antagonist). In conclusion, our study confirms some previous in vitro and in vivo findings in relation to the pharmacological effects of RO5263397 but more importantly provides new insight on intracellular signaling pathway and other neurotransmitter receptors modulated by TAAR1 receptor activation.

Evaluation of magnesium levels in blood and saliva of oral squamous cell carcinoma and potentially malignant disorders by xylidyl blue method.

BACKGROUND: Cancer is Latinized from Greek word 'karkinos' meaning crab, denoting how carcinoma extends its claws like a crab into adjacent tissues. It has been well established by researchers that virtually all oral cancer are preceded by visible clinical changes in the oral mucosa usually in the form of white or red patch (two-step process of cancer development). Mg is an essential mineral that is needed for a broad variety of physiological functions. Imbalances in Mg metabolism are common and are associated with different pathological conditions. The purpose of this study was to evaluate and compare the magnesium concentration in blood serum and saliva of oral squamous cell carcinoma, potentially malignant disorders and healthy subjects to serve as a positive marker or indicator in the process of carcinogenesis. MATERIALS AND METHODS: The study includes 17 precancerous (OSMF + Leukoplakia) patients, 17 OSCC and 17 control group. Blood and saliva was collected; serum and saliva was extracted from both the groups and was biochemically evaluated for magnesium levels. Statistical analysis was performed using ANOVA. RESULTS: The Salivary magnesium Mean ± SD of Healthy group is higher 1.6681 ± 0.0207 mmol mg/l followed by Potentially Malignant Disorder group 1.5532 ± 0.0283 and Oral Squamous Cell Carcinoma 0.5979 ± 0.0659. The mean values differ significantly between 3 groups (P < 0.001) The Serum magnesium Mean ± SD of Healthy group is higher 1.9188 ± 0.0550 mmol mg/l followed by Potentially Malignant Disorder group 1.6951 ± 0.0949 and Oral Squamous Cell Carcinoma 0.7329 ± 0.1561. The mean values differ significantly between 3 groups (P < 0.001) The study revealed decreased serum and salivary magnesium in oral precancerous patients and an Oral Squamous cell carcinoma patients compared to healthy individuals. CONCLUSION: The magnesium concentration was low in both blood plasma and saliva of oral squamous cell carcinoma as compared to potentially malignant disorders and healthy subjects. Thus the magnesium ion concentration in blood plasma and saliva could be considerd as tumor marker, playing an important role in carcinogenesis.

Therapeutic Potential of Selectively Targeting the α2C-Adrenoceptor in Cognition, Depression, and Schizophrenia-New Developments and Future Perspective.

α2A- and α2C-adrenoceptors (ARs) are the primary α2-AR subtypes involved in central nervous system (CNS) function. These receptors are implicated in the pathophysiology of psychiatric illness, particularly those associated with affective, psychotic, and cognitive symptoms. Indeed, non-selective α2-AR blockade is proposed to contribute toward antidepressant (e.g., mirtazapine) and atypical antipsychotic (e.g., clozapine) drug action. Both α2C- and α2A-AR share autoreceptor functions to exert negative feedback control on noradrenaline (NA) release, with α2C-AR heteroreceptors regulating non-noradrenergic transmission (e.g., serotonin, dopamine). While the α2A-AR is widely distributed throughout the CNS, α2C-AR expression is more restricted, suggesting the possibility of significant differences in how these two receptor subtypes modulate regional neurotransmission. However, the α2C-AR plays a more prominent role during states of low endogenous NA activity, while the α2A-AR is relatively more engaged during states of high noradrenergic tone. Although augmentation of conventional antidepressant and antipsychotic therapy with non-selective α2-AR antagonists may improve therapeutic outcome, animal studies report distinct yet often opposing roles for the α2A- and α2C-ARs on behavioral markers of mood and cognition, implying that non-selective α2-AR antagonism may compromise therapeutic utility both in terms of efficacy and side-effect liability. Recently, several highly selective α2C-AR antagonists have been identified that have allowed deeper investigation into the function and utility of the α2C-AR. ORM-13070 is a useful positron emission tomography ligand, ORM-10921 has demonstrated antipsychotic, antidepressant, and pro-cognitive actions in animals, while ORM-12741 is in clinical development for the treatment of cognitive dysfunction and neuropsychiatric symptoms in Alzheimer's disease. This review will emphasize the importance and relevance of the α2C-AR as a neuropsychiatric drug target in major depression, schizophrenia, and associated cognitive deficits. In addition, we will present new prospects and future directions of investigation.

Pharmacology of human trace amine-associated receptors: Therapeutic opportunities and challenges.

The discovery in 2001 of a G protein-coupled receptor family, subsequently termed trace amine-associated receptors (TAAR), triggered a resurgence of interest in so-called trace amines. Initial optimism quickly faded, however, as the TAAR family presented a series of challenges preventing the use of standard medicinal chemistry and pharmacology technologies. Consequently the development of basic tools for probing TAAR and translating findings from model systems to humans has been problematic. Despite these challenges the last 5years have seen considerable advances, in particular with respect to TAAR1, which appears to function as an endogenous rheostat, maintaining central neurotransmission within defined physiological limits, in part through receptor heterodimerization yielding biased signaling outputs. Regulation of the dopaminergic system is particularly well understood and clinical testing of TAAR1 directed ligands for schizophrenia and psychiatric disorders have begun. In addition, pre-clinical animal models have identified TAAR1 as a novel target for drug addiction and metabolic disorders. Growing evidence also suggests a role for TAARs in regulating immune function. This review critically discusses the current state of TAAR research, highlighting recent developments and focussing on human TAARs, their functions, and clinical implications. Current gaps in knowledge are identified, along with the research reagents and translational tools still required for continued advancement of the field. Through this, a picture emerges of an exciting field on the cusp of significant developments, with the potential to identify new therapeutic leads for some of the major unmet medical needs in the areas of neuropsychiatry and metabolic disorders.