Potential anti-inflammatory role of activin A in acute coronary syndromes

AbstractObjectivesWe sought to investigate whether activin A could be involved in the immunopathogenesis of acute coronary syndromes.BackgroundInflammatory mechanisms seem to play a pathogenic role in atherosclerosis and acute coronary syndromes, but the actual mediators have not been fully identified. Activin A, a pleiotropic member of the transforming growth factor-beta cytokine family, has recently been suggested to play a role in inflammation.MethodsWe examined the role of activin A and its endogenous inhibitor follistatin in patients with stable (n = 26) and unstable angina (n = 20) and healthy control subjects (n = 20) by different experimental approaches.Results1) Patients with stable angina had raised activin A concentrations, as assessed by protein levels in serum and messenger ribonucleic acid levels in peripheral blood mononuclear cells (PBMCs). 2) Although several activin A–related mediators were upregulated in PBMCs from patients with stable angina compared with controls (i.e., activin A and Smad3), no changes or even downregulation (i.e., Smad2) were seen in unstable disease. 3) The activin type II receptors, representing the primary ligand-binding proteins, were downregulated in unstable compared with stable angina. 4) Percutaneous coronary intervention induced a decrease in the activin A/follistatin ratio, suggesting downregulatory effects on activin A activity. 5) Although activin A dose-dependently suppressed the release of inflammatory cytokines from PBMCs in angina patients, an opposite effect was found in healthy controls.ConclusionsOur findings suggest an anti-inflammatory potential of activin A in angina patients, and such effects may be of particular relevance in unstable angina in which several of the activin parameters were downregulated

The barley pan-genome reveals the hidden legacy of mutation breeding

Genetic diversity is key to crop improvement. Owing to pervasive genomic structural variation, a single reference genome assembly cannot capture the full complement of sequence diversity of a crop species (known as the ‘pan-genome’1). Multiple high-quality sequence assemblies are an indispensable component of a pan-genome infrastructure. Barley (Hordeum vulgare L.) is an important cereal crop with a long history of cultivation that is adapted to a wide range of agro-climatic conditions2. Here we report the construction of chromosome-scale sequence assemblies for the genotypes of 20 varieties of barley—comprising landraces, cultivars and a wild barley—that were selected as representatives of global barley diversity. We catalogued genomic presence/absence variants and explored the use of structural variants for quantitative genetic analysis through whole-genome shotgun sequencing of 300 gene bank accessions. We discovered abundant large inversion polymorphisms and analysed in detail two inversions that are frequently found in current elite barley germplasm; one is probably the product of mutation breeding and the other is tightly linked to a locus that is involved in the expansion of geographical range. This first-generation barley pan-genome makes previously hidden genetic variation accessible to genetic studies and breeding

Genetic Evidence for Involvement of Neuronally Expressed S1P1 Receptor in Nociceptor Sensitization and Inflammatory Pain

Sphingosine-1-phosphate (S1P) is a key regulator of immune response. Immune cells, epithelia and blood cells generate high levels of S1P in inflamed tissue. However, it is not known if S1P acts on the endings of nociceptive neurons, thereby contributing to the generation of inflammatory pain. We found that the S1P1 receptor for S1P is expressed in subpopulations of sensory neurons including nociceptors. Both S1P and agonists at the S1P1 receptor induced hypersensitivity to noxious thermal stimulation in vitro and in vivo. S1P-induced hypersensitivity was strongly attenuated in mice lacking TRPV1 channels. S1P and inflammation-induced hypersensitivity was significantly reduced in mice with a conditional nociceptor-specific deletion of the S1P1 receptor. Our data show that neuronally expressed S1P1 receptors play a significant role in regulating nociceptor function and that S1P/S1P1 signaling may be a key player in the onset of thermal hypersensitivity and hyperalgesia associated with inflammation

Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits

The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located nearNEDD4LandSLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (R(g)ranging from 0.11 to 0.76, P-values Author summary Although twin studies have shown that body mass index (BMI) is highly heritable, many common genetic variants involved in the development of BMI have not yet been identified, especially in children. We studied associations of more than 40 million genetic variants with childhood BMI in 61,111 children aged between 2 and 10 years. We identified 25 genetic variants that were associated with childhood BMI. Two of these have not been implicated for BMI previously, located close to the genesNEDD4LandSLC45A3. We also show that the genetic background of childhood BMI overlaps with that of birth weight, adult BMI, waist-to-hip-ratio, diastolic blood pressure, type 2 diabetes, and age at menarche. Our results suggest that the biological processes underlying childhood BMI largely overlap with those underlying adult BMI. However, the overlap is not complete. Additionally, the genetic backgrounds of childhood BMI and other cardio-metabolic phenotypes are overlapping. This may mean that the associations of childhood BMI and later cardio-metabolic outcomes are partially explained by shared genetics, but it could also be explained by the strong association of childhood BMI with adult BMI.Peer reviewe

Discovery of novel neutral glycosphingolipids in cereal crops: rapid profiling using reversed-phased HPLC–ESI–QqTOF with parallel reaction monitoring

Abstract This study explores the sphingolipid class of oligohexosylceramides (OHCs), a rarely studied group, in barley (Hordeum vulgare L.) through a new lipidomics approach. Profiling identified 45 OHCs in barley (Hordeum vulgare L.), elucidating their fatty acid (FA), long-chain base (LCB) and sugar residue compositions; and was accomplished by monophasic extraction followed by reverse-phased high performance liquid chromatography electrospray ionisation quadrupole-time-of-flight tandem mass spectrometry (HPLC–ESI–QqTOF–MS/MS) employing parallel reaction monitoring (PRM). Results revealed unknown ceramide species and highlighted distinctive FA and LCB compositions when compared to other sphingolipid classes. Structurally, the OHCs featured predominantly trihydroxy LCBs associated with hydroxylated FAs and oligohexosyl residues consisting of two–five glucose units in a linear 1 → 4 linkage. A survey found OHCs in tissues of major cereal crops while noting their absence in conventional dicot model plants. This study found salinity stress had only minor effects on the OHC profile in barley roots, leaving questions about their precise functions in plant biology unanswered

Modulation of mTOR Signalling Triggers the Formation of Stem Cell-like Memory T Cells

Robust, long-lasting immune responses are elicited by memory T cells that possess properties of stem cells, enabling them to persist long-term and to permanently replenish the effector pools. Thus, stem cell-like memory T (TSCM) cells are of key therapeutic value and efforts are underway to characterize TSCM cells and to identify means for their targeted induction. Here, we show that inhibition of mechanistic/mammalian Target of Rapamycin (mTOR) complex 1 (mTORC1) by rapamycin or the Wnt-β-catenin signalling activator TWS119 in activated human naive T cells leads to the induction of TSCM cells. We show that these compounds switch T cell metabolism to fatty acid oxidation as favoured metabolic programme for TSCM cell generation. Of note, pharmacologically induced TSCM cells possess superior functional features as a long-term repopulation capacity after adoptive transfer. Furthermore, we provide insights into the transcriptome of TSCM cells. Our data identify a mechanism of pharmacological mTORC1 inhibitors, allowing us to confer stemness to human naive T cells which may be significantly relevant for the design of innovative T cell-based cancer immunotherapies

Randomized controlled clinical trial on the efficacy of a novel antimicrobial chewing gum in reducing plaque and gingivitis in adolescent orthodontic patients

Objectives Chewing gums containing antiseptics or other antimicrobial substances may be effective in reducing plaque and gingivitis. Therefore, the aim of this randomized placebo-controlled clinical trial was to investigate the efficacy of a novel antimicrobial chewing gum containing essential oils (cinnamon, lemon, peppermint) and extracts on reduction of dental plaque and gingivitis as well as on oral health-related quality of life (OHRQoL) in adolescent orthodontic patients. Materials 52 patients (11-22 years of age) were randomly assigned to use a test chewing gum (COVIDGUM, Clevergum) or a commercially available control chewing gum over a period of 10 days. Approximal plaque index (API), papillary bleeding index (PBI) and an OHRQoL questionnaire for children (COHIP-G19) were assessed at baseline (BL), after 10 days (10d) and 30 days (30d). In addition, oral health and oral hygiene related questions of the COHIP-G19 questionnaire were evaluated separately in subscales at each timepoint. Data were analyzed using non-parametrical statistical procedures (α = 0.05). Results API and PBI decreased significantly over time from BL to 10d and from BL to 30d in both groups, without significant differences between the groups. In both groups, the COHIP-G19 score, oral health subscale and oral hygiene subscale decreased significantly over time. Regarding the oral hygiene subscale, the test group showed significantly better scores at 30d (p = 0.011). Conclusion Both chewing gums performed similarly effective in terms of reducing plaque accumulation and gingival inflammation and improving OHRQoL. Clinical relevance Chewing gums without antimicrobial ingredients may be sufficient to decrease plaque accumulation and gingival inflammation