New approximations for the cone of copositive matrices and its dual

We provide convergent hierarchies for the cone C of copositive matrices and its dual, the cone of completely positive matrices. In both cases the corresponding hierarchy consists of nested spectrahedra and provide outer (resp. inner) approximations for C (resp. for its dual), thus complementing previous inner (resp. outer) approximations for C (for the dual). In particular, both inner and outer approximations have a very simple interpretation. Finally, extension to K-copositivity and K-complete positivity for a closed convex cone K, is straightforward.Comment: 8

ACTH-Bestimmungen im Plasma aus dem Bulbus cranialis venae jugularis

Der Anstieg der Corticosteroninkretion in das Nebennierenvenenblut frisch hypophysektomierter Ratten diente zur Bestimmung von ACTH-Spiegeln in 1 ml nativen, menschlichen Plasma. Normale ACTH-Plasmaspiegel sind sowohl bei Punktion der Vena cubitalis als auch des Bulbus cranialis venae jugularis durch diese Methode nicht oder nur ungenau zu erfassen. Bei Patienten mit pathologisch erhöhten ACTH-Spiegeln in der Vena cubitalis sind die ACTH-Spiegel im Bulbus cranialis venae jugularis signifikant höher. Es ließ sich eine Beziehung zwischen ACTH-Spiegel in der Peripherie (Vena cubitalis), Differenz der ACTH-Spiegel zwischen Bulbus cranialis venae jugularis und Vena cubitalis und biologischer Halbwertszeit von endogenem ACTH aufstellen. Nach den Ergebnissen der Bestimmung von ACTH-Spiegeln bei Nebennierengesunden läßt sich folgern, daß die biologische Halbwertszeit von endogenem ACTH größer als 4 min sein muß. Bei Patienten mit erhöhten ACTH-Spiegeln ließ sich die biologische Halbwertszeit von endogenem ACTH größenordnungsmäßig mit ca. 40 min berechnen. Bei diesen Patienten betrug die mittlere tägliche ACTH-Inkretion ca. 100 E.ACTH-contents of 1 ml specimens of human plasma were assayed by measurement of increases of corticosterone output in the adrenal vein of acutely hypophysectomized rats. This procedure is not sensitive enough to measure normal ACTH-levels acurately, neither when blood was drawn from the bulbus cranialis venae jugularis, nor from the vena cubitalis. In patients having pathologically elevated ACTH-levels, the ACTH-content of plasma is significantly higher in the bulbus cranialis venae jugularis than in peripheral venous blood. An equation is presented formulating the relation of peripheral ACTH-levels, differences of ACTH-levels between bulbus cranialis venae jugularis and vena cubitalis, and of the biological halflife of endogenous ACTH. On the basis of the results of the determinations of socalled normal ACTH-levels it can be concluded, that the biological halflife of endogenous ACTH is longer than 4 min. From the data of patients with elevated ACTH-levels a halflife of approximately 40 min and a mean ACTH-secretion of approx. 100 units per day could be calculated

Genes controlling vaccine responses and disease resistance to respiratory viral pathogens in cattle

AbstractFarm animals remain at risk of endemic, exotic and newly emerging viruses. Vaccination is often promoted as the best possible solution, and yet for many pathogens, either there are no appropriate vaccines or those that are available are far from ideal. A complementary approach to disease control may be to identify genes and chromosomal regions that underlie genetic variation in disease resistance and response to vaccination. However, identification of the causal polymorphisms is not straightforward as it generally requires large numbers of animals with linked phenotypes and genotypes. Investigation of genes underlying complex traits such as resistance or response to viral pathogens requires several genetic approaches including candidate genes deduced from knowledge about the cellular pathways leading to protection or pathology, or unbiased whole genome scans using markers spread across the genome.Evidence for host genetic variation exists for a number of viral diseases in cattle including bovine respiratory disease and anecdotally, foot and mouth disease virus (FMDV). We immunised and vaccinated a cattle cross herd with a 40-mer peptide derived from FMDV and a vaccine against bovine respiratory syncytial virus (BRSV). Genetic variation has been quantified. A candidate gene approach has grouped high and low antibody and T cell responders by common motifs in the peptide binding pockets of the bovine major histocompatibility complex (BoLA) DRB3 gene. This suggests that vaccines with a minimal number of epitopes that are recognised by most cattle could be designed. Whole genome scans using microsatellite and single nucleotide polymorphism (SNP) markers has revealed many novel quantitative trait loci (QTL) and SNP markers controlling both humoral and cell-mediated immunity, some of which are in genes of known immunological relevance including the toll-like receptors (TLRs).The sequencing, assembly and annotation of livestock genomes and is continuing apace. In addition, provision of high-density SNP chips should make it possible to link phenotypes with genotypes in field populations without the need for structured populations or pedigree information. This will hopefully enable fine mapping of QTL and ultimate identification of the causal gene(s). The research could lead to selection of animals that are more resistant to disease and new ways to improve vaccine efficacy

MHC Class I Bound to an Immunodominant Theileria parva Epitope Demonstrates Unconventional Presentation to T Cell Receptors

T cell receptor (TCR) recognition of peptide-MHC class I (pMHC) complexes is a crucial event in the adaptive immune response to pathogens. Peptide epitopes often display a strong dominance hierarchy, resulting in focusing of the response on a limited number of the most dominant epitopes. Such T cell responses may be additionally restricted by particular MHC alleles in preference to others. We have studied this poorly understood phenomenon using Theileria parva, a protozoan parasite that causes an often fatal lymphoproliferative disease in cattle. Despite its antigenic complexity, CD8+ T cell responses induced by infection with the parasite show profound immunodominance, as exemplified by the Tp1214–224 epitope presented by the common and functionally important MHC class I allele N*01301. We present a high-resolution crystal structure of this pMHC complex, demonstrating that the peptide is presented in a distinctive raised conformation. Functional studies using CD8+ T cell clones show that this impacts significantly on TCR recognition. The unconventional structure is generated by a hydrophobic ridge within the MHC peptide binding groove, found in a set of cattle MHC alleles. Extremely rare in all other species, this feature is seen in a small group of mouse MHC class I molecules. The data generated in this analysis contribute to our understanding of the structural basis for T cell-dependent immune responses, providing insight into what determines a highly immunogenic p-MHC complex, and hence can be of value in prediction of antigenic epitopes and vaccine design

The role of sex in the pathophysiology of pulmonary hypertension

Pulmonary arterial hypertension (PAH) is a progressive disease characterised by increased pulmonary vascular resistance and pulmonary artery remodelling as result of increased vascular tone and vascular cell proliferation, respectively. Eventually, this leads to right heart failure. Heritable PAH is caused by a mutation in the bone morphogenetic protein receptor-II (BMPR-II). Female susceptibility to PAH has been known for some time, and most recent figures show a female-to-male ratio of 4:1. Variations in the female sex hormone estrogen and estrogen metabolism modify FPAH risk, and penetrance of the disease in BMPR-II mutation carriers is increased in females. Several lines of evidence point towards estrogen being pathogenic in the pulmonary circulation, and thus increasing the risk of females developing PAH. Recent studies have also suggested that estrogen metabolism may be crucial in the development and progression of PAH with studies indicating that downstream metabolites such as 16α-hydroxyestrone are upregulated in several forms of experimental pulmonary hypertension (PH) and can cause pulmonary artery smooth muscle cell proliferation and subsequent vascular remodelling. Conversely, other estrogen metabolites such as 2-methoxyestradiol have been shown to be protective in the context of PAH. Estrogen may also upregulate the signalling pathways of other key mediators of PAH such as serotonin

A short history of the 5-HT2C receptor: from the choroid plexus to depression, obesity and addiction treatment

This paper is a personal account on the discovery and characterization of the 5-HT2C receptor (first known as the 5- HT1C receptor) over 30 years ago and how it translated into a number of unsuspected features for a G protein-coupled receptor (GPCR) and a diversity of clinical applications. The 5-HT2C receptor is one of the most intriguing members of the GPCR superfamily. Initially referred to as 5-HT1CR, the 5-HT2CR was discovered while studying the pharmacological features and the distribution of [3H]mesulergine-labelled sites, primarily in the brain using radioligand binding and slice autoradiography. Mesulergine (SDZ CU-085), was, at the time, best defined as a ligand with serotonergic and dopaminergic properties. Autoradiographic studies showed remarkably strong [3H]mesulergine-labelling to the rat choroid plexus. [3H]mesulergine-labelled sites had pharmacological properties different from, at the time, known or purported 5-HT receptors. In spite of similarities with 5-HT2 binding, the new binding site was called 5-HT1C because of its very high affinity for 5-HT itself. Within the following 10 years, the 5-HT1CR (later named 5- HT2C) was extensively characterised pharmacologically, anatomically and functionally: it was one of the first 5-HT receptors to be sequenced and cloned. The 5-HT2CR is a GPCR, with a very complex gene structure. It constitutes a rarity in theGPCR family: many 5-HT2CR variants exist, especially in humans, due to RNA editing, in addition to a few 5-HT2CR splice variants. Intense research led to therapeutically active 5-HT2C receptor ligands, both antagonists (or inverse agonists) and agonists: keeping in mind that a number of antidepressants and antipsychotics are 5- HT2CR antagonists/inverse agonists. Agomelatine, a 5-HT2CR antagonist is registered for the treatment of major depression. The agonist Lorcaserin is registered for the treatment of aspects of obesity and has further potential in addiction, especially nicotine/ smoking. There is good evidence that the 5-HT2CR is involved in spinal cord injury-induced spasms of the lower limbs, which can be treated with 5-HT2CR antagonists/inverse agonists such as cyproheptadine or SB206553. The 5-HT2CR may play a role in schizophrenia and epilepsy. Vabicaserin, a 5-HT2CR agonist has been in development for the treatment of schizophrenia and obesity, but was stopped. As is common, there is potential for further indications for 5-HT2CR ligands, as suggested by a number of preclinical and/or genome-wide association studies (GWAS) on depression, suicide, sexual dysfunction, addictions and obesity. The 5-HT2CR is clearly affected by a number of established antidepressants/antipsychotics and may be one of the culprits in antipsychotic-induced weight gain

The impact of upper-limb position on estimated central blood pressure waveforms

Pulse wave analysis (PWA) utilizes arm blood pressure (BP) waveforms to estimate aortic waveforms. The accuracy of central BP waveform estimation may be influenced by assessment site local haemodynamics. This study investigated whether local haemodynamic changes, induced via arm tilting ±30° relative to heart level, affect estimated central systolic BP (cSBP) and arterial wave reflection (central augmentation index, cAIx; aortic backward pressure wave, Pb). In 20 healthy adults (26.7 years [SD 5.2], 10 F) brachial BP waveforms were simultaneously recorded on experimental and control arms. The experimental arm was randomly repositioned three times (heart level, −30° heart level, +30° heart level), while the control arm remained fixed at heart level. For the experimental arm, arm repositioning resulted in a large (partial eta-squared &gt; 0.14) effect size (ES) change in SBP (ES = 0.75, P &lt; 0.001), cSBP (ES = 0.81, P &lt; 0.001), and cAIx (ES = 0.75, P = 0.002), but not Pb (ES = 0.06, P = 0.38). In the control arm, cAIx (ES = 0.22, P = 0.013) but not SBP or cSBP significantly changed. Change in experimental arm cSBP was partially explained by brachial systolic blood velocity (P = 0.026) and mean diameter (P = 0.012), while change in cAIx was associated with brachial retrograde blood velocity (P = 0.020) and beta stiffness (P = 0.038). In conclusion, manipulation of assessment site local haemodynamics, including the blood velocity profile and local arterial stiffness, had a large effect on estimated cSBP and cAIx, but not on Pb. These findings do not invalidate PWA devices but do suggest that the accuracy of the estimated aortic pressure waveform is dependent on stable peripheral haemodynamics.</p