Inversion of Parahermitian matrices

Parahermitian matrices arise in broadband multiple-input multiple-output (MIMO) systems or array processing, and require inversion in some instances. In this paper, we apply a polynomial eigenvalue decomposition obtained by the sequential best rotation algorithm to decompose a parahermitian matrix into a product of two paraunitary, i.e.lossless and easily invertible matrices, and a diagonal polynomial matrix. The inversion of the overall parahermitian matrix therefore reduces to the inversion of auto-correlation sequences in this diagonal matrix. We investigate a number of different approaches to obtain this inversion, and and assessment of the numerical stability and complexity of the inversion process

Probing the GnRH receptor agonist binding site identifies methylated triptorelin as a new anti-proliferative agent

D-amino acid substitutions at Glycine postion-6 in GnRH-I decapeptide can possess super-agonist activity and enhanced in vivo pharmacokinetics. Agonists elicit growth-inhibition in tumorigenic cells expressing the GnRH receptor above threshold levels. However, new agonists with modified properties are required to improve the anti-proliferative range. Effects of residue substitutions and methylations on tumourigenic HEK293[SCL60] and WPE-1-NB26-3 prostate cells expressing the rat GnRH receptor were compared. Peptides were ranked according to receptor binding affinity, induction of inositol phosphate production and cell growth-inhibition. Analogues possessing D-Trp6 (including Triptorelin), D-Leu6 (including Leuprolide), D-Ala6, D-Lys6, or D-Arg6 exhibited agonist and anti-proliferative activity. Residues His5 or His5,Trp7,Tyr8, corresponding to residues found in GnRH-II , were tolerated, with retention of sub-nanomolar/low nanomolar binding affinities and EC50s for receptor activation and IC50s for cell growth-inhibition. His5D-Arg6-GnRH-I exhibited reduced binding affinity and potency, effective in the mid-nanomolar range. However, all GnRH-II-like analogues were less potent than Triptorelin. By comparison, three methylated-Trp6 Triptorelin variants showed differential binding, receptor activation and anti-proliferation potency. Significantly, 5-Methyl-DL-Trp6-Triptorelin was equipotent to triptorelin. Subsequent studies should determine whether pharmacologically enhanced derivatives of Triptorelin can be developed by further alkylations, without substitutions or cleavable cytotoxic adducts, to improve the extent of growth-inhibition of tumour cells expressing the GnRH receptor

Training based channel estimation algorithms for dual hop MIMO OFDM relay systems

In this paper we consider minimum mean square error (MMSE) training based channel estimation for two-hop multiple-input multiple-output (MIMO) orthogonal frequency division multiplexing (OFDM) relaying systems. The channel estimation process is divided into two main phases. The relay-destination channel is estimated in the first phase and can be obtained using well known point-to-point MIMO OFDM estimation methods. In the second phase, the source-relay channel is estimated at the destination with the use of a known training sequence that is transmitted from the source and forwarded to the destination by a non-regenerative relay. To obtain an estimate of the source-relay channel, the source training sequence, relay precoder, and destination processor, require to be optimised. To solve this problem we derive an iterative algorithm that involves sequentially solving a number of convex optimisation problems to update the source, relay, and destination design variables. Since the iterative algorithm may be too computationally expensive for practical implementation we then derive simplified solutions that have reduced computational complexity. Simulation results demonstrate the effectiveness of the proposed algorithms

Identification of genuine/authentic avian leptin : some answers and more questions

The dogmatic adherence to “what is good for the goose is good for the gander” appears to pervade avian endocrinology research when it comes to vertebrate evolution of hormones and their physiological roles in birds. There appears to be a general acceptance that specific hormones, their cognate receptors, and their regulatory functions identified in other vertebrates should be present and serve the same function in birds. This has been largely the case for leptin (LEP) originally identified in mammals (1– 5), which has been vigorously sought for more than a decade in birds (6 –10), and also more recently for kisspeptin (11, 12). But should we expect to find the same hormones and functions in birds as occurs in other vertebrates? In order for early reptilian bird ancestors to take to the air, phenomenal evolutionary changes in their physiology were required and presumably drove changes in the use of existing hormones and cognate receptors, their modification, or their abandonment. Yet many scientists take the view that major physiological systems present in tetrapods and fish should be present in birds and serve the same function and use of the same hormone/receptor regulators.Grants from the National Research Foundation and Medical Research Council of South Africa, and the Universities of Pretoria and Cape Town.http://press.endocrine.org/journal/endoam201

Amygdala kisspeptin neurons: putative mediators of olfactory control of the gonadotropic axis

Kisspeptins and their receptors are potent regulators of the gonadotropic axis. Kisspeptin neurons are found mainly in the hypothalamic arcuate nucleus and the anteroventral periventricular nucleus. However, there is also a third population of kisspeptin neurons located in the amygdala. We used fluorescence immunohistochemistry to quantify and localize the amygdala kisspeptin neurons and to reveal close apposition and putative innervations by vasopressinergic and tyrosine hydroxylase positive dopaminergic neurons. Using microinjections of retro- and anterograde tracers, and viral transfection systems in rats and transgenic mice, we showed reciprocal connectivity between the accessory olfactory bulb and the amygdala kisspeptin neurons. In vitro recordings indicate an inhibitory action of kisspeptin on mitral cells in the accessory olfactory bulb. Using viral specific-cell gene expression in transgenic mice in combination with double immunofluorescence histochemistry we found that the amygdala kisspeptin neurons also project to gonadotropin-releasing hormone (GnRH) neurons in the preoptic area. Our neuroanatomical and electrophysiological data suggest that amygdala kisspeptin neurons integrate social behaviour and odour information to GnRH neurons in the preoptic area to coordinate the gonadotropic axis and the appropriate output behaviour to odour cues.A MRC grant (ML), the Newton International Fellowship program (RP - Ref. NF130516), the Royal Society and the British Academy and by the British Society for Neuroendocrinology (Project Support Grant).http://www.karger.com/Journal/Home/223855hb2016Mammal Research InstituteZoology and Entomolog

Contribution of growth hormone-releasing hormone and somatostatin to decreased growth hormone secretion in elderly men

Objective. The pathophysiology of the decline in circulating growth hormone (GH) concentrations that may occur with ageing remains elusive. We have investigated the potential contributions of decreased endogenous GH-releasing hormone (GHRH) and increased somatostatin secretion to this phenomenon.Design and methods. The strategy used was to stimulate GH secretion in 8 young (20 - 24 years old, body mass index (BMI) 22.8 ± 2.8 kg/m2) and 8 elderly (68- 82 years old, BMI 23.4 ± 1.6 kg/m2) male subjects on separate occasions by means of: (i) intravenous bolus 0.5 ).lg/kg D-Ala2 GHRH(1-29)-NH alone; (ii) 0.5 μg/kg GHRH after pretreatment with two oral doses of 50 mg atenolol (to inhibit somatostatin secretion); (iii) 1.25 mg oral bromocriptine alone (to increase endogenous GHRH and/or inhibit somatostatin); (iv) 50 mg oral atenolol plus 1.25 mg oral bromocriptine; and (v) 0.5 μg/kg GHRH after pre-treatment with 1.25 mg oral bromocriptine.Results. The elderly men had a significantly lower peak and area under curve (AUC) GH response to intravenous GHRH when compared with 8 young men (peak 3.1 ± 1.0 ng/ml v. 21.6 ± 5.0 ng/ ml, AUC 205 ±56 ng/ ml/min v.1 315 ± 295 ng/ ml/ min, P < 0.05). Pre-treatment with atenolol before GHRH administration produced no significant increase in peak and AUC GH response in both groups, whlch remained lower in the elderly men than in their young counterparts (peak 5.5 ±1.8 ng/ ml v. 29.3 ± 7.0 ng/ml, AUC 327 ± 90 ng/ml/min v. 2 017 ± 590 ng/ ml/min, P < 0.05). Bromocriptine alone did not cause a significant rise in GH concentration in either elderly or young subjects (peak 3.1 ± 1.1 v. 8.8 ± 3.2 ng/ ml, P > 0.05). When atenolol was administered before bromocriptine, both groups responded but the elderly subjects had a significantly greater peak and AUC response (peak 3.6 ± 0.7 v. 10:7 ± 2.1 ng/ ml; AUC 191 ± 39 v. 533 ± 125 ng/ ml/ min, P < 0.05). Bromocriptine given before GHRH failed to potentiate GHRH action on GH release in either group. Of 5 elderly men who tmderwent further evaluation of GH secretory ability, 2 subjects had GH levels > 10 ng/ rnl, either basally or after intravenous GHRH. The remaining 3 had an initially impaired GH response to bolus intravenous GHRH. After 100 μg GHRH subcutaneously twice daily for up to 2 weeks the GH responses to intravenous bolus GHRH (0.5μg /kg) were reassessed. One exhibited a normal response (> 10 ng/ rnl) after 1 week of daily GHRH treatment, another had a nearnormal response after 2 weeks (9.7 ng/ rnl), while the third still had an impaired response by the end of the 2-week treatment period (3.2 ng/ ml).Conclusions. The restoration of endogenous GH secretion in these elderly subjects by means of GHRH priming, and the failure of manipulation of somatostatinergic tone to restore a normal GH response to GHRH suggests that somatotroph atrophy due to a reduction in endogenous GHRH secretion is the principal cause of the diminished GH secretion with ageing

Structural Determinants for Ligand-Receptor Conformational Selection in a Peptide G Protein-coupled Receptor

G protein coupled receptors (GPCRs) modulate the majority of physiological processes through specific intermolecular interactions with structurally diverse ligands and activation of differential intracellular signaling. A key issue yet to be resolved is how GPCRs developed selectivity and diversity of ligand binding and intracellular signaling during evolution. We have explored the structural basis of selectivity of naturally occurring gonadotropin-releasing hormones (GnRHs) from different species in the single functional human GnRH receptor. We found that the highly variable amino acids in position 8 of the naturally occurring isoforms of GnRH play a discriminating role in selecting receptor conformational states. The human GnRH receptor has a higher affinity for the cognate GnRH I but a lower affinity for GnRH II and GnRHs from other species possessing substitutions for Arg(8). The latter were partial agonists in the human GnRH receptor. Mutation of Asn(7.45) in transmembrane domain (TM) 7 had no effect on GnRH I affinity but specifically increased affinity for other GnRHs and converted them to full agonists. Using molecular modeling and site-directed mutagenesis, we demonstrated that the highly conserved Asn(7.45) makes intramolecular interactions with a highly conserved Cys(6.47) in TM 6, suggesting that disruption of this intramolecular interaction induces a receptor conformational change which allosterically alters ligand specific binding sites and changes ligand selectivity and signaling efficacy. These results reveal GnRH ligand and receptor structural elements for conformational selection, and support co-evolution of GnRH ligand and receptor conformations

KISS1R : hallmarks of an effective regulator of the neuroendocrine axis

Kisspeptin (KP) is now well recognized as a potent stimulator of gonadotropin-releasing hormone (GnRH) secretion and thereby a major regulator of the neuroendocrine-reproductive axis. KP signals via KISS1R, a G protein-coupled receptor (GPCR) that activates the G proteins Gαq/11. Modulation of the interaction of KP with KISS1R is therefore a potential new therapeutic target for stimulating (in infertility) or inhibiting (in hormone-dependent diseases) the reproductive hormone cascade. Major efforts are underway to target KISS1R in the treatment of sex steroid hormone-dependent disorders and to stimulate endogenous hormonal responses along the neuroendocrine axis as part of in vitro fertilization protocols. The development of analogs modulating KISS1R signaling will be aided by an understanding of the intracellular pathways and dynamics of KISS1R signaling under normal and pathological conditions. This review focuses on KISS1R recruitment of intracellular signaling (Gαq/11- and β-arrestin-dependent) pathways that mediate GnRH secretion and the respective roles of rapid desensitization, internalization, and recycling of resensitized receptors in maintaining an active population of KISS1R at the cell surface to facilitate prolonged KP signaling. Additionally, this review summarizes and discusses the major findings of an array of studies examining the desensitization of KP signaling in man, domestic and laboratory animals. This discussion highlights the major effects of ligand efficacy and concentration and the physiological, developmental, and metabolic status of the organism on KP signaling. Finally, the potential for the utilization of KP and analogs in stimulating and inhibiting the reproductive hormone cascade as an alternative to targeting the downstream GnRH receptor is discussed.Natural Sciences and Engineering Research Council of Canada (RGPIN/327334-2011), National Research Foundation and Medical Research Council of South Africa, and the Universities of Pretoria and Cape Town.http://www.karger.com/Journal/Home/223855hb201

Current and future applications of GnRH, kisspeptin and neurokinin B analogues

Reproductive hormones affect all stages of life from gamete production, fertilization, fetal development and parturition, neonatal development and puberty through to adulthood and senescence. The reproductive hormone cascade has, therefore, been the target for the development of numerous drugs that modulate its activity at many levels. As the central regulator of the cascade, gonadotropin-releasing hormone (GnRH) agonists and antagonists have found extensive applications in treating a wide range of hormone-dependent diseases, such as precocious puberty, prostate cancer, benign prostatic hyperplasia, endometriosis and uterine fibroids, as well as being an essential component of in vitro fertilization protocols. The neuroendocrine peptides that regulate GnRH neurons, kisspeptin and neurokinin B, have also been identified as therapeutic targets, and novel agonists and antagonists are being developed as modulators of the cascade upstream of GnRH. Here, we review the development and applications of analogues of the major neuroendocrine peptide regulators of the reproductive hormone cascade: GnRH, kisspeptin and neurokinin B.The Medical Research Council (South Africa), the National Research Foundation, the University of Pretoria and the University of Cape Town. CLN is a Claude Leon Foundation Postdoctoral Research Fellow.http://www.nature.com/nrendohb2016Mammal Research InstituteZoology and Entomolog