Serelaxin Elicits Bronchodilation and Enhances β-Adrenoceptor-Mediated Airway Relaxation.

Treatment with β-adrenoceptor agonists does not fully overcome the symptoms associated with severe asthma. Serelaxin elicits potent uterine and vascular relaxation via its cognate receptor, RXFP1, and nitric oxide (NO) signaling, and is being clinically evaluated for the treatment of acute heart failure. However, its direct bronchodilator efficacy has yet to be explored. Tracheal rings were prepared from male Sprague-Dawley rats (250-350 g) and tricolor guinea pigs, and precision cut lung slices (PCLSs) containing intrapulmonary airways were prepared from rats only. Recombinant human serelaxin (rhRLX) alone and in combination with rosiglitazone (PPARγ agonist; recently described as a novel dilator) or β-adrenoceptor agonists (isoprenaline, salbutamol) were added either to pre-contracted airways, or before contraction with methacholine or endothelin-1. Regulation of rhRLX responses by epithelial removal, indomethacin (cyclooxygenase inhibitor), L-NAME (nitric oxide synthase inhibitor), SQ22536 (adenylate cyclase inhibitor) and ODQ (guanylate cyclase inhibitor) were also evaluated. Immunohistochemistry was used to localize RXFP1 to airway epithelium and smooth muscle. rhRLX elicited relaxation in rat trachea and PCLS, more slowly than rosiglitazone or isoprenaline, but potentiated relaxation to both these dilators. It markedly increased β-adrenoceptor agonist potency in guinea pig trachea. rhRLX, rosiglitazone, and isoprenaline pretreatment also inhibited the development of rat tracheal contraction. Bronchoprotection by rhRLX increased with longer pre-incubation time, and was partially reduced by epithelial removal, indomethacin and/or L-NAME. SQ22536 and ODQ also partially inhibited rhRLX-mediated relaxation in both intact and epithelial-denuded trachea. RXFP1 expression in the airways was at higher levels in epithelium than smooth muscle. In summary, rhRLX elicits large and small airway relaxation via epithelial-dependent and -independent mechanisms, likely via RXFP1 activation and generation of NO, prostaglandins and cAMP/cGMP. rhRLX also enhanced responsiveness to other dilators, suggesting its potential as an alternative or add-on therapy for severe asthma

Pulmonary myeloid cell uptake of biodegradable nanoparticles conjugated with an anti-fibrotic agent provides a novel strategy for treating chronic allergic airways disease

Asthma (chronic allergic airways disease, AAD) is characterized by airway inflammation (AI), airway remodeling (AWR) and airway hyperresponsiveness (AHR). Current treatments for AAD mainly focus on targeting AI and its contribution AHR, with the use of corticosteroids. However, there are no therapies for the direct treatment of AWR, which can contribute to airway obstruction, AHR and corticosteroid resistance independently of AI. The acute heart failure drug, serelaxin (recombinant human gene-2 relaxin, RLX), has potential anti-remodeling and anti-fibrotic effects but only when continuously infused or injected to overcome its short half-life. To alleviate this limitation, we conjugated serelaxin to biodegradable and noninflammatory nanoparticles (NP-RLX) and evaluated their therapeutic potential on measures of AI, AWR and AHR, when intranasally delivered to a preclinical rodent model of chronic AAD and TGF-β1-stimulated collagen gel contraction from asthma patient-derived myofibroblasts. NP-RLX was preferentially taken-up by CD206+-infiltrating and CD68+-tissue resident alveolar macrophages. Furthermore, NP-RLX ameliorated the chronic AAD-induced AI, pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), chemokines (CCL2, CCL11) and the pro-fibrotic TGF-β1/IL-1β axis on AWR and resulting AHR, as well as human myofibroblast-induced collagen gel contraction, to a similar extent as unconjugated RLX. Hence, NP-RLX represents a novel strategy for treating the central features of asthma

Scots pine (Pinus sylvestris)

Technical guidelines are targeted to practical forest managers and provide summarized information on the biology and ecology of tree species, distribution ranges, importance and use, genetic knowledge, threats to genetic diversity and recommendations for long-term genetic conservation. For the full list of Technical guidelines produced, please visit http://www.euforgen.org/publications/technical_guidelines.htm

Admixture in Humans of Two Divergent Plasmodium knowlesi Populations Associated with Different Macaque Host Species.

Human malaria parasite species were originally acquired from other primate hosts and subsequently became endemic, then spread throughout large parts of the world. A major zoonosis is now occurring with Plasmodium knowlesi from macaques in Southeast Asia, with a recent acceleration in numbers of reported cases particularly in Malaysia. To investigate the parasite population genetics, we developed sensitive and species-specific microsatellite genotyping protocols and applied these to analysis of samples from 10 sites covering a range of >1,600 km within which most cases have occurred. Genotypic analyses of 599 P. knowlesi infections (552 in humans and 47 in wild macaques) at 10 highly polymorphic loci provide radical new insights on the emergence. Parasites from sympatric long-tailed macaques (Macaca fascicularis) and pig-tailed macaques (M. nemestrina) were very highly differentiated (FST = 0.22, and K-means clustering confirmed two host-associated subpopulations). Approximately two thirds of human P. knowlesi infections were of the long-tailed macaque type (Cluster 1), and one third were of the pig-tailed-macaque type (Cluster 2), with relative proportions varying across the different sites. Among the samples from humans, there was significant indication of genetic isolation by geographical distance overall and within Cluster 1 alone. Across the different sites, the level of multi-locus linkage disequilibrium correlated with the degree of local admixture of the two different clusters. The widespread occurrence of both types of P. knowlesi in humans enhances the potential for parasite adaptation in this zoonotic system

AI Researchers, Video Games Are Your Friends!

If you are an artificial intelligence researcher, you should look to video games as ideal testbeds for the work you do. If you are a video game developer, you should look to AI for the technology that makes completely new types of games possible. This chapter lays out the case for both of these propositions. It asks the question "what can video games do for AI", and discusses how in particular general video game playing is the ideal testbed for artificial general intelligence research. It then asks the question "what can AI do for video games", and lays out a vision for what video games might look like if we had significantly more advanced AI at our disposal. The chapter is based on my keynote at IJCCI 2015, and is written in an attempt to be accessible to a broad audience.Comment: in Studies in Computational Intelligence Studies in Computational Intelligence, Volume 669 2017. Springe

Relaxin: Review of Biology and Potential Role in Treating Heart Failure

Relaxin is a naturally occurring human peptide initially identified as a reproductive hormone. More recently, relaxin has been shown to play a key role in the maternal hemodynamic and renal adjustments that accommodate pregnancy. An understanding of these physiologic effects has led to the evaluation of relaxin as a pharmacologic agent for the treatment of patients with acute heart failure. Preliminary results have been encouraging. In addition, the other known biologic properties of relaxin, including anti-inflammatory effects, extracellular matrix remodeling effects, and angiogenic and anti-ischemic effects, all may play a role in potential benefits of relaxin therapy. Ongoing, large-scale clinical testing will provide additional insights into the potential role of relaxin in the treatment of heart failure

Spontaneous corneal melting in pregnancy: a case report

<p>Abstract</p> <p>Background</p> <p>To report a case of spontaneous corneal melting in pregnancy. We reviewed the literature on corneal melting and the effect of pregnancy on cornea and collagen containing tissues.</p> <p>Case presentation</p> <p>A 29-year-old woman who underwent radial keratotomy in both eyes followed by trabeculectomy in her left eye developed corneal melting in the same eye, in her seventh month of pregnancy. Despite screening, no infectious or immune mediated condition could be identified. She was managed conservatively with cyanoacrylate glue, bandage contact lens, lubricants and antibiotics.</p> <p>Conclusion</p> <p>It may not always be possible to find the underlying cause of corneal melting but the more common underlying causes should be ruled out by proper investigations. Pregnancy with its host of hormonal changes could potentially have some effect on corneal collagen leading to corneal melting in compromised corneas.</p

Genetic Background Can Result in a Marked or Minimal Effect of Gene Knockout (GPR55 and CB2 Receptor) in Experimental Autoimmune Encephalomyelitis Models of Multiple Sclerosis

PMCID: PMC379391

The antisaccade task as an index of sustained goal activation in working memory: modulation by nicotine

The antisaccade task provides a laboratory analogue of situations in which execution of the correct behavioural response requires the suppression of a more prepotent or habitual response. Errors (failures to inhibit a reflexive prosaccade towards a sudden onset target) are significantly increased in patients with damage to the dorsolateral prefrontal cortex and patients with schizophrenia. Recent models of antisaccade performance suggest that errors are more likely to occur when the intention to initiate an antisaccade is insufficiently activated within working memory. Nicotine has been shown to enhance specific working memory processes in healthy adults. MATERIALS AND METHODS: We explored the effect of nicotine on antisaccade performance in a large sample (N = 44) of young adult smokers. Minimally abstinent participants attended two test sessions and were asked to smoke one of their own cigarettes between baseline and retest during one session only. RESULTS AND CONCLUSION: Nicotine reduced antisaccade errors and correct antisaccade latencies if delivered before optimum performance levels are achieved, suggesting that nicotine supports the activation of intentions in working memory during task performance. The implications of this research for current theoretical accounts of antisaccade performance, and for interpreting the increased rate of antisaccade errors found in some psychiatric patient groups are discussed

In vivo imaging of extracellular matrix remodeling by tumor-associated fibroblasts.

Here we integrated multiphoton laser scanning microscopy and the registration of second harmonic generation images of collagen fibers to overcome difficulties in tracking stromal cell-matrix interactions for several days in live mice. We show that the matrix-modifying hormone relaxin increased tumor-associated fibroblast (TAF) interaction with collagen fibers by stimulating beta1-integrin activity, which is necessary for fiber remodeling by matrix metalloproteinases