Monoclonal anti-β1-adrenergic receptor antibodies activate G protein signaling in the absence of β-arrestin recruitment

Thermostabilized G protein-coupled receptors used as antigens for in vivo immunization have resulted in the generation of functional agonistic anti-β1-adrenergic (β1AR) receptor monoclonal antibodies (mAbs). The focus of this study was to examine the pharmacology of these antibodies to evaluate their mechanistic activity at β1AR. Immunization with the β1AR stabilized receptor yielded five stable hybridoma clones, four of which expressed functional IgG, as determined in cell-based assays used to evaluate cAMP stimulation. The antibodies bind diverse epitopes associated with low nanomolar agonist activity at β1AR, and they appeared to show some degree of biased signaling as they were inactive in an assay measuring signaling through β-arrestin. In vitro characterization also verified different antibody-receptor interactions reflecting the different epitopes on the extracellular surface of β1AR to which the mAbs bind. The anti-β1AR mAbs only demonstrated agonist activity when in dimeric antibody format, but not as the monomeric Fab format, suggesting that agonist activation may be mediated through promoting receptor dimerization. Finally, we have also shown that at least one of these antibodies exhibits in vivo functional activity at a therapeutically-relevant dose producing an increase in heart rate consistent with β1AR agonism

Salt Reduction Initiatives around the World – A Systematic Review of Progress towards the Global Target

Objective To quantify progress with the initiation of salt reduction strategies around the world in the context of the global target to reduce population salt intake by 30% by 2025. Methods A systematic review of the published and grey literature was supplemented by questionnaires sent to country program leaders. Core characteristics of strategies were extracted and categorised according to a pre-defined framework. Results A total of 75 countries now have a national salt reduction strategy, more than double the number reported in a similar review done in 2010. The majority of programs are multifaceted and include industry engagement to reformulate products (n = 61), establishment of sodium content targets for foods (39), consumer education (71), front-of-pack labelling schemes (31), taxation on high-salt foods (3) and interventions in public institutions (54). Legislative action related to salt reduction such as mandatory targets, front of pack labelling, food procurement policies and taxation have been implemented in 33 countries. 12 countries have reported reductions in population salt intake, 19 reduced salt content in foods and 6 improvements in consumer knowledge, attitudes or behaviours relating to salt. Conclusion The large and increasing number of countries with salt reduction strategies in place is encouraging although activity remains limited in low- and middle-income regions. The absence of a consistent approach to implementation highlights uncertainty about the elements most important to success. Rigorous evaluation of ongoing programs and initiation of salt reduction programs, particularly in low- and middle- income countries, will be vital to achieving the targeted 30% reduction in salt intake

Failure of a repeat course of cyclooxygenase inhibitor to close a PDA is a risk factor for developing chronic lung disease in ELBW infants

<p>Abstract</p> <p>Background</p> <p>The optimal treatment regimen or protocol for managing a persistent patent ductus arteriosus (PDA) in extremely low birth weight (ELBW) infants has not been well established. This study was aimed at evaluating the failure rate of a cyclooxygenase (COX) inhibitor (COI) for PDA closure and to determine the incidence of a PDA requiring ligation in ELBW infants. We examined the clinical characteristics and risk factors that may predict the clinical consequences of failure of PDA closure by COI.</p> <p>Methods</p> <p>Medical information on 138 infants with birth weight (BW) < 1000 gm who survived for > 48 hours was retrieved. Clinical characteristics and outcomes of patients whose PDAs closed with COI were compared with those who did not close.</p> <p>Results</p> <p>Of the 138 patients, 112 survived to discharge. Eighty (71.4%) of those who survived received 1-3 courses of COI treatment for a symptomatic PDA. A total of 32 (40%) failed COI treatment and underwent PDA ligation. Multivariable logistic regression analysis suggests that the observed differences in the outcomes in infants with or without symptomatic PDA can be explained by the babies with symptomatic PDA being more immature and sicker. No significant difference was seen in the incidence of chronic lung disease (CLD) in infants whose PDA was treated medically versus those who failed medical treatment and then underwent ligation. However, after adjusting for disease severity and other known risk factors, the odds ratio of developing CLD for surviving babies with a persistent PDA compared to those whose PDA was successfully closed with 1-2 courses of COI is 3.24 (1.07-9.81; p = 0.038).</p> <p>Conclusions</p> <p>When successfully treated, PDA in ELBW infants did not contribute significantly to the adverse outcomes such as CLD, retinopathy of prematurity (ROP) and age at discharge. This suggests that it is beneficial for a hemodynamically significant PDA to be closed. The failure of a repeat course of COI to close a PDA is a major risk factor for developing CLD in ELBW infants.</p

Is elevated SUA associated with a worse outcome in young Chinese patients with acute cerebral ischemic stroke?

<p>Abstract</p> <p>Background</p> <p>Elevated serum uric acid (SUA) levels can enhance its antioxidant prosperities and reduce the occurrence of cerebral infarction. Significantly elevated SUA levels have been associated with a better prognosis in patients with cerebral infarction; however, the results from some studies on the relationship between SUA and the prognosis of patients with cerebral infarction remain controversial.</p> <p>Methods</p> <p>We analyzed the relationship between SUA and clinical prognosis of 585 young Chinese adults with acute ischemic stroke as determined by the modified Rankin Scale at discharge. Using multivariate logistic regression modeling, we explore the relationship between SUA levels and patient's clinical prognosis.</p> <p>Results</p> <p>Lower SUA levels at time of admission were observed more frequently in the lowest quintile for patients with severe stroke (P = 0.02). Patients with cerebral infarction patients caused by small-vessel blockage had higher SUA concentrations (P = 0.01) and the lower mRS scores (P < 0.01) were observed in, while the lowest SUA concentrations and the highest mRS scores were seen in patients with cardiogenic cerebral infarction patients. Logistic regression analysis adjusted for confounders confirmed the following independent predictors for young cerebral infarction: uric acid (-0.003: 95%CI 0.994 to 0.999) and platelet (0.004, 95%CI 0.993 to 0.996).</p> <p>Conclusion</p> <p>Elevated SUA is an independent predictor for good clinical outcome of acute cerebral infarction among young adults.</p

SSR and AFLP based genetic diversity of soybean germplasm differing in photoperiod sensitivity

Forty-four soybean genotypes with different photoperiod response were selected after screening of 1000 soybean accessions under artificial condition and were profiled using 40 SSR and 5 AFLP primer pairs. The average polymorphism information content (PIC) for SSR and AFLP marker systems was 0.507 and 0.120, respectively. Clustering of genotypes was done using UPGMA method for SSR and AFLP and correlation was 0.337 and 0.504, respectively. Mantel's correlation coefficients between Jaccard's similarity coefficient and the cophenetic values were fairly high in both the marker systems (SSR = 0.924; AFLP = 0.958) indicating very good fit for the clustering pattern. UPGMA based cluster analysis classified soybean genotypes into four major groups with fairly moderate bootstrap support. These major clusters corresponded with the photoperiod response and place of origin. The results indicate that the photoperiod insensitive genotypes, 11/2/1939 (EC 325097) and MACS 330 would be better choice for broadening the genetic base of soybean for this trait

Single nucleotide polymorphism genotyping in polyploid wheat with the Illumina GoldenGate assay

Single nucleotide polymorphisms (SNPs) are indispensable in such applications as association mapping and construction of high-density genetic maps. These applications usually require genotyping of thousands of SNPs in a large number of individuals. Although a number of SNP genotyping assays are available, most of them are designed for SNP genotyping in diploid individuals. Here, we demonstrate that the Illumina GoldenGate assay could be used for SNP genotyping of homozygous tetraploid and hexaploid wheat lines. Genotyping reactions could be carried out directly on genomic DNA without the necessity of preliminary PCR amplification. A total of 53 tetraploid and 38 hexaploid homozygous wheat lines were genotyped at 96 SNP loci. The genotyping error rate estimated after removal of low-quality data was 0 and 1% for tetraploid and hexaploid wheat, respectively. Developed SNP genotyping assays were shown to be useful for genotyping wheat cultivars. This study demonstrated that the GoldenGate assay is a very efficient tool for high-throughput genotyping of polyploid wheat, opening new possibilities for the analysis of genetic variation in wheat and dissection of genetic basis of complex traits using association mapping approach

Discovery and population genomics of structural variation in a songbird genus

Structural variation (SV) constitutes an important type of genetic mutations providing the raw material for evolution. Here, we uncover the genome-wide spectrum of intra- and interspecific SV segregating in natural populations of seven songbird species in the genus Corvus. Combining short-read (N = 127) and long-read re-sequencing (N = 31), as well as optical mapping (N = 16), we apply both assembly- and read mapping approaches to detect SV and characterize a total of 220,452 insertions, deletions and inversions. We exploit sampling across wide phylogenetic timescales to validate SV genotypes and assess the contribution of SV to evolutionary processes in an avian model of incipient speciation. We reveal an evolutionary young (~530,000 years) cis-acting 2.25-kb LTR retrotransposon insertion reducing expression of the NDP gene with consequences for premating isolation. Our results attest to the wealth and evolutionary significance of SV segregating in natural populations and highlight the need for reliable SV genotyping

Population genetic structure of Aedes polynesiensis in the Society Islands of French Polynesia: implications for control using a Wolbachia-based autocidal strategy

Abstract Background Aedes polynesiensis is the primary vector of Wuchereria bancrofti in the South Pacific and an important vector of dengue virus. An improved understanding of the mosquito population genetics is needed for insight into the population dynamics and dispersal, which can aid in understanding the epidemiology of disease transmission and control of the vector. In light of the potential release of a Wolbachia infected strain for vector control, our objectives were to investigate the microgeographical and temporal population genetic structure of A. polynesiensis within the Society Islands of French Polynesia, and to compare the genetic background of a laboratory strain intended for release into its population of origin. Methods A panel of eight microsatellite loci were used to genotype A. polynesiensis samples collected in French Polynesia from 2005-2008 and introgressed A. polynesiensis and Aedes riversi laboratory strains. Examination of genetic differentiation was performed using F-statistics, STRUCTURE, and an AMOVA. BAYESASS was used to estimate direction and rates of mosquito movement. Results FST values, AMOVA, and STRUCTURE analyses suggest low levels of intra-island differentiation from multiple collection sites on Tahiti, Raiatea, and Maupiti. Significant pair-wise FST values translate to relatively minor levels of inter-island genetic differentiation between more isolated islands and little differentiation between islands with greater commercial traffic (i.e., Tahiti, Raiatea, and Moorea). STRUCTURE analyses also indicate two population groups across the Society Islands, and the genetic makeup of Wolbachia infected strains intended for release is similar to that of wild-type populations from its island of origin, and unlike that of A. riversi. Conclusions The observed panmictic population on Tahiti, Raiatea, and Moorea is consistent with hypothesized gene flow occurring between islands that have relatively high levels of air and maritime traffic, compared to that of the more isolated Maupiti and Tahaa. Gene flow and potential mosquito movement is discussed in relation to trials of applied autocidal strategies.</p