Combined TRPC3 and TRPC6 blockade by selective small-molecule or genetic deletion inhibits pathological cardiac hypertrophy

Chronic neurohormonal and mechanical stresses are central fea-tures of heart disease. Increasing evidence supports a role forthe transient receptor potential canonical channels TRPC3 andTRPC6 in this pathophysiology. Channel expression for both is nor-mally very low but is increased by cardiac disease, and geneticgain- or loss-of-function studies support contributions to hypertro-phy and dysfunction. Selective small-molecule inhibitors remainscarce, and none target both channels, which may be useful giventhe high homology among them and evidence of redundant sig-naling. Here we tested selective TRPC3/6 antagonists (GSK2332255Band GSK2833503A; IC50,3–21 nM against TRPC3 and TRPC6) andfound dose-dependent blockade of cell hypertrophy signaling trig-gered by angiotensin II or endothelin-1 in HEK293T cells as well as inneonatal and adult cardiac myocytes. In vivo efficacy in mice andrats was greatly limited by rapid metabolism and high protein bind-ing, although antifibrotic effects with pressure overload were ob-served. Intriguingly, although gene deletion of TRPC3 or TRPC6alone did not protect against hypertrophy or dysfunction frompressure overload, combined deletion was protective, support-ing the value of dual inhibition. Further development of thispharmaceutical class may yield a useful therapeutic agent forheart disease management.Fil: Seo, Kinya. Johns Hopkins Medical Institutions. Department of Medicine; Estados UnidosFil: Rainer, Peter P.. Johns Hopkins Medical Institutions. Department of Medicine; Estados Unidos. Medical University of Graz. Department of Medicine; AustriaFil: Shalkey Hahn, Virginia. Johns Hopkins Medical Institutions. Department of Medicine; Estados UnidosFil: Lee, Dong-ik. Johns Hopkins Medical Institutions. Department of Medicine; Estados UnidosFil: Jo, Su-Hyun. Kangwon National University School of Medicine; Corea del Sur. Johns Hopkins Medical Institutions. Department of Medicine; Estados UnidosFil: Andersen, Asger. Aarhus University Hospital. Department of Cardiology; DinamarcaFil: Liu, Ting. Johns Hopkins Medical Institutions. Department of Medicine; Estados UnidosFil: Xu, Xiaoping. GlaxoSmithKline Heart Failure Discovery Performance Unit; Estados UnidosFil: Willette, Robert N.. GlaxoSmithKline Heart Failure Discovery Performance Unit; Estados UnidosFil: Lepore, John J.. GlaxoSmithKline Heart Failure Discovery Performance Unit; Estados UnidosFil: Marino, Joseph P.. GlaxoSmithKline Heart Failure Discovery Performance Unit; Estados UnidosFil: Birnbaumer, Lutz. ational Institute of Environmental Health Sciences; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; ArgentinaFil: Schnackenberg, Christine G.. GlaxoSmithKline Heart Failure Discovery Performance Unit; Estados UnidosFil: Kass, David A.. Johns Hopkins Medical Institutions. Department of Medicine; Estados Unido

DNA barcoding cannot discriminate between Sardinella tawilis and S. hualiensis (Clupeiformes: Clupeidae)

Sardinella tawilis, the only known freshwater sardinella in the world, is endemic to Taal Lake, Philippines. Previous studies found the Taiwan sardinella, S. hualiensis, to be morphologically very similar to S. tawilis and identified it as the marine sister species of S. tawilis. In this study, DNA barcoding using the mitochondrial cytochrome c oxidase I (COI) gene was carried out to analyze species demarcation in the Sardinella genus, focusing primarily on the relationship between S. tawilis and S. hualiensis. The neighbour-joining (NJ) tree that was constructed using Kimura 2-parameter (K2P) model showed a single clade for the two species with 100% bootstrap support. K2P interspecific genetic divergence ranged from 0% to 0.522%, which is clearly below the suggested 3–3.5% cutoff for species discrimination. Recombination activating gene 1 (RAG1), mitochondrial control region (CR), cytochrome b, 16S rRNA, and S7 markers were used to further validate the results. Sardinella tawilis and S. hualiensis clustered together with a bootstrap support of 99–100% in each of the NJ trees. Low interspecific genetic distances between S. tawilis and S. hualiensis for all the markers except CR could be attributed to incipient allopatric speciation

Generation and quality control of lipidomics data for the alzheimers disease neuroimaging initiative cohort.

Alzheimers disease (AD) is a major public health priority with a large socioeconomic burden and complex etiology. The Alzheimer Disease Metabolomics Consortium (ADMC) and the Alzheimer Disease Neuroimaging Initiative (ADNI) aim to gain new biological insights in the disease etiology. We report here an untargeted lipidomics of serum specimens of 806 subjects within the ADNI1 cohort (188 AD, 392 mild cognitive impairment and 226 cognitively normal subjects) along with 83 quality control samples. Lipids were detected and measured using an ultra-high-performance liquid chromatography quadruple/time-of-flight mass spectrometry (UHPLC-QTOF MS) instrument operated in both negative and positive electrospray ionization modes. The dataset includes a total 513 unique lipid species out of which 341 are known lipids. For over 95% of the detected lipids, a relative standard deviation of better than 20% was achieved in the quality control samples, indicating high technical reproducibility. Association modeling of this dataset and available clinical, metabolomics and drug-use data will provide novel insights into the AD etiology. These datasets are available at the ADNI repository at http://adni.loni.usc.edu/

So, You Want to Use Next Generation Sequencing In Marine Systems? Insight from the Pan Pacific Advanced Studies Institute

The emerging field of next-generation sequencing (NGS) is rapidly expanding capabilities for cutting edge genomic research, with applications that can help meet marine conservation challenges of food security, biodiversity loss, and climate change. Navigating the use of these tools, however, is complex at best. Furthermore, applications of marine genomic questions are limited in developing nations where both marine biodiversity and threats to marine biodiversity are most concentrated. This is particularly true in Southeast Asia. The first Pan-Pacific Advanced Studies Institute (PacASI) entitled Genomic Applications to Marine Science and Resource Management in Southeast Asia was held in July 2012 in Dumaguete, Philippines, with the intent to draw together leading scientists from both sides of the Pacific Ocean to understand the potential of NGS in helping address the aforementioned challenges. Here we synthesize discussions held during the PacASI to provide perspectives and guidance to help scientists new to NGS choose among the variety of available advanced genomic methodologies specifically for marine science questions

So, You Want to Use Next-Generation Sequencing in Marine Systems? Insight from the Pan-Pacific Advanced Studies Institute

The emerging field of next-generation sequencing (NGS) is rapidly expanding capabilities for cutting edge genomic research, with applications that can help meet marine conservation challenges of food security, biodiversity loss, and climate change. Navigating the use of these tools, however, is complex at best. Furthermore, applications of marine genomic questions are limited in developing nations where both marine biodiversity and threats to marine biodiversity are most concentrated. This is particularly true in Southeast Asia. The first Pan-Pacific Advanced Studies Institute (PacASI) entitled “Genomic Applications to Marine Science and Resource Management in Southeast Asia” was held in July 2012 in Dumaguete, Philippines, with the intent to draw together leading scientists from both sides of the Pacific Ocean to understand the potential of NGS in helping address the aforementioned challenges. Here we synthesize discussions held during the PacASI to provide perspectives and guidance to help scientists new to NGS choose among the variety of available advanced genomic methodologies specifically for marine science questions

Interleukin-6 gene (IL-6): a possible role in brain morphology in the healthy adult brain

Background: Cytokines such as interleukin 6 (IL-6) have been implicated in dual functions in neuropsychiatric disorders. Little is known about the genetic predisposition to neurodegenerative and neuroproliferative properties of cytokine genes. In this study the potential dual role of several IL-6 polymorphisms in brain morphology is investigated. Methodology: In a large sample of healthy individuals (N = 303), associations between genetic variants of IL-6 (rs1800795; rs1800796, rs2069833, rs2069840) and brain volume (gray matter volume) were analyzed using voxel-based morphometry (VBM). Selection of single nucleotide polymorphisms (SNPs) followed a tagging SNP approach (e.g., Stampa algorigthm), yielding a capture 97.08% of the variation in the IL-6 gene using four tagging SNPs. Principal findings/results: In a whole-brain analysis, the polymorphism rs1800795 (−174 C/G) showed a strong main effect of genotype (43 CC vs. 150 CG vs. 100 GG; x = 24, y = −10, z = −15; F(2,286) = 8.54, puncorrected = 0.0002; pAlphaSim-corrected = 0.002; cluster size k = 577) within the right hippocampus head. Homozygous carriers of the G-allele had significantly larger hippocampus gray matter volumes compared to heterozygous subjects. None of the other investigated SNPs showed a significant association with grey matter volume in whole-brain analyses. Conclusions/significance: These findings suggest a possible neuroprotective role of the G-allele of the SNP rs1800795 on hippocampal volumes. Studies on the role of this SNP in psychiatric populations and especially in those with an affected hippocampus (e.g., by maltreatment, stress) are warranted.Bernhard T Baune, Carsten Konrad, Dominik Grotegerd, Thomas Suslow, Eva Birosova, Patricia Ohrmann, Jochen Bauer, Volker Arolt, Walter Heindel, Katharina Domschke, Sonja Schöning, Astrid V Rauch, Christina Uhlmann, Harald Kugel and Udo Dannlowsk

In Vitro and In Vivo Characterization of Intrinsic Sympathomimetic Activity in Normal and Heart Failure Rats

ABSTRACT Clinical studies conducted with carvedilol suggest that ␤-adrenoceptor antagonism is an effective therapeutic approach to the treatment of heart failure. However, many ␤-adrenoceptor antagonists are weak partial agonists and possess significant intrinsic sympathomimetic activity (ISA), which may be problematic in the treatment of heart failure. In the present study, the ISAs of bucindolol, xamoterol, bisoprolol, and carvedilol were evaluated and compared in normal rats [Sprague-Dawley (SD)], in rats with confirmed heart failure [spontaneously hypertensive heart failure (SHHF)], and in isolated neonatal rat cardiomyocytes. At equieffective ␤ 1 -adrenolytic doses, the administration of xamoterol and bucindolol produced a prolonged, equieffective, and dose-related increase in heart rate in both pithed SD rats (ED 50 ϭ 5 and 40 g/kg, respectively) and SHHF rats (ED 50 ϭ 6 and 30 g/kg, respectively). The maximum effect of both compounds in SHHF rats was approximately 50% of that observed in SD rats. In contrast, carvedilol and bisoprolol had no significant effect on resting heart rate in the pithed SD or SHHF rat. The maximum increase in heart rate elicited by xamoterol and bucindolol was inhibited by treatment with propranolol, carvedilol, and betaxolol (␤ 1 -adrenoceptor antagonist) but not by ICI 118551 (␤ 2 -adrenoceptor antagonist) in neonatal rat. When the ␤-adrenoceptor-mediated cAMP response was examined in cardiomyocytes, an identical partial agonist/antagonist response profile was observed for all compounds, demonstrating a strong correlation with the in vivo results. In contrast, GTP-sensitive ligand binding and tissue adenylate cyclase activity were not sensitive methods for detecting ␤-adrenoceptor partial agonist activity in the heart. In summary, xamoterol and bucindolol, but not carvedilol and bisoprolol, exhibited direct ␤ 1 -adrenoceptor-mediated ISA in normal and heart failure rats

CHARITY: Chagas cardiomyopathy bisoprolol intervention study: a randomized double-blind placebo force-titration controlled study with Bisoprolol in patients with chronic heart failure secondary to Chagas cardiomyopathy [NCT00323973]

BACKGROUND: Chagas' disease is the major cause of disability secondary to tropical diseases in young adults from Latin America, and around 20 million people are currently infected by T. cruzi. Heart failure due to Chagas cardiomyopathy is the main clinical presenation in Colombia. Heart failure due to Chagas' disease may respond to digoxin, diuretics and vasodilator therapy. Beta-adrenoreceptor antagonism seems to protect against the increased risk of cardiac arrhythmia and sudden death due to chronic sympathetic stimulation. The aim of this study is to evaluate the effects of the selective beta-adrenergic receptor blocker Bisoprolol on cardiovascular mortality, hospital readmission due to progressive heart failure and functional status in patients with heart failure secondary to Chagas' cardiomyopathy. METHODS/DESIGN: A cohort of 500 T. cruzi seropositive patients (250 per arm) will be selected from several institutions in Colombia. During the pretreatment period an initial evaluation visit will be scheduled in which participants will sign consent forms and baseline measurements and tests will be conducted including blood pressure measurements, twelve-lead ECG and left ventricular ejection fraction assessment by 2D echocardiography. Quality of life questionnaire will be performed two weeks apart during baseline examination using the "Minnesota living with heart failure" questionnaire. A minimum of two 6 minutes corridor walk test once a week over a two-week period will be performed to measure functional class. During the treatment period patients will be randomly assigned to receive Bisoprolol or placebo, initially taking a total daily dose of 2.5 mgrs qd. The dose will be increased every two weeks to 5, 7.5 and 10 mgrs qd (maximum maintenance dose). Follow-up assessment will include clinical check-up, and blood collection for future measurements of inflammatory reactants and markers. Quality of life measurements will be obtained at six months. This study will allow us to explore the effect of beta-blockers in chagas' cardiomyopathy