Showing papers by "Victor Chang Cardiac Research Institute published in 2006"
TL;DR: This study demonstrates that a specific mammalian gene can be subjected to germ-line epigenetic change, and that the altered state is retained through the epigenetic resetting that takes place in gametogenesis and embryogenesis.
Abstract: Environmental effects on phenotype can be mediated by epigenetic modifications. The epigenetic state of the murine A vy allele is highly variable, and determines phenotypic effects that vary in a mosaic spectrum that can be shifted by in utero exposure to methyl donor supplementation. We have asked if methyl donor supplementation affects the germ-line epigenetic state of the A vy allele. We find that the somatic epigenetic state of A vy is affected by in utero methyl donor supplementation only when the allele is paternally contributed. Exposure to methyl donor supplementation during midgestation shifts A vy phenotypes not only in the mice exposed as fetuses, but in their offspring. This finding indicates that methyl donors can change the epigenetic state of the A vy allele in the germ line, and that the altered state is retained through the epigenetic resetting that takes place in gametogenesis and embryogenesis. Thus a mother's diet may have an enduring influence on succeeding generations, independent of later changes in diet. Although other reports have suggested such heritable epigenetic changes, this study demonstrates that a specific mammalian gene can be subjected to germ-line epigenetic change.
382 citations
TL;DR: Beneficial effects of a recombinant 61-residue neuregulin-1 receptor-active peptide make rhNRG-1 promising as a broad-spectrum therapeutic for the treatment of heart failure due to a variety of common cardiac diseases.
279 citations
TL;DR: It is shown that both zinc and copper ions have a number of actions on selected members of the voltage-gated-like ion channel superfamily, which may contribute to the etiology of certain disease states such as Alzheimer's disease (AD) and epilepsy.
239 citations
TL;DR: This work has used a candidate-gene approach to identify a mutation in a third Notch pathway gene, LUNATIC FRINGE (LFNG), in a family with autosomal recessive SCD, and reinforces the hypothesis that proper regulation of the Notch signaling pathway is an absolute requirement for the correct patterning of the axial skeleton.
Abstract: The spondylocostal dysostoses (SCDs) are a heterogeneous group of vertebral malsegmentation disorders that arise during embryonic development by a disruption of somitogenesis. Previously, we had identified two genes that cause a subset of autosomal recessive forms of this disease: DLL3 (SCD1) and MESP2 (SCD2). These genes are important components of the Notch signaling pathway, which has multiple roles in development and disease. Here, we have used a candidate-gene approach to identify a mutation in a third Notch pathway gene, LUNATIC FRINGE (LFNG), in a family with autosomal recessive SCD. LFNG encodes a glycosyltransferase that modifies the Notch family of cell-surface receptors, a key step in the regulation of this signaling pathway. A missense mutation was identified in a highly conserved phenylalanine close to the active site of the enzyme. Functional analysis revealed that the mutant LFNG was not localized to the correct compartment of the cell, was unable to modulate Notch signaling in a cell-based assay, and was enzymatically inactive. This represents the first known mutation in the human LFNG gene and reinforces the hypothesis that proper regulation of the Notch signaling pathway is an absolute requirement for the correct patterning of the axial skeleton.
224 citations
TL;DR: These findings indicate that at least two components are involved in functionally coupling the allosteric site and active center of TG2, namely GTP binding to mask a conformationally destabilizing switch residue, Arg-579, and to facilitate interdomain interactions that promote adoption of a compact, catalytically inactive conformation.
Abstract: Allosteric regulation is a fundamental mechanism of biological control. Here, we investigated the allosteric mechanism by which GTP inhibits cross-linking activity of transglutaminase 2 (TG2), a multifunctional protein, with postulated roles in receptor signaling, extracellular matrix assembly, and apoptosis. Our findings indicate that at least two components are involved in functionally coupling the allosteric site and active center of TG2, namely (i) GTP binding to mask a conformationally destabilizing switch residue, Arg-579, and to facilitate interdomain interactions that promote adoption of a compact, catalytically inactive conformation and (ii) stabilization of the inactive conformation by an uncommon H bond between a cysteine (Cys-277, an active center residue) and a tyrosine (Tyr-516, a residue located on a loop of the β-barrel 1 domain that harbors the GTP-binding site). Although not essential for GTP-mediated inhibition of cross-linking, this H bond enhances the rate of formation of the inactive conformer.
140 citations
TL;DR: The thermodynamics of these unusual features were examined by exploring the effect of temperature on the activation and inactivation processes of hERG channels expressed in Chinese hamster ovary cells and it is emphasized that one cannot extrapolate results obtained at room temperature to 37 degrees C by using a single temperature scale factor.
Abstract: The function of voltage-gated human ether-a-go-gorelated gene (hERG) K+ channels is critical for both normal cardiac repolarization and suppression of arrhythmias initiated by premature excitation....
117 citations
TL;DR: It is concluded that Cited2 is required for normal placental development and vascularisation, and hence for embryo viability.
107 citations
TL;DR: It is shown that scube2 has homology to cubilin, which encodes an endocytic receptor involved in protein trafficking suggesting a possible mode of function for Scube2 during HH signal transduction.
96 citations
TL;DR: Findings are consistent with the notion that intracellularly, under physiological conditions, TG2 is maintained largely as a latent enzyme, its calcium-activated cross-linking activity being suppressed allosterically by guanine nucleotide binding.
81 citations
TL;DR: It is found that Ccr4 cooperated with the Dun1 branch of the replication checkpoint, such that ccr4Δ dun1Δ strains exhibited irreversible hypersensitivity to HU and persistent activation of Rad53.
Abstract: In Saccharomyces cerevisiae , DNA replication stress activates the replication checkpoint, which slows S-phase progression, stabilizes slowed or stalled replication forks, and relieves inhibition of the ribonucleotide reductase (RNR) complex. To identify novel genes that promote cellular viability after replication stress, the S. cerevisiae non-essential haploid gene deletion set (4812 strains) was screened for sensitivity to the RNR inhibitor hydroxyurea (HU). Strains bearing deletions in either CCR4 or CAF1 / POP2 , which encode components of the cytoplasmic mRNA deadenylase complex, were particularly sensitive to HU. We found that Ccr4 cooperated with the Dun1 branch of the replication checkpoint, such that ccr4 Δ dun1 Δ strains exhibited irreversible hypersensitivity to HU and persistent activation of Rad53. Moreover, because ccr4 Δ and chk1 Δ exhibited epistasis in several genetic contexts, we infer that Ccr4 and Chk1 act in the same pathway to overcome replication stress. A counterscreen for suppressors of ccr4 Δ HU sensitivity uncovered mutations in CRT1 , which encodes the transcriptional repressor of the DNA-damage-induced gene regulon. Whereas Dun1 is known to inhibit Crt1 repressor activity, we found that Ccr4 regulates CRT1 mRNA poly(A) tail length and may subtly influence Crt1 protein abundance. Simultaneous overexpression of RNR2 , RNR3 and RNR4 partially rescued the HU hypersensitivity of a ccr4 Δ dun1 Δ strain, consistent with the notion that the RNR genes are key targets of Crt1. These results implicate the coordinated regulation of Crt1 via Ccr4 and Dun1 as a crucial nodal point in the response to DNA replication stress.
70 citations
TL;DR: Enhanced inotropy resulting from transgenic overexpression of alpha1A-AR is well maintained chronically after MI and limits echocardiography-determined LV remodeling, preserves function, and reduces acute heart failure death.
Abstract: Objective: Myocardial contractility is enhanced in transgenic (TG) mice with cardiac-restricted overexpression ofthe α1A-adrenergic receptors (α1A-AR). We tested the hypothesis that this enhanced inotropy protects against dysfunction and remodeling after myocardial infarction (MI). Methods: We subjected α1A-TG and non-TG mice (NTG) to MI and determined changes in left ventricular (LV) function and diastolic dimension (LVDd) by echocardiography prior to and at 1, 3, 7, 12 and 15 weeks thereafter. Results: Although infarct size was similar in the NTG and α1A-TG groups (32±2 vs. 29±2% of LV, P=NS), mortality due to heart failure was lower after MI in the α1A-TG (37%, n=39) than that in the NTG animals (63%, n=56, P=0.026). NTG and α1A-TG mice showed similar reductions in LV fractional shortening (FS) and increases in LVDd at week-1 after MI. However, whereas NTG mice showed continuous deterioration over a 15-week period after MI in FS (fell by 40%, from 30±2 to 18±1%, P<0.01) and LVDd (increased by 24%, from 4.2±0.1 to 5.2±0.1 mm, P<0.01), the changes in both FS (fell by 14%, from 42±2 to 36±2%) and LVDd (increased by 8%, from 3.8±0.1 to 4.1±0.1 mm, both changes P<0.01 vs. NTG) were significantly less severe in the α1A-TG mice and did not progress after 3 weeks. At 15 weeks after MI, LV catheterization revealed better preservation of dP/dtmax in the α1A-TG vs. NTG mice (7270±324, vs. 5938±372 mmHg/s, P<0.05). Conclusion: Enhanced inotropy resulting from transgenic overexpression of α1A-AR is well maintained chronically after MI and limits echocardiography-determined LV remodeling, preserves function, and reduces acute heart failure death.
TL;DR: Two studies show that charged residues on the α‐helix of the S5P linker contribute significantly to the differences in inactivation characteristics of the EAG family channels.
Abstract: The ether-a-go-go (EAG) family of voltage-gated K+ channels contains three subfamilies, EAG, ether-a-go-go related (ERG) and ether-a-go-go like (ELK). The human ether-a-go-go related gene (hERG) K+ channel has been of significant interest because loss of function in the hERG channel is associated with a markedly increased risk of cardiac arrhythmias. The hERG channel has unusual kinetics with slow activation and deactivation but very rapid and voltage-dependent inactivation. The outer pore region of the hERG K+ channel is predicted to be different from that of other members of the voltage-gated K+ channel family. HERG has a much longer linker between the fifth transmembrane domain (SS) and the pore helix (S5P linker) compared to other families of voltage-gated K+ channels (43 amino acids compared to 14–23 amino acids). Further, the S5P linker contains an amphipathic α-helix that in hERG channels probably interacts with the mouth of the pore to modulate inactivation. The human EAG and rat ELK2 channels (hEAG and rELK2) show reduced or no inactivation in comparison to hERG channels, yet both channels are predicted to contain a similarly long S5P linker to that of hERG. In this study, we have constructed a series of chimaeric channels consisting of the S1–S6 of hERG but with the S5P α-helical region of either hEAG or rELK2, and one consisting of the S1–S6 of rELK2 but with the S5P α-helical region of hERG to investigate the role of the S5P linker in inactivation. Our studies show that charged residues on the α-helix of the S5P linker contribute significantly to the differences in inactivation characteristics of the EAG family channels. Further, individually mutating each of the hydrophilic residues on the S5P α-helix of hERG to a charged residue had significant effects on the voltage dependence of inactivation and the two residues with the greatest affect when mutated to a lysine, N588 and Q592, both lie on the same face of the S5P α -helix. We suggest that inactivation of hERG involves the interaction of this face of the S5P α-helix with a charged residue on the remainder of the outer pore domain of the channel.
TL;DR: The down-regulation of IL-4Rα diminishedIL-4 signaling and the Th2 response and enhanced the Th1 response under suboptimal polarizing conditions and determines the ratio of Th1 and Th2 cell differentiation.
Abstract: The intrinsic features of naive CD4 T cells that affect their ability to respond to polarizing signals for Th cell differentiation are not well understood. In this study, we show that naive CD4 T cells from mice transgenic for the Hlx gene expressed lower levels of IL-4Ralpha. The down-regulation of IL-4Ralpha diminished IL-4 signaling and the Th2 response and enhanced the Th1 response under suboptimal polarizing conditions. In nontransgenic CD4 T cells, blocking IL-4Ralpha with Abs had the same effect in an Ab dose-dependent manner. Conversely, Hlx haploinsufficiency caused higher expression of IL-4Ralpha to favor Th2 cell differentiation. Thus, the IL-4Ralpha level on naive CD4 T cells is genetically controlled by Hlx and determines the ratio of Th1 and Th2 cell differentiation.
TL;DR: Long-term augmentation of cardiac alpha( 1A)-adrenergic drive leads to premature death and progressive LV fibrosis with reactivation of matricellular protein genes, the first evidence in vivo for a role of the alpha(1A)-AR in ventricular fibrosis and in pathological cardiac remodeling.
TL;DR: A functional interdependence between the NK2 class homeodomain and YRD in cardiac development and evolution is suggested, and a new model for analysis of Nkx2-5 function in CHD is established.
Abstract: Homeodomain factor Nkx2-5 is a central component of the transcription factor network that guides cardiac development; in humans, mutations in NKX2.5 lead to congenital heart disease (CHD). We have genetically defined a novel conserved tyrosine-rich domain (YRD) within Nkx2-5 that has co-evolved with its homeodomain. Mutation of the YRD did not affect DNA binding and only slightly diminished transcriptional activity of Nkx2-5 in a context-specific manner in vitro. However, the YRD was absolutely essential for the function of Nkx2-5 in cardiogenesis during ES cell differentiation and in the developing embryo. Furthermore, heterozygous mutation of all nine tyrosines to alanine created an allele with a strong dominant-negative-like activity in vivo: ES cell↔embryo chimaeras bearing the heterozygous mutation died before term with cardiac malformations similar to the more severe anomalies seen in NKX2.5 mutant families. These studies suggest a functional interdependence between the NK2 class homeodomain and YRD in cardiac development and evolution, and establish a new model for analysis of Nkx2-5 function in CHD.
TL;DR: The stable integration of transgenes into embryos of the frog Xenopus laevis is achieved using the procedure described here, which is well suited to the production of transgenic reporter frog lines.
Abstract: The stable integration of transgenes into embryos of the frog Xenopus laevis is achieved using the procedure described here. Linear DNA containing the transgene is incorporated randomly into sperm nuclei that have had their membranes disrupted with detergent treatment. Microinjection of these nuclei into unfertilized eggs produces viable embryos that can be screened for activity of the transgene. The proportion of embryos that harbor the transgene varies from 10 to 40% of the total number of surviving embryos. Multiple copies of the transgene can integrate as a concatemer into the sperm genome, and more than one site of DNA integration might occur within resulting animals. Germ cell transmission of the transgene is routine and the procedure is well suited to the production of transgenic reporter frog lines. One day should be allocated for the preparation of the sperm nuclei, which are stored as aliquots for future use. The transgenesis reaction and egg injection take one morning.
TL;DR: The results suggest that CITED1 functions as a cell cycle-dependent transcriptional cofactor whose activity is regulated by phosphorylation.
TL;DR: The findings demonstrate the feasibility of modeling the genetic basis of common CHD using animal genetic and genomic technologies and demonstrate that multiple anatomical processes under separate genetic control contribute to risk of PFO.
Abstract: Atrial septal defect (ASD) is a common congenital heart disease (CHD) occurring in 5 to 7 per 10 000 live births. Mutations in 5 human genes ( NKX2.5 , TBX5 , GATA4 , MYHC , ACTC ) are known to cause dominant ASD, but these account for a minority of cases. Human and mouse data suggest that ASD exists in an anatomical continuum with milder septal variants patent foramen ovale (PFO) and atrial septal aneurysm, strongly associated with ischemic stroke and migraine. We have previously shown in inbred mice that the incidence of PFO strongly correlates with length of the interatrial septum primum , defining a quantitative trait underlying PFO risk. To better understand genetic causation of atrial septal abnormalities, we mapped quantitative trait loci (QTL) influencing septal morphology using mouse strains (QSi5 and 129T2/SvEms) maximally informative for PFO incidence and 3 quantitative septal anatomical traits including septum primum length. [QSi5×129T2/SvEms]F2 intercross animals (n=1437) were phenotyped and a whole genome scan performed at an average 17-cM interval. Statistical methodology scoring PFO as a binary phenotype was developed as a confirmatory mapping technique. We mapped 7 significant and 6 suggestive QTL modifying quantitative phenotypes, with 4 supported by binary analysis. Quantitative traits, although strongly associated with PFO ( P
TL;DR: Two conditional null alleles allowing Cre‐recombinase‐mediated somatic cell gene inactivation are reported, which are useful genetic tools for dissecting the functions of Cited2 in the formation of different organs and patterning of the developing embryo.
Abstract: Cited2 is a transcriptional co-factor that is widely expressed in both embryonic and extraembryonic cells during early development. It is essential for embryonic development with Cited2 null embryos showing abnormal development of organs including heart, neural tube, adrenal glands, and placenta (both in trophoblast derivatives and invading fetal vasculature), as well as having defects in the establishment of the left-right body axis. We report the generation of two conditional null alleles allowing Cre-recombinase-mediated somatic cell gene inactivation. Mice heterozygous or homozygous for these alleles are viable and fertile. Crossing conditional mutants with CMV-Cre transgenic mice produces an embryonic-lethal phenotype in the offspring indistinguishable from germline null mutants. We also demonstrate that conditional deletion results in lacZ expression under the control of the Cited2 promoter. These alleles are therefore useful genetic tools for dissecting the functions of Cited2 in the formation of different organs and patterning of the developing embryo. genesis
TL;DR: The flow characteristics and flow responses of the RA graft suggest that it is a more physiological conduit than the LSV graft, which may have implications on coronary artery bypass graft (CABG) survival.
Abstract: The morphological and functional differences between arteries and veins may have implications on coronary artery bypass graft (CABG) survival. Although subjective differences have been observed between radial artery (RA) and long saphenous venous (LSV) grafts, these have not been quantified. This study assessed and compared the flow characteristics and in-vivo graft flow responses of RA and LSV aorto-coronary grafts. Angiograms from 52 males taken 3.7 ± 1.0 months after CABG surgery were analyzed using adjusted Thrombolysis in Myocardial Infarction (TIMI) frame count. Graft and target coronary artery dimensions were measured using quantitative coronary angiography. Estimated TIMI velocity (VE) and volume flow (FE) were then calculated. A further 7 patients underwent in-vivo graft flow responses assessments to adenosine, acetylcholine and isosorbide dinitrate (ISDN) using intravascular Doppler. The VE for RA grafts was significantly greater than LSV grafts (P = 0.002), however there was no difference in volume FE (P = 0.20). RA grafts showed positive endothelium-dependent and -independent vasodilatation, and LSV grafts showed no statistically significant response to adenosine and acetylcholine. There was no difference in flow velocity or volume responses. Seven RA grafts (11%) had compromised patency (4 (6%) ≥ 50% stenosis in the proximal/distal anastomoses, and 3 (5%) diffuse narrowing). Thirty-seven (95%) LSV grafts achieved perfect patency and 2 (5%) were occluded. The flow characteristics and flow responses of the RA graft suggest that it is a more physiological conduit than the LSV graft. The clinical relevance of the balance between imperfect patency versus the more physiological vascular function in the RA graft may be revealed by the 5-year angiographic follow-up of this trial.
TL;DR: Transglutaminases effect posttranslational modification of proteins by amine incorporation, or stabilization of protein assemblies by their cross-linking, which profoundly influence critical biological processes such as blood clotting and protection from infection and dehydration by establishing the barrier function of skin.
Abstract: Transglutaminases are a family of calcium- and thiol-dependent acyl transferases that catalyze the formation of an amide bond between the gamma-carboxamide groups of peptide-bound glutamine residues and the primary amino groups in various compounds, including the epsilon-amino group of lysines in certain proteins. As a result, these enzymes effect posttranslational modification of proteins by amine incorporation, or stabilization of protein assemblies by their cross-linking; such actions profoundly influence critical biological processes such as blood clotting and protection from infection and dehydration by establishing the barrier function of skin. In addition, transglutaminases have other more diverse actions, including involvement in signaling by the superfamily of heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) in one of three ways: (i) through actions as guanosine triphosphate-binding proteins that activate intracellular effectors, such as phospholipase C; (ii) by cross-linking GPCR monomers to enhance signaling as a result of covalent dimer formation; or (iii) by interacting with an apparent growth inhibitory orphan GPCR, GPR56, to limit metastatic spread of melanoma cells. The implications of these receptor-coupled actions of transglutaminases are discussed.
TL;DR: A better understanding of molecular genetic aetiologies for sudden cardiac death will be required for future study toward unveiling aetiology in sudden cardiacdeath in small animals.
Abstract: Sudden cardiac death in small animals is uncommon but often occurs due to cardiac conduction defects or myocardial diseases. Primary cardiac conduction defects are mainly caused by mutations in genes involved in impulse conduction processes (e.g., gap-junction genes and transcription factors) or repolarisation processes (e.g., ion-channel genes), whereas primary cardiomyopathies are mainly caused by defective force generation or force transmission due to gene mutations in either sarcomeric or cytoskeleton proteins. Although over 50 genes have been identified in humans directly or indirectly related to sudden cardiac death, no genetic aetiologies have been identified in small animals. Sudden cardiac deaths have been also reported in German Shepherds and Boxers. A better understanding of molecular genetic aetiologies for sudden cardiac death will be required for future study toward unveiling aetiology in sudden cardiac death in small animals.
TL;DR: The conditional allele described herein is a genetic tool for studying tissue‐specific, RALDH2‐dependent functions of retinoic acid during development and in adult life.
Abstract: Retinoic acid, the active vitamin A derivative, has pleiotropic functions during vertebrate development and postnatal life. Retinaldehyde dehydrogenase 2 (RALDH2) acts as the main retinoic acid-synthesizing enzyme during development. Mouse Raldh2 germline null mutants are early embryonic lethal and exhibit complex abnormalities that include defective heart looping morphogenesis. To investigate later functions of this enzyme, we have engineered a "floxed" (loxP-flanked) allele allowing Cre-mediated somatic gene inactivations. Mice heterozygous or homozygous for the floxed Raldh2 allele are viable and fertile. We tested whether the novel Raldh2 allele behaves as a null mutation after Cre-mediated in vivo excision by crossing the conditional mutants with CMV-Cre transgenic mice. An embryonic lethal phenotype indistinguishable from that of germline mutants was obtained. The conditional allele described herein is a genetic tool for studying tissue-specific, RALDH2-dependent functions of retinoic acid during development and in adult life.
TL;DR: The relationship between conformations of disulfides and their location in protein secondary structures is examined, to address whether the high torsional energy of a cross-strand disulfide is sufficient to confer redox activity or whether other factors, such as the presence of the cross- Strand Disulfide in a strained beta-sheet, are required.
Abstract: Redox-active disulfides are capable of being oxidized and reduced under physiological conditions. The enzymatic role of redox-active disulfides in thiol-disulfide reductases is well-known, but redox-active disulfides are also present in non-enzymatic protein structures where they may act as switches of protein function. Here, we examine disulfides linking adjacent β-strands (cross-strand disulfides), which have been reported to be redox-active. Our previous work has established that these cross-strand disulfides have high torsional energies, a quantity likely to be related to the ease with which the disulfide is reduced. We examine the relationship between conformations of disulfides and their location in protein secondary structures. By identifying the overlap between cross-strand disulfides and various conformations, we wish to address whether the high torsional energy of a cross-strand disulfide is sufficient to confer redox activity or whether other factors, such as the presence of the cross-strand disulfide in a strained β-sheet, are required.
TL;DR: The general features and pathogenesis of major CHDs in humans and small animals are discussed and the known genetic aetiologies in human CHDs have been considered in parallel toCHDs in small animals.
Abstract: Comparative genetics provides veterinary researchers and clinicians with invaluable information for the understanding the possible genetic aetiologies and the disease process in congenital heart defects (CHDs) of dogs and cats. Although, the demand on this type of research has increased in the veterinary field, to date no fundamental genetic studies have been reported in the veterinary literature. In this second part of a two-part review, the general features and pathogenesis of major CHDs in humans and small animals are discussed. In addition, the known genetic aetiologies in human CHDs have been considered in parallel to CHDs in small animals.
01 Jan 2006
TL;DR: A plethora of structure-function studies have provided major insights into the molecular determinants of adrenergic receptor ligand-binding, activation, and signaling, many of which are relevant not only to the adrenergic receptors family but also to the broader superfamily of G protein-coupled receptors.
Abstract: Adrenergic receptors are critical mediators of sympaiMolecular Cardiology Program, Vihysiological responses. Activated by the neurotransmitter and neurohormone, norepinephrine and epinephrine, released from sympathetic nerve endings and the adrenal medulla, respectively, they play a central role in this evolutionarily ancient defense system that regulates many physiological functions, including those involved in circulatory, metabolic, respiratory, and central nervous system homeostasis. In addition, alterations in the regulation and molecular structure of adrenergic receptors have been implicated in a variety of diseases, and drugs targeting these receptors are important and widely used therapeutics. The molecular cloning of the first adrenergic receptor in 1986 revealed structural homology with the functionally related rhodopsin visual transduction system—a finding that led to the realization that these receptors formed a new superfamily of proteins, now known as G protein-coupled receptors. Since that time, a plethora of structure-function studies have provided major insights into the molecular determinants of adrenergic receptor ligand-binding, activation, and signaling, many of which are relevant not only to the adrenergic receptor family but also, more generally, to the broader superfamily of G protein-coupled receptors. These advances in our understanding of adrenergic receptor activation, regulation, and functioning are reviewed in this chapter.
TL;DR: The major genetic pathways for cardiomorphogenesis and important candidate genes for CHDs, based on mouse knock-out and human genetic studies are discussed.
Abstract: Proper cardiac morphogenesis requires a series of specific cell and tissue interactions driven by several cardiac transcription factors and downstream cardiac genes. To date, a number of genetic aetiologies responsible for human congenital heart defects (CHDs) have been identified, although none has been found for CHDs in small animals. Most gene mutations responsible for human CHDs exist in genetic pathways associated with cardiomorphogenesis. Insights into cardiomorphogenesis from human and mouse genetic studies will help us to identify potential genetic aetiologies in CHDs in small animals. Therefore, in this first part of a two-part review, the major genetic pathways for cardiomorphogenesis and important candidate genes for CHDs, based on mouse knock-out and human genetic studies are discussed.
TL;DR: The finding that brachial blood pressure but not central (carotid) waveforms predicts mortality contradicts the authors' previous study, which showed the reverse, as well as a host of recent studies, including the Conduit Artery Function Evaluation (CAFE) study.
Abstract: To the Editor:
The report by Dart et al in Hypertension 1 on a selected cohort of the Australian National Blood Pressure Study 2 (ANBP2) trial appears just to extend the controversy created by the original trial2 The finding that brachial blood pressure but not central (carotid) waveforms predicts mortality contradicts the authors’ previous study, which showed the reverse (in males),3 as well as a host of recent studies, including the Conduit Artery Function Evaluation (CAFE) study4 The finding also …
TL;DR: In this paper, the alpha(1D)-adrenergic receptor (AR) was shown to have increased cell-surface expression and the formation of a novel functional entity, which is called alpha-1D-AR.
Abstract: This Perspective focuses on the alpha(1D)-adrenergic receptor (AR), the often neglected sibling of the alpha(1)-AR family. This neglect is due in part to its poor cell-surface expression. However, it has recently been shown that dimerization of the alpha(1D)-AR with either the alpha(1B)-AR or the beta(2)-AR increases alpha(1D)-AR cell-surface expression, and in this issue of Molecular Pharmacology, Hague et al. (p. 45) demonstrate that dimerization of the alpha(1D)-AR with the alpha(1B)-AR not only leads to increased cell-surface expression but also results in the formation of a novel functional entity.
TL;DR: The debate surrounding the recreation of the 1918 (Spanish) human influenza virus, focuses solely on the question of publication, giving little attention to the possibility of regulating potentially harmful experiments before they are started.
Abstract: SIR — Your Special Report “The 1918 flu virus is resurrected” (Nature 437, 794–795; 2005), on the debate surrounding the recreation of the 1918 (Spanish) human influenza virus, focuses solely on the question of publication, giving little attention to the possibility of regulating potentially harmful experiments before they are started. A key element of co-operative security is trust and confidence. Only a high level of transparency will enable nations to judge others’ intentions correctly, act to discourage unfounded suspicion and build confidence in compliance with arms-control treaties. Withholding critical information on dualuse research would undermine arms-control efforts. Once a research project has been conducted, it should be published in full. The preferred option for research where potential risks are considered to outweigh potential benefits is to stop the research before it even starts. Both the UK Royal Society and the US National Academy of Sciences have proposed a systematic review of scientific research proposals before work starts, but this approach is entirely neglected in the debate about the Spanish flu virus. The consequences of this project could, and should, have been assessed ten years ago or at any time since. Another shortcoming of the current debate is the lack of a systematic approach to risk–benefit analysis. Any intervention in the scientific process should be based on a scientifically sound assessment of both risks and benefits. Criteria to assess the potential misuse of dual-use research include its military usefulness and the level of technical expertise needed to apply this knowledge for malign purposes, taking into account a variety of potential actors. The availability of risk-management tools, such as effective arms-control measures, is also an important factor in risk assessment. Although most commentators agree that the misuse potential of the Spanish-flu work is comparatively high, it seems that the objective assessment of benefits is the more contentious part of the equation. Your Special Report claims that the Spanish-flu work increases understanding of virulence and pathogenicity factors, and might contribute to identifying the next pandemic strain or developing appropriate drugs. These general statements hold true for most biomedical research projects. But generalities contribute little to a systematic risk–benefit analysis, which should include an assessment of the importance of the research in a health and humanitarian context, whether alternative research avenues are available and the added value of any particular experimental approach. Influenza pandemics are an important public-health problem, but it is questionable whether a reconstructed viral strain from 1918 is necessary to address this problem. Hundreds of other influenza strains from the past five decades, varying highly in terms of contagiousness and pathogenicity, provide an abundant research resource for comparative studies. The added value of one additional strain — and thus the concrete benefit of the reconstructed Spanish flu strain — is very limited. Dr Jan van Aken Hamburg Centre of Biological Arms Control, Hamburg University, Falkenried 94, 20251 Hamburg, Germany