Cardiac MIBG imaging at the edge of clinical application in heart failure

Neuronal innervation plays a crucial role in cardiac function. The heart is richly innervated with sympathetic and parasympathetic fibers that work in conjunction with circulating catecholamine mediators, such as norepinephrine (NE), to tightly regulate cardiac output at rest and during periods of increased cardiac demand. An impairment of cardiac autonomic function, most often the result of cardiac disease (ischemic or nonischemic cardiomyopathy), can reflect the severity of the condition, and in many cases is associated with and likely contributing to worsening of the clinical condition, increasing the potential for life-threatening cardiac arrhythmias and death. Because cardiac autonomic function involves numerous molecular processes, use of radiotracers for imaging is an ideal method of assessment.     

Proteomic Profiling of Purified Rabies Virus Particles

While host proteins incorporated into virions during viral budding from infected cell are known to play essential roles in multiple process of the life cycle of progeny virus, these characteristics have been largely neglected in studies on rabies virus(RABV). Here, we purified the RABV virions with good purity and integrity, and analyzed their proteome by nano LC–MS/MS, followed by the confirmation with immunoblot and immuno-electronic microscopy. In addition to the 5 viral proteins, 49 cellular proteins were reproducibly identified to be incorporated into matured RABV virions. Function annotation suggested that 24 of them were likely involved in virus replication. Furthermore, cryo-EM was employed to observe the purified RABV virions, generating high-resolution pictures of the bullet-shaped virion structure of RABV. This study has provided new insights into the host proteins composition in RABV virion and shed the light for further investigation on molecular mechanisms of RABV infection, as well as the discovery of new anti-RABV therapeutics.     

Demography in stochastic environments. I. Exact distributions of age structure

The steady state distribution of age structure is studied for populations with two age classes and stochastic vital rates. For a serially uncorrelated dichotomic vital rate the distribution of age structure is found analytically to be a singular steplike function; outside a specific region of vital rate values the singular function crosses a threshold to a smooth function. For a vital rate following a correlated two state Markov process the joint distributions of age structure and environment are found analytically to be singular steplike functions; again a threshold marks a transition to a smooth function. For fecundities which are serially uncorrelated but continuously distributed the age structure distribution is obtained as a smooth analytic function for all parameter values. These explicit results have applications to studies of age structure and average growth rate.     

Getting to the heart of the matter: CCN2 plays a role in cardiomyocyte hypertrophy

Connective tissue growth factor (CTGF/CCN2) is overexpressed in diabetes. Diabetic rats possess myocardial and cardiomyocyte hypertrophy. In a recent report, Wang and colleagues (Am J Physiol Cell Physiol. 2009 Jul 22. [Epub ahead of print]) show that CCN2 directly mediates cardiomyocyte hypertrophy as well as that induced by high glucose and fatty acid. CCN2 acted via the TrkA receptor. These data are the subject of this commentary, and emphasize that CCN2 may be an excellent target for therapy in diabetes.     

Modeling of substrate and inhibitor binding to phospholipase A2.

Molecular graphics and molecular mechanics techniques have been used to study the mode of ligand binding and mechanism of action of the enzyme phospholipase A2. A substrate-enzyme complex was constructed based on the crystal structure of the apoenzyme. The complex was minimized to relieve initial strain, and the structural and energetic features of the resultant complex analyzed in detail, at the molecular and residue level. The minimized complex was then used as a basis for examining the action of the enzyme on modified substrates, binding of inhibitors to the enzyme, and possible reaction intermediate complexes. The model is compatible with the suggested mechanism of hydrolysis and with experimental data about stereoselectivity, efficiency of hydrolysis of modified substrates, and inhibitor potency. In conclusion, the model can be used as a tool in evaluating new ligands as possible substrates and in the rational design of inhibitors, for the therapeutic treatment of diseases such as rheumatoid arthritis, atherosclerosis, and asthma.     

Absolute configuration and conformation of the pure opioid antagonist (+)-2,9 alpha-dimethyl-5-(m-hydroxyphenyl)morphan.

(+)-2,9 alpha-Dimethyl-5-(m-hydroxyphenyl)morphan is the only phenylmorphan analog whose affinity for opioid kappa-receptors is greater than its affinity for opioid mu-receptors. Pharmacologically, the compound is a pure opioid antagonist devoid of agonist activity in in vivo assays of antinociception. The absolute configuration of the compound has been determined to be (1R,5S,9R) from an X-ray crystallographic study of the chloride salt. Thus, the absolute configuration corresponds to that of the atypical opioid agonist (-)-phenylmorphan while the weak atypical agonist (-)-2,9 alpha-dimethyl-5-(m- hydroxyphenyl)morphan corresponds to the potent morphine-like (+)-phenylmorphan. The preferred orientations of the phenyl ring for the two stereoisomers were determined using the molecular mechanics program MM2-87 and found to vary from that of the two parent compounds. The atypical properties of the two 9 alpha-methyl analogs is consistent with an opioid ligand model which proposes that morphine-like properties require a particular range of phenyl orientations. There was good agreement between the structure obtained from X-ray crystallography and computed with the MM2-87 program.     

Typologie des rivières oligotrophes du massif Ardennais (Belgique) par l'analyse multivariée de relevés de diatomées benthiques

Typology of oligotrophic streams of the Ardenne (Belgium) by multivariate analysis of benthic diatoms records.During three years, samples of water and algae has been taken in 72 stations distributed on the river system of the northern part of the Ardennes. 357 taxa of diatoms have been identified. Principal component analysis and cluster analysis, applied to diatoms counts, allowed to classify the records in a table comparable to phytosociological tables. A continuum in the data is an indication of the progressive modification of the communities according to the physico-chemical characteristics of the water. Ten diatoms assemblages have been described and this typology has been compared to some algal associations defined in the literature. In natural environments, these 10 assemblages are strictly correlated with the nature of the geological substrate and the physico-chemical characteristics of the water. The sensibility of the oligotrophic streams is revealed by the speedy changes in the communities after following a small modification of the environmental factors (seasonal variations or light eutrophication).

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Typologie des rivières oligotrophes du massif Ardennais (Belgique) par l'analyse multivariée de relevés de diatomées benthiques

     

Rapid reprogramming of haemoglobin structure‐function exposes multiple dual‐antimicrobial potencies

The intrinsic cytotoxicity of cell‐free haemoglobin (Hb) has hampered the development of reliable Hb‐based blood substitutes for over seven decades. Notably, recent evidence shows that the Hb deploys this cytotoxic attack against invading microbes, albeit, through an unknown mechanism. Here, we unraveled a rapid molecular reprogramming of the Hb structure‐function triggered by virulent haemolytic pathogens that feed on the haem‐iron. On direct contact with the microbe, the Hb unveils its latent antimicrobial potency, where multiple antimicrobial fragments are released, each harbouring coordinated ‘dual‐action centres’: microbe binding and pseudoperoxidase (POX) cycle activity. The activated Hb fragments anchor onto the microbe while the juxtaposed POX instantly unleashes a localized oxidative shock, killing the pathogen‐in‐proximity. This concurrent action conceivably restricts the diffusion of free radicals. Furthermore, the host astutely protects itself from self‐cytotoxicity by simultaneously releasing endogenous antioxidants. We found that this decryption mechanism of antimicrobial potency is conserved in the ancient invertebrate respiratory protein, indicating its fundamental significance. Our definition of dual‐antimicrobial centres in the Hb provides vital clues for designing a safer Hb‐based oxygen carrier blood substitute.