The mitochondrial trifunctional protein: centre of a beta-oxidation metabolon?

The trifunctional enzyme comprises three consecutive steps in the mitochondrial beta-oxidation of long-chain acyl-CoA esters: 2-enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase and 3-ketoacyl-CoA thiolase. Deficiencies in either 3-hydroxyacyl-CoA dehydrogenase activity, or all three activities, are important causes of human disease. The dehydrogenase and thiolase have a requirement for NAD+ and CoA respectively, whose levels are conserved within the mitochondrion and thus provide possible means for control and regulation of beta-oxidation. Using analysis of the intact CoA ester intermediates produced by the complex, we have examined the sensitivity of the complex to NAD+/NADH and acetyl-CoA. We consider the evidence for channelling within the trifunctional protein and propose a model for a beta-oxidation 'metabolon'.     

The area postrema: a cardiovascular control centre at the blood-brain interface?

The area postrema (AP) is one of the circumventricular organs of the brain and as such it is highly vascular and lacks the normal blood-brain barrier. Anatomical tracing studies have demonstrated afferent projections to AP originating from the paraventricular nucleus, lateral parabrachial nucleus (l-PBN), nucleus tractus solitarius (NTS), as well as the vagus nerve. AP neurons have been shown to project primarily to l-PBN, and NTS. Receptor localization studies have reported dense aggregations of many specific peptide receptors in AP including those for angiotensin II (ANG), atrial natriuretic peptide (ANP), and endothelin (ET). Electrical stimulation studies have shown that activation of AP neurons at low frequencies (less than 15 Hz) results in decreases in blood pressure and heart rate, while higher frequency (greater than 20 Hz) stimulation causes increases in blood pressure. These low frequency effects on blood pressure and heart rate appear to result from activation of separate components of the autonomic nervous system. Extracellular single unit recordings have identified two functionally separate populations of AP neurons: one responsive to circulating ANG and a second apparently responsive to changes in blood pressure. In addition, AP neurons are activated by increases in circulating ET. Afferent inputs to AP neurons from 1-PBN have separate excitatory (12% of AP neurons) or inhibitory (12% of AP neurons) effects on a relatively small proportion of AP neurons. In contrast, preliminary evidence suggests a much more broadly distributed excitatory input to approximately 70% of tested AP neurons originating from the aortic depressor nerve. These studies provide considerable evidence implicating the AP as a significant neural structure regulating the cardiovascular system.     

The antihypertensive effect of peptides: a novel alternative to drugs?

Many types of bioactive peptides that inhibit angiotensin I, angiotensin I converting enzyme (ACE) and Ang II type 1 receptor (AT1) in the cardiovascular system contribute to the prevention and treatment of hypertension. These inhibitory peptides are derived from many food proteins or artificial synthetic products. Further research examining the bioavailability of ACE inhibitory peptides will lead to the development of more effective ACE inhibitory peptides and foods. Our research also demonstrates that ACE inhibitory peptide LAP may lower blood pressure with no adverse effects.     

The short-latency dopamine signal: a role in discovering novel actions?

An influential concept in contemporary computational neuroscience is the reward prediction error hypothesis of phasic dopaminergic function. It maintains that midbrain dopaminergic neurons signal the occurrence of unpredicted reward, which is used in appetitive learning to reinforce existing actions that most often lead to reward. However, the availability of limited afferent sensory processing and the precise timing of dopaminergic signals suggest that they might instead have a central role in identifying which aspects of context and behavioural output are crucial in causing unpredicted events.     

The extravascular compartment of the bone marrow: a niche for Plasmodium falciparum gametocyte maturation?

ABSTRACT: BACKGROUND: Plasmodium falciparum immature gametocytes accumulate in the bone marrow, but their exact location in this tissue remains unclear. METHODS: The stage and deposition pattern of gametocytes was analysed on histological sections of a bone marrow sample collected in a patient with subacute P. falciparum malaria. RESULTS: A majority (89%) of immature stages II to IV gametocytes and a minority (29%) of mature stage V gametocytes were observed in extravascular spaces. Discussion and conclusion These observations represent a valuable step towards understanding sequestration patterns of P. falciparum gametocytes and may ultimately lead to novel transmission-blocking interventions.     

Neuropeptide S: a novel activating anxiolytic?

Many different neuropharmacological agents modulate arousal and anxiety, yet to date, few endogenous substances have produced arousal with an anxiolytic effect. In this issue of Neuron, Xu et al. describe the localization and characterization of a novel neuropeptide, neuropeptide S (and its cognate receptor), that is unique in its arousing and anxiolytic-like properties.     

The novel cytochrome c6 of chloroplasts: a case of evolutionary bricolage?

Cytochrome c6 has long been known as a redox carrier of the thylakoid lumen of cyanobacteria and some eukaryotic algae that can substitute for plastocyanin in electron transfer. Until recently, it was widely accepted that land plants lack a cytochrome c6. However, a homologue of the protein has now been identified in several plant species together with an additional isoform in the green alga Chlamydomonas reinhardtii. This form of the protein, designated cytochrome c6A, differs from the 'conventional' cytochrome c6 in possessing a conserved insertion of 12 amino acids that includes two absolutely conserved cysteine residues. There are conflicting reports of whether cytochrome c6A can substitute for plastocyanin in photosynthetic electron transfer. The evidence for and against this is reviewed and the likely evolutionary history of cytochrome c6A is discussed. It is suggested that it has been converted from a primary role in electron transfer to one in regulation within the chloroplast, and is an example of evolutionary 'bricolage'.     

Pharmacomicrobiomics: a novel route towards personalized medicine?

Inter-individual heterogeneity in drug response is a serious problem that affects the patient’s wellbeing and poses enormous clinical and financial burdens on a societal level. Pharmacogenomics has been at the forefront of research into the impact of individual genetic background on drug response variability or drug toxicity, and recently the gut microbiome, which has also been called the second genome, has been recognized as an important player in this respect. Moreover, the microbiome is a very attractive target for improving drug efficacy and safety due to the opportunities to manipulate its composition. Pharmacomicrobiomics is an emerging field that investigates the interplay of microbiome variation and drugs response and disposition (absorption, distribution, metabolism and excretion). In this review, we provide a historical overview and examine current state-of-the-art knowledge on the complex interactions between gut microbiome, host and drugs. We argue that combining pharmacogenomics and pharmacomicrobiomics will provide an important foundation for making major advances in personalized medicine.     

TWEAK: a novel biomarker for lupus nephritis?

Renal involvement is common in systemic lupus erythematosus. Early diagnosis of lupus nephritis (LN), allowing the instigation of appropriate therapy, remains an important clinical challenge. Current biomarkers in clinical practice are less than ideal, lacking both sensitivity and specificity. In the previous issue of Arthritis Research & Therapy, Schwartz and colleagues demonstrated the potential value of urinary TNF-like weak inducer of apoptosis (uTWEAK) as a biomarker for LN. They showed that uTWEAK is elevated in subjects with LN at diagnosis compared with those with systemic lupus erythematosus but no renal disease, and correlates with the degree of clinical disease activity. These data are thought-provoking and provide the platform for future longer-term studies.     

Embryonic induction: Is the Nieuwkoop centre a useful concept?

Regionalisation of the amphibian embryo is classically thought to involve induction by the Spemann organiser, itself induced by the Nieuwkoop centre. This model has now been extended to teleosts, with the identification of a gene that appears to define the zebrafish equivalent of the Nieuwkoop centre.     

The wonder exerkines—novel insights: a critical state-of-the-art review

Molecular and Cellular Biochemistry - Several benefits can be acquired through physical exercise. Different classes of biomolecules are responsible for the cross-talk between distant organs. The...     

The AngioGuard: a simplified snare?

We describe a case of successful retrieval of a lost intracoronary stent using the ANGIOGUARD XP emboli retraction guidewire system (Cordis Corporation) as a safe and innovative method for management of this critical issue in an 80-year old male patient.     

Character displacement: in situ evolution of novel phenotypes or sorting of pre‐existing variation?

Character displacement - the divergence of traits between species in response to competition for resources or mates - has long been viewed as a major cause of adaptive diversification and species coexistence. Yet, we lack answers to basic questions concerning the causes and consequences of character displacement, not the least of which is why some species are more prone than others to undergo character displacement. Here, we address these questions by describing how character displacement can proceed through two nonexclusive routes that differ in the source of phenotypic variation, and, hence, in the ease with which character displacement may unfold. During in situ evolution of novel phenotypes, new traits that are divergent from a heterospecific competitor are generated and spread in sympatry. During sorting of pre-existing variation, such traits are initially favoured in allopatry before the two species encounter one another. Later, when they come into contact, character displacement transpires when these pre-existing divergent phenotypes increase in frequency in sympatry relative to allopatry. Because such sorting of pre-existing variation should unfold relatively rapidly, we suggest that species that express resource or mating polymorphism prior to interactions with heterospecifics may be more prone to undergo character displacement. We discuss the key differences between these two routes, review possible examples of each, and describe how the distinction between them provides unique insights into the evolutionary consequences of species interactions, the origins of diversity, and the factors that govern species coexistence.     

Chitinase: a novel target for blocking parasite transmission?

In many species of blood-sucking arthropod, the internal tissues are covered by chitinous material that may hinder parasite invasion. To circumvent this potential barrier, therefore, parasites have developed mechanisms that involve the enzyme chitinase. In this review, Mohammed Shohobuddin and David C. Kaslow examine the relationship between chitinase and parasite transmission.     

Vertebrate somitogenesis: a novel paradigm for animal segmentation?

In vertebrates, the primary segmented tissue of the body axis is the paraxial mesoderm, which lies bilaterally to the axial organs, neural tube and notochord. The segmental pattern of the paraxial mesoderm is established during embryogenesis through the production of the somites which are transient embryonic segments giving rise to the vertebrae, the skeletal muscles and the dorsal dermis. Somitogenesis can be subdivided into three major phases (see Fig. 1). First a growth phase during which new paraxial mesoderm cells are produced by a growth zone (epiblast and blastopore margin or primitive streak and later on tail bud) and become organized as two rods of mesenchymal tissue,forming the presomitic mesoderm. Second a patterning phase occuring in the PSM, during which the segmental pattern is established at the molecular level. Third, the somitic boundaries are formed during the morphological segmentation phase. In all vertebrates, all cells of the paraxial mesoderm, during their maturation in the PSM, go successively through these three phases, which are tightly regulated at the spatio-temporal level. The first phase of paraxial mesoderm production falls out of the scope of this review, as it essentially pertains to the gastrulation process. Here, I essentially discuss the segmental patterning phase in vertebrates. Recent data suggest that establishment of the segmental pattern relies on a clock and wavefront mechanism which has been conserved in vertebrates. Furthermore, conservation of this system could extend to invertebrates, suggesting that the clock and wavefront is an ancestral mechanism.     

Histamine in cardiac sympathetic ganglia: a novel neurotransmitter?

Although ganglia in the heart are well known to be cholinergic, many other neurotransmitters and neuropeptides also influence (and are produced in) cardiac neurons, including adrenergic and purinergic compounds. Recently, histamine was suggested as a possible neurotransmitter in cardiac tissue. Although histamine does elicit many effects in the heart, does it stand up to rigorous scrutiny and fulfill certain criteria that are used to define neurotransmitters?