Cardiac arrhythmia induced by genetic silencing of 'funny' (f) channels is rescued by GIRK4 inactivation.

The mechanisms underlying cardiac automaticity are still incompletely understood and controversial. Here we report the complete conditional and time-controlled silencing of the 'funny' current (If) by expression of a dominant-negative, non-conductive HCN4-channel subunit (hHCN4-AYA). Heart-specific If silencing caused altered [Ca(2+)]i release and Ca(2+) handling in the sinoatrial node, impaired pacemaker activity and symptoms reminiscent of severe human disease of pacemaking.

Repeated stimulation of dopamine D1-like receptor and hyperactivation of mTOR signaling lead to generalized seizures, altered dentate gyrus plasticity, and memory deficits.

The acute activation of the dopamine D1-like receptors (D1R) is involved in a plethora of functions ranging from increased locomotor activity to the facilitation of consolidation, storage, and retrieval of memories. Although much less characterized, epileptiform activities, usually triggered by disruption of the glutamate and GABA balance, have also been reported to involve the dopaminergic transmission. Using a combination of biochemical, immunohistochemical, electrophysiological, and behavioral approaches we have investigated the consequences of repeated stimulation of D1R using the selective D1R-like agonist SKF81297.

Reports of long-lasting insecticidal bed nets catching on fire: a threat to bed net users and to successful malaria control?

Background: One of the control tools to reduce malaria transmission is the use of LLINs. However, several studies show that household bed net use is quite low. A study was developed to better understand the cultural factors that might explain these gaps in Benin.

Glucose and glutamine metabolism regulate human hematopoietic stem cell lineage specification.

The metabolic state of quiescent hematopoietic stem cells (HSCs) is an important regulator of self-renewal, but it is unclear whether or how metabolic parameters contribute to HSC lineage specification and commitment. Here, we show that the commitment of human and murine HSCs to the erythroid lineage is dependent upon glutamine metabolism. HSCs require the ASCT2 glutamine transporter and active glutamine metabolism for erythroid specification.

Gd3+ and calcium sensitive, sodium leak currents are features of weak membrane-glass seals in patch clamp recordings.

The properties of leaky patch currents in whole cell recording of HEK-293T cells were examined as a means to separate these control currents from expressed sodium and calcium leak channel currents from snail NALCN leak channels possessing both sodium (EKEE) and calcium (EEEE) selectivity filters. Leak currents were generated by the weakening of gigaohm patch seals by artificial membrane rupture using the ZAP function on the patch clamp amplifier. Surprisingly, we found that leak currents generated from the weakened membrane/glass seal can be surprisingly stable and exhibit behavior that is consistent with a sodium leak current derived from an expressible channel.

The stoichiometry of scaffold complexes in living neurons - DLC2 functions as a dimerization engine for GKAP.

Quantitative spatio-temporal characterization of protein interactions in living cells remains a major challenge facing modern biology. We have investigated in living neurons the spatial dependence of the stoichiometry of interactions between two core proteins of the N-methyl-D-aspartate (NMDA)-receptor-associated scaffolding complex, GKAP (also known as DLGAP1) and DLC2 (also known as DYNLL2), using a novel variation of fluorescence fluctuation microscopy called two-photon scanning number and brightness (sN&B). We found that dimerization of DLC2 was required for its interaction with GKAP, which, in turn, potentiated GKAP self-association.

Cdk5 induces constitutive activation of 5-HT6 receptors to promote neurite growth.

The serotonin6 receptor (5-HT6R) is a promising target for treating cognitive deficits of schizophrenia often linked to alterations of neuronal development. This receptor controls neurodevelopmental processes, but the signaling mechanisms involved remain poorly understood. Using a proteomic strategy, we show that 5-HT6Rs constitutively interact with cyclin-dependent kinase 5 (Cdk5).

Contrasting forms of cocaine-evoked plasticity control components of relapse.

Nucleus accumbens neurons serve to integrate information from cortical and limbic regions to direct behaviour. Addictive drugs are proposed to hijack this system, enabling drug-associated cues to trigger relapse to drug seeking. However, the connections affected and proof of causality remain to be established.

Synthesis, discovery, and quantitation of dihomo-isofurans: biomarkers for in vivo adrenic acid peroxidation.

The growing importance of lipidomics, and the interest of non-enzymatic metabolites of polyunsaturated fatty acids (PUFAs) prompted us to initiate the synthesis of novel dihomo-IsoF compounds. Such metabolites of adrenic acid, the main PUFA in white matter, were synthesized using a divergent approach based on an orthoester cyclization. LC-MS/MS investigation on pig brains showed the potential of this novel biomarker for the first time, as a powerful new tool for brain lipid peroxidation assessment.

Phosphorylation of KasB regulates virulence and acid-fastness in Mycobacterium tuberculosis.

Mycobacterium tuberculosis bacilli display two signature features: acid-fast staining and the capacity to induce long-term latent infections in humans. However, the mechanisms governing these two important processes remain largely unknown. Ser/Thr phosphorylation has recently emerged as an important regulatory mechanism allowing mycobacteria to adapt their cell wall structure/composition in response to their environment.

Zebrafish as a model of cardiac disease.

The zebrafish has been rapidly adopted as a model for cardiac development and disease. The transparency of the embryo, its limited requirement for active oxygen delivery, and ease of use in genetic manipulations and chemical exposure have made it a powerful alternative to rodents. Novel technologies like TALEN/CRISPR-mediated genome engineering and advanced imaging methods will only accelerate its use.

T-type calcium channel Cav3.2 deficient mice show elevated anxiety, impaired memory and reduced sensitivity to psychostimulants.

The fine-tuning of neuronal excitability relies on a tight control of Ca(2+) homeostasis. The low voltage-activated (LVA) T-type calcium channels (Cav3.1, Cav3.

Complex GABAB receptor complexes: how to generate multiple functionally distinct units from a single receptor.

The main inhibitory neurotransmitter, GABA, acts on both ligand-gated and G protein-coupled receptors, the GABAA/C and GABAB receptors, respectively. The later play important roles in modulating many synapses, both at the pre- and post-synaptic levels, and are then still considered as interesting targets to treat a number of brain diseases, including addiction. For many years, several subtypes of GABAB receptors were expected, but cloning revealed only two genes that work in concert to generate a single type of GABAB receptor composed of two subunits.

Lipid profiling following intake of the omega 3 fatty acid DHA identifies the peroxidized metabolites F4-neuroprostanes as the best predictors of atherosclerosis prevention.

The anti-atherogenic effects of omega 3 fatty acids, namely eicosapentaenoic (EPA) and docosahexaenoic acids (DHA) are well recognized but the impact of dietary intake on bioactive lipid mediator profiles remains unclear. Such a profiling effort may offer novel targets for future studies into the mechanism of action of omega 3 fatty acids. The present study aimed to determine the impact of DHA supplementation on the profiles of polyunsaturated fatty acids (PUFA) oxygenated metabolites and to investigate their contribution to atherosclerosis prevention.

Bacterial serine/threonine protein kinases in host-pathogen interactions.

In bacterial pathogenesis, monitoring and adapting to the dynamically changing environment in the host and an ability to disrupt host immune responses are critical. The virulence determinants of pathogenic bacteria include the sensor/signaling proteins of the serine/threonine protein kinase (STPK) family that have a dual role of sensing the environment and subverting specific host defense processes. STPKs can sense a wide range of signals and coordinate multiple cellular processes to mount an appropriate response.

Microtubule-associated protein 9 (Map9/Asap) is required for the early steps of zebrafish development.

Microtubules are structural components of the cell cytoskeleton and key factors for mitosis and ciliogenesis in eukaryotes. The regulation of MT dynamics requires non-motor MAPs. We previously showed that, in human cells in culture, MAP9 (also named ASAP) is involved in MT dynamics and is essential for mitotic spindle formation and mitosis progression.

Zika virus in Gabon (Central Africa)--2007: a new threat from Aedes albopictus?

Background: Chikungunya and dengue viruses emerged in Gabon in 2007, with large outbreaks primarily affecting the capital Libreville and several northern towns. Both viruses subsequently spread to the south-east of the country, with new outbreaks occurring in 2010. The mosquito species Aedes albopictus, that was known as a secondary vector for both viruses, recently invaded the country and was the primary vector involved in the Gabonese outbreaks.

First detection of Mycobacterium ulcerans DNA in environmental samples from South America.

The occurrences of many environmentally-persistent and zoonotic infections are driven by ecosystem changes, which in turn are underpinned by land-use modifications that alter the governance of pathogen, biodiversity and human interactions. Our current understanding of these ecological changes on disease emergence however remains limited. Buruli ulcer is an emerging human skin disease caused by the mycobacterium, Mycobacterium ulcerans, for which the exact route of infection remains unclear.

Early administration of RS 67333, a specific 5-HT4 receptor agonist, prevents amyloidogenesis and behavioral deficits in the 5XFAD mouse model of Alzheimer's disease.

Amyloid β (Aβ) accumulation is considered the main culprit in the pathogenesis of Alzheimer's disease (AD). Recent studies suggest that decreasing Aβ production at very early stages of AD could be a promising strategy to slow down disease progression. Serotonin 5-HT4 receptor activation stimulates α-cleavage of the amyloid precursor protein (APP), leading to the release of the soluble and neurotrophic sAPPα fragment and thus precluding Aβ formation.

Analysis of RXR/THR and RXR/PPARG2 heterodimerization by bioluminescence resonance energy transfer (BRET).

Background: Nuclear receptors (NR) regulate transcription of genes involved in many biological processes such as development, cell proliferation, differentiation and cell death. Amongst them, PPARG2 and THR control tissue glucose and lipid homeostasis which are deregulated in severe pathophysiological conditions such as metabolic syndromes.

Methodology/principal Findings: Here, we describe a real time BRET approach to monitor heterodimerization between RXR and PPARG2 or THR in vitro or in living cells.

Gap junction signalling is a stress-regulated component of adrenal neuroendocrine stimulus-secretion coupling in vivo.

Elucidating the mechanisms whereby neuroendocrine tissues coordinate their input and output signals to ensure appropriate hormone secretion is currently a topical issue. In particular, whether a direct communication mediated by gap junctions between neurosecretory cells contributes to hormone release in vivo still remains unknown. Here we address this issue using a microsurgical approach allowing combined monitoring of adrenal catecholamine secretion and splanchnic nerve stimulation in anaesthetised mice.

Disruption of the coxsackievirus and adenovirus receptor-homodimeric interaction triggers lipid microdomain- and dynamin-dependent endocytosis and lysosomal targeting.

The coxsackievirus and adenovirus receptor (CAR) serves as a docking factor for some adenovirus (AdV) types and group B coxsackieviruses. Its role in AdV internalization is unclear as studies suggest that its intracellular domain is dispensable for some AdV infection. We previously showed that in motor neurons, AdV induced CAR internalization and co-transport in axons, suggesting that CAR was linked to endocytic and long-range transport machineries.

Vasopressin receptors and pharmacological chaperones: from functional rescue to promising therapeutic strategies.

Conformational diseases result from protein misfolding and/or aggregation and constitute a major public health problem. Congenital Nephrogenic Diabetes Insipidus is a typical conformational disease. In most of the cases, it is associated to inactivating mutations of the renal arginine-vasopressin V2 receptor gene leading to misfolding and intracellular retention of the receptor, causing the inability of patients to concentrate their urine in response to the antidiuretic hormone.

Cognitive dysfunction, elevated anxiety, and reduced cocaine response in circadian clock-deficient cryptochrome knockout mice.

The circadian clock comprises a set of genes involved in cell-autonomous transcriptional feedback loops that orchestrate the expression of a range of downstream genes, driving circadian patterns of behavior. Cognitive dysfunction, mood disorders, anxiety disorders, and substance abuse disorders have been associated with disruptions in circadian rhythm and circadian clock genes, but the causal relationship of these associations is still poorly understood. In the present study, we investigate the effect of genetic disruption of the circadian clock, through deletion of both paralogs of the core gene cryptochrome (Cry1 and Cry2).

Investigation of 5-HT4 receptors in bronchial hyperresponsiveness in cigarette smoke-exposed mice.

Background: Chronic obstructive pulmonary disease (COPD) arises from an interaction between genetic host factors and environmental exposures (mainly cigarette smoke (CS)). Genome Wide Association studies have demonstrated that genetic variations in the gene encoding 5-hydroxytryptamine 4 receptors (5-HT(4)R), HTR4, were associated with measures of airway obstruction and with COPD. We hypothesised that 5-HT(4) receptors, in addition to 5-HT2AR and muscarinic receptors, contribute to the pathogenesis of COPD by facilitating cholinergic bronchoconstriction.