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Chronic granulomatous disease is a genetic disorder responsible for a defect in the NADPH oxidase of phagocytic cells. It impairs the oxidative burst necessary to the intracellular inactivation of microorganisms and predisposes to an increased risk of infections by various microorganisms, including fungi like Aspergillus spp. and other less frequently encountered or emerging fungal species. Here we review the genetic basis, pathogenesis and clinical presentation associated with fungal infections in chronic granulomatous disease as well as the current prophylaxis and newly available therapies.

The voltage-gated potassium channel subunit Kv2.1 forms heterotetrameric channels with the silent subunit Kv6.4. Chimeric Kv2.1 channels containing a single transmembrane segment from Kv6.4 have been shown to be functional. However, a Kv2.1 chimera containing both S1 and S5 from Kv6.4 was not functional. Back mutation of individual residues in this chimera (to the Kv2.1 counterpart) identified four positions that were critical for functionality: A200V and A203T in S1, and T343M and P347S in S5. To test for possible interactions in Kv2.1, we used substitutions with charged residues and tryptophan for the outermost pair 203/347. Combinations of substitutions with opposite charges at both T203 and S347 were tolerated but resulted in channels with altered gating kinetics, as did the combination of negatively charged aspartate substitutions. Double mutant cycle analysis with these mutants indicated that both residues are energetically coupled. In contrast, replacing both residues with a positively charged lysine together (T203K + S347K) was not tolerated and resulted in a folding or trafficking deficiency. The nonfunctionality of the T203K + S347K mutation could be restored by introducing the R300E mutation in the S4 segment of the voltage sensor. These results indicate that these specific S1, S4, and S5 residues are in close proximity and interact with each other in the functional channel, but are also important determinants for Kv2.1 channel maturation. These data support the view of an anchoring interaction between S1 and S5, but indicate that this interaction surface is more extensive than previously proposed.

In the brain of vertebrates, glutamate receptor ion channels (iGluR) mediate fast neurotransmission at excitatory synapses. They exist as distinct subfamilies (AMPA, Kainate and NMDA) differing in their functional properties. Yet, all iGluR are tetramers sharing a common molecular architecture, and a common scheme applies for the general mechanisms of their activation, which are discussed in this review. The dissection of the molecular mechanisms responsible for the operation of iGluR explain how they match their physiological requirements and paves the way to new strategies for pharmacological regulations of these receptors. This could prove useful for the discovery of drugs of therapeutic interest, such as cognitive enhancers, pain killers or anti-psychotics.

The key role of NEMO, the regulatory subunit of IKK, in the NF-kB activation process is firmly established. A series of recent publications suggests that this protein also participates in the genotoxic response, after modification by sumoylation in the nucleus, and coordinates the activation of both NF-kB and IRFs during viral infection, through its interaction with TANK adaptor and TBK1/IKKepsilon kinases.

In the kidney, the fine control of NaCl absorption takes place in the distal nephron and is controlled by aldosterone and vasopressin. This review summarizes the effects of vasopressin on Na+ transport mediated by the amiloride-sensitive epithelial sodium channel (ENaC) and the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel in immortalized or primary cultured cortical collecting duct cells, expressing either the wild-type ENaC subunits, or mutations, or deletions of the PY domain of the beta- or gamma-ENaC subunits responsible for Liddle's syndrome, an inherited form of hypertension due to excessive salt absorption.

International audience; Voltage-dependent calcium channels represent a major pathway of calcium entry into neurons, where they participate actively to cell excitability and to the molecular processes of synaptic transmission. For that reason, they have been the direct or indirect pharmacological targets of analgesics and this long before their implication in the physiology of nociception had been demonstrated. These last years, the still more refined molecular characterization of these channels and their associated regulatory subunits and the demonstration of their implication in nociceptive processes indicates that these structures are prime pharmacological targets for the management of pain. Herein, we detail the recent breakthroughs on calcium channel structure, function and pharmacology, review the implication of calcium channels in the transmission of nociception, and evaluate their importance as targets for the treatment of pain perception. The search for specific inhibitors of voltage-dependent calcium channels appears as a prelude to the development of new promising analgesic molecules.

The 5' AMP-activated protein kinase (AMPK) is a sensor of cellular energy homeostasis well conserved in all eukaryotic cells. AMPK is activated by rising AMP and falling ATP, either by inhibiting ATP production or by accelerating ATP consumption, by a complex mechanism that results in an ultrasensitive response. AMPK is a heterotrimeric enzyme complex consisting of a catalytic subunit alpha and two regulatory subunits beta and gamma. AMP activates the system by binding to the gamma subunit that triggers phosphorylation of the catalytic alpha subunit by the upstream kinases LKB1 and CaMKKbeta. Once activated, it switches on catabolic pathways (such as fatty acid oxidation and glycolysis) and switches off ATP-consuming pathways (such as lipogenesis) both by short-term effect on phosphorylation of regulatory proteins and by long-term effect on gene expression. Dominant mutations in the regulatory gamma subunit isoforms cause hypertrophy of cardiac and skeletal muscle providing a link in human diseases caused by defects in energy metabolism. As well as acting at the level of the individual cell, the system also regulates food intake and energy expenditure at the whole body level, in particular by mediating the effects of adipokines such as leptin and adiponectin. Moreover, the AMPK system is one of the probable target for the anti-diabetic drug metformin and rosiglitazone. The relationship between AMPK activation and beneficial metabolic effects provides the rationale for the development of new therapeutic strategies. Thus, pharmacological AMPK activation may, through signaling, metabolic and gene expression effects, reduce the risk of Type 2 diabetes, metabolic syndrome and cardiac diseases.

This study conducted from 1999 to 2000 in the suburbs of Bobo Dioulasso a town in the South of Burkina, aimed at investigating the susceptibility of the local population of Culex quinquefasciatus to various insecticides and proposing alternative strategies allowing a better management of insecticide resistance in the field. Eggs of C. quinquefasciatus were first collected in stagnant waste water places. The larvae were reared to early 4rth instar and tested by larval bioassays to determine the LC50/95 and the resistance ratios (RR50 and RR95) as well as their confidence intervals. A susceptible reference Strain "Slab" was used as control. Resistance was found to DDT and pyrethroids, but reduced susceptibility was found for carbamates, organophosphorates, phenyl pyrazole and in a less extend to Bacillus sphaericus. Resistance to pyrethroides is quite alarming since these insecticides are mainly used for bed net impregnation for the Roll Back malaria programme implemented in Africa. The high levels of insecticide resistance in C. quinquefasciatus suggest that alternative strategies have to be implemented to minimize the pressure of selection on resistant genes. The use of bio-larvicides (Bacillus sphaericus) alone or in rotation with different compounds may be a promising strategy for controlling C. quinquefasciatus in Bobo Dioulasso.

The maintenance of cellular homeostasis and the ability of cells to respond to their environment depend on the degradation of bulk proteins and orderly degradation of key regulatory proteins and their inhibitors. The 26S proteasome plays an essential role in these degradations. It is involved in the activation and inactivation of many cellular processes such as cell cycle progression, apoptosis and regulation of gene expression. It presents unique structural and functional properties. It degrades proteins by an unusual mechanism. Several series of proteasome inhibitors have been developed, useful to elucidate the biological roles of this multicatalytic enzyme. Velcade (bortezomid) was the first proteasome inhibitor to undergo, in may 2003, clinical trials in cancer patients.

A 27-year-old man complained of cervicoscapular and forearm weakness and amyotrophy. Electromyographic evaluation showed neuromuscular transmission dysfunction and a repetitive compound muscle action potential to a single stimulus. Prostigmine did not improve neuromuscular transmission. The genetic analysis of the patient's lymphocytes demonstrated a chromosomic 2q31-9p27 translocation. The combination of the clinical and electrophysiological data as well as the lack of auto-immunity signs against neuromuscular junction constituents led to the diagnosis to congenital postsynaptic myasthenic syndrome also called slow channel syndrome. This congenital myasthenic syndrome is for the first time associated with an autosomal translocation 2q31-9p27.

Selective susceptibility to poorly pathogenic mycobacteria, such as bacille Calmette-Guérin (BCG) vaccine and environmental non-tuberculous mycobacteria (NTM), bas long been suspected to be a mendelian disorder but its molecular basis has remained elusive. Recently, recessive mutations in the interferon gamma receptor ligand-binding chain (IFN gamma R1), interferon gamma receptor signalling chain (IFN gamma R2), interleukin 12 p40 subunit (IL-12 p40), and interleukin 12 receptor beta 1 chain (IL-12R beta 1) genes have been identified in a number of patients with disseminated BCG or NTM infection. Although genetically distinct, these conditions are immunologically related and highlight the essential role of interferon gamma-mediated immunity in the control of mycobacteria in man.