Signaling with phosphoinositides: better than binary

When the outside of cell is stimulated,the inside generates a flurry of signals. Phosphates are sprinkled over lipids and proteins,where they are recognized within diverse signaling pathways. The kinases that congregate beneath the cell surface to provide the phosphate tags that mediate signaling have become major targets of new wave of drug design. Phosphoinositide signaling presents a particularly intriguing network whose many mysteries are now being unlocked. Research into protein domains that specifically recognize phosphoinositides have established the ENTH, FYVE,Phox,and pleckstrin homology domains s four cornerstones of phosphoinositide signaling.     

Rabbit nasal mucosa: nanospheres coated with polypeptides bound to specific anti-polypeptide IgG are better transported than nanospheres coated with polypeptides or IgG alone

In rabbit nasal mucosa, polypeptides and polypeptide-coated nanospheres are actively transported from lumen to blood by M-cells present in specialized transport areas of the epithelium. The largest transport is shown here to occur when some molecules of the polypeptides coating the nanospheres, after adsorption, are bound to the specific anti-polypeptide IgG, e.g. when insulin is bound to the anti-insulin IgG. The transport kinetics of nanospheres coated by insulin bound to its antibody, as a function of bead concentration or of the antibody/insulin coating ratio, have been analyzed. On this basis it was possible to assess the maximal transport capacity of the epithelium and to calculate the percentage of M-cells involved.     

When one is better than two: RNA with dual functions

The central dogma of biology, until not long ago, held that genetic information stored on DNA molecules was translated into the final protein products through RNA as intermediate molecules. Then, an additional level of complexity in the regulation of genome expression was added, implicating new classes of RNA molecules called non-coding RNA (ncRNA). These ncRNA are also often referred to as functional RNA in that, although they do not contain the capacity to encode proteins, do have a function as RNA molecules. They have been thus far considered as truly non-coding RNA since no ORF long enough to be considered, nor protein, have been associated with them. However, the recent identification and characterization of bifunctional RNA, i.e. RNA for which both coding capacity and activity as functional RNA have been reported, suggests that a definite categorization of some RNA molecules is far from being straightforward.Indeed, several RNA primarily classified as non-protein-coding RNA has been showed to hold coding capacities and associated peptides. Conversely, mRNA, usually regarded as strictly protein-coding, may act as functional RNA molecules. Here, we describe several examples of these bifunctional RNA that have been already characterized from bacteria to mammals. We also extend this concept to fortuitous acquisition of dual function in pathological conditions and to the recently highlighted duality between information carried by a gene and its pseudogenes counterparts.     

Invasive aspergillosis: treatment

Invasive aspergillosis is a severe disease, affecting essentially congenital or acquired immunodepressed patients, as well as neutropenic or transplanted ones, and those undergoing prolonged chemotherapy or treatment with corticoids. At present, the physician only disposes of the following treatment: amphotericin B desoxycolate, lipidic amphotericins and itraconazole p.o. or intravenously. Very soon, other drugs like voriconazole, posaconazole, liposomal nystatin and echinocandins probably will have a role in the treatment. It is most important to know thoroughly the patients's base disease and its specific treatment and the role of the drugs at present available, their relevant dosage, biodisponibility and pharmacokinetics, as well as adverse effects and evidence-based criterions of application. It is very important indeed to maintain a high suspicion of the disease and a rapid start of treatment. It is equally important to assess the role of coadjuvant treatments. We insist in the importance of surgery in solving of the disease in some cases (progressive pulmonar aspergillosis, sinusitis) combined with appropriate antifungal treatment.     

Finger vasodilation correlates better with tympanic than esophageal temperature

The relationship of finger blood flow (FBF) measured by venous occlusion plethysmography to tympanic temperature (Tty) was compared with that of FBF to esophageal temperature (Tes) during exercise at 50% VO2max for 40 min at an ambient temperature of 25 degrees C. The relationship of FBF to Tes showed an inflexion as Tes increased during exercise. The slope of the regression line showing the relationship between FBF and Tes was initially moderate, and then suddenly became steeper at the inflexion point. The relationship of FBF to Tty, however, was linear, without an inflexion. The results suggest that finger vasodilation during moderate exercise correlates better with tympanic than esophageal temperature.     

Pharmacological chaperoning: two 'hits' are better than one

Protein folding disorders comprise a rapidly growing group of diseases that involve virtually every organ system and affect individuals of all ages. Their principal pathology is the inability of a protein to acquire or maintain its physiological three-dimensional structure. In cells, this generally results in one of three outcomes: accumulation of misfolded protein aggregates, cell death, or recognition by cellular quality control machinery and rapid degradation. Large-scale screening efforts to identify and design small molecules that either repair the folding defect or enable the protein to escape degradation have been encouraging. However, most compounds identified to date restore only a small fraction of molecules to the normal folding pathway, and hence are relatively poor therapeutic candidates. Results published by Wang et al. in this issue of the Biochemical Journal show that, for mutant forms of two ABC (ATP-Binding-Cassette) transporters, P-glycoprotein and CFTR (cystic fibrosis transmembrane conductance regulator), modest correction of trafficking by single agents can be additive when multiple compounds are used in combination. These findings raise the intriguing possibility that corrector molecules acting at different steps along the folding pathway might provide a multidrug approach to human protein folding disorders.     

Targeting Plasmodium liver stages: better late than never

The worldwide burden of malaria can be substantially reduced using existing public health interventions. However, elimination of Plasmodium will require fundamentally different approaches. Novel experimental attenuation strategies for active immunization using knockout strains have recently stimulated renewed interest in whole-parasite vaccine approaches. Preventive drug administration during transmission of wild-type sporozoites is a complementary strategy for eliciting protective immune responses. These whole-cell immunization strategies are based on one fundamental principle: inducing protection by blocking parasite conversion from the clinically silent liver phase to the pathogenic intra-erythrocytic replication cycle. Here, we review the basis, evidence and targets for whole-cell-based vaccination strategies against the liver stage bottleneck in Plasmodium infections and discuss preclinical and clinical research opportunities.     

Dynein motility: four heads are better than two

Cytoplasmic dynein is a microtubule-based motor protein that transports membranes in cells. The movement driven by a single dynein molecule in vitro is not as robust as dynein-driven movements in cells. A new study suggests that transport by multiple dyneins is more similar to cellular motions.     

Vital imaging: Two photons are better than one

The recently developed technique of two-photon fluorescence microscopy causes much less photodamage than conventional confocal microscopy, expanding the possibilities for imaging living specimens.     

Circadian clockwork: two loops are better than one

The spectacularly successful race over the past three years to place our understanding of the circadian clockwork of mammals into a molecular framework is beginning to yield the cardinal example of the molecular-genetic control of behaviour. This perspective describes recent evidence for the conservation of a double-loop, autoregulatory feedback mechanism across the best understood eukaryotic circadian systems, and discusses how these findings may illuminate some long-standing puzzles concerning our subliminal sense of circadian time.