Vaccines targeting drugs of abuse: is the glass half-empty or half-full?

The advent of vaccines targeting drugs of abuse heralded a fundamentally different approach to treating substance-related disorders. In contrast to traditional pharmacotherapies for drug abuse, vaccines act by sequestering circulating drugs and terminating the drug-induced 'high' without inducing unwanted neuromodulatory effects. Drug-targeting vaccines have entered clinical evaluation, and although these vaccines show promise from a biomedical viewpoint, the ethical and socioeconomic implications of vaccinating patients against drugs of abuse merit discussion within the scientific community.     

The avian immune genome--a glass half-full or half-empty?

Although in broad terms the avian immune response is remarkably similar to that of mammals, when one looks at specifics birds have a different repertoire of immune organs, cells and molecules compared to those characterized in mammals. Birds lack organized lymph nodes, yet have the Bursa of Fabricius. Birds lack neutrophils and functional eosinophils, yet have a distinct group of polymorphonuclear granulocytes known as heterophils. Birds also have a different repertoire of cytokines, chemokines, Toll-like receptors, defensins and integrins, as detailed in this review.     

TonB or not TonB: is that the question?

Bacteria are able to survive in low-iron environments by sequestering this metal ion from iron-containing proteins and other biomolecules such as transferrin, lactoferrin, heme, hemoglobin, or other heme-containing proteins. In addition, many bacteria secrete specific low molecular weight iron chelators termed siderophores. These iron sources are transported into the Gram-negative bacterial cell through an outer membrane receptor, a periplasmic binding protein (PBP), and an inner membrane ATP-binding cassette (ABC) transporter. In different strains the outer membrane receptors can bind and transport ferric siderophores, heme, or Fe3+ as well as vitamin B12, nickel complexes, and carbohydrates. The energy that is required for the active transport of these substrates through the outer membrane receptor is provided by the TonB/ExbB/ExbD complex, which is located in the cytoplasmic membrane. In this minireview, we will briefly examine the three-dimensional structure of TonB and the current models for the mechanism of TonB-dependent energy transduction. Additionally, the role of TonB in colicin transport will be discussed.     

Sulfur signaling: is the agent sulfide or sulfane?

Triplex-forming oligonucleotides (TFOs) are sequence-dependent DNA binders that may be useful for DNA targeting and detection. A sensitive and convenient method to monitor triplex formation by a TFO and its target DNA duplex is required for the application of TFO probes. Here we describe a novel design by which triplex formation can be monitored homogeneously without prelabeling the target duplex. The design uses a TFO probe tagged with a fluorophore that undergoes fluorescence resonance energy transfer with fluorescent dyes that intercalate into the target duplex. Through color compensation analysis, the specific emission of the TFO probe reveals the status of the triple helices. We used this method to show that triple helix formation with TFOs is magnesium dependent. We also demonstrated that the TFO probe can be used for detection of sequence variation in melting analysis and for DNA quantitation in real-time polymerase chain reaction.     

Vaccination against shigellosis: is it the path that is difficult or is it the difficult that is the path?

Following several decades of research, there is not yet a convincing vaccine against shigellosis. It is still difficult, in spite of the breadth of strategies (i.e. live attenuated oral, killed oral, subunit parenteral) to select an optimal option. Two approaches are clearly emerging: (i) live attenuated deletion mutants based on rational selection of genes that are key in the pathogenic process, and (ii) conjugated detoxified polysaccharide parenteral vaccines, or more recently conjugated synthetic carbohydrates. Some of these approaches have already undergone phase I and II clinical trials with promising results, but important issues have also emerged, particularly the discrepancy between colonization and immunogenic potential of live attenuated vaccine candidates depending upon the population concerned (i.e. non endemic vs. endemic areas). Efforts are needed to definitely establish the proof of concept of these approaches, and thus the need for clinical trials which should also soon explore the possibility to associate different serotypes, in response to serotype specific protection against shigellosis. More basic research is also required to improve what we can still consider as first-generation vaccines, and to explore possible new paradigms including the search for cross-protective antigens.     

Pex13p: docking or cargo handling protein?

The Src homology 3 (SH3) domain-containing peroxisomal membrane protein Pex13p is an essential component of the import machinery for matrix proteins and forms a binding site for the peroxisomal targeting type I (PTS1) receptor Pex5p. The interaction between these two proteins can be described as novel in several ways. In the yeasts Saccharomyces cerevisiae and Pichia pastoris, the SH3 domain itself is responsible for the interaction but not via the typical P-x-x-P motifs that are common to SH3 ligands as Pex5p lacks such a motif. Instead, a region of Pex5p containing a W-x-x-x-F/Y motif is crucial for this binding. In mammals, again W-x-x-x-F/Y motifs appear to be important for the interaction but the SH3 domain seems not to be the site for Pex5p binding, this being located in the N-terminus of Pex13p. Despite these differences in the details of the Pex13p-Pex5p interaction, the association of the two proteins is a crucial step in Pex5p-mediated protein import into peroxisomes in both yeasts and mammals.     

Pennisetum squamulatum: is the predominant cytotype hexaploid or octaploid?

Apomixis is a mode of asexual reproduction where maternal clones are produced through seeds. Consequently, genetic segregation is prevented in hybrid progenies. Pennisetum squamulatum has been used to transfer apomixis into the related sexual species Pennisetum glaucum by the introgression of an apospory-specific genomic region (ASGR)-carrier chromosome. Crosses between P. glaucum and P. squamulatum or Pennisetum purpureum have been relatively easy to make even though P. squamulatum has been reported to have a different basic chromosome number than the other 2 species (9 vs. 7) and to be hexaploid (2n = 6x = 54). Our extensive examination of one accession had shown a chromosome number of 2n = 56. In order to determine if there was a variation among accessions, we counted the number of chromosomes in 5 accessions of P. squamulatum using centromeric and 18S-5.8S-26S rDNA probes as molecular cytological markers. Our results showed that P. squamulatum is most likely octaploid with a basic chromosome number of 7 (2n = 8x = 56) and may belong to the secondary gene pool of Pennisetum. Moreover, a morphologically similar ASGR-carrier chromosome that confers apomixis was observed in all accessions.     

Neurogenesis: is the adult stem cell young or old?

Stem cell biology is one of the most exciting, controversial, and debated fields in science today. It has been suggested that neuronal replacement therapy using stem cell transplants may be one possible answer to a host of neuropathological disorders including spinal cord injury, stroke, and neurodegenerative diseases. Important sources for stem cells include the developing embryo and adult central nervous system, but will these populations of cells exhibit similar behavior and responses to stimuli? This review will discuss some important similarities and differences between the embryonic and adult stem cell, as well as the basis for developing therapeutic approaches for stem cell replacement.     

Amyloids or prions? That is the question

ABSTRACT

Despite major efforts devoted to understanding the phenomenon of prion transmissibility, it is still poorly understood how this property is encoded in the amino acid sequence. In recent years, experimental data on yeast prion domains allow to start at least partially decrypting the sequence requirements of prion formation. These experiments illustrate the need for intrinsically disordered sequence regions enriched with a particularly high proportion of glutamine and asparagine. Bioinformatic analysis suggests that these regions strike a balance between sufficient amyloid nucleation propensity on the one hand and disorder on the other, which ensures availability of the amyloid prone regions but entropically prevents unwanted nucleation and facilitates brittleness required for propagation.     

Implications of cnidarian gene expression patterns for the origins of bilaterality is the glass half full or half empty?

The past two years have seen a dramatic increase in the availabledata on gene sequence and gene expression for cnidarians andother "lower" Metazoa, and a flurry of recent papers has drawnon these to address the origins of bilaterality. Cnidarian homologsof many genes that play key roles in the specification of boththe A/P and D/V axes of bilaterians have been characterized,and their patterns of expression determined. Some of these expressionpatterns are consistent with the possibility of conservationof function between Cnidaria and Bilateria, but others clearlydiffer. Moreover, in some cases very different interpretationshave been made on the basis of the same, or similar, data. Inpart, these differences reflect the inevitable uncertaintiesassociated with the depth of the divergence between cnidariansand bilaterians. In this article, we briefly summarize the cnidariandata on gene expression and organization relevant to axis formation,the varying interpretations of these data, and where they conflict.Our conclusion is that the presently available data do not allowus to unequivocally homologize the single overt axis of cnidarianswith either of the bilaterian axes.     

Paraoxonase 1 and atherosclerosis: is the gene or the protein more important?

The oxidation of low-density lipoprotein (LDL) is centrally involved in the initiation and progression of atherosclerosis. High-density lipoprotein (HDL) paraoxonase 1 (PON1) retards the oxidation of LDL and is a major antiatherosclerotic component of HDL. The PON1 gene contains a number of functional polymorphisms in both the coding and the promoter regions, which affect either the level or the substrate specificity of PON1. Genetic case-control and prospective studies conducted to date have produced confusing results. Meta-analysis of these studies indicates no simple relationship between the PON1 polymorphisms and the presence of coronary heart disease (CHD). However, at the present moment in time, it seems that PON1 status, i.e., activity and/or concentration, is more closely related to CHD, and indeed, PON1 has shown to be an independent risk factor for CHD in a prospective study, compared to the genetic polymorphisms. PON1 levels can also be modulated by environmental\lifestyle and possibly pharmaceutical factors. Larger, better designed, preferably prospective studies are needed to determine further the association of PON1 genetic polymorphisms and status with CHD.     

MUC genes: mucin or not mucin? That is the question

Mucins are macromolecules lying the cells in contact with external environment and protect the epithelium against constant attacks such as digestive fluids, microorganisms, pollutants, and toxins. Mucins are the main components of mucus and are synthesized and secreted by specialized cells of the epithelium (goblet cells, cells of mucous glands) or non mucin-secreting cells. Human mucin genes show common features: large size of their mRNAs, large nucleotide tandem repeat domains, complex expression both at tissular and cellular level. Since 1987, 21 MUC symbols have been used to designate genes encoding O-glycoproteins containing tandem repeat domains rich in serine, threonine and proline. Some of these genes encode true mucins while others encode non mucin adhesion O-glycoproteins. In this paper, we propose a classification based on sequence similarities and expression areas. Two main families can be distinguished: secreted mucins or gel-forming mucins (MUC2, MUC5AC, MUC5B, MUC6), and membrane-bound mucins (MUC1, MUC3, MUC4, MUC12, MUC17). Muc-deficient mice will provide important models in the study of functional relationships between these two mucin families.     

Which is the most preventive measure against tail damage in finisher pigs: tail docking,straw provision or lowered stocking density?

One challenge of intensive pig production is tail damage caused by tail biting, and farmers often decrease the prevalence of tail damage through tail docking. However, tail docking is not an optimal preventive measure against tail damage and thus, it would be preferable to replace it. The aim of the current study was to investigate the relative effect of three possible preventive measures against tail damage. The study included 112 pens with 1624 finisher pigs divided between four batches. Pens were randomly assigned to one level of each of three treatments: (1) tail-docked (n=60 pens) v. undocked (n=52 pens), (2) 150 g of straw provided per pig per day on the solid floor (n=56 pens) v. no straw provided (n=56 pens), (3) stocking density of 1.21 m²/pig (11 pig/pen; n=56 pens) v. 0.73 m²/pig (18 pigs/pen; n=56 pens). Tail damage was recorded three times per week throughout the finisher period by scoring the tail of each individual pig. A pen was recorded as a tail damage pen and no longer included in the study if at least one pig in a pen had a bleeding tail wound; thus, only the first incidence of tail damage on pen level was recorded. Data were analysed by a Cox regression for survival analysis assuming proportional hazards. Results are presented as hazards, and a higher hazard means that a pen has a higher risk of tail damage and of it happening earlier in the finisher period. Pens with undocked pigs had a 4.32-fold higher hazard of tail damage compared with pens with docked pigs (P<0.001). Pens with no straw provided had a 2.22-fold higher hazard of tail damage compared with pens with straw provided (P<0.01). No interactions was seen between the treatments, but the effect of tail docking was higher than the effect of straw provision (P<0.001). Stocking density did not have a significant effect on the hazard of tail damage (hazard rate ratios (HRR)=1.67; P=0.064). However, a combination of straw provision and lowered stocking density showed a similar hazard of tail damage as seen with only tail docking (HRR=1.58; P=0.39). In conclusion, tail docking and straw provision were preventive measures against tail damage, and tail docking reduced the risk more than straw provision. A combination of other preventive measures is necessary to reduce the risk of tail damage in undocked pigs to the same level as in docked pigs.     

Oviparity or viviparity? That is the question…

The modes of reproduction undoubtedly represent one of the most critical life-history traits because they profoundly affect fitness and survival. The parent–offspring conflict over the degree of parental investment may be the main selective factor in the evolution of reproduction. Although the modes of sexual reproduction are remarkably diversified in animals, the traditional typology spanning three classes does not seem to be adequate to clarify the level of parental investment. Thus, lecithotrophy does not provide any information on the retention of the zygotes inside the parent's body and matrotrophy only indicates that nutrients are provided by mother but does not make any distinction between various types of maternal care. I here present a scientific typology of the reproductive modes comprising five classes: ovuliparity, oviparity, ovo-viviparity, histotrophic viviparity and hemotrophic viviparity. Based on the development stage of the zygote and on its interrelation with the parent, my classification details the degree of contrivances by which animals provide alternative parental investment in their offspring. Hence, this typology possesses a great heuristic value, both in reproduction and evolutionary biology. These different modes of reproduction do represent a sequence, with ovuliparity being the most primitive and hemotrophic viviparity the most advanced mode. Lastly, the comparative analysis of different reproductive modes in vertebrates suggests that climatic conditions (cold) could be one of the strongest selection pressures for extending egg retention and the establishment of viviparity.