Origin of immunoglobulin isotype switching

1. Download : Download high-res image (158KB)
2. Download : Download full-size image

Highlights? Switching in sharks consistent with immunization and cytidine deaminase expression ? Isotype switching can be reciprocal between genes of established positions ? Switch joints show DNA double-strand breakage repaired by nonhomologous end-joining ? Unlike in tetrapods, switching in shark is bidirection between IgM and IgW     

Temporal encoding of spatial information during active visual fixation

Humans and other species continually perform microscopic eye movements, even when attending to a single point. These movements, which include drifts and microsaccades, are under oculomotor control, elicit strong neural responses, and have been thought to serve important functions. The influence of these fixational eye movements on the acquisition and neural processing of visual information remains unclear. Here, we show that during viewing of natural scenes, microscopic eye movements carry out a crucial information-processing step: they remove predictable correlations in natural scenes by equalizing the spatial power of the retinal image within the frequency range of ganglion cells' peak sensitivity. This transformation, which had been attributed to center-surround receptive field organization, occurs prior to any neural processing and reveals a form of matching between the statistics of natural images and those of normal eye movements. We further show that the combined effect of microscopic eye movements and retinal receptive field organization is to convert spatial luminance discontinuities into synchronous firing events, beginning the process of edge detection. Thus, microscopic eye movements are fundamental to two goals of early visual processing: redundancy reduction and feature extraction.     

Pre-vaccination nasopharyngeal pneumococcal carriage in a Nigerian population: epidemiology and population biology

Background

Introduction of pneumococcal vaccines in Nigeria is a priority as part of the Accelerated Vaccine Introduction Initiative (AVI) of the Global Alliance for Vaccines and Immunisation (GAVI). However, country data on the burden of pneumococcal disease (IPD) is limited and coverage by available conjugate vaccines is unknown. This study was carried out to describe the pre vaccination epidemiology and population biology of pneumococcal carriage in Nigeria.

Methods

This was a cross sectional survey. Nasopharyngeal swabs (NPS) were obtained from a population sample in 14 contiguous peri-urban Nigerian communities. Data on demographic characteristics and risk factor for carriage were obtained from all study participants. Pneumococci isolated from NPS were characterised by serotyping, antimicrobial susceptibility and Multi Locus Sequencing Typing (MLST).

Results

The prevalence of pneumococcal carriage was 52.5%. Carriage was higher in children compared to adults (67.4% vs. 26%), highest (≈90%) in infants aged <9 months and reduced significantly with increasing age (P<0.001). Serotypes 19F (18.6%) and 6A (14.4%) were most predominant. Potential vaccine coverage was 43.8%, 45.0% and 62% for PCV-7, PCV-10 and PCV-13 respectively. There were 16 novel alleles, 72 different sequence types (STs) from the isolates and 3 Sequence Types (280, 310 and 5543) were associated with isolates of more than one serotype indicative of serotype switching. Antimicrobial resistance was high for cotrimoxazole (93%) and tetracycline (84%), a third of isolates had intermediate resistance to penicillin. Young age was the only risk factor significantly associated with carriage.

Conclusions

Pneumococcal carriage and serotype diversity is highly prevalent in Nigeria especially in infants. Based on the coverage of serotypes in this study, PCV-13 is the obvious choice to reduce disease burden and prevalence of drug resistant pneumococci. However, its use will require careful monitoring. Our findings provide sound baseline data for impact assessment following vaccine introduction in Nigeria.     

Interspecific hybridization increased in congeneric flatfishes after the Prestige oil spill

Marine species with relatively low migratory capacity are threatened by habitat alterations derived from human activities. In November 2002 the tanker Prestige sank off the Spanish northwest coast releasing 70,000 tons of fuel and damaging biota in the area. Despite efforts to clean the damaged areas, fuel remnants have affected marine species over the last nine years. This study is focused on two flatfish, Lepidorhombus boscii (four-spotted megrim) and L. whiffiagonis (megrim), whose spawning areas are located at the edge of the continental platform. We have analyzed megrim samples from North Spanish and French waters obtained before and after the oil spill. Genotypes at the nuclear marker 5S rDNA indicate a significant increase in interspecific hybridization after the Prestige accident, likely due to forced spawning overlap. The mitochondrial D-Loop region was employed for determining the direction of hybrid crosses, which were most frequently L. boscii female x L. whiffiagonis male. Reduced ability of L. boscii females to select conspecific mates would explain such asymmetric hybridization. To our knowledge this is the first time that increased hybridization between fish species can be associated to an oil spill. These results illustrate the potential long-term effect of petrol wastes on wild fish species.     

Does cerclage improve neonatal outcomes in a molar pregnancy and a coexistent fetus? a case report

Background

Complete hydatiform mole and coexistent viable fetus is very rare. The use of a cervical cerclage for cervical indications in the presence of this condition has never been reported. Although the diagnosis was made postnatal, the objective is to present a case with good neonatal outcome.

Case presentation

A patient presented with vaginal spotting around 23 weeks. She has a history of four preterm deliveries. Her cervix was dilated and a cerclage was placed. She presented again with PPROM around 25 weeks. She went into spontaneous preterm labor and delivered a viable fetus that is a healthy girl today. Eventually the pathology of the placenta showed a complete hydatidiform mole.

Conclusion

It is necessary to inform patients about the potential risks and poor outcomes of this condition. For those who desire all potential interventions, cerclage placement could be considered.     

Stasis is an Inevitable Consequence of Every Successful Evolution

Evolutionary stasis is discussed in light of the idea that the common output of every successful evolution is the creation of the entities that are increasingly resistant to further change. The moving force of evolution is entropy. This general aspiration for chaos is a cause of the mortality of organisms and extinction of species. However, being a prerequisite for any motion, entropy generates (by chance) novelties, which may happen to be (by chance) more resistant to further decay and thus survive. The entities that change rapidly disappear. All existing entities are endowed with an ability to resist further change. In simple organisms, the stasis is primarily achieved by means of the high fidelity of DNA reproduction. In organisms with a large genome and complex development, the achievable fidelity of genome reproduction fails to guarantee homeorhetic reproduction: there is more mutation than reproduction. Such species must be capable of surviving and remain phenotypically unchanged at continuous changes of their genes. This capability (canalization or robustness) reflects a global degeneracy of the link structure-function: there are more genotypes than phenotypes. Hence, function (i.e. meaning), not structure, is selected. The selection for successful ontogenesis in a varying environment creates developmental robustness to mutational and environmental perturbations and, consequently, to the halt of evolution. Evolution is resistance to entropy, the adaptation to environment being only one of the means of this resistance. Everything essential in biology is determined not by physical causality but by semantic rules and goal-directed programs. This principal operates on various levels of biological organization.     

Pharmacokinetic profiles of artesunate following multiple intravenous doses of 2, 4, and 8 mg/kg in healthy volunteers: Phase 1b study

ABSTRACT: BACKGROUND: Severe malaria results in over a million deaths every year, most of them in children aged less than five years and living in sub-Saharan Africa. Injectable artesunate (AS) was recommended as initial treatment for severe malaria by WHO in 2006. The Walter Reed Army Institute of Research (WRAIR) has been developing a novel good manufacturing practice (GMP) injection of AS, which was approved by the US FDA for investigational drug use and distribution by the CDC. METHODS: Tolerability and pharmacokinetics of current GMP intravenous AS, as an anti-malarial agent, were evaluated after ascending multiple doses of 2, 4, and 8 mg/kg daily for three days with 2-minute infusion in 24 healthy subjects (divided into three groups) in the Phase 1 clinical trial study. RESULTS: Results showed that there were no dose-dependent increases in any adverse events. Drug concentrations showed no accumulation and no decline of the drug during the three days of treatment. After intravenous injection, parent drug rapidly declined and was converted to dihydroartemisinin (DHA) with overall mean elimination half-lives ranging 0.15-0.23 hr for AS and 1.23-1.63 hr for DHA, but the peak concentration (Cmax) of AS was much higher than that of DHA with a range of 3.08-3.78-folds. In addition, the AUC and Cmax values of AS and DHA were increased proportionally to the AS climbing multiple doses. DISCUSSION: The safety of injectable AS, even at the highest dose of 8 mg/kg increases the probability of therapeutic success of the drug even in patients with large variability of parasitaemia.     

Proteomic profile of reversible protein oxidation using PROP, purification of reversibly oxidized proteins

Signal transduction pathways that are modulated by thiol oxidation events are beginning to be uncovered, but these discoveries are limited by the availability of relatively few analytical methods to examine protein oxidation compared to other signaling events such as protein phosphorylation. We report here the coupling of PROP, a method to purify reversibly oxidized proteins, with the proteomic identification of the purified mixture using mass spectrometry. A gene ontology (GO), KEGG enrichment and Wikipathways analysis of the identified proteins indicated a significant enrichment in proteins associated with both translation and mRNA splicing. This methodology also enabled the identification of some of the specific cysteine residue targets within identified proteins that are reversibly oxidized by hydrogen peroxide treatment of intact cells. From these identifications, we determined a potential consensus sequence motif associated with oxidized cysteine residues. Furthermore, because we identified proteins and specific sites of oxidation from both abundant proteins and from far less abundant signaling proteins (e.g. hepatoma derived growth factor, prostaglandin E synthase 3), the results suggest that the PROP procedure was efficient. Thus, this PROP-proteomics methodology offers a sensitive means to identify biologically relevant redox signaling events that occur within intact cells.     

Proteomics characterization of cytoplasmic and lipid-associated membrane proteins of human pathogen Mycoplasma fermentans M64

Mycoplasma fermentans is a potent human pathogen which has been implicated in several diseases. Notably, its lipid-associated membrane proteins (LAMPs) play a role in immunomodulation and development of infection-associated inflammatory diseases. However, the systematic protein identification of pathogenic M. fermentans has not been reported. From our recent sequencing results of M. fermentans M64 isolated from human respiratory tract, its genome is around 1.1 Mb and encodes 1050 predicted protein-coding genes. In the present study, soluble proteome of M. fermentans was resolved and analyzed using two-dimensional gel electrophoresis. In addition, Triton X-114 extraction was carried out to enrich amphiphilic proteins including putative lipoproteins and membrane proteins. Subsequent mass spectrometric analyses of these proteins had identified a total of 181 M. fermentans ORFs. Further bioinformatics analysis of these ORFs encoding proteins with known or so far unknown orthologues among bacteria revealed that a total of 131 proteins are homologous to known proteins, 11 proteins are conserved hypothetical proteins, and the remaining 39 proteins are likely M. fermentans-specific proteins. Moreover, Triton X-114-enriched fraction was shown to activate NF-kB activity of raw264.7 macrophage and a total of 21 lipoproteins with predicted signal peptide were identified therefrom. Together, our work provides the first proteome reference map of M. fermentans as well as several putative virulence-associated proteins as diagnostic markers or vaccine candidates for further functional study of this human pathogen.     

Monoclonal antibodies directed against human FcRn and their applications

The MHC class I-like Fc receptor (FcRn) is an intracellular trafficking Fc receptor that is uniquely responsible for the extended serum half-life of antibodies of the IgG subclass and their ability to transport across cellular barriers. By performing these functions, FcRn affects numerous facets of antibody biology and pathobiology. Its critical role in controlling IgG pharmacokinetics has been leveraged for the design of therapeutic antibodies and related biologics. FcRn also traffics serum albumin and is responsible for the enhanced pharmacokinetic properties of albumin-conjugated therapeutics. The understanding of FcRn and its therapeutic applications has been limited by a paucity of reliable serological reagents against human FcRn. Here, we describe the properties of a new panel of highly specific monoclonal antibodies (mAbs) directed against human FcRn with diverse epitope specificities. We show that this antibody panel can be used to study the tissue expression pattern of human FcRn, to selectively block IgG and serum albumin binding to human FcRn in vitro and to inhibit FcRn function in vivo. This mAb panel provides a powerful resource for probing the biology of human FcRn and for the evaluation of therapeutic FcRn blockade strategies.Key words: FcRn, IgG, monoclonal antibody, albumin, therapy