Erasing the Epigenetic Memory and Beginning to Switch—The Onset of Antigenic Switching of var Genes in Plasmodium falciparum

Antigenic variation in Plasmodium falciparum is regulated by transcriptional switches among members of the var gene family, each expressed in a mutually exclusive manner and encoding a different variant of the surface antigens collectively named PfEMP1. Antigenic switching starts when the first merozoites egress from the liver and begin their asexual proliferation within red blood cells. By erasing the epigenetic memory we created parasites with no var background, similar to merozoites that egress from the liver where no var gene is expressed. Creating a null-var background enabled us to investigate the onset of antigenic switches at the early phase of infection. At the onset of switching, var transcription pattern is heterogeneous with numerous genes transcribed at low levels including upsA vars, a subtype that was implicated in severe malaria, which are rarely activated in growing cultures. Analysis of subsequent in vitro switches shows that the probability of a gene to turn on or off is not associated with its chromosomal position or promoter type per se but on intrinsic properties of each gene. We concluded that var switching is determined by gene specific associated switch rates rather than general promoter type or locus associated switch rates. In addition, we show that fine tuned reduction in var transcription increases their switch rate, indicating that transcriptional perturbation can alter antigenic switching

QTL Fine Mapping by Measuring and Testing for Hardy-Weinberg and Linkage Disequilibrium at a Series of Linked Marker Loci in Extreme Samples of Populations

It has recently been demonstrated that fine-scale mapping of a susceptibility locus for a complex disease can be accomplished on the basis of deviations from Hardy-Weinberg (HW) equilibrium at closely linked marker loci among affected individuals. We extend this theory to fine-scale localization of a quantitative-trait locus (QTL) from extreme individuals in populations, by means of HW and linkage-disequilibrium (LD) analyses. QTL mapping and/or linkage analyses can establish a large genomic region (∼30 cM) that contains a QTL. The QTL can be fine mapped by examination of the degree of deviation from HW and LD at a series of closely linked marker loci. The tests can be performed for samples of individuals belonging to either high or low percentiles of the phenotype distribution or for combined samples of these extreme individuals. The statistical properties (the power and the size) of the tests of this fine-mapping approach are investigated and are compared extensively, under various genetic models and parameters for the QTL and marker loci. On the basis of the results, a two-stage procedure that uses extreme samples and different tests (for HW and LD) is suggested for QTL fine mapping. This two-step procedure is economic and powerful and can accurately narrow a genomic region containing a QTL from ∼30–1 cM, a range that renders physical mapping feasible for identification of the QTL. In addition, the relationship between parameterizations of complex diseases, by means of penetrance, and those of complex quantitative traits, by means of genotypic values, is outlined. This means that many statistical genetic methods developed for searching for susceptibility loci of complex diseases can be directly adopted and/or extended to QTL mapping for quantitative traits

The antigenic switching network of Plasmodium falciparum and its implications for the immuno-epidemiology of malaria

Published onlineJournal ArticleResearch Support, Non-U.S. Gov'tAntigenic variation in the human malaria parasite Plasmodium falciparum involves sequential and mutually exclusive expression of members of the var multi-gene family and appears to follow a non-random pattern. In this study, using a detailed in vitro gene transcription analysis of the culture-adapted HB3 strain of P. falciparum, we show that antigenic switching is governed by a global activation hierarchy favouring short and highly diverse genes in central chromosomal location. Longer and more conserved genes, which have previously been associated with severe infection in immunologically naive hosts, are rarely activated, however, implying an in vivo fitness advantage possibly through adhesion-dependent survival rates. We further show that a gene's activation rate is positively associated sequence diversity, which could offer important new insights into the evolution and maintenance of antigenic diversity in P. falciparum malaria. DOI:http://dx.doi.org/10.7554/eLife.01074.001.The work was funded by the Wellcome Trust (Grant No. 082130/Z/07/Z to CN), the Biotechnology and Biological Sciences Research Council (studentship to RN) and the Royal Society (University Research Fellowship to MR)

Recent Advances in Proteomics and Cancer Biomarker Discovery

Early diagnosis and prevention is a key factor in reducing the mortality and morbidity of cancer. However, currently available screening tools lack enough sensitivity for early diagnosis. It is important to develop noninvasive techniques and methods that can screen and identify asymptomatic patients who have cancer. Biomarkers of cancer status can also serve as powerful tools in monitoring the course of cancer and in determining the efficacy and safety of novel therapies. Thus, discovery of novel specific biomarkers are needed that may provide informative clues for early diagnosis and treatment of cancer. Recently, remarkable progress has been made in the development of new proteomics technology. The progress that has been made in this field is helpful in identifying biomarkers that can be used for early diagnosis of cancer and improving the understanding of the molecular etiological mechanism of cancer. This article describes the current state of the art in this field

Editorial Board Diversity at the Basket of Eight Journals: A Report to the College of Senior Scholars

At the 2019 International Conference on Information Systems (ICIS), the College of Senior Scholars appointed a committee to investigate diversity in the editorial boards of their Basket of Eight journals. Editorial board diversity signals that a journal welcomes and includes all authors. The committee compared the gender, regional and ethnic diversity of the editorial boards to that of AIS members in the Academic membership category. This comparison showed that the editorial boards overall had fewer female members, more members from Region 1, and fewer from Region 3 than one would reasonably expect. Furthermore, several ethnicities appeared on the boards in smaller or larger numbers than one would expect, in comparison to their proportions among AIS Academic members. The individual journals also differed a great deal among themselves with respect to these diversity criteria. Regrettably, every journal fell below what one would reasonably expect with respect to either gender, regional, or ethnic diversity. Based on these findings, we make recommendations for the College of Senior Scholars, editors in chief of the Basket of Eight journals, the AIS Council, and individuals who lead other organizations of IS scholars

Issues in modern bone histomorphometry

This review reports on proceedings of a bone histomorphometry session conducted at the Fortieth International IBMS Sun Valley Skeletal Tissue Biology Workshop held on August 1, 2010. The session was prompted by recent technical problems encountered in conducting histomorphometry on bone biopsies from humans and animals treated with anti-remodeling agents such as bisphosphonates and RANKL antibodies. These agents reduce remodeling substantially, and thus cause problems in calculating bone remodeling dynamics using in vivo fluorochrome labeling. The tissue specimens often contain few or no fluorochrome labels, and thus create statistical and other problems in analyzing variables such as mineral apposition rates, mineralizing surface and bone formation rates. The conference attendees discussed these problems and their resolutions, and the proceedings reported here summarize their discussions and recommendations

Harold M. Frost T J Musculoskel Neuron Interact 2001; 2(2):117-119 William F. Neuman Awardee 2001

Tribute to Harold M. Frost, honorary president of ISMNI, who received the William F. Neuman Award from the American Society of Bone and Mineral Research October 2001

A pilot study on the nanoscale properties of bone tissue near lacunae in fracturing women

The goal of this study is to investigate the causes of osteoporosis-related skeletal fragility in postmenopausal women. We hypothesize that bone fragility in these individuals is largely due to mineral, and/or intrinsic material properties in the osteocyte lacunar/peri-lacunar regions of bone tissue. Innovative measurements with nanoscale resolution, including scanning electron microscope (SEM), an atomic force microscope that is integrated with infrared spectroscopy (AFM-IR), and nanoindentation, were used to characterize osteocyte lacunar and peri-lacunar properties in bone biopsies from fracturing (Cases) and matched (Age, BMD), non-fracturing (Controls) postmenopausal healthy women. In the peri-lacunar space, the nanoindentation results show that the modulus and hardness of the Controls are lower than the Cases. The AFM-IR results conclusively show that the mineral matrix, maturity (peak) (except in outer/far regions in Controls) were greater in Controls than in Cases. Furthermore, these results indicate that while mineral-to-matrix area ratio tend to be greater, the mineral maturity and crystallinity peak ratio “near” lacunae is greater than at regions “far” or more distance from lacunae in the Controls only. Due to the heterogeneity of bone structure, additional measurements are needed to provide more convincing evidence of altered lacunar characteristics and changes in the peri-lacunar bone as mechanisms related to postmenopausal women and fragility. Such findings would motivate new osteocyte-targeted treatments to reduce fragility fracture risks in these groups

A Statistically Rigorous Method for Determining Antigenic Switching Networks

Many vector-borne pathogens rely on antigenic variation to prolong infections and increase their likelihood of onward transmission. This immune evasion strategy often involves mutually exclusive switching between members of gene families that encode functionally similar but antigenically different variants during the course of a single infection. Studies of different pathogens have suggested that switching between variant genes is non-random and that genes have intrinsic probabilities of being activated or silenced. These factors could create a hierarchy of gene expression with important implications for both infection dynamics and the acquisition of protective immunity. Inferring complete switching networks from gene transcription data is problematic, however, because of the high dimensionality of the system and uncertainty in the data. Here we present a statistically rigorous method for analysing temporal gene transcription data to reconstruct an underlying switching network. Using artificially generated transcription profiles together with in vitro var gene transcript data from two Plasmodium falciparum laboratory strains, we show that instead of relying on data from long-term parasite cultures, accuracy can be greatly improved by using transcription time courses of several parasite populations from the same isolate, each starting with different variant distributions. The method further provides explicit indications about the reliability of the resulting networks and can thus be used to test competing hypotheses with regards to the underlying switching pathways. Our results demonstrate that antigenic switch pathways can be determined reliably from short gene transcription profiles assessing multiple time points, even when subject to moderate levels of experimental error. This should yield important new information about switching patterns in antigenically variable organisms and might help to shed light on the molecular basis of antigenic variation

Current limitations of SNP data from the public domain for studies of complex disorders: a test for ten candidate genes for obesity and osteoporosis

BACKGROUND: Public SNP databases are frequently used to choose SNPs for candidate genes in the association and linkage studies of complex disorders. However, their utility for such studies of diseases with ethnic-dependent background has never been evaluated. RESULTS: To estimate the accuracy and completeness of SNP public databases, we analyzed the allele frequencies of 41 SNPs in 10 candidate genes for obesity and/or osteoporosis in a large American-Caucasian sample (1,873 individuals from 405 nuclear families) by PCR-invader assay. We compared our results with those from the databases and other published studies. Of the 41 SNPs, 8 were monomorphic in our sample. Twelve were reported for the first time for Caucasians and the other 29 SNPs in our sample essentially confirmed the respective allele frequencies for Caucasians in the databases and previous studies. The comparison of our data with other ethnic groups showed significant differentiation between the three major world ethnic groups at some SNPs (Caucasians and Africans differed at 3 of the 18 shared SNPs, and Caucasians and Asians differed at 13 of the 22 shared SNPs). This genetic differentiation may have an important implication for studying the well-known ethnic differences in the prevalence of obesity and osteoporosis, and complex disorders in general. CONCLUSION: A comparative analysis of the SNP data of the candidate genes obtained in the present study, as well as those retrieved from the public domain, suggests that the databases may currently have serious limitations for studying complex disorders with an ethnic-dependent background due to the incomplete and uneven representation of the candidate SNPs in the databases for the major ethnic groups. This conclusion attests to the imperative necessity of large-scale and accurate characterization of these SNPs in different ethnic groups