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1.  Gateways to the FANTOM5 promoter level mammalian expression atlas 
Genome Biology  2015;16(1):22.
The FANTOM5 project investigates transcription initiation activities in more than 1,000 human and mouse primary cells, cell lines and tissues using CAGE. Based on manual curation of sample information and development of an ontology for sample classification, we assemble the resulting data into a centralized data resource (http://fantom.gsc.riken.jp/5/). This resource contains web-based tools and data-access points for the research community to search and extract data related to samples, genes, promoter activities, transcription factors and enhancers across the FANTOM5 atlas.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-014-0560-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s13059-014-0560-6
PMCID: PMC4310165
2.  The Effectiveness of Convalescent Plasma and Hyperimmune Immunoglobulin for the Treatment of Severe Acute Respiratory Infections of Viral Etiology: A Systematic Review and Exploratory Meta-analysis 
Background. Administration of convalescent plasma, serum, or hyperimmune immunoglobulin may be of clinical benefit for treatment of severe acute respiratory infections (SARIs) of viral etiology. We conducted a systematic review and exploratory meta-analysis to assess the overall evidence.
Methods. Healthcare databases and sources of grey literature were searched in July 2013. All records were screened against the protocol eligibility criteria, using a 3-stage process. Data extraction and risk of bias assessments were undertaken.
Results. We identified 32 studies of SARS coronavirus infection and severe influenza. Narrative analyses revealed consistent evidence for a reduction in mortality, especially when convalescent plasma is administered early after symptom onset. Exploratory post hoc meta-analysis showed a statistically significant reduction in the pooled odds of mortality following treatment, compared with placebo or no therapy (odds ratio, 0.25; 95% confidence interval, .14–.45; I2 = 0%). Studies were commonly of low or very low quality, lacked control groups, and at moderate or high risk of bias. Sources of clinical and methodological heterogeneity were identified.
Conclusions. Convalescent plasma may reduce mortality and appears safe. This therapy should be studied within the context of a well-designed clinical trial or other formal evaluation, including for treatment of Middle East respiratory syndrome coronavirus CoV infection.
doi:10.1093/infdis/jiu396
PMCID: PMC4264590  PMID: 25030060
MERS coronavirus; convalescent plasma; severe acute respiratory infection; systematic review; meta-analysis
3.  Transcriptional profiling of the human fibrillin/LTBP gene family, key regulators of mesenchymal cell functions 
The fibrillins and latent transforming growth factor binding proteins (LTBPs) form a superfamily of extracellular matrix (ECM) proteins characterized by the presence of a unique domain, the 8-cysteine transforming growth factor beta (TGFβ) binding domain. These proteins are involved in the structure of the extracellular matrix and controlling the bioavailability of TGFβ family members. Genes encoding these proteins show differential expression in mesenchymal cell types which synthesize the extracellular matrix. We have investigated the promoter regions of the seven gene family members using the FANTOM5 CAGE database for human. While the protein and nucleotide sequences show considerable sequence similarity, the promoter regions were quite diverse. Most genes had a single predominant transcription start site region but LTBP1 and LTBP4 had two regions initiating different transcripts. Most of the family members were expressed in a range of mesenchymal and other cell types, often associated with use of alternative promoters or transcription start sites within a promoter in different cell types. FBN3 was the lowest expressed gene, and was found only in embryonic and fetal tissues. The different promoters for one gene were more similar to each other in expression than to promoters of the other family members. Notably expression of all 22 LTBP2 promoters was tightly correlated and quite distinct from all other family members. We located candidate enhancer regions likely to be involved in expression of the genes. Each gene was associated with a unique subset of transcription factors across multiple promoters although several motifs including MAZ, SP1, GTF2I and KLF4 showed overrepresentation across the gene family. FBN1 and FBN2, which had similar expression patterns, were regulated by different transcription factors. This study highlights the role of alternative transcription start sites in regulating the tissue specificity of closely related genes and suggests that this important class of extracellular matrix proteins is subject to subtle regulatory variations that explain the differential roles of members of this gene family.
Highlights
•We examine expression, promoter use and enhancers for the fibrillin/LTBP gene family.•Promoter switching was observed for most family members.•Multiple enhancers were identified for all family members.•Family members overlapped in tissue specificity with some unique expression patterns.•A degree of redundancy among family members is possible.
doi:10.1016/j.ymgme.2013.12.006
PMCID: PMC4019825  PMID: 24703491
FANTOM, Functional Annotation of Mammals; CAGE, cap analysis of gene expression; ECM, extracellular matrix; TB domain, latent transforming growth factor β binding domain; Fibrillin; Latent transforming growth factor β binding protein; Transcription start sites; Gene regulation; Extracellular matrix; Promoter
4.  Heteroresistance at the Single-Cell Level: Adapting to Antibiotic Stress through a Population-Based Strategy and Growth-Controlled Interphenotypic Coordination 
mBio  2014;5(1):e00942-13.
ABSTRACT
Heteroresistance refers to phenotypic heterogeneity of microbial clonal populations under antibiotic stress, and it has been thought to be an allocation of a subset of “resistant” cells for surviving in higher concentrations of antibiotic. The assumption fits the so-called bet-hedging strategy, where a bacterial population “hedges” its “bet” on different phenotypes to be selected by unpredicted environment stresses. To test this hypothesis, we constructed a heteroresistance model by introducing a blaCTX-M-14 gene (coding for a cephalosporin hydrolase) into a sensitive Escherichia coli strain. We confirmed heteroresistance in this clone and that a subset of the cells expressed more hydrolase and formed more colonies in the presence of ceftriaxone (exhibited stronger “resistance”). However, subsequent single-cell-level investigation by using a microfluidic device showed that a subset of cells with a distinguishable phenotype of slowed growth and intensified hydrolase expression emerged, and they were not positively selected but increased their proportion in the population with ascending antibiotic concentrations. Therefore, heteroresistance—the gradually decreased colony-forming capability in the presence of antibiotic—was a result of a decreased growth rate rather than of selection for resistant cells. Using a mock strain without the resistance gene, we further demonstrated the existence of two nested growth-centric feedback loops that control the expression of the hydrolase and maximize population growth in various antibiotic concentrations. In conclusion, phenotypic heterogeneity is a population-based strategy beneficial for bacterial survival and propagation through task allocation and interphenotypic collaboration, and the growth rate provides a critical control for the expression of stress-related genes and an essential mechanism in responding to environmental stresses.
IMPORTANCE
Heteroresistance is essentially phenotypic heterogeneity, where a population-based strategy is thought to be at work, being assumed to be variable cell-to-cell resistance to be selected under antibiotic stress. Exact mechanisms of heteroresistance and its roles in adaptation to antibiotic stress have yet to be fully understood at the molecular and single-cell levels. In our study, we have not been able to detect any apparent subset of “resistant” cells selected by antibiotics; on the contrary, cell populations differentiate into phenotypic subsets with variable growth statuses and hydrolase expression. The growth rate appears to be sensitive to stress intensity and plays a key role in controlling hydrolase expression at both the bulk population and single-cell levels. We have shown here, for the first time, that phenotypic heterogeneity can be beneficial to a growing bacterial population through task allocation and interphenotypic collaboration other than partitioning cells into different categories of selective advantage.
doi:10.1128/mBio.00942-13
PMCID: PMC3950525  PMID: 24520060
5.  An expression atlas of human primary cells: inference of gene function from coexpression networks 
BMC Genomics  2013;14:632.
Background
The specialisation of mammalian cells in time and space requires genes associated with specific pathways and functions to be co-ordinately expressed. Here we have combined a large number of publically available microarray datasets derived from human primary cells and analysed large correlation graphs of these data.
Results
Using the network analysis tool BioLayout Express3D we identify robust co-associations of genes expressed in a wide variety of cell lineages. We discuss the biological significance of a number of these associations, in particular the coexpression of key transcription factors with the genes that they are likely to control.
Conclusions
We consider the regulation of genes in human primary cells and specifically in the human mononuclear phagocyte system. Of particular note is the fact that these data do not support the identity of putative markers of antigen-presenting dendritic cells, nor classification of M1 and M2 activation states, a current subject of debate within immunological field. We have provided this data resource on the BioGPS web site (http://biogps.org/dataset/2429/primary-cell-atlas/) and on macrophages.com (http://www.macrophages.com/hu-cell-atlas).
doi:10.1186/1471-2164-14-632
PMCID: PMC3849585  PMID: 24053356
Clustering; Meta-analysis; Human; Primary cells; Dendritic cell; Macrophage; Microarray; Transcriptomics
6.  Modelling mutational and selection pressures on dinucleotides in eukaryotic phyla –selection against CpG and UpA in cytoplasmically expressed RNA and in RNA viruses 
BMC Genomics  2013;14:610.
Background
Loss of CpG dinucleotides in genomic DNA through methylation-induced mutation is characteristic of vertebrates and plants. However, these and other eukaryotic phyla show a range of other dinucleotide frequency biases with currently uncharacterized underlying mutational or selection mechanisms. We developed a parameterized Markov process to identify what neighbour context-dependent mutations best accounted for patterns of dinucleotide frequency biases in genomic and cytoplasmically expressed mRNA sequences of different vertebrates, other eukaryotic groups and RNA viruses that infect them.
Results
Consistently, 11- to 14-fold greater frequencies of the methylation-associated mutation of C to T upstream of G (depicted as C→T,G) than other transitions best modelled dinucleotide frequencies in mammalian genomic DNA. However, further mutations such as G→T,T (5-fold greater than the default transversion rate) were required to account for the full spectrum of dinucleotide frequencies in mammalian sequence datasets. Consistent with modeling predictions for these two mutations, instability of both CpG and CpT dinucleotides was identified through SNP frequency analysis of human DNA sequences. Different sets of context-dependent mutations were modelled in other eukaryotes with non-methylated genomic DNA. In contrast to genomic DNA, best-fit models of dinucleotide frequencies in transcribed RNA sequences expressed in the cytoplasm from all organisms were dominated by mutations that eliminated UpA dinucleotides, observations consistent with cytoplasmically driven selection for mRNA stability. Surprisingly, mRNA sequences from organisms with methylated genomes showed evidence for additional selection against CpG through further context-dependent mutations (eg. C→A,G). Similar mutation or selection processes were identified among single-stranded mammalian RNA viruses; these potentially account for their previously described but unexplained under-representations of CpG and UpA dinucleotides.
Conclusions
Methods we have developed identify mutational processes and selection pressures in organisms that provide new insights into nucleotide compositional constraints and a wealth of biochemical and evolutionarily testable predictions for the future.
doi:10.1186/1471-2164-14-610
PMCID: PMC3829696  PMID: 24020411
Dinucleotide; Methylation; Exon; RNA virus; Markov modelling
8.  Endogenous Retrotransposition Activates Oncogenic Pathways in Hepatocellular Carcinoma 
Cell  2013;153(1):101-111.
Summary
LINE-1 (L1) retrotransposons are mobile genetic elements comprising ∼17% of the human genome. New L1 insertions can profoundly alter gene function and cause disease, though their significance in cancer remains unclear. Here, we applied enhanced retrotransposon capture sequencing (RC-seq) to 19 hepatocellular carcinoma (HCC) genomes and elucidated two archetypal L1-mediated mechanisms enabling tumorigenesis. In the first example, 4/19 (21.1%) donors presented germline retrotransposition events in the tumor suppressor mutated in colorectal cancers (MCC). MCC expression was ablated in each case, enabling oncogenic β-catenin/Wnt signaling. In the second example, suppression of tumorigenicity 18 (ST18) was activated by a tumor-specific L1 insertion. Experimental assays confirmed that the L1 interrupted a negative feedback loop by blocking ST18 repression of its enhancer. ST18 was also frequently amplified in HCC nodules from Mdr2−/− mice, supporting its assignment as a candidate liver oncogene. These proof-of-principle results substantiate L1-mediated retrotransposition as an important etiological factor in HCC.
Graphical Abstract
Highlights
► L1 retrotransposons promote tumorigenesis in hepatocellular carcinoma (HCC) ► Germline L1 and Alu insertions in MCC activate β-catenin/Wnt signaling ► L1 mobilization in tumor cells accelerates transformation of the HCC genome ► A tumor-specific L1 insertion interrupts a negative feedback loop regulating ST18
L1 retrotransposons, which are widespread in the human genome, can mobilize and activate oncogenes in the livers of individuals infected with the hepatitis B or hepatitis C virus, promoting the development and growth of hepatocellular carcinoma. Genes identified by the L1 insertions present new options for cancer screening and intervention.
doi:10.1016/j.cell.2013.02.032
PMCID: PMC3898742  PMID: 23540693
9.  A gene expression atlas of the domestic pig 
BMC Biology  2012;10:90.
Background
This work describes the first genome-wide analysis of the transcriptional landscape of the pig. A new porcine Affymetrix expression array was designed in order to provide comprehensive coverage of the known pig transcriptome. The new array was used to generate a genome-wide expression atlas of pig tissues derived from 62 tissue/cell types. These data were subjected to network correlation analysis and clustering.
Results
The analysis presented here provides a detailed functional clustering of the pig transcriptome where transcripts are grouped according to their expression pattern, so one can infer the function of an uncharacterized gene from the company it keeps and the locations in which it is expressed. We describe the overall transcriptional signatures present in the tissue atlas, where possible assigning those signatures to specific cell populations or pathways. In particular, we discuss the expression signatures associated with the gastrointestinal tract, an organ that was sampled at 15 sites along its length and whose biology in the pig is similar to human. We identify sets of genes that define specialized cellular compartments and region-specific digestive functions. Finally, we performed a network analysis of the transcription factors expressed in the gastrointestinal tract and demonstrate how they sub-divide into functional groups that may control cellular gastrointestinal development.
Conclusions
As an important livestock animal with a physiology that is more similar than mouse to man, we provide a major new resource for understanding gene expression with respect to the known physiology of mammalian tissues and cells. The data and analyses are available on the websites http://biogps.org and http://www.macrophages.com/pig-atlas.
doi:10.1186/1741-7007-10-90
PMCID: PMC3814290  PMID: 23153189
pig; porcine; Sus scrofa; microarray; transcriptome; transcription network; pathway; gastrointestinal tract
10.  Identification of Novel Genes Selectively Expressed in the Follicle-Associated Epithelium from the Meta-Analysis of Transcriptomics Data from Multiple Mouse Cell and Tissue Populations 
The follicle-associated epithelium (FAE) overlying the Peyer's patches and the microfold cells (M cells) within it are important sites of antigen transcytosis across the intestinal epithelium. Using a meta-analysis approach, we identified a transcriptional signature that distinguished the FAE from a large collection of mouse cells and tissues. A co-expressed cluster of 21 FAE-specific genes was identified, and the analysis of the transcription factor binding site motifs in their promoter regions indicated that these genes shared an underlying transcriptional programme. This cluster contained known FAE- (Anxa10, Ccl20, Psg18 and Ubd) and M-cell-specific (Gp2) genes, suggesting that the others were novel FAE-specific genes. Some of these novel candidate genes were expressed highly by the FAE and M cells (Calcb, Ces3b, Clca2 and Gjb2), and others only by the FAE (Ascl2, Cftr, Fgf15, Gpr133, Kcna1, Kcnj15, Mycl1, Pgap1 and Rps6kl). We also identified a subset of novel FAE-related genes that were induced in the intestinal epithelium after receptor activator of nuclear factor (NF)-κB ligand stimulation. These included Mfge8 which was specific to FAE enterocytes. This study provides new insight into the FAE transcriptome. Further characterization of the candidate genes identified here will aid the identification of novel regulators of cell function in the FAE.
doi:10.1093/dnares/dss022
PMCID: PMC3473373  PMID: 22991451
follicle-associated epithelium; M cells; intestine; meta-analysis; clustering
11.  Somatic retrotransposition alters the genetic landscape of the human brain 
Nature  2011;479(7374):534-537.
Retrotransposons are mobile genetic elements that employ a germ line “copy-and-paste” mechanism to spread throughout metazoan genomes1. At least 50% of the human genome is derived from retrotransposons, with three active families (L1, Alu and SVA) associated with insertional mutagenesis and disease2-3. Epigenetic and post-transcriptional suppression block retrotransposition in somatic cells4-5, excluding early embryo development and some malignancies6-7. Recent reports of L1 expression8-9 and copy number variation10-11 (CNV) in the human brain suggest L1 mobilization may also occur during later development. However, the corresponding integration sites have not been mapped. Here we apply a high-throughput method to identify numerous L1, Alu and SVA germ line mutations, as well as 7,743 putative somatic L1 insertions in the hippocampus and caudate nucleus of three individuals. Surprisingly, we also found 13,692 and 1,350 somatic Alu and SVA insertions, respectively. Our results demonstrate that retrotransposons mobilize to protein-coding genes differentially expressed and active in the brain. Thus, somatic genome mosaicism driven by retrotransposition may reshape the genetic circuitry that underpins normal and abnormal neurobiological processes.
doi:10.1038/nature10531
PMCID: PMC3224101  PMID: 22037309
12.  The Role of Host Genetics in Susceptibility to Influenza: A Systematic Review 
PLoS ONE  2012;7(3):e33180.
Background
The World Health Organization has identified studies of the role of host genetics on susceptibility to severe influenza as a priority. A systematic review was conducted to summarize the current state of evidence on the role of host genetics in susceptibility to influenza (PROSPERO registration number: CRD42011001380).
Methods and Findings
PubMed, Web of Science, the Cochrane Library, and OpenSIGLE were searched using a pre-defined strategy for all entries up to the date of the search. Two reviewers independently screened the title and abstract of 1,371 unique articles, and 72 full text publications were selected for inclusion. Mouse models clearly demonstrate that host genetics plays a critical role in susceptibility to a range of human and avian influenza viruses. The Mx genes encoding interferon inducible proteins are the best studied but their relevance to susceptibility in humans is unknown. Although the MxA gene should be considered a candidate gene for further study in humans, over 100 other candidate genes have been proposed. There are however no data associating any of these candidate genes to susceptibility in humans, with the only published study in humans being under-powered. One genealogy study presents moderate evidence of a heritable component to the risk of influenza-associated death, and while the marked familial aggregation of H5N1 cases is suggestive of host genetic factors, this remains unproven.
Conclusion
The fundamental question “Is susceptibility to severe influenza in humans heritable?” remains unanswered. Not because of a lack of genotyping or analytic tools, nor because of insufficient severe influenza cases, but because of the absence of a coordinated effort to define and assemble cohorts of cases. The recent pandemic and the ongoing epizootic of H5N1 both represent rapidly closing windows of opportunity to increase understanding of the pathogenesis of severe influenza through multi-national host genetic studies.
doi:10.1371/journal.pone.0033180
PMCID: PMC3305291  PMID: 22438897
13.  Use and perceived effectiveness of non-analgesic medical therapies for chronic pancreatitis in the United States 
Background
Effectiveness of medical therapies in chronic pancreatitis (CP) has been described in small studies of selected patients.
Aim
To describe frequency and perceived effectiveness of non-analgesic medical therapies in CP patients evaluated at U.S. referral centers.
Methods
Using data on 516 CP patients prospectively enrolled in the NAPS2 Study, we evaluated how often medical therapies (pancreatic enzyme replacement therapy [PERT], vitamins/antioxidants [AO], octreotide, celiac plexus block [CPB]) were utilized and considered useful by physicians.
Results
Oral PERT was commonly used (70.3%), more frequently in the presence of exocrine insufficiency (EI) (87.8 vs. 61%, p<0.001), and pain (73.7 vs. 59.2%, p<0.002). On multivariable analyses, predictors of PERT usage were EI (OR 5.14, 95% CI 2.87-9.18), constant (OR 3.42, 95% CI 1.93-6.04) or intermittent pain (OR 1.98, 95% CI 1.14-3.45). Efficacy of PERT was predicted only by EI (OR 2.16, 95% CI 1.36-3.42). AO were tried less often (13.8%) and were more effective in idiopathic and obstructive vs. alcoholic CP (25% vs. 3.6%, p=0.03). Other therapies were infrequently used (CPB-5.4%, octreotide-6.6%) with efficacy generally <50%.
Conclusions
PERT is commonly utilized, but is considered useful in only subsets of CP patients. Other medical therapies are used infrequently and have limited efficacy.
doi:10.1111/j.1365-2036.2010.04491.x
PMCID: PMC3142582  PMID: 21083584
chronic pancreatitis; medical therapy; pancreatic enzymes; antioxidants; octreotide; celiac plexus block
14.  Is somatic retrotransposition a parasitic or symbiotic phenomenon? 
Mobile Genetic Elements  2011;1(4):279-282.
The extraordinary evolutionary success of transposable elements (TEs) invites us to question the nature of the co-evolutionary dynamics between TE and host. Although sometimes assumed to be wholly parasitic, TEs have penetrated and spread throughout eukaryotic genomes at a rate unparalleled by other parasites. This near-ubiquity, occurring despite the potentially deleterious effects of insertional mutagenesis, raises the possibility that a counterbalancing benefit exists for the host. Such a benefit may act at the population level to generate genomic diversity within a species and hence greater adaptability under new selective pressures, or at the level of primary gain for the individual. Recent studies have highlighted the occurrence of retrotransposition events in the germline and discovered a surprisingly high rate of mobilization in somatic cells. Here we examine the available evidence for somatic retrotransposition and discuss how this phenomenon may confer a selective advantage upon an individual or species.
doi:10.4161/mge.18422
PMCID: PMC3337137  PMID: 22545239
Alu; LINE-1; parasitism; retrotransposon; somatic retrotransposition; SVA; symbiotism; transposable element
15.  High altitude adaptation in Daghestani populations from the Caucasus 
Human Genetics  2011;131(3):423-433.
We have surveyed 15 high-altitude adaptation candidate genes for signals of positive selection in North Caucasian highlanders using targeted re-sequencing. A total of 49 unrelated Daghestani from three ethnic groups (Avars, Kubachians, and Laks) living in ancient villages located at around 2,000 m above sea level were chosen as the study population. Caucasian (Adygei living at sea level, N = 20) and CEU (CEPH Utah residents with ancestry from northern and western Europe; N = 20) were used as controls. Candidate genes were compared with 20 putatively neutral control regions resequenced in the same individuals. The regions of interest were amplified by long-PCR, pooled according to individual, indexed by adding an eight-nucleotide tag, and sequenced using the Illumina GAII platform. 1,066 SNPs were called using false discovery and false negative thresholds of ~6%. The neutral regions provided an empirical null distribution to compare with the candidate genes for signals of selection. Two genes stood out. In Laks, a non-synonymous variant within HIF1A already known to be associated with improvement in oxygen metabolism was rediscovered, and in Kubachians a cluster of 13 SNPs located in a conserved intronic region within EGLN1 showing high population differentiation was found. These variants illustrate both the common pathways of adaptation to high altitude in different populations and features specific to the Daghestani populations, showing how even a mildly hypoxic environment can lead to genetic adaptation.
Electronic supplementary material
The online version of this article (doi:10.1007/s00439-011-1084-8) contains supplementary material, which is available to authorized users.
doi:10.1007/s00439-011-1084-8
PMCID: PMC3312735  PMID: 21904933
16.  Pericardial effusions in healthy lowlanders after acute ascent to high altitude 
Heart  2006;92(4):539-540.
doi:10.1136/hrt.2005.065375
PMCID: PMC1860857  PMID: 16537774
altitude; antioxidant; echocardiography; hypoxia; pericardial effusions
17.  Recurrent bile duct stones after endoscopic sphincterotomy 
Gut  2004;53(12):1725-1727.
doi:10.1136/gut.2004.046185
PMCID: PMC1774339  PMID: 15542503
endoscopic sphincterotomy; endoscopic retrograde cholangiopancreatography; recurrent choledocholithiasis; bile duct stones
18.  Measuring the fate of plant diversity: towards a foundation for future monitoring and opportunities for urgent action 
Vascular plants are often considered to be among the better known large groups of organisms, but gaps in the available baseline data are extensive, and recent estimates of total known (described) seed plant species range from 200 000 to 422 000. Of these, global assessments of conservation status using International Union for the Conservation of Nature (IUCN) categories and criteria are available for only approximately 10 000 species. In response to recommendations from the Conference of the Parties to the Convention on Biological Diversity to develop biodiversity indicators based on changes in the status of threatened species, and trends in the abundance and distribution of selected species, we examine how existing data, in combination with limited new data collection, can be used to maximum effect. We argue that future work should produce Red List Indices based on a representative subset of plant species so that the limited resources currently available are directed towards redressing taxonomic and geographical biases apparent in existing datasets. Sampling the data held in the world's major herbaria, in combination with Geographical Information Systems techniques, can produce preliminary conservation assessments and help to direct selective survey work using existing field networks to verify distributions and gather population data. Such data can also be used to backcast threats and potential distributions through time. We outline an approach that could result in: (i) preliminary assessments of the conservation status of tens of thousands of species not previously assessed, (ii) significant enhancements in the coverage and representation of plant species on the IUCN Red List, and (iii) repeat and/or retrospective assessments for a significant proportion of these. This would result in more robust Sampled Red List Indices that can be defended as more representative of plant diversity as a whole; and eventually, comprehensive assessments at species level for one or more major families of angiosperms. The combined results would allow scientifically defensible generalizations about the current status of plant diversity by 2010 as well as tentative comments on trends. Together with other efforts already underway, this approach would establish a firmer basis for ongoing monitoring of the status of plant diversity beyond 2010 and a basis for comparison with the trend data available for vertebrates.
doi:10.1098/rstb.2004.1596
PMCID: PMC1569457  PMID: 15814350
global biodiversity; species richness; conservation assessments; extinction risk; IUCN Red List; Living Planet Index
19.  Using Red List Indices to measure progress towards the 2010 target and beyond 
The World Conservation Union (IUCN) Red List is widely recognized as the most authoritative and objective system for classifying species by their risk of extinction. Red List Indices (RLIs) illustrate the relative rate at which a particular set of species change in overall threat status (i.e. projected relative extinction-risk), based on population and range size and trends as quantified by Red List categories. RLIs can be calculated for any representative set of species that has been fully assessed at least twice. They are based on the number of species in each Red List category, and the number changing categories between assessments as a result of genuine improvement or deterioration in status. RLIs show a fairly coarse level of resolution, but for fully assessed taxonomic groups they are highly representative, being based on information from a high proportion of species worldwide. The RLI for the world's birds shows that that their overall threat status has deteriorated steadily during the years 1988–2004 in all biogeographic realms and ecosystems. A preliminary RLI for amphibians for 1980–2004 shows similar rates of decline. RLIs are in development for other groups. In addition, a sampled index is being developed, based on a stratified sample of species from all major taxonomic groups, realms and ecosystems. This will provide extinction-risk trends that are more representative of all biodiversity.
doi:10.1098/rstb.2004.1583
PMCID: PMC1569445  PMID: 15814344
indicators; birds; amphibians; IUCN Red List; threatened species; extinction-risk
20.  Pharmacokinetics, Toxicities, and Efficacies of Sodium Stibogluconate Formulations after Intravenous Administration in Animals 
The pharmacokinetics and toxicities of free sodium stibogluconate (SSG) and two vesicular formulations of this drug (a nonionic surfactant vesicular formulation of SSG [SSG-NIV] and SSG-NIV-dextran) were determined after treatment with a single intravenous dose in healthy dogs and were related to their antileishmanial efficacies in mice. Analysis of the curves of the concentrations in plasma after intravenous administration of SSG and SSG-NIV in dogs showed that both formulations produced similar antimony (Sb) pharmacokinetics. In contrast, treatment with SSG-NIV-dextran significantly modified the pharmacokinetics of the drug. The elimination half-life was four times longer (280 min) than that observed after administration of SSG (71 min) (P = 0.01), and the volume of distribution at steady state (VSS) was also increased (VSS for SSG, 0.21 liters/kg; VSS for SSG-NIV-dextran, 0.34 liters/kg [P = 0.02]), thus indicating that drug encapsulation favors the distribution of Sb into organs and increases its residence time in tissues. This would explain the superior antileishmanial efficacy of this formulation compared to those of the free drug in mice. No signs of toxicity were found in dogs after SSG and SSG-NIV administration. However, SSG-NIV-dextran treatment was associated with short-term toxicity, demonstrated by the development of chills and diarrhea, which cleared by 24 h postdosing, and hepatic dysfunction at 24 h postdosing (P < 0.05). The levels of all the biochemical parameters had returned to normal at 1 month postdosing. No signs of toxicity were observed in mice treated with all three formulations.
doi:10.1128/AAC.47.9.2781-2787.2003
PMCID: PMC182616  PMID: 12936974
21.  Human Cytomegalovirus Infection Inhibits Tumor Necrosis Factor Alpha (TNF-α) Signaling by Targeting the 55-Kilodalton TNF-α Receptor 
Journal of Virology  2003;77(12):7007-7016.
Infection with human cytomegalovirus (HCMV) results in complex interactions between viral and cellular factors which perturb many cellular functions. HCMV is known to target the cell cycle, cellular transcription, and immunoregulation, and it is believed that this optimizes the cellular environment for viral DNA replication during productive infection or during carriage in the latently infected host. Here, we show that HCMV infection also prevents external signaling to the cell by disrupting the function of TNFRI, the 55-kDa receptor for tumor necrosis factor alpha (TNF-α), one of the receptors for a potent cytokine involved in eliciting a wide spectrum of cellular responses, including antiviral responses. HCMV infection of fully permissive differentiated monocytic cell lines and U373 cells resulted in a reduction in cell surface expression of TNFRI. The reduction appeared to be due to relocalization of TNFRI from the cell surface and was reflected in the elimination of TNF-α-induced Jun kinase activity. Analysis of specific phases of infection suggested that viral early gene products were responsible for this relocalization. However, a mutant HCMV in which all viral gene products known to be involved in down-regulation of major histocompatibility complex (MHC) class I were deleted still resulted in relocalization of TNFRI. Consequently, TNFRI relocalization by HCMV appears to be mediated by a novel viral early function not involved in down-regulation of cell surface MHC class I expression. We suggest that upon infection, HCMV isolates the cell from host-mediated signals, forcing the cell to respond only to virus-specific signals which optimize the cell for virus production and effect proviral responses from bystander cells.
doi:10.1128/JVI.77.12.7007-7016.2003
PMCID: PMC156201  PMID: 12768019
22.  ERCP training: for the few, not for all 
Gut  1999;45(1):9-10.
PMCID: PMC1727590  PMID: 10369696
23.  The Cured Immune Phenotype Achieved by Treatment of Visceral Leishmaniasis in the BALB/c Mouse with a Nonionic Surfactant Vesicular Formulation of Sodium Stibogluconate Does Not Protect against Reinfection 
Single-dose treatment with sodium stibogluconate solution (SSG) and treatment with a nonionic surfactant vesicular formulation of sodium stibogluconate (SSG-NIV) were compared for the ability to protect BALB/c mice against infection with Leishmania donovani. Prophylactic treatment with SSG-NIV protected against infection, although its effects were time and organ dependent; protection was not obtained with SSG. Protection against reinfection with L. donovani was observed only in mice cured by treatment with SSG-NIV. However, this protective effect was probably due to the presence of residual drug rather than an immune effect, since prophylactic SSG-NIV treatment gave similar results. Transfer of enriched spleen T-cell populations from L. donovani-infected mice or from infected SSG-NIV-treated mice gave no protection against L. donovani infection in the recipients. T cells from infected mice, but not from infected SSG-NIV-treated mice, were infectious to recipients. SSG-NIV treatment was equally effective against visceral leishmaniasis in immunocompetent and SCID mice, whereas SSG treatment was less effective in the latter. The results of this study suggest that the high antileishmanial activity of SSG-NIV is due to favorable modification of SSG delivery and does not require a fully functional immune response. Cure of visceral leishmaniasis by SSG-NIV treatment in the BALB/c mouse did not protect against reinfection.
PMCID: PMC95661  PMID: 9874665
24.  Visceral Leishmaniasis in the BALB/c Mouse: A Comparison of the Efficacy of a Nonionic Surfactant Formulation of Sodium Stibogluconate with Those of Three Proprietary Formulations of Amphotericin B 
Antimicrobial Agents and Chemotherapy  1998;42(10):2722-2725.
In this study, treatment efficacies of a nonionic surfactant vesicle formulation of sodium stibogluconate (SSG-NIV) and of several formulations of amphotericin B were compared in a murine model of visceral leishmaniasis. Treatment with multiple doses of AmBisome, Abelcet, and Amphocil (total dose, 12.5 mg of amphotericin B/kg of body weight) resulted in a significant suppression of parasite burdens in liver (P < 0.0005) and spleen (P < 0.0005) compared with those of controls, with Abelcet having the lowest activity. Only AmBisome and Amphocil gave significant suppression of parasites in bone marrow (compared to control values, P < 0.005). In the acute-infection model, single-dose treatments of SSG-NIV (296 mg of SbV/kg), SSG solution (296 mg of SbV/kg), or AmBisome (8 mg of amphotericin B/kg) were equally effective against liver parasites (compared to control values, P < 0.0005). SSG-NIV and AmBisome treatment also significantly suppressed parasites in bone marrow and spleen (P < 0.005), with SSG-NIV treatment being more suppressive (>98% suppression in all three sites). Free-SSG treatment failed to suppress spleen or bone marrow parasites. Infection status influenced treatment outcome. In the chronic-infection model, the AmBisome single-dose treatment was less effective in all three infection sites and the SSG-NIV single-dose treatment was less effective in the spleen. The results of this study suggest that the antileishmanial efficacy of SSG-NIV compares favorably with those of the novel amphotericin B formulations.
PMCID: PMC105926  PMID: 9756784
25.  Acute pancreatitis. 
BMJ : British Medical Journal  1998;316(7124):44-48.
PMCID: PMC2665345  PMID: 9451268

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