The human malaria parasite Plasmodium vivax is responsible for 25-40% of the approximately 515 million annual cases of malaria worldwide. Although seldom fatal, the parasite elicits severe and ...incapacitating clinical symptoms and often causes relapses months after a primary infection has cleared. Despite its importance as a major human pathogen, P. vivax is little studied because it cannot be propagated continuously in the laboratory except in non-human primates. We sequenced the genome of P. vivax to shed light on its distinctive biological features, and as a means to drive development of new drugs and vaccines. Here we describe the synteny and isochore structure of P. vivax chromosomes, and show that the parasite resembles other malaria parasites in gene content and metabolic potential, but possesses novel gene families and potential alternative invasion pathways not recognized previously. Completion of the P. vivax genome provides the scientific community with a valuable resource that can be used to advance investigation into this neglected species.
The methodologies used to generate genome and metagenome annotations are diverse and vary between groups and laboratories. Descriptions of the annotation process are helpful in interpreting genome ...annotation data. Some groups have produced Standard Operating Procedures (SOPs) that describe the annotation process, but standards are lacking for structure and content of these descriptions. In addition, there is no central repository to store and disseminate procedures and protocols for genome annotation. We highlight the importance of SOPs for genome annotation and endorse an online repository of SOPs.
The development of efficient and inexpensive genome sequencing methods has revolutionized the study of human bacterial pathogens and improved vaccine design. Unfortunately, the sequence of a single ...genome does not reflect how genetic variability drives pathogenesis within a bacterial species and also limits genome-wide screens for vaccine candidates or for antimicrobial targets. We have generated the genomic sequence of six strains representing the five major disease-causing serotypes of Streptococcus agalactiae, the main cause of neonatal infection in humans. Analysis of these genomes and those available in databases showed that the S. agalactiae species can be described by a pan-genome consisting of a core genome shared by all isolates, accounting for ≈80% of any single genome, plus a dispensable genome consisting of partially shared and strain-specific genes. Mathematical extrapolation of the data suggests that the gene reservoir available for inclusion in the S. agalactiae pan-genome is vast and that unique genes will continue to be identified even after sequencing hundreds of genomes.
Species of malaria parasite that infect rodents have long been used as models for malaria disease research. Here we report the whole-genome shotgun sequence of one species, Plasmodium yoelii yoelii, ...and comparative studies with the genome of the human malaria parasite Plasmodium falciparum clone 3D7. A synteny map of 2,212 P. y. yoelii contiguous DNA sequences (contigs) aligned to 14 P. falciparum chromosomes reveals marked conservation of gene synteny within the body of each chromosome. Of about 5,300 P. falciparum genes, more than 3,300 P. y. yoelii orthologues of predominantly metabolic function were identified. Over 800 copies of a variant antigen gene located in subtelomeric regions were found. This is the first genome sequence of a model eukaryotic parasite, and it provides insight into the use of such systems in the modelling of Plasmodium biology and disease.
The genomes of three strains of Listeria monocytogenes that have been associated with food-borne illness in the USA were subjected to whole genome comparative analysis. A total of 51, 97 and 69 ...strain-specific genes were identified in L.monocytogenes strains F2365 (serotype 4b, cheese isolate), F6854 (serotype 1/2a, frankfurter isolate) and H7858 (serotype 4b, meat isolate), respectively. Eighty-three genes were restricted to serotype 1/2a and 51 to serotype 4b strains. These strain- and serotype-specific genes probably contribute to observed differences in pathogenicity, and the ability of the organisms to survive and grow in their respective environmental niches. The serotype 1/2a-specific genes include an operon that encodes the rhamnose biosynthetic pathway that is associated with teichoic acid biosynthesis, as well as operons for five glycosyl transferases and an adenine-specific DNA methyltransferase. A total of 8603 and 105 050 high quality single nucleotide polymorphisms (SNPs) were found on the draft genome sequences of strain H7858 and strain F6854, respectively, when compared with strain F2365. Whole genome comparative analyses revealed that the L.monocytogenes genomes are essentially syntenic, with the majority of genomic differences consisting of phage insertions, transposable elements and SNPs.
We report the genome sequence of Theileria parva, an apicomplexan pathogen causing economic losses to smallholder farmers in Africa. The parasite chromosomes exhibit limited conservation of gene ...synteny with Plasmodium falciparum, and its plastid-like genome represents the first example where all apicoplast genes are encoded on one DNA strand. We tentatively identify proteins that facilitate parasite segregation during host cell cytokinesis and contribute to persistent infection of transformed host cells. Several biosynthetic pathways are incomplete or absent, suggesting substantial metabolic dependence on the host cell. One protein family that may generate parasite antigenic diversity is not telomere-associated.
Purpose
To examine whether a conventional bioequivalence approach is sufficient to ensure the therapeutic equivalence of liposomal products, the pharmacokinetics, efficacy and toxicity of different ...formulation variants of the marketed Doxil
®
/Caelyx
®
product, pegylated liposomal doxorubicin (PLD), were evaluated in several preclinical models.
Methods
Six different variants of the marketed PLD formulation were prepared by incorporating minor changes in the composition and liposome size of the original formulation. The pharmacokinetics of 5 formulations were evaluated in albino mice following i.v. administration at 6 mg/kg. Selected variants along with Doxil
®
/Caelyx
®
(formulation 1, Doxil-control) were tested for antitumor activity in the MDA-MB-231 xenograft mouse model following 3 repeated administrations at 2 mg/kg or 3 mg/kg (once weekly for 3 weeks) and/or toxicity in Cynomolgus monkeys following 6 repeated administrations at 2.5 or 4.0 mg/kg. Formulations 1–4 were tested for antitumor activity and formulations 1, 2, 6 and 7 were evaluated in a monkey toxicity study. The toxicokinetics of total doxorubicin was determined after the first and last dose in the monkey toxicity study.
Results
In the albino mouse, formulations 2 and 3 had plasma pharmacokinetic profiles similar to Doxil-control (formulation 1). Although these three formulations had similar pharmacokinetic profiles, formulation 2 showed significantly (
P
< 0.05) longer survival time and better efficacy (reduced tumor volume) over other formulations tested for antitumor activity at the 3 mg/kg dose. In monkeys, formulation 2 gave systemic exposure of doxorubicin approximately the same as formulation 1; however, multi-focal degeneration of renal cortical tubules and hypocellularity of the bone marrow were observed with formulation 2 but not with formulation 1 (Doxil-control). Formulations 6 and 7 gave lower exposure to doxorubicin compared to Doxil-control, but were associated with higher severity and frequency of toxic effects (hematological effects, elevated liver enzymes). It was concluded that plasma pharmacokinetics and systemic exposure of doxorubicin did not correlate well with the antitumor activity and toxicity profiles for PLD products. Hence, a conventional bioequivalence approach is not appropriate for establishing therapeutic equivalence of generic PLD products. A carefully designed clinical study evaluating clinical safety, efficacy and pharmacokinetics should be considered for establishing the therapeutic equivalency of generic versions of Doxil
®
.
We sequenced the complete genome of Bacillus cereus ATCC 10987, a non‐lethal dairy isolate in the same genetic subgroup as Bacillus anthracis. Comparison of the chromosomes demonstrated that B.cereus ...ATCC 10987 was more similar to B.anthracis Ames than B.cereus ATCC 14579, while containing a number of unique metabolic capabilities such as urease and xylose utilization and lacking the ability to utilize nitrate and nitrite. Additionally, genetic mechanisms for variation of capsule carbohydrate and flagella surface structures were identified. Bacillus cereus ATCC 10987 contains a single large plasmid (pBc10987), of ∼208 kb, that is similar in gene content and organization to B.anthracis pXO1 but is lacking the pathogenicity‐associated island containing the anthrax lethal and edema toxin complex genes. The chromosomal similarity of B.cereus ATCC 10987 to B.anthracis Ames, as well as the fact that it contains a large pXO1‐like plasmid, may make it a possible model for studying B.anthracis plasmid biology and regulatory cross‐talk.
The availability of the genome sequences of multiple Aspergillus spp. presents the research community with an unprecedented opportunity for discovery. The genomes of Neosartorya fischeri and ...Aspergillus clavatus have been sequenced in order to extend our knowledge of Aspergillus fumigatus, the primary cause of invasive aspergillosis. Through comparative genomic analysis, we hope to elucidate both obvious and subtle differences between genomes, developing new hypotheses that can be tested in the laboratory. A preliminary examination of the genomes and their predicted proteomes reveals extensive conservation between protein sequences and significant synteny, or conserved gene order. Comparative genomic analysis at the level of these closely related aspergilli should provide important insight into the evolutionary forces at play and their effect on gene content, regulation and expression.
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