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Human malaria is caused by four species of the parasitic protozoan genus Plasmodium . Of these four species, Plasmodium falciparum is responsible for the vast majority of the 300–500 million episodes of malaria worldwide and accounts for 0.7–2.7 million annual deaths. In many endemic countries, malaria is responsible f... | 12929205_p0 | 12929205 | Introduction | 4.381112 | biomedical | Review | [
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The 22.8 Mb genome of P. falciparum is comprised of 14 linear chromosomes, a circular plastid-like genome, and a linear mitochondrial genome. The malaria genome sequencing consortium estimates that more than 60% of the 5,409 predicted open reading frames (ORFs) lack sequence similarity to genes from any other known org... | 12929205_p1 | 12929205 | Introduction | 4.287888 | biomedical | Study | [
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The complete P. falciparum lifecycle encompasses three major developmental stages: the mosquito, liver, and blood stages. It has long been a goal to understand the regulation of gene expression throughout each developmental stage. Previous attempts to apply functional genomics methods to address these questions used va... | 12929205_p2 | 12929205 | Introduction | 4.180849 | biomedical | Study | [
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The 48-h P. falciparum IDC initiates with merozoite invasion of red blood cells (RBCs) and is followed by the formation of the parasitophorous vacuole (PV) during the ring stage. The parasite then enters a highly metabolic maturation phase, the trophozoite stage, prior to parasite replication. In the schizont stage, th... | 12929205_p3 | 12929205 | Introduction | 4.415376 | biomedical | Study | [
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Our laboratory has developed a P. falciparum– specific DNA microarray using long (70 nt) oligonucleotides as representative elements for predicted ORFs in the sequenced genome (strain 3D7) . Using this DNA microarray, we have examined expression profiles across 48 individual 1-h timepoints from the IDC of P. falciparum... | 12929205_p4 | 12929205 | Introduction | 4.207411 | biomedical | Study | [
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The genome-wide transcriptome of the P. falciparum IDC was generated by measuring relative mRNA abundance levels in samples collected from a highly synchronized in vitro culture of parasites. The strain used was the well-characterized Honduran chloroquine-sensitive HB3 strain, which was used in the only two experimenta... | 12929205_p5 | 12929205 | Expression Profiling of the IDC | 4.21763 | biomedical | Study | [
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The DNA microarray used in this study consists of 7,462 individual 70mer oligonucleotides representing 4,488 of the 5,409 ORFs manually annotated by the malaria genome sequencing consortium . Of the 4,488 ORFs, 990 are represented by more than one oligonucleotide. Since our oligonucleotide design was based on partially... | 12929205_p6 | 12929205 | Expression Profiling of the IDC | 4.164729 | biomedical | Study | [
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To measure the relative abundance of mRNAs throughout the IDC, total RNA from each timepoint was compared to an arbitrary reference pool of total RNA from all timepoints in a standard two-color competitive hybridization . The transcriptional profile of each ORF is represented by the mean-centered series of ratio measur... | 12929205_p7 | 12929205 | Expression Profiling of the IDC | 4.392786 | biomedical | Study | [
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Periodicity in genome-wide gene expression datasets has been used to identify cell-cycle-regulated genes in both yeast and human cells . Owing to the cyclical nature of the P. falciparum IDC dataset, a similar computational approach was taken. We performed simple Fourier analysis, which allowed us to calculate both the... | 12929205_p8 | 12929205 | Expression Profiling of the IDC | 4.14594 | biomedical | Study | [
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We have used the FFT data for the purpose of filtering the expression profiles that are inherently noisy (i.e., that have low signal) or that lack differential expression throughout the IDC. Since the majority of the profiles display a single low-frequency peak in the power spectrum, we have taken advantage of this fea... | 12929205_p9 | 12929205 | Expression Profiling of the IDC | 4.142359 | biomedical | Study | [
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To provide an overview of the IDC transcriptome, we selected all 3,719 microarray elements whose profiles exhibited greater than 70% of the power in the maximum frequency window and that were also in the top 75% of the maximum frequency magnitudes. Although hierarchical clustering is extremely useful for comparing any ... | 12929205_p10 | 12929205 | P. falciparum Transcriptome Overview | 4.145405 | biomedical | Study | [
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The IDC phaseogram depicts a cascade of continuous expression lacking clear boundaries or sharp transitions. During the first half of the IDC, a large number of genes involved in general eukaryotic cellular functions are induced with broad expression profiles. This gradual continuum includes the transition from the rin... | 12929205_p11 | 12929205 | P. falciparum Transcriptome Overview | 4.47647 | biomedical | Study | [
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In the following text, we have grouped the genes according to temporal expression phases based on their association with the common P. falciparum cytological stages. | 12929205_p12 | 12929205 | Ring and Early-Trophozoite Stage | 2.944431 | biomedical | Study | [
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Following invasion, approximately 950 ORFs are induced during the ring and early trophozoite stage, including genes associated with the cytoplasmic transcriptional and translational machinery, glycolysis and ribonucleotide biosynthesis . Represented in this group are 23 ORFs involved in transcription, including the fou... | 12929205_p13 | 12929205 | Ring and Early-Trophozoite Stage | 4.478033 | biomedical | Study | [
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Another set of 33 ORFs with homology to components of the translational machinery displayed an entirely distinct expression pattern, being induced during the late-trophozoite and early-schizont stage. This group includes 11 homologues of chloroplast ribosomal proteins, four mitochondrial/chloroplast elongation factors,... | 12929205_p14 | 12929205 | Ring and Early-Trophozoite Stage | 4.283979 | biomedical | Study | [
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] | en | 0.999998 |
In addition to transcription and translation, genes involved in several basic metabolic pathways were also induced during the ring and early-trophozoite stage, including glycolysis and ribonucleotide biosynthesis . Unlike the majority of P. falciparum biochemical processes, most of the enzymes involved in nucleotide me... | 12929205_p15 | 12929205 | Ring and Early-Trophozoite Stage | 4.432044 | biomedical | Study | [
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] | [
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] | en | 0.999997 |
P. falciparum parasites generate pyrimidines through a de novo synthesis pathway while purines must be acquired by the organism through a salvage pathway . The mRNA levels of 16 enzymes corresponding to members of the pyrimidine ribonucleotide synthesis pathway, beginning with carbamoyl phosphate synthetase and ending ... | 12929205_p16 | 12929205 | Ring and Early-Trophozoite Stage | 4.292218 | biomedical | Study | [
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] | [
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] | en | 0.999996 |
The mRNA expression data indicate that ribonucleotide and deoxyribonucleotide production is clearly bifurcated into two distinct temporal classes. While ribonucleotide synthesis is required in the early stages of the IDC, deoxyribonucleotide metabolism is a trophozoite/early-schizont function. mRNA transcripts for enzy... | 12929205_p17 | 12929205 | Trophozoite and Early-Schizont Stage | 4.31563 | biomedical | Study | [
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] | [
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Thirty-two ORFs with homologies to various eukaryotic DNA replication machinery components are transcribed during the late-trophozoite and early-schizont stage. The timing of their transcription presages cell division. This functional gene group , with peak expression around 32 hpi, contains the previously characterize... | 12929205_p18 | 12929205 | Trophozoite and Early-Schizont Stage | 4.376419 | biomedical | Study | [
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] | [
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] | en | 0.999996 |
All genes necessary for the completion of the tricarboxylic acid (TCA) cycle were detected in the Plasmodium genome , although earlier studies indicate an unconventional function for this metabolic cycle. These studies suggest that the TCA cycle does not play a major role in the oxidation of glycolytic products. Instea... | 12929205_p19 | 12929205 | Trophozoite and Early-Schizont Stage | 4.455936 | biomedical | Study | [
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] | [
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A transition from early to mid-schizont is marked by the maximal induction of 29 ORFs predicted to encode various subunits of the proteasome . Seven α and six β subunits of the 20S particle and 16 ORFs of the 19S regulatory particle were identified in this gene group. The common expression profile for the subunits of b... | 12929205_p20 | 12929205 | Schizont Stage | 4.400574 | biomedical | Study | [
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] | [
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In the schizont stage, one of the first specialized processes induced was expression from the plastid genome . The essential extrachromosomal plastid (or apicoplast) genome contains 60 potentially expressed sequences, including ribosomal proteins, RNA polymerase subunits, ribosomal RNAs, tRNAs, and nine putative ORFs, ... | 12929205_p21 | 12929205 | Schizont Stage | 4.275912 | biomedical | Study | [
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Offset from the plastid by approximately 6 h, a set of approximately 500 ORFs exhibited peak expression during the late-schizont stage. Merozoite invasion of a new host cell is a complex process during which the parasite must recognize and dock onto the surface of the target erythrocyte, reorient with its apical tip to... | 12929205_p22 | 12929205 | Schizont Stage | 4.715103 | biomedical | Study | [
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] | [
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The sensitivity of invasion to protease and kinase inhibitors indicates an essential role for these activities in merozoite release as well as in the reinvasion process . The merozoite invasion gene group contains three serine proteases, including PfSUB1, PfSUB2, and an additional homologue to plasmodial subtilases , a... | 12929205_p23 | 12929205 | Schizont Stage | 4.464591 | biomedical | Study | [
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Another functionally related gene group whose expression is sharply induced during the late-schizont stage includes components of actin–myosin motors . As in other apicomplexa, actin and myosin have been implicated in host cell invasion . Schizont-specific expression was observed for three previously described class XI... | 12929205_p24 | 12929205 | Schizont Stage | 4.298283 | biomedical | Study | [
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The expression data are continuous throughout the invasion process, with no observable abrupt change in the expression program upon successful reinvasion. However, a set of approximately 300 ORFs whose expression is initiated in the late-schizont stage persists throughout the invasion process and peaks during the early... | 12929205_p25 | 12929205 | Early-Ring Stage | 4.598055 | biomedical | Study | [
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] | en | 0.999996 |
Overall, the genes expressed during the mid- to late-schizont and early-ring stage encode proteins predominantly involved in highly parasite-specific functions facilitating various steps of host cell invasion. The expression profiles of these genes are unique in the IDC because of the large amplitudes and narrow peak w... | 12929205_p26 | 12929205 | Early-Ring Stage | 4.183219 | biomedical | Study | [
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] | en | 0.999998 |
Transcriptional regulation of chromosomal gene expression in P. falciparum is thought to be monocistronic, with transcriptional control of gene expression occurring through regulatory sequence elements upstream and downstream of the coding sequence . This is in contrast to several other parasites, such as Leishmania sp... | 12929205_p27 | 12929205 | IDC Transcriptional Regulation and Chromosomal Structure | 4.46079 | biomedical | Study | [
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The largest group demonstrating coregulation on the nuclear chromosomes corresponds to seven genes of the SERA family found on Chromosome 2 . Besides the SERA gene cluster and a group containing three ribosomal protein genes, no additional functional relationship was found among the other chromosomally adjacent, transc... | 12929205_p28 | 12929205 | IDC Transcriptional Regulation and Chromosomal Structure | 4.19033 | biomedical | Study | [
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] | [
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] | en | 0.999995 |
Three major surface antigens, the var , rifin , and stevor families, have a high degree of genomic variability and are highly polymorphic between strains and even within a single strain . Expression profiles for only a small subset of these genes were detected in the IDC transcriptome and were typically characterized b... | 12929205_p29 | 12929205 | IDC Transcriptional Regulation and Chromosomal Structure | 4.509686 | biomedical | Study | [
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The majority of the nuclear-encoded proteins targeted to the plastid are of prokaryotic origin, making them excellent drug targets . Moreover, inhibitors of plastid-associated isoprenoid biosynthesis, DNA replication, and translation have been shown to kill the P. falciparum parasite, demonstrating that the plastid is ... | 12929205_p30 | 12929205 | Implications for Drug Discovery | 4.49309 | biomedical | Study | [
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Given that over 10% of the ORFs in the P. falciparum genome are predicted to contain an apicoplast-targeting sequence, we sought to use the IDC transcriptome as a means to narrow the search space for candidate apicoplast-targeted genes. As mentioned above, the expression profiles for genes encoded on the plastid genome... | 12929205_p31 | 12929205 | Implications for Drug Discovery | 4.427141 | biomedical | Study | [
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Similarly, P. falciparum proteases have received much attention, since they are candidates as drug targets and have been shown to play important roles in regulation as well as metabolism throughout the IDC . A temporal ordering of expression profiles for several well-characterized P. falciparum proteases is shown in Fi... | 12929205_p32 | 12929205 | Implications for Drug Discovery | 4.219264 | biomedical | Study | [
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A family of ten aspartyl proteases, the plasmepsins (PMs), has been identified in the P. falciparum genome, four of which have been characterized as bona fide hemoglobinases: PM I, II, III (a histo-aspartic protease [HAP]), and IV . Our data reveal that the PMs are expressed at different times throughout the lifecycle,... | 12929205_p33 | 12929205 | Implications for Drug Discovery | 4.625272 | biomedical | Study | [
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] | [
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] | en | 0.999996 |
In addition to the hemoglobinases, P. falciparum contains a variety of proteases involved in cellular processing, including a group of Clps and signal peptidases that are all expressed maximally at the late-trophozoite stage . The timing of these genes may play a key role in protein maturation during trafficking to var... | 12929205_p34 | 12929205 | Implications for Drug Discovery | 4.378706 | biomedical | Study | [
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] | [
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0.0002690916007850319,
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0.00008926494047045708
] | en | 0.999999 |
Merozoite invasion is one of the most promising target areas for antimalarial vaccine development . Many vaccine efforts thus far have focused primarily on a set of plasmodial antigens that facilitate receptor–ligand interaction between the parasite and the host cell during the invasion process . Merozoite invasion ant... | 12929205_p35 | 12929205 | Implications for New Vaccine Therapies | 4.231023 | biomedical | Study | [
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We utilized the IDC transcriptome to predict a set of likely invasion proteins by identifying expression profiles with characteristics similar to previously studied merozoite invasion proteins. The expression profiles for all known invasion factors undergo a sharp induction during the mid- to late-schizont stage and ar... | 12929205_p36 | 12929205 | Implications for New Vaccine Therapies | 4.423789 | biomedical | Study | [
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] | [
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0.0002732535940594971,
0.0005669877864420414,
0.00013267876056488603
] | en | 0.999996 |
A number of antigens are presently in various stages of clinical trials and are yielding encouraging results . However, many single-antigen vaccine studies indicate that the most promising approach will require a combination of antigenic determinants from multiple stages of the complex plasmodial lifecycle . Searches f... | 12929205_p37 | 12929205 | Implications for New Vaccine Therapies | 4.141826 | biomedical | Study | [
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] | [
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] | en | 0.999997 |
The transcriptome of the IDC of P. falciparum constitutes an essential tool and baseline foundation for the analysis of all future gene expression studies in this organism, including response to drugs, growth conditions, environmental perturbations, and genetic alterations. Essentially all experiments involving asexual... | 12929205_p38 | 12929205 | Discussion | 4.025006 | biomedical | Study | [
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In our global analysis of the P. falciparum transcriptome, over 80% of the ORFs revealed changes in transcript abundance during the maturation of the parasite within RBCs. The P. falciparum IDC significantly differs from the cell cycles of the yeast S. cerevisiae and human HeLa cells, during which only 15% of the total... | 12929205_p39 | 12929205 | Discussion | 4.3319 | biomedical | Study | [
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The lack of continuous chromosomal domains with common expression characteristics suggests that the genes are regulated individually, presumably via distinct sets of cis - and trans -acting elements. However, the extent and the simple mechanical character of transcriptional control observed in the IDC suggest a fundame... | 12929205_p40 | 12929205 | Discussion | 4.489669 | biomedical | Study | [
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] | en | 0.999995 |
In general, the timing of mRNA expression for a given gene during the IDC correlates well with the function of the resultant protein. For example, replication of the genome occurs in the early-schizont stage and correlates well with the peak expression of all factors of DNA replication and DNA synthesis. Also, organell... | 12929205_p41 | 12929205 | Discussion | 4.213074 | biomedical | Study | [
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] | [
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0.0002098289260175079,
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0.00006087136353016831
] | en | 0.999998 |
We initially expected that a high percentage of the genome would be specialized for each lifecycle stage (mosquito, liver, blood), yet this was not observed; the mRNA transcripts for 75% of proteins determined to be gamete-, gametocyte-, or sporozoite-specific by mass spectrometry are also transcribed in the plasmodial... | 12929205_p42 | 12929205 | Discussion | 4.343694 | biomedical | Study | [
0.9995362758636475,
0.0002752883592620492,
0.00018854800146073103
] | [
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0.00033784087281674147,
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0.00008468347368761897
] | en | 0.999995 |
These findings also outline two contrasting properties of the P. falciparum genome. The Plasmodium parasite devotes 3.9% of its genome to a complex system of antigenic determinants essential for host immune evasion during a single developmental stage . On the other hand, large portions of the genome encode proteins use... | 12929205_p43 | 12929205 | Discussion | 4.192957 | biomedical | Study | [
0.9996237754821777,
0.00019742704171221703,
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] | [
0.9925368428230286,
0.0013977003982290626,
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0.00011898259253939614
] | en | 0.999997 |
With malaria continuing to be a major worldwide disease, advances toward understanding the basic biology of P. falciparum remain essential. Our analysis of the IDC transcriptome provides a first step toward a comprehensive functional analysis of the genome of P. falciparum . The genome-wide transcriptome will be useful... | 12929205_p44 | 12929205 | Discussion | 4.094419 | biomedical | Study | [
0.9996932744979858,
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0.00013394006236921996
] | [
0.9967082738876343,
0.0012389803305268288,
0.0019342480227351189,
0.0001184934881166555
] | en | 0.999998 |
A large-scale culture of P. falciparum (HB3 strain) was grown in a standard 4.5 l microbial bioreactor (Aplikon, Brauwweg, Netherlands) equipped with a Bio Controller unit ADI 1030 (Aplikon, Brauwweg, Netherlands). Cells were initially grown in a 2% suspension of purified human RBCs and RPMI 1640 media supplemented wit... | 12929205_p45 | 12929205 | Cell culture. | 4.278765 | biomedical | Study | [
0.9993442893028259,
0.00047179285320453346,
0.00018394464859738946
] | [
0.9988369345664978,
0.0005693382699973881,
0.00046054719132371247,
0.00013322668382897973
] | en | 0.999997 |
P. falciparum RNA sample isolation, cDNA synthesis, labeling, and DNA microarray hybridizations were performed as described by Bozdech et al. . Samples for individual timepoints (coupled to Cy5) were hybridized against a reference pool (coupled to Cy3). The reference pool was comprised of RNA samples representing all d... | 12929205_p46 | 12929205 | RNA preparation and reference pool. | 4.136348 | biomedical | Study | [
0.9995924830436707,
0.00022746220929548144,
0.0001800550235202536
] | [
0.998915433883667,
0.0006154048023745418,
0.0004014016594737768,
0.00006775055226171389
] | en | 0.999998 |
In total, 55 DNA microarray hybridizations covering 46 timepoints were performed. Timepoints 1, 7, 11, 14, 18, 20, 27, and 31 were represented by more than one array hybridization. Data were acquired and analyzed by GenePix Pro 3 (Axon Instruments, Union City, California, United States). Array data were stored and norm... | 12929205_p47 | 12929205 | DNA microarray hybridizations and quality control. | 4.124937 | biomedical | Study | [
0.9995213747024536,
0.0002738008042797446,
0.00020486324501689523
] | [
0.999339759349823,
0.0002376193442614749,
0.00035757230944000185,
0.00006501091411337256
] | en | 0.999998 |
Fourier analysis was performed on each profile in the quality-controlled set (5,081 oligonucleotides). Profiles were smoothed with missing values imputed using a locally weighted regression algorithm with local weighting restricted to 12% using R ( http://www.R-project.org ). Fourier analysis was performed on each prof... | 12929205_p48 | 12929205 | FFT analysis of the expression profiles. | 4.223322 | biomedical | Study | [
0.999495267868042,
0.0002690516703296453,
0.00023571649217046797
] | [
0.9992519021034241,
0.0002683906350284815,
0.00040809615165926516,
0.00007155421917559579
] | en | 0.999997 |
The raw results files ( Dataset S1 ), the fully assembled raw dataset ( Dataset S2 , the overview dataset ( Dataset S3 , and the quality control dataset ( Dataset S4 ) are available as downloads. | 12929205_p49 | 12929205 | FFT analysis of the expression profiles. | 1.188807 | biomedical | Other | [
0.9554800987243652,
0.0014258072478696704,
0.04309409111738205
] | [
0.0922011062502861,
0.9047799110412598,
0.00191466452088207,
0.0011043191188946366
] | en | 0.999994 |
The evaluation of coexpression of genes along chromosomes was carried out as follows. The Pearson correlation coefficient was calculated for each pair of profiles. For ORFs with multiple oligonucleotides, the average profile was calculated. The neighborhood of each ORF profile was defined as a window of between one and... | 12929205_p50 | 12929205 | Evaluation of coexpression along chromosomes. | 4.110623 | biomedical | Study | [
0.9994854927062988,
0.00027287082048133016,
0.00024160195607692003
] | [
0.9992402791976929,
0.0003397178079467267,
0.00035916134947910905,
0.000060917114751646295
] | en | 0.999997 |
P. falciparum strains 3D7 and HB3 were cultured as previously described at a concentration of 10% parasitaemia. Genomic DNA (gDNA) was isolated from a minimum of 500 ml of total culture for each P. falciparum strain, as previously described . Isolated gDNA from each strain was sheared by sonication to an average fragme... | 12929205_p51 | 12929205 | Comparative genomic hybridization. | 4.163295 | biomedical | Study | [
0.9995402097702026,
0.0002732229477260262,
0.0001865777448983863
] | [
0.9992719292640686,
0.0002946292224805802,
0.0003637355985119939,
0.00006977286102483049
] | en | 0.999998 |
The range of FFT-based phases for the expression profiles of the plastid genome is between 0.32 and 1.05 (or roughly π/9 −π/3). Using the list of 551 apicoplast-targeted genes available at PlasmoDB.org , we first ordered these genes by phase and then grouped all genes with a phase range between 0.00 and 1.40 (0–4π/9), ... | 12929205_p52 | 12929205 | Calculation for in-phase plastid-targeted genes. | 4.115124 | biomedical | Study | [
0.9994906187057495,
0.000218309010961093,
0.0002911071351263672
] | [
0.9994301199913025,
0.00028890935936942697,
0.00022787903435528278,
0.00005302489080349915
] | en | 0.999996 |
To select the expression profiles most related to the AMA1, MSP1, MSP3, MSP5, EBA175, RAP1, and RESA1 vaccine candidates, we calculated the similarity of all expression profiles in the dataset to those of these antigens by Euclidian distance. The minimum Euclidian distance calculated for every profile was then binned i... | 12929205_p53 | 12929205 | Calculation for vaccine targets. | 4.055602 | biomedical | Study | [
0.9993947744369507,
0.00022944978263694793,
0.00037579925265163183
] | [
0.9995181560516357,
0.0002141738950740546,
0.0002239349123556167,
0.000043831725633936
] | en | 0.999996 |
From a clinical perspective, inadequate protection from sunlight has a major impact on human health . In Australia, the lifetime cumulative incidence of skin cancer approaches 50%, yet the oxymoronic “smart tanning” industry continues to grow, and there is controversy over the extent to which different types of melanin... | 14551921_p0 | 14551921 | Why Should We Care? | 3.958494 | biomedical | Review | [
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] | [
0.03780406713485718,
0.019821317866444588,
0.941734790802002,
0.0006397769902832806
] | en | 0.999996 |
From a basic science perspective, variation in human skin color represents an unparalleled opportunity for cell biologists, geneticists, and anthropologists to learn more about the biogenesis and movement of subcellular organelles, to better characterize the relationship between genotypic and phenotypic diversity, to f... | 14551921_p1 | 14551921 | Why Should We Care? | 3.797789 | biomedical | Other | [
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0.0012915332335978746
] | [
0.06129336729645729,
0.8368473649024963,
0.10066109895706177,
0.0011982362484559417
] | en | 0.999995 |
Historically, measurement of human skin color is often based on subjective categories, e.g., “moderate brown, rarely burns, tans very easily.” More recently, quantitative methods based on reflectance spectrophotometry have been applied, which allow reddening caused by inflammation and increased hemoglobin to be disting... | 14551921_p2 | 14551921 | The Color Variation Toolbox | 4.450313 | biomedical | Study | [
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0.0003190151182934642,
0.0008982797153294086
] | [
0.8441895842552185,
0.003256283001974225,
0.15216326713562012,
0.0003908830985892564
] | en | 0.999997 |
More important than the ratio of melanin types is the total amount of melanin produced. In addition, histological characteristics of different-colored skin provide some clues as to cellular mechanisms that are likely to drive pigmentary variation . For the same body region, light- and dark-skinned individuals have simi... | 14551921_p3 | 14551921 | The Color Variation Toolbox | 4.275906 | biomedical | Study | [
0.9994639754295349,
0.0001896102912724018,
0.0003464725741650909
] | [
0.9635220766067505,
0.0020995759405195713,
0.03420024365186691,
0.00017816915351431817
] | en | 0.999997 |
Of equal importance to what happens inside melanocytes is what happens outside. Each pigment cell actively transfers its melanosomes to about 40 basal keratinocytes; ultimately, skin reflectance is determined by the amount and distribution of pigment granules within keratinocytes rather than melanocytes. In general, me... | 14551921_p4 | 14551921 | The Color Variation Toolbox | 4.169575 | biomedical | Study | [
0.9994503855705261,
0.00014144896704237908,
0.00040817001718096435
] | [
0.9708126783370972,
0.017994118854403496,
0.010940277017652988,
0.0002529266057536006
] | en | 0.999994 |
For any quantitative trait with multiple contributing factors, the most important questions are the overall heritability, the number of genes likely to be involved, and the best strategies for identifying those genes. For skin color, the broad sense heritability (defined as the overall effect of genetic vs. nongenetic ... | 14551921_p5 | 14551921 | Genetics of Skin Color | 3.811101 | biomedical | Study | [
0.9970149993896484,
0.00025288580218330026,
0.002732125809416175
] | [
0.5219131708145142,
0.458249032497406,
0.01943693682551384,
0.0004008837277069688
] | en | 0.999999 |
Statements regarding the number of human skin color genes are attributed to several studies; one of the most complete is by Harrison and Owen . In that study, skin reflectance measurements were obtained from 70 residents of Liverpool whose parents, grandparents, or both were of European (“with a large Irish component”)... | 14551921_p6 | 14551921 | Genetics of Skin Color | 4.079592 | biomedical | Study | [
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0.000195983680896461,
0.0015370273031294346
] | [
0.9987277388572693,
0.00025031575933098793,
0.0009830361232161522,
0.00003882318196701817
] | en | 0.999996 |
An alternative approach for considering the number of potential human pigmentation genes is based on mouse coat color genetics, one of the original models to define and study gene action and interaction, for which nearly 100 different genes have been recognized . Setting aside mouse mutations that cause white spotting ... | 14551921_p7 | 14551921 | Genetics of Skin Color | 4.080781 | biomedical | Study | [
0.9994408488273621,
0.00014211908273864537,
0.00041702581802383065
] | [
0.954731285572052,
0.008382566273212433,
0.03665059804916382,
0.0002356236072955653
] | en | 0.999996 |
This brings us to the question of candidate genes for skin color, since, like any quantitative trait, a reasonable place to start is with rare mutations known to cause an extreme phenotype, in this case Mendelian forms of albinism. The underlying assumption is that if a rare null allele causes a complete loss of pigmen... | 14551921_p8 | 14551921 | Genetics of Skin Color | 4.117462 | biomedical | Study | [
0.9991787075996399,
0.0001297376147704199,
0.0006916038109920919
] | [
0.9934843182563782,
0.0037167901173233986,
0.0027056820690631866,
0.00009323774429503828
] | en | 0.999994 |
Independent of phenotype, a gene responsible for selection of different skin colors should exhibit a population signature with a large number of alleles and rates of sequence substitution that are greater for nonsynonymous (which change an amino acid in the protein) than synonymous (which do not change any amino acid) ... | 14551921_p9 | 14551921 | Genetics of Skin Color | 4.219145 | biomedical | Study | [
0.999552309513092,
0.00013691162166651338,
0.0003107110096607357
] | [
0.9983250498771667,
0.0007587939035147429,
0.0008549870108254254,
0.00006113437848398462
] | en | 0.999999 |
Credit for describing the relationship between latitude and skin color in modern humans is usually ascribed to an Italian geographer, Renato Basutti, whose widely reproduced “skin color maps” illustrate the correlation of darker skin with equatorial proximity . More recent studies by physical anthropologists have subst... | 14551921_p10 | 14551921 | Selection for Skin Color? | 3.796851 | biomedical | Review | [
0.9252098202705383,
0.0011630429653450847,
0.07362719625234604
] | [
0.18235692381858826,
0.006719660013914108,
0.8105507493019104,
0.00037259809323586524
] | en | 0.999998 |
Regardless, most anthropologists accept the notion that differences in UV irradiation have driven selection for dark human skin at the equator and for light human skin at greater latitudes. What remains controversial are the exact mechanisms of selection. The most popular theory posits that protection offered by dark s... | 14551921_p11 | 14551921 | Selection for Skin Color? | 4.348969 | biomedical | Review | [
0.9947113990783691,
0.0007170272874645889,
0.004571558907628059
] | [
0.24665313959121704,
0.00442161550745368,
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] | en | 0.999998 |
Recent developments in several areas provide a tremendous opportunity to better understand the diversity of human pigmentation. Improved spectrophotometric tools, advances in epidemiology and statistics, a wealth of genome sequences, and efficient techniques for assaying sequence variation offer the chance to replace m... | 14551921_p12 | 14551921 | Solving the Mystery | 3.977202 | biomedical | Review | [
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0.04062803462147713,
0.08514383435249329,
0.873169481754303,
0.0010586143471300602
] | en | 0.999996 |
This approach is especially appealing given the dismal success rate in molecular identification of complex genetic diseases. In fact, understanding more about the genetic architecture of skin color may prove helpful in designing studies to investigate other quantitative traits. Current debates in the human genetics com... | 14551921_p13 | 14551921 | Solving the Mystery | 4.041118 | biomedical | Review | [
0.9976766705513,
0.0010292206425219774,
0.0012941360473632812
] | [
0.039315614849328995,
0.04014872387051582,
0.919705867767334,
0.000829841650556773
] | en | 0.999995 |
Harrison and Owen concluded their 1964 study of human skin color by stating, “The deficiencies in the data in this study are keenly appreciated by the writers, but since there appear at present to be no opportunities for improving the data, it seems justifiable to take the analysis as far as possible.” Nearly 40 years ... | 14551921_p14 | 14551921 | Solving the Mystery | 1.229632 | other | Other | [
0.062353309243917465,
0.0016473910072818398,
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] | [
0.014389448799192905,
0.9512582421302795,
0.0328829362988472,
0.001469406415708363
] | en | 0.999998 |
The heart of PKS function is the synthesis of long chains of carbon atoms by joining (condensing) together small organic acids, such as acetic and malonic acid, by a so-called ketosynthase function. This uses the building units in the form of activated derivatives, called coenzyme A (CoA) esters, so we speak of acetyl-... | 14966534_p0 | 14966534 | Molecular Diversity | 4.513179 | biomedical | Study | [
0.9984568357467651,
0.00086791324429214,
0.0006751937908120453
] | [
0.9190252423286438,
0.06829223781824112,
0.011501244269311428,
0.0011812277371063828
] | en | 0.999997 |
Choices of the number and type of the building units are variables in determining polyketide structure. Another concerns the keto groups (C=O) that appear at every alternate carbon atom in the growing chain as a result of the condensation process (accounting for the name polyketide). They may remain intact. Alternative... | 14966534_p1 | 14966534 | Molecular Diversity | 4.614054 | biomedical | Study | [
0.998562753200531,
0.0008164480677805841,
0.0006207837141118944
] | [
0.9174168109893799,
0.015488379634916782,
0.06625400483608246,
0.0008408863795921206
] | en | 0.999996 |
During the 1990s, the ability to manipulate actinomycete genes, developed over previous decades, mainly using the model species Streptomyces coelicolor , was combined with chemical and biochemical experiments to begin to crack this ‘polyketide code’. The first studies were on organisms making antibiotics of the ‘aromat... | 14966534_p2 | 14966534 | Molecular Diversity | 4.536855 | biomedical | Study | [
0.9991875290870667,
0.0005194561672396958,
0.00029298849403858185
] | [
0.973414957523346,
0.0006508264341391623,
0.025623111054301262,
0.00031106884125620127
] | en | 0.999997 |
The big surprise, though, was the finding of six sets, or modules, of such active sites, corresponding to the six rounds of condensation needed to build the carbon chain . The modules each contain an acyl transferase (to load the extender unit onto the enzyme), as well as a ketosynthase and an ACP domain, together with... | 14966534_p3 | 14966534 | Molecular Diversity | 4.584112 | biomedical | Study | [
0.9990338087081909,
0.0006920962478034198,
0.00027416643570177257
] | [
0.987136721611023,
0.0039034506771713495,
0.00842655822634697,
0.000533294805791229
] | en | 0.999998 |
The model arose from the gene sequence, but was rapidly tested by mutating individual domains or adding or deleting whole modules and by observing predicted changes in the polyketide product. Soon, dozens of engineered compounds had been made, and the field mushroomed with the isolation of more and more clusters of gen... | 14966534_p4 | 14966534 | Molecular Diversity | 3.839457 | biomedical | Review | [
0.9989294409751892,
0.00031896153814159334,
0.0007515471079386771
] | [
0.20224085450172424,
0.29362937808036804,
0.5023317933082581,
0.0017980332486331463
] | en | 0.999997 |
Meanwhile, the programming of the aromatic PKSs was harder to understand. They had been found to contain only a single ketosynthase, which has to operate a specific number of times to build a carbon chain of the correct length, so how is this determined? How does a single reductive enzyme know which keto groups to modi... | 14966534_p5 | 14966534 | Aromatic PKS Programming | 4.479023 | biomedical | Review | [
0.9975119829177856,
0.001002411125227809,
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] | [
0.22263823449611664,
0.004327776841819286,
0.7722508907318115,
0.0007830517715774477
] | en | 0.999999 |
In the first paper , the authors explore the hypothesis that the CLF exerts control over carbon chain length by associating closely with the ketosynthase, a protein with which it shares considerable amino acid sequence similarity, giving rise to a channel of a certain size at the interface between the two proteins. By ... | 14966534_p6 | 14966534 | Aromatic PKS Programming | 4.299766 | biomedical | Study | [
0.9994975328445435,
0.0003030617372132838,
0.0001993020559893921
] | [
0.998063862323761,
0.0003231586888432503,
0.0015152826672419906,
0.00009765376307768747
] | en | 0.999998 |
What about the choice of starter unit? Most aromatic polyketides start with acetyl-CoA. An important earlier publication by Leadlay and colleagues had shown that this is not loaded directly onto the PKS, as had been assumed, but is derived by loss of carbon dioxide from a molecule of malonyl-CoA previously loaded onto ... | 14966534_p7 | 14966534 | Aromatic PKS Programming | 4.189018 | biomedical | Study | [
0.9993127584457397,
0.00028033286798745394,
0.0004069231799803674
] | [
0.9149789810180664,
0.031109148636460304,
0.05327079817652702,
0.0006411127978935838
] | en | 0.999997 |
What Tang et al. have deduced, as described in this issue of PloS Biology , is that the PKSs for these compounds consist of two modules of active sites. The components of each module are not activities carried on the same protein, as in the PKSs for the complex polyketides, but are all separate proteins. They form func... | 14966534_p8 | 14966534 | Aromatic PKS Programming | 4.355721 | biomedical | Study | [
0.9994480013847351,
0.0003293772751931101,
0.00022252651979215443
] | [
0.9836116433143616,
0.005416316911578178,
0.010589039884507656,
0.0003830477362498641
] | en | 0.999998 |
The excitement of the work for biotechnology is that it offers the prospect of engineering promising drug candidates by making novel combinations of starter and extender modules and perhaps of feeding the starter modules with a whole range of unnatural substrates . It is encouraging that already, in the proof-of-princi... | 14966534_p9 | 14966534 | Aromatic PKS Programming | 3.142076 | biomedical | Study | [
0.9971022009849548,
0.0003068348451051861,
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] | [
0.4872440993785858,
0.41171103715896606,
0.09967945516109467,
0.0013653693022206426
] | en | 0.999997 |
Antibiotics have traditionally been plucked from nature's battleground. For billions of years, tiny organisms have engaged in an arms race, hurling toxic molecules at each other in the struggle to prosper. Nearly all of today's antibiotics are versions of weapons long wielded by microbes and fungi. Chemical synthesis o... | 14966545_p0 | 14966545 | Tried and True—and Tired? | 3.859791 | biomedical | Review | [
0.998256504535675,
0.0007832435076124966,
0.0009601946221664548
] | [
0.06987663358449936,
0.30452582240104675,
0.6233862638473511,
0.002211277838796377
] | en | 0.999997 |
The usual way to find a new antibiotic has been laborious screening of immense libraries of compounds, natural and otherwise. Some argue that screening chemical libraries is approaching a deadend. There may be diminishing returns from screening, but it's not quite dead yet: in October, researchers at the University of ... | 14966545_p1 | 14966545 | Tried and True—and Tired? | 2.946149 | biomedical | Other | [
0.9979597330093384,
0.0004170424654148519,
0.0016232288908213377
] | [
0.3365307152271271,
0.6367872953414917,
0.024545852094888687,
0.0021361010149121284
] | en | 0.999996 |
Christopher T. Walsh of Harvard Medical School says screening's problem may be simply that libraries aren't good enough. Marine organisms have not been studied well, he points out, and 90% of organisms in the biosphere can't be cultured in standard ways. He says, “We're missing 90% of them every time we go and look in ... | 14966545_p2 | 14966545 | Tried and True—and Tired? | 1.386335 | biomedical | Other | [
0.8033398389816284,
0.0070805330760777,
0.18957959115505219
] | [
0.004654659423977137,
0.9933932423591614,
0.0011955321533605456,
0.0007565567502751946
] | en | 0.999996 |
Walsh is doing his bit to create new libraries. He and his colleagues have recently employed combinatorial biosynthesis to learn how to use part of the machinery for assembling cyclic peptide antibiotics to control their architecture. The result was a small library of natural product analogs, some of which have improve... | 14966545_p3 | 14966545 | Tried and True—and Tired? | 3.603796 | biomedical | Other | [
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Walsh collaborates with Chaitan Khosla of Stanford University on finding ways to make existing antibiotics better. They are studying biosynthesis of rifamycin, an antibiotic that is increasingly less effective against its prime target, tuberculosis (TB) . “In the course of learning about that pathway, we've learned a f... | 14966545_p4 | 14966545 | Improving on Nature | 2.908768 | biomedical | Other | [
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“Basically, what we do is to try and figure out new ways to hijack the biosynthesis of antibiotics in nature so as to modify their structures with the goal of improving them,” Khosla explains. He works with an important class of natural antibiotics called polyketides that have generated dozens of drugs, including eryth... | 14966545_p5 | 14966545 | Improving on Nature | 2.292137 | biomedical | Other | [
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Polyketides are secondary metabolites (which give their producers a competitive advantage in their environment) produced mostly by bacteria and fungi and made by a complex and structurally diverse family of enzymes called polyketide synthases (see the primer by David Hopwood in this issue of PLoS Biology ). Among them ... | 14966545_p6 | 14966545 | Improving on Nature | 4.324804 | biomedical | Study | [
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The researchers didn't study the new anthracyclines' effects on bacteria, but Khosla notes that the general principle should apply to other classes of compounds, although the details of how it's implemented will vary from system to system. He says, “The upshot of this paper is that it is now possible to modify a partic... | 14966545_p7 | 14966545 | Improving on Nature | 2.476222 | biomedical | Other | [
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Instead of searching for new antibiotics by modifying existing ones, some researchers are trying something completely different—first finding the most vulnerable targets in a bacterium and then designing something that hits one or more of them hard. “You have to understand a helluva lot more about how these little cell... | 14966545_p8 | 14966545 | Finding New Targets | 2.948305 | biomedical | Other | [
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So instead of screening libraries of existing compounds, Shapiro prefers using structural information about drug targets or their natural ligands to create new drugs, an approach known as rational drug design. And instead of looking at all essential genes in a bacterium and choosing one to target, she and her colleague... | 14966545_p9 | 14966545 | Finding New Targets | 4.175383 | biomedical | Study | [
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Antibiotic discovery is all chemistry, Shapiro says, which is why she joined with biochemist Stephen J. Benkovic of Pennsylvania State University. They didn't know the structure of CcrM, Benkovic explains, but the literature about other methyltransferases suggested that the adenine molecule, which is the substrate for ... | 14966545_p10 | 14966545 | Finding New Targets | 2.500357 | biomedical | Other | [
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The researchers designed adenine-like molecules that would bind to CcrM and then developed inhibitors. Benkovic says, “We already knew what kind of structure we wanted, and we simply fine-tuned it.” They worked their way through 1,000 inhibitor candidates, ending up with a small subset—no more than about 20—that not on... | 14966545_p11 | 14966545 | Finding New Targets | 2.758052 | biomedical | Other | [
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And not only inoffensive Caulobacter . The compounds knock out other gram-negative bacteria, such as the pathogens Brucella abortus and Francisella tularensis . Some even killed off anthrax, a big surprise because it is gram-positive and so has much thicker cell walls than gram-negative bacteria. The researchers undert... | 14966545_p12 | 14966545 | Finding New Targets | 3.257598 | biomedical | Other | [
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More recently, Shapiro reports, they have demonstrated efficacy against rats infected with anthrax or multidrug-resistant Staph , although the compounds save only about 60% of the rats at present. She notes, “So we have a long way to go. But this has proven that if you go after something using some rational approach in... | 14966545_p13 | 14966545 | Finding New Targets | 2.077317 | biomedical | Other | [
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Benkovic points out that theirs is an entirely new class of compounds, small molecular weight compounds that can be made in a few steps. He says, “They don't look like the normal antibiotic, so that's why I think they're fairly unique.” The basic research was done under a grant from the Defense Advanced Research Projec... | 14966545_p14 | 14966545 | Finding New Targets | 3.127236 | biomedical | Other | [
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The most radical approach to new antibiotics may be the resurrection of an old idea: bacteriophage therapy . Late in the 19th century, a researcher noticed that water from some of India's sacred rivers combated cholera. Some years later, the active agents were identified as viruses that infected bacteria. Such viruses ... | 14966545_p15 | 14966545 | Phage Therapy | 2.476352 | biomedical | Other | [
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Phage were the model organisms of choice for genetics research in the 1930s and 1940s, but became less fashionable as research tools when investigators moved on to eukaryotes. A few held on, like Ry Young of Texas A&M University, who has made phage-induced cell lysis his life's work. “The cell is basically genetically ... | 14966545_p16 | 14966545 | Phage Therapy | 2.67466 | biomedical | Other | [
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Antibiotic resistance has led to new interest in phage therapy by several small biotech companies. Young continues basic research at Texas A&M, but has also joined one of them, GangaGen, providing bacteriophage expertise to its labs. | 14966545_p17 | 14966545 | Phage Therapy | 1.200519 | biomedical | Other | [
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Phage do kill pathogenic bacteria effectively, and they do it without penetrating human cells, which they can't even recognize. So what is keeping phage therapy out of the clinic? Problems that some doubt can be overcome. | 14966545_p18 | 14966545 | Phage Therapy | 1.675982 | biomedical | Other | [
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Because bacteria develop resistance to phage rapidly, phage therapy companies will need to direct cocktails against a single pathogen, according to Vincent Fischetti at The Rockefeller University. Phage are also antigenic, and the antibodies they stimulate will neutralize their effects during subsequent treatment, he s... | 14966545_p19 | 14966545 | Phage Therapy | 2.963112 | biomedical | Other | [
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Fischetti chose a different approach to phage therapy. It does not rely on phage themselves, but on enzymes that phage produce to smash their way out of their host bacteria so they can infect new hosts. He and his colleagues employ these enzymes externally to kill bacteria. He reports, “We now have enzymes that will ki... | 14966545_p20 | 14966545 | Phage Therapy | 2.916337 | biomedical | Other | [
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