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About f1000

F1000 is a scientific literature awareness tool where selected researchers review and comment on current papers. I'm a faculty member since 2013 after serving as an associate member since 2009. Please find my posts below.

41: Analysis of protein-coding genetic variation in 60,706 humans. (2017-07-12)

Lek and colleagues report on a meta-analysis of a large cohort of human genomes to build a massive resource of protein-coding genetic variations. The technical challenges in processing data at this scale are non-trivial; as the authors provide detailed descriptions of their computational analysis, they enable others to carry out larger experiments in the future. Importantly, the authors make their results readily accessible.

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40: Enhancing reproducibility for computational methods. (2017-04-18)

Reproducibility of scientific results is a cornerstone of the scientific endeavor; scientific and other news sources have reported that reproducibility of many studies published in high-impact journals and elsewhere is lower than expected. This article by Stodden and colleagues lists a number of recommendations that, if implemented by everybody, would improve the reproducibility of computational methods. Some of the recommendations are challenging, but nevertheless, this paper is a must-read for anybody that is using computational methods.

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39: The cytotoxic Staphylococcus aureus PSMα3 reveals a cross-α amyloid-like fibril. (2017-03-02)

Pathogens interact with their hosts in a wide variety of ways; understanding how and why can play a vital role in solving the antimicrobial resistance problem. This paper by Tayeb-Fligelman and colleagues reports on the 1.45A crystal structure of the PSMalpha3 amyloid fibril. The fibril is cytotoxic to host cells in contrast to the monomer. Interestingly, this fibril is formed by two 'sheets' made up by alpha helices and thereby differs from previously solved fibril structures whose cores are made mostly from beta sheets. The authors speculate that the cytotoxicity results from the fibrils deforming the host cell membrane.

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38: SPLASH, a hashed identifier for mass spectra. (2016-11-11)

Wohlgemuth and colleagues have written SPLASH, a small application implemented in several programming languages, that generates database-independent hashes for MS spectra. It is already supported by several online data repositories and hence facilitates cross-database searches. This technology, if widely adapted, will make referring to a specific spectrum simpler, and this can play an important role in tra cing data sources used to, for example, create spectral libraries. Spectral libraries are increasingly used to increase the sensitivity of both DDA and DIA experiments. I believe that SPLASH will provide an opportunity to more easily trace the flow of information through the increasingly complex MS analysis workflows.

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37: An interbacterial NAD(P)(+) glycohydrolase toxin requires elongation factor Tu for delivery to target cells. (2016-11-04)

This paper by Whitney and colleagues describes the function of Tse6, a Pseudomonas aeruginosa toxin that is delivered to neighboring recipient cells via type VI secretion. Tse6 forms a complex with elongation factor Tu of the recipient cell to enter through the inner membrane; once inside, it depletes NAD(P)+ through catalysis. This article provides an example of how complex the interactions between bacterial cells can be; P. aeruginosa is altering the energy state of recipient cells competing for resources using a system that a) needs the donor and recipient cells to be in physical contact; b) requires that type VI secretion is able to deliver the toxin to the periplasm; and c) that Tse6 is able to form a complex with an essential and conserved host protein to gain access to the cytosol.

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36: Targeted proteomics identifies liquid-biopsy signatures for extracapsular prostate cancer. (2016-07-05)

This article by Kim and colleagues describes a rigorous study developing prostate cancer biomarkers. They applied quantitative, targeted mass spectrometry on a 74-patient cohort to identify a panel of 34 candidate peptides. Importantly, the performance of the biomarkers was evaluated in a larger, independent cohort consisting of 207 patients. This paper is a worthwhile read for anybody developing biomarkers using mass spectrometry.

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35: Rapid antibiotic-resistance predictions from genome sequence data for Staphylococcus aureus and Mycobacterium tuberculosis. (2016-06-29)

This article by Bradley and colleagues describe a software application, Mykrobe predictor, that uses DNA sequencing data for fast and accurate antibiotic resistance profile predictions. While the ideas are not new, Mykrobe predictor is both faster and more accurate that previous software, and, importantly, can detect minor resistant populations. Both demonstrated models (S. aureus and M. tuberculosis) show significant overall speed increases compared to the technologies in use today. As vastly more sequencing data will become available over time, resource-efficient tools like Mykrobe predictor will become important to survey these datasets and track the spread of resistance genes; this will be of importance in our efforts to avoid entering the looming post-antibiotic era.

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34: Single-molecule sequencing to track plasmid diversity of hospital-associated carbapenemase-producing Enterobacteriaceae. (2016-01-22)

The looming threat of the post-antibiotic era urgently calls for studying the spread of both virulent strains and plasmids; plasmids can play a critical role as they can carry antibiotic resistance genes. This study by Conlan and colleagues describes a thorough study where long-term in-patients and their environment were regularly surveyed using a sequencing technique optimal for sequencing complete plasmids. Their findings reveal a complex story described at length. Key findings include a surprising diversity among the isolated plasmids and a lower-than-expected rate of horizontal transfer. In general, the complexity that this article is hinting at might mean that additional effort needs to be invested to identify important reservoirs in society at large, not just in the health-care institutions that were studied here.

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33: Unusual biology across a group comprising more than 15% of domain Bacteria. (2015-09-28)

Our inability to culture a large fraction of all bacterial strains is biasing our information and understanding of the bacterial communities that colonize our environment. Technological advances such as growing bacteria in their natural environment and/or our ability to directly sequence environmental samples is partly mitigating this. In this particular study, the authors isolated tiny cells from an aquifer and sequenced them. Analysis of the resulting genomes revealed that these bacteria seem to belong to uncharacterized phyla and that they lack important metabolic pathways. They also had unusual introns in genes such as 16S rRNA and the authors crucially made the observation that many of these genomes would not be detected using standard 16S rRNA gene amplicon surveys.

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32: Origins of major archaeal clades correspond to gene acquisitions from bacteria. (2015-09-28)

Understanding bacterial evolution and speciation is challenging because rapid adaption through point mutations or other DNA alterations is accompanied by the influx of foreign DNA via lateral gene transfers. Sequenced genomes are snapshots in time and offer little direct information on the evolutionary processes involved in shaping them. Studying large cohorts of genomes can reveal some of the history shaping individual genomes. Nelson-Sathi and colleagues use this approach in this study and were able to work out the origin of a subset of genes transferred laterally between archaeal bacteria and eubacteria. The authors made the observation that the transfer was more commonly originating from the eubacteria. Finally, the authors found that these transfers seem to coincide with speciation. This paper represents a step forward in understanding bacterial evolution and speciation and is a worthwhile read.

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31: A new antibiotic kills pathogens without detectable resistance. (2015-08-06)

This exceptional paper by Ling and colleagues describes the results of a relatively simple, yet remarkably powerful strategy to grow bacteria in their natural environment and screen for desirable properties of the resulting cultures. In this case, the authors detect and characterize a new antimicrobial compound produced by a bacteria of the Aquabacteria genus. The compound, Teixobactin, might allow us to avoid the catastrophic consequences of pan-resistant bacteria becoming more prevalent; perhaps more importantly, the strategy used is generally applicable and will provide an opportunity to find more anti-microbial compounds.

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30: Genome-wide identification of genes required for fitness of group A Streptococcus in human blood. (2014-11-11)

The paper by Le Breton et al. describes a high-throughput technology to find genes that are important in a clinically relevant selection experiment. The authors disrupt random genes in the genome using transposons, then grow the pool of mutants in rich growth media to reduce or remove any transposon insertions that affect growth. They then grow the pool in three successive four-hour incubations in blood donated from three individuals. They then quantify the relative amount of mutants in the input pool with the output pool. The authors then show that the genes found to reduce viability in blood are highly relevant for transporting and metabolizing nutrients in blood (high in peptides and fat, low in carbohydrates and nucleotides), or are involved in protecting the bacteria from anti-microbial factors. One of the key concepts highlighted in this paper is the strategy to remove mutants with growth defects in rich media, as these otherwise show up as positives in the screen despite having little to do with fitness in blood, a highly relevant parameter in clinical settings.

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29: Molecular anatomy of a trafficking organelle. (2014-11-13)

We are inching closer to atomic resolution models of entire molecular systems, and hybrid structural approaches combing two or more orthogonal technologies are gaining popularity. The paper by Takamori and colleagues is a landmark paper that combined pseudo-atomic models of proteins and membranes together with quantitative data to seed a starting model. They then used molecular dynamics to minimize the energy of the system and arrived at a model of a synaptic vesicle. While the model is not predictive, it provides a graphical model of the entire systems and this, of course, can result in new insights.

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28: Epistasis and allele specificity in the emergence of a stable polymorphism in Escherichia coli. (2014-11-12)

Epistasis' role in evolution is becoming increasingly well supported; to understand the role for a given single-nucleotide polymorphism (SNP), one needs to consider all the epistatic interactions, many which remain unknown. In this paper, Plucain and co-authors provide further proof of epistasis as they explore the mutations underlying the stable coexistence of two strains of Escherichia coli. By comparing the fitness (through an invasion assay) of several mutations, they could quantitatively show that the effect of the mutation had a strong dependency on the genetic background.

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27: Bacterial cell wall. MurJ is the flippase of lipid-linked precursors for peptidoglycan biogenesis. (2014-11-11)

Close to all bacteria synthesize a cell wall protecting them from the environment. Punching holes or inhibiting cell wall biosynthesis kills bacteria, and it is therefore no surprise that several bactericidal antibiotics target just the cell wall and its biosynthesis. Detailed understanding of this machinery gives us more opportunities to disrupt it. Here, Sham and colleagues report that MurJ is an essential flippase in Escherichia coli. The flippase transports lipid II from the cytosol into the periplasmic space. While MurJ has been a suspect for a while, the data presented in this paper make a compelling case that this is indeed true.

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26: Functional discovery via a compendium of expression profiles. (2014-06-10)

This paper by Hughes and colleagues is important for numerous reasons, in addition to the many new insights into yeast biology that it reported. The paper was cited over 2400 times between the years 2000 and 2013, and it is still frequently cited with over 80 citations in 2013. The basic idea of the study was to create a compendium of transcription profiles measured on yeast strains with specific genes knocked-out. The compendium was then used to hypothesize on the functions of unknown gene knock-outs or chemical perturbations. What set this study apart was the use of 67 control experiments, which were used to create error models accounting for gene-specific fluctuations. These error models allowed the authors to detect relatively small changes in genes that are usually transcribed stably and to down-weigh changes in highly volatile genes. Despite the success of this study, the use of gene-specific error models remains relatively little utilized, and the reason for this is likely the cost that it involved. I believe that gene-specific error models bring a lot of power to studies and hope that their use will increase as the cost of many high-throughput experiments are decreasing.

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25: Evolutionary pathway to increased virulence and epidemic group A Streptococcus disease derived from 3,615 genome sequences. (2014-05-21)

Nasser and colleagues present the largest bacterial genome sequencing study to date - 3615 clinical isolates of a human pathogen. The earliest isolates were collected in the 1920s and the latest in 2013. The data allowed the authors to pinpoint key evolutionary events in time and could thus shed light on the factors that led to a sharp increase of infections in the 1980s. Analysis of single nucleotide polymorphisms and mobile genetic elements provides insight into which genes are under high evolutionary pressure, and this information can be used to select for proteins that are likely playing key roles in the infection process.

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24: The innate growth bistability and fitness landscapes of antibiotic-resistant bacteria. (2014-04-29)

Detailed understanding of the mechanisms of antibiotic drug resistance is crucial when developing new strategies to address this global and growing problem. Deris and colleagues present a quantitative model, backed by experimental data, showing that resistance is coupled to the growth state of the bacterium. Importantly, the model shows and explains that growth rate at certain drug concentrations is bistable: growth of individual bacteria is either completely absent, i.e. the bacterium is in a persistent state, or not affected much.

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23: Naturally occurring single amino acid replacements in a regulatory protein alter streptococcal gene expression and virulence in mice. (2014-02-06)

Large genome sequencing projects of many strains of the same bacterial species show that some proteins are significantly more mutated than is expected by chance. In this paper, Musser and colleagues follow up on a large genome sequencing study by investigating the consequences of non-synonymous mutations of one of the most mutated genes, ropB. Interestingly, RopB regulates, among many targets, various virulence factors. The study is interesting in that it found that RopB regulates different target genes depending on the isoform and genetic background and that this has a significant effect on the virulence. This hints at a complicated relationship between specific isoforms of the regulatory protein and the promoter regions.

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22: Activated ClpP kills persisters and eradicates a chronic biofilm infection. (2013-12-31)

Antibiotics are not always equally efficient in killing all bacteria underlying an infection despite the bacteria being close to genetically identical. One of the most studied causes of this is persisters, bacteria in a lower activity or dormant phenotypic state, where the low energy levels of the cell render the antibiotics less efficient. Conlon et al. show that activating a protease using acyldepsipeptide antibiotic (ADEP4) in combination with other antibiotics effectively cleared infections, whereas individual antibiotics by themselves were unable to clear the infection completely, and this is explained by them targeting different sub-populations. Importantly, Conlon et al. showed that they were able to cure deep-rooted infections in a mouse model with the drug combination. Targeting all sub-populations is important, as described here, and should be systematically investigated as more facets of infections are described and more possibilities to treat infection become available.

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21: High-resolution mapping of the spatial organization of a bacterial chromosome. (2013-12-05)

Chromosome conformation capture, together with deep sequencing, is a technology that can measure DNA-DNA interactions in vivo. Le et al. report on the structure of a bacterial chromosome under the cell cycle progression as well as comparisons between wild-type and various perturbations. These perturbations include treatment of rifampicin and knockouts of proteins known to have an impact on the organization of chromosomes, such as the histone-like protein HU and the structural maintenance of chromosomes (SMC) protein. The authors observe several important features: the chromosome seems to have regions with many local interactions called chromosomal interaction domains, or CID, separated by regions with few interactions. Regions with few interactions correlate with highly expressed genes and this is supported by the observation that these low-interaction regions seems to disappear when treating with rifampicin. These findings give an insight into the organization of bacterial chromosomes but, perhaps more importantly, they set the stage to test which perturbations have an impact on chromosome organization in a more systematic way.

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20: Genomically recoded organisms expand biological functions. (2013-10-30)

Genomically recoded organisms (GROs) are likely to 1) be resistant to viral infections and 2) be resistant to horizontal gene transfers, both in terms of incorporating genes from the environment but also making engineered traits available to naturally occurring organisms. Both features are useful when engineering organisms for use outside of labs. Lajoie and colleagues recoded a nonsense codon in Escherichia coli to a sense codon, which allowed for the deletion of a release factor and showed that one of two phages had attenuated virulence in the GRO compared to wildtype. The recoding was accomplished on a relatively small budget and it is likely that more heavily modified organisms will be created in the near future and this work indicates that they will be even more resistant to infections and, by extension, to horizontal gene transfers.

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19: Use of collateral sensitivity networks to design drug cycling protocols that avoid resistance development. (2013-10-03)

This paper demonstrates that anti-microbial resistance against one antibiotic can lead to so-called collateral sensitivity to antibiotics of one or more different antibiotic class. The authors systematically mapped out the collateral sensitivity relationships for 23 antibiotics by first eliciting resistance in wild-type Escherichia coli by increasing drug concentration over time until the resistant bacteria were growing faster than wild-type bacteria. The growth rate of the resistant bacteria was then compared to wild-type with a different drug present. Slower-growing resistant bacteria meant that bacteria resistant to the first drug were collaterally sensitive to the second drug. The authors defined optimal cycles of drugs that can be used to increase the overall drug efficacy. Importantly, two clinical isolates were shown to have largely the same pattern of collateral sensitivity compared to the laboratory strains. Antibiotics resistance is a growing clinical problem and strategies like the one described in this paper can alleviate some of these problems without the need for developing and approving new drugs.

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18: Structural systems biology evaluation of metabolic thermotolerance in Escherichia coli (2013-08-30)

Chang et al. combined a network model of the Escherichia coli metabolism iJO1366 with experimental and predicted protein structures. They used the model to predict temperature-sensitive enzymes catalyzing key reactions limiting growth rates at super-optimal temperatures. The predictions were experimentally verified, showing that the predictions reasonably well reflected the experimental data. This paper is an important contribution to the field of structural systems biology and it is likely that the strategies presented here and variations thereof will play a bigger role as structural coverage of model organisms increases.

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17: A "dock, lock, and latch" structural model for a staphylococcal adhesin binding to fibrinogen. (2013-06-14)

This important paper describes a novel structural mechanism for how a surface-associated bacterial protein, the receptor, can achieve a high binding affinity to a human molecule, the ligand, even in cases where the bound ligands amino acid sequence segment does not optimally fit into the binding pocket. The authors call this the dock-lock-and-latch mechanism and it depends on the ligand binding in a groove between two domains. A beta-sheet (the latch) is then donated from one of the domains, N3, and becomes strand-paired on the second domain, N2. The authors further show that the particular receptor studied SdrG has a higher affinity to different peptides other than the fibrinogen peptide co-crystalized. This can be the result of SdrG binding to molecules other than fibrinogen. It is tempting to speculate that this could also be a mechanism for the receptor to bind tightly to several fibrinogen isoforms likely to be present in the human population. Finally, the authors described the conserved sequence motif for the latch and used it to show that the dock-lock-and-latch mechanism is present in several other bacteria.

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16: Stabilization of cooperative virulence by the expression of an avirulent phenotype. (2013-05-08)

Pathogens that produce and secrete expensive virulence factors (producers) often grow slower than genetically identical ‘non-producers’ or similar individuals (a ‘defector’ unable to produce the virulence factors, for example) who do not produce virulence factors. Evolutionary theory states that the producers eventually will be outcompeted given that the producers and others within the same population benefit equally from the secreted factors. Diard and colleagues demonstrate that carefully controlled bistable expression of these virulence factors provides a means to keep the defectors at bay long enough to allow the transmittal of the more virulent wild-type, despite its slower growth.

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15: An integrated map of genetic variation from 1,092 human genomes. (2013-02-13)

The 1000 Genomes Project aims to map genomic variation in humans by low-coverage whole-genome and deep-coverage exome sequencing of over 1000 genomes selected from 14 distinct populations across the world. The scale of the project allows for the mapping out of single nucleotide polymorphisms (SNPs) present in < 1% of the population confidently, and this in turn allows the team to estimate how local these mutations are and, to some extent, human migrations between the various geographical locations. This paper describes how the data were processed to ensure high quality and gives some examples of how the data can be used. Among the highlights are 38 million SNPs, 14 million small insertions and deletions and 14,000 larger deletions. Additionally, they describe some global trends that can be read out of the data set. All of the project data are available on the web both for download and through various other means, such as custom Ensembl browser. The data in the project are a treasure trove for anybody interested in the evolution of human genes and genomes and provide a valuable resource to which one's own data can be compared.

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14: Global landscape of HIV-human protein complexes. (2012-12-20)

Viruses rely on hijacking various cellular functions of the host cell to ultimately produce and release new copies of the virus. Mechanistically, this hijacking is presumably heavily reliant on protein-protein interaction where virus proteins physically interact with human proteins to alter their function. In this paper, the complete interactome between all HIV proteins and the proteins from two cell lines is presented. These interactions can be used in many ways, such as gaining understanding in which interactions likely play a key role, and also which protein-protein interfaces are important. This paper is the first complete interaction map between a pathogen and its host, making it an important contribution to the field of infectious deceases.

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13: Epistasis as the primary factor in molecular evolution. (2012-11-02)

Molecular evolution is the study of the evolution of RNA, DNA and proteins. Several studies have reported that the evolutionary rate of amino acid substitutions cannot be explained without including the genetic background of the organism. In other words, the evolutionary rate of individual amino acids is dependent on long-range contacts within the genome, a phenomenon often referred to as epistasis. In this study, the authors use deep sequence alignments to compare the expected evolutionary rate to the observed rate and conclude that the actual rate is indeed much smaller than that predicted, indicating that the evolution of these molecules is constrained by the genetic background. However, it is worth noting that the proteins in this study are all highly conserved and therefore might not be representative of proteins in general.

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12: The dynamics of cooperative bacterial virulence in the field. (2012-10-08)

Bacterial populations undergo rapid adaption when under selective pressure. These adaptations can be genetic (mutations for example) but they can also be changes to the relative prevalence of a particular genetic trait compared to another, as sub-populations might have different selective pressure depending on population attributes such as density. Secreted virulence factors, exotoxins for example, can be expensive to produce but benefit all bacteria occupying the same clinical site. It is therefore conceivable that bacteria of a population can benefit from not producing the toxin and instead rely on their neighbors. This paper demons trated that there is an optimal relation between bacteria producing the toxin and bacteria that are not, and that this fraction is reached from different starting points (under constant density). Selective pressure on an individual is hence dependent on population density and composition where bacteria not producing toxins would be at an advantage at high density but at a disadvantage at lower densities assuming the relative fraction of producers and non-producers are the same.

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11: Population genomics of early events in the ecological differentiation of bacteria. (2012-06-21)

This article demonstrates how genomic traits are spread through bacterial populations in oceans and the authors find that certain genetic elements sweep through the populations similarly to how genetic traits are swept through sexual eukaryotes. The authors conclude that ecological differentiation is driven by gene-specific sweeps and not genomic sweeps. These findings are important as they demonstrate that evolution in bacteria is a complex interplay between mutations, selection, and specific and unspecific exchange of genetic material.

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10: High-throughput decoding of antitrypanosomal drug efficacy and resistance. (2012-04-19)

The authors of this paper utilized high-throughput RNA interference (RNAi) in combination with five known drugs used to treat human African trypanosomiasis to reveal the proteins involved in the drug mechanism. The infection caused by African trypanosomes, the causative agent of sleeping sickness, is treated using five different drugs. The underlying mechanism of the drug efficacy is partly unknown. Deep insight into the protein networks involved is provided by this paper where high-throughput RNAi was used to knock down genes in a systematic fashion and monitor pathogen viability. Proteins involved in the drug action could be identified when knocked down by increased viability of the protozoa. The paper nicely demonstrates how to use high-throughput technologies to arrive at relatively detailed information on how a particular drug is operating.

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9: Evolution of increased complexity in a molecular machine. (2012-02-10)

This paper provides credible evidence on how complexity in protein complexes can increase based on high-probability mutations and gene duplications. Plausible ancient proteins were re-created and shown to functionally replace the more complex modern version of the yeast vacuolar-type H(+)-ATPase (V-ATPase) proton pump.

Protein complexes carry out fundamental processes in all living systems. Experimentally verified ways on how these complexes evolve are rare since the ancestral proteins are lost. This paper used maximum likelihood phylogeny to identify key mutations and then reconstruct plausible ancestral proteins. The authors show, through a simple functional assay, how an ancient gene duplication and subsequent evolution altered the structure of the yeast V-ATPase proton pump from a two-paralog hexamer to a three-paralog hexamer in which all three paralogs are essential.

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8: Chromosome organization by a nucleoid-associated protein in live bacteria. (2011-12-21)

This paper demonstrates the application of super-resolution microscopy to elucidate the spatial distribution of chromosome-organizing proteins in live bacterial cells that are too small to study with more conventional microscopy methods.

Cells display a high degree of organization and yet re-organize themselves in response to various stimuli. Elucidating the mechanisms underlying this organization and dynamics is likely required to achieve a deeper understanding of how cells function. The super-resolution microscopy technology used in this paper allows the authors to study how the bacteria organize their chromosome and demonstrate that this organization have an impact on gene expression. This paper is important as it directly links the spatial distribution of a protein to its function. We believe that super-resolution microscopy will contribute with valuable knowledge as the technology becomes more readily available.

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7: Phenotypic landscape of a bacterial cell. (2011-10-20)

This paper systematically screens 3979 knock-out strains of Escherichia coli over 324 conditions-for-growth phenotypes. This large dataset, which is available for download, is an invaluable resource for anybody interested in environmental perturbation/protein interactions.

This work describes a systematic study in which 3979 gene knockouts are tested in 324 conditions-for-growth phenotypes. The authors attempt to be as inclusive as possible in both relevant conditions and gene knockouts. This makes the resulting data set a unique resource for hypothesis generation. The simple readout of growth phenotype is surprisingly informative and is currently one of the few technologies accessible to studies of this magnitude where almost 1.3 million environmental perturbation/gene interactions were tested. Focused follow-up experiments where selected conditions are tested by more involved technologies such as transcript or proteomic analyses, will be easier to design and hence benefit from this study.

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6: Distinct signatures of diversifying selection revealed by genome analysis of respiratory tract and invasive bacterial populations. (2011-07-15)

Large-scale full-genome sequencing of the pathogen Streptococcus pyogenes reveals that strains causing pharyngitis can also become invasive.

S. pyogenes is a common pathogen that causes pharyngitis but can also become invasive, in which case the mortality rate increases significantly. Musser and colleagues genome-sequenced 86 strains isolated in pharyngitis patients and over 200 invasive strains isolated in the same geographical area at the same time. The comparison revealed that all four primary genetic lineages identified in the study caused pharyngitis and all four could also become invasive. Furthermore, the study revealed that certain genes are more strongly diverged between the pharyngitis isolates compared to the invasive isolates than expected by chance. This can be explained by different selective pressures exerted on the bacteria in the different anatomical sites. This study gives insight into disease progression and also provides information on genes that play key roles for survival in the distinct anatomical sites, all using a technology that is rapidly becoming accessible to all.

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5: Second-order selection for evolvability in a large Escherichia coli population. (2011-04-04)

This paper shows that genomic epistasis plays a key role in evolution where initially favorable mutations alter the effect of subsequent synergistic mutations.

Fitness in bacteria can be evaluated by the competitiveness of one sub-strain among many under a certain condition. Descendants of the fittest bacteria will constitute the majority in a population after enough time has passed. In this paper, initially less-fit bacteria (eventual winner [EW]) would eventually achieve higher fitness than bacteria that were initially more fit (eventual loser [EL]). The authors prove that this is due to the fact that EL bacteria cannot benefit to the same degree as EW from a mutation in spoT. This paper convincingly shows that this is due to epistasis, where the genetic background of EL (specifically, in gene topA) does not benefit to the same extent as EW.

In other words, EW has a higher degree of evolvability or evolutionary potential compared to EL under the tested condition. This is an important finding with implications for, among other fields, directed evolution experiments, as early beneficial mutations might exclude parts of the evolutionary space where even more-fit bacteria could be possible.

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4: The CRISPR/Cas bacterial immune system cleaves bacteriophage and plasmid DNA. (2011-01-19)

This important paper shows that the adaptive immune system of some bacteria can cut double-stranded DNA (dsDNA) sequences, and that the cut site is specified by a short nucleic acid sequence.

The 'clustered regularly interspaced short palindromic repeats' (CRISPR)/ CRISPR-associated (Cas) immune system of Streptococcus thermophilus can acquire specific CRISPR spacers from various sources, such as self-replicating plasmids. Plasmids that match these spacers are cut at a specific site determined by the spacer and produce blunt ends. The now linear plasmid is rapidly lost. This is important as this can be exploited by manipulating the CRISPR of bacteria so they cannot acquire plasmids that, for example, carry anti-biotic resistance genes. This paper also shows that the CRISPR/Cas system specifically cleaves dsDNA at specific sites. It is plausible that this system can also be exploited in the future to develop technology in which specifying where to cut DNA is as simple as synthesizing a matching CRISPR spacer.

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3: Systematic analysis of human protein complexes identifies chromosome segregation proteins. (2010-10-26)

In this exciting work, high-throughput technologies were used to characterize protein complexes involved in chromosome segregation, and new members of these complexes were identified and verified.

Proteins organize into complexes to perform many cellular tasks. Knowledge about the composition and dynamics of these complexes will further the understanding of fundamental processes in biology. In this study, protein complexes involved in chromosome segregation were characterized using a combination of high-throughput imaging and immunoprecipitation (IP)-based mass spectrometry. Some of the more interesting finds were followed up and shown to be correct. The authors were able to use the genome-wide RNA interference (RNAi) screen (where testable hypotheses are difficult to generate) to identify potential targets, process all of them with high-throughput technologies and generate hypotheses that could be tested using traditional biochemical approaches. They tackled a well-studied system and came up with novel information.

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2: Evolution of MRSA during hospital transmission and intercontinental spread. (2010-04-27)

Genome sequencing of methicillin-resistant Staphylococcus aureus (MRSA) from multiple temporal and spatial isolates has revealed information about infection paths and mutation rates.

Antibiotic-resistant bacteria are a growing global health problem. An obvious strategy to prevent the spread of such strains is to reduce transmission between individuals. This ultimately relies on our understanding of the transmission paths. In this paper, multiple strains were sequenced and single-nucleotide polymorphisms (SNPs) were analyzed in great detail generating a high-resolution dendrogram. The study demonstrates how genome sequencing of bacterial isolates (isolated across time and space) of a particular strain of MRSA, TW20, provides a high-resolution map on how bacteria spread between patients at the same hospital and provides information about intercontinental spread. The applied technology lays the foundation for investigating how the bacteria are spread long after the outbreak has occurred provided that a sufficient number of isolates were collected and catalogued.

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1: Structure and mechanisms of a protein-based organelle in Escherichia coli. (2010-01-13)

In this study, X-ray structures of four microcompartment proteins that are the components of the protein-based organelle capsule explain how bent conformations are achieved and reveal an active gating function.

There is growing evidence that bacteria are, in fact, not devoid of internal compartmentalization but are rather highly organized. For example, bacterial proteins are to a large extent organized in protein complexes {1} and are sometimes localized to specific regions of the cytosol {2}; in addition, there is also evidence for protein-encapsulated organelles (see ref {3}, on which Ruedi Aebersold is an author). In this paper, Tanaka and colleagues reveal how one of the shell proteins has a bent conformation which allows these microcompartments to close. They also show that there is an active gate that presumably regulates the in- and out-flow of various molecular species. This paper adds to the evidence that the proteomes of bacteria are highly structured and compartmentalized.

References: {1} Kuehner et al. Science 2009, 326:1235-40 [PMID:16081736]. {2} Shapiro et al. Science 2009, 326:1225-8 [PMID:19965466]. {3} Kerfeld et al. Science 2005, 309:936-8 [PMID:19965468].

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