Proceedings of the National Academy of Sciences

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Wed, 12/17/2014 - 03:20
Drug discovery for malaria has been transformed in the last 5 years by the discovery of many new lead compounds identified by phenotypic screening. The process of developing these compounds as drug leads and studying the cellular responses they induce is revealing new targets that regulate key processes in the...
Wed, 12/17/2014 - 03:20
Erythritol is an important nutrient for several α-2 Proteobacteria, including N2-fixing plant endosymbionts and Brucella, a worldwide pathogen that finds this four-carbon polyol in genital tissues. Erythritol metabolism involves phosphorylation to l-erythritol-4-phosphate by the kinase EryA and oxidation of the latter to l-3-tetrulose 4-phosphate by the dehydrogenase EryB. It is...
Wed, 11/26/2014 - 01:35
As in most bacteria, topological problems arising from the circularity of the two Vibrio cholerae chromosomes, chrI and chrII, are resolved by the addition of a crossover at a specific site of each chromosome, dif, by two tyrosine recombinases, XerC and XerD. The reaction is under the control of a...
Wed, 10/01/2014 - 06:20
Vibrio cholerae is the bacterium that causes the diarrheal disease cholera. The bacteria experience a temperature shift as V. cholerae transition from contaminated water at lower temperatures into the 37 °C human intestine. Within the intestine, V. cholerae express cholera toxin (CT) and toxin-coregulated pilus (TCP), two main virulence factors...
Wed, 10/01/2014 - 06:20
Because mutation is the ultimate source of genetic variation, understanding mutational patterns and mechanisms is of fundamental importance. Previous studies provided genomic evidence that, in the bacteria Escherichia coli and Salmonella typhimurium, yeast Saccharomyces cerevisiae, and human germ line, the mutation rate of a gene generally increases with the expression...
Wed, 09/03/2014 - 06:20
Enteropathogenic bacteria, exemplified by Escherichia coli, rely on acid-resistance systems (ARs) to survive the acidic environment of the stomach. AR3 consumes intracellular protons through decarboxylation of arginine (Arg) in the cytoplasm and exchange of the reaction product agmatine (Agm) with extracellular Arg. The latter process is mediated by the Arg:Agm...
Wed, 08/20/2014 - 06:20
For rapid and effective clinical translation, polymer-based anticancer therapeutics need long circulating conjugates that produce a sustained concentration gradient between the vasculature and solid tumor. To this end, we designed second-generation backbone-degradable diblock N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer carriers and evaluated sequential combination therapy of HPMA copolymer...
Wed, 08/20/2014 - 06:20
Fastidious anaerobic bacteria play critical roles in environmental bioremediation of halogenated compounds. However, their characterization and application have been largely impeded by difficulties in growing them in pure culture. Thus far, no pure culture has been reported to respire on the notorious polychlorinated biphenyls (PCBs), and functional genes responsible for...
Wed, 08/20/2014 - 06:20
It has taken three decades from the first report of microbial polychlorinated biphenyl (PCB) dechlorination to identify even one of the enzymes responsible. By combining conventional techniques with their own ingenuity, the latest technologies, and a bit of luck, Wang et al., in PNAS, have identified not one, but three...
Wed, 08/13/2014 - 03:20
Mononuclear Cr(III) surface sites were synthesized from grafting [Cr(OSi(OtBu)3)3(tetrahydrofurano)2] on silica partially dehydroxylated at 700 °C, followed by a thermal treatment under vacuum, and characterized by infrared, ultraviolet-visible, electron paramagnetic resonance (EPR), and X-ray absorption spectroscopy (XAS). These sites are highly active in ethylene polymerization to yield...
Wed, 08/13/2014 - 03:20
Trichothecene mycotoxins are natural contaminants of small grain cereals and are encountered in the environment, posing a worldwide threat to human and animal health. Their mechanism of toxicity is poorly understood, and little is known about cellular protection mechanisms against trichothecenes. We previously identified inhibition of mitochondrial protein synthesis as...
Wed, 07/23/2014 - 03:20
Outbreaks of highly pathogenic strains of avian influenza viruses (AIVs) cause considerable economic losses to the poultry industry and also pose a threat to human life. The possibility that one of these strains will evolve to become transmissible between humans, sparking a major influenza pandemic, is a matter of great...
Wed, 07/09/2014 - 07:20
Shigella flexneri proliferate in infected human epithelial cells at exceptionally high rates. This vigorous growth has important consequences for rapid progression to life-threatening bloody diarrhea, but the underlying metabolic mechanisms remain poorly understood. Here, we used metabolomics, proteomics, and genetic experiments to determine host and Shigella metabolism during infection in...
Wed, 07/09/2014 - 07:20
The seventh cholera pandemic caused by Vibrio cholerae O1 El Tor (ET) has been superseded in Asia and Africa by altered ET possessing the cholera toxin (CTX) gene of classical (CL) biotype. The CL biotype of V. cholerae was isolated, along with prototypic and altered ET, during the 1991 cholera...
Wed, 06/25/2014 - 06:20
Ler, a homolog of H-NS in enteropathogenic Escherichia coli (EPEC), plays a critical role in the expression of virulence genes encoded by the pathogenic island, locus of enterocyte effacement (LEE). Although Ler acts as an antisilencer of multiple LEE operons by alleviating H-NS–mediated silencing, it represses its own expression from...
Thu, 06/19/2014 - 06:20
G protein-coupled receptor kinase-interactor 2 (GIT2) regulates thymocyte positive selection, neutrophil-direction sensing, and cell motility during immune responses by regulating the activity of the small GTPases ADP ribosylation factors (Arfs) and Ras-related C3 botulinum toxin substrate 1 (Rac1). Here, we show that Git2-deficient mice were more susceptible to dextran sodium...
Wed, 06/04/2014 - 07:20
The source, timing, and geographical origin of the 1918–1920 pandemic influenza A virus have remained tenaciously obscure for nearly a century, as have the reasons for its unusual severity among young adults. Here, we reconstruct the origins of the pandemic virus and the classic swine influenza and (postpandemic) seasonal H1N1...
Wed, 05/28/2014 - 03:20
Enterohemorrhagic Escherichia coli (EHEC) is an extracellular pathogen that causes hemorrhagic colitis and hemolytic uremic syndrome. The proinflammatory cytokine, interleukin-1β, has been linked to hemolytic uremic syndrome. Here we identify the nucleotide-binding domain and leucine rich repeat containing family, pyrin domain containing 3 (NLRP3) inflammasome as an essential mediator of...
Wed, 05/14/2014 - 03:20
Cadmium (Cd) is a micronutrient and a tracer of biological productivity and circulation in the ocean. The correlation between dissolved Cd and the major algal nutrients in seawater has led to the use of Cd preserved in microfossils to constrain past ocean nutrient distributions. However, linking Cd to marine biological...
Wed, 02/26/2014 - 03:20
The intracellular pathogen Salmonella enterica serovar Typhimurium requires the mgtC gene to cause disease. The mgtC transcript includes a long leader region that harbors a short proline codon-rich ORF—termed mgtP—the translation of which is predicted to favor formation of one of two alternative stem-loop structures. We now report that the...
Tue, 01/07/2014 - 14:58
Proceedings of the National Academy of Sciences
Antibiotic-resistant isolates of Salmonella enterica were selected on plates containing lethal concentrations of rifampicin, kanamycin, and nalidixic acid. The stability of the resistance phenotype was scored after nonselective growth. Rifampicin-resistant (Rifr) isolates were stable, suggesting that they had...
Tue, 01/07/2014 - 14:58
Proceedings of the National Academy of Sciences
The nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 12 (NLRP12) plays a protective role in intestinal inflammation and carcinogenesis, but the physiological function of this NLR during microbial infection is largely unexplored. Salmonella enterica serovar...
Tue, 12/17/2013 - 15:17
Proceedings of the National Academy of Sciences
Capsular polysaccharides (CPSs) are high-molecular-mass cell-surface polysaccharides, that act as important virulence factors for many pathogenic bacteria. Several clinically important Gram-negative pathogens share similar systems for CPS biosynthesis and export; examples include Escherichia coli,...
Tue, 12/17/2013 - 15:17
Proceedings of the National Academy of Sciences
MICROBIOLOGY Correction for “Intracellular Shigella remodels its LPS to dampen the innate immune recognition and evade inflammasome activation,” by Ida Paciello, Alba Silipo, Luigi Lembo-Fazio, Laura Curcurù, Anna Zumsteg, Gaëlle Noël, Valeria Ciancarella, Luisa Sturiale, Antonio Molinaro, and Maria Lina...
Tue, 12/10/2013 - 14:13
Proceedings of the National Academy of Sciences
Genome-scale models (GEMs) of metabolism were constructed for 55 fully sequenced Escherichia coli and Shigella strains. The GEMs enable a systems approach to characterizing the pan and core metabolic capabilities of the E. coli species. The majority of pan metabolic content was found to consist of alternate...
Tue, 12/03/2013 - 14:58
Proceedings of the National Academy of Sciences
Successful macrophage colonization by Coxiella burnetii, the cause of human Q fever, requires pathogen-directed biogenesis of a large, growth-permissive parasitophorous vacuole (PV) with phagolysosomal characteristics. The vesicular trafficking pathways co-opted by C. burnetii for PV development are poorly...
Tue, 11/26/2013 - 16:13
Proceedings of the National Academy of Sciences
We appreciate the interest taken in our recent work (1) by Blair et al. (2), who are “perplexed” that we did not observe induction of ramA expression in Salmonella typhimurium treated with 50–125 μM indole. It is important to note, however, that induction of the Salmonella typhimurium ramA gene by.....
Tue, 11/12/2013 - 14:35
Proceedings of the National Academy of Sciences
LPS is a potent bacterial effector triggering the activation of the innate immune system following binding with the complex CD14, myeloid differentiation protein 2, and Toll-like receptor 4. The LPS of the enteropathogen Shigella flexneri is a hexa-acylated isoform possessing an optimal inflammatory activity...
Tue, 11/12/2013 - 14:35
Proceedings of the National Academy of Sciences
Efflux pumps belonging to the ubiquitous resistance–nodulation–cell division (RND) superfamily transport substrates out of cells by coupling proton conduction across the membrane to a conformationally driven pumping cycle. The heavy metal-resistant bacteria Cupriavidus metallidurans CH34 relies notably on as...
Tue, 10/22/2013 - 13:48
Proceedings of the National Academy of Sciences
Shigella sonnei is a human-adapted pathogen that is emerging globally as the dominant agent of bacterial dysentery. To investigate local establishment, we sequenced the genomes of 263 Vietnamese S. sonnei isolated over 15 y. Our data show that S. sonnei was introduced into Vietnam in the 1980s and has...
Tue, 10/01/2013 - 14:59
Proceedings of the National Academy of Sciences
Identifying the major sources of risk in disease transmission is key to designing effective controls. However, understanding of transmission dynamics across species boundaries is typically poor, making the design and evaluation of controls particularly challenging for zoonotic pathogens. One such global...
Tue, 10/01/2013 - 14:59
Proceedings of the National Academy of Sciences
We recently showed that infection by Listeria monocytogenes causes mitochondrial network fragmentation through the secreted pore-forming toxin listeriolysin O (LLO). Here, we examine factors involved in canonical fusion and fission. Strikingly, LLO-induced mitochondrial fragmentation does not require the...
Tue, 09/10/2013 - 13:57
Proceedings of the National Academy of Sciences
Robust cytotoxic CD8+ T-cell response is important for immunity to intracellular pathogens. Here, we show that the transcription factor IFN Regulatory Factor 4 (IRF4) is crucial for the protective CD8+ T-cell response to the intracellular bacterium Listeria monocytogenes. IRF4-deficient (Irf4−/−) mice could...
Tue, 08/27/2013 - 13:57
Proceedings of the National Academy of Sciences
Inflammasome mediated by central nucleotide-binding and oligomerization domain (NOD)-like receptor (NLR) protein is critical for defense against bacterial infection. Here we show that type III secretion system (T3SS) needle proteins from several bacterial pathogens, including Salmonella typhimurium,...
Tue, 08/06/2013 - 14:12
Proceedings of the National Academy of Sciences
Riboswitches are ligand-binding elements located in 5′ untranslated regions of messenger RNAs, which regulate expression of downstream genes. In Listeria monocytogenes, a vitamin B12-binding (B12) riboswitch was identified, not upstream of a gene but downstream, and antisense to the adjacent gene, pocR,...
Tue, 07/30/2013 - 13:57
Proceedings of the National Academy of Sciences
The attaching and effacing Escherichia coli (AEEC) are characterized by the presence of a type III secretion system encoded by the locus of enterocyte effacement (LEE). Enterohemorrhagic E. coli (EHEC) are often identified as isolates that are LEE+ and carry the Shiga toxin (stx)-encoding phage, which are...
Tue, 07/16/2013 - 13:42
Proceedings of the National Academy of Sciences
Genome-wide association studies have the potential to identify causal genetic factors underlying important phenotypes but have rarely been performed in bacteria. We present an association mapping method that takes into account the clonal population structure of bacteria and is applicable to both core and...
Tue, 07/16/2013 - 13:42
Proceedings of the National Academy of Sciences
Oral feed-based passive immunization can be a promising strategy to prolong maternal lactogenic immunity against postweaning infections. Enterotoxigenic Escherichia coli (ETEC)-caused postweaning diarrhea in piglets is one such infection that may be prevented by oral passive immunization and might avert...
Tue, 07/16/2013 - 13:42
Proceedings of the National Academy of Sciences
The efficacy of antibiotics and host defenses has been linked to the metabolic and redox states of bacteria. In this study we report that a stress-induced export pump belonging to the major facilitator superfamily effluxes citrate and iron from the enteric pathogen Salmonella Typhimurium to arrest growth and...
Tue, 07/09/2013 - 14:27
Proceedings of the National Academy of Sciences
Caseinolytic proteases (ClpPs) are large oligomeric protein complexes that contribute to cell homeostasis as well as virulence regulation in bacteria. Although most organisms possess a single ClpP protein, some organisms encode two or more ClpP isoforms. Here, we elucidated the crystal structures of ClpP1 and...
Tue, 07/09/2013 - 14:27
Proceedings of the National Academy of Sciences
Defects in normal autophagic pathways are implicated in numerous human diseases—such as neurodegenerative diseases, cancer, and cardiomyopathy—highlighting the importance of autophagy and its proper regulation. Herein we show that Vibrio parahaemolyticus uses the type III effector VopQ (Vibrio outer protein Q...