Proceedings of the National Academy of Sciences

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Tue, 06/28/2016 - 13:02
RNA structures are fundamentally important for RNA function. Dynamic, condition-dependent structural changes are able to modulate gene expression as shown for riboswitches and RNA thermometers. By parallel analysis of RNA structures, we mapped the RNA structurome of Yersinia pseudotuberculosis at three different temperatures. This human pathogen is exquisitely responsive to...
Tue, 06/14/2016 - 13:48
Polysaccharide capsules are surface structures that are critical for the virulence of many Gram-negative pathogenic bacteria. Salmonella enterica serovar Typhi is the etiological agent of typhoid fever. It produces a capsular polysaccharide known as “Vi antigen,” which is composed of nonstoichiometrically O-acetylated α-1,4-linked N-acetylgalactosaminuronic acid residues. This glycan is a...
Tue, 06/07/2016 - 12:33
The Q fever bacterium Coxiella burnetii replicates inside host cells within a large Coxiella-containing vacuole (CCV) whose biogenesis relies on the Dot/Icm-dependent secretion of bacterial effectors. Several membrane trafficking pathways contribute membranes, proteins, and lipids for CCV biogenesis. These include the endocytic and autophagy pathways, which are characterized by...
Tue, 05/31/2016 - 12:27
Vibrio parahaemolyticus is the most common cause of seafood-borne gastroenteritis worldwide and a blight on global aquaculture. This organism requires a horizontally acquired type III secretion system (T3SS2) to infect the small intestine, but knowledge of additional factors that underlie V. parahaemolyticus pathogenicity is limited. We used transposon-insertion sequencing to...
Tue, 05/24/2016 - 12:13
To acquire essential Fe(III), bacteria produce and secrete siderophores with high affinity and selectivity for Fe(III) to mediate its uptake into the cell. Here, we show that the periplasmic binding protein CeuE of Campylobacter jejuni, which was previously thought to bind the Fe(III) complex of the hexadentate siderophore enterobactin (Kd...
Tue, 05/17/2016 - 12:47
Listeria monocytogenes is responsible for gastroenteritis in healthy individuals and for a severe invasive disease in immunocompromised patients. Among the three identified L. monocytogenes evolutionary lineages, lineage I strains are overrepresented in epidemic listeriosis outbreaks, but the mechanisms underlying the higher virulence potential of strains of this lineage remain elusive....
Tue, 04/26/2016 - 13:02
Upon entry into host cells, intracellular bacterial pathogens establish a variety of replicative niches. Although some remodel phagosomes, others rapidly escape into the cytosol of infected cells. Little is currently known regarding how professional intracytoplasmic pathogens, including Shigella, mediate phagosomal escape. Shigella, like many other Gram-negative bacterial pathogens, uses a...
Tue, 03/29/2016 - 12:15
Although it is known that diverse bacterial flagellar motors produce different torques, the mechanism underlying torque variation is unknown. To understand this difference better, we combined genetic analyses with electron cryo-tomography subtomogram averaging to determine in situ structures of flagellar motors that produce different torques, from Campylobacter and Vibrio species....
Tue, 03/08/2016 - 13:49
Common environmental contaminants such as bisphenols and phthalates and persistent contaminants such as polychlorinated biphenyls are thought to influence tissue homeostasis and carcinogenesis by acting as disrupters of endocrine function. In this study we investigated the direct effects of exposure to bisphenol A (BPA), mono-n-butyl phthalate (Pht), and polychlorinated biphenyl...
Tue, 01/19/2016 - 14:53
Necrotizing fasciitis (NF) caused by flesh-eating bacteria is associated with high case fatality. In an earlier study, we reported infection of an immunocompetent individual with multiple strains of Aeromonas hydrophila (NF1–NF4), the latter three constituted a clonal group whereas NF1 was phylogenetically distinct. To understand the complex interactions of these...
Tue, 01/12/2016 - 12:07
Pigs are important intermediate hosts for generating novel influenza viruses. The Eurasian avian-like H1N1 (EAH1N1) swine influenza viruses (SIVs) have circulated in pigs since 1979, and human cases associated with EAH1N1 SIVs have been reported in several countries. However, the biologic properties of EAH1N1 SIVs are largely unknown. Here, we...
Tue, 12/22/2015 - 19:58
Pain management would be greatly enhanced by a formulation that would provide local anesthesia at the time desired by patients and with the desired intensity and duration. To this end, we have developed near-infrared (NIR) light-triggered liposomes to provide on-demand adjustable local anesthesia. The liposomes contained tetrodotoxin (TTX), which has...
Tue, 12/08/2015 - 13:14
Hepatitis A virus (HAV) is an ancient and ubiquitous human pathogen recovered previously only from primates. The sole species of the genus Hepatovirus, existing in both enveloped and nonenveloped forms, and with a capsid structure intermediate between that of insect viruses and mammalian picornaviruses, HAV is enigmatic in its origins....
Tue, 12/08/2015 - 13:14
The History of HAV Earliest descriptions of epidemic liver disease, most likely due to hepatitis A virus (HAV), can be found in ancient Chinese literature, and similar observations, often in association with conflict and social disruption, have appeared on many occasions. However, evidence that the infection was of viral etiology...
Tue, 10/06/2015 - 12:03
Enterohemorrhagic Escherichia coli (EHEC) is one of the leading causes of bacterial enteric infections worldwide, causing ∼100,000 illnesses, 3,000 hospitalizations, and 90 deaths annually in the United States alone. These illnesses have been linked to consumption of contaminated animal products and vegetables. Currently, other than thermal inactivation, there are no...
Tue, 10/06/2015 - 12:03
Food safety is a critical issue worldwide, and responsibility for ensuring and enhancing safety in the food chain is collectively shared by all involved, from producers to preparation to food service. Just over a century ago, the issues of food safety and production were brought to the forefront of public...
Wed, 09/30/2015 - 03:20
MICROBIOLOGY Correction for “The opportunistic marine pathogen Vibrio parahaemolyticus becomes virulent by acquiring a plasmid that expresses a deadly toxin,” by Chung-Te Lee, I-Tung Chen, Yi-Ting Yang, Tzu-Ping Ko, Yun-Tzu Huang, Jiun-Yan Huang, Ming-Fen Huang, Shin-Jen Lin, Chien-Yu Chen, Shih-Shuen Lin, Donald V. Lightner, Han-Ching Wang, Andrew H.-J. Wang, Hao-Ching...
Wed, 09/30/2015 - 03:20
Methylmercury (MeHg) is a potent neurotoxin that is biomagnified approximately 1–10 million-fold in aquatic carnivores such as the Northern elephant seal (Mirounga angustirostris), whose excreta and molted pelage, in turn, constitute a source of environmental MeHg contamination at the base of marine food chains. The potential for this top-down contamination...
Wed, 09/30/2015 - 03:20
Mercury and marine mammals Northern elephant seals accumulate MeHg from their prey in the North Pacific. Image courtesy of James Harvey (Moss Landing Marine Laboratories, Moss Landing, CA). Methylmercury (MeHg) is a neurotoxin that accumulates in marine food chains, posing a threat to environmental and human health. High Hg concentrations...
Wed, 09/23/2015 - 03:20
Elevated levels of neurotoxic methylmercury in Arctic food-webs pose health risks for indigenous populations that consume large quantities of marine mammals and fish. Estuaries provide critical hunting and fishing territory for these populations, and, until recently, benthic sediment was thought to be the main methylmercury source for coastal fish. New...
Thu, 09/03/2015 - 03:20
In 2006, a deadly Escherichia coli O157:H7 outbreak in bagged spinach was traced to California’s Central Coast region, where >70% of the salad vegetables sold in the United States are produced. Although no definitive cause for the outbreak could be determined, wildlife was implicated as a disease vector. Growers were...
Wed, 08/26/2015 - 06:20
Acute hepatopancreatic necrosis disease (AHPND) is a severe, newly emergent penaeid shrimp disease caused by Vibrio parahaemolyticus that has already led to tremendous losses in the cultured shrimp industry. Until now, its disease-causing mechanism has remained unclear. Here we show that an AHPND-causing strain of V. parahaemolyticus contains a 70-kbp...
Wed, 08/19/2015 - 01:21
The estuarine gram-negative rod and human diarrheal pathogen Vibrio cholerae synthesizes a VPS exopolysaccharide-dependent biofilm matrix that allows it to form a 3D structure on surfaces. Proteins associated with the matrix include, RbmA, RbmC, and Bap1. RbmA, a protein whose crystallographic structure suggests two binding surfaces, associates with cells...
Wed, 08/19/2015 - 01:21
Natural transformation is one mechanism of horizontal gene transfer (HGT) in Vibrio cholerae, the causative agent of cholera. Recently, it was found that V. cholerae isolates from the Haiti outbreak were poorly transformed by this mechanism. Here, we show that an integrating conjugative element (ICE)-encoded DNase, which we name...
Wed, 07/15/2015 - 06:20
We have functionally and structurally defined an essential protein phosphorelay that regulates expression of genes required for growth, division, and intracellular survival of the global zoonotic pathogen Brucella abortus. Our study delineates phosphoryl transfer through this molecular pathway, which initiates from the sensor kinase CckA and proceeds through the ChpT...
Wed, 06/24/2015 - 06:20
Few studies within the pathogenic field have used advanced imaging and analytical tools to quantitatively measure pathogenicity in vivo. In this work, we present a novel approach for the investigation of host–pathogen processes based on medium-throughput 3D fluorescence imaging. The guinea pig model for Shigella flexneri invasion of the colonic...
Wed, 04/29/2015 - 06:20
Major changes in bacterial physiology including biofilm and spore formation involve signaling by the cyclic dinucleotides c-di-GMP and c-di-AMP. Recently, another second messenger dinucleotide, c-AMP-GMP, was found to control chemotaxis and colonization by Vibrio cholerae. We have identified a superregulon of genes controlled by c-AMP-GMP in numerous Deltaproteobacteria, including Geobacter...
Wed, 04/29/2015 - 06:20
Cyclic dinucleotides are an expanding class of signaling molecules that control many aspects of bacterial physiology. A synthase for cyclic AMP-GMP (cAG, also referenced as 3′-5′, 3′-5′ cGAMP) called DncV is associated with hyperinfectivity of Vibrio cholerae but has not been found in many bacteria, raising questions about the prevalence...
Wed, 04/29/2015 - 06:20
Enterohemorrhagic Escherichia coli (EHEC) is a foodborne pathogen causing hemorrhagic colitis and hemolytic uremic syndrome. EHEC colonizes the intestinal tract through a range of virulence factors encoded by the locus of enterocyte effacement (LEE), as well as Shiga toxin. Although the factors involved in colonization and disease are well characterized,...
Wed, 04/22/2015 - 06:20
Cellulose is the most abundant organic polymer on Earth. In bacteria, cellulose confers protection against environmental insults and is a constituent of biofilms typically formed on abiotic surfaces. We report that, surprisingly, Salmonella enterica serovar Typhimurium makes cellulose when inside macrophages. We determine that preventing cellulose synthesis increases virulence, whereas...
Wed, 04/08/2015 - 06:20
RecQ helicases unwind remarkably diverse DNA structures as key components of many cellular processes. How RecQ enzymes accommodate different substrates in a unified mechanism that couples ATP hydrolysis to DNA unwinding is unknown. Here, the X-ray crystal structure of the Cronobacter sakazakii RecQ catalytic core domain bound to duplex DNA...
Wed, 04/01/2015 - 06:20
Tuberculosis (TB) is a devastating disease that affects humans and many animal species. In humans, TB is mainly caused by Mycobacterium tuberculosis, whereas most cases in cattle are caused by Mycobacterium bovis. However, M. bovis can also cause, albeit rarely, human TB. In PNAS, Wu et al. (1) report the...
Wed, 02/18/2015 - 03:20
Quorum sensing (QS) is a process of cell-to-cell communication that enables bacteria to transition between individual and collective lifestyles. QS controls virulence and biofilm formation in Vibrio cholerae, the causative agent of cholera disease. Differential RNA sequencing (RNA-seq) of wild-type V. cholerae and a locked low-cell-density QS-mutant strain identified 7,240...
Wed, 02/11/2015 - 03:20
Flagella are multiprotein complexes necessary for swimming and swarming motility. In Salmonella enterica serovar Typhimurium, flagella-mediated motility is repressed by the PhoP/PhoQ regulatory system. We now report that Salmonella can move on 0.3% agarose media in a flagella-independent manner when experiencing the PhoP/PhoQ-inducing signal low Mg2+. This motility requires the...
Wed, 02/04/2015 - 03:20
Bisphenol A (BPA), a ubiquitous endocrine disruptor that is present in many household products, has been linked to obesity, cancer, and, most relevant here, childhood neurological disorders such as anxiety and hyperactivity. However, how BPA exposure translates into these neurodevelopmental disorders remains poorly understood. Here, we used zebrafish to link...
Wed, 01/21/2015 - 01:18
Many bacterial pathogens are specialized, infecting one or few hosts, and this is often associated with more acute disease presentation. Specific genomes show markers of this specialization, which often reflect a balance between gene acquisition and functional gene loss. Within Salmonella enterica subspecies enterica, a single lineage exists that includes...
Wed, 01/21/2015 - 01:18
Advances in high-throughput sequencing have made genomic comparison an increasingly powerful tool for understanding pathogen evolution. From these analyses, elevated genome degradation has surfaced as a common trait among pathogens with a specialized lifestyle. Prime examples of this trend can be found within the species Salmonella enterica, wherein genomes of...
Thu, 01/08/2015 - 03:20
Vesicle fusion governs many important biological processes, and imbalances in the regulation of membrane fusion can lead to a variety of diseases such as diabetes and neurological disorders. Here we show that the Vibrio parahaemolyticus effector protein VopQ is a potent inhibitor of membrane fusion based on an in vitro...
Thu, 01/08/2015 - 03:20
The spatial spread of the highly pathogenic avian influenza virus H5N1 and its long-term persistence in Asia have resulted in avian influenza panzootics and enormous economic losses in the poultry sector. However, an understanding of the regional long-distance transmission and seasonal patterns of the virus is still lacking. In this...
Wed, 12/31/2014 - 06:20
The arthropod-borne transmission route of Yersinia pestis, the bacterial agent of plague, is a recent evolutionary adaptation. Yersinia pseudotuberculosis, the closely related food-and water-borne enteric species from which Y. pestis diverged less than 6,400 y ago, exhibits significant oral toxicity to the flea vectors of plague, whereas Y. pestis does...
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...

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