Proceedings of the National Academy of Sciences

Wed, 10/09/2019 - 03:17
Detoxification of the highly toxic cadmium element is essential for the survival of living organisms. Pseudomonas putida CadR, a MerR family transcriptional regulator, has been reported to exhibit an ultraspecific response to the cadmium ion. Our crystallographic and spectroscopic studies reveal that the extra cadmium selectivity of CadR is mediated...
Tue, 09/17/2019 - 12:01
MICROBIOLOGY Correction to Supporting Information for “Analysis of lipoprotein transport depletion in Vibrio cholerae using CRISPRi,” by Florence Caro, Nicole M. Place, and John J. Mekalanos, which was first published August 1, 2019; 10.1073/pnas.1906158116 (Proc. Natl. Acad. Sci. U.S.A. 116, 17013–17022). The authors note that Fig. S14 in the SI...
Tue, 09/17/2019 - 12:01
In bacteria, a primary σ-factor associates with the core RNA polymerase (RNAP) to control most transcription initiation, while alternative σ-factors are used to coordinate expression of additional regulons in response to environmental conditions. Many alternative σ-factors are negatively regulated by anti–σ-factors. In Escherichia coli, Salmonella enterica, and many other γ-proteobacteria,...
Tue, 09/03/2019 - 12:01
The human pathogenic bacterium Clostridium perfringens secretes an enterotoxin (CpE) that targets claudins through its C-terminal receptor-binding domain (cCpE). Isoform-specific binding by CpE causes dissociation of claudins and tight junctions (TJs), resulting in cytotoxicity and breakdown of the gut epithelial barrier. Here, we present crystal structures of human claudin-9 (hCLDN-9)...
Tue, 09/03/2019 - 12:01
Botulinum neurotoxin type B (BoNT/B) recognizes nerve terminals by binding to 2 receptor components: a polysialoganglioside, predominantly GT1b, and synaptotagmin 1/2. It is widely thought that BoNT/B initially binds to GT1b then diffuses in the plane of the membrane to interact with synaptotagmin. We have addressed the hypothesis that a...
Tue, 08/13/2019 - 13:11
Spin-orbit coupling (SOC), the interaction between the electron spin and the orbital angular momentum, can unlock rich phenomena at interfaces, in particular interconverting spin and charge currents. Conventional heavy metals have been extensively explored due to their strong SOC of conduction electrons. However, spin-orbit effects in classes of materials such...
Tue, 07/02/2019 - 12:16
Intracellular trafficking pathways in eukaryotic cells are essential to maintain organelle identity and structure, and to regulate cell communication with its environment. Shigella flexneri invades and subverts the human colonic epithelium by the injection of virulence factors through a type 3 secretion system (T3SS). In this work, we report the...
Tue, 06/25/2019 - 13:52
Noroviruses are a leading cause of foodborne illnesses worldwide. Although GII.4 strains have been responsible for most norovirus outbreaks, the assembled virus shell structures have been available in detail for only a single strain (GI.1). We present high-resolution (2.6- to 4.1-Å) cryoelectron microscopy (cryo-EM) structures of GII.4, GII.2, GI.7, and...
Tue, 06/18/2019 - 12:48
The adaptive in vivo mechanisms underlying the switch in Salmonella enterica lifestyles from the infectious form to a dormant form remain unknown. We employed Caenorhabditis elegans as a heterologous host to understand the temporal dynamics of Salmonella pathogenesis and to identify its lifestyle form in vivo. We discovered that Salmonella...
Tue, 04/23/2019 - 12:13
Ascofuranone (AF) and ascochlorin (AC) are meroterpenoids produced by various filamentous fungi, including Acremonium egyptiacum (synonym: Acremonium sclerotigenum), and exhibit diverse physiological activities. In particular, AF is a promising drug candidate against African trypanosomiasis and a potential anticancer lead compound. These compounds are supposedly biosynthesized through...
Tue, 03/26/2019 - 12:02
Salmonella Typhimurium can invade and survive within macrophages where the bacterium encounters a range of host environmental conditions. Like many bacteria, S. Typhimurium rapidly responds to changing environments by the use of second messengers such as cyclic di-GMP (c-di-GMP). Here, we generate a fluorescent biosensor to measure c-di-GMP concentrations in...
Tue, 03/26/2019 - 12:02
The Bay of Bengal is known as the epicenter for seeding several devastating cholera outbreaks across the globe. Vibrio cholerae, the etiological agent of cholera, has extraordinary competency to acquire exogenous DNA by horizontal gene transfer (HGT) and adapt them into its genome for structuring metabolic processes, developing drug resistance,...
Tue, 03/05/2019 - 12:02
MICROBIOLOGY Correction for “Sequential evolution of virulence and resistance during clonal spread of community-acquired methicillin-resistant Staphylococcus aureus,” by Richard Copin, William E. Sause, Yi Fulmer, Divya Balasubramanian, Sophie Dyzenhaus, Jamil M. Ahmed, Krishan Kumar, John Lees, Anna Stachel, Jason C. Fisher, Karl Drlica, Michael Phillips, Jeffrey N. Weiser, Paul J....
Tue, 03/05/2019 - 12:02
The Feo ferrous iron transporter is widely distributed among bacteria and archaea, but its mechanism of transport has not been fully elucidated. In Vibrio cholerae, the transport system requires three proteins: the small cytosolic proteins FeoA and FeoC and a large cytoplasmic-membrane–associated protein FeoB, which has an N-terminal G-protein domain....
Tue, 01/29/2019 - 14:06
Vibrio cholerae, the causative agent of cholera, has reservoirs in fresh and brackish water where it interacts with virulent bacteriophages. Phages are the most abundant biological entity on earth and coevolve with bacteria. It was reported that concentrations of phage and V. cholerae inversely correlate in aquatic reservoirs and in...
Tue, 01/22/2019 - 13:11
The factors and mechanisms that govern tRNA stability in bacteria are not well understood. Here, we investigated the influence of posttranscriptional modification of bacterial tRNAs (tRNA modification) on tRNA stability. We focused on ThiI-generated 4-thiouridine (s4U), a modification found in bacterial and archaeal tRNAs. Comprehensive quantification of Vibrio cholerae tRNAs...
Wed, 12/26/2018 - 14:31
To overcome the action of antibiotics, bacteria have evolved a variety of different strategies, such as drug modification, target mutation, and efflux pumps. Recently, we performed a genome-wide analysis of Listeria monocytogenes gene expression after growth in the presence of antibiotics, identifying genes that are up-regulated upon antibiotic treatment. One...
Tue, 11/13/2018 - 15:16
Cell death and inflammation are intimately linked during Yersinia infection. Pathogenic Yersinia inhibits the MAP kinase TGFβ-activated kinase 1 (TAK1) via the effector YopJ, thereby silencing cytokine expression while activating caspase-8–mediated cell death. Here, using Yersinia pseudotuberculosis in corroboration with costimulation of lipopolysaccharide and (5Z)-7-Oxozeaenol, a small-molecule...
Tue, 11/06/2018 - 13:41
The gut metabolic landscape is complex and is influenced by the microbiota, host physiology, and enteric pathogens. Pathogens have to exquisitely monitor the biogeography of the gastrointestinal tract to find a suitable niche for colonization. To dissect the important metabolic pathways that influence virulence of enterohemorrhagic Escherichia coli (EHEC), we...
Tue, 10/02/2018 - 12:06
Intestinal epithelial cells (IECs) play a key role in regulating immune responses and controlling infection. However, the direct role of IECs in restricting pathogens remains incompletely understood. Here, we provide evidence that IL-22 primed intestinal organoids derived from healthy human induced pluripotent stem cells (hIPSCs) to restrict Salmonella enterica serovar...
Tue, 09/18/2018 - 12:52
Enterotoxigenic Escherichia coli (ETEC) is a global diarrheal pathogen that utilizes adhesins and secreted enterotoxins to cause disease in mammalian hosts. Decades of research on virulence factor regulation in ETEC has revealed a variety of environmental factors that influence gene expression, including bile, pH, bicarbonate, osmolarity, and glucose. However, other...
Tue, 09/18/2018 - 12:52
Diarrheal diseases are still one of the biggest global health burdens. According to the World Health Organization (WHO), diarrhea ranks as the ninth cause of death worldwide, being the fourth among children. One of the most prevalent diarrheagenic pathogens is enterotoxigenic Escherichia coli (ETEC) (1). ETEC’s classic virulence mechanisms include...
Tue, 08/07/2018 - 14:31
Agents that remodel the tumor microenvironment (TME), prime functional tumor-specific T cells, and block inhibitory signaling pathways are essential components of effective immunotherapy. We are evaluating live-attenuated, double-deleted Listeria monocytogenes expressing tumor antigens (LADD-Ag) in the clinic. Here we show in numerous mouse models that while treatment with nonrecombinant LADD...
Tue, 07/31/2018 - 12:01
The type 6 secretion system (T6SS) is a nanomachine used by many Gram-negative bacteria, including Vibrio cholerae, to deliver toxic effector proteins into adjacent eukaryotic and bacterial cells. Because the activity of the T6SS is dependent on direct contact between cells, its activity is limited to bacteria growing on solid...
Tue, 07/24/2018 - 13:56
The huntingtin N17 domain is a modulator of mutant huntingtin toxicity and is hypophosphorylated in Huntington’s disease (HD). We conducted high-content analysis to find compounds that could restore N17 phosphorylation. One lead compound from this screen was N6-furfuryladenine (N6FFA). N6FFA was protective in HD model neurons, and N6FFA treatment of...
Tue, 07/10/2018 - 12:36
Initial attachment and subsequent colonization of the intestinal epithelium comprise critical events allowing enteric pathogens to survive and express their pathogenesis. In enterotoxigenic Escherichia coli (ETEC), these are mediated by a long proteinaceous fiber termed type IVb pilus (T4bP). We have reported that the colonization factor antigen/III (CFA/III), an operon-encoded...
Tue, 07/03/2018 - 16:26
While the structure and regulatory networks that govern type-six secretion system (T6SS) activity of Vibrio cholerae are becoming increasingly clear, we know less about the role of T6SS in disease. Under laboratory conditions, V. cholerae uses T6SS to outcompete many Gram-negative species, including other V. cholerae strains and human commensal...
Tue, 06/26/2018 - 12:16
Novel reassortant avian influenza H7N9 virus and pandemic 2009 H1N1 (H1N1pdm) virus cause human infections, while avian H7N2 and swine H1N1 virus mainly infect birds and pigs, respectively. There is no robust in vitro model for assessing the infectivity of emerging viruses in humans. Based on a recently established method,...
Tue, 06/26/2018 - 12:16
Sensing and responding to environmental changes is essential for bacteria to adapt and thrive, and nucleotide-derived second messengers are central signaling systems in this process. The most recently identified bacterial cyclic dinucleotide second messenger, 3′, 3′-cyclic GMP-AMP (cGAMP), was first discovered in the El Tor biotype of Vibrio cholerae. The...
Tue, 05/22/2018 - 12:06
AGRICULTURAL SCIENCES Correction for “Ion-beam irradiation, gene identification, and marker-assisted breeding in the development of low-cadmium rice,” by Satoru Ishikawa, Yasuhiro Ishimaru, Masato Igura, Masato Kuramata, Tadashi Abe, Takeshi Senoura, Yoshihiro Hase, Tomohito Arao, Naoko K. Nishizawa, and Hiromi Nakanishi, which was first published November 6, 2012; 10.1073/pnas.1211132109 (Proc...
Tue, 05/22/2018 - 12:06
Capsules are surface layers of hydrated capsular polysaccharides (CPSs) produced by many bacteria. The human pathogen Salmonella enterica serovar Typhi produces “Vi antigen” CPS, which contributes to virulence. In a conserved strategy used by bacteria with diverse CPS structures, translocation of Vi antigen to the cell surface is driven by...
Tue, 04/17/2018 - 14:36
Host-associated microbiota help defend against bacterial pathogens; however, the mechanisms by which pathogens overcome this defense remain largely unknown. We developed a zebrafish model and used live imaging to directly study how the human pathogen Vibrio cholerae invades the intestine. The gut microbiota of fish monocolonized by symbiotic strain Aeromonas...
Tue, 04/17/2018 - 14:36
Our studies of the SNP rs8060947 determine that the A allele is associated with increased invasion of Salmonella enterica serovar Typhi and increased susceptibility to typhoid fever (1). Gilchrist et al. (2) now provide evidence that the A allele is also associated with increased risk for bacteremia, and the association...
Tue, 04/17/2018 - 14:36
Performing a genome-wide association study of Salmonella enterica serovar Typhi (S. Typhi) invasion, Alvarez et al. (1) identify a trait-associated SNP, rs8060947, in VAC14. rs8060947 is an expression quantitative trait locus for VAC14 RNA expression, and carriage of the A allele is associated with reduced VAC14 RNA and protein expression,...
Tue, 03/13/2018 - 13:26
Salmonella enterica serovar Typhimurium ST313 is a relatively newly emerged sequence type that is causing a devastating epidemic of bloodstream infections across sub-Saharan Africa. Analysis of hundreds of Salmonella genomes has revealed that ST313 is closely related to the ST19 group of S. Typhimurium that cause gastroenteritis across the world....
Tue, 03/06/2018 - 12:21
The facultative human pathogen Vibrio cholerae changes its transcriptional profile upon oral ingestion by the host to facilitate survival and colonization fitness. Here, we used a modified version of recombination-based in vivo expression technology to investigate gene silencing during the in vivo passage, which has been understudied. Using a murine...
Tue, 12/19/2017 - 13:41
In a pet food factory in Reno, NV, researchers from IBM Research and Mars, Inc. are conducting an experiment that may someday revolutionize food safety. For more than two years, they’ve taken regular samples of poultry meal—a protein-rich mash of chicken parts—as it enters the factory on its way to...
Tue, 11/28/2017 - 13:26
Bacterial cells modulate transcription in response to changes in iron availability. The ferric uptake regulator (Fur) senses intracellular iron availability and plays a central role in maintaining iron homeostasis in Bacillus subtilis. Here we utilized FrvA, a high-affinity Fe2+ efflux transporter from Listeria monocytogenes, as an inducible genetic tool to...
Tue, 09/19/2017 - 12:06
Campylobacter jejuni, a leading cause of bacterial gastroenteritis, is naturally competent. Like many competent organisms, C. jejuni restricts the DNA that can be used for transformation to minimize undesirable changes in the chromosome. Although C. jejuni can be transformed by C. jejuni-derived DNA, it is poorly transformed by the same...
Tue, 09/19/2017 - 12:06
Heavy metals from urban runoff preserved in sedimentary deposits record long-term economic and industrial development via the expansion and contraction of a city’s infrastructure. Lead concentrations and isotopic compositions measured in the sediments of the harbor of Ostia—Rome’s first harbor—show that lead pipes used in the water supply networks of...
Tue, 09/12/2017 - 16:40
The enteroinvasive bacterium Shigella is a facultative intracellular bacterium known, in vitro, to invade a large diversity of cells through the delivery of virulence effectors into the cell cytoplasm via a type III secretion system (T3SS). Here, we provide evidence that the injection of T3SS effectors does not necessarily result...
Tue, 09/05/2017 - 12:50
Picornaviruses use internal ribosome entry sites (IRESs) to translate their genomes into protein. A typical feature of these IRESs is their ability to bind directly to the eukaryotic initiation factor (eIF) 4G component of the eIF4F cap-binding complex. Remarkably, the hepatitis A virus (HAV) IRES requires eIF4E for its translation,...
Tue, 08/29/2017 - 12:15
Cyclic di-3′,5′-adenosine monophosphate (c-di-AMP) is a broadly conserved bacterial second messenger that has been implicated in a wide range of cellular processes. Our earlier studies showed that c-di-AMP regulates central metabolism in Listeria monocytogenes by inhibiting its pyruvate carboxylase (LmPC), a biotin-dependent enzyme with biotin carboxylase (BC) and carboxyltransferase (CT)...
Tue, 07/11/2017 - 12:59
Trained in both human medical and veterinary sciences, Xiang-Jin Meng has made numerous contributions to the field of comparative viral pathogenesis. His achievements concerning emerging, reemerging, and zoonotic viral diseases include the discovery of swine and avian hepatitis E viruses (HEV) and the invention of a commercial vaccine against porcine...
Tue, 06/27/2017 - 14:09
Botulism is characterized by flaccid paralysis, which can be caused by intoxication with any of the seven known serotypes of botulinum neurotoxin (BoNT), all of which disrupt synaptic transmission by endoproteolytic cleavage of SNARE proteins. BoNT serotype A (BoNT/A) has the most prolonged or persistent effects, which can last several...
Tue, 06/20/2017 - 12:04
The Picornaviridae are a diverse family of RNA viruses including many pathogens of medical and veterinary importance. Classically considered “nonenveloped,” recent studies show that some picornaviruses, notably hepatitis A virus (HAV; genus Hepatovirus) and some members of the Enterovirus genus, are released from cells nonlytically in membranous vesicles. To better...
Tue, 06/13/2017 - 12:29
Listeria monocytogenes is a common food-borne pathogen that can disseminate from the intestine and infect multiple organs. Here, we used sequence tag-based analysis of microbial populations (STAMP) to investigate L. monocytogenes population dynamics during infection. We created a genetically barcoded library of murinized L. monocytogenes and then used deep sequencing...
Tue, 05/30/2017 - 12:39
XIAP-associated factor 1 (XAF1) is a tumor suppressor that is commonly inactivated in multiple human neoplasms. However, the molecular mechanism underlying its proapoptotic function remains largely undefined. Here, we report that XAF1 induction by heavy metals triggers an apoptotic switch of stress response by destabilizing metallothionein 2A (MT2A). XAF1 directly...
Tue, 04/18/2017 - 12:47
Global distribution of hepatocellular carcinomas (HCCs) is dominated by its incidence in developing countries, accounting for >700,000 estimated deaths per year, with dietary exposures to aflatoxin (AFB1) and subsequent DNA adduct formation being a significant driver. Genetic variants that increase individual susceptibility to AFB1-induced HCCs are poorly understood. Herein, it...
Tue, 04/11/2017 - 13:39
Aflatoxin B1 (AFB1) and/or hepatitis B and C viruses are risk factors for human hepatocellular carcinoma (HCC). Available evidence supports the interpretation that formation of AFB1-DNA adducts in hepatocytes seeds a population of mutations, mainly G:C→T:A, and viral processes synergize to accelerate tumorigenesis, perhaps via inflammation. Responding to a need...

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