bluuebunny/crossref_metadata_2025_split huggingface dataset:
Repression of Salmonella Host Cell Invasion by Aromatic Small Molecules from the Human Fecal Metabolome
Authors: Peixoto Rafael J. M. , Alves Eduardo S. , Wang Melody , Ferreira Rosana B. R. , Granato Alessandra , Han Jun , Gill Hira , Jacobson Kevan , Lobo Leandro A. , Domingues Regina M. C. P. , Borchers Christoph H. , Davies Julian E. , Finlay B. Brett , Antunes L. Caetano M. 
Published: July 2017

ABSTRACT

The human microbiome is a collection of microorganisms that inhabit every surface of the body that is exposed to the environment, generally coexisting peacefully with their host. These microbes have important functions, such as producing vitamins, aiding in maturation of the immune system, and protecting against pathogens. We have previously shown that a small-molecule extract from the human fecal microbiome has a strong repressive effect on
Salmonella enterica
serovar Typhimurium host cell invasion by modulating the expression of genes involved in this process. Here, we describe the characterization of this biological activity. Using a series of purification methods, we obtained fractions with biological activity and characterized them by mass spectrometry. These experiments revealed an abundance of aromatic compounds in the bioactive fraction. Selected compounds were obtained from commercial sources and tested with respect to their ability to repress the expression of
hilA
, the gene encoding the master regulator of invasion genes in
Salmonella
. We found that the aromatic compound 3,4-dimethylbenzoic acid acts as a strong inhibitor of
hilA
expression and of invasion of cultured host cells by
Salmonella
. Future studies should reveal the molecular details of this phenomenon, such as the signaling cascades involved in sensing this bioactive molecule.

IMPORTANCE
Microbes constantly sense and adapt to their environment. Often, this is achieved through the production and sensing of small extracellular molecules. The human body is colonized by complex communities of microbes, and, given their biological and chemical diversity, these ecosystems represent a platform where the production and sensing of molecules occur. In previous work, we showed that small molecules produced by microbes from the human gut can significantly impair the virulence of the enteric pathogen
Salmonella enterica
. Here, we describe a specific compound from the human gut that produces this same effect. The results from this work not only shed light on an important biological phenomenon occurring in our bodies but also may represent an opportunity to develop drugs that can target these small-molecule interactions to protect us from enteric infections and other diseases.
Coronafacoyl Phytotoxin Biosynthesis and Evolution in the Common Scab Pathogen Streptomyces scabiei
Authors: Bown Luke , Li Yuting , Berrué Fabrice , Verhoeven Joost T. P. , Dufour Suzanne C. , Bignell Dawn R. D. 
Published: July 2017

ABSTRACT

Coronafacoyl phytotoxins are an important family of plant toxins that are produced by several different phytopathogenic bacteria, including the gammaproteobacterium
Pseudomonas syringae
and the actinobacterium
Streptomyces scabiei
(formerly
Streptomyces scabies
). The phytotoxins consist of coronafacic acid (CFA) linked via an amide bond to different amino acids or amino acid derivatives. Previous work suggested that
S. scabiei
and
P. syringae
use distinct biosynthetic pathways for producing CFA, which is subsequently linked to its amino acid partner to form the complete phytotoxin. Here, we provide further evidence that the
S. scabiei
CFA biosynthetic pathway is novel by characterizing the role of CYP107AK1, a predicted cytochrome P450 that has no homologue in
P. syringae
. Deletion of the
CYP107AK1
gene abolished production of coronafacoyl-isoleucine (CFA-Ile), the primary coronafacoyl phytotoxin produced by
S. scabiei
. Structural elucidation of accumulated biosynthetic intermediates in the Δ
CYP107AK1
mutant indicated that CYP107AK1 is required for introducing the oxygen atom that ultimately forms the carbonyl group in the CFA backbone. The
CYP107AK1
gene along with two additional genes involved in CFA-Ile biosynthesis in
S. scabiei
were found to be associated with putative CFA biosynthetic genes in other actinobacteria but not in other organisms. Analysis of the overall genetic content and organization of known and putative CFA biosynthetic gene clusters, together with phylogenetic analysis of the core biosynthetic genes, indicates that horizontal gene transfer has played an important role in the dissemination of the gene cluster and that rearrangement, insertion, and/or deletion events have likely contributed to the divergent biosynthetic evolution of coronafacoyl phytotoxins in bacteria.

IMPORTANCE
The ability of plants to defend themselves against invading pathogens relies on complex signaling pathways that are controlled by key phytohormones such as jasmonic acid (JA). Some phytopathogenic bacteria have evolved the ability to manipulate JA signaling in order to overcome host defenses by producing coronatine (COR), which functions as a potent JA mimic. COR and COR-like molecules, collectively referred to as coronafacoyl phytotoxins, are produced by several different plant-pathogenic bacteria, and this study provides supporting evidence that different biosynthetic pathways are utilized by different bacteria for production of these phytotoxins. In addition, our study provides a greater understanding of how coronafacoyl phytotoxin biosynthesis may have evolved in phylogenetically distinct bacteria, and we demonstrate that production of these compounds may be more widespread than previously recognized and that their role for the producing organism may not be limited to host-pathogen interactions.
Critical Knowledge Gaps in Our Understanding of Environmental Cycling and Transmission of Leptospira spp
Authors: Barragan Veronica , Olivas Sonora , Keim Paul , Pearson Talima 
Published: July 2017

ABSTRACT

Exposure to soil or water contaminated with the urine of
Leptospira
-infected animals is the most common way in which humans contract leptospirosis. Entire populations can be at high risk of leptospirosis while working in inundated fields, when engaging in aquatic sports, or after periods of heavy rainfall. The risk of infection after contact with these environmental sources depends on the ability of
Leptospira
bacteria to survive, persist, and infect new hosts. Multiple variables such as soil and water pH, temperature, and even environmental microbial communities are likely to shape the environmental conditions needed by the pathogen to persist. Here we review what is known about the environmental phase of the infectious
Leptospira
transmission cycle and identify knowledge gaps that will serve as a guide for future research.
The Sortase-Dependent Fimbriome of the Genus Bifidobacterium: Extracellular Structures with Potential To Modulate Microbe-Host Dialogue
Authors: Milani Christian , Mangifesta Marta , Mancabelli Leonardo , Lugli Gabriele Andrea , Mancino Walter , Viappiani Alice , Faccini Andrea , van Sinderen Douwe , Ventura Marco , Turroni Francesca 
Published: July 2017

ABSTRACT

Bifidobacteria are important gut commensals of mammals, including humans, of any age. However, the molecular mechanisms by which these microorganisms establish themselves in the mammalian gut and persist in this environment are largely unknown. Here, we analyzed the genetic diversity of the predicted arsenal of sortase-dependent pili of known and sequenced members of the
Bifidobacterium
genus and constructed a bifidobacterial sortase-dependent fimbriome database. Our analyses revealed considerable genetic variability of the sortase-dependent fimbriome among bifidobacterial (sub)species, which appears to have been due to horizontal gene transfer events and for which we were able to perform evolutionary mapping. Functional assessment by transcriptome analysis and binding assays involving different substrates demonstrates how bifidobacterial pili are pivotal in promoting various abilities for adhesion to glycans and extracellular matrix proteins, thereby supporting the ecological success of bifidobacteria in the mammalian gut.

IMPORTANCE
Adhesion of bifidobacterial cells to the mucosa of the large intestine is considered a hallmark for the persistence and colonization of these bacteria in the human gut. In this context, we analyzed the genetic diversity of the predicted arsenal of sortase-dependent pili of known and sequenced members of the
Bifidobacterium
genus, and constructed a bifidobacterial sortase-dependent fimbriome database. Our analyses revealed considerable genetic variability of the sortase-dependent fimbriome among bifidobacterial (sub)species, which appears to have been due to horizontal gene transfer events. In addition, functional assessment by transcriptome analysis and binding assays involving different substrates demonstrates how bifidobacterial pili are crucial in promoting various abilities for adhesion to glycans and extracellular matrix proteins, thereby supporting the ecological success of bifidobacteria in the mammalian gut. This study represents a complete genomic study regarding the presence of fimbriae in the genus
Bifidobacterium
.
In VivoRoles of Fatty Acid Biosynthesis Enzymes in Biosynthesis of Biotin and α-Lipoic Acid in Corynebacterium glutamicum
Authors: Ikeda Masato , Nagashima Takashi , Nakamura Eri , Kato Ryosuke , Ohshita Masakazu , Hayashi Mikiro , Takeno Seiki 
Published: July 2017

ABSTRACTFor fatty acid biosynthesis,Corynebacterium glutamicumuses two type I fatty acid synthases (FAS-I), FasA and FasB, in addition to acetyl-coenzyme A (CoA) carboxylase (ACC) consisting of AccBC, AccD1, and AccE. Thein vivoroles of the enzymes in supplying precursors for biotin and α-lipoic acid remain unclear. Here, we report genetic evidence demonstrating that the biosynthesis of these cofactors is linked to fatty acid biosynthesis through the FAS-I pathway. For this study, we used wild-typeC. glutamicumand its derived biotin vitamer producer BFI-5, which was engineered to expressEscherichia coli bioBFandBacillus subtilis bioI. Disruption of eitherfasAorfasBin strain BFI-5 led to decreased production of biotin vitamers, whereas its amplification contributed to increased production, with a larger impact offasAin both cases. Double disruptions offasAandfasBresulted in no biotin vitamer production. Theaccgenes showed a positive effect on production when amplified simultaneously. Augmented fatty acid biosynthesis was also reflected in pimelic acid production when carbon flow was blocked at the BioF reaction. These results indicate that carbon flow down the FAS-I pathway is destined for channeling into the biotin biosynthesis pathway, and that FasA in particular has a significant impact on precursor supply. In contrast,fasBdisruption resulted in auxotrophy for lipoic acid or its precursor octanoic acid in both wild-type and BFI-5 strains. The phenotypes were fully complemented by plasmid-mediated expression offasBbut notfasA. These results reveal that FasB plays a specific physiological role in lipoic acid biosynthesis inC. glutamicum.IMPORTANCEFor thede novobiosynthesis of fatty acids,C. glutamicumexceptionally uses a eukaryotic multifunctional type I fatty acid synthase (FAS-I) system comprising FasA and FasB, in contrast to most bacteria, such asE. coliandB. subtilis, which use an individual nonaggregating type II fatty acid synthase (FAS-II) system. In this study, we reported genetic evidence demonstrating that the FAS-I system is the source of the biotin precursorin vivoin the engineered biotin-prototrophicC. glutamicumstrain. This study also uncovered the important physiological role of FasB in lipoic acid biosynthesis. Here, we present an FAS-I enzyme that functions in supplying the lipoic acid precursor, although its biosynthesis has been believed to exclusively depend on FAS-II in organisms. The findings obtained here provide new insights into the metabolic engineering of this industrially important microorganism to produce these compounds effectively.
Glucosylglycerate Phosphorylase, an Enzyme with Novel Specificity Involved in Compatible Solute Metabolism
Authors: Franceus Jorick , Pinel Denise , Desmet Tom 
Published: July 2017

ABSTRACT

Family GH13_18 of the carbohydrate-active enzyme database consists of retaining glycoside phosphorylases that have attracted interest with their potential for synthesizing valuable α-sugars and glucosides. Sucrose phosphorylase was believed to be the only enzyme with specificity in this subfamily for many years, but recent work revealed an enzyme with a different function and hinted at an even broader diversity that is left to discover. In this study, a putative sucrose phosphorylase from
Meiothermus silvanus
that resides in a previously unexplored branch of the family's phylogenetic tree was expressed and characterized. Unexpectedly, no activity on sucrose was observed. Guided by a thorough inspection of the genomic landscape surrounding other genes in the branch, the enzyme was found to be a glucosylglycerate phosphorylase, with a specificity never before reported. Homology modeling, docking, and mutagenesis pinpointed particular acceptor site residues (Asn275 and Glu383) involved in the binding of glycerate. Various organisms known to synthesize and accumulate glucosylglycerate as a compatible solute possess a putative glucosylglycerate phosphorylase gene, indicating that the phosphorylase may be a regulator of its intracellular levels. Moreover, homologs of this novel enzyme appear to be distributed among diverse bacterial phyla, a finding which suggests that many more organisms may be capable of assimilating or synthesizing glucosylglycerate than previously assumed.

IMPORTANCE
Glycoside phosphorylases are an intriguing group of carbohydrate-active enzymes that have been used for the synthesis of various economically appealing glycosides and sugars, and they are frequently subjected to enzyme engineering to further expand their application potential. The novel specificity discovered in this work broadens the diversity of these phosphorylases and opens up new possibilities for the efficient production of glucosylglycerate, which is a remarkably potent and versatile stabilizer for protein formulations. Finally, it is a new piece of the puzzle of glucosylglycerate metabolism, being the only known enzyme capable of catalyzing the breakdown of glucosylglycerate in numerous bacterial phyla.
Acquired haemophilia A with a recalcitrant high-titre factor VIII inhibitor in the setting of interstitial lung disease
Authors: Sun Lova , Sykes David B 
Published: July 2017

Acquired haemophilia A (AHA) is a bleeding disorder that results from autoantibodies against factor VIII (FVIII). A 70-year-old man with a history of interstitial lung disease presented with spontaneous bleeding into his thigh. He had undetectable FVIII levels and a high-titre FVIII inhibitor (>2000Ã¢â‚¬â€°Bethesda units/mL) and was diagnosed with AHA. He had several relapses, required multiple haemostatic and immunosuppressive treatments but eventually achieved a stable remission after 2Ã¢â‚¬â€°years of therapy.Our patient matches the typical elderly male demographic of AHA. His relapsing course with remarkably high and persistent inhibitor titre highlights the need for close monitoring and aggressive upfront treatment. Whereas cyclophosphamide and steroids are often used first line in AHA, rituximab has also shown efficacy in refractory patients with high inhibitor levels. The FVIII and inhibitor concentration on presentation have been associated with treatment response and may be used as prognostic factors to tailor immunosuppressive regimens.
Derivation and validation of a universal vital assessment (UVA) score: a tool for predicting mortality in adult hospitalised patients in sub-Saharan Africa
Authors: Moore Christopher C , Hazard Riley , Saulters Kacie J , Ainsworth John , Adakun Susan A , Amir Abdallah , Andrews Ben , Auma Mary , Baker Tim , Banura Patrick , Crump John A , Grobusch Martin P , Huson Michaëla A M , Jacob Shevin T , Jarrett Olamide D , Kellett John , Lakhi Shabir , Majwala Albert , Opio Martin , Rubach Matthew P , Rylance Jamie , Michael Scheld W , Schieffelin John , Ssekitoleko Richard , Wheeler India , Barnes Laura E 
Published: July 2017

BackgroundCritical illness is a leading cause of morbidity and mortality in sub-Saharan Africa (SSA). Identifying patients with the highest risk of death could help with resource allocation and clinical decision making. Accordingly, we derived and validated a universal vital assessment (UVA) score for use in SSA.MethodsWe pooled data from hospital-based cohort studies conducted in six countries in SSA spanning the years 2009–2015. We derived and internally validated a UVA score using decision trees and linear regression and compared its performance with the modified early warning score (MEWS) and the quick sepsis-related organ failure assessment (qSOFA) score.ResultsOf 5573 patients included in the analysis, 2829 (50.8%) were female, the median (IQR) age was 36 (27–49) years, 2122 (38.1%) were HIV-infected and 996 (17.3%) died in-hospital. The UVA score included points for temperature, heart and respiratory rates, systolic blood pressure, oxygen saturation, Glasgow Coma Scale score and HIV serostatus, and had an area under the receiver operating characteristic curve (AUC) of 0.77 (95% CI 0.75 to 0.79), which outperformed MEWS (AUC 0.70 (95% CI 0.67 to 0.71)) and qSOFA (AUC 0.69 (95% CI 0.67 to 0.72)).ConclusionWe identified predictors of in-hospital mortality irrespective of the underlying condition(s) in a large population of hospitalised patients in SSA and derived and internally validated a UVA score to assist clinicians in risk-stratifying patients for in-hospital mortality. The UVA score could help improve patient triage in resource-limited environments and serve as a standard for mortality risk in future studies.
The use of patient feedback by hospital boards of directors: a qualitative study of two NHS hospitals in England
Authors: Lee Robert , Baeza Juan I , Fulop Naomi J 
Published: July 2017

BackgroundAlthough previous research suggests that different kinds of patient feedback are used in different ways to help improve the quality of hospital care, there have been no studies of the ways in which hospital boards of directors use feedback for this purpose.ObjectivesTo examine whether and how boards of directors of hospitals use feedback from patients to formulate strategy and to assure and improve the quality of care.MethodsWe undertook an in-depth qualitative study in two acute hospital National Health Service foundation trusts in England, purposively selected as contrasting examples of the collection of different kinds of patient feedback. We collected and analysed data from interviews with directors and other managers, from observation of board meetings, and from board papers and other documents.ResultsThe two boards used in-depth qualitative feedback and quantitative feedback from surveys in different ways to help develop strategies, set targets for quality improvement and design specific quality improvement initiatives; but both boards made less subsequent use of any kinds of feedback to monitor their strategies or explicitly to assure the quality of services.Discussion and conclusionsWe have identified limitations in the uses of patient feedback by hospital boards that suggest that boards should review their current practice to ensure that they use the different kinds of patient feedback that are available to them more effectively to improve, monitor and assure the quality of care.
Outpatient CPOE orders discontinued due to ‘erroneous entry’: prospective survey of prescribers’ explanations for errors
Authors: Hickman Thu-Trang T , Quist Arbor Jessica Lauren , Salazar Alejandra , Amato Mary G , Wright Adam , Volk Lynn A , Bates David W , Schiff Gordon 
Published: July 2017

BackgroundComputerised prescriber order entry (CPOE) systems users often discontinue medications because the initial order was erroneous.ObjectiveTo elucidate error types by querying prescribers about their reasons for discontinuing outpatient medication orders that they had self-identified as erroneous.MethodsDuring a nearly 3 year retrospective data collection period, we identified 57 972 drugs discontinued with the reason ‘Error (erroneous entry).” Because chart reviews revealed limited information about these errors, we prospectively studied consecutive, discontinued erroneous orders by querying prescribers in near-real-time to learn more about the erroneous orders.ResultsFrom January 2014 to April 2014, we prospectively emailed prescribers about outpatient drug orders that they had discontinued due to erroneous initial order entry. Of 2 50 806 medication orders in these 4 months, 1133 (0.45%) of these were discontinued due to error. From these 1133, we emailed 542 unique prescribers to ask about their reason(s) for discontinuing these mediation orders in error. We received 312 responses (58% response rate). We categorised these responses using a previously published taxonomy. The top reasons for these discontinued erroneous orders included: medication ordered for wrong patient (27.8%, n=60); wrong drug ordered (18.5%, n=40); and duplicate order placed (14.4%, n=31). Other common discontinued erroneous orders related to drug dosage and formulation (eg, extended release versus not). Oxycodone (3%) was the most frequent drug discontinued error.ConclusionDrugs are not infrequently discontinued ‘in error.’ Wrong patient and wrong drug errors constitute the leading types of erroneous prescriptions recognised and discontinued by prescribers. Data regarding erroneous medication entries represent an important source of intelligence about how CPOE systems are functioning and malfunctioning, providing important insights regarding areas for designing CPOE more safely in the future.
Enhancing problem list documentation in electronic health records using two methods: the example of prior splenectomy
Authors: McEvoy Dustin , Gandhi Tejal K , Turchin Alexander , Wright Adam 
Published: July 2017

BackgroundQuality improvement professionals often choose between patient-specific interventions, like clinical decision support (CDS), and population-based interventions, like registries or care management. In this paper, we explore the synergy of these two strategies, targeting the problem of procedure documentation for patients with a history of splenectomy.MethodsWe developed a population health documentation (PHD) intervention and a CDS intervention to improve splenectomy documentation within our electronic health record. Rates of splenectomy documentation were collected before and after the implementation of both interventions to assess their impact on the rate of procedure documentation.ResultsBoth the PHD and CDS interventions led to statistically significant (p<0.001) increases in the baseline rate of splenectomy documentation of 27.4 documentations per month. During the PHD intervention, 444.7 splenectomies were documented per month, while 40.8 splenectomies per month were documented during the CDS intervention.DiscussionBoth approaches were successful, with the PHD intervention leading to a larger number of incremental procedure documentations, in batches, and the CDS intervention augmenting procedure documentation on an ongoing basis. Our results suggest that population health and CDS strategies complement each other and, where possible, should be used in conjunction.ConclusionsPHD and CDS strategies may best be used in conjunction to create a symbiotic relationship in which current problem and procedure documentation gaps are closed using PHD strategies, while new gaps are prevented through ongoing CDS interventions