bluuebunny/crossref_metadata_2025_split huggingface dataset:
Myocardial extracellular volume quantified by magnetic resonance is increased in cirrhosis and related to poor outcome
Authors: Wiese Signe , Hove Jens , Mo Silje , Mookerjee Rajeshwar P. , Petersen Claus L. , Vester‐Andersen Marianne K. , Mygind Naja D. , Goetze Jens P. , Kjær Andreas , Bendtsen Flemming , Møller Søren 
Published: May 2018

AbstractBackground & AimsThe underlying pathogenesis of cirrhotic cardiomyopathy remains unclear. Structural myocardial changes including diffuse fibrosis may be involved and can be accurately assessed by cardiac MRI (CMR) with quantification of the extracellular volume (ECV).This is the first application of this technique in patients with cirrhosis. We aimed to investigate the presence of diffuse myocardial fibrosis and to determine the relation to disease severity, cardiac function and outcome.MethodsA prospective study including 52 cirrhotic patients and 10 healthy controls. All patients underwent CMR with ECV quantification, tissue Doppler echocardiography, and biochemical assessments. Patients were followed up for a median of 25 months with registration of death and liver transplantation (LT).ResultsMyocardial ECV was higher in the patients compared with healthy controls (31.2 ± 6 vs 27.4 ± 3%, P = .04). Furthermore, ECV increased across the Child Pugh A/B/C classes (26.9 ± 4/31.5 ± 5/34.4 ± 6%, P = .02). Four‐teen patients experienced the composite end‐point of death/LT during follow‐up and these patients had higher ECV (33.2 ± 4 vs 30.4 ± 6%, P = .04). In a univariate Cox regression analysis ECV was associated with poor transplant‐free survival (HR 3.6 [1.1‐11.6]; P = .03). However, MELD and CRP remained the strongest predictors in a multivariate analysis. ECV correlated with cardiac index (r = 0.44, P = .001), CRP (r = 0.46, P = .001), proANP (r = 0.50, P < .001), and proBNP (r = 0.40, P = .005).ConclusionsMyocardial ECV is increased in patients with cirrhosis and seems related to disease severity and transplant‐free survival. These changes most likely reflect subclinical diffuse myocardial fibrosis and may represent a structural element of cirrhotic cardiomyopathy.
Vasomotion as an oscillatory sign of functional impairment in the human internal thoracic artery: A study based on risk factors and vessel reactivity
Authors: Fonseca Diogo A. , Antunes Pedro E. , Antunes Manuel J. , Cotrim Maria Dulce 
Published: May 2018

New Findings
What is the central question of this study?
Vasomotion has been viewed as a rhythmic oscillation of the vascular tone that is physiologically important for optimal tissue perfusion. Also, it has been studied primarily in the microcirculation. However, the precise underlying mechanisms and the physiological significance remain unknown.

What is the main finding and its importance?
Vasomotion is not specific to the microcirculation, as shown by our findings. In human arteries from patients undergoing cardiac surgery, an increased incidence was associated with endothelial dysfunction settings. Therefore, this oscillatory behaviour might be a signal of functional impairment and not of integrity.

AbstractVasomotion has been defined as the rhythmic oscillation of the vascular tone, involved in the control of the blood flow and subsequent tissue perfusion. Our aims were to study the incidence of vasomotion in the human internal thoracic artery and the correlation of this phenomenon with the clinical profile and parameters of vascular reactivity. In our study, vasomotion was elicited with a single‐dose contractile stimulation of noradrenaline (10 μm) in internal thoracic artery segments, from patients undergoing coronary artery bypass grafting, mounted in tissue organ bath chambers. The incidence was 29.1%. Vessel samples with vasomotion presented significantly higher contractility in response to both potassium chloride (maximal response or Emax of 7.65 ± 5.81 mN versus 4.52 ± 3.73 mN in control vessels, P = 0.024) and noradrenaline (Emax of 7.60 ± 5.93 mN versus 2.96 ± 4.41 mN in control vessels, P < 0.001). Predictive modelling through multivariable logistic regression analysis showed that female sex (odds ratio = 9.82) and increasing maximal response to noradrenaline (odds ratio = 1.19, per 1 mN increase) were associated with a higher probability of the occurrence of vasomotion, whereas increasing kidney function (expressed as estimated glomerular filtration rate) was associated with a lower probability (odds ratio = 0.97, per 1 ml min−1 (1.73 m)−2]. Our results provide a characterization of the phenomenon of vasomotion in the internal thoracic artery and suggest that vasomotion might be associated with endothelial dysfunction settings, as determined by a multivariable analysis approach. Considering the associations observed in our results, vasomotion might be a signal of functional impairment and not of integrity.
Mutant Variants of the Substrate-Binding Protein DppA from Escherichia coli Enhance Growth on Nonstandard γ-Glutamyl Amide-Containing Peptides
Authors: Kuenzl Tilmann , Li-Blatter Xiaochun , Srivastava Puneet , Herdewijn Piet , Sharpe Timothy , Panke Sven 
Published: May 2018

ABSTRACT

The import of nonnatural molecules is a recurring problem in fundamental and applied aspects of microbiology. The dipeptide permease (Dpp) of
Escherichia coli
is an ABC-type multicomponent transporter system located in the cytoplasmic membrane, which is capable of transporting a wide range of di- and tripeptides with structurally and chemically diverse amino acid side chains into the cell. Given this low degree of specificity, Dpp was previously used as an entry gate to deliver natural and nonnatural cargo molecules into the cell by attaching them to amino acid side chains of peptides, in particular, the γ-carboxyl group of glutamate residues. However, the binding affinity of the substrate-binding protein dipeptide permease A (DppA), which is responsible for the initial binding of peptides in the periplasmic space, is significantly higher for peptides consisting of standard amino acids than for peptides containing side-chain modifications. Here, we used adaptive laboratory evolution to identify strains that utilize dipeptides containing γ-substituted glutamate residues more efficiently and linked this phenotype to different mutations in DppA.
In vitro
characterization of these mutants by thermal denaturation midpoint shift assays and isothermal titration calorimetry revealed significantly higher binding affinities of these variants toward peptides containing γ-glutamyl amides, presumably resulting in improved uptake and therefore faster growth in media supplemented with these nonstandard peptides.

IMPORTANCE
Fundamental and synthetic biology frequently suffer from insufficient delivery of unnatural building blocks or substrates for metabolic pathways into bacterial cells. The use of peptide-based transport vectors represents an established strategy to enable the uptake of such molecules as a cargo. We expand the scope of peptide-based uptake and characterize in detail the obtained DppA mutant variants. Furthermore, we highlight the potential of adaptive laboratory evolution to identify beneficial insertion mutations that are unlikely to be identified with existing directed evolution strategies.
Effects of Ceftiofur and Chlortetracycline on the Resistomes of Feedlot Cattle
Authors: Weinroth Margaret D. , Scott H. Morgan , Norby Bo , Loneragan Guy H. , Noyes Noelle R. , Rovira Pablo , Doster Enrique , Yang Xiang , Woerner Dale R. , Morley Paul S. , Belk Keith E. 
Published: May 2018

ABSTRACT

Treatment of food-producing animals with antimicrobial drugs (AMD) is controversial because of concerns regarding promotion of antimicrobial resistance (AMR). To investigate this concern, resistance genes in metagenomic bovine fecal samples during a clinical trial were analyzed to assess the impacts of treatment on beef feedlot cattle resistomes. Four groups of cattle were exposed, using a 2-by-2 factorial design, to different regimens of antimicrobial treatment. Injections of ceftiofur crystalline-free acid (a third-generation cephalosporin) were used to treat all cattle in treatment pens or only a single animal, and either chlortetracycline was included in the feed of all cattle in a pen or the feed was untreated. On days 0 and 26, respectively, pre- and posttrial fecal samples were collected, and resistance genes were characterized using shotgun metagenomics. Treatment with ceftiofur was not associated with changes to β-lactam resistance genes. However, cattle fed chlortetracycline had a significant increase in relative abundance of tetracycline resistance genes. There was also an increase of an AMR class not administered during the study, which is a possible indicator of coselection of resistance genes. Samples analyzed in this study had previously been evaluated by culture characterization (
Escherichia coli
and
Salmonella
) and quantitative PCR (qPCR) of metagenomic fecal DNA, which allowed comparison of results with this study. In the majority of samples, genes that were selectively enriched through culture and qPCR were not identified through shotgun metagenomic sequencing in this study, suggesting that changes previously documented did not reflect changes affecting the majority of bacterial genetic elements found in the predominant fecal resistome.

IMPORTANCE
Despite significant concerns about public health implications of AMR in relation to use of AMD in food animals, there are many unknowns about the long- and short-term impact of common uses of AMD for treatment, control, and prevention of disease. Additionally, questions commonly arise regarding how to best measure and quantify AMR genes in relation to public health risks and how to determine which genes are most important. These data provide an introductory view of the utility of using shotgun metagenomic sequencing data as an outcome for clinical trials evaluating the impact of using AMD in food animals.
Characterization of Chlamydial Rho and the Role of Rho-Mediated Transcriptional Polarity during Interferon Gamma-Mediated Tryptophan Limitation
Authors: Ouellette Scot P. , Messerli Parker R. , Wood Nicholas A. , Hajovsky Heather 
Published: May 2018

ABSTRACTAs an obligate intracellular, developmentally regulated bacterium,Chlamydiais sensitive to amino acid fluctuations within its host cell. When human epithelial cells are treated with the cytokine interferon gamma (IFN-γ), the tryptophan (Trp)-degrading enzyme, indoleamine-2,3-dioxygenase, is induced. Chlamydiae within such cells are starved for Trp and enter a state of so-called persistence.Chlamydialacks the stringent response used by many eubacteria to respond to this stress. Unusually, chlamydial transcription is globally elevated during Trp starvation with transcripts for Trp codon-containing genes disproportionately increased. Yet, the presence of Trp codons destabilized 3′ ends of transcripts in operons or large genes. We initially hypothesized that ribosome stalling on Trp codons rendered the 3′ ends sensitive to RNase activity. The half-life of chlamydial transcripts containing different numbers of Trp codons was thus measured in untreated and IFN-γ-treated infected cells to determine whether Trp codons influenced the stability of transcripts. However, no effect of Trp codon content was detected. Therefore, we investigated whether Rho-dependent transcription termination could play a role in mediating transcript instability. Rho is expressed as a midcycle gene product, interacts with itself as predicted, and is present in all chlamydial species. Inhibition of Rho via the Rho-specific antibiotic, bicyclomycin, and overexpression of Rho are detrimental to chlamydiae. Finally, when we measured transcript abundance 3′ to Trp codons in the presence of bicyclomycin, we observed that transcript abundance increased. These data are the first to demonstrate the importance of Rho inChlamydiaand the role of Rho-dependent transcription polarity during persistence.
Selective Packaging in Murine Coronavirus Promotes Virulence by Limiting Type I Interferon Responses
Authors: Athmer Jeremiah , Fehr Anthony R. , Grunewald Matthew E. , Qu Wen , Wheeler D. Lori , Graepel Kevin W. , Channappanavar Rudragouda , Sekine Aimee , Aldabeeb Dana Saud , Gale Michael , Denison Mark R. , Perlman Stanley 
Published: May 2018

ABSTRACT

Selective packaging is a mechanism used by multiple virus families to specifically incorporate genomic RNA (gRNA) into virions and exclude other types of RNA. Lineage A betacoronaviruses incorporate a 95-bp stem-loop structure, the packaging signal (PS), into the nsp15 locus of ORF1b that is both necessary and sufficient for the packaging of RNAs. However, unlike other viral PSs, where mutations generally resulted in viral replication defects, mutation of the coronavirus (CoV) PS results in large increases in subgenomic RNA packaging with minimal effects on gRNA packaging
in vitro
and on viral titers. Here, we show that selective packaging is also required for viral evasion of the innate immune response and optimal pathogenicity. We engineered two distinct PS mutants in two different strains of murine hepatitis virus (MHV) that packaged increased levels of subgenomic RNAs, negative-sense genomic RNA, and even cellular RNAs. All PS mutant viruses replicated normally
in vitro
but caused dramatically reduced lethality and weight loss
in vivo
. PS mutant virus infection of bone marrow-derived macrophages resulted in increased interferon (IFN) production, indicating that the innate immune system limited the replication and/or pathogenesis of PS mutant viruses
in vivo
. PS mutant viruses remained attenuated in MAVS
−/−
and Toll-like receptor 7-knockout (TLR7
−/−
) mice, two well-known RNA sensors for CoVs, but virulence was restored in interferon alpha/beta receptor-knockout (IFNAR
−/−
) mice or in MAVS
−/−
mice treated with IFNAR-blocking antibodies. Together, these data indicate that coronaviruses promote virulence by utilizing selective packaging to avoid innate immune detection.

IMPORTANCE
Coronaviruses (CoVs) produce many types of RNA molecules during their replication cycle, including both positive- and negative-sense genomic and subgenomic RNAs. Despite this, coronaviruses selectively package only positive-sense genomic RNA into their virions. Why CoVs selectively package their genomic RNA is not clear, as disruption of the packaging signal in MHV, which leads to loss of selective packaging, does not affect genomic RNA packaging or virus replication in cultured cells. This contrasts with other viruses, where disruption of selective packaging generally leads to altered replication. Here, we demonstrate that in the absence of selective packaging, the virulence of MHV was significantly reduced. Importantly, virulence was restored in the absence of interferon signaling, indicating that selective packaging is a mechanism used by CoVs to escape innate immune detection.
Signature Arsenic Detoxification Pathways in
Halomonas
sp. Strain GFAJ-1
Authors: Wu Shuangju , Wang Lianrong , Gan Rui , Tong Tong , Bian Hao , Li Zhiqiang , Du Shiming , Deng Zixin , Chen Shi 
Published: May 2018

ABSTRACT

Since the original report that
Halomonas
sp. strain GFAJ-1 was capable of using arsenic instead of phosphorus to sustain growth, additional studies have been conducted, and GFAJ-1 is now considered a highly arsenic-resistant but phosphorus-dependent bacterium. However, the mechanisms supporting the extreme arsenic resistance of the GFAJ-1 strain remain unknown. In this study, we show that GFAJ-1 has multiple distinct arsenic resistance mechanisms. It lacks the genes to reduce arsenate, which is the essential step in the well-characterized resistance mechanism of arsenate reduction coupled to arsenite extrusion. Instead, GFAJ-1 has two arsenic resistance operons,
arsH1
-
acr3
-
2
-
arsH2
and
mfs1
-
mfs2
-
gapdh
, enabling tolerance to high levels of arsenate.
mfs2
and
gapdh
encode proteins homologous to
Pseudomonas aeruginosa
ArsJ and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), respectively, which constitute the equivalent of an As(V) efflux system to catalyze the transformation of inorganic arsenate to pentavalent organoarsenical 1-arseno-3-phosphoglycerate and its subsequent extrusion. Surprisingly, the
arsH1
-
acr3
-
2
-
arsH2
operon seems to consist of typical arsenite resistance genes, but this operon is sufficient to confer both arsenite and arsenate resistance on
Escherichia coli
AW3110 even in the absence of arsenate reductase, suggesting a novel pathway of arsenic detoxification. The simultaneous occurrence of these two unusual detoxification mechanisms enables the adaptation of strain GFAJ-1 to the particularly arsenic-rich environment of Mono Lake.

IMPORTANCE
Halomonas
sp. strain GFAJ-1 was previously reported to use arsenic as a substitute for phosphorus to sustain life under phosphate-limited conditions. Although this claim was later undermined by several groups, how GFAJ-1 can thrive in environments with high arsenic concentrations remains unclear. Here, we determined that this ability can be attributed to the possession of two arsenic detoxification operons,
arsH1
-
acr3
-
2
-
arsH2
and
mfs1
-
mfs2
-
gapdh
.
mfs2
and
gapdh
encode proteins homologous to ArsJ and GAPDH in
Pseudomonas aeruginosa
; these proteins create an arsenate efflux pathway to reduce cellular arsenate accumulation. Interestingly, the combination of
acr3
-
2
with either
arsH
gene was sufficient to confer resistance to both arsenite and arsenate in
E. coli
AW3110, even in the absence of arsenate reductase, suggesting a new strategy for bacterial arsenic detoxification. This study concludes that the survival of GFAJ-1 in high arsenic concentrations is attributable to the cooccurrence of these two unusual arsenic detoxification mechanisms.
Pseudomonas aeruginosa
Protease IV Exacerbates Pneumococcal Pneumonia and Systemic Disease
Authors: Bradshaw Jessica L. , Caballero Armando R. , Bierdeman Michael A. , Adams Kristen V. , Pipkins Haley R. , Tang Aihua , O’Callaghan Richard J. , McDaniel Larry S. 
Published: May 2018

S. pneumoniae
remains the leading cause of bacterial pneumonia despite widespread use of pneumococcal vaccines, forcing the necessity for appropriate treatment to control pneumococcal infections. Coinfections involving
S. pneumoniae
with other bacterial pathogens threaten antibiotic treatment strategies and disease outcomes. Currently, there is not an effective treatment for alveolar-capillary barrier dysfunction that precedes bacteremia. An understanding of the dynamics of host-pathogen interactions during single and mixed pulmonary infections could elucidate proper treatment strategies needed to prevent or reduce invasive disease. Antibiotic treatment decreases bacterial burden in the lung but also increases acute pathology due to cytotoxins released via antibiotic-induced bacterial lysis. Therefore, targeted therapeutics that inhibit or counteract the effects of bacterial proteases and toxins are needed in order to limit pathology and disease progression. This study identifies the cooperative effect of PIV and Ply, products of separate lung pathogens that additively alter the lung environment and facilitate invasive disease.
Improved Subtyping of Staphylococcus aureus Clonal Complex 8 Strains Based on Whole-Genome Phylogenetic Analysis
Authors: Bowers Jolene R. , Driebe Elizabeth M. , Albrecht Valerie , McDougal Linda K. , Granade Mitchell , Roe Chandler C. , Lemmer Darrin , Rasheed J. Kamile , Engelthaler David M. , Keim Paul , Limbago Brandi M. 
Published: May 2018

Staphylococcus aureus
is a major human pathogen worldwide in both community and health care settings. Surveillance for
S. aureus
strains is important to our understanding of their spread and to informing infection prevention and control. Confusion surrounding the strain nomenclature of one of the most prevalent lineages of
S. aureus
, clonal complex 8 (CC8), and the imprecision of current tools for typing
S. aureus
make surveillance and source tracing difficult and sometimes misleading. In this study, we clarify the CC8 strain designations and propose a new typing scheme for CC8 isolates that is rapid and easy to use. This typing scheme is based on relatively stable genomic markers, and we demonstrate its superiority over traditional typing techniques. This scheme has the potential to greatly improve epidemiological investigations of
S. aureus
.
ThreadScan
Authors: Alistarh Dan , Leiserson William , Matveev Alexander , Shavit Nir 
Published: May 2018

The concurrent memory reclamation problem is that of devising a way for a deallocating thread to verify that no other concurrent threads hold references to a memory block being deallocated. To date, in the absence of automatic garbage collection, there is no satisfactory solution to this problem; existing tracking methods like hazard pointers, reference counters, or epoch-based techniques like RCU are either prohibitively expensive or require significant programming expertise to the extent that implementing them efficiently can be worthy of a publication. None of the existing techniques are automatic or even semi-automated.
In this article, we take a new approach to concurrent memory reclamation. Instead of manually tracking access to memory locations as done in techniques like hazard pointers, or restricting shared accesses to specific epoch boundaries as in RCU, our algorithm, called ThreadScan, leverages operating system signaling to automatically detect which memory locations are being accessed by concurrent threads.
Initial empirical evidence shows that ThreadScan scales surprisingly well and requires negligible programming effort beyond the standard use of Malloc and Free.
A Cohort Study of Metformin and Colorectal Cancer Risk among Patients with Diabetes Mellitus
Authors: Bradley Marie C. , Ferrara Assiamira , Achacoso Ninah , Ehrlich Samantha F. , Quesenberry Charles P. , Habel Laurel A. 
Published: May 2018

Abstract
Background: Several epidemiologic studies have reported strong inverse associations between metformin use and risk of colorectal cancer, although time-related biases, such as immortal time bias, may in part explain these findings. We reexamined this association using methods to minimize these biases.
Methods: A cohort study was conducted among 47,351 members of Kaiser Permanente Northern California with diabetes and no history of cancer or metformin use. Follow-up for incident colorectal cancer occurred from January 1, 1997, until June 30, 2012. Cox regression was used to calculate HRs and 95% confidence intervals (CIs) for colorectal cancer risk associated with metformin use (ever use, total duration, recency of use, and cumulative dose).
Results: No association was observed between ever use of metformin and colorectal cancer risk (HR, 0.90; 95% CI, 0.76–1.07) and there was no consistent pattern of decreasing risk with increasing total duration, dose, or recency of use. However, long-term use (≥5.0 years) appeared to be associated with reduced risk of colorectal cancer in the full population (HR, 0.78; 95% CI, 0.60–1.02), among current users (HR, 0.78; 95% CI, 0.59–1.04), and in men (HR, 0.65; 95% CI, 0.45–0.94) but not in women. Higher cumulative doses of metformin were associated with reduced risk. In initial users of sulfonylureas, switching to or adding metformin was also associated with decreased colorectal cancer risk.
Conclusions: Our findings showed an inverse association between long-term use of metformin and colorectal cancer risk. Findings, especially the risk reduction among men, need to be confirmed in large, well-conducted studies.
Impact: If our findings are confirmed, metformin may have a role in the chemoprevention of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 27(5); 525–30. ©2018 AACR.
See related commentary by Jackson and García-Albéniz, p. 520