bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of Specific Components of the Eicosanoid Biosynthetic and Signaling Pathway Involved in Pathological Inflammation during Intra-abdominal Infection with Candida albicans and Staphylococcus aureus
Authors: Ikeh Mélanie A. C. , Fidel Paul L. , Noverr Mairi C. 
Published: May 2018

ABSTRACT

Polymicrobial intra-abdominal infections (IAIs) are a significant cause of morbidity and mortality, particularly when fungal pathogens are involved. Our experimental murine model of IAI involving intraperitoneal inoculation of
Candida albicans
and
Staphylococcus aureus
results in synergistic lethality (∼80%) due to exacerbated inflammation. Monomicrobial infection results in no mortality, despite a microbial burden and dissemination similar to those in a coinfection. In the coinfection model, the immunomodulatory eicosanoid prostaglandin E
2
(PGE
2
) was determined to be necessary and sufficient to induce mortality, implicating PGE
2
as the central mediator of the amplified inflammatory response. The aim of this study was to identify key components of the PGE
2
biosynthetic and signaling pathway involved in the inflammatory response and explore whether these can be targeted to prevent or reduce mortality. Using selective pharmacological inhibitors of cyclooxygenases (COX) or PGE
2
receptor antagonists in the
C. albicans
-
S. aureus
IAI mouse model, we found that inhibition of COX and/or blocking of PGE
2
receptor 1 (EP1) or PGE
2
receptor 3 (EP3) signaling reduced proinflammatory cytokine production, promoted interleukin-10 production, reduced cellular damage in the peritoneal cavity, and, most importantly, significantly improved survival. The greatest effect on survival was obtained by the simultaneous inhibition of COX-1 activity and EP1 and EP3 receptor signaling. Importantly, early inhibition of PGE
2
pathways dramatically improved the survival of fluconazole-treated mice compared with that achieved with fluconazole treatment alone. These findings indicate that COX-1 and the EP1 and EP3 receptors mediate the downstream pathological effects of PGE
2
during polymicrobial IAI and may serve as effective therapeutic targets.
Disruption of a Novel Iron Transport System Reverses Oxidative Stress Phenotypes of a
dpr
Mutant Strain of Streptococcus mutans
Authors: Ganguly Tridib , Kajfasz Jessica K. , Miller James H. , Rabinowitz Eric , Galvão Lívia C. C. , Rosalen Pedro L. , Abranches Jacqueline , Lemos José A. 
Published: May 2018

ABSTRACT

The Dps-like peroxide resistance protein (Dpr) is essential for H
2
O
2
stress tolerance and aerobic growth of the oral pathogen
Streptococcus mutans
. Dpr accumulates during oxidative stress, protecting the cell by sequestering iron ions and thereby preventing the generation of toxic hydroxyl radicals that result from the interaction of iron with H
2
O
2
. Previously, we reported that the SpxA1 and SpxA2 regulators positively regulate expression of
dpr
in
S. mutans
. Using an antibody raised against
S. mutans
Dpr, we confirmed at the protein level the central and cooperative nature of SpxA1 and SpxA2 regulation in Dpr production. During phenotypic characterization of the
S. mutans
Δ
dpr
strain, we observed the appearance of distinct colony variants, which sometimes lost the oxidative stress sensitivity typical of Δ
dpr
strains. Whole-genome sequencing of these phenotypically distinct Δ
dpr
isolates revealed that a putative iron transporter operon,
smu995-smu998
, was a genomic hot spot with multiple single nucleotide polymorphisms identified within the different isolates. Deletion of
smu995
or the entire
smu995-smu998
operon in the Δ
dpr
background strain completely reversed the oxidative stress-sensitive phenotypes associated with
dpr
inactivation. Conversely, inactivation of genes encoding the ferrous iron transport system FeoABC did not alleviate phenotypes of the Δ
dpr
strain. Preliminary characterization of strains lacking
smu995-smu998
,
feoABC
, and the iron/manganese transporter gene
sloABC
revealed the interactive nature of these three systems in iron transport but also indicated that there may be additional iron uptake systems in
S. mutans
.

IMPORTANCE
The dental caries-associated pathogen
Streptococcus mutans
routinely encounters oxidative stress within the human plaque biofilm. Previous studies revealed that the iron-binding protein Dpr confers protection toward oxidative stress by limiting free iron availability, which is associated with the generation of toxic hydroxyl radicals. Here, we report the identification of spontaneously occurring mutations within Δ
dpr
strains. Several of those mutations were mapped to the operon
smu995-smu998
, revealing a previously uncharacterized system that appears to be important in iron acquisition. Disruption of the
smu995-smu998
operon resulted in reversion of the stress-sensitive phenotype typical of a Δ
dpr
strain. Our data suggest that the Smu995-Smu998 system works along with other known metal transport systems of
S. mutans
, i.e., FeoABC and SloABC, to coordinate iron uptake.
Measurement of Internal pH in Helicobacter pylori by Using Green Fluorescent Protein Fluorimetry
Authors: Wen Yi , Scott David R. , Vagin Olga , Tokhtaeva Elmira , Marcus Elizabeth A. , Sachs George 
Published: May 2018

ABSTRACT

Helicobacter pylori
is an organism known to colonize the normal human stomach. Previous studies have shown that the bacterium does this by elevating its periplasmic pH via the hydrolysis of urea. However, the value of the periplasmic pH was calculated indirectly from the proton motive force equation. To measure the periplasmic pH directly in
H. pylori
, we fused enhanced green fluorescent protein (EGFP) to the predicted twin-arginine signal peptides of HydA and KapA from
H. pylori
and TorA from
Escherichia coli
. The fusion proteins were expressed in the
H. pylori
genome under the control of the
cagA
promoter. Confocal microscopic and cell fractionation/immunoblotting analyses detected TorA-EGFP in the periplasm and KapA-EGFP in both the periplasm and cytoplasm, while the mature form of HydA-EGFP was seen at low levels in the periplasm, with major cytoplasmic retention of the precursor form. With
H. pylori
expressing TorA-EGFP, we established a system to directly measure periplasmic pH based on the pH-sensitive fluorimetry of EGFP. These measurements demonstrated that the addition of 5 mM urea has little effect on the periplasmic pH at a medium pH higher than pH 6.5 but rapidly increases the periplasmic pH to pH 6.1 at an acidic medium pH (pH 5.0), corresponding to the opening of the proton-gated channel, UreI, and confirming the basis of gastric colonization. Measurements of the periplasmic pH in an HP0244 (FlgS)-deficient mutant of
H. pylori
expressing TorA-EGFP revealed a significant loss of the urea-dependent increase in the periplasmic pH at an acidic medium pH, providing additional evidence that FlgS is responsible for recruitment of urease to the inner membrane in association with UreI.

IMPORTANCE
Helicobacter pylori
has been identified as the major cause of chronic superficial gastritis and peptic ulcer disease. In addition, persistent infection with
H. pylori
, which, if untreated, lasts for the lifetime of an infected individual, predisposes one to gastric malignancies, such as adenocarcinoma and mucosa-associated lymphoid tissue (MALT) lymphoma. A unique feature of the neutralophilic bacterium
H. pylori
is its ability to survive in the extremely acidic environment of the stomach through its acid acclimation mechanism. The presented results on measurements of periplasmic pH in
H. pylori
based on fluorimetry of fully active green fluorescent protein fusion proteins exported with the twin-arginine translocase system provide a reliable and rapid tool for the investigation of acid acclimation in
H. pylori
.
Prehospital haemostatic dressings for trauma: a systematic review
Authors: Boulton Adam J , Lewis Christopher T , Naumann David N , Midwinter Mark J 
Published: May 2018

BackgroundHaemorrhage is a major cause of mortality and morbidity following both military and civilian trauma. Haemostatic dressings may offer effective haemorrhage control as part of prehospital treatment.AimTo conduct a systematic review of the clinical literature to assess the prehospital use of haemostatic dressings in controlling traumatic haemorrhage, and determine whether any haemostatic dressings are clinically superior.MethodsMEDLINE and EMBASE databases were searched using predetermined criteria. The reference lists of all returned review articles were screened for eligible studies. Two authors independently undertook the search, performed data extraction, and risk of bias and Grading of Recommendations, Assessment, Development and Evaluation quality assessments. Meta-analysis could not be undertaken due to study and clinical heterogeneity.ResultsOur search yielded 470 studies, of which 17 met eligibility criteria, and included 809 patients (469 military and 340 civilian). There were 15 observational studies, 1 case report and 1 randomised controlled trial. Indications for prehospital haemostatic dressing use, wound location, mechanism of injury, and source of bleeding were variable. Seven different haemostatic dressings were reported with QuikClot Combat Gauze being the most frequently applied (420 applications). Cessation of bleeding ranged from 67% to 100%, with a median of 90.5%. Adverse events were only reported with QuikClot granules, resulting in burns. No adverse events were reported with QuikClot Combat Gauze use in three studies. Seven of the 17 studies did not report safety data. All studies were at risk of bias and assessed of ‘very low’ to ‘moderate’ quality.ConclusionsHaemostatic dressings offer effective prehospital treatment for traumatic haemorrhage. QuikClot Combat Gauze may be justified as the optimal agent due to the volume of clinical data and its safety profile, but there is a lack of high-quality clinical evidence, and randomised controlled trials are warranted.Level of evidenceSystematic review, level IV.
Exercise training in heart failure
Authors: Abela Mark 
Published: May 2018

AbstractExercise training (ET) in heart failure (HF) has long been established as an important part of HF care. ET is known to improve quality of life and functional capacity in a number of ways. Despite its proposed benefits, evidence supporting its routine inclusion in standard rehabilitation programme is at times conflicting, partly because of the significant heterogeneity present in available randomised controlled trials. There is lack of evidence with regard to the duration of the overall benefit, the optimal exercise regimen and whether certain types of HF aetiologies benefit more than others. The aim of this review is to provide an update to date literature review of the positive and negative evidence surrounding ET in HF, while proposing an efficient novel in-hospital exercise-based rehabilitation programme for patients with HF in addition to a pre-existing HF clinic.
Microfluidic mixing through oscillatory transverse perturbations
Authors: Wu J. W. , Xia H. M. , Zhang Y. Y. , Zhu P. 
Published: May 2018

Fluid mixing in miniaturized fluidic devices is a challenging task. In this work, the mixing enhancement through oscillatory transverse perturbations coupling with divergent circular chambers is studied. To simplify the design, an autonomous microfluidic oscillator is used to produce the oscillatory flow. It is then applied to four side-channels that intersect with a central channel of constant flow. The mixing performance is tested at high fluid viscosities of up to 16 cP. Results show that the oscillatory flow can cause strong transverse perturbations which effectively enhance the mixing. The influence of a fluidic capacitor in the central channel is also examined, which at low viscosities can intensify the perturbations and further improve the mixing.
Brachial artery endothelial function is stable across a menstrual and oral contraceptive pill cycle but lower in premenopausal women than in age-matched men
Authors: Shenouda Ninette , Priest Stacey E. , Rizzuto Vanessa I. , MacDonald Maureen J. 
Published: May 2018

Sex hormone concentrations differ between men, premenopausal women with natural menstrual cycles (NAT), and premenopausal women using oral contraceptive pills (OCP), as well as across menstrual or OCP phases. This study sought to investigate how differences in sex hormones, particularly estradiol, between men and women and across cycle phases might influence brachial artery endothelial function. Fifty-three healthy adults (22 ± 3 yr, 20 men, 15 NAT women, and 18 second-, third-, or fourth-generation OCP women) underwent assessments of sex hormones and endothelial [flow-mediated dilation (FMD) test] and smooth muscle [nitroglycerin (NTG) test] function. Men were tested three times at 1-wk intervals, and women were tested three times throughout a single menstrual or OCP cycle (NAT: menstrual, midfollicular, and luteal phases and OCP: placebo/no pill, “early”, and “late” active pill phases). Endogenous estradiol concentration was comparable between men and women in their NAT menstrual or OCP placebo phase ( P = 0.36) but increased throughout a NAT cycle ( P < 0.001). Allometrically scaled FMD did not change across a NAT or OCP cycle but was lower in both groups of women than in men ( P = 0.005), whereas scaled NTG was lower only in NAT women ( P = 0.001). Changes in estradiol across a NAT cycle were not associated with changes in relative FMD ( r2 = 0.01, P = 0.62) or NTG ( r2 = 0.09, P = 0.13). Duration of OCP use was negatively associated with the average relative FMD for second-generation OCP users only ( r = −0.65, P = 0.04). Our findings suggest that brachial endothelial function is unaffected by cyclic hormonal changes in premenopausal women but may be negatively impacted by longer-term use of second-generation OCPs. NEW & NOTEWORTHY We demonstrate that brachial artery flow-mediated dilation does not change across a menstrual or oral contraceptive pill cycle in premenopausal women but is lower in women than in men. Although unaffected by within-cycle changes in estradiol, brachial flow-mediated dilation is negatively correlated with duration of oral contraceptive pill use for second-generation pills. Listen to this article’s corresponding podcast at https://ajpheart.podbean.com/e/behind-the-bench-episode-2/ .
Association Between Amplitude of Seasonal Variation in Self‐Measured Home Blood Pressure and Cardiovascular Outcomes: HOMED‐BP (Hypertension Objective Treatment Based on Measurement By Electrical Devices of Blood Pressure) Study
Authors: Hanazawa Tomohiro , Asayama Kei , Watabe Daisuke , Tanabe Ayumi , Satoh Michihiro , Inoue Ryusuke , Hara Azusa , Obara Taku , Kikuya Masahiro , Nomura Kyoko , Metoki Hirohito , Imai Yutaka , Ohkubo Takayoshi ,   the HOMED‐BP (Hypertension Objective Treatment Based on Measurement by Electrical Devices of Blood Pressure) Investigators
Published: May 2018

Background

The clinical significance of long‐term seasonal variations in self‐measured home blood pressure (
BP
) has not been elucidated for the cardiovascular disease prevention.

Methods and Results

Eligible 2787 patients were classified into 4 groups according to the magnitude of their seasonal variation in home
BP
, defined as an average of all increases in home
BP
from summer (July–August) to winter (January–February) combined with all decreases from winter to summer throughout the follow‐up period, namely inverse‐ (systolic/diastolic, <0/<0 mm Hg), small‐ (0–4.8/0–2.4 mm Hg), middle‐ (4.8–9.1/2.4–4.5 mm Hg), or large‐ (≥9.1/≥4.5 mm Hg) variation groups. The overall cardiovascular risks illustrated U‐shaped relationships across the groups, and hazard ratios for all cardiovascular outcomes compared with the small‐variation group were 3.07 (
P
=0.004) and 2.02 (
P
=0.041) in the inverse‐variation group and large‐variation group, respectively, based on systolic
BP
, and results were confirmatory for major adverse cardiovascular events. Furthermore, when the summer‐winter home
BP
difference was evaluated among patients who experienced titration and tapering of antihypertensive drugs depending on the season, the difference was significantly smaller in the early (September–November) than in the late (December–February) titration group (3.9/1.2 mm Hg versus 7.3/3.1 mm Hg,
P
<0.001) as well as in the early (March–May) than in the late (June–August) tapering group (4.4/2.1 mm Hg versus 7.1/3.4 mm Hg,
P
<0.001).

Conclusions

The small‐to‐middle seasonal variation in home
BP
(0–9.1/0–4.5 mm Hg), which may be partially attributed to earlier adjustment of antihypertensive medication, were associated with better cardiovascular outcomes.
Ideal Cardiovascular Health Metrics in Couples: A Community‐Based Study
Authors: Erqou Sebhat , Ajala Oluremi , Bambs Claudia E. , Althouse Andrew D. , Sharbaugh Michael S. , Magnani Jared , Aiyer Aryan , Reis Steven E. 
Published: May 2018

Background
Determination of the correlation of ideal cardiovascular health variables among spousal or cohabitating partners may guide the development of couple‐based interventions to reduce cardiovascular disease risk.

Method and Results

We used data from the Heart
SCORE
(Heart Strategies Concentrating on Risk Evaluation) study. Ideal cardiovascular health, defined by the American Heart Association, comprises nonsmoking, body mass index <25 kg/m
2
, physical activity at goal, diet consistent with guidelines, untreated total cholesterol <200 mg/dL, untreated blood pressure <120/80 mm Hg, and untreated fasting glucose <100 mg/dL. McNemar test and logistic regression were used to assess concordance patterns in these variables among partners (ie, concordance in achieving ideal factor status, concordance in not achieving ideal factor status, or discordance—only one partner achieving ideal factor status). Overall, there was a low prevalence of ideal cardiovascular health among the 231 couples studied (median age 61 years, 78% white). The highest concordances in achieving ideal factor status were for nonsmoking (26.1%), ideal fruit and vegetable consumption (23.9%), and ideal fasting blood glucose (35.6%). The strongest odds of intracouple concordance were for smoking (odds ratio, 3.6; 95% confidence interval, 1.9–6.5), fruit and vegetable consumption (odds ratio, 4.8; 95% confidence interval, 2.5–9.3) and blood pressure (odds ratio, 3.0; 95% confidence interval, 1.2–7.9). A participant had 3‐fold higher odds of attaining ≥3 ideal cardiovascular health variables if he or she had a partner who attained ≥3 components (odds ratio 3.0; 95% confidence interval, 1.6–5.6).

Conclusions
Intracouple concordance of ideal cardiovascular health variables supports the development and testing of couple‐based interventions to promote cardiovascular health. Fruit and vegetable consumption and smoking may be particularly good intervention targets.
Why America's Grand Strategy Has Not Changed: Power, Habit, and the U.S. Foreign Policy Establishment
Authors: Porter Patrick 
Published: May 2018

Abstract
Why has U.S. grand strategy persisted since the end of the Cold War? Despite shocks such as the 2008 global financial crisis and the costs of the war in Iraq—circumstances that ought to have stimulated at least a revision—the United States remains committed to a grand strategy of “primacy.” It strives for military preponderance, dominance in key regions, the containment and reassurance of allies, nuclear counterproliferation, and the economic “Open Door.” The habitual ideas of the U.S. foreign policy establishment, or the “Blob,” make U.S. grand strategy hard to change. The United States' military and economic capabilities enable the U.S. government to pursue primacy, but the embedded assumptions of the Blob make primacy the seemingly natural choice. Thanks to the Blob's constraining power, alternative grand strategies based on restraint and retrenchment are hardly entertained, and debate is narrowed mostly into questions of execution and implementation. Two cases—the presidency of Bill Clinton and the first year of the presidency of Donald Trump—demonstrate this argument. In each case, candidates promising change were elected in fluid conditions that we would expect to stimulate a reevaluation of the United States' commitments. In each case, the Blob asserted itself successfully, at least on the grand strategic fundamentals. Change in grand strategy is possible, but it would require shocks large enough to shake the assumptions of the status quo and a president willing to be an agent of change and prepared to absorb the political costs of overhauling Washington's traditional design.
Do U.S. Drone Strikes Cause Blowback? Evidence from Pakistan and Beyond
Authors: Shah Aqil 
Published: May 2018

Abstract
Many analysts argue that U.S. drone strikes generate blowback: by killing innocent civilians, such strikes radicalize Muslim populations at the local, national, and even transnational levels. This claim, however, is based primarily on anecdotal evidence, unreliable media reports, and advocacy-driven research by human rights groups. Interview and survey data from Pakistan, where, since 2004, the U.S. Central Intelligence Agency has launched more than 430 drone strikes, show little or no evidence that drone strikes have a significant impact on militant Islamist recruitment either locally or nationally. Rather, the data reveal the importance of factors such as political and economic grievances, the Pakistani state's selective counterterrorism policies, its indiscriminate repression of the local population, and forced recruitment of youth by militant groups. Similarly, trial testimony and accounts of terrorists convicted in the United States, as well as the social science scholarship on Muslim radicalization in the United States and Europe, provide scant evidence that drone strikes are the main cause of militant Islamism. Instead, factors that matter include a transnational Islamic identity's appeal to young immigrants with conflicted identities, state immigration and integration policies that marginalize Muslim communities, the influence of peers and social networks, and online exposure to violent jihadist ideologies within the overall context of U.S. military interventions in Muslim countries.
Active Denial: Redesigning Japan's Response to China's Military
Challenge
Authors: Heginbotham Eric , Samuels Richard J. 
Published: May 2018

Abstract
The growth of Chinese military power poses significant challenges to Japan. China's military spending, which was half that of Japan's in 1996, is now three and a half times as large. Japan has taken a range of measures to buttress its military forces and loosen the restrictions on their operations, but much remains to be done. Most important, Tokyo needs to reexamine its strategy to maximize Japan's deterrent leverage. Of the three general approaches to conventional deterrence—punishment, forward defense, and denial—Japan's best option is to shift to a denial strategy. Such a strategy, built around a resilient force that can survive attack and attrite an encroaching adversary, can make the risks to a potential attacker unacceptably high. In Japan's case, such a strategy would leverage the inherent dangers that Beijing would face in contemplating a prolonged war against Japan and its U.S. ally. The strategy, updated to reflect the imperatives of air and maritime warfare in the precision strike era, would require a high level of dispersion and mobility and might therefore be labeled “active denial.” Adopting an active denial strategy would buttress Japan's defense and deterrent capability while reducing first-strike incentives and improving crisis stability.