bluuebunny/crossref_metadata_2025_split huggingface dataset:
Selective Killing of Dormant Mycobacterium tuberculosis by Marine Natural Products
Authors: Rodrigues Felix Carolina , Gupta Rashmi , Geden Sandra , Roberts Jill , Winder Priscilla , Pomponi Shirley A. , Diaz Maria Cristina , Reed John K. , Wright Amy E. , Rohde Kyle H. 
Published: June 2017

ABSTRACT

The dormant phenotype acquired by
Mycobacterium tuberculosis
during infection poses a major challenge in disease treatment, since these bacilli show tolerance to front-line drugs. Therefore, it is imperative to find novel compounds that effectively kill dormant bacteria. By screening 4,400 marine natural product samples against dual-fluorescent
M. tuberculosis
under both replicating and nonreplicating conditions, we have identified compounds that are selectively active against dormant
M. tuberculosis
. This validates our strategy of screening all compounds in both assays as opposed to using the dormancy model as a secondary screen. Bioassay-guided deconvolution enabled the identification of unique pharmacophores active in each screening model. To confirm the activity of samples against dormant
M. tuberculosis
, we used a luciferase reporter assay and enumerated CFU. The structures of five purified active compounds were defined by nuclear magnetic resonance (NMR) and mass spectrometry. We identified two lipid compounds with potent activity toward dormant and actively growing
M. tuberculosis
strains. One of these was commercially obtained and showed similar activity against
M. tuberculosis
in both screening models. Furthermore, puupehenone-like molecules were purified with potent and selective activity against dormant
M. tuberculosis
. In conclusion, we have identified and characterized antimycobacterial compounds from marine organisms with novel activity profiles which appear to target
M. tuberculosis
pathways that are conditionally essential for dormancy survival.
Drug Sensitivity and Resistance Mechanism in Aspergillus Section
Nigri
Strains from Japan
Authors: Hashimoto Aki , Hagiwara Daisuke , Watanabe Akira , Yahiro Maki , Yikelamu Alimu , Yaguchi Takashi , Kamei Katsuhiko 
Published: June 2017

ABSTRACT

Aspergillus niger
and its related species, known as
Aspergillus
section
Nigri
, are ubiquitously distributed across the globe and are often isolated from clinical specimens. In Japan,
Aspergillus
section
Nigri
is second most often isolated from clinical specimens following
Aspergillus fumigatus
. We determined the species of
Aspergillus
section
Nigri
isolated in Japan by DNA sequencing of partial β-tubulin genes and investigated drug susceptibility by the CLSI M38-A2 method. The collection contained 20
Aspergillus niger
, 59
Aspergillus welwitschiae
, and 39
Aspergillus tubingensis
strains. Drug susceptibility testing revealed 30 to 55% of
A. niger
, 6.8 to 18.6% of
A. welwitschiae
, and 79.5 to 89.7% of
A. tubingensis
isolates to be less susceptible (so-called resistant) to itraconazole (ITC) and/or voriconazole (VRC) according to the epidemiologic cutoff values (ECVs) proposed for
A. niger
previously. MIC distributions of ITC or VRC showed no remarkable differences between clinical and environmental isolates. When the
cyp51A
sequences were compared between susceptible and resistant strains, 18 amino acid mutations were specific for resistant isolates of
A. niger
and
A. tubingensis
; however, none of them were confirmed to be associated with azole resistance. Three nonrelated
A. welwitschiae
isolates possessed a partial deletion in
cyp51A
, likely attributable to being more susceptible to azoles than other isolates. One of five ITC-resistant
A. tubingensis
isolates showed higher expression of
cyp51A
than did susceptible strains. Our results show that
cyp51A
point mutations may have no association with azole resistance but that in some cases the overexpression of
cyp51A
may lead to the azole resistance in these species.
Inhibition of Host Cell Lysosome Spreading by Trypanosoma cruzi Metacyclic Stage-Specific Surface Molecule gp90 Downregulates Parasite Invasion
Authors: Rodrigues João Paulo Ferreira , Sant'ana Guilherme Hideki Takahashi , Juliano Maria Aparecida , Yoshida Nobuko 
Published: June 2017

ABSTRACT

Successful infection by
Trypanosoma cruzi
, the agent of Chagas' disease, is critically dependent on host cell invasion by metacyclic trypomastigote (MT) forms. Two main metacyclic stage-specific surface molecules, gp82 and gp90, play determinant roles in target cell invasion
in vitro
and in oral
T. cruzi
infection in mice. The structure and properties of gp82, which is highly conserved among
T. cruzi
strains, are well known. Information on gp90 is still rather sparse. Here, we attempted to fill that gap. gp90, purified from poorly invasive G strain MT and expressing gp90 at high levels, inhibited HeLa cell lysosome spreading and the gp82-mediated internalization of a highly invasive CL strain MT expressing low levels of a diverse gp90 molecule. A recombinant protein containing the conserved C-terminal domain of gp90 exhibited the same properties as the native G strain gp90: it counteracted the host cell lysosome spreading induced by recombinant gp82 and exhibited an inhibitory effect on HeLa cell invasion by CL strain MT. Assays to identify the gp90 sequence associated with the property of downregulating MT invasion, using synthetic peptides spanning the gp90 C-terminal domain, revealed the sequence GVLYTADKEW. These data, plus the findings that lysosome spreading was induced upon HeLa cell interaction with CL strain MT, but not with G strain MT, and that in mixed infection CL strain MT internalization was inhibited by G strain MT, suggest that the inhibition of target cell lysosome spreading is the mechanism by which the gp90 molecule exerts its downregulatory role.
Transition structures and timing of transfer from paediatric to adult-based care after kidney transplantation in Germany: a qualitative study
Authors: Prüfe Jenny , Dierks Marie-Luise , Bethe Dirk , Oldhafer Martina , Müther Silvia , Thumfart Julia , Feldkötter Markus , Büscher Anja , Sauerstein Katja , Hansen Matthias , Pohl Martin , Drube Jens , Thiel Florian , Rieger Susanne , John Ulrike , Taylan Christina , Dittrich Katalin , Hollenbach Sabine , Klaus Günter , Fehrenbach Henry , Kranz Birgitta , Montoya Carmen , Lange-Sperandio Bärbel , Ruckenbrod Bettina , Billing Heiko , Staude Hagen , Brunkhorst Reinhard , Rusai Krisztina , Pape Lars , Kreuzer Martin 
Published: June 2017

ObjectivesIt is known that transition, as a shift of care, marks a vulnerable phase in the adolescents’ lives with an increased risk for non-adherence and allograft failure. Still, the transition process of adolescents and young adults living with a kidney transplant in Germany is not well defined. The present research aims to assess transition-relevant structures for this group of young people. Special attention is paid to the timing of the process.SettingIn an observational study, we visited 21 departments of paediatric nephrology in Germany. Participants were doctors (n=19), nurses (n=14) and psychosocial staff (n=16) who were responsible for transition in the relevant centres. Structural elements were surveyed using a short questionnaire. The experiential viewpoint was collected by interviews which were transcribedverbatim before thematic analysis was performed.ResultsThis study highlights that professionals working within paediatric nephrology in Germany are well aware of the importance of successful transition. Key elements of transitional care are well understood and mutually agreed on. Nonetheless, implementation within daily routine seems challenging, and the absence of written, structured procedures may hamper successful transition.ConclusionsWhile professionals aim for an individual timing of transfer based on medical, social, emotional and structural aspects, rigid regulations on transfer age as given by the relevant health authorities add on to the challenge.Trial registration numberISRCTN Registry no 22988897; results (phase I) and pre-results (phase II).
A randomised comparison of Conventional versus Intentional straTegy in patients with high Risk prEdiction of Side branch OccLusion in coronary bifurcation interVEntion: rationale and design of the CIT-RESOLVE trial
Authors: Zhang Dong , Yin Dong , Song Chenxi , Zhu Chengang , Kirtane Ajay J , Xu Bo , Dou Kefei 
Published: June 2017

IntroductionThe intentional strategy (aggressive side branch (SB) protection strategy: elective two-stent strategy or jailed balloon technique) is thought to be associated with lower SB occlusion rate than conventional strategy (provisional two-stent strategy or jailed wire technique). However, most previous studies showed comparable outcomes between the two strategies, probably due to no risk classification of SB occlusion when enrolling patients. There is still no randomised trial compared the intentional and conventional strategy when treating bifurcation lesions with high risk of SB occlusion. We aim to investigate if intentional strategy is associated with significant reduction of SB occlusion rate compared with conventional strategy in high-risk patients.Methods and analysisThe Conventional versus Intentional straTegy in patients with high Risk prEdiction of Side branch OccLusion in coronary bifurcation interVEntion (CIT-RESOLVE) is a prospective, randomised, single-blind, multicentre clinical trial comparing the rate of SB occlusion between the intentional strategy group and the conventional strategy group (positive control group) in a consecutive cohort of patients with high risk of side branch occlusion defined by V-RESOLVE score, which is a validated angiographic scoring system to evaluate the risk of SB occlusion in bifurcation intervention and used as one of the inclusion criteria to select patients with high SB occlusion risk (V-RESOLVE score ≥12). A total of 21 hospitals from 10 provinces in China participated in the present study. 566 patients meeting all inclusion/exclusion criteria are randomised to either intentional strategy group or conventional strategy group. The primary endpoint is SB occlusion (defined as any decrease in thrombolysis in myocardial infarction flow grade or absence of flow in SB after main vessel stenting). All patients are followed up for 12-month postdischarge.Ethics and disseminationThe protocol has been approved by all local ethics committee. The ethics committee have approved the study protocol, evaluated the risk to benefit ratio, allowed operators with a minimum annual volume of 200 cases to participate in the percutaneous coronary intervention procedure and permitted them to perform both conventional and intentional strategies. Written informed consent would be acquired from all participants. The findings of the trial will be shared by the participant hospitals and disseminated through peer-reviewed journals.Trial registration numberNCT02644434; Pre-results.
FIRST-line support for Assistance in Breathing in Children (FIRST-ABC): protocol for a multicentre randomised feasibility trial of non-invasive respiratory support in critically ill children
Authors: Ramnarayan Padmanabhan , Lister Paula , Dominguez Troy , Habibi Parviz , Edmonds Naomi , Canter Ruth , Mouncey Paul , Peters Mark J 
Published: June 2017

IntroductionOver 18 000 children are admitted annually to UK paediatric intensive care units (PICUs), of whom nearly 75% receive respiratory support (invasive and/or non-invasive). Continuous positive airway pressure (CPAP) has traditionally been used to provide first-line non-invasive respiratory support (NRS) in PICUs; however, high-flow nasal cannula therapy (HFNC), a novel mode of NRS, has recently gained popularity despite the lack of high-quality trial evidence to support its effectiveness. This feasibility study aims to inform the design and conduct of a future definitive randomised clinical trial (RCT) comparing the two modes of respiratory support.Methods and analysisWe will conduct a three-centre randomised feasibility study over 12 months. Patients admitted to participating PICUs who satisfy eligibility criteria will be recruited to either group A (primary respiratory failure) or group B (postextubation). Consent will be obtained from parents/guardians prior to randomisation in ‘planned’ group B, and deferred in emergency situations (group A and ‘rescue’ group B). Participants will be randomised (1:1) to either CPAP or HFNC using sealed, opaque envelopes, from a computer-generated randomisation sequence with variable block sizes. The study protocol specifies algorithms for the initiation, maintenance and weaning of HFNC and CPAP. The primary outcomes are related to feasibility, including the number of eligible patients in each group, feasibility of randomising >50% of eligible patients and measures of adherence to the treatment protocols. Data will also be collected on patient outcomes (eg, mortality and length of PICU stay) to inform the selection of an appropriate outcome measure in a future RCT. We aim to recruit 120 patients to the study.Ethics and disseminationEthical approval was granted by the National Research Ethics Service Committee North East—Tyne&Wear South (15/NE/0296). Study findings will be disseminated through peer-reviewed journals, national and international conferences.Trials registration numberNCT02612415; pre-results.
Physical activity during pregnancy and infant’s birth weight: results from the 3D Birth Cohort
Authors: Bisson Michèle , Croteau Jordie , Guinhouya Benjamin C , Bujold Emmanuel , Audibert François , Fraser William D , Marc Isabelle 
Published: June 2017

AimTo evaluate the association between maternal physical activity and infant’s birth weight or risk of inappropriate weight for gestational age (GA), and whether this association differs by infant’s sex, maternal body mass index (BMI) or pregnancy complications in a prospective cohort study.Methods1913 pregnant women from the 3D Birth Cohort (Québec, Canada) completed the Pregnancy Physical Activity Questionnaire at each trimester. Energy expenditure (metabolic equivalent of task (MET)*hours/week) for total activity, sports and exercise and vigorous intensity activities was calculated. The associations with birth weight and risk of inappropriate weight for GA were evaluated by regression modelling. Interactions were tested with infant’s sex, maternal prepregnancy BMI, gestational diabetes, hypertensive disorders and prematurity.ResultsEach 1 MET/hours/week increase in sports and exercise in the first trimester was associated with a 2.5 g reduction in infant’s birth weight (95% CI −4.8 to −0.3) but was not associated with the risk of small weight for GA. In contrast, although not significant, a 17% reduction in the risk of large weight for GA was observed with increasing sports and exercise. Furthermore, in women with subsequent pre-eclampsia (but not normotensive or hypertensive women), each 1 MET/hours/week increment spent in any vigorous exercise in the first trimester reduced the infant’s birth weight by 19.8 g (95% CI −35.2 to −4.3).ConclusionsPregnant women with higher sports and exercise levels in the first trimester delivered infants with a lower birth weight. The risk of reducing infant’s birth weight with vigorous exercise in women who develop pre-eclampsia later in pregnancy requires evaluation.
Plasma levels of intact and cleaved urokinase plasminogen activator receptor (uPAR) in men with clinically localised prostate cancer
Authors: Kristensen Gitte , Berg Kasper Drimer , Lippert Solvej , Christensen Ib Jarle , Brasso Klaus , Høyer-Hansen Gunilla , Røder Martin Andreas 
Published: June 2017

AimsLymph node metastasis (N1) is an adverse prognostic factor for men with clinically localised prostate cancer (PCa), but the prediction of N1 disease remains difficult. Urokinase plasminogen activator receptor (uPAR) plays an important role in angiogenesis and tumorigenesis. We analysed whether plasma levels of the soluble uPAR forms uPAR(I-III), uPAR(II-III) and uPAR(I) were associated with the risk of N1 disease in men with clinically localised PCa.MethodsThe present study includes all men (n=518) who underwent radical prostatectomy (RP) for clinically localised PCa, 29 of whom had N1 disease. Soluble uPAR forms were measured using three time-resolved fluorescence immunoassays. The prognostic value of the different uPAR forms together with clinicopathological parameters for N1 disease were analysed using logistic regression, receiver operating characteristic (ROC) regression analysis and quantified using the areas under the ROC curve (AUC).ResultsAll soluble uPAR levels were significantly (p=0.03) higher in patients with N1 disease compared with patients with N0/x disease. ROC curves including clinical tumour stage, biopsy Gleason score, prostate-specific antigen and percent positive biopsies had an AUC of 87.7% for prediction of N1 disease. With the addition of uPAR(I) to the model, the AUC increased to 88.4%.ConclusionsAddition of uPAR(I) level to known diagnostic parameters did not increase the prediction of N1 disease following RP in men with clinically localised PCa. Our results indicate that the plasma levels at diagnosis of the different uPAR forms do not hold important predictive or prognostic information in men with clinically localised PCa.
Lazy Exact Deduplication
Authors: Ma Jingwei , Stones Rebecca J. , Ma Yuxiang , Wang Jingui , Ren Junjie , Wang Gang , Liu Xiaoguang 
Published: June 2017

Deduplication aims to reduce duplicate data in storage systems by removing redundant copies of data blocks, which are compared to one another using fingerprints. However, repeated on-disk fingerprint lookups lead to high disk traffic, which results in a bottleneck.
In this article, we propose a “lazy” data deduplication method, which buffers incoming fingerprints that are used to perform on-disk lookups in batches, with the aim of improving subsequent prefetching. In deduplication in general, prefetching is used to improve the cache hit rate by exploiting locality within the incoming fingerprint stream. For lazy deduplication, we design a buffering strategy that preserves locality in order to facilitate prefetching. Furthermore, as the proportion of deduplication time spent on I/O decreases, the proportion spent on fingerprint calculation and chunking increases. Thus, we also utilize parallel approaches (utilizing multiple CPU cores and a graphics processing unit) to further improve the overall performance.
Experimental results indicate that the lazy method improves fingerprint identification performance by over 50% compared with an “eager” method with the same data layout. The GPU improves the hash calculation by a factor of 4.6 and multithreaded chunking by a factor of 4.16. Deduplication performance can be improved by over 45% on SSD and 80% on HDD in the last round on the real datasets.
Invasive Management Strategies and Antithrombotic Treatments in Patients With Non–ST-Segment–Elevation Acute Coronary Syndrome in China
Authors: Yang Qing , Wang Ying , Liu Jing , Liu Jun , Hao Yongchen , Smith Sidney C. , Huo Yong , Fonarow Gregg C. , Ma Changsheng , Ge Junbo , Taubert Kathryn A. , Morgan Louise , Guo Yang , Wang Wei , Zhou Yujie , Zhao Dong 
Published: June 2017

Background—
Early invasive strategies and antithrombotic treatments are key treatments of non–ST-segment–elevation acute coronary syndrome (NSTE-ACS). Few studies have examined the use of these strategies in patients with NSTE-ACS in China. This study aimed to assess the applications of invasive strategies and antithrombotic treatments in patients with NSTE-ACS and compare their outcomes.

Methods and Results—
A nationwide registry study, Improving CCC (Care for Cardiovascular Disease in China) ACS project, was launched in 2014 as a collaborative study of the American Heart Association and Chinese Society of Cardiology (CSC), with 142 participating hospitals reporting details of clinical management and outcomes of patients with NSTE-ACS. The use of invasive strategies and antithrombotic treatments was examined based on updated guidelines. Major adverse cardiovascular events were analyzed. A total of 9953 patients with NSTE-ACS were enrolled. Angiography was performed in 63.1% of these patients, and 58.2% underwent percutaneous coronary intervention (PCI). However, 40.6% of patients did not undergo early risk assessment, and very-high-risk patients had the lowest proportion of PCI (41.7%). PCI was performed within recommended times in 11.1% of very-high-risk patients and 26.3% of high risk patients. Those who underwent PCI within 2 hours had higher mortality in high-risk and very-high-risk patients who received PCI. Early dual antiplatelet treatment was given in 88.3% of patients.

Conclusions—
There are notable differences between guideline recommendations and the clinical management of patients with NSTE-ACS in China. The reasons for very-high-risk NSTE-ACS patients not undergoing PCI, and the optimal timing of PCI, require further clarification.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT02306616.
Placental Vesicles Carry Active Endothelial Nitric Oxide Synthase and Their Activity is Reduced in Preeclampsia
Authors: Motta-Mejia Carolina , Kandzija Neva , Zhang Wei , Mhlomi Vuyane , Cerdeira Ana Sofia , Burdujan Alexandra , Tannetta Dionne , Dragovic Rebecca , Sargent Ian L. , Redman Christopher W. , Kishore Uday , Vatish Manu 
Published: June 2017

Preeclampsia, a multisystem hypertensive disorder of pregnancy, is associated with increased systemic vascular resistance. Placentae from patients with preeclampsia have reduced levels of endothelial nitric oxide synthase (eNOS) and, thus, less nitric oxide (NO). Syncytiotrophoblast extracellular vesicles (STBEV), comprising microvesicles (STBMV) and exosomes, carry signals from the syncytiotrophoblast to the mother. We hypothesized that STBEV-bound eNOS (STBEV-eNOS), capable of producing NO, are released into the maternal circulation. Dual-lobe ex vivo placental perfusion and differential centrifugation was used to isolate STBEV from preeclampsia (n=8) and normal pregnancies (NP; n=11). Plasma samples of gestational age–matched preeclampsia and NP (n=6) were used to isolate circulating STBMV. STBEV expressed placental alkaline phosphatase, confirming placental origin. STBEV coexpressed eNOS, but not inducible nitric oxide synthase, confirmed using Western blot, flow cytometry, and immunodepletion. STBEV-eNOS produced NO, which was significantly inhibited by
N

G
-nitro-
l
-arginine methyl ester (eNOS inhibitor;
P
<0.05) but not by
N
-(3-(aminomethyl) bezyl) acetamidine) (inducible nitric oxide synthase inhibitor). STBEV-eNOS catalytic activity was confirmed by visualizing eNOS dimerization. STBEV-eNOS was more abundant in uterine vein compared with peripheral blood, indicating placental origin. STBEV isolated from preeclampsia-perfused placentae had lower levels of STBEV-eNOS (STBMV;
P
<0.05) and overall lower NO activity (STBMV, not significant; syncytiotrophoblast extracellular exosomes,
P
<0.05) compared with those from NP. Circulating plasma STBMV from preeclampsia women had lower STBEV-eNOS expression compared with that from NP women (
P
<0.01). This is the first observation of functional eNOS expressed on STBEV from NP and preeclampsia placentae, as well as in plasma. The lower STBEV-eNOS NO production seen in preeclampsia may contribute to the decreased NO bioavailability in this disease.