bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epidemiology and genetics of cystic fibrosis in Asia: In preparation for the next‐generation treatments
Authors: Singh Meenu , Rebordosa Cristina , Bernholz Juliane , Sharma Neeraj 
Published: October 2015

AbstractCystic fibrosis (CF) in the Asian population is less frequently reported due to under‐diagnosis and lack of centralized CF patient registries. Clinical studies on CF cases from Asia have documented a severe course of the disease. The spectrum of the cystic fibrosis transmembrane conductance regulator (CFTR) variants in this population is quite heterogeneous. In total, 166 variants have been reported on approximately 3700 Asian CF chromosomes. The frequency of F508del among Asians is low compared with Caucasians. Recent in vitro studies have shown promise of small molecule correction and potentiation of 45 different CFTR variants. Of these variants, 16 (including G551D and F508del) have also been observed among Asian CF individuals. We suggest undertaking molecular studies extensively to annotate CFTR variants that will help Asian CF individuals to benefit from the precision medicine gaining momentum in the Western countries.
Reactive transport modelling of reflux dolomitization in the Arab‐D reservoir, Ghawar field, Saudi Arabia
Authors: Lu Peng , Cantrell Dave 
Published: October 2015

AbstractIt has long been recognized that the Arab‐D reservoir in Ghawar field has been significantly dolomitized and that the distribution of dolomites is highly heterogeneous across this reservoir. Previous studies indicated that dolomite occurs with either a stratigraphic or non‐stratigraphic distribution; when mapped, dolomite tends to form several parallel linear trends across the field. Although stratigraphic dolomite was suggested to be formed early from highly evaporated pore fluids sourced from overlying evaporite deposits, non‐stratigraphic dolomite was thought to be generated primarily from hydrothermal fluids sourced from below. This study focuses primarily on these non‐stratigraphic dolomites, and proposes that: (i) these dolomites initially formed via seepage reflux, but were reinforced by late stage hydrothermal dolomitization; and (ii) reflux is also responsible for the formation of parallel, linear trends of dolomite. The reflux model hypothesizes that an evaporative lagoon (which is the source of dolomitizing fluids) formed during the falling stage systems tract of a depositional sequence, and that with continuing sea‐level fall this lagoon migrated progressively towards deeper parts of an intrashelf basin adjacent to the Ghawar field, leaving behind lines of dolomite bodies along a series of temporary coastlines. Two‐dimensional reactive transport models have been built to test this hypothesis, and have resulted in a predicted pattern of dolomite bodies that agrees with both the observed vertical distribution of non‐stratigraphic dolomite, as well as the mapped lateral distribution of the dolomite trends. In addition, the major ion compositions of Late Jurassic seawater are calculated based on fluid inclusion data in the literature. Using Jurassic seawater in current models leads to the absence of anhydrite cements and less potential of over‐dolomitization than using modern seawater.
Time‐dependent stabilization of the +1 nucleosome is an early step in the transition to stable cold‐induced repression of FLC
Authors: Jean Finnegan E. 
Published: October 2015

SummaryIn vernalized Arabidopsis, the extent of FLC repression and promotion of flowering are correlated with the length of winter (low temperature exposure), but how plants measure the duration of winter is unknown. Repression of FLC occurs in two phases: establishment and maintenance. This study investigates the early events in the transition between establishment and maintenance of repression. Initial repression was rapid but transient; within 24 h of being placed at low temperatures FLC transcription was reduced by 40% and repression was complete after 5 days in the cold. The extent to which repression was maintained depended on the length of the cold treatment. Occupancy of the +1 nucleosome in FLC chromatin increased in a time‐dependent manner over a 4‐week low temperature treatment concomitant with decreased histone acetylation and increased trimethylation of histone H3 lysine 27 (H3K27me3). Mutant analyses showed that increased nucleosome occupancy occurred independent of histone deacetylation and increased H3K27me3, suggesting that it is an early step in the switch between transient and stable repression. Both altered histone composition and deacetylation contributed to increased nucleosome occupancy. The time‐dependency of the steps required for the switch between transient and stable repression suggests that the duration of winter is measured by the chromatin state at FLC. A chromatin‐based switch is consistent with finding that each FLC allele in a cell undergoes this transition independently.
Adaptations of skeletal muscle mitochondria to exercise training
Authors: Lundby Carsten , Jacobs Robert A. 
Published: October 2015

New Findings
What is the topic of this review?
We review recent work relating to exercise‐induced alterations in mitochondrial structure and function.
What advances does it highlight?
Training mitochondrial volume density increases due to 1) an increase cross sectional area and 2) longitudinal growth. Specific respiratory alterations appear dependent on exercise training intensity. Low‐moderate endurance training primarily improves the capacity for fat oxidation whereas high‐intensity interval training (HIT) improves global respiratory capacity. The latter includes maximal state 3 mass‐specific respiration, which is the strongest individual measure predictive of endurance performance. This highlights the importance of training specificity in endurance athletes.
Mitochondrial volume density (MitoVD) is composed of two distinct mitochondrial subpopulations— intermyofibrillar mitochondria (MitoIMF) and subsarcolemmal mitochondria (MitoSS). With exercise training, MitoVD may increase by up to 40% and is, for the most part, related to an increase in MitoIMF. Exercise‐induced adaptations in mitochondrial function depend on the intensity of training and appear to be explained predominately by an increased expression of mitochondrial enzymes that facilitate aerobic metabolism. Although mitochondrial content often increases with training, it seems that mitochondrial adaptations are not needed to facilitate maximal oxygen uptake, whereas such adaptations are of greater importance for endurance capacity.
Innervation and neuromuscular control in ageing skeletal muscle
Authors: Hepple Russell T. , Rice Charles L. 
Published: October 2015

AbstractChanges in the neuromuscular system affecting the ageing motor unit manifest structurally as a reduction in motor unit number secondary to motor neuron loss; fibre type grouping due to repeating cycles of denervation‐reinnervation; and instability of the neuromuscular junction that may be due to either or both of a gradual perturbation in postsynaptic signalling mechanisms necessary for maintenance of the endplate acetylcholine receptor clusters or a sudden process involving motor neuron death or traumatic injury to the muscle fibre. Functionally, these changes manifest as a reduction in strength and coordination that precedes a loss in muscle mass and contributes to impairments in fatigue. Regular muscle activation in postural muscles or through habitual physical activity can attenuate some of these structural and functional changes up to a point along the ageing continuum. On the other hand, regular muscle activation in advanced age (>75 years) loses its efficacy, and at least in rodents may exacerbate age‐related motor neuron death. Transgenic mouse studies aimed at identifying potential mechanisms of motor unit disruptions in ageing muscle are not conclusive due to many different mechanisms converging on similar motor unit alterations, many of which phenocopy ageing muscle. Longitudinal studies of ageing models and humans will help clarify the cause and effect relationships and thus, identify relevant therapeutic targets to better preserve muscle function across the lifespan.
image
3-Halo Chloroquine Derivatives Overcome Plasmodium falciparum Chloroquine Resistance Transporter-Mediated Drug Resistance in P. falciparum
Authors: Edaye Sonia , Tazoo Dagobert , Bohle D. Scott , Georges Elias 
Published: October 2015

ABSTRACT

Polymorphism in the
Plasmodium falciparum
chloroquine resistance transporter (PfCRT) was shown to cause chloroquine resistance. In this report, we examined the antimalarial potential of novel 3-halo chloroquine derivatives (3-chloro, 3-bromo, and 3-iodo) against chloroquine-susceptible and -resistant
P. falciparum
. All three derivatives inhibited the proliferation of
P. falciparum
; with 3-iodo chloroquine being most effective. Moreover, 3-iodo chloroquine was highly effective at potentiating and reversing chloroquine toxicity of drug-susceptible and -resistant
P. falciparum
.
Clonal Dissemination of Enterobacter cloacae Harboring
bla
KPC-3
in the Upper Midwestern United States
Authors: Hargreaves Melissa L. , Shaw Kristin M. , Dobbins Ginette , Snippes Vagnone Paula M. , Harper Jane E. , Boxrud Dave , Lynfield Ruth , Aziz Maliha , Price Lance B. , Silverstein Kevin A. T. , Danzeisen Jessica L. , Youmans Bonnie , Case Kyle , Sreevatsan Srinand , Johnson Timothy J. 
Published: October 2015

ABSTRACT

Carbapenemase-producing, carbapenem-resistant
Enterobacteriaceae
, or CP-CRE, are an emerging threat to human and animal health, because they are resistant to many of the last-line antimicrobials available for disease treatment. Carbapenemase-producing
Enterobacter cloacae
harboring
bla
KPC-3
recently was reported in the upper midwestern United States and implicated in a hospital outbreak in Fargo, North Dakota (L. M. Kiedrowski, D. M. Guerrero, F. Perez, R. A. Viau, L. J. Rojas, M. F. Mojica, S. D. Rudin, A. M. Hujer, S. H. Marshall, and R. A. Bonomo, Emerg Infect Dis 20:1583–1585, 2014,
http://dx.doi.org/10.3201/eid2009.140344
). In early 2009, the Minnesota Department of Health began collecting and screening CP-CRE from patients throughout Minnesota. Here, we analyzed a retrospective group of CP-
E. cloacae
isolates (
n
= 34) collected between 2009 and 2013. Whole-genome sequencing and analysis revealed that 32 of the strains were clonal, belonging to the ST171 clonal complex and differing collectively by 211 single-nucleotide polymorphisms, and it revealed a dynamic clone under positive selection. The phylogeography of these strains suggests that this clone existed in eastern North Dakota and western Minnesota prior to 2009 and subsequently was identified in the Minneapolis and St. Paul metropolitan area. All strains harbored identical IncFIA-like plasmids conferring a CP-CRE phenotype and an additional IncX3 plasmid. In a single patient with multiple isolates submitted over several months, we found evidence that these plasmids had transferred from the
E. cloacae
clone to an
Escherichia coli
ST131 bacterium, rendering it as a CP-CRE. The spread of this clone throughout the upper midwestern United States is unprecedented for
E. cloacae
and highlights the importance of continued surveillance to identify such threats to human health.
Complex Regulation Pathways of AmpC-Mediated β-Lactam Resistance in Enterobacter cloacae Complex
Authors: Guérin François , Isnard Christophe , Cattoir Vincent , Giard Jean Christophe 
Published: October 2015

ABSTRACTEnterobacter cloacaecomplex (ECC), an opportunistic pathogen causing numerous infections in hospitalized patients worldwide, is able to resist β-lactams mainly by producing the AmpC β-lactamase enzyme. AmpC expression is highly inducible in the presence of some β-lactams, but the underlying genetic regulation, which is intricately linked to peptidoglycan recycling, is still poorly understood. In this study, we constructed different mutant strains that were affected in genes encoding enzymes suspected to be involved in this pathway. As expected, the inactivation ofampC,ampR(which encodes the regulator protein ofampC), andampG(encoding a permease) abolished β-lactam resistance. Reverse transcription-quantitative PCR (qRT-PCR) experiments combined with phenotypic studies showed that cefotaxime (at high concentrations) and cefoxitin induced the expression ofampCin different ways: one involving NagZ (aN-acetyl-β-d-glucosaminidase) and another independent of NagZ. Unlike the model established forPseudomonas aeruginosa, inactivation of DacB (also known as PBP4) was not responsible for a constitutiveampCoverexpression in ECC, whereas it caused AmpC-mediated high-level β-lactam resistance, suggesting a post-transcriptional regulation mechanism. Global transcriptomic analysis by transcriptome sequencing (RNA-seq) of adacBdeletion mutant confirmed these results. Lastly, analysis of 37 ECC clinical isolates showed that amino acid changes in the AmpD sequence were likely the most crucial event involved in the development of high-level β-lactam resistancein vivoas opposed toP. aeruginosawheredacBmutations have been commonly found. These findings bring new elements for a better understanding of β-lactam resistance in ECC, which is essential for the identification of novel potential drug targets.
Validation and Application of a Dried Blood Spot Ceftriaxone Assay
Authors: Page-Sharp Madhu , Nunn Troy , Salman Sam , Moore Brioni R. , Batty Kevin T. , Davis Timothy M. E. , Manning Laurens 
Published: October 2015

ABSTRACT

Dried blood spot (DBS) antibiotic assays can facilitate pharmacokinetic/pharmacodynamic (PK/PD) studies in situations where venous blood sampling is logistically and/or ethically problematic. In this study, we aimed to develop, validate, and apply a DBS ceftriaxone assay. A liquid chromatography-tandem mass spectroscopy (LC-MS/MS) DBS ceftriaxone assay was assessed for matrix effects, process efficiency, recovery, variability, and limits of quantification (LOQ) and detection (LOD). The effects of hematocrit, protein binding, red cell partitioning, and chad positioning were evaluated, and thermal stability was assessed. Plasma, DBS, and cell pellet ceftriaxone concentrations in 10 healthy adults were compared, and plasma concentration-time profiles of DBS and plasma ceftriaxone were incorporated into population PK models. The LOQ and LOD for ceftriaxone in DBS were 0.14 mg/liter and 0.05 mg/liter, respectively. Adjusting for hematocrit, red cell partitioning, and relative recovery, DBS-predicted plasma concentrations were comparable to measured plasma concentrations (
r
> 0.95,
P
< 0.0001), and Bland-Altman plots showed no significant bias. The final population PK estimates of clearance, volume of distribution, and time above threshold MICs for measured and DBS-predicted plasma concentrations were similar. At 35°C, 21°C, 4°C, −20°C, and −80°C, ceftriaxone retained >95% initial concentrations in DBS for 14 h, 35 h, 30 days, 21 weeks, and >11 months, respectively. The present DBS ceftriaxone assay is robust and can be used as a surrogate for plasma concentrations to provide valid PK and PK/PD data in a variety of clinical situations, including in studies of young children and of those in remote or resource-poor settings.
Multiple Genetic Mutations Associated with Polymyxin Resistance in Acinetobacter baumannii
Authors: Lim Tze Peng , Ong Rick Twee-Hee , Hon Pei-Yun , Hawkey Jane , Holt Kathryn E. , Koh Tse Hsien , Leong Micky Lo-Ngah , Teo Jocelyn Qi-Min , Tan Thean Yen , Ng Mary Mah-Lee , Hsu Li Yang 
Published: October 2015

ABSTRACTWe studied polymyxin B resistance in 10 pairs of clinicalAcinetobacter baumanniiisolates, two of which had developed polymyxin B resistancein vivo. All polymyxin B-resistant isolates had lower growth rates than and substitution mutations in thelpxorpmrBgene compared to their parent isolates. There were significant differences in terms of antibiotic susceptibility and genetic determinants of resistance inA. baumanniiisolates that had developed polymyxin B resistancein vivocompared to isolates that had developed polymyxin B resistancein vitro.
Comparison of the EUCAST and CLSI Broth Microdilution Methods for Testing Isavuconazole, Posaconazole, and Amphotericin B against Molecularly Identified Mucorales Species
Authors: Chowdhary Anuradha , Singh Pradeep Kumar , Kathuria Shallu , Hagen Ferry , Meis Jacques F. 
Published: October 2015

ABSTRACT

We compared EUCAST and CLSI antifungal susceptibility testing (AFST) methods for triazoles and amphotericin B against 124 clinical
Mucorales
isolates. The EUCAST method yielded MIC values 1- to 3-fold dilutions higher than those of the CLSI method for amphotericin B. The essential agreements between the two methods for triazoles were high, i.e., 99.1% (voriconazole), 98.3% (isavuconazole), and 87% (posaconazole), whereas it was significantly lower for amphotericin B (66.1%). Strategies for harmonization of the two methods for
Mucorales
AFST are warranted.
Acquired Multidrug Antifungal Resistance in Candida lusitaniae during Therapy
Authors: Asner Sandra A. , Giulieri Stefano , Diezi Manuel , Marchetti Oscar , Sanglard Dominique 
Published: October 2015

ABSTRACT

Candida lusitaniae
is usually susceptible to echinocandins. Beta-1,3-glucan synthase encoded by
FKS
genes is the target of echinocandins. A few missense mutations in the
C. lusitaniae
FKS1
hot spot 1 (HS1) have been reported. We report here the rapid emergence of antifungal resistance in
C. lusitaniae
isolated during therapy with amphotericin B (AMB), caspofungin (CAS), and azoles for treatment of persistent candidemia in an immunocompromised child with severe enterocolitis and visceral adenoviral disease. As documented from restriction fragment length polymorphism (RFLP) and random amplified polymorphic DNA (RAPD) analysis, the five
C. lusitaniae
isolates examined were related to each other. From antifungal susceptibility and molecular analyses, 5 different profiles (P) were obtained. These profiles included the following: profile 1 (P1) (CAS MIC [μg/ml], 0.5; fluconazole [FLC] MIC, 0.25), determined while the patient was being treated with liposomal AMB for 3 months; P2 (FLC MIC [μg/ml], 0.25; CAS MIC, 4), while the patient was being treated with CAS for 2 weeks; P3 (CAS MIC [μg/ml], 0.5; FLC MIC, 32), while the patient was being treated with azoles and CAS initially followed by azoles alone for a week; P4 (CAS MIC [μg/ml], 8; FLC MIC, 8), while the patient was being treated with both drugs for 3 weeks; and P5 (AMB MIC [μg/ml], 0.125; CAS MIC, 8), while the patient was being treated with AMB and FLC for 2 weeks. CAS resistance was associated with resistance not only to micafungin and anidulafungin but also to AMB. Analysis of CAS resistance revealed 3 novel
FKS1
mutations in CAS-resistant isolates (S638Y in P2; S631Y in P4; S638P in P5). While S638Y and -P are within HS1, S631Y is in close proximity to this domain but was confirmed to confer candin resistance using a site-directed mutagenesis approach. FLC resistance could be linked with overexpression of major facilitator gene 7 (
MFS7
) in
C. lusitaniae
P2 and P4 and was associated with resistance to 5-flurocytosine. This clinical report describes resistance of
C. lusitaniae
to all common antifungals. While candins or azole resistance followed monotherapy, multidrug antifungal resistance emerged during combined therapy.
Global Metabolomic Analysis of a Mammalian Host Infected with Bacillus anthracis
Authors: Nguyen Chinh T. Q. , Shetty Vivekananda , Maresso Anthony W. 
Published: October 2015

ABSTRACT

Whereas DNA provides the information to design life and proteins provide the materials to construct it, the metabolome can be viewed as the physiology that powers it. As such, metabolomics, the field charged with the study of the dynamic small-molecule fluctuations that occur in response to changing biology, is now being used to study the basis of disease. Here, we describe a comprehensive metabolomic analysis of a systemic bacterial infection using
Bacillus anthracis
, the etiological agent of anthrax disease, as the model pathogen. An organ and blood analysis identified approximately 400 metabolites, including several key classes of lipids involved in inflammation, as being suppressed by
B. anthracis
. Metabolite changes were detected as early as 1 day postinfection, well before the onset of disease or the spread of bacteria to organs, which testifies to the sensitivity of this methodology. Functional studies using pharmacologic inhibition of host phospholipases support the idea of a role of these key enzymes and lipid mediators in host survival during anthrax disease. Finally, the results are integrated to provide a comprehensive picture of how
B. anthracis
alters host physiology. Collectively, the results of this study provide a blueprint for using metabolomics as a platform to identify and study novel host-pathogen interactions that shape the outcome of an infection.
Brucella canis Is an Intracellular Pathogen That Induces a Lower Proinflammatory Response than Smooth Zoonotic Counterparts
Authors: Chacón-Díaz Carlos , Altamirano-Silva Pamela , González-Espinoza Gabriela , Medina María-Concepción , Alfaro-Alarcón Alejandro , Bouza-Mora Laura , Jiménez-Rojas César , Wong Melissa , Barquero-Calvo Elías , Rojas Norman , Guzmán-Verri Caterina , Moreno Edgardo , Chaves-Olarte Esteban 
Published: October 2015

ABSTRACT

Canine brucellosis caused by
Brucella canis
is a disease of dogs and a zoonotic risk.
B. canis
harbors most of the virulence determinants defined for the genus, but its pathogenic strategy remains unclear since it has not been demonstrated that this natural rough bacterium is an intracellular pathogen. Studies of
B. canis
outbreaks in kennel facilities indicated that infected dogs displaying clinical signs did not present hematological alterations. A virulent
B. canis
strain isolated from those outbreaks readily replicated in different organs of mice for a protracted period. However, the levels of tumor necrosis factor alpha, interleukin-6 (IL-6), and IL-12 in serum were close to background levels. Furthermore,
B. canis
induced lower levels of gamma interferon, less inflammation of the spleen, and a reduced number of granulomas in the liver in mice than did
B. abortus
. When the interaction of
B. canis
with cells was studied
ex vivo
, two patterns were observed, a predominant scattered cell-associated pattern of nonviable bacteria and an infrequent intracellular replicative pattern of viable bacteria in a perinuclear location. The second pattern, responsible for the increase in intracellular multiplication, was dependent on the type IV secretion system VirB and was seen only if the inoculum used for cell infections was in early exponential phase. Intracellular replicative
B. canis
followed an intracellular trafficking route undistinguishable from that of
B. abortus
. Although
B. canis
induces a lower proinflammatory response and has a stealthier replication cycle, it still displays the pathogenic properties of the genus and the ability to persist in infected organs based on the ability to multiply intracellularly.