bluuebunny/crossref_metadata_2025_split huggingface dataset:
Subregional differences in the generation of fast network oscillations in the rat medial prefrontal cortex (mPFC) in vitro
Authors: Glykos Vasileios , Whittington Miles A. , LeBeau Fiona E. N. 
Published: June 2015

Key points
Fast network oscillations in the beta (20–30 Hz) frequency range can be evoked with combined activation of muscarinic and kainate receptors in different subregions of the medial prefrontal cortex (mPFC).

Subregional differences were observed as the oscillations in the dorsal prelimbic cortex (PrL) were smaller in magnitude than those in the ventral dorsopeduncular (DP) region, and these differences persisted in trimmed slices containing only PrL and DP regions.
Oscillations in both regions were dependent upon GABAA and AMPA receptor activation but NMDA receptor blockade decreased oscillations only in the DP region.
Subregional differences in neuronal properties of the presumed pyramidal cells were found between PrL and DP, with many more cells in DP firing rhythmically compared to the PrL region.
Presumed inhibitory synaptic potentials (IPSPs) recorded from principal cells were more rhythmic and coherent, and significantly larger in amplitude, in the DP region; the data suggest that variation in the patterns of activity between subregions may reflect distinct functional roles.
AbstractFast network oscillations in the beta (20–30 Hz) and low gamma (30–80 Hz) range underlie higher cognitive functions associated with the medial prefrontal cortex (mPFC) including attention and working memory. Using a combination of kainate (KA, 200 nm) and the cholinergic agonist carbachol (Cb, 10 μm) fast network oscillations, in the beta frequency range, were evoked in the rat mPFC in vitro. Oscillations were elicited in the prelimbic (PrL), infralimbic (IL) and the dorsopeduncular (DP) cortex, with the largest oscillations observed in DP cortex. Oscillations in both the PrL and DP were dependent, with slightly different sensitivities, on γ‐aminobutyric acid (GABA)A, α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) and kainate receptors, but only oscillations in the DP were significantly reduced by N‐methyl‐d‐aspartate (NMDA) receptor blockade. Intracellular recordings showed that 9/20 regular spiking (RS) cells in the PrL exhibited a notable cAMP‐dependent hyperpolarisation activated current (Ih) in contrast to 16/17 in the DP cortex. Extracellular single unit recordings showed that the majority of cells in the PrL, and DP regions had interspike firing frequencies (IFFs) at beta (20–30 Hz) frequencies and fired at the peak negativity of the field oscillation. Recordings in DP revealed presumed inhibitory postsynaptic potentials (IPSPs) that were larger in amplitude and more rhythmic than those in the PrL region. Our data suggest that each PFC subregion may be capable of generating distinct patterns of network activity with different cell types involved. Variation in the properties of oscillations evoked in the PrL and DP probably reflects the distinct functional roles of these different PFC regions.
Genomic Context of Azole Resistance Mutations in Aspergillus fumigatus Determined Using Whole-Genome Sequencing
Authors: Abdolrasouli Alireza , Rhodes Johanna , Beale Mathew A. , Hagen Ferry , Rogers Thomas R. , Chowdhary Anuradha , Meis Jacques F. , Armstrong-James Darius , Fisher Matthew C. 
Published: June 2015

ABSTRACT

A rapid and global emergence of azole resistance has been observed in the pathogenic fungus
Aspergillus fumigatus
over the past decade. The dominant resistance mechanism appears to be of environmental origin and involves mutations in the
cyp51A
gene, which encodes a protein targeted by triazole antifungal drugs. Whole-genome sequencing (WGS) was performed for high-resolution single-nucleotide polymorphism (SNP) analysis of 24
A. fumigatus
isolates, including azole-resistant and susceptible clinical and environmental strains obtained from India, the Netherlands, and the United Kingdom, in order to assess the utility of WGS for characterizing the alleles causing resistance. WGS analysis confirmed that TR
34
/L98H (a mutation comprising a tandem repeat [TR] of 34 bases in the promoter of the
cyp51A
gene and a leucine-to-histidine change at codon 98) is the sole mechanism of azole resistance among the isolates tested in this panel of isolates. We used population genomic analysis and showed that
A. fumigatus
was panmictic, with as much genetic diversity found within a country as is found between continents. A striking exception to this was shown in India, where isolates are highly related despite being isolated from both clinical and environmental sources across >1,000 km; this broad occurrence suggests a recent selective sweep of a highly fit genotype that is associated with the TR
34
/L98H allele. We found that these sequenced isolates are all recombining, showing that azole-resistant alleles are segregating into diverse genetic backgrounds. Our analysis delineates the fundamental population genetic parameters that are needed to enable the use of genome-wide association studies to identify the contribution of SNP diversity to the generation and spread of azole resistance in this medically important fungus.

IMPORTANCE
Resistance to azoles in the ubiquitous ascomycete fungus
A. fumigatus
was first reported from clinical isolates collected in the United States during the late 1980s. Over the last decade, an increasing number of
A. fumigatus
isolates from the clinic and from nature have been found to show resistance to azoles, suggesting that resistance is emerging through selection by the widespread usage of agricultural azole antifungal compounds. Aspergillosis is an emerging clinical problem, with high rates of treatment failures necessitating the development of new techniques for surveillance and for determining the genome-wide basis of azole resistance in
A. fumigatus
.
Defining the Roles of TcdA and TcdB in Localized Gastrointestinal Disease, Systemic Organ Damage, and the Host Response during Clostridium difficile Infections
Authors: Carter Glen P. , Chakravorty Anjana , Pham Nguyen Tu Anh , Mileto Steven , Schreiber Fernanda , Li Lucy , Howarth Pauline , Clare Simon , Cunningham Bliss , Sambol Susan P. , Cheknis Adam , Figueroa Iris , Johnson Stuart , Gerding Dale , Rood Julian I. , Dougan Gordon , Lawley Trevor D. , Lyras Dena 
Published: June 2015

ABSTRACT

Clostridium difficile
is a leading cause of antibiotic-associated diarrhea, a significant animal pathogen, and a worldwide public health burden. Most disease-causing strains secrete two exotoxins, TcdA and TcdB, which are considered to be the primary virulence factors. Understanding the role that these toxins play in disease is essential for the rational design of urgently needed new therapeutics. However, their relative contributions to disease remain contentious. Using three different animal models, we show that TcdA
+
TcdB
−
mutants are attenuated in virulence in comparison to the wild-type (TcdA
+
TcdB
+
) strain, whereas TcdA
−
TcdB
+
mutants are fully virulent. We also show for the first time that TcdB alone is associated with both severe localized intestinal damage and systemic organ damage, suggesting that this toxin might be responsible for the onset of multiple organ dysfunction syndrome (MODS), a poorly characterized but often fatal complication of
C. difficile
infection (CDI). Finally, we show that TcdB is the primary factor responsible for inducing the
in vivo
host innate immune and inflammatory responses. Surprisingly, the animal infection model used was found to profoundly influence disease outcomes, a finding which has important ramifications for the validation of new therapeutics and future disease pathogenesis studies. Overall, our results show unequivocally that TcdB is the major virulence factor of
C. difficile
and provide new insights into the host response to
C. difficile
during infection. The results also highlight the critical nature of using appropriate and, when possible, multiple animal infection models when studying bacterial virulence mechanisms.

IMPORTANCE
Clostridium difficile
is a leading cause of antibiotic-associated diarrhea and an important hospital pathogen. TcdA and TcdB are thought to be the primary virulence factors responsible for disease symptoms of
C. difficile
infections (CDI). However, the individual contributions of these toxins to disease remain contentious. Using three different animal models of infection, we show for the first time that TcdB alone causes severe damage to the gut, as well as systemic organ damage, suggesting that this toxin might be responsible for MODS, a serious but poorly understood complication of CDI. These findings provide important new insights into the host response to
C. difficile
during infection and should guide the rational development of urgently required nonantibiotic therapeutics for the treatment of CDI.
Bacteriophages Limit the Existence Conditions for Conjugative Plasmids
Authors: Harrison Ellie , Wood A. Jamie , Dytham Calvin , Pitchford Jonathan W. , Truman Julie , Spiers Andrew , Paterson Steve , Brockhurst Michael A. 
Published: June 2015

ABSTRACT
Bacteriophages are a major cause of bacterial mortality and impose strong selection on natural bacterial populations, yet their effects on the dynamics of conjugative plasmids have rarely been tested. We combined experimental evolution, mathematical modeling, and individual-based simulations to explain how the ecological and population genetics effects of bacteriophages upon bacteria interact to determine the dynamics of conjugative plasmids and their persistence. The ecological effects of bacteriophages on bacteria are predicted to limit the existence conditions for conjugative plasmids, preventing persistence under weak selection for plasmid accessory traits. Experiments showed that phages drove faster extinction of plasmids in environments where the plasmid conferred no benefit, but they also revealed more complex effects of phages on plasmid dynamics under these conditions, specifically, the temporary maintenance of plasmids at fixation followed by rapid loss. We hypothesized that the population genetic effects of bacteriophages, specifically, selection for phage resistance mutations, may have caused this. Further mathematical modeling and individual-based simulations supported our hypothesis, showing that conjugative plasmids may hitchhike with phage resistance mutations in the bacterial chromosome.

IMPORTANCE
Conjugative plasmids are infectious loops of DNA capable of transmitting DNA between bacterial cells and between species. Because plasmids often carry extra genes that allow bacteria to live in otherwise-inhospitable environments, their dynamics are central to understanding bacterial adaptive evolution. The plasmid-bacterium interaction has typically been studied in isolation, but in natural bacterial communities, bacteriophages, viruses that infect bacteria, are ubiquitous. Using experiments, mathematical models, and computer simulations we show that bacteriophages drive plasmid dynamics through their ecological and evolutionary effects on bacteria and ultimately limit the conditions allowing plasmid existence. These results advance our understanding of bacterial adaptation and show that bacteriophages could be used to select against plasmids carrying undesirable traits, such as antibiotic resistance.
Inhibiting the Mammalian Target of Rapamycin Blocks the Development of Experimental Cerebral Malaria
Authors: Gordon Emile B. , Hart Geoffrey T. , Tran Tuan M. , Waisberg Michael , Akkaya Munir , Skinner Jeff , Zinöcker Severin , Pena Mirna , Yazew Takele , Qi Chen-Feng , Miller Louis H. , Pierce Susan K. 
Published: June 2015

ABSTRACTMalaria is an infectious disease caused by parasites of severalPlasmodiumspp. Cerebral malaria (CM) is a common form of severe malaria resulting in nearly 700,000 deaths each year in Africa alone. At present, there is no adjunctive therapy for CM. Although the mechanisms underlying the pathogenesis of CM are incompletely understood, it is likely that both intrinsic features of the parasite and the human host's immune response contribute to disease. The kinase mammalian target of rapamycin (mTOR) is a central regulator of immune responses, and drugs that inhibit the mTOR pathway have been shown to be antiparasitic. In a mouse model of CM, experimental CM (ECM), we show that the mTOR inhibitor rapamycin protects against ECM when administered within the first 4 days of infection. Treatment with rapamycin increased survival, blocked breakdown of the blood-brain barrier and brain hemorrhaging, decreased the influx of both CD4+and CD8+T cells into the brain and the accumulation of parasitized red blood cells in the brain. Rapamycin induced marked transcriptional changes in the brains of infected mice, and analysis of transcription profiles predicted that rapamycin blocked leukocyte trafficking to and proliferation in the brain. Remarkably, animals were protected against ECM even though rapamycin treatment significantly increased the inflammatory response induced by infection in both the brain and spleen. These results open a new avenue for the development of highly selective adjunctive therapies for CM by targeting pathways that regulate host and parasite metabolism.IMPORTANCEMalaria is a highly prevalent infectious disease caused by parasites of severalPlasmodiumspp. Malaria is usually uncomplicated and resolves with time; however, in about 1% of cases, almost exclusively among young children, malaria becomes severe and life threatening, resulting in nearly 700,000 deaths each year in Africa alone. Among the most severe complications ofPlasmodium falciparuminfection is cerebral malaria with a fatality rate of 15 to 20%, despite treatment with antimalarial drugs. Cerebral malaria takes a second toll on African children, leaving survivors at high risk of debilitating neurological defects. At present, we have no effective adjunctive therapies for cerebral malaria, and developing such therapies would have a large impact on saving young lives in Africa. Here we report results that open a new avenue for the development of highly selective adjunctive therapies for cerebral malaria by targeting pathways that regulate host and parasite metabolism.
Holocene fluvial landforms and depositional environments of the Lower Mississippi Valley
Authors: Saucier Roger T. 
Published: June 2015

Abstract
Holocene fluvial land forms are exposed along a 46-mi (74 km) circuitous route west of Natchez, Mississippi, in Concordia Parish, northeastern Louisiana. The route encompasses U.S. 84 and Louisiana 129, 565, and 15 through the communities of Ferriday, Stacy, Monterey, and Deer Park (Fig. 1).
Road shoulders are adequate for safe temporary parking at al locations. All lands beyond highway rights-of-way are privately owned. Best observation is in winter to early spring due to an absence of foliage and crops.
Influence of adiposity on health-related quality of life in the Gateshead Millennium Study cohort: longitudinal study at 12 years
Authors: Parkinson Kathryn N , Adamson Ashley J , Basterfield Laura , Reilly Jessica K , Le Couteur Ann , Reilly John J 
Published: June 2015

ObjectiveTo examine whether adiposity is associated with an impaired quality of life (an individual's perception of their life) in general population samples in early adolescence.Design and methodsRelationships between a direct measure of adiposity (fat mass index from bioimpedance) and a proxy measure (waist circumference), and a generic (KIDSCREEN-27) and a weight-specific measure of health-related quality of life (HRQoL, Impact of Weight on Quality of Life-Kids (IWQOL-Kids)) were examined in a longitudinal population-based cohort of young adolescents aged 12 years (n=519). The effects of change in adiposity over time (from 7 years and 9 years) were also examined (n=331–445 in longitudinal analyses).ResultsImpairment in HRQoL was associated with current adiposity but it was not predicted by earlier adiposity. At 12 years, higher adiposity was associated with lowerPhysical Well-Beingon KIDSCREEN-27, and with lowerTotal Scoreson the weight-specific IWQOL-Kids instrument, the latter particularly in girls.ConclusionsHealth and education professionals need to be aware in their clinical practice that higher adiposity impairs HRQoL in general populations of young adolescents. Further research would be useful to determine whether or not children of primary school age self-reporting lower HRQoL are more likely to develop higher adiposity later in adolescence or early adulthood.
Structured exercise improves mobility after hip fracture: a meta-analysis with meta-regression
Authors: Diong Joanna , Allen Natalie , Sherrington Catherine 
Published: June 2015

ObjectivesTo determine the effect of structured exercise on overall mobility in people after hip fracture. To explore associations between trial-level characteristics and overall mobility.DesignSystematic review, meta-analysis and meta-regression.Data sourcesMEDLINE, EMBASE, CINAHL, the Cochrane Central Register of Controlled Trials, the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register and the Physiotherapy Evidence Database to May 2014.Study eligibility criteria, participants and interventionsRandomised controlled trials of structured exercise, which aimed to improve mobility compared with a control intervention in adult participants after surgery for hip fracture were included.Data extraction and synthesisData were extracted by one investigator and checked by an independent investigator. Standardised mean differences (SMD) of overall mobility were meta-analysed using random effects models. Random effects meta-regression was used to explore associations between trial-level characteristics and overall mobility.Results13 trials included in the meta-analysis involved 1903 participants. The pooled Hedges’ g SMD for overall mobility was 0.35 (95% CI 0.12 to 0.58, p=0.002) in favour of the intervention. Meta-regression showed greater treatment effects in trials that included progressive resistance exercise (change in SMD=0.58, 95% CI 0.17 to 0.98, p=0.008, adjusted R2=60%) and delivered interventions in settings other than hospital alone (change in SMD=0.50, 95% CI 0.08 to 0.93, p=0.024, adjusted R2=49%).Conclusions and implicationsStructured exercise produced small improvements on overall mobility after hip fracture. Interventions that included progressive resistance training and were delivered in other settings were more effective, although the latter may have been confounded by duration of interventions.
Variations in Health-Related Quality of Life (HRQoL) and survival 1 year after stroke: five European population-based registers
Authors: Ayis Salma , Wellwood Ian , Rudd Anthony G , McKevitt Christopher , Parkin David , Wolfe Charles D A 
Published: June 2015

ObjectiveThere were two main objectives: to describe and compare clinical outcomes and Patient-Reported Outcome Measures (PROMs) collected using standardised procedures across the European Registers of Stroke (EROS) at 3 and 12 months after stroke; and to examine the relationship between patients’ Health-Related Quality of Life (HRQoL) at 3 months after stroke and survival up to 1 year across the 5 populations.DesignAnalysis of data from population-based stroke registers.SettingEuropean populations in Dijon (France); Kaunas (Lithuania); London (UK); Warsaw (Poland) and Sesto Fiorentino (Italy).ParticipantsPatients with ischaemic or intracerebral haemorrhage (ICH) stroke, registered between 2004 and 2006.Outcome measures(1) HRQoL, assessed by the physical component summary (PCS) and mental component summary (MCS) of the Short-Form Health Survey (SF-12), mapped into the EQ-5D to estimate responses on 5 dimensions (mobility, activity, pain, anxiety and depression, and self-care) and utility scores. (2) Mortality within 3 months and within 1 year of stroke.ResultsOf 1848 patients, 325 were lost to follow-up and 500 died within a year of stroke. Significant differences in mortality, HRQoL and utility scores were found, and remained after adjustments. Kaunas had an increased risk of death; OR 2.34, 95% CI (1.32 to 4.14) at 3 months after stroke in Kaunas, compared with London. Sesto Fiorentino had the highest adjusted PCS: 43.54 (SD=0.96), and Dijon had the lowest adjusted MCS: 38.67 (SD=0.67). There are strong associations between levels of the EQ-5D at 3 months and survival within the year. The trend across levels suggests a dose–response relationship.ConclusionsThe study demonstrated significant variations in survival, HRQoL and utilities across populations that could not be explained by stroke severity and sociodemographic factors. Strong associations between HRQoL at 3 months and survival to 1 year after stroke were identified.
Insulin treatment of maternal diabetes mellitus and respiratory outcome in late-preterm and term singletons
Authors: Becquet Odile , El Khabbaz Fares , Alberti Corinne , Mohamed Damir , Blachier Audrey , Biran Valérie , Sibony Olivier , Baud Olivier 
Published: June 2015

ObjectivesWhile the incidence of diabetes mellitus (DM) during pregnancy has been steadily increasing in recent years, the link between gestational DM and respiratory outcome in neonates has not been definitely established. We asked the question whether DM status and its treatment during pregnancy could influence the risk of neonatal respiratory distress.DesignWe studied in a large retrospective cohort the relationship between maternal DM status (non-DM, insulin-treated DM (IT-DM) and non-insulin-treated DM (NIT-DM)), and respiratory distress in term and near-term inborn singletons.ResultsAmong 18 095 singletons delivered at 34 weeks of gestation or later, 412 (2.3%) were admitted to the neonatal intensive care unit (NICU) for respiratory distress within the first hours of life. The incidence of NICU admission due to respiratory distress groups was 2.2%, 5.7% and 2.1% in the non-DM, IT-DM and NIT-DM groups, respectively. Insulin treatment of DM, together with several other perinatal factors, was associated with a significant increased risk for respiratory distress. Several markers of the severity of respiratory illness, including durations of mechanical ventilation and supplemental oxygen, and hypertrophic cardiomyopathy were also found increased following IT-DM as compared with NIT-DM. In a multivariate model, we found that IT-DM, but not NIT-DM, was significantly associated with respiratory distress independent of gestational age and caesarean section, with an incidence rate ratio of 1.44 (1.00–2.08).ConclusionsThis study shows that the treatment of maternal DM with insulin during pregnancy is an independent risk factor for respiratory distress in term and near-term newborns.