bluuebunny/crossref_metadata_2025 huggingface dataset:
Pineal hypoplasia, reduced melatonin and sleep disturbance in patients with PAX6 haploinsufficiency
Authors: Hanish Alyson E. , Butman John A. , Thomas Francine , Yao Jianhua , Han Joan C.
Published: October 2015

In rodent studies, paired box 6 (PAX6) appears to play an important role in the development of the pineal, the primary source of the circadian regulating hormone, melatonin. Pineal hypoplasia has been previously reported in patients with PAX6 haploinsufficiency (+/−); however, pineal measurement, melatonin concentrations and sleep quality have not been reported. This cross‐sectional descriptive study examined pineal volume, melatonin secretion and sleep disturbance in 37 patients with PAX6+/− (age 15.3 ± 9.9 years) and 17 healthy controls (16.0 ± 7.2 years), within an inpatient setting at the Clinical Research Center of the National Institutes of Health, Bethesda, Maryland, USA. Pineal volume was evaluated by magnetic resonance imaging. Diurnal serum cortisol, serum melatonin and urine 6‐sulphatoxymelatonin concentrations were measured by enzyme‐linked immunosorbent assay. The Child Sleep Habits Questionnaire was administered for patients <13 years old. Pineal volume was fivefold lower in PAX6+/− versus controls (mean ± SD: 25 ± 15 versus 129 ± 50 μL, P < 0.001). Midnight serum cortisol was similar in PAX6+/− versus controls (P = 0.14). Midnight serum melatonin was > twofold lower in PAX6+/− versus controls [median (25th–75th): 28 (22–42) versus 71 (46–88) pg mL−1, P < 0.001]. First morning void urinary 6‐sulphatoxymelatonin was fourfold lower in PAX6+/− versus controls [11 (6–26) versus 45 (34–61) ng mg−1 Cr, P = 0.001]. Child Sleep Habits Questionnaire score was higher in PAX6+/− versus controls (48 ± 6 versus 41 ± 5, P = 0.03). The current findings suggest that PAX6+/− is associated with smaller pineal size, lower melatonin secretion and greater parental report of sleep disturbances in children. Further studies are needed to explore the potential use of melatonin replacement for improving sleep quality in patients with PAX6+/−.
Temperature and Time‐Dependent Relaxation of Compressed Cheese Curd Cubes: Effect on Structuring of Pasta‐Filata Cheese
Authors: Bähler Balz , Nägele Michaela , Weiss Jochen , Hinrichs Jörg
Published: October 2015

Production of pasta‐filata cheese comprises a particular scalding and stretching step to obtain the unique fibrous structure. A simulation of this process on small scale was conducted with cheese curd cubes of 10 × 10 × 10 mm. Stretching was initiated with a texture analyzer and a custom‐built geometry in a water bath at 60C. Three parameters were varied: compression rate, pretempering time before compression and duration of compression. The force decline during compression was linearized to receive time independent parameters k1 (y‐axis intercept), k2 (slope) and stress relaxation (SR). Further, relaxation time (RT) and Deborah number (De) were calculated. The RT decreased from 2 to 0.6 s with a temperature increase from 40 to 60C. The SR after 20 s of compression increased from 10 to 23% with increasing temperature due to network formation as shown by confocal laser scanning microscopy. Anisotropy increased with decreasing De.

Practical Applications

When producing pasta‐filata cheese, time and temperature behavior of cheese curd has to be considered during plasticization to obtain the typical fibrous structure. Conclusions for the industry are: (1) plasticization needs time (preheating) as heat transfer in the curd is slow; (2) relaxation of the soft material limits anisotropic structuring; (3) with increasing temperatures relaxation time (RT) decreases, and the process time for stretching can be shortened; and (4) structural changes in the microgel particles during heating induce a continuous protein network with elastic properties which is typical for pasta‐filata cheese production. These results indicate that pasta‐filata cheese with less strings when manually teared, or less anisotropy when visualized by confocal laser scanning microscopy can be modified by adapting the process parameters. Fibrous, anisotropic structure (stringiness) is claimed to be enhanced with increasing residence times and/or higher process temperatures during the stretching process.
Evidence for polymorphism in the cytochrome P450 2D50 gene in horses
Authors: Corado C. R. , McKemie D. S. , Young A. , Knych H. K.
Published: October 2015

Metabolism is an essential factor in the clearance of many drugs and as such plays a major role in the establishment of dosage regimens and withdrawal times. CYP2D6, the human orthologue to equine CYP2D50, is a drug‐metabolizing enzyme that is highly polymorphic in humans leading to widely differing levels of metabolic activity. As CYP2D6 is highly polymorphic, in this study it was hypothesized that the gene coding for the equine orthologue, CYP2D50, may also be prone to polymorphism. Blood samples were collected from 150 horses, the CYP2D50 gene was cloned and sequenced; and full‐length sequences were analyzed for single nucleotide polymorphisms (SNPs), deletions, or insertions. Pharmacokinetic data were collected from a subset of horses following the administration of a single oral dose of tramadol and probit analysis used to calculate metabolic ratios. Prior to drug administration, the ability of recombinant CYP2D50 to metabolize tramadol to O‐desmethyltramadol was confirmed. Sequencing of CYP2D50 identified 126 exonic SNPs, with 31 of those appearing in multiple horses. Oral administration of tramadol to a subset of these horses revealed variable metabolic ratios (tramadol: O‐desmethyltramadol) in individual horses and separation into three metabolic groups. While a limited number of horses of primarily a single breed were studied, the variability in tramadol metabolism to O‐desmethyltramadol between horses and preliminary evidence of what appears to be poor, extensive, and ultra‐rapid metabolizers supports further study of the potential for genetic polymorphisms in the CYP2D50 gene in horses.
The use of PCR-DGGE to determine bacterial fingerprints for poultry and red meat abattoir effluent
Authors: de Smidt O.
Published: October 2015

Strict legislation and chemical composition monitoring of effluent may be useful, but the data generated do not allow for source tracking, and enforcing legislation remains problematic in the South African setting. These difficulties emphasize the necessity for effluent source traceability. Denaturing gradient gel electrophoresis (DGGE) targeting the V3 region of the 16S rRNA gene was considered as fingerprinting technique for effluent originating from abattoirs slaughtering different animal species. The influence of treatment to remove excess fat from effluent prior to molecular analyses and different PCR approaches on the detection of bacterial diversity were considered. Use of a treatment option to remove fat and a nested PCR approach resulted in up to 51% difference in inter-sample diversity similarity. A robust approach with no pre-treatment to remove PCR inhibitors, such as fat, and direct amplification from genomic DNA yielded optimal/maximal bacterial diversity fingerprints. Repeatable fingerprints were obtained for poultry abattoir effluent over a 4-month period, but profiles for the red meat abattoir varied with maximum similarity detected only 33·2%. Genetic material from faecal indicators Aeromona spp and Clostridium spp were detected. Genera unique to each effluent were present; Anoxybacillus, Patulibacter and Oleispira in poultry abattoir effluent and Porphyromonas and Peptostreptococcus in red meat abattoir effluent.

Significance and Impact of the Study

This study was the first to demonstrate the application of denaturing gradient gel electrophoresis (DGGE) to construct bacterial diversity fingerprints for high-throughput abattoir effluents. Proved redundancy of fat removal as PCR inhibitor and change in diversity similarity introduced by nested PCR approach. The importance of limiting excessive handling/processing which could lead to misrepresented diversity profiles was emphasized.
Motivation, Vision, and Gender: A Survey of Learners of English in China
Authors: You Chenjing (Julia) , Dörnyei Zoltán , Csizér Kata
Published: October 2015

This study reports on the second phase of a large‐scale stratified survey in China, examining the role of vision and imagery in the learners’ motivation to learn English as a foreign language. Understanding visualization has been a featured area of recent developments in second language (L2) motivation theory, and this study is the first to offer a broad overview of the extent to which the capacity of vision contributes to the overall motivational setup of a whole language learning community. Besides surveying several imagery‐related variables in an extensive sample of Chinese secondary school and university students (N > 10,000) by comparing male and female Chinese L2 learners’ (often different) motivational dispositions with and without any prior visualization experience, the study also explores the visionary trajectories of learners who reported positive and negative changes in their imagery capacity over time, thereby examining the impact of the change in vision on motivational development.

Open Practices

This article has been awarded an Open Materials badge. All materials are publicly accessible in the IRIS digital repository at http://www.iris‐database.org. Learn more about the Open Practices badges from the Center for Open Science: https://osf.io/tvyxz/wiki
Novel genetic capacitors and potentiators for the natural genetic variation of sensory bristles and their trait specificity in Drosophila melanogaster
Authors: Takahashi Kazuo H.
Published: October 2015

Cryptic genetic variation (CGV) is defined as the genetic variation that has little effect on phenotypic variation under a normal condition, but contributes to heritable variation under environmental or genetic perturbations. Genetic buffering systems that suppress the expression of CGV and store it in a population are called genetic capacitors, and the opposite systems are called genetic potentiators. One of the best‐known candidates for a genetic capacitor and potentiator is the molecular chaperone protein, HSP90, and one of its characteristics is that it affects the genetic variation in various morphological traits. However, it remains unclear whether the wide‐ranging effects of HSP90 on a broad range of traits are a general feature of genetic capacitors and potentiators. In the current study, I searched for novel genetic capacitors and potentiators for quantitative bristle traits of Drosophila melanogaster and then investigated the trait specificity of their genetic buffering effect. Three bristle traits of D. melanogaster were used as the target traits, and the genomic regions with genetic buffering effects were screened using the 61 genomic deficiencies examined previously for genetic buffering effects in wing shape. As a result, four and six deficiencies with significant effects on increasing and decreasing the broad‐sense heritability of the bristle traits were identified, respectively. Of the 18 deficiencies with significant effects detected in the current study and/or by the previous study, 14 showed trait‐specific effects, and four affected the genetic buffering of both bristle traits and wing shape. This suggests that most genetic capacitors and potentiators exert trait‐specific effects, but that general capacitors and potentiators with effects on multiple traits also exist.
Impact of anaemia treatment for left ventricular remodelling prior to initiation of dialysis in chronic kidney disease patients: Efficacy and stability of long acting erythropoietin stimulating agents
Authors: Io Hiroaki , Aizawa Masashi , Funabiki Kazuhiko , Horikoshi Satoshi , Tomino Yasuhiko
Published: October 2015

Aim

Anaemia is a common complication in patients with chronic kidney disease (CKD), which may initiate or accelerate left ventricular (LV) hypertrophy (LVH). The present study is a retrospective analysis to assess whether anaemia treatment is independently associated with LV remodelling prior to initiation of dialysis in CKD patients.

Methods

Biochemical and physical values were collected over a period of more than 120 days prior to the initiation of dialysis in 27 patients with CKD. The left ventricular mass index (LVMI) was evaluated by echocardiography twice (at the baseline and the follow‐up at the initiation of the dialysis period).

Results

Patients using long‐acting erythropoietin stimulating agents (L‐ESA) had the tendency of maintaining higher levels of haemoglobin (Hb) than those using short‐acting ESA (S‐ESA). Patients using L‐ESA showed a more significant improvement in the erythropoietin resistance index (ERI) than those of using S‐ESA. In a multivariate regression analysis, the average Hb level for the observational period, the level of Hb at the initiation of dialysis and the use of L‐ESA were independently associated factors for the LVMI at the initiation of dialysis. A lower LVMI at the initiation of dialysis and an improvement of the LVMI during the observational period were detected in the highest tertile of average Hb (10.4 g/dL).

Conclusion

Long‐acting ESA was effective and stable when treating anaemia until the start of dialysis. It is important to treat anaemia for the prevention of LV remodelling in CKD patients. These findings have some therapeutic implications for treatment strategies for pre‐dialysis patients.
Sugar‐sweetened beverage consumption and risk of incident chronic kidney disease: Tehran lipid and glucose study
Authors: Yuzbashian Emad , Asghari Golaleh , Mirmiran Parvin , Zadeh‐Vakili Azita , Azizi Fereidoun
Published: October 2015

Aim

To evaluate cross‐sectional and longitudinal relationships between sugar sweetened beverages (SSBs), sugar sweetened carbonated soft drinks (SSSDs), and fruit juice drink consumption and risk of chronic kidney disease (CKD) in a population based study.

Method

At baseline, 2382 participants, aged >27 years, of the Tehran Lipid and Glucose Study with complete data on serum creatinine, cardio‐metabolic risk factors, and diet were included for cross‐sectional analysis. After 3 years, 1690 subjects, free of baseline CKD and with complete follow‐up data, were included for longitudinal analysis. Estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease Study equation and CKD was defined as eGFR < 60 mL/min per 1.73 m2. Dietary intake was collected using a food‐frequency questionnaire and SSSDs and all kinds of fruit juice drinks were combined to estimate the intake of SSBs. To assess the association of SSBs and CKD, logistic regression adjusted for age, sex, energy intake, smoking, physical activity, body mass index, sodium, diabetes, and hypertension were used.

Results

The mean age of participants and serving of SSBs/week were 45.0 years and 2.3, respectively. Compared to participants taking <0.5 serving/week, consumption of more than four servings of SSBs and SSSDs per week was associated with increased odds ratio (OR) of prevalent CKD (1.77 and 2.14, respectively). In longitudinal analyses, the risk of incident CKD increased by consumption of four servings/week, compared to less than 0.5 serving/week of SSBs (OR: 1.96; 95% confidence interval (CI):1.23–3.15) and SSSDs (OR: 2.45; 95% CI:1.55–3.89).

Conclusion

Consumption of over four servings per week of SSBs and SSSDs was associated with higher prevalence and incidence of CKD.
Genetic diversity and pathogenicity of Monilinia polystroma – the new pathogen of cherries
Authors: Poniatowska A. , Michalecka M. , Puławska J.
Published: October 2015

Brown rot caused by fungi belonging to the genus Monilinia is one of the major limiting factors of sour and sweet cherry production. Up to now, three species, M. fructigena, M. laxa and M. fructicola, have been identified as causal agents of brown rot on cherries worldwide. From 2010 to 2013, during the monitoring of cherry orchards in different areas of Poland, a fourth species, M. polystroma, was isolated from brown rot symptoms on sour and sweet cherry fruits. To the best of the authors’ knowledge, this is the first time M. polystroma has been reported as the causal agent of brown rot on cherries. The genetic diversity of M. polystroma isolates from cherries and other hosts was analysed using PCR MP, ISSR and RAPD techniques and showed its clear distinctness from other Monilinia spp. tested. The cluster analysis of fingerprinting data revealed a high similarity of M. polystroma isolates from Poland and their close relationship with the reference strain from Japan, indicating that this species is a recently introduced pathogen. The highest genetic distance between the examined isolates and the highest number of different genotypes was observed in an ISSR assay. Detailed genetic diversity characteristics revealed that M. polystroma isolates from cherries did not create a distinct group but were intermingled with M. polystroma isolates from other hosts. The results of the pathogenicity test conducted on different fruit species indicated a lack of host specificity for M. polystroma isolates.
Serum insulin‐like growth factor‐I and amyloid beta protein in Alzheimer's disease: relationship with cognitive function
Authors: Kimoto Ayako , Kasanuki Koji , Kumagai Ryo , Shibata Nobuto , Ichimiya Yosuke , Arai Heii
Published: October 2015

Aims

Previous studies have suggested that insulin‐like growth factor‐I (IGF‐I) deficiency may lead to cognitive deficits in neurodegenerative diseases such as Alzheimer's disease. The present study aimed to investigate the possible relationship between cognitive function and concentration of IGF‐I or amyloid beta protein (Aβ) in serum in Alzheimer's patients.

Methods

A total of 81 Japanese patients were enrolled in this study. Concentrations of IGF‐I, Aβ42, and Aβ40 in serum were measured. Two neuropsychological tests, Mini‐Mental State Examination and Hasegawa's Dementia Scale‐Revised (HDS‐R), were also performed. Linear correlations among the age, serum IGF‐I, serum Aβ42 or Aβ40, Aβ42/Aβ40 ratio, Mini‐Mental State Examination or HDS‐R total score, and the scores for six HDS‐R subscales were analyzed by regression analysis.

Results

IGF‐I showed a significant negative correlation with age (β = −0.357, P = 0.002) and a positive correlation with Aβ42/Aβ40 ratio (β = 0.318, P = 0.007). Serum IGF‐I and both the Mini‐Mental State Examination and the HDS‐R total score also correlated (β = 0.505, β = 0.524, P < 0.01). Among the HDS‐R subscales, ‘Recall’ (ρ = 0.379, P < 0.01), ‘Verbal fluency’ (ρ = 0.360, P < 0.01), and ‘Attention and calculation’ (ρ = 0.389, P < 0.01) showed significant positive correlations with serum IGF‐I.

Conclusion

The results, specifically that lower serum IGF‐I was associated with cognitive impairment, suggest that metabolism of IGF‐I may be involved in the pathogenesis of cognitive deficits in Alzheimer's disease.
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

Cystic 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

It 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

In 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

Changes 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.

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Mechanistic modeling study on process optimization and precursor utilization with atmospheric spatial atomic layer deposition
Authors: Deng Zhang , He Wenjie , Duan Chenlong , Chen Rong , Shan Bin
Published: October 2015

Spatial atomic layer deposition (SALD) is a promising technology with the aim of combining the advantages of excellent uniformity and conformity of temporal atomic layer deposition (ALD), and an industrial scalable and continuous process. In this manuscript, an experimental and numerical combined model of atmospheric SALD system is presented. To establish the connection between the process parameters and the growth efficiency, a quantitative model on reactant isolation, throughput, and precursor utilization is performed based on the separation gas flow rate, carrier gas flow rate, and precursor mass fraction. The simulation results based on this model show an inverse relation between the precursor usage and the carrier gas flow rate. With the constant carrier gas flow, the relationship of precursor usage and precursor mass fraction follows monotonic function. The precursor concentration, regardless of gas velocity, is the determinant factor of the minimal residual time. The narrow gap between precursor injecting heads and the substrate surface in general SALD system leads to a low Péclet number. In this situation, the gas diffusion act as a leading role in the precursor transport in the small gap rather than the convection. Fluid kinetics from the numerical model is independent of the specific structure, which is instructive for the SALD geometry design as well as its process optimization.
Combined Effects of Sedentary Behavior and Moderate-to-Vigorous Physical Activity on Cardiovascular Health in Older, Community-Dwelling Latinos
Authors: Halloway Shannon , Wilbur JoEllen , Schoeny Michael E. , Semanik Pamela A. , Marquez David X.
Published: October 2015

This study examined the combined effects of sedentary behavior and moderate-to-vigorous physical activity (MVPA) on cardiovascular health in older Latinos. In a cross-sectional sample of 147 older, community-dwelling Latinos, time spent in sedentary behavior and MVPA were obtained using accelerometers. Analyses examined the effects of a measure of physical activity that combined levels of sedentary behavior (± 10 daily hours) and MVPA (< 30, 30–150, or > 150 weekly minutes) on cardiovascular health outcomes (blood pressure, BMI, waist circumference, cardiorespiratory fitness). Results suggest that cardiovascular health benefits of MVPA on BMI (p = .005), waist circumference (p = .002), and cardiorespiratory fitness (p = .012) may depend on a participant’s level of sedentary behavior. For all three, health benefits of 30–150 weekly minutes of MVPA were found only for those without excessive sedentary behavior (≥ 10 hr). Sedentary behavior may negatively impact cardiovascular health despite moderate participation in MVPA. Health guidelines should suggest reducing sedentary behavior while increasing MVPA.
A Pilot Study to Assess the Feasibility of Group Exercise and Animal-Assisted Therapy in Older Adults
Authors: Grubbs Brandon , Artese Ashley , Schmitt Karla , Cormier Eileen , Panton Lynn
Published: October 2015

This pilot study assessed the feasibility of incorporating animal-assisted therapy teams (ATT) into a 6-week group exercise program for older adults (77 ± 6 years). Fifteen participants were randomly assigned to an exercise with ATT (E+ATT; n = 8) or exercise only (E; n = 7) group. Groups exercised 3x/week for 45 min. Feasibility was assessed by three objectives: (1) ATT will not need extensive preparation beyond their original therapy training; (2) the study will require minimal cost; and (3) ATT must not impair the effectiveness of the exercise program. By the study conclusion, all objectives were met. Time and cost were minimal for ATT, and adherence was 93% and 90% for E+ATT and E, respectively. There were significant improvements in both groups (p ≤ .05) for arm curls, get-up and go, and 6-min walk. The results of this pilot study suggest that it is feasible to incorporate ATT into group exercise programming for older adults.
The kinases NDR1/2 act downstream of the Hippo homolog MST1 to mediate both egress of thymocytes from the thymus and lymphocyte motility
Authors: Tang Fengyuan , Gill Jason , Ficht Xenia , Barthlott Thomas , Cornils Hauke , Schmitz-Rohmer Debora , Hynx Debby , Zhou Dawang , Zhang Lei , Xue Gongda , Grzmil Michal , Yang Zhongzhou , Hergovich Alexander , Hollaender Georg A. , Stein Jens V. , Hemmings Brian A. , Matthias Patrick
Published: October 2015

Signaling by kinases downstream of the Hippo homolog mediates thymocyte migration.
Tumor-selective proteotoxicity of verteporfin inhibits colon cancer progression independently of YAP1
Authors: Zhang Huabing , Ramakrishnan Sadeesh K. , Triner Daniel , Centofanti Brook , Maitra Dhiman , Győrffy Balázs , Sebolt-Leopold Judith S. , Dame Michael K. , Varani James , Brenner Dean E. , Fearon Eric R. , Omary M. Bishr , Shah Yatrik M.
Published: October 2015

In an oxygen- and nutrient-deprived environment, verteporfin kills colon cancer cells by inducing proteotoxicity.
Serotonergic regulation of melanocyte conversion: A bioelectrically regulated network for stochastic all-or-none hyperpigmentation
Authors: Lobikin Maria , Lobo Daniel , Blackiston Douglas J. , Martyniuk Christopher J. , Tkachenko Elizabeth , Levin Michael
Published: October 2015

Computational modeling reveals mechanisms for the stochastic whole-body conversion of pigment cells in frogs.
An alternative way of making GABA
Authors: Stern Peter
Published: October 2015

Midbrain projection neurons synthesize the neurotransmitter GABA from putrescine rather than glutamate.
Memory consolidation by gene suppression
Authors: Stern Peter
Published: October 2015

Certain genes are repressed at various time points after memory formation, and this is associated with activity-dependent plasticity.
DELivering new therapies for chronic inflammation
Authors: Frisk Megan L.
Published: October 2015

Developmental endothelial locus–1 (DEL-1) is an endogenous homeostatic regulator of osteoclasts that blocks inflammatory bone loss in nonhuman primates.
Metabolic competition between tumors and T cells
Authors: Wong Wei
Published: October 2015

The increased aerobic glycolysis in tumors restricts glucose availability to infiltrating T cells and suppresses immune responses.
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

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

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

Enterobacter 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

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

We 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

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

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

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

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.