bluuebunny/crossref_metadata_2025 huggingface dataset:
Prostaglandin dehydrogenase is a target for successful induction of cervical ripening
Authors: Kishore Annavarapu Hari , Liang Hanquan , Kanchwala Mohammed , Xing Chao , Ganesh Thota , Akgul Yucel , Posner Bruce , Ready Joseph M. , Markowitz Sanford D. , Word Ruth Ann
Published: July 2017

Significance

Prostaglandin E
2
(PGE
2
), a cervical ripening agent, mediates unique EP2 receptor signaling pathways in human cervical stromal cells targeting its own synthesis by increasing cyclooxygenase-2 (COX-2) and PGE synthase (PTGES) expression and decreasing its metabolism by loss of its degradative enzyme 15-hydroxy prostaglandin dehydrogenase (15-PGDH). Here, we show that down-regulation of 15-PGDH is crucial for PGE
2
-induced cervical ripening and preterm birth. This report details unique mechanisms of PGE
2
action in the cervix and serves as a catalyst for (
i
) use of PGDH inhibitors to initiate, or amplify, PGE
2
-mediated cervical ripening and (
ii
) EP2 receptor antagonists, histone deacetylase 4 (HDAC4) inhibitors, or 15-PGDH activators to prevent preterm cervical ripening and preterm birth.
Autophagy-related protein Vps34 controls the homeostasis and function of antigen cross-presenting CD8α+dendritic cells
Authors: Parekh Vrajesh V. , Pabbisetty Sudheer K. , Wu Lan , Sebzda Eric , Martinez Jennifer , Zhang Jianhua , Van Kaer Luc
Published: July 2017

Significance

Dendritic cells (DCs) of the immune system are critical for displaying foreign antigens to T lymphocytes, a process called “antigen presentation.” This process may involve Vacuolar protein sorting 34 (Vps34), a protein implicated in diverse cellular processes, including endocytosis, an extracellular product uptake system, and autophagy, an intracellular degradation system. Here we have generated and analyzed mice in which theVps34gene is specifically knocked out in DCs. These animals displayed defects in the survival and function of a subset of DCs specialized in presenting antigens from dead cells to T cells. Thus our findings have revealed a critical contribution of Vps34 in DC functions that may have important implications for targeting this pathway for therapeutic purposes.
MitoNEET-dependent formation of intermitochondrial junctions
Authors: Vernay Alexandre , Marchetti Anna , Sabra Ayman , Jauslin Tania N. , Rosselin Manon , Scherer Philipp E. , Demaurex Nicolas , Orci Lelio , Cosson Pierre
Published: July 2017

Significance

Mitochondria form dynamic networks in eukaryotic cells by constantly fusing with and separating from each other. Alterations in the mitochondrial network are observed in many pathological situations, such as diabetes, neurodegeneration, and cancer. In this study, we observe at the ultrastructural level the formation of direct contacts between mitochondria, called intermitochondrial junctions, by a mechanism distinct from that allowing fusion and fission of mitochondria. MitoNEET, a protein exposed at the cytosolic surface of mitochondria, controls the formation of intermitochondrial junctions. Its overexpression increases intermitochondrial junctions, whereas its absence reduces their frequency. Together, these observations reveal the existence of a new mechanism controlling the morphology of the cellular mitochondrial network and its adaptation to various physiological or pathological situations.
Clinical application of the head impulse test of semicircular canal function
Authors: Curthoys I. S. , Manzari L.
Published: July 2017

Objective:

To review the theory, the validity and the clinical application and the new developments of the video head impulse test (vHIT) of semicircular canal function. vHIT has now superseded the caloric test as the first-line clinical test for vestibular patients.

Outcomes:

This review examines the origin and rationale for vHIT: how it is carried out; pitfalls in testing; the validation of the test; the interpretation of overt and covert compensatory saccades in patients with vestibular loss; how the area VOR gain is calculated.

Results:

The advantages of the test are considered: it is so innocuous that it can be given to patients even during acute vertigo attacks, and given repeatedly at short intervals; it is very successful for testing young children; it tests all six semicircular canals, and, unlike the caloric test, provides measures of the absolute level of canal function and so is valuable for monitoring the effect of ototoxic antibiotics as well as identifying bilateral vestibular loss. Patients with Menière’s disease have normal canal function, although their caloric results generally indicate otherwise, with hydrops being the possible cause for that divergence. vHIT has shown the new vestibular syndrome of bilateral loss of vertical canal function and it is now being used for identifying the likely cause of vertigo of patients arriving at a hospital Emergency Room – normal semicircular canal function in such patients indicating increased probability of a stroke. The theory and application of the new, but already widely used, variant called the suppression head impulse test (SHIMPs) is explained. SHIMPs is even simpler and more intuitive than the standard vHIT test and probably even better for testing children.

Conclusion:

This review provides the theoretical foundations for the practical application of the clinical vHIT test which has revolutionized the clinical testing of semicircular canal function.
Interventions and Counternomic Reasoning
Authors: Tan Peter
Published: July 2017

Counternomics—counterfactuals whose antecedents run contrary to the laws of nature—are commonplace in science but have enjoyed relatively little philosophical attention. This article discusses a puzzle about our counternomic epistemology, focusing on cases in which experimental observations are used as evidence for counternomic claims. I show that these cases resist being characterized in familiar interventionist lines, and I suggest a characterization of my own.
Metagenomic assembly through the lens of validation: recent advances in assessing and improving the quality of genomes assembled from metagenomes
Authors: Olson Nathan D , Treangen Todd J , Hill Christopher M , Cepeda-Espinoza Victoria , Ghurye Jay , Koren Sergey , Pop Mihai
Published: July 2017

Metagenomic samples are snapshots of complex ecosystems at work. They comprise hundreds of known and unknown species, contain multiple strain variants and vary greatly within and across environments. Many microbes found in microbial communities are not easily grown in culture making their DNA sequence our only clue into their evolutionary history and biological function. Metagenomic assembly is a computational process aimed at reconstructing genes and genomes from metagenomic mixtures. Current methods have made significant strides in reconstructing DNA segments comprising operons, tandem gene arrays and syntenic blocks. Shorter, higher-throughput sequencing technologies have become the de facto standard in the field. Sequencers are now able to generate billions of short reads in only a few days. Multiple metagenomic assembly strategies, pipelines and assemblers have appeared in recent years. Owing to the inherent complexity of metagenome assembly, regardless of the assembly algorithm and sequencing method, metagenome assemblies contain errors. Recent developments in assembly validation tools have played a pivotal role in improving metagenomics assemblers. Here, we survey recent progress in the field of metagenomic assembly, provide an overview of key approaches for genomic and metagenomic assembly validation and demonstrate the insights that can be derived from assemblies through the use of assembly validation strategies. We also discuss the potential for impact of long-read technologies in metagenomics. We conclude with a discussion of future challenges and opportunities in the field of metagenomic assembly and validation.
Genetic Diversity of Stenocarpella maydis in the Major Corn Production Areas of the United States
Authors: Romero Luna Martha P. , Aime M. Catherine , Chilvers Martin I. , Wise Kiersten A.
Published: July 2017

The fungus Stenocarpella maydis (Berk.) B. Sutton, causal agent of Diplodia ear rot, is a prevalent corn (Zea mays L.) pathogen in the United States. Although S. maydis reduces grain quality, causes yield loss, and can produce mycotoxins in some countries, few studies have examined its biology and genetic diversity. We analyzed the genetic diversity of 174 S. maydis isolates sampled across the major corn production areas in the United States using nine different microsatellites. In all, 55 unique multilocus genotypes (MLG) were observed out of the 174 S. maydis isolates tested. After conducting a Bayesian clustering analysis by STRUCTURE, it was observed that the most probable number of genetic groups was two; however, no separation by their geographical location was identified. According to the minimum spanning network, the S. maydis population is linked across geographic regions of the United States but also contains private genotypes. Temporal diversity in the inoculum source was also observed at one location across 4 years. The haploid stage of S. maydis was confirmed and both mating type genes were amplified among selected isolates with unique MLG. We theorize that, although S. maydis is primarily an asexual fungus, sporadic cryptic recombination may occur, which could contribute to the genetic diversity observed in this study.
Development and Validation of KASP-SNP Markers for QTL Underlying Resistance to Stripe Rust in Common Wheat Cultivar P10057
Authors: Wu Jianhui , Wang Qilin , Kang Zhensheng , Liu Shengjie , Li Haiyang , Mu Jingmei , Dai Miaofei , Han Dejun , Zeng Qingdong , Chen Xianming
Published: July 2017

Stripe rust (Puccinia striiformis f. sp. tritici) is among the most important diseases of wheat (Triticum aestivum L.) globally. Utilization of adult plant resistance (APR) constitutes a key tool for maintaining protection against this disease. The CIMMYT wheat cultivar P10057 displayed a high level of APR to stripe rust in germplasm evaluation in field environments. To clarify the genetic basis and identify quantitative trait loci (QTLs) involved in stripe rust resistance in P10057, three wheat populations were used: 150 F5:6 recombinant inbred lines (RILs) derived from the cross Mingxian 169 × P10057, and 161 and 140 F2:3 lines from Avocet S × P10057 and Zhengmai 9023 × P10057, respectively. These three populations were evaluated for infection type (IT) and disease severity (DS) in Shaanxi, Gansu, and Sichuan during the 2014–15 and 2015–16 cropping seasons. Genotyping was performed with Kompetitive Allelic Specific PCR (KASP) and simple sequence repeat (SSR) markers linked to the resistance loci. Using QTL analysis, two genomic regions associated with resistance were found on chromosome arms 2BS and 3BS, respectively. These two stable QTLs, designated Qyrlov.nwafu-2BS and Qyrlov.nwafu-3BS, were detected across all environments and explained average 22.6 to 31.6% and 21.3 to 32.3% of stripe rust severity phenotypic variation, respectively. Qyrlov.nwafu-2BS may be the resistance allele derived from CIMMYT germplasm and Qyrlov.nwafu-3BS likely corresponds to the locus Sr2/Lr27/Yr30/Pbc. The KASP markers IWA5377, IWA2674, and IWA5830 linked to QYrlov.nwafu-2BS and IWB57990 and IWB6491 linked to Qyrlov.nwafu-3BS were reliable for marker-assisted selection (MAS) in the Zhengmai 9023 × P10057 population. These QTLs with KASP markers are expected to contribute in developing wheat cultivars with improved stripe rust resistance.
Evaluation of a new genetic family history screening questionnaire for identifying Lynch syndrome
Authors: Harrison Dawn S. , Handley Marilyn
Published: July 2017

Family history is essential when screening for hereditary cancer syndromes. This article explores if a detailed genetic family history questionnaire is more effective in identifying at-risk individuals for Lynch syndrome than a basic family health questionnaire.
Fracture Table Application for Pediatric Femur Fractures: Incidence and Risk Factors Associated With Adverse Outcomes
Authors: Kelly Brian A. , Naqvi Manahil , Rademacher Emily S. , Miller Patricia E. , Hedequist Daniel J. , Glotzbecker Michael P. , Matheney Travis H. , Shore Benjamin J.
Published: July 2017

Background:

Flexible elastic nails, submuscular plating, and rigid locked intramedullary nails are common methods of fixation for pediatric femur fractures (PFF) in which the fracture table is used to aid reduction. Little is known about complications associated with fracture table application in PFF. The purpose of this study was to determine the incidence and risk factors associated with adverse outcomes related to fracture table application for the treatment of PFF.

Methods:

A retrospective chart review of all children (younger than 18 y) treated for a femur fracture with the use of the fracture table between 2004 and 2015 at a single tertiary pediatric hospital was performed. Data on demographics, mechanism of injury, treatment modality, radiographic characteristics, and fracture table–related complications were gathered. Complications of interest included nerve palsy, skin breakdown/ulceration, vascular injury, and compartment syndrome. Penalized likelihood logistic regression was used to determine risk factors associated with adverse outcomes.

Results:

In total, 260 patients were included. There were 8 patients with nerve palsies related to positioning and traction on the fracture table (1 bilateral and 6 ipsilateral peroneal nerve palsies, 1 contralateral tibial nerve palsy; incidence of 3.1%). No other fracture table–related complications were recorded. Patients who developed a nerve palsy were significantly heavier (78.7 vs. 44.3 kg, P<0.001) and had a significantly longer mean surgical time (188.6 vs. 117.0 min, P<0.001). Multivariate analysis demonstrated weight to be the only significant risk factor for complications, with a 5% increase in odds of complication with each additional kilogram (odds ratio, 1.05; confidence interval, 1.03-1.08; P<0.001).

Conclusions:

Nerve palsy related to the use of the fracture table during the fixation of PFF occurred in 3.1% of patients in our series. Patients who developed nerve palsies were significantly heavier and had significantly longer surgical times. Although the use of the fracture table for fixation of PFF is safe, every effort should be made to minimize time in traction to avoid iatrogenic nerve palsy, particularly in heavier children (>80 kg).

Level of Evidence:

Level III.
Growth Modulation in Achondroplasia
Authors: McClure Philip K. , Kilinc Eray , Birch John G.
Published: July 2017

Introduction:

Achondroplasia is the most common skeletal dysplasia with a rate of nearly 1/10,000. The development of lower extremity deformity is well documented, and various modes of correction have been reported. There are no reports on the use of growth modulation to correct angular deformity in achondroplasia.

Methods:

Medical Records from 1985 to 2015 were reviewed for the diagnosis of achondroplasia and growth modulation procedures. Patients who had been treated for angular deformity of the legs by growth modulation were identified. A detailed analysis of their medical record and preoperative and final lower extremity radiographs was completed.

Results:

Four patients underwent growth modulation procedures, all to correct existing varus deformity of the legs. Three of the 4 patients underwent bilateral distal femoral and proximal tibial growth modulation. The remaining patient underwent tibial correction only. Two of the 4 patients had a combined proximal fibular epiphysiodesis. All limbs had some improvement of alignment; however, 1 patient went on to bilateral osteotomies. Only 1 limb corrected to a neutral axis with growth modulation alone at last follow-up, initial implantation was done before 5 years of age.

Conclusions:

Growth modulation is an effective means for deformity correction in the setting of achondroplasia. However implantation may need to be done earlier than would be typical for patients without achondroplasia. Osteotomy may still be required after growth modulation for incomplete correction.
Association Between Television Viewing and Parent-Child Reading in the Early Home Environment
Authors: Khan Kiren S. , Purtell Kelly M. , Logan Jessica , Ansari Arya , Justice Laura M.
Published: July 2017

Objective:

This study examines whether there is an association between time spent by preschoolers in parent-child shared book reading versus TV viewing in two distinct samples.

Methods:

Data were used from both the preschool wave of the Early Childhood Longitudinal Study Cohort, a nationally representative sample of 4-year-olds (N = 8900), as well as a low-income, rural sample of children enrolled in the Preschool Experience in Rural Classrooms study (N = 407). Information regarding frequency of shared book reading and daily TV consumption was obtained through caregiver report. A regression approach was used to estimate how the frequency of parent-child book reading accounted for variance in TV consumption. Estimated marginal mean values were then compared for the amount of TV viewed by children who were reported as being read to daily, frequently, occasionally, and not at all.

Results:

Parent–child book reading was negatively associated with the amount of TV viewed by children in both samples. Specifically, television consumption was significantly lower for children who were read to daily as compared to those who were read to occasionally. This inverse association was not moderated by contextual factors including maternal education, household size, and composition, or time spent in nonparental care.

Conclusion:

This study provides empirical support for an inverse association between TV viewing and parent-child book reading activities. Implications for policy and practice are discussed.
Feasibility of Conducting Autism Biomarker Research in the Clinical Setting
Authors: Sices Laura , Pawlowski Katherine , Farfel Laura , Phillips Deirdre , Howe Yamini , Cochran David M. , Choueiri Roula , Forbes Peter W. , Brewster Stephanie J. , Frazier Jean A. , Neumeyer Ann , Bridgemohan Carolyn ,   on behalf of the Autism Consortium Biomarkers Study Clinicians
Published: July 2017

Objective:

Recruitment and completion of research activities during regular clinical care has the potential to increase research participation in complex neurodevelopmental disorders. We evaluated the feasibility, and effect on clinical care, of conducting biomarker research within a subspecialty clinical visit for autism spectrum disorder (ASD).

Methods:

Children, aged 5 to 10 years, were recruited by providers in ASD clinics at 5 institutions. Biomarkers collected were growth measurements, head circumference, neurologic and dysmorphology examinations, digit ratio (2D:4D) measurement, and platelet serotonin and urinary melatonin sulfate excretion levels. Parents completed the Aberrant Behavior Checklist—Community and a medical/demographic questionnaire. Cognitive level was abstracted from the medical record. Parents and clinicians completed surveys on the effect of the study on the clinical visit.

Results:

Eighty-three children and their caregivers participated. Factors limiting participation included difficulty reaching families by phone and parent concern about the study blood draw requirement. All children completed at least 4 of 7 planned research activities. Demographic factors, educational placement, and child behavior were not associated with completion of study activities. Lower nonverbal cognitive function was weakly associated with fewer activities completed. Forty-four percent of clinicians reported an effect of the research study on the clinical visit. However, neither parent-reported nor clinician-reported effect was associated with the degree of study activity completion.

Conclusion:

Recruiting study participants in the context of scheduled ASD clinical visits required significant effort. However, once recruited, participants completed most study activities, regardless of behavioral symptom severity. Research activities did not adversely affect the clinical visit.
LEAN SIX SIGMA TECHNIQUES TO IMPROVE OPHTHALMOLOGY CLINIC EFFICIENCY
Authors: Ciulla Thomas A. , Tatikonda Mohan V. , ElMaraghi Yehya A. , Hussain Rehan M. , Hill Amanda L. , Clary Julie M. , Hattab Eyas
Published: July 2017

Purpose:

Ophthalmologists serve an increasing volume of a growing elderly population undergoing increasingly complex outpatient medical care, including extensive diagnostic testing and treatment. The resulting prolonged patient visit times (“patient flow times”) limit quality, patient and employee satisfaction, and represent waste. Lean Six Sigma process improvement was used in a vitreoretinal practice to decrease patient flow time, demonstrating that this approach can yield significant improvement in health care.

Methods:

Process flow maps were created to determine the most common care pathways within clinic. Three months' visits from the electronic medical record system, which tracks patient task times at each process step in the office were collected. Care tasks and care pathways consuming the greatest time and variation were identified and modified. Follow-up analysis from 6 weeks' visits was conducted to assess improvement.

Results:

Nearly all patients took one of five paths through the office. Patient flow was redesigned to reduce waiting room time by having staff members immediately start patients into one of those five paths; staffing was adjusted to address high demand tasks, and scheduling was optimized around derived predictors of patient flow times. Follow-up analysis revealed a statistically significant decline in mean patient flow time by 18% and inpatient flow time SD by 4.6%. Patient and employee satisfaction scores improved.

Conclusion:

Manufacturing industry techniques, such as Lean and Six Sigma, can be used to improve patient care, minimize waste, and enhance patient and staff satisfaction in outpatient clinics.
Anterior Chamber Angle and Trabecular Meshwork Measurements Made by Fourier-domain Optical Coherence Tomography in Healthy White Children
Authors: Fernández-Vigo José I. , De-Pablo-Gómez-de-Liaño Lucía , Fernández-Vigo Cristina , Arcos-Villegas Gabriel , Fernández-Pérez Cristina , García-Feijóo Julián , Fernández-Vigo José Á.
Published: July 2017

Purpose:

To obtain anterior chamber angle and trabecular meshwork (TM) measurements by Fourier-domain optical coherence tomography (FD-OCT) in a population of healthy white children.

Materials and Methods:

This was a cross-sectional study examining 409 right eyes of 409 children. Trabecular-iris angle (TIA) and TM length and area were measured by FD-OCT (RTVue 100) in the nasal and temporal quadrants to analyze correlations between angle or TM measurements and age, sex, and refractive error.

Results:

Mean participant age was 10.5±3.4 years (range, 3 to 18 y); 51% were boys. Mean spherical error was 0.56±2.4 D (range, −9 to +7.5 D). TIA could be measured in 99%, whereas TM measurements could only be made in 83%. Mean TIA was 43.1±10.0 degrees (range, 16 to 76 degrees). No differences were observed in angle width according to sex (P=0.299; t test). TIA was correlated with age (R=0.204; P<0.001) and with spherical error (R=−0.457; P<0.001). Mean TM length was 530±106 μm (range, 299 to 891 μm) and mean TM area was 0.065±0.021 mm2 (range, 0.030 to 0.180 mm2). No correlation was observed between TM metrics and age, sex or refractive error (R<0.08; P≥0.172).

Conclusions:

FD-OCT proved useful for the noninvasive measurement of TIA and TM metrics in children. Spherical error was the main determinant of TIA.
Evaluation of the Adequacy of the 2010 Revised World Health Organization Recommended Dosages of the First-line Antituberculosis Drugs for Children
Authors: Yang Hongmei , Enimil Anthony , Gillani Fizza S. , Antwi Sampson , Dompreh Albert , Ortsin Antoinette , Adu Awhireng Eugene , Owusu Maxwell , Wiesner Lubbe , Peloquin Charles A. , Kwara Awewura
Published: July 2017

Background:

The World Health Organization recommended increased dosages of the first-line antituberculosis (anti-TB) drugs for children in 2010. We examined the frequency of and factors associated with low plasma maximum concentration (Cmax) of each drug in children treated with the revised dosages.

Methods:

Children on anti-TB therapy for at least 4 weeks underwent pharmacokinetic testing. Plasma Cmax below the lower limit of proposed reference range was considered low. Bivariate and multivariate analyses were used to examine the factors associated with low Cmax of each drug.

Results:

Of the 100 children, 58% were male, 50% HIV-infected and 49% younger than 5 years old. The median (interquartile range) Cmax was 5.9 (4.5–7.7) µg/mL for isoniazid, 6.5 (4.9–8.8) µg/mL for rifampin, 26.0 (21.2–33.4) µg/mL for pyrazinamide and 1.7 (0.9–2.7) µg/mL for ethambutol. There was a strong correlation between Cmax and AUC0-8h for all drugs. Low Cmax occurred in 9/100 (9.0%), 61/100 (61.0%), 17/97 (17.5%) and 60/97 (61.9%) for isoniazid, rifampin, pyrazinamide and ethambutol, respectively. In addition, 75/97 (77.3%) children had pyrazinamide Cmax < 35 µg/mL. Factors associated with low Cmax were NAT2 metabolizer phenotype status for isoniazid; height, dosage and HIV coinfection status for rifampin; height for pyrazinamide; and age, dosage and HIV coinfection status for ethambutol.

Conclusions:

The high frequency of low rifampin and ethambutol Cmax in our study is consistent with emerging pharmacokinetic data in children treated according to the new WHO recommendations. Higher dosages than currently recommended especially for rifampin may be necessary in children.
Safety of Quadrivalent Meningococcal Conjugate Vaccine in Children 2–10 Years
Authors: Tartof Sara Yee , Sy Lina S. , Ackerson Bradley K. , Hechter Rulin C. , Haag Mendel , Slezak Jeffrey M. , Luo Yi , Fischetti Christine A. , Takhar Harp S. , Miao Yan , Solano Zendi , Jacobsen Steven J. , Tseng Hung-Fu
Published: July 2017

Background:

Quadrivalent meningococcal conjugate vaccine is recommended for children, adolescents and adults at increased risk of meningococcal disease. In 2011, MenACWY-CRM (Menveo, GSK, Siena, Italy) was approved for children 2–10 years of age in the United States. Although no safety concerns arose from clinical trials, it remains important to monitor its safety in routine clinical settings.

Methods:

Kaiser Permanente Southern California members 2–10 years old who received MenACWY-CRM between September 2011 and September 2014 were included. Electronic health records were searched using a validated algorithm to identify 26 prespecified events of interests (EOIs) and serious medically attended events (SMAEs) from inpatient or emergency settings up to 1 year after MenACWY-CRM vaccination. SMAEs were categorized by International Classification of Diseases, 9th revision diagnostic categories. All events were reviewed to confirm the diagnosis and symptom onset date. The study was descriptive (NCT01452438); no statistical tests were performed.

Results:

Among 387 vaccinated children, 327 with ≥6 months membership before vaccination were analyzed. Among EOIs, 9 asthma cases and 1 myasthenia gravis case underwent chart review which confirmed 1 incident asthma case occurring 237 days after concomitant vaccination with MenACWY-CRM and typhoid vaccine. Thirty-one children experienced SMAEs, most commonly because of unrelated injury and poisoning. The remaining events occurred sporadically after vaccination and most were unlikely related to vaccination based on medical record review.

Conclusions:

One incident EOI of asthma late in the 1-year observation period and sporadic distribution of SMAEs were observed. These data do not suggest safety concerns associated with MenACWY-CRM vaccination in children 2–10 years old.
Fecal Matrix Metalloprotease-9 and Lipocalin-2 as Biomarkers in Detecting Endoscopic Activity in Patients With Inflammatory Bowel Diseases
Authors: Buisson Anthony , Vazeille Emilie , Minet-Quinard Régine , Goutte Marion , Bouvier Damien , Goutorbe Félix , Pereira Bruno , Barnich Nicolas , Bommelaer Gilles
Published: July 2017

Background:

Fecal biomarkers are emerging tools in the assessment of mucosal healing in inflammatory bowel diseases (IBD).

Goals:

We aimed to evaluate the accuracy of fecal matrix metalloprotease-9 (MMP-9) and fecal lipocalin-2 (LCN-2) compared with calprotectin in detecting endoscopic activity in IBD

Study:

Overall, 86 IBD adults underwent colonoscopy consecutively and prospectively, with Crohn’s disease Endoscopic Index of Severity (CDEIS) in Crohn’s disease (CD) patients or Mayo endoscopic subscore calculation for ulcerative colitis (UC) patients, and stool collection. Fecal calprotectin was measured using quantitative immunochromatographic testing. Fecal MMP-9 and LCN-2 was quantified by enzyme-linked immunosorbent assay. MMP-9 and LCN-2 thresholds were determined using receiver operating curves.

Results:

In 54 CD patients, fecal calprotectin, MMP-9 and LCN-2 correlated with CDEIS and were significantly increased in patients with endoscopic ulcerations. MMP-9 >350 ng/g detected endoscopic ulceration in CD with a sensitivity of 90.0% and a specificity of 63.6%, compared with fecal calprotectin >250 μg/g (sensitivity=90.5% and specificity=59.1%). Fecal LCN-2 demonstrated lower performances than the 2 other biomarkers (sensitivity=85.7% and specificity=45.5%).

In 32 UC patients, fecal MMP-9, LCN-2, and calprotectin levels were significantly increased in patients with endoscopic activity. In UC patients, fecal MMP-9 >900 ng/g had the best efficacy to detect endoscopic activity (sensitivity=91.0% and specificity=80.0%, compared with fecal calprotectin >250 μg/g (sensitivity=86.4% and specificity=80.0%) and LCN-2 >6700 ng/g (sensitivity=82.0% and specificity=80.0%).

Conclusions:

Fecal MMP-9 is a reliable biomarker in detecting endoscopic activity in both UC and CD patients.
Risk of Colorectal Cancer in Chronic Kidney Disease
Authors: Komaki Yuga , Komaki Fukiko , Micic Dejan , Ido Akio , Sakuraba Atsushi
Published: July 2017

Background:

Association between chronic kidney disease and colorectal cancer (CRC) remains unclear.

Goals:

To assess the risk of CRC in patients with various chronic kidney diseases before and after kidney transplantation.

Study:

Electronic databases were searched for cohort studies assessing the risk of CRC in patients with chronic kidney diseases. The primary outcome was the risk of CRC among studies that reported the risk as standardized incidence rate (SIR).

Results:

Fifty-four studies, including 1,208,767 patients that reported the incidence of CRC in chronic kidney diseases were identified. SIR of CRC were obtained from 17 retrospective cohort studies. Among the 3 studies (4 reports) that included chronic kidney disease patients without kidney transplantation, there was a significant increased risk of CRC (pooled SIR 1.18) (95% confidence interval, 1.01-1.37; P=0.033). High heterogeneity was seen (I
2=85.6%), and metaregression showed that there were positive correlations between the risk of CRC and the proportions of males, age and follow-up period. Among the 15 studies (17 reports) that included postkidney transplant patients, the pooled SIR was significantly increased at 1.40 (95% confidence interval, 1.15-1.71; P=0.00080). High heterogeneity was seen (I
2=88.9%), and metaregression showed that the follow-up period correlated with the risk of CRC.

Conclusions:

In the present systematic review and meta-analysis, we demonstrated that patients with chronic kidney disease, regardless of a history of transplant, have a significant increased risk of CRC. A more intensive surveillance for CRC is required in this population.
INSM1 Demonstrates Superior Performance to the Individual and Combined Use of Synaptophysin, Chromogranin and CD56 for Diagnosing Neuroendocrine Tumors of the Thoracic Cavity
Authors: Rooper Lisa M. , Sharma Rajni , Li Qing Kay , Illei Peter B. , Westra William H.
Published: July 2017

Despite the importance of recognizing neuroendocrine differentiation when diagnosing tumors of the thoracic cavity, the sensitivity of traditional neuroendocrine markers is suboptimal, particularly for high-grade neuroendocrine carcinomas such as small cell lung carcinoma and large cell neuroendocrine carcinoma. To increase sensitivity, neuroendocrine markers are routinely ordered as panels of multiple immunostains where any single positive marker is regarded as sufficient evidence of neuroendocrine differentiation. Insulinoma-associated protein 1 (INSM1) is a well-validated transcription factor of neuroendocrine differentiation that has only recently been evaluated for diagnostic use. We performed INSM1 immunohistochemistry on a large series of thoracic neuroendocrine and non-neuroendocrine tumors and compared its performance to synaptophysin, chromogranin, and CD56. INSM1 was positive in 94.9% of small cell lung carcinomas and 91.3% of large cell neuroendocrine carcinomas, compared with 74.4% and 78.3% with the combined panel of traditional markers. INSM1 also stained all (100%) of the atypical carcinoids, typical carcinoids and mediastinal paragangliomas, but only 3.3% of adenocarcinomas and 4.2% of squamous cell carcinomas. Overall, INSM1 demonstrated a sensitivity of 96.4% across all grades of thoracic neuroendocrine tumors, significantly more than the 87.4% using the panel of traditional markers (P=0.02). INSM1 is sufficiently sensitive and specific to serve as a standalone first-line marker of neuroendocrine differentiation. A more restrained approach to immunohistochemical analysis of small thoracic biopsies is appropriate given the expanding demand on this limited material for therapeutic biomarker analysis.
Investigating mixotrophic metabolism in the model diatomPhaeodactylum tricornutum
Authors: Villanova Valeria , Fortunato Antonio Emidio , Singh Dipali , Bo Davide Dal , Conte Melissa , Obata Toshihiro , Jouhet Juliette , Fernie Alisdair R. , Marechal Eric , Falciatore Angela , Pagliardini Julien , Le Monnier Adeline , Poolman Mark , Curien Gilles , Petroutsos Dimitris , Finazzi Giovanni
Published: July 2017

Diatoms are prominent marine microalgae, interesting not only from an ecological point of view, but also for their possible use in biotechnology applications. They can be cultivated in phototrophic conditions, using sunlight as the sole energy source. Some diatoms, however, can also grow in a mixotrophic mode, wherein both light and external reduced carbon contribute to biomass accumulation. In this study, we investigated the consequences of mixotrophy on the growth and metabolism of the pennate diatomPhaeodactylum tricornutum, using glycerol as the source of reduced carbon. Transcriptomics, metabolomics, metabolic modelling and physiological data combine to indicate that glycerol affects the central-carbon, carbon-storage and lipid metabolism of the diatom. In particular, provision of glycerol mimics typical responses of nitrogen limitation on lipid metabolism at the level of triacylglycerol accumulation and fatty acid composition. The presence of glycerol, despite provoking features reminiscent of nutrient limitation, neither diminishes photosynthetic activity nor cell growth, revealing essential aspects of the metabolic flexibility of these microalgae and suggesting possible biotechnological applications of mixotrophy.

This article is part of the themed issue ‘The peculiar carbon metabolism in diatoms'.
Modulation of lipid biosynthesis by stress in diatoms
Authors: Sayanova Olga , Mimouni Virginie , Ulmann Lionel , Morant-Manceau Annick , Pasquet Virginie , Schoefs Benoît , Napier Johnathan A.
Published: July 2017

Diatoms are responsible for up to 40% of the carbon fixation in our oceans. The fixed carbon is moved through carbon metabolism towards the synthesis of organic molecules that are consumed through interlocking foodwebs, and this process is strongly impacted by the abiotic environment. However, it has become evident that diatoms can be used as ‘platform’ organisms for the production of high valuable bio-products such as lipids, pigments and carbohydrates where stress conditions can be used to direct carbon metabolism towards the commercial production of these compounds. In the first section of this review, some aspects of carbon metabolism in diatoms and how it is impacted by environmental factors are briefly described. The second section is focused on the biosynthesis of lipids and in particular omega-3 long-chain polyunsaturated fatty acids and how low temperature stress impacts on the production of these compounds. In a third section, we review the recent advances in bioengineering for lipid production. Finally, we discuss new perspectives for designing strains for the sustainable production of high-value lipids.

This article is part of the themed issue ‘The peculiar carbon metabolism in diatoms’.
Genealogical properties of subsamples in highly fecund populations
Authors: Eldon Bjarki , Freund Fabian
Published: July 2017

We consider some genealogical properties of nested samples. The complete sample is assumed to have been drawn from a natural population characterised by high fecundity and sweepstakes reproduction (abbreviated HFSR). The random gene genealogies of the samples are — due to our assumption of HFSR — modelled by coalescent processes which admit multiple mergers of ancestral lineages looking back in time. Among the genealogical properties we consider are the probability that the most recent common ancestor is shared between the complete sample and the subsample nested within the complete sample; we also compare the lengths of ‘internal’ branches of nested genealogies between different coalescent processes. The results indicate how ‘informative’ a subsample is about the properties of the larger complete sample, how much information is gained by increasing the sample size, and how the ‘informativeness’ of the subsample varies between different coalescent processes.
Synaptically driven phosphorylation of ribosomal protein S6 is differentially regulated at active synapses versus dendrites and cell bodies by MAPK and PI3K/mTOR signaling pathways
Authors: Pirbhoy Patricia Salgado , Farris Shannon , Steward Oswald
Published: July 2017

High-frequency stimulation of the medial perforant path triggers robust phosphorylation of ribosomal protein S6 (rpS6) in activated dendritic domains and granule cell bodies. Here we dissect the signaling pathways responsible for synaptically driven rpS6 phosphorylation in the dentate gyrus using pharmacological agents to inhibit PI3-kinase/mTOR and MAPK/ERK-dependent kinases. Using phospho-specific antibodies for rpS6 at different sites (ser235/236 versus ser240/244), we show that delivery of the PI3-kinase inhibitor, wortmannin, decreased rpS6 phosphorylation throughout the somatodendritic compartment (granule cell layer, inner molecular layer, outer molecular layer), especially in granule cell bodies while sparing phosphorylation at activated synapses (middle molecular layer). In contrast, delivery of U0126, an MEK inhibitor, attenuated rpS6 phosphorylation specifically in the dendritic laminae leaving phosphorylation in the granule cell bodies intact. Delivery of the mTOR inhibitor, rapamycin, abolished activation of rpS6 phosphorylation in granule cell bodies and dendrites, whereas delivery of a selective S6K1 inhibitor, PF4708671, or RSK inhibitor, SL0101-1, attenuated rpS6 phosphorylation throughout the postsynaptic cell. These results reveal that MAPK/ERK-dependent signaling is predominately responsible for the selective induction of rpS6 phosphorylation at active synapses. In contrast, PI3-kinase/mTOR-dependent signaling induces rpS6 phosphorylation throughout the somatodendritic compartment but plays a minimal role at active synapses. Collectively, these results suggest a potential mechanism by which PI3-kinase/mTOR and MAPK/ERK pathways regulate translation at specific subcellular compartments in response to synaptic activity.
AMPA receptors control fear extinction through an Arc-dependent mechanism
Authors: Trent Simon , Barnes Philip , Hall Jeremy , Thomas Kerrie L.
Published: July 2017

Activity-regulated cytoskeleton-associated protein (Arc) supports fear memory through synaptic plasticity events requiring actin cytoskeleton rearrangements. We have previously shown that reducing hippocampal Arc levels through antisense knockdown leads to the premature extinction of contextual fear. Here we show that the AMPA receptor antagonist CNQX elevates hippocampal Arc levels during extinction and blocks extinction that can be rescued by reducing Arc. Increasing Arc levels with CNQX also overcomes the actin-destabilizing properties of cytochalasin D and promotes extinction. Therefore, extinction is dependent on AMPA-mediated reductions of Arc via a mechanism consistent with a role for Arc in stabilizing the actin cytoskeleton to constrain extinction.
Acute exercise enhances the consolidation of fear extinction memory and reduces conditioned fear relapse in a sex-dependent manner
Authors: Bouchet Courtney A. , Lloyd Brian A. , Loetz Esteban C. , Farmer Caroline E. , Ostrovskyy Mykola , Haddad Natalie , Foright Rebecca M. , Greenwood Benjamin N.
Published: July 2017

Fear extinction-based exposure therapy is the most common behavioral therapy for anxiety and trauma-related disorders, but fear extinction memories are labile and fear tends to return even after successful extinction. The relapse of fear contributes to the poor long-term efficacy of exposure therapy. A single session of voluntary exercise can enhance the acquisition and consolidation of fear extinction in male rats, but the effects of exercise on relapse of fear after extinction are not well understood. Here, we characterized the effects of 2 h of voluntary exercise during the consolidation phase of contextual or auditory fear extinction learning on long-term fear extinction memory and renewal in adult, male and female, Long-Evans rats. Results indicate that exercise enhances consolidation of fear extinction memory and reduces fear relapse after extinction in a sex-dependent manner. These data suggest that brief bouts of exercise could be used as an augmentation strategy for exposure therapy, even in previously sedentary subjects. Fear memories of discrete cues, rather than of contextual ones, may be most susceptible to exercise-augmented extinction, especially in males. Additionally, exercise seems to have the biggest impact on fear relapse phenomena, even if fear extinction memories themselves are only minimally enhanced.
Differential involvement of the medial prefrontal cortex across variants of contextual fear conditioning
Authors: Heroux Nicholas A. , Robinson-Drummer Patrese A. , Sanders Hollie R. , Rosen Jeffrey B. , Stanton Mark E.
Published: July 2017

The context preexposure facilitation effect (CPFE) is a contextual fear conditioning paradigm in which learning about the context, acquiring the context-shock association, and retrieving/expressing contextual fear are temporally dissociated into three distinct phases. In contrast, learning about the context and the context-shock association happens concurrently in standard contextual fear conditioning (sCFC). By infusing the GABAAreceptor agonist muscimol into medial prefrontal cortex (mPFC) in adolescent Long-Evans rats, the current set of experiments examined the functional role of the mPFC in each phase of the CPFE and sCFC. In the CPFE, the mPFC is necessary for the following: acquisition and/or consolidation of context memory (Experiment 1), reconsolidation of a context memory to include shock (Experiment 2), and expression of contextual fear memory during a retention test (Experiment 3). In contrast to the CPFE, inactivation of the mPFC prior to conditioning in sCFC has no effect on acquisition, consolidation, or retention of a contextual fear memory (Experiment 4). Interestingly, the mPFC is not required for acquiring a context-shock association (measured by post-shock freezing) in the CPFE or sCFC (Experiment 2b and 4). Taken together, these results indicate that the mPFC is differentially recruited across stages of learning and variants of contextual fear conditioning (CPFE versus sCFC). More specifically, separating out learning about the context and the context-shock association necessitates activation of the medial prefrontal cortex during early learning and/or consolidation.
A comparison of behavioral and pharmacological interventions to attenuate reactivated fear memories
Authors: Ferrer Monti Roque I. , Alfei Joaquín M. , Mugnaini Matías , Bueno Adrián M. , Beckers Tom , Urcelay Gonzalo P. , Molina Victor A.
Published: July 2017

Two experiments using rats in a contextual fear memory preparation compared two approaches to reduce conditioned fear: (1) pharmacological reconsolidation blockade and (2) reactivation-plus-extinction training. In Experiment 1, we explored different combinations of reactivation-plus-extinction parameters to reduce conditioned fear and attenuate reacquisition. In Experiment 2, memory reactivation was followed by extinction training or administration of midazolam (MDZ) (vs. vehicle) to reduce conditioned fear and attenuate spontaneous recovery. We found both treatments to be equally effective in both experiments. This study suggests that parameters leading to memory destabilization during reactivation are critical to observe long-lasting effects of MDZ or reactivation plus extinction.
Crystal structure and DFT study of 2-(pyren-1-yl)-1H-benzimidazole
Authors: Faizi Md. Serajul Haque , Dege Necmi , Malinkin S.
Published: July 2017

In the title compound, C23H14N2, (I), the dihedral angle between the mean planes of the pyrene and benzimidazole ring systems is 42.08 (5)°, with a bridging C—C bond length of 1.463 (3) Å. In the crystal, molecules are linked by N—H...N hydrogen bonds, forming columns propagating along the b-axis direction. The columns are linked via C—H...π interactions, forming slabs parallel to the ab plane. There are no significant π–π interactions present in the crystal structure. The density functional theory (DFT) optimized structure, at the B3LYP/ 6-311G(d,p) level, is compared with the experimentally determined solid-state structure of the title compound.
fac-Bis[bis(pyridin-2-yl)methanamine]iron(II) bis(1,1,3,3-tetracyano-2-ethoxypropenide) dihydrate
Authors: Setifi Zouaoui , Bernès Sylvain , Setifi Fatima , Kaur Manpreet , Jasinski Jerry P.
Published: July 2017

The hydrated complex [Fe(DIPA)2](tcnoet)2·2H2O [DIPA is bis(pyridin-2-yl)methanamine, C11H11N3, and tcnoet is the anion 1,1,3,3-tetracyano-2-ethoxypropenide, C9H5N4O−], crystallizes with the [Fe(DIPA)2]2+ cation located on an inversion centre. The coordination geometry for FeII is strongly distorted from octahedral, as a consequence of the bite angles formed by the tridentate DIPA ligand. The water molecules included in the voids left by the cations and anions form hydrogen bonds with the cyano and amine groups.