bluuebunny/crossref_metadata_2025 huggingface dataset:
VALUE OF FRACTAL ANALYSIS OF OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY IN VARIOUS STAGES OF DIABETIC RETINOPATHY
Authors: Bhardwaj Suruchi , Tsui Edmund , Zahid Sarwar , Young Emma , Mehta Nitish , Agemy Steven , Garcia Patricia , Rosen Richard B. , Young Joshua A.
Published: July 2017

Purpose:

To use fractal dimensional analysis to investigate retinal vascular disease patterns in patients with diabetic retinopathy using spectral domain optical coherence tomography angiography.

Methods:

A retrospective study was conducted which included 49 eyes from 26 control subjects and 58 eyes from 35 patients known to have diabetic retinopathy. Of the 58 eyes with known retinopathy, 31 were categorized as nonproliferative diabetic retinopathy (13 mild, 9 moderate, and 9 severe) and 27 were categorized as proliferative diabetic retinopathy. Optical coherence tomography angiography images were acquired using the RTVue XR Avanti (Optovue, Inc). Automated segmentation was obtained through both the superficial and deep capillary plexuses for each eye. Grayscale optical coherence tomography angiography images were standardized and binarized using ImageJ (National Institutes of Health). Fractal box-counting analyses were conducted using Fractalyse (ThéMA). Fractal dimensions (FDs) and correlation coefficient of the superficial and deep capillary plexuses were compared between control eyes and those in various stages of diabetic retinopathy.

Results:

The superficial and deep capillary plexuses from diabetic and control eyes were analyzed. The average FD for diabetic eyes was significantly lower than in control eyes in the superficial plexus (P = 2.4 × 10−6) and in the deep capillary plexus (P = 1.87 × 10 −12) with a more statistically significant difference noted in the deep capillary plexus. When analyzing diabetic patients without edema noted on optical coherence tomography, the FD was significantly reduced in the superficial (P = 0.001) and deep (P = 1.49 × 10−6) plexuses. When analyzing diabetic patients with edema noted on optical coherence tomography, the FD was significantly reduced in the superficial (P = 2.0 × 10−5) and deep (P = 1.85 × 10−9) plexuses.

Conclusion:

The optical coherence tomography angiography FD is significantly lower in both superficial and deep capillary plexuses in eyes with all stages studied of diabetic retinopathy. The results were more often significant for the deep capillary plexus. The use of fractal analysis provides an objective criterion to assess microvascular disease burden in diabetic retinopathy.
Prevalence of Persistent Renal Dysfunction in Perinatally HIV-infected Thai Adolescents
Authors: Bunupuradah Torsak , Phupitakphol Tanit , Sophonphan Jiratchaya , Prasitsuebsai Wasana , Anugulruengkitt Suvaporn , Jantarabenjakul Watsamon , Sopa Bunruan , Ruxrungtham Kiat , Chanakul Ankanee , Puthanakit Thanyawee
Published: July 2017

Background:

Persistent renal dysfunction (PRD) has been reported in up to 22% of perinatally HIV-infected adolescents (PHAs) in the United States and Europe. There are limited data available on PRD among PHAs in resource-limited settings regarding access to antiretroviral therapy (ART) at more advanced HIV stages.

Methods:

We retrospectively described the prevalence of PRD and associated factors in a Thai PHA cohort. Inclusion criteria were current age ≥10 years old and at least 2 serum creatinine (Cr) measurements after ART initiation. Cr and urine examination were performed every 6–12 months. PRD was defined as having ≥2 measurements of low estimated glomerular filtration rate (eGFR); either <60 mL/min/1.73 m2 or elevated Cr for age and eGFR 60–89 mL/min/1.73 m2, or proteinuria (dipstick proteinuria ≥1+). Factors associated with PRD were analyzed using a multivariate logistic regression analysis.

Results:

This study included 255 PHAs with median (interquartile range) age of 16.7 (14.5–18.8) and ART duration of 10.3 (7.1–12.4) years. Fifty-six percentage used boosted protease inhibitor (bPI)–based regimens, and 63% used tenofovir disoproxil fumarate (TDF). The overall PRD prevalence was 14.1% [95% confidence interval (CI): 10.1–19.0]; low eGFR 6.7%, proteinuria 3.5% and both 3.9%. Among 109 users of TDF with bPI, 22.9% had PRD and 2.8% discontinued/adjusted dosing of TDF because of nephrotoxicity. Factors associated with PRD were age 10–15 years old (adjusted odd ratio (aOR): 10.1, 95% CI: 4.1–25.2), male (aOR: 3.2, 95% CI: 1.4–7.7), CD4 nadir <150 cells/mm3 (aOR: 2.6, 95% CI: 1.1–6.1) and use of TDF with bPI (aOR: 9.6, 95% CI: 3.2–28.9).

Conclusions:

PRD is common among PHAs. Almost one-fifth of adolescents using TDF with bPI had PRD. These adolescents should be a priority group for renal monitoring.
A Retrospective Cohort Study of the Incidence, Health Care Resource Utilization and Costs of International Classification of Diseases, Clinical Modification, 9th Revision Diagnosed Influenza and Related Complications in US Children
Authors: Buck Philip O. , Smith David M. , Shenolikar Rahul , Irwin Debra E.
Published: July 2017

Background:

There is a paucity of data on the clinical and economic impact of seasonal influenza in children. This study estimated the incidence of diagnosed influenza and related complications and associated health care resource utilization and costs in US children.

Methods:

Children ≥6 months and <18 years old diagnosed with influenza using International Classification of Diseases, Clinical Modification, 9th revision codes and enrolled in a health plan during at least one influenza season between 2010 and 2014 were matched to similar patients without diagnosed influenza (GSK study identifier: HO-15-15728). Outcomes included incidence of influenza and complications, health care resource utilization frequency and health care costs during 21 days of follow-up. Adjusted costs were estimated using generalized linear models.

Results:

Incidence (per 1000) of influenza was 20.3 (commercially insured) and 32.6 (Medicaid), with the highest incidence among 6–35 months old (Commercial: 26.8; Medicaid: 47.9). Approximately 12%–17% of influenza patients experienced complications, with the 6–35 months group having the highest percentage (25%–30%). The 6–35-month-old influenza patients with complications had the highest proportion with hospitalizations (5%–6%) and emergency room visits (Commercial: 19%; Medicaid: 36%). Influenza patients with (vs. without) complications had greater adjusted mean influenza-specific costs (Commercial: $1161 vs. $337; Medicaid: $1199 vs. $354; P<0.05), and influenza cases (vs. controls) had greater adjusted mean all-cause costs (Commercial: $688 vs. $470; Medicaid: $818 vs. $453; P < 0.05).

Conclusions:

Pediatric patients with influenza incurred higher health care costs compared with matched controls, and influenza-specific costs were greater among those with complications.
Safety and Immunogenicity of 13-Valent Pneumococcal Conjugate Vaccine in Children 6–17 Years of Age in India
Authors: Agarkhedkar Sharad , Juergens Christine , Balasundaram Krishnamurthy , Agarkhedkar Shalaka , Sundaraiyer Vani , Le Dren-Narayanin Natacha , Cutler Mark W. , Gruber William C. , Scott Daniel A. , Schmoele-Thoma Beate
Published: July 2017

In an open-label study in India, 200 healthy participants 6–17 years of age received 13-valent pneumococcal conjugate vaccine (PCV13). PCV13 elicited robust functional antibody immune responses. No adverse events were reported by caregivers at the 1-month follow-up visit. The immunogenicity results together with the known favorable risk–benefit profile of PCV13 support extension of the indication to this age group in India.
Four-year Outcomes After Cessation of Tenofovir in Immune-tolerant Chronic Hepatitis B Patients
Authors: Wong Vincent Wai-Sun , Hui Aric J. , Wong Grace Lai-Hung , Chan Rosita Suk-Yi , Chim Angel Mei-Ling , Lo Angeline Oi-Shan , Chan Henry Lik-Yuen
Published: July 2017

Goals:

To study the long-term outcome after cessation of antiviral therapy in immune-tolerant patients.

Background:

Experience in the treatment of immune-tolerant chronic hepatitis B is scanty. Some immune-tolerant patients may receive temporary antiviral therapy, such as for prevention of vertical transmission at pregnancy or prophylaxis for chemotherapy.

Study:

This was a follow-up study of a phase 2 trial at 2 centers. Immune-tolerant patients received tenofovir disoproxil fumarate and/or emtricitabine for 4 years and were followed for another 4 years after treatment cessation. Virological relapse was defined as hepatitis B virus (HBV) DNA>2000 IU/mL; clinical relapse was defined as HBV DNA>2000 IU/mL; and alanine aminotransferase (ALT)>2 times the upper limit of normal.

Results:

In total, 20 patients stopped treatment and were followed up for 206±14 weeks. All patients developed virological relapse at posttreatment week 4 (HBV DNA, 7.07±1.45 log IU/mL). A total of 10 (50%) patients developed clinical relapse at 15±11 weeks (highest ALT, 1149 U/L). In total, 11 (55%) patients were restarted on antiviral therapy; 4 achieved complete HBV DNA suppression and 1 achieved hepatitis B e antigen (HBeAg) seroconversion. Among the 9 patients not restarted on therapy, 2 patients had HBeAg seroconversion with normal ALT and HBV DNA of 7.12 and 1.62 IU/mL, respectively. The remaining 7 untreated patients continued to have positive HBeAg, high HBV DNA, and normal ALT.

Conclusions:

Rapid virological relapse is universal and clinical relapse is common after stopping antiviral therapy in patients with immune-tolerant chronic hepatitis B. HBeAg seroconversion is rare regardless of treatment reinitiation.
Medicaid and Uninsured Hepatocellular Carcinoma Patients Have More Advanced Tumor Stage and Are Less Likely to Receive Treatment
Authors: Wang Jennifer , Ha John , Lopez Aristeo , Bhuket Taft , Liu Benny , Wong Robert J.
Published: July 2017

Goals:

To evaluate the impact of insurance status on tumor stage at diagnosis, treatment received, and overall survival among adults with hepatocellular carcinoma (HCC).

Background:

Insurance status affects access to care, which impacts timely access to cancer screening for early detection and treatment.

Study:

Using the 2007 to 2012 Surveillance, Epidemiology, and End Results (SEER) database, we retrospectively evaluated US adults with HCC. Insurance status included Medicare/commercial insurance (MC), Medicaid (MA), and no insurance (NI). HCC tumor stage was evaluated using SEER staging system and Milan criteria. HCC treatment and survival were evaluated using multivariate logistic regression and Cox proportional hazards models.

Results:

Among 32,388 HCC patients (71.2% MC, 23.9% MA, and 4.9% NI), patients with MA or NI were significantly less likely to have localized tumor stage at time of diagnosis compared with MC [NI vs. MC; odds ratio, 0.41; 95% confidence interval (CI), 0.78-0.92; P<0.001]. MA and NI patients were less likely to receive treatment, and specifically less likely to receive surgical resection or liver transplantation compared with MC patients, even after correcting for tumor stage at diagnosis (odds of surgical resection or liver transplant in NI vs. MC: odds ratio, 0.26; 95% CI, 0.21-0.33; P<0.001). NI patients (hazard ratio, 1.39; 95% CI, 1.29-1.50; P<0.001) had significantly lower survival compared with MC patients.

Conclusions:

Among US adults with HCC, MA, or NI patients had more advanced tumor stage at diagnosis, lower rates treatment, and significantly lower overall survival. Ensuring equal insurance coverage may improve access to care and mitigate some disparities in HCC outcomes.
Management of chest pain in the French emergency healthcare system: the prospective observational EPIDOULTHO study
Authors: Charpentier Sandrine , Beaune Sebastien , Joly Luc Marie , Khoury Abdo , Duchateau François-Xavier , Briot Raphael , Renaud Bertrand , Ageron François-Xavier
Published: July 2017

Objective

The aim of this paper was to describe the epidemiology, and diagnostic and therapeutic strategies that emergency physicians use to manage patients presenting with chest pain at all three levels of the French emergency medical system – that is, dispatch centres (SAMUs: the medical emergency system), which operate the mobile intensive care units (MICUs), and hospitals’ emergency departments (EDs), with a focus on acute coronary syndrome (ACS).

Patients and methods

All patients with chest pain who contacted a SAMU and/or were managed by a MICU and/or were admitted into an ED were included in a 1-day multicentre prospective study carried out in January 2013. Data on diagnostic and therapeutic management and disposition were collected. An in-hospital follow-up was performed.

Results

In total, 1339 patients were included: 537 from SAMU, 187 attended by a MICU and 615 in EDs. Diagnosing ACS was the main diagnostic strategy of the French emergency care system, diagnosed in 16% of SAMU patients, 25% of MICU patients and 10% of ED patients. Among patients calling the SAMU, 76 (14%) received only medical advice, 15 (8%) patients remained at home after being seen by a MICU and 454 (74%) were discharged from an ED.

Conclusion

Management of chest pain at the three levels of the French medical emergency system is mainly oriented towards ruling out ACS. The strategy of diagnostic management is based on minimizing missed diagnoses of ACS.
Pediatric mitochondrial diseases and the heart
Authors: Enns Gregory M.
Published: July 2017

Purpose of review

Mitochondrial disorders are an increasingly recognized cause of heart dysfunction, with the primary manifestations being cardiomyopathy and conduction defects. This review focuses on the complex genetics of mitochondrial disease and recently discovered conditions that affect mitochondrial function.

Recent findings

Next-generation sequencing techniques, especially whole-exome sequencing, have led to the discovery of a number of conditions that cause mitochondrial dysfunction and subsequent cardiac abnormalities. Nuclear DNA defects are the main cause of mitochondrial disease in children, with disease pathogenesis being related to either abnormalities in specific mitochondrial electron transport chain subunits or in proteins related to subunit or mitochondrial DNA maintenance, mitochondrial protein translation, lipid bilayer structure, or other aspects of mitochondrial function.

Currently, symptomatic therapy using standard medications targeting relief of complications is the primary approach to treatment. There are no US Food and Drug Administration-approved therapies for the specific treatment of mitochondrial disease. However, on the basis of recent advances in understanding of the pathophysiology of these complex disorders, various novel approaches are either in clinical trials or in development.
A Pediatric Case of Persistent Thrombocytopenia in a Patient Who Developed All
Authors: Shaukat Haroon , O’Mara Jessica , Neier Michelle
Published: July 2017

Inherited thrombocytopenia is a topic that was expanded greatly over the last decade and many new genes are being identified. However, inheritance patterns are not always easy to identify because sporadic cases from de novo mutations may in fact be more common. Few studies have assessed the relationship between thrombocytopenia and malignancies, specifically acute lymphoblastic leukemia (ALL). Here we present a pediatric case of persistent thrombocytopenia associated with T-cell ALL. Our patient was initially diagnosed with immune thrombocytopenic purpura with no evidence of malignancy on bone marrow biopsy but presented shortly after with ALL.
Critical Evaluation of Metallization in Electric Injury
Authors: Laima Sigitas , Bytautaite Jana , Chmieliauskas Sigitas , Fomin Dmitrij , Jasulaitis Algimantas , Jukna Arturas , Mazeikiene Sandra , Stasiuniene Jurgita
Published: July 2017

The article presents 3 forensic medicine cases in the field of electric injury. In addition to traditional findings in electric injury (electric mark and histological findings), the forensic medicine experts in Lithuania also perform an atomic absorption spectrometry analysis. This method confirms the effects of electric current to the body through the electric conductor. Typical macroscopic finding in the skin is electric mark. Histologically, the damaged skin possesses characteristic features of thermal burns. The atomic absorption spectroscopy analysis identifies traces of metal particles devolved from the electrical conductor, which confirms a premortal contact with it. In one of our presented cases, the metallization was negative, although there were obvious data of electric current effect. This shows that it is not always worth to rely on the method of atomic absorption spectrometry analysis recognized worldwide in forensic medicine. The determination of electrical injury diagnosis requires a critical and comprehensive assessment of all the available data and laboratory tests.
Somatotopic Fascicular Lesions of the Brachial Plexus Demonstrated by High-Resolution Magnetic Resonance Neurography
Authors: Hilgenfeld Tim , Jende Johann , Schwarz Daniel , Bäumer Philipp , Kollmer Jennifer , Heiland Sabine , Bendszus Martin , Pham Mirko
Published: July 2017

Objectives

The aim of this study was to evaluate whether high-resolution brachial plexus (BP) magnetic resonance neurography (MRN) is capable of (1) distinguishing patients with compressive neuropathy or noncompressive plexopathy from age- and sex-matched controls, (2) discriminating between patients with compressive neuropathy and noncompressive plexopathy, and (3) detecting spatial lesion patterns suggesting somatotopic organization of the BP.

Materials and Methods

Thirty-six patients (50.9 ± 12.7 years) with clinical symptoms, nerve conduction studies, and needle electromyography findings suggestive of brachial plexopathy and 36 control subjects matched for age and sex (50.8 ± 12.6 years) underwent high-resolution MRN of the BP. Lesion determination and localization was performed by 2 blinded neuroradiologists at the anatomical levels of the plexus trunks and cords.

Results

By applying defined criteria of structural plexus lesions on high-resolution MRN, all patients were correctly rated as affected, whereas 34 of 36 controls were correctly rated as unaffected by independent and blinded reading from 2 neuroradiologists with overall good to excellent interrater reliability. In all cases, plexopathies with a compressive etiology (n = 12) were correctly distinguished from noncompressive plexopathies with inflammatory origin (n = 24). Pathoanatomical contiguity of lesion from trunk into cord level allowed recognition of distinct somatotopical patterns of fascicular involvement, which correlated closely with the spatial distribution of clinical symptoms and electrophysiological data.

Conclusions

Brachial plexus MRN is highly accurate for differentiating patients with symptomatic plexopathy from healthy controls and for distinguishing patients with compressive neuropathy and noncompressive plexopathy. Furthermore, BP MRN revealed evidence for somatotopic organization of the BP. Therefore, as an addition to functional information of electrodiagnostic studies, anatomical information gained by BP MRN may help to improve the efficiency and accuracy of patient care.
The role of intraspecific variation in the ecological and evolutionary success of diatoms in changing environments
Authors: Godhe Anna , Rynearson Tatiana
Published: July 2017

Intraspecific variation in diatoms has been shown to play a key role in species' responses to several important environmental factors such as light, salinity, temperature and nutrients. Furthermore, modelling efforts indicate that this variation within species extends bloom periods, and likely provides sufficient variability in competitive interactions between species under hydrographically variable conditions. The intraspecific variation most likely corresponds to optimal fitness in temporary microhabitats and may help to explain the paradox of the plankton. Here, we examine the implications of intraspecific variation for the ecology and success of diatoms in general and emphasize the potential implications for our understanding of carbon metabolism in these important organisms. Additionally, data from palaeoecological studies have the potential for evaluating genetic variation through past climate changes, going thousands of years back in time. We suggest pathways for future research including the adoption of multiple strains of individual species into studies of diatom carbon metabolism, to refine our understanding of the variation within and between species, and the inclusion of experimental evolution as a tool for understanding potential evolutionary responses of diatom carbon metabolism to climate change.

This article is part of the themed issue ‘The peculiar carbon metabolism in diatoms’.
Regulation of the Calvin–Benson–Bassham cycle in the enigmatic diatoms: biochemical and evolutionary variations on an original theme
Authors: Jensen Erik , Clément Romain , Maberly Stephen C. , Gontero Brigitte
Published: July 2017

In Plantae, the Calvin–Benson–Bassham (CBB) cycle is highly regulated and most of its enzymes have been thoroughly studied. Since diatoms arose as a result of secondary endosymbiosis with one or more Plantae ancestors, their precise evolutionary history is enigmatic and complex resulting in biochemical variations on the original CBB cycle theme. The Rubisco Michaelis constant for CO
2
is higher in diatoms than land plants and the nuclear-encoded Rubisco activase in Plantae is replaced by an analogous chloroplast-encoded CbbX (Calvin–Benson–Bassham protein X) in diatoms. In the CBB cycle reduction phase, phosphoglycerate kinase in diatoms is redox-regulated and similar to that in red algae; however, glyceraldehyde phosphate dehydrogenase (GAPDH) is not redox-regulated, unlike in Plantae. The phosphoribulokinase (PRK)-GAPDH-CP12 complex found in many photosynthetic organisms has not yet been found in diatoms, but a ferredoxin-NADP reductase (FNR)-GAPDH-CP12 complex has been found in one species. In the CBB cycle regeneration phase, sedoheptulose 1,7-bisphosphatase and PRK are not redox-regulated in diatoms, unlike in Plantae. Regulation at the transcriptional level seems to be important in diatoms. CBB cycle enzyme properties appear to be variable among diatoms, but this view relies on results from a few model species: a greater range of diatoms need to be studied to test this.

This article is part of the themed issue ‘The peculiar carbon metabolism in diatoms’.
The effects of phosphorus limitation on carbon metabolism in diatoms
Authors: Brembu Tore , Mühlroth Alice , Alipanah Leila , Bones Atle M.
Published: July 2017

Phosphorus is an essential element for life, serving as an integral component of nucleic acids, lipids and a diverse range of other metabolites. Concentrations of bioavailable phosphorus are low in many aquatic environments. Microalgae, including diatoms, apply physiological and molecular strategies such as phosphorus scavenging or recycling as well as adjusting cell growth in order to adapt to limiting phosphorus concentrations. Such strategies also involve adjustments of the carbon metabolism. Here, we review the effect of phosphorus limitation on carbon metabolism in diatoms. Two transcriptome studies are analysed in detail, supplemented by other transcriptome, proteome and metabolite data, to gain an overview of different pathways and their responses. Phosphorus, nitrogen and silicon limitation responses are compared, and similarities and differences discussed. We use the current knowledge to propose a suggestive model for the carbon flow in phosphorus-replete and phosphorus-limited diatom cells.

This article is part of the themed issue ‘The peculiar carbon metabolism in diatoms’.
pyABC: distributed, likelihood-free inference
Authors: Klinger Emmanuel , Rickert Dennis , Hasenauer Jan
Published: July 2017

Likelihood-free methods are often required for inference in systems biology. While Approximate Bayesian Computation (ABC) provides a theoretical solution, its practical application has often been challenging due to its high computational demands. To scale likelihood-free inference to computationally demanding stochastic models we developed pyABC: a distributed and scalable ABC-Sequential Monte Carlo (ABC-SMC) framework. It implements computation-minimizing and scalable, runtime-minimizing parallelization strategies for multi-core and distributed environments scaling to thousands of cores. The framework is accessible to non-expert users and also enables advanced users to experiment with and to custom implement many options of ABC-SMC schemes, such as acceptance threshold schedules, transition kernels and distance functions without alteration of pyABC’s source code. pyABC includes a web interface to visualize ongoing and 1nished ABC-SMC runs and exposes an API for data querying and post-processing.

Availability and Implementation

pyABC is written in Python 3 and is released under the GPLv3 license. The source code is hosted onhttps://github.com/neuralyzer/pyabcand the documentation onhttp://pyabc.readthedocs.io. It can be installed from the Python Package Index (PyPI).
Comparative genomic analyses highlight the contribution of pseudogenized protein-coding genes to human lincRNAs
Authors: Liu Wan-Hsin , Tsai Zing Tsung-Yeh , Tsai Huai-Kuang
Published: July 2017

Background

The regulatory roles of long intergenic noncoding RNAs (lincRNAs) in humans have been revealed through the use of advanced sequencing technology. Recently, three possible scenarios of lincRNA origin have been proposed:de novoorigination from intergenic regions, duplication from long noncoding RNA, and pseudogenization from protein. The first two scenarios are largely studied and supported, yet few studies focused on the evolution from pseudo genized protein-coding sequence to lincRNA. Due to the non-mutually exclusive nature that these three scenarios have, accompanied by the need of systematic investigation of lincRNA origination, we conduct a comparative genomics study to investigate the evolution of human lincRNAs.

Results

Combining with syntenic analysis and stringent Blastne-value cutoff, we found that the majority of lincRNAs are aligned to the intergenic regions of other species. Interestingly, 193 human lincRNAs could have protein-coding orthologs in at least two of nine vertebrates. Transposable elements in these conserved regions in human genome are much less than expectation. Moreover, 19% of these lincRNAs have overlaps with or are close to pseudogenes in the human genome.

Conclusions

We suggest that a notable portion of lincRNAs could be derived from pseudogenized protein-coding genes. Furthermore, based on our computational analysis, we hypothesize that a subset of these lincRNAs could have potential to regulate their paralogs by functioning as competing endogenous RNAs. Our results provide evolutionary evidence of the relationship between human lincRNAs and protein-coding genes.
Genome-wide Association Studies Reveal Similar Genetic Architecture with Shared and Unique QTL for Bacterial Cold Water Disease Resistance in Two Rainbow Trout Breeding Populations
Authors: Vallejo Roger L. , Gao Guangtu , Liu Sixin , Fragomeni Breno O. , Hernandez Alvaro G. , Parsons James E. , Martin Kyle E. , Evenhuis Jason P. , Welch Timothy J. , Leeds Timothy D. , Wiens Gregory D. , Palti Yniv
Published: July 2017

Bacterial cold water disease (BCWD) causes significant mortality and economic losses in salmonid aquaculture. In previous studies, we identified moderate-large effect QTL for BCWD resistance in rainbow trout (Oncorhynchus mykiss). However, the recent availability of a 57K SNP array and a genome physical map have enabled us to conduct genome-wide association studies (GWAS) that overcome several experimental limitations from our previous work. In the current study, we conducted GWAS for BCWD resistance in two rainbow trout breeding populations using two genotyping platforms, the 57K Affymetrix SNP array and restriction-associated DNA (RAD) sequencing. Overall, we identified 14 moderate-large effect QTL that explained up to 60.8% of the genetic variance in one of the two populations and 27.7% in the other. Four of these QTL were found in both populations explaining a substantial proportion of the variance, although major differences were also detected between the two populations. Our results confirm that BCWD resistance is controlled by the oligogenic inheritance of few moderate-large effect loci and a large-unknown number of loci each having a small effect on BCWD resistance. We detected differences in QTL number and genome location between two GWAS models (weighted single-step GBLUP and Bayes B), which highlights the utility of using different models to uncover QTL. The RAD-SNPs detected a greater number of QTL than the 57K SNP array in one population, suggesting that the RAD-SNPs may uncover polymorphisms that are more unique and informative for the specific population in which they were discovered.
Rapid DNA Replication Origin Licensing Protects Stem Cell Pluripotency
Authors: Matson Jacob Peter , Dumitru Raluca , Coryell Phillip , Baxley Ryan M , Chen Weili , Twaroski Kirk , Webber Beau R. , Tolar Jakub , Bielinsky Anja-Katrin , Purvis Jeremy , Cook Jeanette Gowen
Published: July 2017

Complete and robust human genome duplication requires loading MCM helicase complexes at many DNA replication origins, an essential process termed origin licensing. Licensing is restricted to G1 phase of the cell cycle, but G1 length varies widely among cell types. Using quantitative single cell analyses we found that pluripotent stem cells with naturally short G1 phases load MCM much faster than their isogenic differentiated counterparts with long G1 phases. During the earliest stages of differentiation towards all lineages, MCM loading slows concurrently with G1 lengthening, revealing developmental control of MCM loading. In contrast, ectopic Cyclin E overproduction uncouples short G1 from fast MCM loading. Rapid licensing in stem cells is caused by accumulation of the MCM loading protein, Cdt1. Prematurely slowing MCM loading in pluripotent cells not only lengthens G1 but also accelerates differentiation. Thus, rapid origin licensing is an intrinsic characteristic of stem cells that contributes to pluripotency maintenance.
COMPENSATION FOR CHRONIC OXIDATIVE STRESS IN ALADIN NULL MICE
Authors: Jühlen Ramona , Peitzsch Mirko , Gärtner Sebastian , Landgraf Dana , Eisenhofer Graeme , Huebner Angela , Koehler Katrin
Published: July 2017

Background

Mutations in theAAASgene coding for the nuclear pore complex protein ALADIN lead to the autosomal recessive disorder triple A syndrome. Triple A patients present with a characteristic phenotype including alacrima, achalasia and adrenal insufficiency. Patient fibroblasts show increased levels of oxidative stress and severalin vitrostudies demonstrated that the nucleoporin ALADIN is involved in the cellular oxidative stress response and in adrenal steroidogenesis. We showed that ALADIN knock-out mice lack a phenotype resembling human triple A syndrome. Thus, we hypothesized that application of chronic oxidative stress by ingestion of paraquat will generate triple A-like phenotype in ALADIN null mice.

Results

We demonstrate that ALADIN knock-out mice present with an unexpected compensated glutathione metabolism still lacking a phenotype resembling human triple A syndrome after application of chronic oxidative stress. We could not observe increased levels of oxidative stress and alterations in adrenal steroidogenesis in mice depleted for ALADIN.

Conclusions

This study stresses the species-specific role of the nucleoporin ALADIN presenting a novel compensatory mechanism of the cellular glutathione redox response and shedding light on the role of ALADIN in the cell.
Using mitochondrial genomes to infer phylogenetic relationships among the oldest extant winged insects (Palaeoptera)
Authors: Rutschmann Sereina , Chen Ping , Zhou Changfa , Monaghan Michael T.
Published: July 2017

Phylogenetic relationships among the basal orders of winged insects remain unclear, in particular the relationship of the Ephemeroptera (mayflies) and the Odonata (dragonflies and damselflies) with the Neoptera. Insect evolution is thought to have followed rapid divergence in the distant past and phylogenetic reconstruction may therefore be susceptible to problems of taxon sampling, choice of outgroup, marker selection, and tree reconstruction method. Here we newly sequenced three mitochondrial genomes representing the two most diverse families of the Ephemeroptera, one of which is a basal lineage of the order. We then used an additional 90 insect mitochondrial genomes to reconstruct their phylogeny using Bayesian and maximum likelihood approaches. Bayesian analysis supported a basal Odonata hypothesis, with Ephemeroptera as sister group to the remaining insects. This was only supported when using an optimized data matrix from which rogue taxa and terminals affected by long-branch attraction were removed. None of our analyses supported a basal Ephemeroptera hypothesis or Ephemeroptera + Odonata as monophyletic clade sister to other insects (i.e., the Palaeoptera hypothesis). Our newly sequenced mitochondrial genomes ofBaetis rutilocylindratus,Cloeon dipterum, andHabrophlebiodes zijinensishad a complete set of protein coding genes and a conserved orientation except for two inverted tRNAs inH. zijinensis.Increased mayfly sampling, removal of problematic taxa, and a Bayesian phylogenetic framework were needed to infer phylogenetic relationships within the three ancient insect lineages of Odonata, Ephemeroptera, and Neoptera. Pruning of rogue taxa improved the number of supported nodes in all phylogenetic trees. Our results add to previous evidence for the Odonata hypothesis and indicate that the phylogenetic resolution of the basal insects can be resolved with more data and sampling effort.
Questioning the role of selected somaticPIK3C2Bmutations in squamous non-small cell lung cancer oncogenesis
Authors: Kind Marcus , Klukowska-Rötzler Jolanta , Berezowska Sabina , Arcaro Alexandre , Charles Roch-Philippe
Published: July 2017

PI3K signaling is frequently dysregulated in NSCLC-SQCC. In contrast to well characterized components of the PI3K signaling network contributing to the formation of SQCC, potential oncogenic effects of alterations inPIK3C2Bare poorly understood. Here, a large cohort (n=362) of NSCLC-SQCC was selectively screened for four reported somatic mutations inPIK3C2Bvia Sanger sequencing. In addition, two mutations leading to an amino acid exchange in the kinase domain (C1181, H1208R) were examined on a functional level for their oncogenic potential.

None of the mutations were identified in the cohort while well characterized hotspotPIK3CAmutations were observed at the expected frequency. Ultimately, kinase domain mutations in PI3KC2β were found to have no altering effect on downstream signaling. A set of SQCC tumors sequenced by The Cancer Genome Atlas (TCGA) equally indicates a lack of oncogenic potential of the kinase domain mutations orPIK3C2Bin general.

Taken together, this study suggests thatPIK3C2Bmight only have a minor role in SQCC oncogenesis.
TASI: A software tool for spatial-temporal quantification of tumor spheroid dynamics
Authors: Hou Yue , Konen Jessica , Brat Daniel J , Marcus Adam I. , Cooper Lee
Published: July 2017

Spheroid cultures derived from explanted cancer specimens are an increasingly utilized resource for studying complex biological processes like tumor cell invasion and metastasis, representing an important bridge between the simplicity and practicality of 2D monolayer cultures and the complexity and realism ofin vivoanimal models. Temporal imaging of spheroids can capture the dynamics of cell behaviors and microenvironments, and when combined with quantitative image analysis methods, enables deep interrogation of biological mechanisms. This paper presents a comprehensive open-source software framework forTemporalAnalysis ofSpheroid Imaging (TASI) that allows investigators to objectively characterize spheroid growth and invasion dynamics. TASI performs spatiotemporal segmentation of spheroid cultures, extraction of features describing spheroid morpho-phenotypes, mathematical modeling of spheroid dynamics, and statistical comparisons of experimental conditions. We demonstrate the utility of this tool in an analysis of non-small cell lung cancer spheroids that exhibit variability in metastatic and proliferative behaviors.
Estimating inflation in GWAS summary statistics due to variance distortion from cryptic relatedness
Authors: Holland Dominic , Fan Chun-Chieh , Frei Oleksandr , Shadrin Alexey A. , Smeland Olav B. , Sundar V. S. , Andreassen Ole A. , Dale Anders M.
Published: July 2017

Cryptic relatedness is inherently a feature of large genome-wide association studies (GWAS), and can give rise to considerable inflation in summary statistics for single nucleotide polymorphism (SNP) associations with phenotypes. It has proven difficult to disentangle these inflationary effects from true polygenic effects. Here we present results of a model that enables estimation of polygenicity, mean strength of association, and residual inflation in GWAS summary statistics. We show that there is substantial residual inflation in recent large GWAS of height and schizophrenia; correcting for this reduces the number of independent genome-wide significant loci from the reported values of 697 for height and 108 for schizophrenia to 368 and 61, respectively. In contrast, a larger GWAS of educational attainment shows no residual inflation. Additionally, we find that height has a relatively low polygenicity, with approximately 8k SNPs having causal association, more than an order of magnitude less than has been reported. The residual inflation in GWAS summary statistics can be corrected using the standard genomic control procedure with the estimated residual inflation factor.
A Mixed Periodic Paralysis & Myotonia Mutant, P1158S, Imparts pH Sensitivity in Skeletal Muscle Voltage-gated Sodium Channels
Authors: Ghovanloo Mohammad-Reza , Abdelsayed Mena , Peters Colin H. , Ruben Peter C.
Published: July 2017

Skeletal muscle channelopathies, many of which are inherited as autosomal dominant mutations, include both myotonia and periodic paralysis. Myotonia is defined by a delayed relaxation after muscular contraction, whereas periodic paralysis is defined by episodic attacks of weakness. One sub-type of periodic paralysis, known as hypokalemic periodic paralysis (hypoPP), is associated with low potassium levels. Interestingly, the P1158S missense mutant, located in the third domain S4-S5 linker of the ‘‘skeletal muscle’’ voltage-gated sodium channel, Nav1.4, has been implicated in causing both myotonia and hypoPP. A common trigger for these conditions is physical activity. We previously reported that Nav1.4 is relatively insensitive to changes in extracellular pH compared to Nav1.2 and Nav1.5. Given that intense exercise is often accompanied by blood acidosis, we decided to test whether changes in pH would push gating in P1158S towards either phenotype. Our results indicate that, unlike in WT Nav1.4, low pH depolarizes the voltage-dependence of activation and steady-state fast inactivation, decreases current density, and increases late currents in P1185S. Thus, P1185S turns the normally pH-insensitive Nav1.4 into a proton-sensitive channel. Using action potential modeling we also predict a pH-to-phenotype correlation in patients with P1158S. We conclude that activities which alter blood pH may trigger myotonia or periodic paralysis in P1158S patients.

SIGNIFICANCE STATEMENT

Voltage-gated sodium channels (Nav) contribute to the physiology and pathophysiology of electrical signaling in excitable cells. Nav subtypes are expressed in a tissue-specific manner, thus they respond differently to physiological modulators. For instance, the cardiac subtype, Nav1.5, can be modified by changes in blood pH; however, the skeletal muscle subtype, Nav1.4, is mostly pH-insensitive. Nav1.4 mutants can mostly cause either hyper-or hypo-excitability in skeletal muscles, leading to conditions such as myotonia or periodic paralysis. P1158S uniquely causes both phenotypes. This study investigates pH-sensitivity in P1158S, and describes how physiological pH changes can push P1158S to cause myotonia and periodic paralysis.
A novel in vitro analog expressing learning-induced cellular correlates in distinct neural circuits
Authors: Weisz Harris A. , Wainwright Marcy L. , Mozzachiodi Riccardo
Published: July 2017

When presented with noxious stimuli, Aplysia exhibits concurrent sensitization of defensive responses, such as the tail-induced siphon withdrawal reflex (TSWR) and suppression of feeding. At the cellular level, sensitization of the TSWR is accompanied by an increase in the excitability of the tail sensory neurons (TSNs) that elicit the reflex, whereas feeding suppression is accompanied by decreased excitability of B51, a decision-making neuron in the feeding neural circuit. The goal of this study was to develop an in vitro analog coexpressing the above cellular correlates. We used a reduced preparation consisting of buccal, cerebral, and pleural-pedal ganglia, which contain the neural circuits controlling feeding and the TSWR, respectively. Sensitizing stimuli were delivered in vitro by electrical stimulation of afferent nerves. When trained with sensitizing stimuli, the in vitro analog expressed concomitant increased excitability in TSNs and decreased excitability in B51, which are consistent with the occurrence of sensitization and feeding suppression induced by in vivo training. This in vitro analog expressed both short-term (15 min) and long-term (24 h) excitability changes in TSNs and B51, depending on the amount of training administered. Finally, in vitro application of serotonin increased TSN excitability without altering B51 excitability, mirroring the in vivo application of the monoamine that induces sensitization, but not feeding suppression.
Crystal structure of 2-tert-butyl-2,3-dihydro-1H-benzo[c]pyrrol-1-one
Authors: Donkeng Dazie Joel , Ludvík Jiří , Fábry Jan , Eigner Václav
Published: July 2017

The asymmetric unit of the title compound, C12H15NO, comprises two symmetry-independent molecules which differ mainly in the conformations of the tert-butyl groups. The molecules contain an essentially planar five-membered 3-pyrroline ring incorporating a carbonyl substituent (pyrrolinone) which forms part of an isoindolinone skeleton. The planarity of the pyrrole ring is compared to other structures with isoindolinone. There are only weak intra- and intermolecular C—H...O and C—H...π-electron-ring interactions in the crystal structure.
Community pharmacists as vaccine providers
Authors: Rhodes Laura A. , Williams Dennis M. , Marciniak Macary W. , Weber David Jay
Published: July 2017

Purpose

The purpose of this paper is to describe the history of pharmacist involvement as vaccine providers in the USA and discuss examples of growing interests in other parts of the world.

Design/methodology/approach

Literature searches were performed in PubMed as well as pharmacy-related journals.

Findings

Pharmacists have been involved with the storage and management of vaccines for more than a century. Based on the unmet needs in meeting national goals for vaccination rates among adults in the USA, efforts led to training and recognizing pharmacists as vaccine providers which is now within the scope of practice for a pharmacist in all US states and territories. Pharmacists complete a comprehensive training program in vaccine sciences, regulatory considerations, as well as demonstration of skills in administering vaccines. Over 300,000 pharmacists have been trained in vaccine delivery and this represents the majority of the pharmacist workforce in the USA. There are examples of the beneficial impact of pharmacist involvement as vaccine providers in community pharmacy settings.

Research limitations/implications

This review is based on a thorough review of the literature but was not conducted in a systematic fashion.

Originality/value

This review provides a historical perspective and evidence of the benefit of pharmacists as vaccine providers.
Does lean cure variability in health care?
Authors: Roemeling Oskar , Land Martin , Ahaus Kees
Published: July 2017

Purpose

The purpose of this paper is to investigate the roles that employee-initiated Lean improvement projects play in health care. Lean ideas are introduced to improve flow in health care. Although variability is detrimental to flow performance, it is unclear whether Lean initiatives set out to reduce this variability and the associated buffers.

Design/methodology/approach

Longitudinal field research is combined with an exploratory field-quasi-experiment. First, a large set of Lean interventions were explored and their focus classified. Semi-structured interviews with practitioners supported the initial findings regarding the focus. Second, this study investigated whether a knowledge deficiency could explain the identified focus through a quasi-experiment in which the authors’ stimulated knowledge on the roles of variability and buffers and then classified subsequent interventions.

Findings

The results reflected a narrow application of Lean, with most interventions directed at reducing direct waste. A quasi-experiment demonstrated that a small investment in knowledge enables the focus to shift toward buffers and variability issues – i.e. toward a more complete Lean approach.

Research limitations/implications

This research supports the commonly held view that there is a tendency to focus on waste. Furthermore, a lengthy experience of Lean does not guarantee interventions will focus on buffers and variability, issues with arguably a higher complexity compared to obvious waste. However, small investments in knowledge can broaden the focus of practitioners’ interventions.

Originality/value

This study is one of the first to research the focus of Lean interventions through a data set spanning several years. The results are based on a unique data set covering a large number of documented Lean interventions.
How performance measurement influences stakeholders in not-for-profit organizations
Authors: Beer Haley Allison , Micheli Pietro
Published: July 2017

Purpose

The purpose of this paper is to examine the influences of performance measurement (PM) on not-for-profit (NFP) organizations’ stakeholders by studying how PM practices interact with understandings of legitimate performance goals. This study invokes institutional logics theory to explain interactions between PM and stakeholders.

Design/methodology/approach

An in-depth case study is conducted in a large NFP organization in the UK. Managers, employees, and external partners are interviewed and observed, and performance-related documents analyzed.

Findings

Both stakeholders and PM practices are found to have dominant institutional logics that portray certain goals as legitimate. PM practices can reinforce, reconcile, or inhibit stakeholders’ understandings and propensity to act toward goals, depending on the extent to which practices share the dominant logic of the stakeholders they interact with.

Research limitations/implications

A theoretical framework is proposed for how PM practices first interact with stakeholders at a cognitive level and second influence action. This research is based on a single case study, which limits generalizability of findings; however, results may be transferable to other environments where PM is aimed at balancing competing stakeholder objectives and organizational priorities.

Practical implications

PM affects the experience of stakeholders by interacting with their understanding of legitimate performance goals. PM systems should be designed and implemented on the basis of both their formal ability to represent organizational aims and objectives, and their influence on stakeholders.

Originality/value

Findings advance PM theory by offering an explanation for how PM influences attention and actions at an individual micro level.