bluuebunny/crossref_metadata_2025_split huggingface dataset:
HYPERREFLECTIVE DEPOSITION IN THE BACKGROUND OF ADVANCED STARGARDT DISEASE
Authors: Ciccone Lyam , Lee Winston , Zernant Jana , Tanaka Koji , Schuerch Kaspar , Tsang Stephen H. , Allikmets Rando 
Published: October 2017

Purpose:
To describe an unusual manifestation of hyperreflective deposits in the subretinal space in a group of patients with clinically and genetically confirmed Stargardt disease.

Methods:
Retrospective review of color fundus, autofluorescence, infrared reflectance, red-free images, and spectral domain optical coherence tomography in 296 clinically diagnosed and genetically confirmed (2 expected disease-causing mutations in ABCA4) patients with Stargardt disease. Full-field electroretinogram (ffERG), medical history, and genotype data (in silico predictions) were further analyzed from the selected cohort.

Results:
Eight of 296 patients (2.7%) were found to exhibit small crystalline deposits that were detectable on certain imaging modalities, such as color, infrared reflectance and red-free images, but not autofluorescence. The deposits were most prevalent in the superior region of the macula, and spectral domain optical coherence tomography revealed their presence in the subretinal space. All patients presented with these findings at a notably advanced disease stage with abnormal ffERG and a high proportion of highly deleterious ABCA4 alleles.

Conclusion:
Hyperreflective subretinal deposits may be a manifestation of advanced ABCA4 disease, particularly in regions susceptible to disease-related changes, such as lipofuscin accumulation.
Surgical Outcomes of Gonioscopy-assisted Transluminal Trabeculotomy (GATT) in Patients With Open-angle Glaucoma
Authors: Rahmatnejad Kamran , Pruzan Noelle L. , Amanullah Sarah , Shaukat Bilal A. , Resende Arthur F. , Waisbourd Michael , Zhan Tingting , Moster Marlene R. 
Published: October 2017

Purpose:
To evaluate the efficacy and safety of gonioscopy-assisted transluminal trabeculotomy (GATT) in patients with open-angle glaucoma.

Participants and Methods:
A retrospective chart review of adult patients who underwent GATT due to inadequately controlled intraocular pressure (IOP) or intolerance to medication. Main outcome measures were success rate, IOP, and number of glaucoma medications. Success was defined as IOP reduction >20% from baseline or IOP between 5 to 21 mm Hg, and no need for further glaucoma surgery. When success criteria were not met for any postoperative visit >3 months after surgery, failure was determined.

Results:
In total, 66 patients, average age 62.9±14.9 years (50.8% female) were included in the analysis. Average follow-up was 11.9 months (range, 3 to 30 mo) and overall success rate was 63.0%. Mean IOP was 26.1±9.9 mm Hg preoperatively and 14.6±4.7 mm Hg at 12 months (44% IOP decrease; P<0.001). Mean number of medications decreased from 3.1±1.1 preoperatively to 1.2±0.9 at 12 months (P<0.001). No significant differences between patients with primary open-angle glaucoma and other types of glaucoma were found.
The rate of hyphema at 1 week and 1 month postoperatively was 38% and 6%, respectively. Overall GATT success rate among white and black patients was 69% and 42%, respectively, which was statistically significant (P<0.05).

Conclusions:
The future of GATT as a minimally invasive glaucoma surgery in adults seems promising. This position is supported by its low rate of long-term complications and the conjunctiva-sparing nature of the surgery.
Rapid Deployment Aortic Valves Deliver Superior Hemodynamic Performance in Vitro
Authors: Ai Lisong , Chen Harvey , Lin Virginia , Bapat Vinayak N. 
Published: October 2017

Objective Clinical studies have demonstrated excellent hemodynamic performance of rapid deployment aortic valves; however, few studies have directly compared the performance of these valves with conventional bioprosthetic valves. Thus, the hemodynamic function of the EDWARDS INTUITY valve (rapid deployment valve) was compared with the Edwards Magna Ease valve in vitro (Edwards Lifesciences Corp, Irvine, CA USA). Methods Elastomeric material was used to create an aortic root model that included a left ventricular outflow tract and aortic annulus. The model was based on reconstructions from 3-dimensional multislice computed tomography images in patients with aortic stenosis; the aortic root was scaled to a 21-mm effective annulus diameter. EDWARDS INTUITY valves (21-mm diameter) were deployed by stent frame expansion within the aortic root; Edwards Magna Ease valves (21-mm diameter) were sutured to the annulus. The left ventricular outflow tract area index (left ventricular outflow tract area/baseline area) and ellipticity or noncircularity as indexed by Dmax/Dmin were measured under a video microscope after valve placement. Hemodynamic data were collected under pulsatile flow with saline (70 beats per minute, 5 L/min, 100 mm Hg aortic pressure). Results Compared with the Edwards Magna Ease valve (n = 4), the EDWARDS INTUITY valve (n = 4) had a greater effective orifice area (1.56 ± 0.01 vs 1.85 ± 0.06 cm2, P < 0.001) and a lower transvalvular pressure gradient (23.4 ± 0.51 vs 16.8 ± 1.3 mm Hg, P < 0.001). Multiple regression analysis showed that 93% of the variation in the effective orifice area and transvalvular pressure gradient was due to variation in the left ventricular outflow tract area index and ellipticity index. Conclusions A clinically relevant aortic root model was developed to evaluate aortic valve performance. The superior performance of the EDWARDS INTUITY valve seemed to be related to both a greater inflow area and a more circular left ventricular outflow tract.
Biomarkers of drug-induced kidney injury
Authors: Redahan Lynn , Murray Patrick T. 
Published: October 2017

Purpose of review
Drug-induced kidney injury (DIKI) is an important and potentially modifiable cause of acute kidney injury (AKI). The reliance on traditional markers of kidney injury to diagnose DIKI impedes early detection. Biomarkers of DIKI that facilitate early diagnosis and the identification of high-risk patients are essential to ameliorate the clinical burden of this complication.

Recent findings
Recent progress in this area supports the potential utility of several biomarkers for the diagnosis of DIKI, for the prediction of outcomes and also for monitoring responses to potential nephrotoxic or beneficial therapies. Data regarding the impact of clinically relevant factors, such as chronic kidney disease, on biomarker levels represents a further recent advancement. Emerging novel biomarkers include microRNAs, which are showing promise as markers of drug-induced tubular damage. They may also have a role in elucidating the molecular mechanisms of AKI.

Summary
There is compelling evidence to support the use of biomarkers for the early detection of DIKI. Ongoing research is required to delineate their role in prognostication and for the prediction of outcomes. The inclusion of biomarkers in more clinical studies of DIKI would be a welcome advance, which may accelerate their integration into clinical diagnostics.
Exchangeable Zinc Pool Size at Birth in Pakistani Small for Gestational Age and Appropriate for Gestational Age Infants Do Not Differ But Are Lower Than in US Infants
Authors: Ariff Shabina , Krebs Nancy F. , Westcott Jamie E. , Hambidge Michael , Miller Leland V. , Rizvi Arjumand , Soofi Sajid B. , Bhutta Zulfiqar A. 
Published: October 2017

ABSTRACTObjectives:Small for gestational age (SGA) infants are more susceptible to infectious morbidity and growth faltering compared to their appropriate for gestational age (AGA) counterparts. Zinc supplementation of SGA infants may be beneficial but the underlying susceptibility to zinc deficiency of SGA infants has not been examined.Methods:In a community‐based, observational, longitudinal study in a peri‐urban settlement of Karachi, Pakistan, we compared the size of the exchangeable zinc pools (EZPs) in term SGA and AGA infants at birth and at 6 months of age, hypothesizing that the EZP would be lower in the SGA group. To measure EZP size, a zinc stable isotope was intravenously administered within 48 hours of birth (n = 17 and 22) at 6 months (n = 11 and 14) in SGA and AGA infants, respectively. Isotopic enrichment in urine was used to determine EZP.Results:No significant difference was detected in the mean (±standard deviation) EZP between SGA and AGA infants at birth, with values of 9.8 ± 3.5 and 10.1 ± 4.1 mg/kg, respectively (P = 0.86), or at 6 months. Longitudinal EZP measurements demonstrated a significant decline in EZP relative to body weight in both groups at 6 months (P < 0.001). Mean EZP (adjusted for body weight) size at birth for the combined Pakistani groups was significantly lower than AGA infants at birth in the United States (P = 0.017).Conclusions:These results did not support a difference in zinc endowment between SGA and AGA Pakistani infants. They, however, do suggest lower in utero zinc transfer to the fetus in a setting where poor maternal nutritional status may confer a high susceptibility to postnatal zinc deficiency.
Psychometric Properties and Factor Structure of a Long and Shortened Version of the Cognitive and Behavioural Responses Questionnaire
Authors: Ryan Elizabeth G. , Vitoratou Silia , Goldsmith Kimberley A. , Chalder Trudie 
Published: October 2017

ABSTRACT

Objective
Symptoms of chronic fatigue syndrome (CFS) can be perpetuated by cognitive and behavioral responses to the illness. We aimed to determine the factor structure, reliability, and validity of the 40-item Cognitive and Behavioural Responses Questionnaire (CBRQ) using data gathered from CFS patients. We also propose a short-version CBRQ for greater clinical utility.

Methods
The psychometric analysis was performed on data sets drawn from two sources: a clinical service for CFS patients (n = 576) and the PACE randomized controlled trial of CFS treatments (n = 640). An exploratory factor analysis was conducted on the clinical data set and a confirmatory factor analysis was performed on the randomized controlled trial data set. Using these results, a short version of the CBRQ was proposed. Reliability, metric invariance across age and sex, and construct validity were assessed.

Results
The exploratory factor analysis (relative χ2 = 2.52, root mean square error of approximation = 0.051, comparative fit index = 0.964, Taylor-Lewis Index = 0.942) and confirmatory factor analysis (relative χ2 = 4.029, root mean square error of approximation = 0.069, comparative fit index = 0.901, Taylor-Lewis Index = 0.892) revealed that eight-factor models fitted the data well. Satisfactory Cronbach's α values were obtained for the final subscales (≥0.76). The shortened CBRQ was obtained by removing items that cross-loaded onto other factors and/or were the lowest loading items in each factor. The shortened CBRQ contained 18 items that had high factor loadings, good face validity, and reliability (Cronbach's α = 0.67–0.88).

Conclusions
The CBRQs, long and short versions, are reliable and valid scales for measuring cognitive and behavioral responses of patients with CFS. Further research is needed to examine the utility of the CBRQ in other long-term conditions.
Detection of functional protein domains by unbiased genome-wide forward genetic screening
Authors: Herzog Mareike , Puddu Fabio , Coates Julia , Geisler Nicola , Forment Josep V , Jackson Stephen P. 
Published: October 2017

ABSTRACTGenetic and chemo-genetic interactions have played key roles in elucidating the molecular mechanisms by which certain chemicals perturb cellular functions. Many studies have employed gene knockout collections or gene disruption/depletion strategies to identify routes for evolving resistance to chemical agents. By contrast, searching for point-mutational genetic suppressors that can identify separation- or gain-of-function mutations, has been limited even in simpler, genetically amenable organisms such as yeast, and has not until recently been possible in mammalian cell culture systems. Here, by demonstrating its utility in identifying suppressors of cellular sensitivity to the drugs camptothecin or olaparib, we describe an approach allowing systematic, large-scale detection of spontaneous or chemically-induced suppressor mutations in yeast and in haploid mouse embryonic stem cells in a short timeframe, and with potential applications in essentially any other haploid system. In addition to its utility for molecular biology research, this protocol can be used to identify drug targets and to predict mechanisms leading to drug resistance. Mapping suppressor mutations on the primary sequence or three-dimensional structures of protein suppressor hits provides insights into functionally relevant protein domains, advancing our molecular understanding of protein functions, and potentially helping to improve drug design and applicability.
Development of a novelFrancisella tularensisLive Vaccine Strain expressing ovalbumin provides insight intoFrancisella tularensis-specific CD8+T cell responses
Authors: Place David E. , Williamson David R. , Yuzefpolskiy Yevgeniy , Katkere Bhuvana , Sarkar Surojit , Kalia Vandana , Kirimanjeswara Girish S. 
Published: October 2017

ABSTRACTProgress towards a safe and effective vaccine for the prevention of tularemia has been hindered by a lack of knowledge regarding the correlates of protective adaptive immunity and a lack of tools to generate this knowledge. CD8+T cells are essential for protective immunity against virulent strains ofFrancisella tularensis, but to-date, it has not been possible to study these cells in a pathogen-specific manner. Here, we report the development of a tool for expression of the model antigen ovalbumin (OVA) inF. tularensis, which allows for the study of CD8+T cell responses to the bacterium. We demonstrate that in response to intranasal infection with theF. tularensisLive Vaccine Strain, pathogen-specific CD8+T cells expand after the first week and produce IFN-γ but not IL-17. Effector and central memory subsets develop with disparate kinetics in the lungs, draining lymph node and spleen. Notably,F. tularensis-specific cells are poorly retained in the lungs after clearance of infection. We also show that intranasal vaccination leads to more pathogen-specific CD8+T cells in the lung-draining lymph node compared to scarification vaccination, but that an intranasal booster overcomes this difference. Together, our data show that this novel tool can be used to study multiple aspects of the CD8+T cell response toF. tularensis. Use of this tool will enhance our understanding of immunity to this deadly pathogen.
Compensatory evolution via cryptic genetic variation: Distinct trajectories to phenotypic and fitness recovery
Authors: Chari Sudarshan , Marier Christian , Porter Cody , Northrop Emmalee , Belinky Alexandra , Dworkin Ian 
Published: October 2017

AbstractPopulations are constantly exposed to deleterious alleles, most of which are purged via natural selection. However, deleterious fitness effects of alleles can also be suppressed by compensatory adaptation. Compensatory mutations can act directly to reduce deleterious effects of an allele. Alternatively, compensation may also occur by altering other aspects of an organisms’ phenotype or performance, without suppressing the phenotypic effects of the deleterious allele. Moreover, the origin of allelic variation contributing to compensatory adaptation remains poorly understood. Compensatory evolution driven by mutations that arise during the selective process are well studied. However less is known about the role standing (cryptic) genetic variation plays in compensatory adaptation. To address these questions, we examined evolutionary trajectories of natural populations ofDrosophila melanogasterfixed for mutations that disrupt wing morphology, resulting in deleterious effects on several components of fitness. Lineages subjected only to natural selection, evolved modifications to courtship behavior and several life history traits without compensation in wing morphology. Yet, we observed rapid phenotypic compensation of wing morphology under artificial selection, consistent with segregating variation for compensatory alleles. We show that alleles contributing to compensation of wing morphology have deleterious effects on other fitness components. These results demonstrate the potential for multiple independent avenues for rapid compensatory adaptation from standing genetic variation, which ultimately may reveal novel adaptive trajectories.
Energetic costs, precision, and efficiency of a biological motor in cargo transport
Authors: Hwang Wonseok , Hyeon Changbong 
Published: October 2017

AbstractMolecular motors play key roles in organizing the interior of cells. An efficient motor in cargo transport would travel with a high speed and a minimal error in transport time (or distance) while consuming minimal amount of energy. The travel distance and its variance of motor are, however, physically constrained by energy consumption, the principle of which has recently been formulated into thethermodynamic uncertainty relation. Here, we reinterpret the uncertainty measure (𝒬) defined in the thermodynamic uncertainty relation such that a motor efficient in cargo transport is characterized with a small 𝒬. Analyses on the motility data from several types of molecular motors show that 𝒬 is a nonmonotic function of ATP concentration and load (f). For kinesin-1, 𝒬 is locally minimized at [ATP] ≈ 200μM andf≈ 4 pN. Remarkably, for the mutant with a longer neck-linker this local minimum vanishes, and the energetic cost to achieve the same precision as the wild-type increases significantly, which underscores the importance of molecular structure in transport properties. For the biological motors studied here, their value of 𝒬 is semi-optimized under the cellular condition ([ATP] ≈ 1 mM,f= 0 − 1 pN). We find that among the motors, kinesin-1 at single molecule level is the most efficient in cargo transport.
Variants in RNA-Seq data show a continued mutation rate during strain preservation ofSchizophyllum commune
Authors: Gehrmann Thies , Pelkmans Jordi F. , Lugones Luis G. , Wösten Han A.B. , Abeel Thomas , Reinders Marcel J.T. 
Published: October 2017

AbstractBackgroundTypical microorganism studies link genetic markers to physiological observations, like growth and survival. Experiments are carefully designed, comparing wildtype strains with knockout strains, and replications are conducted to capture biological variation. To maintain monoclonal strains, strain preservation systems are used to keep the number of generations between the primary stock and the experimental measurement low, to decrease the influence of spontaneous mutations on the experimental outcome. The impact of spontaneous mutations during the minimal number of growth cycles for the experimental design is, however, poorly studied.ResultsWe set out to characterize the mutation landscape using a transcriptomic dataset ofSchizophyllum commune, a laboratory model for mushroom formation. We designed a methodology to detect SNPs from the RNA-seq data, and found a mutation rate of 1.923 10−8per haploid genome per base per generation, highly similar to the previously described mutation rate ofS. communein the wild. Our results imply that approximately 300 mutations are generated during growth of a colony on an agar plate, of which 5 would introduce stop codons. Knock-outs did not incur an increase of mutations and chromosomal recombination occurring at mating type loci was frequent. We found that missense and nonsense SNPs were selected against throughout the experiment. Also, most mutations show a low variant allele frequency and appear only in a small part of the population. Yet, we found 40 genes that gained a nonsense mutation affecting one of its annotated protein domains, and more than 400 genes having a missense mutation inside an annotated protein domain. Further, we found transcription factors, metabolic genes and cazymes having gained a mutation. Hence, the mutation landscape is wide-spread and has many functional annotations.ConclusionsWe have shown that spontaneous mutations accumulate in typical microorganism experiments, where one usually assumes that these do not happen. As these mutations possibly confound experiments they should be minimized as much as possible, or, at least, be trackable. Therefore, we recommend labs to ensure that biological replicates originate from different parental plates, as much as possible.
Bayesian Optimisation for Neuroimaging Pre-processing in Brain Age Prediction
Authors: Lancaster Jenessa , Lorenz Romy , Leech Rob , Cole James H 
Published: October 2017

AbstractNeuroimaging-based age predictions using machine learning have been shown to relate to cognitive performance, health outcomes and progression of neurodegenerative disease. However, even leading age-prediction algorithms contain measurement error, motivating efforts to improve experimental pipelines. T1-weighted MRI is commonly used for age prediction, and the pre-processing of these scans involves normalisation to a common template and resampling to a common voxel size, followed by spatial smoothing. Resampling parameters are often selected arbitrarily. Here, we sought to improve brain-age prediction accuracy by optimising resampling parameters using Bayesian optimisation.Using data on N=2001 healthy individuals (aged 16-90 years) we trained support vector machines to i) distinguish between young (<50 years) and old (>50 years) brains and ii) predict chronological age, with accuracy assessed using cross-validation. We also evaluated model generalisability to the Cam-CAN dataset (N=648, aged 18-88 years). Bayesian optimisation was used to identify optimal voxel size and smoothing kernel size for each task. This procedure adaptively samples the parameter space to evaluate accuracy across a range of possible parameters, using independent sub-samples to iteratively assess different parameter combinations to arrive at optimal values.When distinguishing between young and old brains a classification accuracy of 96.25% was achieved, with voxel size = 11.5mm3and smoothing kernel = 2.3mm. For predicting chronological age, a mean absolute error (MAE) of 5.08 years was achieved, with voxel size = 3.73mm3and smoothing kernel = 3.68mm. This was compared to performance using default values of 1.5mm3and 4mm respectively, which gave a MAE = 5.48 years, a 7.3% improvement. When assessing generalisability, best performance was achieved when applying the entire Bayesian optimisation framework to the new dataset, out-performing the parameters optimised for the initial training dataset.Our study demonstrates the proof-of-principle that neuroimaging models for brain age prediction can be improved by using Bayesian optimisation to select more appropriate pre-processing parameters. Our results suggest that different parameters are selected and performance improves when optimisation is conducted in specific contexts. This motivates use of optimisation techniques at many different points during the experimental process, which may result in improved statistical sensitivity and reduce opportunities for experimenter-led bias.