bluuebunny/crossref_metadata_2025_split huggingface dataset:
CRISPR RNA-guided FokI nucleases repair a PAH variant in a phenylketonuria model
Authors: Pan Yi , Shen Nan , Jung-Klawitter Sabine , Betzen Christian , Hoffmann Georg F. , Hoheisel Jörg D. , Blau Nenad 
Published: October 2016

AbstractThe CRISPR/Cas9 system is a recently developed genome editing technique. In this study, we used a modified CRISPR system, which employs the fusion of inactive Cas9 (dCas9) and the FokI endonuclease (FokI-dCas9) to correct the most common variant (allele frequency 21.4%) in the phenylalanine hydroxylase (PAH) gene - c.1222C>T (p.Arg408Trp) - as an approach toward curing phenylketonuria (PKU). PKU is the most common inherited diseases in amino acid metabolism. It leads to severe neurological and neuropsychological symptoms if untreated or late diagnosed. Correction of the disease-causing variants could rescue residual PAH activity and restore normal function. Co-expression of a single guide RNA plasmid, a FokI-dCas9-zsGreen1 plasmid, and the presence of a single-stranded oligodeoxynucleotide in PAH_c.1222C>T COS-7 cells – an in vitro model for PKU – corrected the PAH variant and restored PAH activity. Also in this system, the HDR enhancer RS-1 improved correction efficiency. This proof-of-concept indicates the potential of the FokI-dCas9 system for precision medicine, in particular for targeting PKU and other monogenic metabolic diseases.
Dissipative phases across the superconductor-to-insulator transition
Authors: Couëdo F. , Crauste O. , Drillien A. A. , Humbert V. , Bergé L. , Marrache-Kikuchi C. A. , Dumoulin L. 
Published: October 2016

AbstractCompeting phenomena in low dimensional systems can generate exotic electronic phases, either through symmetry breaking or a non-trivial topology. In two-dimensional (2D) systems, the interplay between superfluidity, disorder and repulsive interactions is especially fruitful in this respect although both the exact nature of the phases and the microscopic processes at play are still open questions. In particular, in 2D, once superconductivity is destroyed by disorder, an insulating ground state is expected to emerge, as a result of a direct superconductor-to-insulator quantum phase transition. In such systems, no metallic state is theoretically expected to survive to the slightest disorder. Here we map out the phase diagram of amorphous NbSi thin films as functions of disorder and film thickness, with two metallic phases in between the superconducting and insulating ones. These two dissipative states, defined by a resistance which extrapolates to a finite value in the zero temperature limit, each bear a specific dependence on disorder. We argue that they originate from an inhomogeneous destruction of superconductivity, even if the system is morphologically homogeneous. Our results suggest that superconducting fluctuations can favor metallic states that would not otherwise exist.
Revealing the diversity of extracellular vesicles using high-dimensional flow cytometry analyses
Authors: Marcoux Geneviève , Duchez Anne-Claire , Cloutier Nathalie , Provost Patrick , Nigrovic Peter A. , Boilard Eric 
Published: October 2016

AbstractExtracellular vesicles (EV) are small membrane vesicles produced by cells upon activation and apoptosis. EVs are heterogeneous according to their origin, mode of release, membrane composition, organelle and biochemical content, and other factors. Whereas it is apparent that EVs are implicated in intercellular communication, they can also be used as biomarkers. Continuous improvements in pre-analytical parameters and flow cytometry permit more efficient assessment of EVs; however, methods to more objectively distinguish EVs from cells and background, and to interpret multiple single-EV parameters are lacking. We used spanning-tree progression analysis of density-normalized events (SPADE) as a computational approach for the organization of EV subpopulations released by platelets and erythrocytes. SPADE distinguished EVs, and logically organized EVs detected by high-sensitivity flow cytofluorometry based on size estimation, granularity, mitochondrial content, and phosphatidylserine and protein receptor surface expression. Plasma EVs were organized by hierarchy, permitting appreciation of their heterogeneity. Furthermore, SPADE was used to analyze EVs present in the synovial fluid of patients with inflammatory arthritis. Its algorithm efficiently revealed subtypes of arthritic patients based on EV heterogeneity patterns. Our study reveals that computational algorithms are useful for the analysis of high-dimensional single EV data, thereby facilitating comprehension of EV functions and biomarker development.
A model for cyclic mechanical reinforcement
Authors: Li Zhenhai , Kong Fang , Zhu Cheng 
Published: October 2016

AbstractMechanical force regulates a broad range of molecular interactions in biology. Three types of counterintuitive mechanical regulation of receptor–ligand dissociation have been described. Catch bonds are strengthened by constant forces, as opposed to slip bonds that are weakened by constant forces. The phenomenon that bonds become stronger with prior application of cyclic forces is termed cyclic mechanical reinforcement (CMR). Slip and catch bonds have respectively been explained by two-state models. However, they assume fast equilibration between internal states and hence are inadequate for CMR. Here we propose a three-state model for CMR where both loading and unloading regulate the transition of bonds among the short-lived, intermediate, and long-lived state. Cyclic forces favor bonds in the long-lived state, hence greatly prolonging their lifetimes. The three-state model explains the force history effect and agrees with the experimental CMR effect of integrin α5β1–fibronectin interaction. This model helps decipher the distinctive ways by which molecular bonds are mechanically strengthened: catch bonds by constant forces and CMR by cyclic forces. The different types of mechanical regulation may enable the cell to fine tune its mechanotransduction via membrane receptors.
Neuromodulatory effects of offline low-frequency repetitive transcranial magnetic stimulation of the motor cortex: A functional magnetic resonance imaging study
Authors: Min Yu-Sun , Park Jang Woo , Jin Seong Uk , Jang Kyung Eun , Lee Byung-Joo , Lee Hui Joong , Lee Jongmin , Lee Yang-Soo , Chang Yongmin , Jung Tae-Du 
Published: October 2016

AbstractRepetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex (M1) can modulate cortical excitability and is thought to influence activity in other brain areas. In this study, we investigated the anatomical and functional effects of rTMS of M1 and the time course of after-effects from a 1-Hz subthreshold rTMS to M1. Using an “offline” functional magnetic resonance imaging (fMRI)-rTMS paradigm, neural activation was mapped during simple finger movements after 1-Hz rTMS over the left M1 in a within-subjects repeated measurement design, including rTMS and sham stimulation. A significant decrease in the blood oxygen level dependent (BOLD) signal due to right hand motor activity during a simple finger-tapping task was observed in areas remote to the stimulated motor cortex after rTMS stimulation. This decrease in BOLD signal suggests that low frequency subthreshold rTMS may be sufficiently strong to elicit inhibitory modulation of remote brain regions. In addition, the time course patterns of BOLD activity showed this inhibitory modulation was maximal approximately 20 minutes after rTMS stimulation.
Molecular evidence of RNA polymerase II gene reveals the origin of worldwide cultivated barley
Authors: Wang Yonggang , Ren Xifeng , Sun Dongfa , Sun Genlou 
Published: October 2016

AbstractThe origin and domestication of cultivated barley have long been under debate. A population-based resequencing and phylogenetic analysis of the single copy ofRPB2gene was used to address barley domestication, to explore genetic differentiation of barley populations on the worldwide scale, and to understand gene-pool exchanges during the spread and subsequent development of barley cultivation. Our results revealed significant genetic differentiation among three geographically distinct wild barley populations. Differences in haplotype composition among populations from different geographical regions revealed that modern cultivated barley originated from two major wild barley populations: one from the Near East Fertile Crescent and the other from the Tibetan Plateau, supporting polyphyletic origin of cultivated barley. The results of haplotype frequencies supported multiple domestications coupled with widespread introgression events that generated genetic admixture between divergent barley gene pools. Our results not only provide important insight into the domestication and evolution of cultivated barley, but also enhance our understanding of introgression and distinct selection pressures in different environments on shaping the genetic diversity of worldwide barley populations, thus further facilitating the effective use of the wild barley germplasm.
Homophily in coauthorship networks of East European sociologists
Authors: Hâncean Marian-Gabriel , Perc Matjaž 
Published: October 2016

AbstractWe study to what degree and how homophily and network properties affect individual citation counts of researchers in the sociology departments of three East European countries, namely Poland, Romania, and Slovenia. We built first-order personal coauthorship networks out of the Web of Science publication records. Each sociologist is assigned as a focal node or ego, while her coauthors are alters. We analyze the data using structural measurements methods, hierarchical regression models, and we make visualizations based on the clustered graph technique. For all three populations, our results indicate that the mean score of the citations of alters substantially predicts the citation counts of egos. In particular, citation similarity increases the chances for coauthorship ties. Evidence for the impact of network properties on the citation levels of egos is mixed. For Poland, normalized ego-betweenness shows a negative effect on citation counts, while network density displays a positive one. For Romania and Slovenia, network characteristics have only a minor impact. Even if the visual summarization of the personal networks uncovers a wide palette of coauthorship patterns, homophily appears to be pervasive. These results are relevant for domestic policy makers who aim to improve the aggregated research performance in East European countries.
Xanthine oxidoreductase and its inhibitors: relevance for gout
Authors: Day Richard O. , Kamel Bishoy , Kannangara Diluk R.W. , Williams Kenneth M. , Graham Garry G. 
Published: October 2016

Xanthine oxidoreductase (XOR) is the rate-limiting enzyme in purine catabolism and converts hypoxanthine to xanthine, and xanthine into uric acid. When concentrations of uric acid exceed its biochemical saturation point, crystals of uric acid, in the form of monosodium urate, emerge and can predispose an individual to gout, the commonest form of inflammatory arthritis in men aged over 40 years. XOR inhibitors are primarily used in the treatment of gout, reducing the formation of uric acid and thereby, preventing the formation of monosodium urate crystals. Allopurinol is established as first-line therapy for gout; a newer alternative, febuxostat, is used in patients unable to tolerate allopurinol. This review provides an overview of gout, a detailed analysis of the structure and function of XOR, discussion on the pharmacokinetics and pharmacodynamics of XOR inhibitors–allopurinol and febuxostat, and the relevance of XOR in common comorbidities of gout.
Processing Binding Relations in Specific Language Impairment
Authors: Schwartz Richard G. , Hestvik Arild , Seiger-Gardner Liat , Almodovar Diana 
Published: October 2016

Purpose
This sentence processing experiment examined the abilities of children with specific language impairment (SLI) and children with typical language development (TD) to establish relations between pronouns or reflexives and their antecedents in real time.

Method
Twenty-two children with SLI and 24 age-matched children with TD (7;3–10;11 [years;months]) participated in a cross-modal picture priming experiment to determine whether they selectively activated the correct referent at the pronoun or reflexive in sentences. Triplets of auditory sentences, identical except for the presence of a pronoun, a reflexive, or a noun phrase along with a picture probe were used.

Results
The children with TD were slightly more accurate in their animacy judgments of pictures, but the groups exhibited the same reaction time (RT) pattern. Both groups were slower for sentences with pronouns than with reflexives or noun phrases. The children with SLI had longer RTs than their peers with TD.

Conclusions
Children with SLI activated only the appropriate antecedent at the pronoun or reflexive, reflecting intact core knowledge of binding as was true for their TD peers. The overall slower RT for children with SLI suggests that any deficit may be the result of processing deficits, perhaps attributable to interference effects.
Abscisic acid controlled sex before transpiration in vascular plants
Authors: McAdam Scott A. M. , Brodribb Timothy J. , Banks Jo Ann , Hedrich Rainer , Atallah Nadia M. , Cai Chao , Geringer Michael A. , Lind Christof , Nichols David S. , Stachowski Kye , Geiger Dietmar , Sussmilch Frances C. 
Published: October 2016

Significance
Since the dawn of land plants, the phytohormone abscisic acid (ABA) has played a critical role in regulating plant responses to water availability. Here we seek to explain the origins of the core ABA signaling pathway found in modern seed plants. Using the characterization of mutants and gene silencing in a fern species, we find that the same hormone signaling components are used in sex determination of ferns as are used for the control of seed dormancy and transpiration in seed plants. Ferns are shown to lack downstream functionality of stomatal components, suggesting that the origins of the core ABA signaling pathway in seed plants may lie in the sexual differentiation of ferns.
Chronic use of PAH‐specific therapy in World Health Organization Group III Pulmonary Hypertension: a systematic review and meta‐analysis
Authors: Prins Kurt W. , Duval Sue , Markowitz Jeremy , Pritzker Marc , Thenappan Thenappan 
Published: October 2016

Pulmonary hypertension (PH) complicating chronic obstructive pulmonary disease (COPD‐PH) and interstitial lung disease (ILD‐PH) (World Health Organization [WHO] Group III PH) increases medical costs and reduces survival. Despite limited data, many clinicians are using pulmonary arterial hypertension (PAH)‐specific therapy to treat WHO Group III PH patients. To further investigate the utility of PAH‐specific therapy in WHO Group III PH, we performed a systematic review and meta‐analysis. Relevant studies from January 2000 through May 2016 were identified in the MEDLINE, EMBASE, and COCHRANE electronic databases and www.clinicaltrials.gov. Change in six‐minute walk distance (6MWD) was estimated using random effects meta‐analysis techniques. Five randomized controlled trials (RCTs) in COPD‐PH (128 placebo or standard treatment and 129 PAH‐medication treated patients), two RCTs in ILD‐PH (23 placebo and 46 treated patients), and four single‐arm clinical trials (50 patients) in ILD‐PH were identified. Treatment in both COPD‐PH and ILD‐PH did not worsen hypoxemia. Symptomatic burden was not consistently reduced but there were trends for reduced pulmonary artery pressures and pulmonary vascular resistance with PAH‐specific therapy. As compared to placebo, 6MWD was not significantly improved with PAH‐specific therapy in the five COPD‐PH RCTs (42.7 m; 95% confidence interval [CI], –1.0 – 86.3). In the four single‐arm studies in ILD‐PH patients, there was a significant improvement in 6MWD after PAH‐specific treatment (46.2 m; 95% CI, 27.9–64.4), but in the two ILD‐PH RCTs there was not an improvement (21.6 m; 95% CI, –17.8 – 61.0) in exercise capacity when compared to placebo. Due to the small numbers of patients evaluated and inconsistent beneficial effects, the utility of PAH‐specific therapy in WHO Group III PH remains unproven. A future clinical trial that is appropriately powered is needed to definitively determine the efficacy of this widely implemented treatment approach.
Key comparison BIPM.RI(I)-K3 of the air-kerma standards of the VSL, The Netherlands and the BIPM in medium-energy x-rays
Authors: Burns D T , Kessler C , Pooter J A de , Jansen B J 
Published: October 2016

A key comparison has been made between the air-kerma standards of the VSL, The Netherlands and the BIPM in the medium-energy x-ray range. The results show the standards to be in agreement at the level of the standard uncertainty of the comparison of 3.2 parts in 103. The results are analysed and presented in terms of degrees of equivalence, suitable for entry in the BIPM key comparison database.

Main text

To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/.
The final report has been peer-reviewed and approved for publication by the CCRI, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).
Overview of ATX-101 (Deoxycholic Acid Injection): A Nonsurgical Approach for Reduction of Submental Fat
Authors: Dayan Steven H. , Humphrey Shannon , Jones Derek H. , Lizzul Paul F. , Gross Todd M. , Stauffer Karen , Beddingfield Frederick C. 
Published: October 2016

Abstract
In 2015, ATX-101 (deoxycholic acid injection; Kybella in the United States and Belkyra in Canada; Kythera Biopharmaceuticals, Inc., Westlake Village, CA [an affiliate of Allergan plc, Dublin, Ireland]) was approved as a first-in-class injectable drug for improvement in the appearance of moderate to severe convexity or fullness associated with submental fat. ATX-101 has been evaluated in a clinical development program that included 18 Phase 1 to 3 studies supporting the current indication. Since 2007, the toxicity and safety profiles of ATX-101 have been characterized in numerous preclinical studies, its pharmacokinetics, pharmacodynamics, and optimal treatment paradigm have been defined in multiple Phase 1 and 2 studies, and its efficacy and clinical safety have been confirmed in 4 large Phase 3 trials (2 conducted in Europe and 2 in the United States and Canada [REFINE-1 and REFINE-2]). As subcutaneous injection of deoxycholic acid has been shown to cause adipocytolysis, the reduction in submental fat achieved after ATX-101 treatment is expected to be long lasting. This prediction is confirmed by data from long-term follow-up studies of up to 4 years after last treatment with ATX-101, which demonstrate that the treatment response is maintained over time in most subjects. ATX-101 offers a durable, minimally invasive alternative to liposuction and surgery for addressing submental fullness.
Pembrolizumab
Authors: Nguyen Catherine M. , Jacob Sharon E. 
Published: October 2016

ABSTRACT
Drugs are medications or substances that are used to modify physiologic responses and alleviate associated symptoms. In dermatology, medications and substances are utilized on a daily basis and include topical treatments to anesthetics in micrographic surgery to biologic-acting immunologic agents. The purposes of this section are to focus on drug, specifically how it works and how it is utilized, and to discuss routine alternatives (if available). In this column, we will focus on the uses, mechanism of action, adverse effects, and alternatives to pembrolizumab, a new immunotherapy used for advanced melanoma.
Surgeon-Controlled Study and Meta-Analysis Comparing FlexHD and AlloDerm in Immediate Breast Reconstruction Outcomes
Authors: Sobti Nikhil , Liao Eric C. 
Published: October 2016

Background:
The use of acellular dermal matrix has facilitated immediate prosthesis-based breast reconstruction. However, few studies directly compare surgical outcomes following acellular dermal matrix–based reconstruction with two of the most commonly available materials, AlloDerm and FlexHD. Those studies that are available often do not adequately control for the surgeon as a variable. The authors hypothesize that complication rates will not differ significantly between AlloDerm and FlexHD when practice and surgeon variables are properly controlled.

Methods:
Retrospective review was conducted to identify consecutive implant-based reconstruction procedures performed at a tertiary academic medical institution by a single plastic surgeon over 6 years. Univariate and binomial regression analyses were conducted to compare patient characteristics and clinical endpoints across acellular dermal matrix groups (AlloDerm/AlloDerm ready-to-use versus FlexHD Pliable/Perforated).

Results:
Of the 233 patients that underwent matrix-based breast reconstruction, 11 (4.7 percent) developed surgical-site infection. The infection rate was not statistically different between patients who received FlexHD [n = 5 (5.0 percent)] versus AlloDerm [n = 6 (4.6 percent)] on either univariate (p = 0.89) or binomial regression analysis (p = 0.56). Likewise, there were no statistical differences in rates of seroma, hematoma, explantation, or delayed wound healing.

Conclusions:
Clinical endpoints of interest were all equivalent between acellular dermal matrix types. This study uniquely reports a single-surgeon case series comparing outcomes between different acellular dermal matrix types. Instead of focusing on acellular dermal matrix as a predictor of outcome, other patient and surgeon factors should be addressed to improve results and innovate better alternatives.

CLINICAL QUESTION/LEVEL OF EVIDENCE:
Therapeutic, III.
Determining the Cost of Incidental Findings for Patients Undergoing Preoperative Planning for Abdominally Based Perforator Free Flap Breast Reconstruction with Computed Tomographic Angiography
Authors: Agarwal Shailesh , Talia Jordan , Liu Peter S. , Momoh Adeyiza O. , Kozlow Jeffrey H. 
Published: October 2016

Background:
Computed tomographic angiography is increasingly used during surgical planning for abdominally based microvascular breast reconstruction. Cost-analysis studies have demonstrated a benefit to the use of computed tomographic angiography, although the secondary costs of incidental findings have not been previously reported. This study investigates the cost of computed tomographic angiography, taking into account the cost of incidental findings found during imaging.

Methods:
Patients undergoing preoperative computed tomographic angiography in preparation for autologous abdominally based breast reconstruction from July of 2010 through May of 2014 were included in this study. Patient medical records were reviewed for imaging findings, need for follow-up, and any additional procedures. Costs were determined using the publicly available Healthcare Bluebook.

Results:
A total of 135 patients underwent computed tomographic angiography in preparation for abdominally based microvascular breast reconstruction. Twenty-eight patients (21 percent) were noted to have clinically significant incidental findings recommended for follow-up imaging or procedures. Inclusion of chest imaging with computed tomographic angiography of the abdomen/pelvis to assess for internal mammary and/or thoracodorsal artery patency increased the incidental findings approximately five-fold. The mean cost of computed tomographic angiography increased by 32 percent, from $1267 to $1677 per patient, when incidental findings were included.

Conclusions:
Computed tomography angiography is a tool for the preoperative evaluation of patients desiring autologous breast reconstruction. The true cost of preoperative computed tomographic angiography is likely 30 percent greater than the baseline cost when the subsequent evaluation of incidental findings is included and should be accounted for in future cost-analysis studies.