bluuebunny/crossref_metadata_2025_split huggingface dataset:
Scarless Enriched selection of Genome edited Human Pluripotent Stem Cells Using Induced Drug Resistance
Authors: Kim Keun-Tae , Park Ju-Chan , Lee Haeseung , Jang Hyeon-Ki , Jin Yan , Kim Wankyu , Lee Jeongmi , Kim Hyongbum Henry , Bae Sang-Su , Cha Hyuk-Jin 
Published: January 2019

SummaryAn efficient gene editing technique for use in human pluripotent stem cells (hPSCs) would have great potential value in regenerative medicine, as well as in drug discovery based on isogenic human disease models. However, the extremely low efficiency of gene editing in hPSCs is a major technical hurdle that remains to be resolved. Previously, we demonstrated that YM155, a survivin inhibitor developed as an anti-cancer drug, induces highly selective cell death in undifferentiated hPSCs. In this study, we demonstrated that the high cytotoxicity of YM155 in hPSCs, which is mediated by selective cellular uptake of the drug, is due to high expression of SLC35F2 in these cells. Consistent with this, knockout of SLC35F2 with CRISPR-Cas9 or depletion with siRNAs made hPSCs highly resistant to YM155. Simultaneous gene editing of a gene of interest and transient knockdown of SLC35F2 following YM155 treatment enabled genome-edited hPSCs to survive because YM155 resistance was temporarily induced, thereby achieving enriched selection of genome-edited clonal populations. This precise and efficient genome editing approach took as little as 3 weeks without cell sorting or introduction of additional genes.
Hydraulic resistance of perivascular spaces in the brain
Authors: Tithof Jeffrey , Kelley Douglas H. , Mestre Humberto , Nedergaard Maiken , Thomas John H. 
Published: January 2019

AbstractBackgroundPerivascular spaces (PVSs) are annular channels that surround blood vessels and carry cerebrospinal fluid through the brain, sweeping away metabolic waste. In vivo observations reveal that they are not concentric, circular annuli, however: the outer boundaries are often oblate, and the blood vessels that form the inner boundaries are often offset from the central axis.MethodsWe model PVS cross-sections as circles surrounded by ellipses and vary the radii of the circles, major and minor axes of the ellipses, and two-dimensional eccentricities of the circles with respect to the ellipses. For each shape, we solve the governing Navier-Stokes equation to determine the velocity profile for steady laminar flow and then compute the corresponding hydraulic resistance.ResultsWe find that the observed shapes of PVSs have lower hydraulic resistance than concentric, circular annuli of the same size, and therefore allow faster, more efficient flow of cerebrospinal fluid. We find that the minimum hydraulic resistance (and therefore maximum flow rate) for a given PVS cross-sectional area occurs when the ellipse is elongated and intersects the circle, dividing the PVS into two lobes, as is common around pial arteries. We also find that if both the inner and outer boundaries are nearly circular, the minimum hydraulic resistance occurs when the eccentricity is large, as is common around penetrating arteries.ConclusionsThe concentric circular annulus assumed in recent studies is not a good model of the shape of actual PVSs observed in vivo, and it greatly overestimates the hydraulic resistance of the PVS. Our parameterization can be used to incorporate more realistic resistances into hydraulic network models of flow of cerebrospinal fluid in the brain. Our results demonstrate that actual shapes observed in vivo are nearly optimal, in the sense of offering the least hydraulic resistance. This optimization may well represent an evolutionary adaptation that maximizes clearance of metabolic waste from the brain.
Reconfiguration of neuronal subpopulation associated with disease-associated microglia in human Alzheimer’s disease brain
Authors: Choi Hongyoon , Choi Yoori , Hwang Do Won , Lee Dong Soo 
Published: January 2019

ABSTRACTThere is a growing evidence that a subset of microglia, disease-associated microglia (DAM), is crucially involved in the onset and progression of Alzheimer Disease (AD). However, it has been challenging to comprehensively know how DAM affects neuronal loss and reconstitute the complicated cellular composition. Here, we describe the relationship between neuronal reconfiguration and microglia by digitally dissecting the human brain transcriptome. We observed DAM enrichment associated with neuronal loss and the degree of amyloid deposits, which was commonly found in different brain regions. The neuronal subtype analyses showed that DAM enrichment was correlated with the proportion of two excitatory neurons located in the cortical layer 4. The direction of these relations was opposite, which implied excitatory neuronal reconfiguration in the specific cortical layer. Our results suggested immune reaction represented by DAM might mediate the reconfiguration of cellular components in AD, which may eventually have implications for diagnostics and therapeutics.One sentence summaryThe enrichment of disease-associated microglia signature is associated with the reconfiguration of neuronal subtypes, particularly excitatory neurons in the cortical layer 4.
Enhancing Cardiac Reprogramming by Suppressing Specific C-C Chemokine Signaling Pathways
Authors: Guo Yijing , Lei Ienglam , Tian Shuo , Gao Wenbin , Hacer Karatas , Li Yangbing , Wang Shaomeng , Liu Liu , Wang Zhong 
Published: January 2019

ABSTRACTReprogramming fibroblasts into induced cardiomyocytes (iCMs) is a potentially promising strategy for heart regeneration. Yet a major challenge is the low conversion rate. To address this challenge, we screened and identified four chemicals, insulin-like growth factor-1, Mll1 inhibitor MM589, transforming growth factor-β inhibitor A83-01, and Bmi1 inhibitor PTC-209, termed as IMAP, that coordinately enhanced reprogramming efficiency.Using α-muscle heavy chain -green fluorescent protein mouse embryo fibroblasts as the staring cell type, we observed a six-fold increase of iCM formation with IMAP treatment. IMAP stimulated higher cardiac troponin T and α-actinin expression and more sarcomere formation with up-regulation of many cardiac genes and down-regulation of fibroblast genes. Furthermore, IMAP promoted higher spontaneous beating and calcium transient activities of iCMs derived from neonatal cardiac fibroblasts. Intriguingly, we identified that many genes involved in immune responses, particularly those in specific C-C chemokine signaling pathways, were repressed with IMAP treatment. We next tested C-C chemokine ligands Ccl3, Ccl6, and Ccl17 in cardiac reprogramming and observed inhibitory effect on iCM formation, while corresponding inhibitors of Ccr1, Ccr4, and Ccr5 had the opposite effect. These results indicated that suppression of specific C-C chemokine signaling pathways was a direct down-stream event of IMAP treatment that enhanced cardiac reprogramming.In conclusion, we identified a combination of four chemicals IMAP in suppressing specific C-C chemokine signaling pathways and facilitating MGT-induced cardiac reprogramming. Our studies revealed the role of these specific C-C chemokine signaling pathways in cardiac reprogramming and provide potential targets in iCM formation and its clinical applications.
Estimation the porosity of the valves of centric diatom Minidiscus vodyanitskiyi Lyakh & Bedoshvili using SEM images
Authors: Lyakh Anton M. , Bedoshvili Yekaterina D. , Shikhat Olga V. 
Published: January 2019

AbstractThe diatoms interact with the outer environment through the siliceous walls of a frustule. Because of that the surface area of the frustule determines the ability of diatoms to absorb and excrete material resources. Such as unicellular organisms exchange matter only through the pores in their cell wall, to find relationships between characteristics of material fluxes and surface area of microorganism cover that is penetrable for substance, it is necessary to estimate the total surface area of pores or a porosity – relative area of pores perforated frustule. In the paper we describe a method of estimating the porosity of a diatom valve using SEM images. The method is tested on SEM images of the valves of centric diatom Minidiscus vodyanitskiyi recently described from the Sea of Azov. The results show that the valves porosity is less than 5 % of the total valves area. This value is consistent with the relative perforation of land plants leaves, which is less than 3%. We hypothesize that such value of diatom valves porosity is usual for many other diatom species. To verify this hypothesis additional researches are necessary.
Probing Neural Networks for Dynamic Switches of Communication Pathways
Authors: Finger Holger , Gast Richard , Gerloff Christian , Engel Andreas K. , König Peter 
Published: January 2019

AbstractDynamic communication and routing play important roles in the human brain to facilitate 2exibility in task solving and thought processes. Here, we present a network perturbation methodology that allows to investigate dynamic switching between different network pathways based on phase offsets between two external oscillatory drivers. We apply this method in a computational model of the human connectome with delay-coupled neural masses. To analyze dynamic switching of pathways, we define four new metrics that measure dynamic network response properties for pairs of stimulated nodes. Evaluating these metrics for all network pathways, we found a broad spectrum of pathways with distinct dynamic properties and switching behaviors. Specifically, we found that 60.1% of node pairs can switch their communication from one pathway to another depending on their phase offsets. This indicates that phase offsets and coupling delays play an important computational role for the dynamic switching between communication pathways in the brain.
Lean in healthcare organization: an opportunity for environmental sustainability
Authors: Singh Poonam 
Published: January 2019

PurposeThe purpose of this paper is to provide insights toward the potential of lean healthcare organization for environment sustainability and develop propositions for future studies.Design/methodology/approachThis is a conceptual paper to study the inbuilt capacity of lean healthcare organization to mitigate environmental footprint. As a result, lean compatibility with environmental sustainability (ES) has been explored in areas like manufacturing, supply chain, aviation, construction, etc. The lean philosophy, lean culture and lean tools were analyzed to identify their contribution to ES in the context of healthcare organizations.FindingsBased on the analysis of lean philosophy, culture and tool, this paper theorizes that lean healthcare organizations have huge potential to mitigate environmental footprints. Lean healthcare organizations need not to do any extra effort for ES albeit it is inbuilt in it. Lean philosophy provides a vision to the healthcare organization for ES whereas lean culture bestow healthcare with an epistemology for the same.Research limitations/implicationsThis paper provides insight that ES is embedded in lean healthcare organizations. Lean healthcare organizational culture is ideal for application for constructivism theory where employees construct a new knowledge from their experiences to minimize the waste that eventually help in ES.Originality/valueMajor contributions of the study include a new approach for mitigating the environmental footprints by adopting lean in healthcare organization.
Reliability, availability and maintainability analysis of a cement plant: a case study
Authors: Choudhary Devendra , Tripathi Mayank , Shankar Ravi 
Published: January 2019

Purpose
The demand of cement in India is expected to increase rapidly as the government has been giving immense boost to various housing facilities, infrastructure projects, road networks and railway corridors. One of the ways to meet this rise in the demand of cement is to increase the capacity utilization of the existing cement plants by improving their availability. The availability of a cement plant can be improved by avoiding failures and reducing maintenance time through reliability, availability and maintainability (RAM) analysis of its subsystems. The paper aims to discuss this issue.

Design/methodology/approach
The data related to time between failure (TBF) and time to repair (TTR) of all the critical subsystems of a cement plant were collected over a period of two years for carrying out RAM analysis. Trend test and serial correlation test were performed on TBF and TTR data to verify whether these data are independent and identically distributed or not. Afterwards, the authors use EasyFit 5.6 professional software to find best-fit distribution of TBF and TTR data and their parameters. The effectiveness of a preventive maintenance policy was evaluated by simulating the real and proposed systems.

Findings
The results of the analysis show that the raw mill and the coal mill are critical subsystems of a cement plant from a reliability point of view, whereas the kiln is a critical subsystem from an availability point of view. The analysis shows that the repair time of the cement mill should be reduced for improving the availability of the cement plant. The RAM analysis showed that the capacity of the case study company is 17 percent underutilized due to maintenance-related problems and 15 percent underutilized because of management-related problems.

Practical implications
The study exhibits the usage of RAM analysis in deciding preventive maintenance programs of several cement plant subsystems. Thus, it would serve as a reference for reliability and maintenance managers in deciding maintenance strategies of cement plants as well as in improving their capacity utilization.

Originality/value
The study exhibits the usage of RAM analysis in deciding preventive maintenance programs of several cement plant subsystems. Even more, using a simulation study, the authors show that preventive maintenance of the cement plant beyond a certain level can be disadvantageous as it leads to an increase in downtime and decrease in availability.
Internationalization and failure risk patterns
Authors: Lukason Oliver , Vissak Tiia 
Published: January 2019

PurposeThis paper aims to find out what kind of export and failure risk patterns exist among young Estonian manufacturing exporters and explore their interlinkages.Design/methodology/approachThe sample consisted of 208 young Estonian manufacturing exporters. Based on internationalization literature, export patterns were detected with a consecutive three-stage clustering of export sales share from total sales, outside-Europe sales share from export sales and number of target markets, while failure risk patterns were detected by clustering failure probabilities obtained from a universal prediction model. The interconnection of export patterns with financial ratios and failure risk patterns was studied with statistical tests.FindingsSix main internationalization patterns existed. In all, 49 per cent of firms exported to a single European market and their export share was constantly very low, while even most of the firms with high export shares (39 per cent of the sample) were also active on one European market. In terms of failure risk patterns, 49 per cent of firms had constantly very low failure risk, while 51 per cent of firms had medium risk. Higher export engagement did not lead to better financial performance or lower failure risk.Originality/valueThis study is the first to find out if firms following different export patterns are also characterized by specific financial performance and failure risk. In addition, studies encompassing young exporters’ specific target markets and failure risk development are rare. While exporters’ and non-exporters’ financial performance differences have been frequently documented in favor of the former, this study found no such differences for different types of young exporters.
Application of a DPSIR Modeling Framework to Assess Spatial–Temporal Differences of Water Poverty in China
Authors: Liu Wen‐xin , Sun Cai‐zhi , Zhao Min‐juan , Wu Yong‐jie 
Published: January 2019

AbstractWater shortage is a common problem around the world, especially in developing countries. Water shortage is closely linked to natural and social conditions, but the linkages between these natural and social conditions and their underlying temporal and spatial variation are less well explored. This paper details an application of the Driving‐Force‐Pressure‐State‐Impact‐Response (DPSIR) model, a holistic and sustainable tool for resources planning and management, and uses comprehensive weights to evaluate the water poverty (wp) in China from 1997 to 2014. This study applies the Kernel density estimation model to analyze the temporal variation trend and uses the least square error model to analyze the spatial pattern of wp. The results show the level of wp is gradually declining over time and the improvements in the coastal and inland wp situation are not spatially harmonious, and there are four primary types of wp in China based on drivers and causal mechanisms: D‐P‐I, D‐P‐I‐R, D‐P‐S‐I, and D‐P‐S‐I‐R. Furthermore, we analyze the main causes of spatial difference of wp and put forward corresponding countermeasures. The research findings are intended to provide a new insight for the evaluation of wp in the context of sustainable development, breaking past limitations that arise in simplified analyses using a single method, and to provide a strategy for regional water resources management to relieve wp.
Does time from diagnosis to treatment of high‐ or very‐high‐risk prostate cancer affect outcome?
Authors: Reichard Chad A. , Nyame Yaw A. , Sundi Debasish , Tosoian Jeffrey , Wilkins Lamont , Alam Ridwan , Achim Mary F. , Wang Xuemei , Stephenson Andrew J. , Klein Eric A. , Ross Ashley E. , Davis John W. , Chapin Brian F. 
Published: January 2019

ObjectiveTo determine whether time from diagnosis to treatment impacted outcomes in a multicentre cohort of high‐ and very‐high‐risk (VHR) patients with prostate cancer undergoing radical prostatectomy (RP).Patients and MethodsIn all, 1392 patients from three tertiary centres who underwent RP for either high‐risk or VHR disease, from 2005 to 2015, were identified. The cohort was divided into tertiles based on time from diagnostic biopsy to RP. Cumulative incidence of biochemical recurrence (BCR), metastasis, and prostate cancer‐specific mortality (PCSM) were calculated for each tertile. The Kaplan–Meier method was used to evaluate for differences in all‐cause mortality (ACM) amongst tertiles. Competing risks regression models, as well as Cox proportional hazards regression models, were fitted to assess the association between time‐to‐event outcomes and patient characteristics.ResultsThe median (interquartile range [IQR]) time from biopsy to RP was 68 (50–94) days. The median (IQR) follow‐up was 31 (12.1–55.7) months. The cumulative incidence of BCR (P = 0.14), metastasis (P = 0.15), and PCSM (P = 0.69) did not differ amongst time‐to‐treatment tertiles of VHR patients. Also, Kaplan–Meier estimates of ACM (P = 0.53) did not differ amongst time‐to‐treatment tertiles. Similarly, BCR, metastasis, PCSM, and ACM did not significantly differ amongst time‐to‐treatment tertiles in multivariable modelling.ConclusionIn this pooled meta‐dataset of patients with high‐risk or VHR prostate cancer, time from diagnosis to RP did not appear to significantly contribute to differences in clinical outcomes. This finding supports the safety of enrollment of such patients into neoadjuvant clinical trials.
Diagnostic accuracy, clinical utility and influence on decision‐making of a methylation urine biomarker test in the surveillance of non‐muscle‐invasive bladder cancer
Authors: D'Andrea David , Soria Francesco , Zehetmayer Sonja , Gust Kilian M. , Korn Stephan , Witjes J. Alfred , Shariat Shahrokh F. 
Published: January 2019

ObjectivesTo investigate prospectively the clinical utility and influence on decision‐making of Bladder EpiCheck™, a non‐invasive urine test, in the surveillance of non‐muscle‐invasive bladder cancer (NMIBC).Materials and MethodsUrine samples from 440 patients undergoing surveillance for NMIBC were prospectively collected at five centres and evaluated using the Bladder EpiCheck test (NCT02647112). A multivariable nomogram and decision‐curve analysis (DCA) were used to evaluate the impact of Bladder EpiCheck on decision‐making when used in routine clinical practice. The test was designed to exclude recurrent disease.ResultsData from 357 patients were available for analysis. The test had a specificity of 88% (95% confidence interval [CI] 84–91), a negative predictive value (NPV) of 94.4% (95% CI 91–97) for the detection of any cancer and an NPV of 99.3% for the detection of high‐grade cancer. In multivariable analysis, positive Bladder EpiCheck results were independently associated with any and high‐grade disease recurrence (odds ratio [OR] 18.1, 95% CI 8.7–40.2; P < 0.001 and OR 78.3, 95% CI 19.2–547; P < 0.001). The addition of Bladder EpiCheck to standard variables improved its predictive ability for any and high‐grade disease recurrence by a difference of 16% and 22%, respectively (area under the curve 85.9% and 96.1% for any and high‐grade cancer, respectively). DCA showed an improvement in the net benefit relative to cystoscopy over a large threshold of probability, resulting in a significant reduction in unnecessary investigations. These results were similar in subgroups assessing the impact of specific clinical features.ConclusionsBladder EpiCheck is a robust high‐performing diagnostic test in patients with NMIBC undergoing surveillance that can potentially reduce the number of unnecessary investigations.
Cardiovascular efficacy and safety of sodium‐glucose co‐transporter‐2 inhibitors and glucagon‐like peptide‐1 receptor agonists: a systematic review and network meta‐analysis
Authors: Hussein H. , Zaccardi F. , Khunti K. , Seidu S. , Davies M. J. , Gray L. J. 
Published: January 2019

AbstractAimsTo compare the cardiovascular efficacy and safety of sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors and glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) in adults with Type 2 diabetes.MethodsElectronic databases were searched from inception to 22 October 2018 for randomized controlled trials designed to assess the cardiovascular efficacy of SGLT2 inhibitors or GLP‐1RAs with regard to a three‐point composite measure of major adverse cardiovascular events (non‐fatal stroke, non‐fatal myocardial infarction and cardiovascular mortality). Cardiovascular and safety data were synthesized using Bayesian network meta‐analyses.ResultsEight trials, including 60 082 participants, were deemed eligible for the network meta‐analysis. Both SGLT2 inhibitors [hazard ratio 0.86 (95% credible interval 0.74, 1.01]) and GLP‐1RAs [hazard ratio 0.88 (95% credible interval 0.78, 0.98)] reduced the three‐point composite measure compared to placebo, with no evidence of differences between them [GLP‐1RAs vs SGLT2 inhibitors: hazard ratio 1.02 (95% credible interval 0.83, 1.23)]. SGLT2 inhibitors reduced risk of hospital admission for heart failure compared to placebo [hazard ratio 0.67 (95% credible interval 0.53, 0.85)] and GLP‐1RAs [hazard ratio 0.71 (95% credible interval 0.53, 0.93)]. No differences were found between the two drug classes in non‐fatal stroke, non‐fatal myocardial infarction, cardiovascular mortality, all‐cause mortality or safety outcomes.ConclusionsSGLT2 inhibitors and GLP‐1RAs reduced the three‐point major adverse cardiovascular event risk compared to placebo, with no differences between them. Compared with GLP‐1RAs and placebo, SGLT2 inhibitors led to a larger reduction in hospital admission for heart failure risk.