bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanism of drug extrusion by brain endothelial cells via lysosomal drug trapping and disposal by neutrophils
Authors: Noack Andreas , Gericke Birthe , von Köckritz-Blickwede Maren , Menze Arne , Noack Sandra , Gerhauser Ingo , Osten Felix , Naim Hassan Y. , Löscher Wolfgang 
Published: September 2018

Significance
Located at the apical (blood-facing) site of brain capillary endothelial cells that form the blood–brain barrier (BBB), the efflux transporter P-glycoprotein (Pgp) restricts the brain entry of various lipophilic xenobiotics, which contributes to BBB function. Pgp may become saturated if exposed to too-high drug concentrations. Here, we demonstrate a second-line defense mechanism in human brain capillary endothelial cells—that is, Pgp-mediated intracellular lysosomal drug trapping. Furthermore, we describe a mechanism of drug disposal at the BBB, which is shedding of lysosomal Pgp/substrate complexes at the apical membrane of human and porcine BBB endothelial cells and subsequent phagocytosis by neutrophils. Thus, we have discovered a fascinating mechanism of how Pgp might contribute to brain protection.
Dawn and photoperiod sensing by phytochrome A
Authors: Seaton Daniel D. , Toledo-Ortiz Gabriela , Ganpudi Ashwin , Kubota Akane , Imaizumi Takato , Halliday Karen J. 
Published: September 2018

Significance
The changing seasons subject plants to a variety of challenging environments. To deal with this, many plants have mechanisms for inferring the season by measuring the duration of daylight in a day. A number of well-known seasonal responses such as flowering are responsive to daylength or photoperiod. Here, we describe how the photoreceptor protein phytochrome A senses short photoperiods. This arises from its accumulation during long nights, as happens during winter, and subsequent activation by light at dawn. As a result of this response, the abundance of red anthocyanin pigments is increased in short photoperiods. Thus, we describe a mechanism underlying a seasonal phenotype in an important model plant species.
Siglec-7 engagement by GBS β-protein suppresses pyroptotic cell death of natural killer cells
Authors: Fong Jerry J. , Tsai Chih-Ming , Saha Sudeshna , Nizet Victor , Varki Ajit , Bui Jack D. 
Published: September 2018

SignificanceDirect interactions between natural killer (NK) cells and bacteria are rarely observed, and the consequences of these interactions not well understood. We show that human NK cells exposed to the bacterium group BStreptococcus(GBS) undergo pyroptosis, a type of inflammatory cell death. By releasing inflammatory mediators, pyroptosis is thought to be a way for sentinels to die and alert the immune system of infection. Interestingly, we also found that GBS has a protein that binds to Siglec-7, an inhibitory molecule on NK cells. Siglec-7 inhibits pyroptosis and silences the sentinel activity of NK cells by preventing the release of inflammatory molecules. These studies suggest that a human pathogen can silence the sentinel by specific interaction with a Siglec protein.
Single-molecule analysis of endogenous β-actin mRNA trafficking reveals a mechanism for compartmentalized mRNA localization in axons
Authors: Turner-Bridger Benita , Jakobs Maximillian , Muresan Leila , Wong Hovy Ho-Wai , Franze Kristian , Harris William A. , Holt Christine E. 
Published: September 2018

Significance
De novo protein synthesis in neuronal axons plays important roles in neural circuit formation, maintenance, and disease. Key to the selectivity of axonal protein synthesis is whether an mRNA is present at the right place to be translated, but the mechanisms behind axonal mRNA localization remain poorly understood. In this work, we quantitatively analyze the link between axonal β-actin mRNA trafficking and its localization patterns. By developing a single-molecule approach to live-image β-actin mRNAs in axons, we explore the biophysical drivers behind β-actin mRNA motion and uncover a mechanism for generating increased density at the axon tip by differences in motor protein-driven transport speeds. These results provide mechanistic insight into the control of local translation through mRNA trafficking.
Genetically defined cellular correlates of the baseline brain MRI signal
Authors: Wen Jie , Goyal Manu S. , Astafiev Serguei V. , Raichle Marcus E. , Yablonskiy Dmitriy A. 
Published: September 2018

Significance
Understanding the structure and function of the human brain at a cellular level is a fundamental aim of neuroscience. Tremendous progress has been made in recent years based on different in vivo and ex vivo approaches, including major advances in brain MRI. However, uncertainties remain in determining how brain MRI measurements relate to the brain’s underlying cellular composition. In this paper we use a recently developed MRI technique, quantitative gradient recalled echo (qGRE), and information on gene profiles in the human brain available from the Allen Human Brain Atlas. We demonstrate that qGRE and related MRI techniques can be used to probe the underlying cellular composition of the human brain in vivo.
Optimal protection againstSalmonellainfection requires noncirculating memory
Authors: Benoun Joseph M. , Peres Newton G. , Wang Nancy , Pham Oanh H. , Rudisill Victoria L. , Fogassy Zachary N. , Whitney Paul G. , Fernandez-Ruiz Daniel , Gebhardt Thomas , Pham Quynh-Mai , Puddington Lynn , Bedoui Sammy , Strugnell Richard A. , McSorley Stephen J. 
Published: September 2018

SignificanceEffective vaccination againstSalmonellainfection requires the generation of memory T cells that can be reactivated upon exposure to bacteria in a natural setting. It is unclear whether immunity requires memory T cells that continuously patrol blood, lymphatics, and tissues, whether noncirculating T cells are important, or both. We demonstrate the generation of circulating and noncirculating memory pools after immunization. However, naive mice that previously shared a blood supply with vaccinated partners received recirculating memory T cells, but did not have T cell memory with characteristics of tissue residence, resulting in a failure to acquire robust protective immunity. Thus, noncirculating tissue-resident memory T cells are vital for effective protection againstSalmonella.
Corepressor SMRT is required to maintain Hox transcriptional memory during somitogenesis
Authors: Hong Suk-Hyun , Fang Sungsoon , Lu Benson C. , Nofsinger Russell , Kawakami Yasuhiko , Castro Glenda L. , Yin Yunqiang , Lin Chengqi , Yu Ruth T. , Downes Michael , Izpisúa Belmonte Juan Carlos , Shilatifard Ali , Evans Ronald M. 
Published: September 2018

Significance
Retinoic acid (RA) is an important transcriptional regulator during both vertebrate and invertebrate body pattern formation. The Homeobox (Hox) gene family is activated by a gradient of RA formed along the length of the embryo at specific time points during fetal development. Generation of a genetically modified mouse harboring mutations in the SMRT repressor demonstrated that SMRT-dependent repression of retinoic acid receptor (RAR) is critical to establish and maintain the somitic Hox code and segmental identity during fetal development via epigenetic marking of target loci.
On the control of the proton current in the voltage-gated proton channel Hv1
Authors: Lee Myungjin , Bai Chen , Feliks Mikolaj , Alhadeff Raphael , Warshel Arieh 
Published: September 2018

Significance
Voltage activation of proton transport is an important mechanism that plays a key role in fundamental biological processes, yet the detailed control of such processes is far from clear. Here we investigate the voltage-activated proton channel Hv1 to explore the structure/function basis of its activation by combining empirical valence bond and electrostatic calculations. Our study provides a detailed description of the exquisite use of an ionizable aspartic acid residue and arginine residues in controlling the crucial selectivity of the proton transport through the channel. This type of mechanism is likely to have implications for the action of other related systems.
Earth’s outgoing longwave radiation linear due to H2O greenhouse effect
Authors: Koll Daniel D. B. , Cronin Timothy W. 
Published: September 2018

SignificanceEarth’s climate is set by a balance between incoming solar and outgoing infrared radiation. The physical processes that influence this balance are complex and nonlinear, yet models and satellite measurements counterintuitively show that Earth’s infrared radiation is simply a linear function of surface temperature. Here we explain why: Linearity is due to the cancellation of two nonlinear processes and always arises in an atmosphere dominated by a condensable greenhouse gas. Our work explains a fundamental property of Earth’s climate and has implications for climate change as well as the climates of extrasolar planets with exotic greenhouse gases.
Multiscale wavelet decomposition of time-resolved X-ray diffraction signals in cyclohexadiene
Authors: Osipov Vladimir Al. , Kowalewski Markus , Mukamel Shaul 
Published: September 2018

Significance
Free electron laser sources of ultrafast X-ray pulses can record movies of chemical reactions by measuring snapshots of the charge density along the reaction path on the femtosecond timescale. Only a few valence electrons typically participate in chemical bond breaking and forming. To separate the valence electron density from the strong background of highly localized core electrons we use a wavelet transform, a powerful tool for filtering, and scaling analysis of signals. The wavelet-processed signal from the cyclohexadiene molecule reported here clearly reveals the valence electron rearrangements in the early steps of the photoinduced pericyclic ring opening reaction, which are not resolved in the bare signal. This multiscale analysis of charge densities should be extremely valuable for disentangling complex reaction pathways.
Cold exposure causes cell death by depolarization-mediated Ca2+overload in a chill-susceptible insect
Authors: Bayley Jeppe Seamus , Winther Christian Bak , Andersen Mads Kuhlmann , Grønkjær Camilla , Nielsen Ole Bækgaard , Pedersen Thomas Holm , Overgaard Johannes 
Published: September 2018

SignificanceInsects comprise the largest class of animals and include numerous species of direct importance to humans, including pests and pollinators. Cold tolerance is arguably among the most important traits determining the distribution of insects. Hypothermia has been proposed to induce cell injury directly by promoting membrane phase transitions resulting in cell leak. Additionally, hypothermia induces hemolymph hyperkalemia, and it has been proposed that hypothermia induces injury indirectly through the resulting depolarization by inducing Ca2+influx promoting apoptosis/necrosis. Here we show that depolarization is a principal mechanism for hypothermic cell injury. Furthermore, we show that intracellular Ca2+increases upon depolarization and that this increase must flux through Ca2+channels in the membrane to accumulate and induce injury.
Understanding co-production as a new public governance tool
Authors: Sorrentino Maddalena , Sicilia Mariafrancesca , Howlett Michael 
Published: September 2018

AbstractCo-production has become a buzzword for both scholars and practitioners in the past decade. This introduction to the thematic issue ‘Co-production: Implementation problems, new technologies and new designs’ unpacks the concept of co-production and illustrates how it has been operationalized on the ground in diverse country-specific contexts. To facilitate the analysis, we make a distinction between ‘traditional’ and ‘non-traditional’ forms of co-production, even though the practice has not really been around long enough to have established a tradition in the true sense of the word. However, these two distinct forms of co-production are highly useful conceptual lenses through which to view the finer details and nuances, to identify the enabling conditions and to foreshadow the governance challenges, but also to highlight the innovating role co-production plays in forging public services and public policies. Thanks to the rich and varied ways in which the contributors have approached this central topic; the thematic issue enables the research and practice to more fully appreciate the ins and outs of co-production and suggests the most promising directions for future study.
Presenting and sharing clinical data using the eTRIKS Standards Master Tree for tranSMART
Authors: Barbosa-Silva Adriano , Bratfalean Dorina , Gu Wei , Satagopam Venkata , Houston Paul , Becnel Lauren B , Eifes Serge , Richard Fabien , Tielmann Andreas , Herzinger Sascha , Rege Kavita , Balling Rudi , Peeters Paul , Schneider Reinhard 
Published: September 2018

Abstract

Motivation
Standardization and semantic alignment have been considered one of the major challenges for data integration in clinical research. The inclusion of the CDISC SDTM clinical data standard into the tranSMART i2b2 via a guiding master ontology tree positively impacts and supports the efficacy of data sharing, visualization and exploration across datasets.

Results
We present here a schema for the organization of SDTM variables into the tranSMART i2b2 tree along with a script and test dataset to exemplify the mapping strategy. The eTRIKS master tree concept is demonstrated by making use of fictitious data generated for four patients, including 16 SDTM clinical domains. We describe how the usage of correct visit names and data labels can help to integrate multiple readouts per patient and avoid ETL crashes when running a tranSMART loading routine.

Availability and implementation
The eTRIKS Master Tree package and test datasets are publicly available at https://doi.org/10.5281/zenodo.1009098 and a functional demo installation at https://public.etriks.org/transmart/datasetExplorer/ under eTRIKS—Master Tree branch, where the discussed examples can be visualized.
De novopattern discovery enables robust assessment of functional consequences of non-coding variants
Authors: Yang Hai , Chen Rui , Wang Quan , Wei Qiang , Ji Ying , Zheng Guangze , Zhong Xue , Cox Nancy J , Li Bingshan 
Published: September 2018

AbstractMotivationGiven the complexity of genome regions, prioritize the functional effects of non-coding variants remains a challenge. Although several frameworks have been proposed for the evaluation of the functionality of non-coding variants, most of them used ‘black boxes’ methods that simplify the task as the pathogenicity/benign classification problem, which ignores the distinct regulatory mechanisms of variants and leads to less desirable performance. In this study, we developed DVAR, an unsupervised framework that leverage various biochemical and evolutionary evidence to distinguish the gene regulatory categories of variants and assess their comprehensive functional impact simultaneously.ResultsDVAR performed de novo pattern discovery in high-dimensional data and identified five regulatory clusters of non-coding variants. Leveraging the new insights into the multiple functional patterns, it measures both the between-class and the within-class functional implication of the variants to achieve accurate prioritization. Compared to other two-class learning methods, it showed improved performance in identification of clinically significant variants, fine-mapped GWAS variants, eQTLs and expression-modulating variants. Moreover, it has superior performance on disease causal variants verified by genome-editing (like CRISPR-Cas9), which could provide a pre-selection strategy for genome-editing technologies across the whole genome. Finally, evaluated in BioVU and UK Biobank, two large-scale DNA biobanks linked to complete electronic health records, DVAR demonstrated its effectiveness in prioritizing non-coding variants associated with medical phenotypes.Availability and implementationThe C++ and Python source codes, the pre-computed DVAR-cluster labels and DVAR-scores across the whole genome are available at https://www.vumc.org/cgg/dvar.Supplementary informationSupplementary data are available at Bioinformatics online.
SemGen: a tool for semantics-based annotation and composition of biosimulation models
Authors: Neal Maxwell L , Thompson Christopher T , Kim Karam G , James Ryan C , Cook Daniel L , Carlson Brian E , Gennari John H 
Published: September 2018

Abstract

Summary
As the number and complexity of biosimulation models grows, so do demands for tools that can help users understand models and compose more comprehensive and accurate systems from existing models. SemGen is a tool for semantics-based annotation and composition of biosimulation models designed to address this demand. A key SemGen capability is to decompose and then integrate models across existing model exchange formats including SBML and CellML. To support this capability, we use semantic annotations to explicitly capture the underlying biological and physical meanings of the entities and processes that are modeled. SemGen leverages annotations to expose a model’s biological and computational architecture and to help automate model composition.

Availability and implementation
SemGen is freely available at https://github.com/SemBioProcess/SemGen.

Supplementary information
Supplementary data are available at Bioinformatics online.
Association of Circadian Rhythm of Blood Pressure and Cerebral Small Vessel Disease in Community-Based Elderly Population
Authors: Zhang Hua , Cui Yi , Zhao Yingxin , Dong Yuanli , Wang Juan , Duan Dandan , Ji Tiantian , Zhou Tingting , Hu Wenjing , Chen Yali , Sun Shangwen , Gong Gary , Chai Qiang , Liu Zhendong 
Published: September 2018

Abstract

Background
Although it is accepted that the etiology of cerebral small vessel disease (CSVD) is associated with cardiovascular risk factors, the association between CSVD and the circadian rhythm of blood pressure (BP) is unclear. We aimed to determine if such an association existed in the elderly population.

Method
White matter hyperintensities (WMHs), lacunes, microbleeds, nocturnal dipping pattern (NDP), and morning surge in systolic blood pressure (SBP) were assessed in 2,091 participants ≥60 years of age.

Results
During an average of 63 months of follow-up, WMH and the WMH-to-intracranial volume ratio were significantly increased in extreme dippers, nondippers, and reverse dippers than those in dippers (p < .001). For new-incident Fazekas scale ≥2, the hazard ratios were 1.77 (95% confidence interval [CI], 1.09–2.86) for extreme dippers, 2.20 (95% CI, 1.48–3.28) for nondippers, and 2.43 (95% CI, 1.59–3.70) for reverse dippers compared with dippers, and 1.04 (95% CI, 0.81–1.35) for higher morning surge compared with lower morning surge. Nondippers and reverse dippers were associated with higher risks of new-incident lacunes and microbleeds than dippers (p < .05). Higher morning surge was associated with a higher risk of new-incident microbleeds than lower morning surge (p < .05).

Conclusion
NDPs in SBP played an important role in CSVD, and the morning surge in SBP was associated with cerebral microbleeds in community-based elderly population beyond the average SBP level.
Synergistic Effects of Mesenchymal Stem Cell Transplantation and Repetitive Transcranial Magnetic Stimulation on Promoting Autophagy and Synaptic Plasticity in Vascular Dementia
Authors: Wang Fei , Zhang Chi , Hou Siyuan , Geng Xin 
Published: September 2018

Abstract
Repetitive transcranial magnetic stimulation (rTMS) and mesenchymal stem cells (MSCs) transplantation both showed therapeutic effects on cognition impairment in vascular dementia (VD) model rats. However, whether these two therapies have synergistic effects and the molecular mechanisms remain unclear. In our present study, rats were randomly divided into six groups: control group, sham operation group, VD group, MSC group, rTMS group, and MSC+rTMS group. The VD model rats were prepared using a modified 2VO method. rTMS treatment was implemented at a frequency of 5 Hz, the stimulation intensity for 0.5 Tesla, 20 strings every day with 10 pulses per string and six treatment courses. The results of the Morris water maze test showed that the learning and memory abilities of the MSC group, rTMS group, and MSC+rTMS group were better than that of the VD group, and the MSC+rTMS group showed the most significant effect. The protein expression levels of brain-derived neurotrophic factor, NR1, LC3-II, and Beclin-1 were the highest and p62 protein was the lowest in the MSC+rTMS group. Our findings demonstrated that rTMS could further enhance the effect of MSC transplantation on VD rats and provided an important basis for the combined application of MSC transplantation and rTMS to treat VD or other neurological diseases.
A comprehensive data-driven model of cat primary visual cortex
Authors: Antolík Ján , Cagnol Rémy , Rózsa Tibor , Monier Cyril , Frégnac Yves , Davison Andrew P. 
Published: September 2018

1AbstractKnowledge integration based on the relationship between structure and function of the neural substrate is one of the main targets of neuroinformatics and data-driven computational modeling. However, the multiplicity of data sources, the diversity of benchmarks, the mixing of observables of different natures, and the necessity of a long-term, systematic approach make such a task challenging. Here we present a first snapshot of a long-term integrative modeling program designed to address this issue in the domain of the visual system: a comprehensive spiking model of cat primary visual cortex. The presented model satisfies an extensive range of anatomical, statistical and functional constraints under a wide range of visual input statistics. In the presence of physiological levels of tonic stochastic bombardment by spontaneous thalamic activity, the modelled cortical reverberations self-generate a sparse asynchronous ongoing activity that quantitatively matches a range of experimentally measured statistics. When integrating feed-forward drive elicited by a high diversity of visual contexts, the simulated network produces a realistic, quantitatively accurate interplay between visually evoked excitatory and inhibitory conductances; contrast-invariant orientation-tuning width; center surround interactions; and stimulus-dependent changes in the precision of the neural code. This integrative model offers insights into how the studied properties interact, contributing to a better understanding of visual cortical dynamics. It provides a basis for future development towards a comprehensive model of low-level perception.2Author summaryComputational modeling can integrate fragments of understanding generated by experimental neuroscience. However, most models considered only a few features of neural computation at a time, leading to either poorly constrained models with many parameters, or lack of expressiveness in over-simplified models. A solution is to develop detailed models, but constrain them with a broad range of anatomical and functional data to prevent overfitting. This requires a long-term systematic approach. Here we present a first snapshot of such an integrative program: a large-scale spiking model of cat primary visual cortex, that is constrained by an extensive range of anatomical and functional features. Together with the associated modeling infrastructure, this study lays the groundwork for a broad integrative modeling program seeking an in-depth understanding of vision.