bluuebunny/crossref_metadata_2025 huggingface dataset:
Primary care behind the former “Iron Curtain”: changes and development of primary healthcare provision in the Eastern part of the European Union
Authors: Semánová Csilla , Rurik Sarolta E. , Dózsa Csaba , Jancsó Zoltán , Kolozsvári László R. , Nánási Anna , Pfeiferová Markéta , Rurik Imre
Published: September 2019

Background:

The Alma-Ata Declaration was a big step in the development of primary care, defining the main tasks and populations’ expectation. Celebrating the 40th year’s anniversary is a good opportunity to make an analysis. Development of primary care was not parallel in the Eastern and Western part of Europe.

Aim:

To provide an overview on the societal and economic situation, structural and financial changes of healthcare systems in the former ‘Soviet bloc’ countries, to present an analysis of the primary healthcare (PHC) provision and to find relationships between economic development and epidemiological changes of the respective countries.

Method:

Epidemiological data, healthcare expenditures and structure, and financing schemes were compared; systematic literature search was performed.

Results:

Visible improvements in population health, in the national economic condition, structural changes in healthcare and more focus to primary care were experienced everywhere. Higher life expectancies with high inter-country variation were observed in the former ‘Soviet bloc’ countries, although it could not be clearly linked to the development of healthcare system. PHC provision improved while structural changes were rarely initiated, often only as a project or model initiation. Single-handed practices are yet predominant. The gate-keeping system is usually weak; there were no effective initiatives to improve the education of nurses and to widen their competences. Migrations of workforce to Western countries become a real threat for the Central-East European countries.

Conclusion:

Lack of coordination between practices and interdisciplinary cooperation were recognized as the main barriers for further improvement in the structure.
Mechanisms linking bovine viral diarrhea virus (BVDV) infection with infertility in cattle
Authors: Oguejiofor Chike F. , Thomas Carole , Cheng Zhangrui , Wathes D. Claire
Published: September 2019

Bovine viral diarrhea virus (BVDV) is an important infectious disease agent that causes significant reproductive and economic losses in the cattle industry worldwide. Although BVDV infection is known to cause poor fertility in cattle, a greater part of the underlying mechanisms particularly associated with early reproductive losses are not clearly understood. Previous studies reported viral compromise of reproductive function in infected bulls. In females, BVDV infection is thought to be capable of killing the oocyte, embryo or fetus directly, or to induce lesions that result in fetal abortion or malformation. BVDV infections may also induce immune dysfunction, and predispose cattle to other diseases that cause poor health and fertility. Other reports also suggested BVDV-induced disruption of the reproductive endocrine system, and a disruption of leukocyte and cytokine functions in the reproductive organs. More recent studies have provided evidence of viral-induced suppression of endometrial innate immunity that may predispose to uterine disease. Furthermore, there is new evidence that BVDV may potentially disrupt the maternal recognition of pregnancy or the immune protection of the conceptus. This review brings together the previous reports with the more recent findings, and attempts to explain some of the mechanisms linking this important virus to infertility in cattle.
Property, predation and socialist reality
Authors: Boettke Peter J.
Published: September 2019

Economics as a social science is about exchange and the institutions within which exchange relationships are formed and transactions are executed. Yoram Barzel's contribution to economics and political economy reflect this focus on exchange and institutions. In this paper, I will sketch a theory of real-existing socialist economies from a property rights/public choice perspective. Then I present the puzzles in political economy that such a system confronted in attempting to create a prosperous, regenerating and competitive economic system. I then conclude with a short discussion of the future for a progressive research program in political economy that takes institutionalchangeseriously.
The East Flanders Prospective Twin Survey (EFPTS): 55 Years Later
Authors: Derom Catherine , Thiery Evert , Rutten Bart P.F. , Peeters Hilde , Gielen Marij , Bijnens Esmée , Vlietinck Robert , Weyers Steven
Published: September 2019

The East Flanders Prospective Twin Survey (EFPTS) is a registry of multiple births in the province of East Flanders, Belgium. Since its start in 1964, over 10,000 twin-pairs have been registered. EFPTS has several unique features: it is population-based and prospective, with the possibility of long-term follow-up; the twins (and higher order multiple births) are recruited at birth; basic perinatal data are recorded; chorion type and zygosity are established; since 1969, placental biopsies have been taken and frozen at –20°C for future research. Since its origin, the EFPTS has included placental data and allows differentiation of three subtypes of monozygotic twins based on the time of the initial zygotic division: the dichorionic–diamniotic pairs (early, with splitting before the fourth day after fertilization), the monochorionic–diamniotic pairs (intermediate, splitting between the fourth- and the seventh-day postfertilization) and the monochorionic–monoamniotic pairs (late, splitting after the eighth day postfertilization). Studies can be initiated taking into account primary biases, those originating ‘in utero’. Such studies could throw new light on the consequences of early embryological events and the gene–environment interactions as far as periconceptional and intrauterine environment are concerned.
Drowned Out by the Noise? The Downstream Mobilisation Effects of Party Campaigning between Local and General Elections
Authors: Townsley Joshua
Published: September 2019

Campaign experiments often report positive effects on voter turnout. But do these effects endure at subsequent elections? Existing studies provide mixed evidence on downstream effects, and the rate at which initial mobilisation effects decay. This paper contributes to existing research by presenting a pre-registered analysis of downstream effects in a unique experimental setting. I test whether effects from a UK partisan experiment in a low turnout election in May 2017 persisted at the high turnout general election a month later. The findings show that in this short space of time, the original turnout effects virtually disappeared, suggesting that downstream effects resulting from campaign experiments can be quickly subsumed by the high saliency of subsequent elections.
Nachsorge von bariatrischen Patienten
Authors: Gebhart Martina
Published: September 2019

Zusammenfassung. Bariatrische Patienten benötigen eine regelmässige Nachsorge, um Komplikationen und ungünstige Verläufe frühzeitig erkennen und behandeln zu können. Auch ist die medikamentöse Behandlung der Komorbiditäten laufend anzupassen. Da die Zahl von Patienten, welche einen bariatrischen Eingriff zur Behandlung ihrer Adipositas und ihrer Komorbiditäten erhalten, rasch ansteigt, ist es zunehmend wichtig, dass auch Ärzte in der Praxis Kenntnis der wichtigsten Folgen von bariatrischen Operationen haben. Die Themen in der Nachsorge sind gastrointestinale Symptome wie Schmerzen, Dumping, Diarrhoe, Makro- und Mikronährstoffmängel, Anpassungen von Medikamenten, sowie die Kontrolle des Gewichtsverlaufes, wobei das frühzeitige Erkennen eines ungünstigen Verlaufes, das heisst eine zu grosse Gewichtsabnahme, eine ungenügende Gewichtsabnahme und eine übermässige sekundäre Gewichtszunahme frühzeitig erkannt und behandelt werden sollen. Der folgende Artikel gibt einen Überblick über diese Themen und beschreibt die Behandlungsmöglichkeiten.
Aktuelle molekularpathologische Methoden
Authors: Hench Jürgen , Jermann Philip M. , Bratic Hench Ivana , Matter Matthias S.
Published: September 2019

Zusammenfassung. Die Pathologie beurteilte Tumoren während vieler Jahre fast ausschliesslich mittels makroskopischer und mikroskopischer Untersuchungen. In den letzten Jahren erlebten wir allerdings einen enormen Wissenszuwachs über genetische und epigenetische Veränderungen in Tumoren wie zum Beispiel Mutationen, Translokationen oder dem Methylierungsprofil. Der Nachweis dieser Veränderungen im Rahmen der pathologischen Untersuchung gewinnt stetig an Bedeutung und hat Auswirkungen auf Diagnose, Prognose, Therapie, und Prävention von Tumorleiden. Es ist daher entscheidend, dass wir über geeignete Methoden verfügen, zum Nachweis dieser Veränderungen. In der folgenden Übersichtsarbeit stellen wir daher aktuelle Methoden vor, die in der Molekularpathologie eingesetzt werden, zum Nachweis genetischer und epigenetischer Veränderungen.
Seismic Noise in Central Alaska and Influences From Rivers, Wind, and Sedimentary Basins
Authors: Smith Kyle , Tape Carl
Published: September 2019

Ambient noise is useful for characterizing frequency‐dependent noise levels and for assessing data quality for seismic stations. We use 4 years of ambient noise spectra from 16 stations in central Alaska to examine environmental and structural influences on seismic stations. The region contains a major river (Tanana River) that is ice covered for half the year and is underlain by a sedimentary basin (Nenana basin) that strongly influences the seismic wavefield. Nenana basin amplifies ambient seismic noise by 12–16 dB at 0.1–0.7 Hz and 17–30 dB at 0.7–3 Hz. A meteorological station and river gauge at Nenana provide environmental data for comparison with seismic stations. During the summer, the Tanana River produces noise levels elevated by 30–40 dB at frequencies near 10 Hz, as recorded by all five stations within 100 m of the main river channel. The Tanana River sediment is predominantly silt and sand in this region; therefore, we attribute the 10‐Hz river signal to turbulence within the water and to unsteady shearing on the river bottom. The influence of wind is apparent on seismic noise at low (<0.05 Hz) frequencies, due to atmospheric‐induced tilting, and at high (>2.0 Hz) frequencies, due to unsteady shearing and turbulence near the ground. Our empirical findings motivate future studies, such as how flow from air or water couples to the ground and how deep sedimentary basins influence the ambient noise wavefield. Our results have implications for seismic site selection, environmental monitoring, and detection and characterization of earthquakes.
Determination of the “Wave Turbopause” Using a Numerical Differentiation Method
Authors: Zhao X. R. , Sheng Z. , Li J. W. , Yu H. , Wei K. J.
Published: September 2019

This paper proposes a new algorithm to determine the wave turbopause based on numerical differentiation using temperature data collected from the Sounding of the Atmosphere using Broadband Emission Radiometry onboard the Thermosphere Ionosphere Mesosphere Energetics Dynamics satellite. The vertical gradient profile of the temperature standard deviation, which serves as a proxy of wave activity, is obtained based on Tikhonov regularization. In the vicinity of the altitude of wave turbopause, wave damping is much reduced, and upward wave propagation occurs with little damping effect. The corresponding vertical gradient profile should reach a maximum with values that are no longer negative. Thus, we determine the wave turbopause as the unique maximum that is the first after the last change in the derivative value from negative to positive. The wave turbopause altitudes determined by this new method agree well with those of previous studies, especially regarding the behavior of the monthly variation. The error of the wave turbopause altitude derived from this new method is 1.9 km, which is much improved from the error of 3.3 km estimated by the previous method. Additionally, latitudinal variations of the wave turbopause altitude for different seasons and their monthly variations for 0°, 30°N, and 70°N latitudes during 2016–2018 are presented. Similar to the mesopause, the wave turbopause also exhibits a two‐level structure with a summer minimum at high latitudes.
The Medieval Climate Anomaly in the Mediterranean Region
Authors: Lüning S. , Schulte L. , Garcés‐Pastor S. , Danladi I.B. , Gałka M.
Published: September 2019

The Medieval Climate Anomaly (MCA) is a preindustrial phase of pronounced natural climate variability with a core period from 1000 to 1200 CE. The paper presents a synthesis that integrates palaeotemperature records from the Greater Mediterranean Region encompassing the past 1,500 years based on multiproxy data from 79 published land and marine sites. MCA warming dominated the Western Mediterranean (Iberia, NW Africa) as well as the northern land areas of the Central and Eastern Mediterranean region. MCA cooling prevailed in the Canary Current Upwelling System, southern Levant, and some sea areas of the Central and Eastern Mediterranean. Previous palaeoreconstructions suggest persistent positive Atlantic Multidecadal Oscillation (AMO+) and North Atlantic Oscillation (NAO+) conditions during the MCA, while the Little Ice Age was dominated by an AMO− and NAO− regime. During the past 150 years, AMO+ conditions are typically associated with warming episodes in the Mediterranean area. A similar relationship appears to have also been established during the MCA as the majority of all Mediterranean land sites experienced warm climate conditions. In contrast, the NAO typically leads to a characteristic west‐east temperature dipole pattern in the basin, as documented for the last decades. During NAO+ conditions the Western Mediterranean is generally warm (and dry), while large parts of the Central and Eastern Mediterranean are cold. Similar trends seem to have been developed during the MCA when the NAO+ regime led to consistent warming in the Western Mediterranean, while a significant number of sites with MCA cooling existed in the Central and Eastern Mediterranean.
Distribution‐Based Global Sensitivity Analysis in Hydrology
Authors: Ciriello Valentina , Lauriola Ilaria , Tartakovsky Daniel M.
Published: September 2019

Global sensitivity analysis (GSA) is routinely used in academic setting to quantify the influence of input variability and uncertainty on predictions of a quantity of interest. Practical applications of GSA are hampered by its high computational cost, which arises from the need to run large (e.g., groundwater) models multiple times, and by its reliance on the analysis of variance, which formally requires input parameters to be uncorrelated. The former difficulty can be alleviated by replacing expensive models with inexpensive (e.g., polynomial) surrogates, while adoption of distribution‐based (rather than variance‐based) metrics can, in principle, overcome the latter but at significantly increased computational cost. To make use of distribution‐based GSA feasible for regional‐scale models with a large number of degrees of freedom, we supplement it with a surrogate model built with polynomial chaos expansions with analytically updated coefficients. We demonstrate the computational efficiency of our algorithm on a case study dealing with evaluation of the effects of temperature variability on annual evapotranspiration at the regional scale.
Natural diets promote retention of the native gut microbiota in captive rodents
Authors: Martínez-Mota Rodolfo , Kohl Kevin D , Orr Teri J , Denise Dearing M
Published: September 2019

Wild animals entering captivity experience radical lifestyle changes resulting in microbiome alterations. However, little is known about the factors that drive microbial community shifts in captivity, and what actions could mitigate microbial changes. Using white-throated woodrats (Neotoma albigula), we tested whether offering natural diets in captivity facilitates retention of native microbial communities of captive animals. Wild-caught woodrats were brought to laboratory conditions. Woodrats received either a natural diet of Opuntia cactus or an artificial diet of commercial chow over three weeks. Microbial inventories from woodrat feces at the time of capture and in captivity were generated using Illumina 16S rRNA sequencing. We found that providing woodrats with wild-natural diets significantly mitigated alterations in their microbiota, promoting a 90% retention of native microbial communities across the experiment. In contrast, the artificial diet significantly impacted microbial structure to the extent that 38% of the natural microflora was lost. Core bacteria including Bifidobacterium and Allobaculum were lost, and abundances of microbes related to oxalate degradation decreased in individuals fed artificial but not natural diets. These results highlight the importance of supplementing captive diets with natural foods to maintain native microbiomes of animals kept in artificial conditions for scientific or conservation purposes.
Btbd3 expression regulates compulsive-like and exploratory behaviors in mice
Authors: Thompson Summer L. , Welch Amanda C. , Ho Emily V. , Bessa João M. , Portugal-Nunes Carlos , Morais Mónica , Young Jared W. , Knowles James A. , Dulawa Stephanie C.
Published: September 2019

BTB/POZ domain-containing 3 (BTBD3) was identified as a potential risk gene in the first genome-wide association study of obsessive-compulsive disorder (OCD). BTBD3 is a putative transcription factor implicated in dendritic pruning in developing primary sensory cortices. We assessed whether BTBD3 also regulates neural circuit formation within limbic cortico-striato-thalamo-cortical circuits and behaviors related to OCD in mice. Behavioral phenotypes associated with OCD that are measurable in animals include compulsive-like behaviors and reduced exploration. We tested Btbd3 wild-type, heterozygous, and knockout mice for compulsive-like behaviors including cage-mate barbering, excessive wheel-running, repetitive locomotor patterns, and reduced goal-directed behavior in the probabilistic learning task (PLT), and for exploratory behavior in the open field, digging, and marble-burying tests. Btbd3 heterozygous and knockout mice showed excessive barbering, wheel-running, impaired goal-directed behavior in the PLT, and reduced exploration. Further, chronic treatment with fluoxetine, but not desipramine, reduced barbering in Btbd3 wild-type and heterozygous, but not knockout mice. In contrast, Btbd3 expression did not alter anxiety-like, depression-like, or sensorimotor behaviors. We also quantified dendritic morphology within anterior cingulate cortex, mediodorsal thalamus, and hippocampus, regions of high Btbd3 expression. Surprisingly, Btbd3 knockout mice only showed modest increases in spine density in the anterior cingulate, while dendritic morphology was unaltered elsewhere. Finally, we virally knocked down Btbd3 expression in whole, or just dorsal, hippocampus during neonatal development and assessed behavior during adulthood. Whole, but not dorsal, hippocampal Btbd3 knockdown recapitulated Btbd3 knockout phenotypes. Our findings reveal that hippocampal Btbd3 expression selectively modulates compulsive-like and exploratory behavior.
A positive feedback loop of β-catenin/CCR2 axis promotes regorafenib resistance in colorectal cancer
Authors: Ou Baochi , Cheng Xi , Xu Zhuoqing , Chen Chun , Shen Xiaohui , Zhao Jingkun , Lu Aiguo
Published: September 2019

Resistance to molecular targeted therapies is a significant challenge for advanced colorectal cancer (CRC). Understanding the underlying mechanisms and developing effective strategies against regorafenib resistance are highly desired in the clinic. Here, we screened the expression of chemokine receptors and identified CC chemokine receptor 2 (CCR2) as a top upregulated gene in regorafenib-resistant cells. CCR2 silencing alleviated drug tolerance in regorafenib-resistant cells, while overexpression of CCR2 enhanced CRC cells resistance to regorafenib. Moreover, CCR2-mediated regorafenib tolerance was demonstrated to be associated with AKT/GSK3β-regulated β-catenin stabilization. In turn, β-catenin modulation is sufficient to trigger the transcriptional activation of CCR2 expression. Clinically, high-CCR2 expression was correlated to shorter overall survival and disease-free survival of patients. A positive correlation between CCR2 and nuclear β-catenin expression was observed in a cohort of CRC tissues. Altogether, these findings suggest β-catenin and CCR2 are part of a positive-feedback loop, which sustains a high CCR2 expression level, conferring CRC cells resistance to regorafenib. Thus, targeting CCR2 may be a useful therapeutic strategy to alleviate regorafenib tolerance to increase the efficacy of CRC treatments.
Endothelial CDS2 deficiency causes VEGFA-mediated vascular regression and tumor inhibition
Authors: Zhao Wencao , Cao Le , Ying Hanru , Zhang Wenjuan , Li Dantong , Zhu Xiaolong , Xue Wenzhi , Wu Shuang , Cao Mengye , Fu Cong , Qi Haonan , Hao Yimei , Tang Yun-Chi , Qin Jun , Zhong Tao P. , Lin Xiaoxi , Yu Luyang , Li Xuri , Li Lin , Wu Dianqing , Pan Weijun
Published: September 2019

The response of endothelial cells to signaling stimulation is critical for vascular morphogenesis, homeostasis and function. Vascular endothelial growth factor-a (VEGFA) has been commonly recognized as a pro-angiogenic factor in vertebrate developmental, physiological and pathological conditions for decades. Here we report a novel finding that genetic ablation of CDP-diacylglycerol synthetase-2 (CDS2), a metabolic enzyme that controls phosphoinositide recycling, switches the output of VEGFA signaling from promoting angiogenesis to unexpectedly inducing vessel regression. Live imaging analysis uncovered the presence of reverse migration of the angiogenic endothelium in cds2 mutant zebrafish upon VEGFA stimulation, and endothelium regression also occurred in postnatal retina and implanted tumor models in mice. In tumor models, CDS2 deficiency enhanced the level of tumor-secreted VEGFA, which in-turn trapped tumors into a VEGFA-induced vessel regression situation, leading to suppression of tumor growth. Mechanistically, VEGFA stimulation reduced phosphatidylinositol (4,5)-bisphosphate (PIP2) availability in the absence of CDS2-controlled-phosphoinositide metabolism, subsequently causing phosphatidylinositol (3,4,5)-triphosphate (PIP3) deficiency and FOXO1 activation to trigger regression of CDS2-null endothelium. Thus, our data indicate that the effect of VEGFA on vasculature is context-dependent and can be converted from angiogenesis to vascular regression.
The future of Blue Carbon science
Authors: Macreadie Peter I. , Anton Andrea , Raven John A. , Beaumont Nicola , Connolly Rod M. , Friess Daniel A. , Kelleway Jeffrey J. , Kennedy Hilary , Kuwae Tomohiro , Lavery Paul S. , Lovelock Catherine E. , Smale Dan A. , Apostolaki Eugenia T. , Atwood Trisha B. , Baldock Jeff , Bianchi Thomas S. , Chmura Gail L. , Eyre Bradley D. , Fourqurean James W. , Hall-Spencer Jason M. , Huxham Mark , Hendriks Iris E. , Krause-Jensen Dorte , Laffoley Dan , Luisetti Tiziana , Marbà Núria , Masque Pere , McGlathery Karen J. , Megonigal J. Patrick , Murdiyarso Daniel , Russell Bayden D. , Santos Rui , Serrano Oscar , Silliman Brian R. , Watanabe Kenta , Duarte Carlos M.
Published: September 2019

The term Blue Carbon (BC) was first coined a decade ago to describe the disproportionately large contribution of coastal vegetated ecosystems to global carbon sequestration. The role of BC in climate change mitigation and adaptation has now reached international prominence. To help prioritise future research, we assembled leading experts in the field to agree upon the top-ten pending questions in BC science. Understanding how climate change affects carbon accumulation in mature BC ecosystems and during their restoration was a high priority. Controversial questions included the role of carbonate and macroalgae in BC cycling, and the degree to which greenhouse gases are released following disturbance of BC ecosystems. Scientists seek improved precision of the extent of BC ecosystems; techniques to determine BC provenance; understanding of the factors that influence sequestration in BC ecosystems, with the corresponding value of BC; and the management actions that are effective in enhancing this value. Overall this overview provides a comprehensive road map for the coming decades on future research in BC science.
Spatial oxidation of L-plastin downmodulates actin-based functions of tumor cells
Authors: Balta Emre , Hardt Robert , Liang Jie , Kirchgessner Henning , Orlik Christian , Jahraus Beate , Hillmer Stefan , Meuer Stefan , Hübner Katrin , Wabnitz Guido H. , Samstag Yvonne
Published: September 2019

Several antitumor therapies work by increasing reactive oxygen species (ROS) within the tumor micromilieu. Here, we reveal that L-plastin (LPL), an established tumor marker, is reversibly regulated by ROS-induced thiol oxidation on Cys101, which forms a disulfide bridge with Cys42. LPL reduction is mediated by the Thioredoxin1 (TRX1) system, as shown by TRX1 trapping, TRX1 knockdown and blockade of Thioredoxin1 reductase (TRXR1) with auranofin. LPL oxidation diminishes its actin-bundling capacity. Ratiometric imaging using an LPL-roGFP-Orp1 fusion protein and a dimedone-based proximity ligation assay (PLA) reveal that LPL oxidation occurs primarily in actin-based cellular extrusions and strongly inhibits cell spreading and filopodial extension formation in tumor cells. This effect is accompanied by decreased tumor cell migration, invasion and extracellular matrix (ECM) degradation. Since LPL oxidation occurs following treatment of tumors with auranofin or γ-irradiation, it may be a molecular mechanism contributing to the effectiveness of tumor treatment with redox-altering therapies.
Genome-wide mutational biases fuel transcriptional diversity in the Mycobacterium tuberculosis complex
Authors: Chiner-Oms Álvaro , Berney Michael , Boinett Christine , González-Candelas Fernando , Young Douglas B. , Gagneux Sebastien , Jacobs William R. , Parkhill Julian , Cortes Teresa , Comas Iñaki
Published: September 2019

The Mycobacterium tuberculosis complex (MTBC) members display different host-specificities and virulence phenotypes. Here, we have performed a comprehensive RNAseq and methylome analysis of the main clades of the MTBC and discovered unique transcriptional profiles. The majority of genes differentially expressed between the clades encode proteins involved in host interaction and metabolic functions. A significant fraction of changes in gene expression can be explained by positive selection on single mutations that either create or disrupt transcriptional start sites (TSS). Furthermore, we show that clinical strains have different methyltransferases inactivated and thus different methylation patterns. Under the tested conditions, differential methylation has a minor direct role on transcriptomic differences between strains. However, disruption of a methyltransferase in one clinical strain revealed important expression differences suggesting indirect mechanisms of expression regulation. Our study demonstrates that variation in transcriptional profiles are mainly due to TSS mutations and have likely evolved due to differences in host characteristics.
Structured multimaterial filaments for 3D printing of optoelectronics
Authors: Loke Gabriel , Yuan Rodger , Rein Michael , Khudiyev Tural , Jain Yash , Joannopoulos John , Fink Yoel
Published: September 2019

Simultaneous 3D printing of disparate materials; metals, polymers and semiconductors with device quality interfaces and at high resolution remains challenging. Moreover, the precise placement of discrete and continuous domains to enable both device performance and electrical connectivity poses barriers to current high-speed 3D-printing approaches. Here, we report filaments with disparate materials arranged in elaborate microstructures, combined with an external adhesion promoter, to enable a wide range of topological outcomes and device-quality interfaces in 3D printed media. Filaments, structured towards light-detection, are printed into fully-connected 3D serpentine and spherical sensors capable of spatially resolving light at micron resolution across its entire centimeter-scale surface. 0-dimensional metallic microspheres generate light-emitting filaments that are printed into hierarchical 3D objects dotted with electroluminescent pixels at high device resolution of 55 µm not restricted by surface tension effects. Structured multimaterial filaments provides a path towards custom three-dimensional functional devices not realizable by existing approaches.
Highly selective oxygen reduction to hydrogen peroxide on transition metal single atom coordination
Authors: Jiang Kun , Back Seoin , Akey Austin J. , Xia Chuan , Hu Yongfeng , Liang Wentao , Schaak Diane , Stavitski Eli , Nørskov Jens K. , Siahrostami Samira , Wang Haotian
Published: September 2019

Shifting electrochemical oxygen reduction towards 2e– pathway to hydrogen peroxide (H2O2), instead of the traditional 4e– to water, becomes increasingly important as a green method for H2O2 generation. Here, through a flexible control of oxygen reduction pathways on different transition metal single atom coordination in carbon nanotube, we discovered Fe-C-O as an efficient H2O2 catalyst, with an unprecedented onset of 0.822 V versus reversible hydrogen electrode in 0.1 M KOH to deliver 0.1 mA cm−2 H2O2 current, and a high H2O2 selectivity of above 95% in both alkaline and neutral pH. A wide range tuning of 2e–/4e– ORR pathways was achieved via different metal centers or neighboring metalloid coordination. Density functional theory calculations indicate that the Fe-C-O motifs, in a sharp contrast to the well-known Fe-C-N for 4e–, are responsible for the H2O2 pathway. This iron single atom catalyst demonstrated an effective water disinfection as a representative application.
Roles for DNA polymerase δ in initiating and terminating leading strand DNA replication
Authors: Zhou Zhi-Xiong , Lujan Scott A. , Burkholder Adam B. , Garbacz Marta A. , Kunkel Thomas A.
Published: September 2019

Most current evidence indicates that DNA polymerases ε and δ, respectively, perform the bulk of leading and lagging strand replication of the eukaryotic nuclear genome. Given that ribonucleotide and mismatch incorporation rates by these replicases influence somatic and germline patterns of variation, it is important to understand the details and exceptions to this overall division of labor. Using an improved method to map where these replicases incorporate ribonucleotides during replication, here we present evidence that DNA polymerase δ universally participates in initiating leading strand synthesis and that nascent leading strand synthesis switches from Pol ε to Pol δ during replication termination. Ribonucleotide maps from both the budding and fission yeast reveal conservation of these processes. These observations of replisome dynamics provide important insight into the mechanisms of eukaryotic replication and genome maintenance.
Publisher Correction: Ice sheets matter for the global carbon cycle
Authors: Wadham J. L. , Hawkings J. R. , Tarasov L. , Gregoire L. J. , Spencer R. G. M. , Gutjahr M. , Ridgwell A. , Kohfeld K. E.
Published: September 2019

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Synaptotagmin 1 clamps synaptic vesicle fusion in mammalian neurons independent of complexin
Authors: Courtney Nicholas A. , Bao Huan , Briguglio Joseph S. , Chapman Edwin R.
Published: September 2019

Synaptic vesicle (SV) exocytosis is mediated by SNARE proteins. Reconstituted SNAREs are constitutively active, so a major focus has been to identify fusion clamps that regulate their activity in synapses: the primary candidates are synaptotagmin (syt) 1 and complexin I/II. Syt1 is a Ca2+ sensor for SV release that binds Ca2+ via tandem C2-domains, C2A and C2B. Here, we first determined whether these C2-domains execute distinct functions. Remarkably, the C2B domain profoundly clamped all forms of SV fusion, despite synchronizing residual evoked release and rescuing the readily-releasable pool. Release was strongly enhanced by an adjacent C2A domain, and by the concurrent binding of complexin to trans-SNARE complexes. Knockdown of complexin had no impact on C2B-mediated clamping of fusion. We postulate that the C2B domain of syt1, independent of complexin, is the molecular clamp that arrests SVs prior to Ca2+-triggered fusion.
Palladium-catalyzed α-arylation for the addition of small rings to aromatic compounds
Authors: He Zhi-Tao , Hartwig John F.
Published: September 2019

Small, strained rings have rigid, defined conformations and unique electronic properties. For these reasons, many groups seek to use these subunits to form biologically active molecules. We report a generally applicable approach to attach small rings to a wide range of aromatic compounds by palladium-catalyzed α-arylation of cyclopropyl, cyclobutyl and azetidinyl esters. The direct α-arylation of cyclopropyl esters and cyclobutyl esters is achieved in high yield by ensuring that the rate of coupling exceeds the rate of Claisen condensation. The α-arylation of azetidines is achieved without ring opening of the strained saturated heterocycle by conducting the reactions with an azetidine derivative bearing a benzyl protecting group on nitrogen. Mechanistic studies show that the α-arylation of small rings is challenging because of the weak acidity of α C-H bond (cyclopropanes), strong sensitivity of the strained esters to Claisen condensation (cyclobutatanes), or facile decomposition of the enolates (azetidinyl esters).
Robust and interpretable PAM50 reclassification exhibits survival advantage for myoepithelial and immune phenotypes
Authors: Mathews James C. , Nadeem Saad , Levine Arnold J. , Pouryahya Maryam , Deasy Joseph O. , Tannenbaum Allen
Published: September 2019

We introduce a classification of breast tumors into seven classes which are more clearly defined by interpretable mRNA signatures along the PAM50 gene set than the five traditional PAM50 intrinsic subtypes. Each intrinsic subtype is partially concordant with one of our classes, and the two additional classes correspond to division of the classes concordant with the Luminal B and the Normal intrinsic subtypes along expression of the Her2 gene group. Our Normal class shows similarity with the myoepithelial mammary cell phenotype, including TP63 expression (specificity: 80.8% and sensitivity: 82.8%), and exhibits the best overall survival (89.6% at 5 years). Though Luminal A tumors are traditionally considered the least aggressive, our analysis shows that only the Luminal A tumors which are now classified as myoepithelial have this phenotype, while tumors in our luminal class (concordant with Luminal A) may be more aggressive than previously thought. We also find that patients with basal tumors surviving to 48 months exhibit favorable continued survival rates when certain markers for B lymphocytes are present and poor survival rates when they are absent, which is consistent with recent findings.
Cold Atmospheric Plasma induces accumulation of lysosomes and caspase-independent cell death in U373MG glioblastoma multiforme cells
Authors: Conway Gillian E. , He Zhonglei , Hutanu Ana Lacramioara , Cribaro George Paul , Manaloto Eline , Casey Alan , Traynor Damien , Milosavljevic Vladimir , Howe Orla , Barcia Carlos , Murray James T. , Cullen Patrick J. , Curtin James F.
Published: September 2019

Room temperature Cold Atmospheric Plasma (CAP) has shown promising efficacy for the treatment of cancer but the exact mechanisms of action remain unclear. Both apoptosis and necrosis have been implicated as the mode of cell death in various cancer cells. We have previously demonstrated a caspase-independent mechanism of cell death in p53-mutated glioblastoma multiforme (GBM) cells exposed to plasma. The purpose of this study was to elucidate the molecular mechanisms involved in caspase-independent cell death induced by plasma treatment. We demonstrate that plasma induces rapid cell death in GBM cells, independent of caspases. Accumulation of vesicles was observed in plasma treated cells that stained positive with acridine orange. Western immunoblotting confirmed that autophagy is not activated following plasma treatment. Acridine orange intensity correlates closely with the lysosomal marker Lyso TrackerTM Deep Red. Further investigation using isosurface visualisation of confocal imaging confirmed that lysosomal accumulation occurs in plasma treated cells. The accumulation of lysosomes was associated with concomitant cell death following plasma treatment. In conclusion, we observed rapid accumulation of acidic vesicles and cell death following CAP treatment in GBM cells. We found no evidence that either apoptosis or autophagy, however, determined that a rapid accumulation of late stage endosomes/lysosomes precedes membrane permeabilisation, mitochondrial membrane depolarisation and caspase independent cell death.
Identification of new binding proteins of focal adhesion kinase using immunoprecipitation and mass spectrometry
Authors: Nguyen Binh Thanh , Pyun Jae-Chul , Lee Sang-Guk , Kang Min-Jung
Published: September 2019

Focal adhesion kinase (FAK) is a 125 kDa protein recruited as a participant in focal adhesion dynamics and serves as a signaling scaffold for the assembly and subsequent maturation of focal contact. Identification of new FAK binding proteins could reveal potential signaling targets and contribute to further development of therapeutic drugs in the treatment of colon cancer. Here, we applied a functional proteomic strategy to identify proteins that interact with FAK in human colon cancer cell line HCT-116. Proteins were targeted by coimmunoprecipitation with an anti-FAK antibody and resolved on 1D-SDS-PAGE. The gel was excised, reduced, alkylated, and trypsin digested. Tryptic peptides were separated by nano-LC-MS/MS by an LTQ-Orbitrap-Velos spectrometer. We identified 101 proteins in the immunocomplex under epithelial growth factor (EGF) stimulation. Three proteins, zyxin, nesprin-1, and desmoplakin, were discovered and validated using reciprocal immunoprecipitation and Western blot analysis. Then, we sought to study the biological relevance of these proteins by siRNA transfection of HCT-116 cells. According to the results, zyxin might play a central role as an upstream regulator to mediate critical cancer-related signaling pathways. Zyxin and nesprin-1 depletion significantly impaired cell migration and invasion capabilities. Additionally, we performed ELISA assays on serum samples from patients with colon cancer instead of cell models to quantify the protein levels of zyxin and nesprin-1. Our results suggested that zyxin and nesprin-1 are not only promising therapeutic targets but also potential diagnostic biomarkers for colon cancer.
Human multipotent hematopoietic progenitor cell expansion is neither supported in endothelial and endothelial/mesenchymal co-cultures nor in NSG mice
Authors: Radtke Stefan , Görgens André , da Conceição Castro Symone Vitoriano , Kordelas Lambros , Köninger Angela , Dürig Jan , Möllmann Michael , Horn Peter A. , Giebel Bernd
Published: September 2019

Endothelial and mesenchymal stromal cells (ECs/MSCs) are crucial components of hematopoietic bone marrow stem cell niches. Both cell types appear to be required to support the maintenance and expansion of multipotent hematopoietic cells, i.e. hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs). With the aim to exploit niche cell properties for experimental and potential clinical applications, we analyzed the potential of primary ECs alone and in combination with MSCs to support the ex vivo expansion/maintenance of human hematopoietic stem and progenitor cells (HSPCs). Even though a massive expansion of total CD34+ HSPCs was observed, none of the tested culture conditions supported the expansion or maintenance of multipotent HSPCs. Instead, mainly lympho-myeloid primed progenitors (LMPPs) were expanded. Similarly, following transplantation into immunocompromised mice the percentage of multipotent HSPCs within the engrafted HSPC population was significantly decreased compared to the original graft. Consistent with the in vitro findings, a bias towards lympho-myeloid lineage potentials was observed. In our conditions, neither classical co-cultures of HSPCs with primary ECs or MSCs, even in combination, nor the xenograft environment in immunocompromised mice efficiently support the expansion of multipotent HSPCs. Instead, enhanced expansion and a consistent bias towards lympho-myeloid committed LMPPs were observed.
Increased frequency of CD4+CD57+ senescent T cells in patients with newly diagnosed acute heart failure: exploring new pathogenic mechanisms with clinical relevance
Authors: Youn Jong-Chan , Jung Min Kyung , Yu Hee Tae , Kwon Ji-Soo , Kwak Jeong-Eun , Park Su-Hyung , Kim In-Cheol , Park Myung-Soo , Lee Sun Ki , Choi Suk-Won , Han Seongwoo , Ryu Kyu-Hyung , Kang Seok-Min , Shin Eui-Cheol
Published: September 2019

Recent animal studies showed T cells have a direct pathogenic role in the development of heart failure (HF). However, which subsets of T cells contribute to human HF pathogenesis and progression remains unclear. We characterized immunologic properties of various subsets of T cells and their clinical implications in human HF. Thirty-eight consecutive patients with newly diagnosed acute HF (21 males, mean age 66 ± 16 years) and 38 healthy control subjects (21 males, mean age 62 ± 12 years) were enrolled. We found that pro-inflammatory mediators, including CRP, IL-6 and IP-10 and the frequencies of CD57+ T cells in the CD4+ T cell population were significantly elevated in patients with acute HF compared to control subjects. A functional analysis of T cells from patients with acute HF revealed that the CD4+CD57+ T cell population exhibited a higher frequency of IFN-γ- and TNF-α- producing cells compared to the CD4+CD57− T cell population. Furthermore, the frequency of CD4+CD57+ T cells at baseline and its elevation at the six-month follow-up were significantly related with the development of cardiovascular (CV) events, which were defined as CV mortality, cardiac transplantation, or rehospitalization due to HF exacerbation. In conclusion, CD4+CD57+ senescent T cells showed more inflammatory features and polyfunctionality and were associated with clinical outcome in patients with acute HF. More detailed study for senescent T cells might offer new opportunities for the prevention and treatment of human HF.
Spatial distribution and clusters of pancreatic cancer mortality in Shandong Province, China
Authors: Jiang Fan , Chu Jie , Chen Xianxian , Zhang Jiyu , Fu Zhentao , Sun Jiandong , Lu Zilong , Guo Xiaolei , Xu Aiqiang
Published: September 2019

This study aimed to explore the geographic distribution and risk clusters of pancreatic cancer mortality from 2011 to 2013 in Shandong, China, and to detect the differences between urban and rural areas. Our data were obtained from the Shandong Death Registration System (SDRS) and were adjusted according to the underreporting level. The distribution of mortality was displayed with GIS-based maps at the county level. The results showed an increasing trend in pancreatic cancer mortality from the western region to the eastern region of Shandong. Additionally, four significant risk clusters were detected, and the most likely cluster was focused in the northeastern and northern regions. Urban-rural differences in the mortality distribution and risk clusters were also detected. In conclusion, our study identified pancreatic cancer mortality clusters in Shandong in urban and rural areas; these results can contribute to the development of effective and targeted strategies to control pancreatic cancer in different areas.
Generation of genetically modified mice using SpCas9-NG engineered nuclease
Authors: Fujii Wataru , Ito Haruka , Kanke Takuya , Ikeda Arisa , Sugiura Koji , Naito Kunihiko
Published: September 2019

Although genetically modified mice can be generated with high efficiency by using CRISPR/Cas9-mediated genome editing in mouse zygotes, only the loci with a protospacer-adjacent motif (PAM) sequence are targetable. The present study investigated the usability of engineered Streptococcus pyogenes Cas9 (SpCas9-NG) in mouse zygotes. In addition to the 5′-NGG sequence, SpCas9-NG recognized the 5′-NGA, 5′-NGC and 5′-NGT sequences in mouse zygotes as PAMs that were appropriate for the generation of knockout mice. Moreover, SpCas9-NG-mediated genome editing enabled the generation of knock-in mice untargetable by the conventional SpCas9 in mouse zygotes. These results suggest that SpCas9-NG-mediated genome editing in zygotes is available for the generation of knockout and knock-in mice at the locus corresponding to NGN-PAM.
Comparative adipose transcriptome analysis digs out genes related to fat deposition in two pig breeds
Authors: Xing Kai , Wang Kejun , Ao Hong , Chen Shaokang , Tan Zhen , Wang Yuan , Xitong Zhao , Yang Ting , Zhang Fengxia , liu Yibing , Ni Hemin , Sheng Xihui , Qi Xiaolong , Wang Xiangguo , Guo Yong , Wang Chuduan
Published: September 2019

Fatness traits are important in pigs because of their implications for fattening efficiency, meat quality, reproductive performance and immunity. Songliao black pigs and Landrace pigs show important differences in production and meat quality traits, including fatness and muscle growth. Therefore, we used a high-throughput massively parallel RNA-seq approach to identify genes differentially expressed in backfat tissue between these two breeds (six pigs in each). An average of 37.87 million reads were obtained from the 12 samples. After statistical analysis of gene expression data by edgeR, a total of 877 differentially expressed genes were detected between the two pig breeds, 205 with higher expression and 672 with lower expression in Songliao pigs. Candidate genes (LCN2, CES3, DGKB, OLR1, LEP, PGM1, PCK1, ACACB, FADS1, FADS2, MOGAT2, SREBF1, PPARGC1B) with known effects on fatness traits were included among the DEGs. A total of 1071 lncRNAs were identified, and 85 of these lncRNAs were differentially expressed, including 53 up-regulated and 32 down-regulated lncRNAs, respectively. The differentially expressed genes and lncRNAs involved in glucagon signaling pathway, glycolysis/gluconeogenesis, insulin signaling pathway, MAPK signaling pathway and so on. Integrated analysis potential trans-regulating or cis-regulating relation between DEGs and DE lncRNAs, suggested lncRNA MSTRG.2479.1 might regulate the expressed level of VLDLR affecting porcine fat metabolism. These results provide a number of candidate genes and lncRNAs potentially involved in porcine fat deposition and provide a basis for future research on the molecular mechanisms underlying in fat deposition.
Genome-scale CRISPR knockout screen identifies TIGAR as a modifier of PARP inhibitor sensitivity
Authors: Fang Pingping , De Souza Cristabelle , Minn Kay , Chien Jeremy
Published: September 2019

Treatment of cancer with poly (ADP-ribose) polymerase (PARP) inhibitors is currently limited to cells defective in the homologous recombination (HR) pathway. Identification of genetic targets that induce or mimic HR deficiencies will extend the clinical utility of PARP inhibitors. Here we perform a CRISPR/Cas9-based genome-scale loss-of-function screen, using the sensitivity of PARP inhibitor olaparib as a surrogate. We identify C12orf5, encoding TP53 induced glycolysis and apoptosis regulator (TIGAR), as a modifier of PARP inhibitor response. We show that TIGAR is amplified in several cancer types, and higher expression of TIGAR associates with poor overall survival in ovarian cancer. TIGAR knockdown enhances sensitivity to olaparib in cancer cells via downregulation of BRCA1 and the Fanconi anemia pathway and increases senescence of these cells by affecting metabolic pathways and increasing the cytotoxic effects of olaparib. Our results indicate TIGAR should be explored as a therapeutic target for treating cancer and extending the use of PARP inhibitors.