bluuebunny/crossref_metadata_2025 huggingface dataset:
Determinants of the Current Account Balances among Central and Eastern European Countries in the European Union
Authors: Tang Donny
Published: February 2019

This study examines whether the financial market development and integration have affected the current account balances in the European Union (EU) countries in Central and Eastern Europe (CEE) during 1996–2015. First, the results suggest that the higher bank credit flows have resulted in the current account deficits especially after EU accession. The larger pool of bank lending flows due to the foreign mergers and acquisitions has helped finance domestic investment. This has led to the larger current account deficits. Second, the results indicate that the larger stock market size due to EU accession has caused current account surpluses rather than deficits. This contradicts the findings of previous studies, which find that higher financial market development leads to current account deficit. Finally, the result confirms that financial integration has facilitated higher current account deficits. The European Monetary Union has eliminated the regulatory restrictions on cross-border capital flows. The increase in foreign capital inflows has helped finance the growing local consumption and investment needs, which has made the CEE countries run the larger current account deficits.
Sociodemographic patterns of urine sodium excretion and its association with hypertension in Chile: a cross-sectional analysis
Authors: Petermann-Rocha Fanny , Sillars Anne , Brown Rosemary , Sweeney Lauren , Troncoso Claudia , García-Hermoso Antonio , Leiva Ana María , Martínez María Adela , Diaz-Martínez Ximena , Poblete-Valderrama Felipe , Garrido-Mendez Alex , Cataldo Ximena , Gonzalez José Iturra , Salas Carlos , Lara José , Gray Stuart R , Celis-Morales Carlos
Published: February 2019

Objective

The aim of the study was to determine the main factors (sociodemographic, anthropometric, lifestyle and health status) associated with high Na excretion in a representative population of Chile.

Design

Na excretion (g/d), a valid marker of Na intake, was determined by urine analysis and Tanaka’s formulas. Blood pressure was measured by trained staff and derived from the mean of three readings recorded after 15 min rest. The associations of Na excretion with blood pressure and the primary correlates of high Na excretion were determined using logistic regression.

Setting

Chileans aged ≥15 years.

Participants

Participants (n 2913) from the Chilean National Health Survey 2009–2010.

Results

Individuals aged 25 years or over, those who were obese and those who had hypertension, diabetes or metabolic syndrome were more likely to have higher Na excretion. The odds for hypertension increased by 10·2 % per 0·4 g/d increment in Na excretion (OR=1·10; 95 % CI 1·06, 1·14; P < 0·0001). These findings were independent of major confounding factors.

Conclusions

Age, sex, adiposity, sitting behaviours and existing co-morbidities such as diabetes were associated with higher Na excretion levels in the Chilean population. These findings could help policy makers to implement public health strategies tailored towards individuals who are more likely to consume high levels of dietary salt.
Many roads from pasture to plate: a commodity chain approach to China’s beef trade, 1732–1931
Authors: DuBois Thomas David
Published: February 2019

The advent of refrigerated transport made fresh beef a global commodity, linking South American and Australian producers to hungry consumers in Europe and North America. With vast supplies of cattle, and growing markets in Japan, Russia, and beyond, China was the last great frontier of this global transformation. Rather than a single export trade, China’s beef industry was a complex and multidirectional network of producers, processors, and consumers, its many production chains each facing distinct commercial, logistic, and political challenges. This article examines three such chains, the Qing-era caravan trade that drove live sheep and cattle to Beijing, the Harbin meat-packing industry that grew up around the Russian China Eastern Railway, and Japanese-dominated export of beef from Qingdao. A cross-section of these issues shows how the industry as a whole adapted to the new pressures and opportunities of globalization, as well as those presented by technology, foreign investment, imperialism, and war.
Before UNEP: who was in charge of the global environment? The struggle for institutional responsibility 1968–72
Authors: Borowy Iris
Published: February 2019

Many of the international technical agencies formed after 1945 addressed environmental topics within their specific fields of work. By the late 1960s, a growing awareness of pollution and an emerging environmental movement in Western countries led to a perceived need for more coordinated and institutionalized international cooperation on the environment. Before the landmark United Nations Conference on the Human Environment, held in Stockholm in 1972, and the subsequent creation of the UN Environment Programme, several organizations competed for recognition as principal reference organizations for environmental matters. This article analyses the combination of cooperation and rivalry, involving in particular the North Atlantic Treaty Organization (NATO), the Organisation for Economic Co-operation and Development (OECD) and the United Nations Economic Commission for Europe (ECE). Among other initiatives, the OECD became the first international organization to establish a permanent committee specifically dedicated to environmental issues and the ECE organized a Conference on Environmental Problems, held in Prague in 1971. Both called for a critical review of the dominant growth-centred economic model. Their analysis adds a neglected dimension to the origins of today’s international structure of environmental cooperation as well as to the long-term evolution of economic environmental thinking.
Three‐Dimensional Signature of the Red Sea Eddies and Eddy‐Induced Transport
Authors: Zhan Peng , Krokos George , Guo Daquan , Hoteit Ibrahim
Published: February 2019

Mesoscale eddies are a dominant feature of the Red Sea circulation, yet their three‐dimensional characteristics remain largely unexplored. This hinders our understanding about eddy‐induced transport in the basin. This study analyzes 14‐year outputs from a high‐resolution eddy‐resolving model to investigate the three‐dimensional signature of the Red Sea eddies, their contribution to the air‐sea flux, and the eddy‐induced transport of heat and salt. Eddies are mostly active and energetic in the central and northern Red Sea. Their variability explains ∼8% of the total variance in the surface heat flux and, particularly, ∼39% in the salt flux. The asymmetric eddy structure and meridional gradient drive significant transport of heat and salt across the basin. A negative feedback mechanism is identified that relates the eddy intensity and the meridional steepness of the mixed layer depth in the basin.
Changes in Terrestrial Water Storage During 2003–2014 and Possible Causes in Tibetan Plateau
Authors: Meng Fanchong , Su Fengge , Li Ying , Tong Kai
Published: February 2019

The spatial‐temporal changes in terrestrial water storage (TWS) over the Tibetan Plateau (TP) and six selected basins during 2003–2014 were analyzed by applying the Gravity Recovery and Climate Experiment data and the extended Variable Infiltration Capacity‐glacier model, including the upstream of Yangtze (UYA), Yellow (UYE), Brahmaputra (UB), and Indus river basins and the Inner TP and the Qaidam Basin. The possible causes of TWS changes were investigated from the perspective of surface water balance and TWS components through multisource data and the Variable Infiltration Capacity‐glacier model. There was a strong spatial heterogeneity in changes of Gravity Recovery and Climate Experiment TWS in the TP—with apparent mass accumulation in central and northern TP and a sharp decreasing trend in southern and northwestern TP. The TWS changes in the TP were mostly attributed to variations in precipitation and evapotranspiration from the perspective of land‐surface water balance. Precipitation played a dominant role on the TWS accumulation in the UYA and UYE, while evapotranspiration had a more important role than precipitation in TWS depletion in the UB. From the perspective of TWS components, the TWS increase in the UYA and UYE was mainly caused by an increase in soil moisture, whereas the decrease in TWS in the UB was mostly due to glacier mass loss. TWS was accumulating from March through August in southeastern TP while from November to April/May in northwestern TP. The seasonal variations of TWS are highly modulated by the large‐scale climate system, atmospheric moisture flux, and precipitation regime over the TP.
Changes in the Interannual Summer Drought Variation Along With the Regime Shift Over Northwest China in the Late 1980s
Authors: Zhu Ya Li , Liu Yang , Wang Hui Jun , Sun Jian Qi
Published: February 2019

The arid/semiarid region of Northwest China (NWC, north to 35°N, and west to 100°E in China) experienced significant wetting after the late 1980s. We used both the summer precipitation and standardized precipitation indices (precipitation index [PI] and standardized precipitation index) to reexamine the regime shift. Consistent with the rainfall, the drought condition represented by the standardized precipitation index was significantly alleviated over most areas of NWC during P2 (1989–2016) than that during P1 (1961–1988). Along with the increased rainfall over the NWC, significant changes also occur in the interannual variation‐related circulation. The Ural High (UH) was found to be closely related with the interdecadal change during the late 1980s. The NWC PI‐related wave propagation from the UH weakened after the late 1980s. The persistent tropical Indian Ocean sea surface temperature (SST) from the preceding winter to the summer were also found to influence the NWC PI through modulating the South Asian High during P1. However, during P2, the ENSO signals in the preceding winter, which can be memorized by the Indian Ocean SST in the spring and propagate to the Indo‐Pacific SST in the summer, can influence the NWC PI. The wave train pattern in the convection from the Maritime Continent to NWC and northwestern Europe seems to be a key bridge. The UH seems to be independent of the above SST‐forced atmospheric circulations. The SST signals of the preceding winter can provide useful information for the summer drought prediction in NWC.
A Supercooled Water Cloud Detection Algorithm Using Himawari‐8 Satellite Measurements
Authors: Wang Ziming , Letu Husi , Shang Huazhe , Zhao Chuanfeng , Li Jiming , Ma Run
Published: February 2019

The detection of supercooled water clouds (SWCs) is essential for artificial rain enhancement, the prevention of aircraft ice accretion, and better understanding of radiative energy balance. However, it is challenging to identify SWCs using only passive satellite measurements. We adopt measurements from the Advanced Himawari Imager, which is onboard the new‐generation, high temporal, spatial, and spectral resolution geostationary Himawari‐8 satellite, to develop a time‐continuous Himawari‐8 SWC (HSWC) algorithm. The HSWC algorithm includes a group of tests using comprehensive cloud properties (e.g., cloud phase [CPH], cloud top temperature, cloud optical thickness, and cloud effective radius [CER]). Unlike previous SWC detection algorithms, which are based on cloud top temperature and cloud optical thickness properties, we introduce CER and CPH information into the HSWC algorithm because the distribution of SWCs is sensitive to CER values, and SWCs may appear in mixed‐phase clouds identified by satellites. Our analyses indicate that the additions of the CER and CPH tests could improve the performance of SWC detection by 15.07% and 4.75%, respectively. The full disk SWC detection results identified by the HSWC algorithm in January, May, August, and October of 2017 are validated using lidar measurements. The hit rate and false alarm rate are 93.52% and 25.27%, respectively. Our study provides potential SWC regions for the implementation of artificial rain enhancement.
Modes of Berm and Beachface Recovery Following Storm Reset: Observations Using a Continuously Scanning Lidar
Authors: Phillips M. S. , Blenkinsopp C. E. , Splinter K. D. , Harley M. D. , Turner I. L.
Published: February 2019

Following the rapid and destructive impacts of storm erosion, beach recovery is a key natural process of restoration, returning eroded sediment to the subaerial beach and rebuilding coastal morphology. While the effects of storm erosion have commonly been investigated, detailed studies into poststorm recovery are currently lacking. This study investigates wave‐driven recovery processes of the berm and beachface on a microtidal, swash‐aligned sandy beach. Following complete removal of the berm by a significant storm event, the entire 76‐day rebuilding of a swash berm is analyzed at the timescale of every semidiurnal tidal cycle, utilizing high‐resolution (5 Hz) swash and subaerial beach profile measurements from a continuously scanning fixed lidar. Tide‐by‐tide rates of subaerial volume change during berm recovery were most frequently observed between 1 and 2 m3/m/day, including losses and gains an order of magnitude larger than the more gradual rate of net gain (0.7 m3/m/day) observed for the entire recovery period. Patterns of berm crest formation and vertical growth were found to be primarily governed by the neap‐spring tide variations in total water levels. Tide‐by‐tide beachface and berm volume changes were used to classify four principal behavioral modes of subaerial profile variability during recovery. Using decision tree classification, modes were differentiated according to nearshore dimensionless fall velocity, swash exceedance of the berm crest, and ocean water levels. The findings provide novel behavioral and parametric insight into the tide‐by‐tide rebuilding of the beachface and berm by swash throughout a complete poststorm recovery period.
Geophysical Monitoring of Hydrocarbon Biodegradation in Highly Conductive Environments
Authors: Kimak C. , Ntarlagiannis D. , Slater L. D. , Atekwana E. A. , Beaver C. L. , Rossbach S. , Porter A. , Ustra A.
Published: February 2019

Natural attenuation is very often the remediation method of necessity, rather than choice, for beach environments impacted by offshore exploration/drilling accidents. Robust methods that can be efficiently utilized in difficult to access and ecologically sensitive areas are needed for the long‐term monitoring of such degradation processes. A prime candidate for such a monitoring tool is the spectral induced polarization (SIP) method, a geophysical technique successfully used for characterization and monitoring of hydrocarbon degradation in freshwater environments. In this laboratory experiment the SIP method successfully monitored the natural degradation of beach sediments impacted by the Deepwater Horizon oil spill. Using the SIP, we were able to differentiate between biotic (e.g., microbial driven) and abiotic (e.g., dilution) degradation processes and infer degradation rates. To our knowledge this is the first effort to use the SIP method as a monitoring aid in high salinity environments.
Lingering Carbon Cycle Effects of Hurricane Matthew in North Carolina's Coastal Waters
Authors: Osburn Christopher L. , Rudolph Jacob C. , Paerl Hans W. , Hounshell Alexandria G. , Van Dam Bryce R.
Published: February 2019

In 2016, Hurricane Matthew accounted for 25% of the annual riverine C loading to the Neuse River Estuary‐Pamlico Sound, in eastern North Carolina. Unlike inland watersheds, dissolved organic carbon (DOC) was the dominant component of C flux from this coastal watershed and stable carbon isotope and chromophoric dissolved organic matter evidence indicated the estuary and sound were dominated by wetland‐derived terrigenous organic matter sources for several months following the storm. Persistence of wetland‐derived DOC enabled its degradation to carbon dioxide (CO2), which was supported by sea‐to‐air CO2 fluxes measured in the sound weeks after the storm. Under future increasingly extreme weather events such as Hurricane Matthew, and most recently Hurricane Florence (September 2018), degradation of terrestrial DOC in floodwaters could increase flux of CO2 from estuaries and coastal waters to the atmosphere.
High-resolution respirometry in human endomyocardial biopsies shows reduced ventricular oxidative capacity related to heart failure
Authors: Scheiber Daniel , Jelenik Tomas , Zweck Elric , Horn Patrick , Schultheiss Heinz-Peter , Lassner Dirk , Boeken Udo , Saeed Diyar , Kelm Malte , Roden Michael , Westenfeld Ralf , Szendroedi Julia
Published: February 2019

The lifetime risk of developing heart failure is approximately 20%, and survival rates remain poor. Myocardial mitochondrial function has been suggested to play a pivotal role in heart failure pathophysiology. Human studies on ex vivo mitochondrial function have mostly been limited to atrial tissue obtained during open heart surgery and have provided contradictory results. This study aimed at measuring myocardial mitochondrial function in transcatheter ventricular endomyocardial biopsies and assessing the relationship between oxidative capacity and heart function. We enrolled 40 heart failure patients undergoing ventricular assist device surgery or heart transplantation (34 males, age 57 ± 11 years, body mass index 26.6 ± 4.8 kg/m2) and 29 heart transplant recipients of comparable age and body mass index with normal left ventricular function undergoing surveillance biopsies (23 males, 57 ± 12 years, body mass index 26.2 ± 4.1 kg/m2). High-resolution respirometry was established in the myocardium to measure oxidative capacity ex vivo. The mitochondrial oxidative capacity was 90% higher in ventricular compared to atrial tissues (n = 11, p < 0.01) of explanted hearts. Respiration rates were comparable in ventricular samples of heart failure patients obtained during open heart surgery by standard tissue preparation or ex vivo endomyocardial biopsy (r = 0.9988, p < 0.0001, n = 8), and the mitochondrial oxidative capacity in samples from these patients remained stable for 8 h when stored in either of two common preservation buffers. The oxidative capacity was 44% lower in heart failure than in transplant recipients (67 ± 3 vs. 97 ± 5 pmol/[s mg], p < 0.0001) and correlated positively with heart function (r = 0.49, p < 0.01). High-resolution respirometry of ventricular tissue is feasible in transcatheter biopsies, facilitating clinical studies on myocardial mitochondrial function in patients not undergoing heart surgery.
Molecular basis for the production of cyclic peptides by plant asparaginyl endopeptidases
Authors: Jackson M. A. , Gilding E. K. , Shafee T. , Harris K. S. , Kaas Q. , Poon S. , Yap K. , Jia H. , Guarino R. , Chan L. Y. , Durek T. , Anderson M. A. , Craik D. J.
Published: February 2019

Asparaginyl endopeptidases (AEPs) are proteases that have crucial roles in plant defense and seed storage protein maturation. Select plant AEPs, however, do not function as proteases but as transpeptidases (ligases) catalyzing the intra-molecular ligation of peptide termini, which leads to peptide cyclization. These ligase-type AEPs have potential biotechnological applications ranging from in vitro peptide engineering to plant molecular farming, but the structural features enabling these enzymes to catalyze peptide ligation/cyclization rather than proteolysis are currently unknown. Here, we compare the sequences, structures, and functions of diverse plant AEPs by combining molecular modeling, sequence space analysis, and functional testing in planta. We find that changes within the substrate-binding pocket and an adjacent loop, here named the “marker of ligase activity”, together play a key role for AEP ligase efficiency. Identification of these structural determinants may facilitate the discovery of more ligase-type AEPs and the engineering of AEPs with tailored catalytic properties.
Decadal biomass increment in early secondary succession woody ecosystems is increased by CO2 enrichment
Authors: Walker Anthony P. , De Kauwe Martin G. , Medlyn Belinda E. , Zaehle Sönke , Iversen Colleen M. , Asao Shinichi , Guenet Bertrand , Harper Anna , Hickler Thomas , Hungate Bruce A. , Jain Atul K. , Luo Yiqi , Lu Xingjie , Lu Meng , Luus Kristina , Megonigal J. Patrick , Oren Ram , Ryan Edmund , Shu Shijie , Talhelm Alan , Wang Ying-Ping , Warren Jeffrey M. , Werner Christian , Xia Jianyang , Yang Bai , Zak Donald R. , Norby Richard J.
Published: February 2019

Increasing atmospheric CO2 stimulates photosynthesis which can increase net primary production (NPP), but at longer timescales may not necessarily increase plant biomass. Here we analyse the four decade-long CO2-enrichment experiments in woody ecosystems that measured total NPP and biomass. CO2 enrichment increased biomass increment by 1.05 ± 0.26 kg C m−2 over a full decade, a 29.1 ± 11.7% stimulation of biomass gain in these early-secondary-succession temperate ecosystems. This response is predictable by combining the CO2 response of NPP (0.16 ± 0.03 kg C m−2 y−1) and the CO2-independent, linear slope between biomass increment and cumulative NPP (0.55 ± 0.17). An ensemble of terrestrial ecosystem models fail to predict both terms correctly. Allocation to wood was a driver of across-site, and across-model, response variability and together with CO2-independence of biomass retention highlights the value of understanding drivers of wood allocation under ambient conditions to correctly interpret and predict CO2 responses.
PLCβ2 negatively regulates the inflammatory response to virus infection by inhibiting phosphoinositide-mediated activation of TAK1
Authors: Wang Lin , Zhou Yilong , Chen Zijuan , Sun Lei , Wu Juehui , Li Haohao , Liu Feng , Wang Fei , Yang Chunfu , Yang Juhao , Leng Qibin , Zhang Qingli , Xu Ajing , Shen Lisong , Sun Jinqiao , Wu Dianqing , Fang Caiyun , Lu Haojie , Yan Dapeng , Ge Baoxue
Published: February 2019

Excessive or uncontrolled release of proinflammatory cytokines caused by severe viral infections often results in host tissue injury or even death. Phospholipase C (PLC)s degrade phosphatidylinositol-4, 5-bisphosphate (PI(4,5)P2) lipids and regulate multiple cellular events. Here, we report that PLCβ2 inhibits the virus-induced expression of pro-inflammatory cytokines by interacting with and inhibiting transforming growth factor-β-activated kinase 1 (TAK1) activation. Mechanistically, PI(4,5)P2 lipids directly interact with TAK1 at W241 and N245, and promote its activation. Impairing of PI(4,5)P2’s binding affinity or mutation of PIP2-binding sites on TAK1 abolish its activation and the subsequent production of pro-inflammatory cytokines. Moreover, PLCβ2-deficient mice exhibit increased expression of proinflammatory cytokines and a higher frequency of death in response to virus infection, while the PLCβ2 activator, m-3M3FBS, protects mice from severe Coxsackie virus A 16 (CVA16) infection. Thus, our findings suggest that PLCβ2 negatively regulates virus-induced pro-inflammatory responses by inhibiting phosphoinositide-mediated activation of TAK1.
Retrospective model-based inference guides model-free credit assignment
Authors: Moran Rani , Keramati Mehdi , Dayan Peter , Dolan Raymond J.
Published: February 2019

An extensive reinforcement learning literature shows that organisms assign credit efficiently, even under conditions of state uncertainty. However, little is known about credit-assignment when state uncertainty is subsequently resolved. Here, we address this problem within the framework of an interaction between model-free (MF) and model-based (MB) control systems. We present and support experimentally a theory of MB retrospective-inference. Within this framework, a MB system resolves uncertainty that prevailed when actions were taken thus guiding an MF credit-assignment. Using a task in which there was initial uncertainty about the lotteries that were chosen, we found that when participants’ momentary uncertainty about which lottery had generated an outcome was resolved by provision of subsequent information, participants preferentially assigned credit within a MF system to the lottery they retrospectively inferred was responsible for this outcome. These findings extend our knowledge about the range of MB functions and the scope of system interactions.
Clinical whole genome sequencing as a first-tier test at a resource-limited dysmorphology clinic in Mexico
Authors: Scocchia Alicia , Wigby Kristen M. , Masser-Frye Diane , Del Campo Miguel , Galarreta Carolina I. , Thorpe Erin , McEachern Julia , Robinson Keisha , Gross Andrew ,   ICSL Interpretation and Reporting Team, Bennett Maren , Bluske Krista , Brown Carolyn M. , Buchanan Amanda , Burns Brendan , Burns Nicole J. , Chandrasekhar Anjana , Chawla Aditi , Clause Amanda R. , Coffey Alison J. , Cremona Maria Laura , Gainullin Vlad , Hagelstrom R. Tanner , Malhotra Alka , Rajan Maya , Rajkumar Revathi , Schmidt Sarah , Ajay Subramanian S. , Rajan Vani , Perry Denise L. , Belmont John W. , Bentley David R. , Jones Marilyn C. , Taft Ryan J.
Published: February 2019

Patients with rare, undiagnosed, or genetic disease (RUGD) often undergo years of serial testing, commonly referred to as the “diagnostic odyssey”. Patients in resource-limited areas face even greater challenges—a definitive diagnosis may never be reached due to difficulties in gaining access to clinicians, appropriate specialists, and diagnostic testing. Here, we report on a collaboration of the Illumina iHope Program with the Foundation for the Children of the Californias and Hospital Infantil de Las Californias, to enable deployment of clinical whole genome sequencing (cWGS) as first-tier test in a resource-limited dysmorphology clinic in northern Mexico. A total of 60 probands who were followed for a suspected genetic diagnosis and clinically unresolved after expert examination were tested with cWGS, and the ordering clinicians completed a semi-structured survey to investigate change in clinical management resulting from cWGS findings. Clinically significant genomic findings were identified in 68.3% (n = 41) of probands. No recurrent molecular diagnoses were observed. Copy number variants or gross chromosomal abnormalities accounted for 48.8% (n = 20) of the diagnosed cases, including a mosaic trisomy and suspected derivative chromosomes. A qualitative assessment of clinical management revealed 48.8% (n = 20) of those diagnosed had a change in clinical course based on their cWGS results, despite resource limitations. These data suggest that a cWGS first-tier testing approach can benefit patients with suspected genetic disorders.
Protein–Protein Affinity Determination by Quantitative FRET Quenching
Authors: Jiang Ling , Xiong Zhehao , Song Yang , Lu Yanrong , Chen Younan , Schultz Jerome S. , Li Jun , Liao Jiayu
Published: February 2019

The molecular dissociation constant, Kd, is a well-established parameter to quantitate the affinity of protein-protein or other molecular interactions. Recently, we reported the theoretical basis and experimental procedure for Kd determination using a quantitative FRET method. Here we report a new development of Kd determination by measuring the reduction in donor fluorescence due to acceptor quenching in FRET. A new method of Kd determination was developed from the quantitative measurement of donor fluorescence quenching. The estimated Kd values of SUMO1-Ubc9 interaction based on this method are in good agreement with those determined by other technologies, including FRET acceptor emission. Thus, the acceptor-quenched approach can be used as a complement to the previously developed acceptor excitation method. The new methodology has more general applications regardless whether the acceptor is an excitable fluorophore or a quencher. Thus, these developments provide a complete methodology for protein or other molecule interaction affinity determinations in solution.
Insights into the biogenesis and potential functions of exonic circular RNA
Authors: Ragan Chikako , Goodall Gregory J. , Shirokikh Nikolay E. , Preiss Thomas
Published: February 2019

Circular RNAs (circRNAs) exhibit unique properties due to their covalently closed nature. Models of circRNAs synthesis and function are emerging but much remains undefined about this surprisingly prevalent class of RNA. Here, we identified exonic circRNAs from human and mouse RNA-sequencing datasets, documenting multiple new examples. Addressing function, we found that many circRNAs co-sediment with ribosomes, indicative of their translation potential. By contrast, circRNAs with potential to act as microRNA sponges were scarce, with some support for a collective sponge function by groups of circRNAs. Addressing circRNA biogenesis, we delineated several features commonly associated with circRNA occurrence. CircRNA-producing genes tend to be longer and to contain more exons than average. Back-splice acceptor exons are strongly enriched at ordinal position 2 within genes, and circRNAs typically have a short exon span with two exons being the most prevalent. The flanking introns either side of circRNA loci are exceptionally long. Of note also, single-exon circRNAs derive from unusually long exons while multi-exon circRNAs are mostly generated from exons of regular length. These findings independently validate and extend similar observations made in a number of prior studies. Furthermore, we analysed high-resolution RNA polymerase II occupancy data from two separate human cell lines to reveal distinctive transcription dynamics at circRNA-producing genes. Specifically, RNA polymerase II traverses the introns of these genes at above average speed concomitant with an accentuated slow-down at exons. Collectively, these features indicate how a perturbed balance between transcription and linear splicing creates important preconditions for circRNA production. We speculate that these preconditions need to be in place so that looping interactions between flanking introns can promote back-splicing to raise circRNA production to appreciable levels.
Nutritional and lipidomics biomarkers of docosahexaenoic acid-based multivitamin therapy in pediatric NASH
Authors: Torquato Pierangelo , Giusepponi Danilo , Alisi Anna , Galarini Roberta , Bartolini Desirée , Piroddi Marta , Goracci Laura , Di Veroli Alessandra , Cruciani Gabriele , Crudele Annalisa , Nobili Valerio , Galli Francesco
Published: February 2019

Two recent randomized controlled trials demonstrated improved radiographic, histological and hepatometabolic cues of non-alcoholic steatohepatitis (NASH) in pediatric patients treated with the ω-3 fatty acid docosahexaenoic acid (DHA) in combination with vitamin D (VD) or with choline (CHO) and vitamin E (VE), the DHA-VD and DHA-CHO-VE trials, respectively). In the present study we verified the nutritional compliance to these DHA-based multivitamin treatments; lipidomics biomarkers of the reported outcome on NASH indicators were also investigated. Samples were obtained from 30 biopsy-proven pediatric NASH patients of the DHA-CHO-VE trial randomized in multivitamin treatment group and placebo group (n = 15 each), and from 12 patients of the treatment group of the DHA-VD trial. All patients underwent 6-month therapy plus 6 months of follow-up. Plasma samples and clinical data were obtained at baseline and at the end of the study (12 months). Selected biomarkers included the free form of DHA and other ω-3 fatty acid arachidonic acid (AA), indices of the vitamin E status, and some hepatic metabolites of these lipids. Radiographic and histological improvements of treated patients were associated with increased concentrations of DHA, α-linolenic acid and α-tocopherol (i.e. VE), and with decreased AA that was also investigated in complex lipids by untargetd lipidomics. As a result a significantly lowered AA/DHA ratio was observed to represent the main indicator of the response to the DHA-based therapy. Furthermore, baseline levels of AA/DHA showed strong association with NAS and US improvement. A stable correction of DHA AA metabolism interaction is associated with the curative effect of this therapy and may represent a key nutritional endpoint in the clinical management of pediatric NASH.
LIM homeobox 2 promotes interaction between human iPS-derived hepatic progenitors and iPS-derived hepatic stellate-like cells
Authors: Miyoshi Masato , Kakinuma Sei , Kamiya Akihide , Tsunoda Tomoyuki , Tsuchiya Jun , Sato Ayako , Kaneko Shun , Nitta Sayuri , Kawai-Kitahata Fukiko , Murakawa Miyako , Itsui Yasuhiro , Nakagawa Mina , Azuma Seishin , Nakauchi Hiromitsu , Asahina Yasuhiro , Watanabe Mamoru
Published: February 2019

Human induced pluripotent stem (iPS) cells can differentiate into hepatocyte lineages, although the phenotype of the differentiated cells is immature compared to adult hepatocytes. Improvement of cell-cell interactions between epithelium and mesenchyme is a potential approach to address this phenotype issue. In this study, we developed a model system for improving interactions between human iPS-derived hepatic progenitor cells (iPS-HPCs) and human iPS-derived hepatic stellate cell-like cells (iPS-HSCs). The phenotype of iPS-HSCs, including gene and protein expression profiles and vitamin A storage, resembled that of hepatic stellate cells. Direct co-culture of iPS-HSCs with iPS-HPCs significantly improved hepatocytic maturation in iPS-HPCs, such as their capacity for albumin production. Next, we generated iPS cell lines overexpressing LIM homeobox 2 (LHX2), which suppresses myofibroblastic changes in HSCs in mice. Hepatocytic maturation in iPS-HPCs was significantly increased in direct co-culture with iPS-HSCs overexpressing LHX2, but not in co-culture with a human hepatic stellate cell line (LX-2) overexpressing LHX2. LHX2 regulated the expression of extracellular matrices, such as laminin and collagen, in iPS-HSCs. In conclusion, this study provides an evidence that LHX2 upregulation in iPS-HSCs promotes hepatocytic maturation of iPS-HPCs, and indicates that genetically modified iPS-HSCs will be of value for research into cell-cell interactions.
Enhanced anti-tumor activity of the Multi-Leu peptide PACE4 inhibitor transformed into an albumin-bound tumor-targeting prodrug
Authors: Kwiatkowska Anna , Couture Frédéric , Ait-Mohand Samia , Desjardins Roxane , Dory Yves L. , Guérin Brigitte , Day Robert
Published: February 2019

The proprotein convertase PACE4 has been validated as a potential target to develop new therapeutic interventions in prostate cancer (PCa). So far, the most effective compound blocking the activity of this enzyme has been designed based on the structure of a small peptide Ac-LLLLRVKR-NH2 known as the Multi-Leu (ML) peptide. Optimization of this scaffold led to the synthesis of compound C23 (Ac-[DLeu]LLLRVK-amidinobenzylamide) with a potent in vivo inhibitory effect on the tumor growth. However, further developments of PACE4 inhibitors may require additional improvements to counter their rapid renal clearance and to increase their tumor targeting efficiency. Herein, we explored the transformation of the ML-peptide into an albumin-binding prodrug containing a tumor specific release mechanism based on the prostate-specific antigen. Our data confirms that intravenous treatment using the ML-peptide alone has little effect on tumor growth, whereas by using the ML-prodrug in LNCaP xenograft-bearing mice it was significantly reduced. Additionally, excellent in vivo stability and tumor-targeting efficiency was demonstrated using a radiolabelled version of this compound. Taken together, these results provide a solid foundation for further development of targeted PACE4 inhibition in PCa.
Electroceutical Treatment of Pseudomonas aeruginosa Biofilms
Authors: Dusane Devendra H. , Lochab Varun , Jones Travis , Peters Casey W. , Sindeldecker Devin , Das Amitava , Roy Sashwati , Sen Chandan K. , Subramaniam Vish V. , Wozniak Daniel J. , Prakash Shaurya , Stoodley Paul
Published: February 2019

Electroceutical wound dressings, especially those involving current flow with silver based electrodes, show promise for treating biofilm infections. However, their mechanism of action is poorly understood. We have developed an in vitro agar based model using a bioluminescent strain of Pseudomonas aeruginosa to measure loss of activity and killing when direct current was applied. Silver electrodes were overlaid with agar and lawn biofilms grown for 24 h. A 6 V battery with 1 kΩ ballast resistor was used to treat the biofilms for 1 h or 24 h. Loss of bioluminescence and a 4-log reduction in viable cells was achieved over the anode. Scanning electron microscopy showed damaged cells and disrupted biofilm architecture. The antimicrobial activity continued to spread from the anode for at least 2 days, even after turning off the current. Based on possible electrochemical ractions of silver electrodes in chlorine containing medium; pH measurements of the medium post treatment; the time delay between initiation of treatment and observed bactericidal effects; and the presence of chlorotyrosine in the cell lysates, hypochlorous acid is hypothesized to be the chemical agent responsible for the observed (destruction/killing/eradication) of these biofilm forming bacteria. Similar killing was obtained with gels containing only bovine synovial fluid or human serum. These results suggest that our in vitro model could serve as a platform for fundamental studies to explore the effects of electrochemical treatment on biofilms, complementing clinical studies with electroceutical dressings.
A Surface Plasmon Resonance-based assay to measure serum concentrations of therapeutic antibodies and anti-drug antibodies
Authors: Beeg Marten , Nobili Alessandro , Orsini Barbara , Rogai Francesca , Gilardi Daniela , Fiorino Gionata , Danese Silvio , Salmona Mario , Garattini Silvio , Gobbi Marco
Published: February 2019

Therapeutic drug and immunogenicity monitoring (TDIM) is increasingly proposed to guide therapy with biologics, characterised by high inter-individual variability of their blood levels, to permit objective decisions for the management of non-responders and reduce unnecessary interventions with these expensive treatments. However, TDIM has not yet entered clinical practice partly because of uncertainties regarding the accuracy and precision of enzyme-linked immunosorbent assays (ELISA). Here we report the characterisation of a novel surface plasmon resonance (SPR)-based TDIM, applied to the measurement of serum concentrations of infliximab, an antibody against tumour necrosis factor α (anti-TNFα), and anti-infliximab antibodies. SPR has the obvious advantages of directly detecting and measuring serum antibodies in minutes, avoiding the long incubation/separation/washing/detection steps of the methods proposed so far, reducing complexity and variability. Moreover, drug and anti-drug antibodies can be measured simultaneously. This new method was validated for sensitivity and reproducibility, and showed cost-effectiveness over commercial ELISA kits. This method may be applied to other biotherapeutics. These data pave the way for the development of SPR-based point-of-care devices for rapid on-site analysis.
Asymmetric controlled bidirectional remote preparation of two- and three-qubit equatorial state
Authors: Sun Yi-Ru , Chen Xiu-Bo , Xu Gang , Yuan Kai-Guo , Yang Yi-Xian
Published: February 2019

In this paper, a novel asymmetric controlled bidirectional remote preparation scheme is proposed. In our scheme, Alice and Bob are not only the senders but also the receivers with the control of Charlie. By using the eleven-qubit entangled state as the quantum channel, Alice prepares an arbitrary two-qubit equatorial state for Bob and Bob prepares an arbitrary three-qubit equatorial state for Alice simultaneously. Firstly, we give the construction process of the quantum channel. Secondly, the whole recovery operations are given. Alice and Bob can recover the prepared state determinately. Thirdly, we consider the effect of the noisy environment (amplitude-damping and phase-damping) in our scheme and calculate the fidelities of the output states. Finally, since our scheme does not need additional operations and auxiliary qubits, the efficiency of our scheme is higher than that of the previous schemes.
Combining Multiple Magnetic Resonance Imaging Sequences Provides Independent Reproducible Radiomics Features
Authors: Lecler A. , Duron L. , Balvay D. , Savatovsky J. , Bergès O. , Zmuda M. , Farah E. , Galatoire O. , Bouchouicha A. , Fournier L. S.
Published: February 2019

To evaluate the relative contribution of different Magnetic Resonance Imaging (MRI) sequences for the extraction of radiomics features in a cohort of patients with lacrimal gland tumors. This prospective study was approved by the Institutional Review Board and signed informed consent was obtained from all participants. From December 2015 to April 2017, 37 patients with lacrimal gland lesions underwent MRI before surgery, including axial T1-WI, axial Diffusion-WI, coronal DIXON-T2-WI and coronal post-contrast DIXON-T1-WI. Two readers manually delineated both lacrimal glands to assess inter-observer reproducibility, and one reader performed two successive delineations to assess intra-observer reproducibility. Radiomics features were extracted using an in-house software to calculate 85 features per region-of-interest (510 features/patient). Reproducible features were defined as features presenting both an intra-class correlation coefficient ≥0.8 and a concordance correlation coefficient ≥0.9 across combinations of the three delineations. Among these features, the ones yielding redundant information were identified as clusters using hierarchical clustering based on the Spearman correlation coefficient. All the MR sequences provided reproducible radiomics features (range 14(16%)−37(44%)) and non-redundant clusters (range 5–14). The highest numbers of features and clusters were provided by the water and in-phase DIXON T2-WI and water and in-phase post-contrast DIXON T1-WI (37, 26, 26 and 26 features and 14,12, 9 and 11 clusters, respectively). A total of 145 reproducible features grouped into 51 independent clusters was provided by pooling all the MR sequences. All MRI sequences provided reproducible radiomics features yielding independent information which could potentially serve as biomarkers.
Multi Band Gap Electronic Structure in CH3NH3PbI3
Authors: Ong Khuong P. , Wu Shunnian , Nguyen Tien Hoa , Singh David J. , Fan Zhen , Sullivan Michael B. , Dang Cuong
Published: February 2019

Organo-lead halide perovskite solar cells represent a revolutionary shift in solar photovoltaics, introducing relatively soft defect containing semiconductors as materials with excellent charge collection for both electrons and holes. Although they are based on the nominally simple cubic perovskite structure, these compounds are in fact very complex. For example, in (CH3NH3)PbI3 the dynamics and ensuing structural fluctuations associated with the (CH3NH3)+ ions and the interplay with the electronic properties are still not fully understood, despite extensive study. Here, using ab-initio calculations, we show that at room and higher temperature, the rotation of CH3NH3 molecules can be viewed as effectively giving local structures that are cubic and tetragonal like from the point of view of the PbI3 framework, though in fact having lower symmetry. Both of these structures are locally polar, with sizable polarization, ~10 μC/cm2 due to the dipoles on the organic. They become energetically degenerate in the volume range, V ~ 250 Å3/f.u–265 Å3/f.u. We also find very significant dependence of the band gap on the local structure. This type of transition is analogous to a transition between two ferroelectric structures, where in-spite of strong electron phonon coupling, there is strong screening of charged defects which can lead to enhanced mobility and charge collection. The results provide insights into the enhanced light absorption near the band edge and good charge collection in this material.
PDGF-BB serum levels are decreased in adult onset Pompe patients
Authors: Fernández-Simón Esther , Carrasco-Rozas Ana , Gallardo Eduard , Figueroa-Bonaparte Sebastián , Belmonte Izaskun , Pedrosa Irene , Montiel Elena , Suárez-Calvet Xavier , Alonso-Pérez Jorge , Segovia Sonia , Nuñez-Peralta Claudia , Llauger Jaume , Mayos Mercedes , Illa Isabel ,   Spanish Pompe Study Group, Barba-Romero Miguel Angel , Barcena Joseba , Carzorla María Rosario , Creus Carlota , Coll-Cantí Jaume , de Luna Noemí , Díaz Manuel , Domínguez Cristina , Fernández-Torrón Roberto , García-Antelo María José , Grau Josep María , Gómez-Caravaca María Teresa , León-Hernández Juan Carlos , López de Munáin Adolfo , Martínez-García Francisco Antonio , Morgado Yolanda , Moreno Antonio , Morís Germán , Muñoz-Blanco Miguel Angel , Nascimento Andres , Paradas Carmen , Parajuá-Pozo José Luis , Querol Luis , Robledo-Strauss Arturo , Rojas-García Ricard , Rojas-Marcos Íñigo , Salazar Jose Antonio , Usón Mercedes , Díaz-Manera Jordi
Published: February 2019

Adult onset Pompe disease is a genetic disorder characterized by slowly progressive skeletal and respiratory muscle weakness. Symptomatic patients are treated with enzymatic replacement therapy with human recombinant alfa glucosidase. Motor functional tests and spirometry are commonly used to follow patients up. However, a serological biomarker that correlates with the progression of the disease could improve follow-up. We studied serum concentrations of TGFβ, PDGF-BB, PDGF-AA and CTGF growth factors in 37 adult onset Pompe patients and 45 controls. Moreover, all patients performed several muscle function tests, conventional spirometry, and quantitative muscle MRI using 3-point Dixon. We observed a statistically significant change in the serum concentration of each growth factor in patients compared to controls. However, only PDGF-BB levels were able to differentiate between asymptomatic and symptomatic patients, suggesting its potential role in the follow-up of asymptomatic patients. Moreover, our results point to a dysregulation of muscle regeneration as an additional pathomechanism of Pompe disease.
Detection of ‘Candidatus Phytoplasma solani’ in roots from Bois noir symptomatic and recovered grapevines
Authors: Landi Lucia , Murolo Sergio , Romanazzi Gianfranco
Published: February 2019

‘Candidatus Phytoplasma solani’ is the causal agent of Bois noir (BN) in grapevine (Vitis vinifera). It is usually detected in leaves, where typical disease symptoms are seen. However, little information is available on the presence of this phytoplasma in grapevine roots. Here, we investigated ‘Ca. P. solani’ in roots collected from 28 symptomatic, 27 recovered and eight asymptomatic grapevine plants. Protocols based on high-resolution melting (HRM) combined with real-time quantitative PCR (qPCR-HRM) and nested-qPCR-HRM were developed to identify ‘Ca. P. solani’ tuf-type variants with single nucleotide polymorphisms. In all, 21.4% of roots from symptomatic plants were positive to ‘Ca. P. solani’ using qPCR-HRM, and 60.7% with nested-qPCR HRM. Also, 7.4% of roots from recovered plants were positive using qPCR-HRM, which reached 44.4% using nested-qPCR HRM. These analyses identified tuf-type b1 on 88.2% of the positive samples from symptomatic grapevines, and 66.6% from recovered grapevines, with all other samples identified as tuf-type a. This study reports the presence of ‘Ca. P. solani’ in the roots of both symptomatic and recovered grapevines. These qPCR-HRM and nested-qPCR-HRM protocols can be applied to increase the sensitivity of detection of, and to simplify and speed up the screening for, ‘Ca. P. solani’ tuf-types.