bluuebunny/crossref_metadata_2025 huggingface dataset:
Serum Selenium, Iron, Zinc, and Copper Concentrations in Renal Transplant Recipients Treated with Mycophenolate Mofetil
Authors: Wilk Aleksandra , Szypulska-Koziarska Dagmara , Marchelek-Myśliwiec Małgorzata , Głazek Wojciech , Wiszniewska Barbara
Published: February 2020

There are data available in the literature on bioelement concentrations in the serum of various groups of patients; however, very little is known about the serum concentration of selenium (Se), iron (Fe), zinc (Zn), and copper (Cu) in renal transplant patients treated with immunosuppressive drugs, including mycophenolate mofetil (MMF). Monitoring of serum bioelement concentrations in renal transplant recipients is of profound importance, as the proper bioelement levels seem to prolong the normal function of the transplanted organ. Thus, the aim of this current study was to examine and carry out comparative analysis involving serum concentrations of Se, Fe, Cu, and Zn of renal transplant recipients treated with MMF and without MMF. The material consisted of blood samples from 115 patients of the Department of Nephrology, Transplantology, and Internal Medicine of Independent Public Clinical Hospital No. 2, Pomeranian Medical University, in the city of Szczecin in the northwestern Poland. Serum Se, Fe, Cu, and Zn levels were quantified by inductively coupled mass spectroscopy (ICP-MS). Taking into account all patients, MMF increases Cu level. Cu and Fe concentrations were significantly higher in women treated with MMF; in group of younger patients treated with MMF, Se level was significantly lower comparing with those whose regimen did not include MMF. Additionally, MMF in combination with prednisone increased Se concentration in blood of transplant recipients. Our study highlights that trace elements should be monitored to allow for an early detection of trace elements deficits, which can easily be corrected for by an adjusted diet or supplemental intake.
Praktiken des Beschreibens – Zu Funktionen der Sprache bei der Erarbeitung des Teilschrittverfahrens im Zahlenraum bis 100
Authors: Tiedemann Kerstin
Published: February 2020

Die Sprache ist im Zusammenhang des Mathematiklernens nicht erst in Leistungs-, sondern ganz wesentlich schon für die soziale Verständigung und die individuelle Bedeutungskonstruktion in Lernsituationen von Bedeutung. Im vorliegenden Beitrag werden Ergebnisse aus einer qualitativ-interpretativen Studie zum mündlichen Beschreiben von Materialhandlungen vorgestellt. Die zugrunde liegenden Daten stammen aus universitären Fördersituationen mit rechenschwachen Kindern, in denen anhand von Handlungen am Hunderter-Rechenrahmen die Strategie des Teilschrittverfahrens für den Aufgabentyp ZE ±E im Zahlenraum bis 100 zielgerichtet erarbeitet wird. Dabei werden die Kinder aufgefordert, ihr Materialhandeln zu beschreiben. Als Ergebnis der Studie zeigt sich, dass es dabeidasBeschreiben gar nicht gibt. Vielmehr konnten drei Praktiken des Beschreibens unterschieden werden, die in der interaktionalen Erarbeitung des Teilschrittverfahrens unterschiedliche Funktionen erfüllen und im vorliegenden Beitrag anhand von Analysebeispielen vorgestellt werden: In den Fördersituationen wird mit Beschreibungen die Materialhandlung gesteuert und zielgerichtet ausgestaltet, das Charakteristische des Teilschrittverfahrens fokussiert und schließlich das Beschreiben selbst verdichtet.
A deep learning-based model for defect detection in laser-powder bed fusion using in-situ thermographic monitoring
Authors: Baumgartl Hermann , Tomas Josef , Buettner Ricardo , Merkel Markus
Published: February 2020

Additive manufacturing of metal components with laser-powder bed fusion is a very complex process, since powder has to be melted and cooled in each layer to produce a part. Many parameters influence the printing process; however, defects resulting from suboptimal parameter settings are usually detected after the process. To detect these defects during the printing, different process monitoring techniques such as melt pool monitoring or off-axis infrared monitoring have been proposed. In this work, we used a combination of thermographic off-axis imaging as data source and deep learning-based neural network architectures, to detect printing defects. For the network training, a k-fold cross validation and a hold-out cross validation were used. With these techniques, defects such as delamination and splatter can be recognized with an accuracy of 96.80%. In addition, the model was evaluated with computing class activation heatmaps. The architecture is very small and has low computing costs, which means that it is suitable to operate in real time even on less powerful hardware.
Increasing Parental Leave Uptake: A Systems Social Marketing Approach
Authors: Duffy Sarah , Van Esch Patrick , Yousef Murooj
Published: February 2020

Ineffective paid paternity leave policies perpetuate gender inequality and have significant, long-lasting outcomes for families, organisations, and the economy. They maintain unequal divisions in child-rearing and household chores that restrict families’ decisions about workforce participation and caring responsibilities. Low levels of uptake of paternity leave are caused by workplace practices, social norms, and economic factors that influence the choices fathers make when their children are born, and which become entrenched over time. Fathers’ early involvement in children's lives is profoundly beneficial for families, therefore, we recommend to policy makers and organisations how they can change internal workplace cultures to allow for a more inclusive image of parenting and a more nuanced image of the ideal male worker. We outline a systems social marketing approach that addresses change at the macro, meso and micro levels through the three E's model (establish, explore, and enable), to help policy makers, organisations, and families consider the implications of meaningful parental leave and the importance of increasing fathers’ uptake. Future research questions for increasing parental leave uptake are presented.
How cyber insurance can still leave you vulnerable to risks
Authors: Stephens Sarah
Published: February 2020

Welcome to the 2020s, where every sector and company, regardless of size, is heavily reliant on technology to facilitate its operations, communication and dealings with its supply chain. In this digital climate, cyber attacks pose an increasingly significant business risk, which has resulted in cyber security steadily climbing up the C-suite's priorities agenda.

Companies are still struggling to grasp the extent of their cyber risk exposure, and this creates an unnecessary roadblock for every organisation that could benefit from cyber risk transfer.

It would be reasonable to assume that companies are shifting their risk perception from the physical to the digital and in turn adjusting the way they insure against risk. However, firms remain chronically underinsured against cyber risk. Senior management and board-level leadership must embrace cyber risk as an issue so the conversation can be driven top down and bottom up, says Sarah Stephens of Marsh JLT Specialty.
Materially Identical to Mistaken Payment
Authors: Cutts Tatiana
Published: February 2020

Mistaken payment is the ‘core case’ of unjust enrichment, and it has had a powerful effect on the development of this area of private law. For Peter Birks, unjust enrichment was simply ‘the law of all events materially identical to mistaken payment’—to be shaped through a process of abstraction from that core case. But this begs the question: how do we work out what counts as ‘materially identical’ to mistaken payment? The most obvious starting point, and that which Birks chose, is the central characteristic of money: money is valuable. Thus, ‘the law of all events materially identical to mistaken payments’ is ‘the law of all events that unjustly enrich one party at another’s expense’.

In this article, I argue that this starting point is incorrect. Rather than looking for some factual similarity between mistaken payment and other events, we should identify the role that money plays in justifying restitution. And what justifies restitution in the core case is not the ‘value’ or ‘benefit’ that money confers; rather, it is a defect in the legal transaction that links payor with payee. The payee is not liable because she has been ‘enriched’, but because she is the counterparty to a legal transaction which exhibits traits that there are institutional reasons to disavow. Just like contract and torts, the role of value is secondary: where correcting the injustice in specie is impossible or undesirable, the defendant must pay whichever sum will most nearly achieve that goal.
Hobbes’s Third Jurisprudence: Legal Pragmatism and the Dualist Menace
Authors: Nelson B.L.S.
Published: February 2020

This paper explores the possibility that Hobbesian jurisprudence is best understood as a “third way”? in legal theory, irreducible to classical natural law or legal positivism. I sketch two potential “third theories”? of law—legal pragmatism and legal dualism—and argue that, when considered in its broadest sense, Leviathan is best viewed as an example of legal pragmatism. I consider whether this legal pragmatist interpretation can be sustained in the examination of Leviathan’s treatment of civil law, and argue that the pragmatic interpretation can only be successful if we can resolve two textual issues in that chapter. First, while Hobbes argues that law entails the existence of public (sharable) reasons, he does not adequately defend the view that the sovereign is the unique authority over such reasons in all cases, especially as far as they concern known collective emergencies. Second, Hobbes both affirms and denies that a sovereign can fail to do justice, which is paradoxical. Both problems are best resolved by legal pragmatism, though the second problem resists a fully satisfying resolution. The upshot is that, although Leviathan ought to be regarded as an episode of legal pragmatism, there are trade-offs on every reading.
Entropy of general diffeomorphisms on line
Authors: HE BAOLIN
Published: February 2020

We study the continuity of topological entropy of general diffeomorphisms on line. First, we prove that the entropy map is continuous with respect to the strong $C^{0}$-topology on the union of uniformly topologically hyperbolic diffeomorphisms contained in $\text{Diff}_{0}^{r}(\mathbb{R})$ (whose first derivative is uniformly away from zero), which is a $C^{0}$-open and $C^{r}$-dense subset of $\text{Diff}_{0}^{r}(\mathbb{R})$, $r=1,2,\ldots ,\infty$, and $\unicode[STIX]{x1D714}$ (real analytic). Second, we give some examples where entropy map is not continuous. Finally, we prove some results on the continuity of entropy of general diffeomorphisms on the (real) line.
Geothermal play typing in Germany, case study Molasse Basin: a modern concept to categorise geothermal resources related to crustal permeability
Authors: Moeck Inga S. , Dussel Michael , Weber Josef , Schintgen Tom , Wolfgramm Markus
Published: February 2020

The majority of running geothermal plants worldwide are located in geological settings with convection- or advection-dominant heat transport. In Germany as in most regions in Europe, conduction is the dominating heat transport mechanism, with a resulting average geothermal gradient. The geothermal play type concept is a modern methodology to group geothermal resources according to their geological setting, and characteristic heat transport mechanisms. In particular, the quantity of heat transport is related to fluid flow in natural or engineered geothermal reservoirs. Hence, the permeability structure is a key element for geothermal play typing. Following the existing geothermal play type catalogue, four major geothermal play types can be identified for Germany: intracratonic basins, foreland basins and basement/crystalline rock provinces as conduction-dominated play types, and extensional terrains as the convection-dominated play type. The installed capacity of geothermal facilities sums up to 397.1 MWthby the end of 2018. District heating plants accounted for the largest portion, with about 337.0 MWth. The majority of these installations are located in the play type ‘foreland basin’, namely the Molasse Basin in southern Germany. The stratigraphic unit for geothermal use is the Upper Jurassic, also known as ‘Malm’ formation, a carbonate reservoir with high variability in porosity and permeability. Recently drilled wells in the southernmost Molasse Basin indicate the Upper Jurassic as a tight, fracture-controlled reservoir, not usable for conventional hydrothermal well doublets. Our new data compilation including the recently drilled deep geothermal well Geretsried reveals the relation of porosity and permeability to depth. The results suggest that obviously diagenetic processes control permeability with depth in carbonate rock, diminishing the predictability of reservoir porosity and permeability. The play type concept helps to delineate these property variations in play type levels because it is based on geological constraints, common for exploration geology. Following the general idea of play typing, the results from this play analysis can be transferred to geological analogues as carbonate rock play levels in varying depth.
Managing Ethno-National Diversity in Cyprus: Asymmetrical Federalism
Authors: Umaner-Duba Gülay
Published: February 2020

This article explains a normative political theory of asymmetrical federalism as it relates to the accommodation of national minorities within multinational states, using Cyprus as a case study. Many normative prescriptions emerging from traditional liberal and federal political theories and models rest on monist assumptions; therefore, there is a need to highlight the cultural and national limits of those theories and models in order to attain a democratic system in Cyprus that respects and promotes its bicommunal structure. It is suggested that multinational federalism in Cyprus necessitates constitutional asymmetry, which is likely to provide a basis for political accommodation. The article also demonstrates the necessity of multinational federalism to accommodate common and distinct identities by promoting a fuller understanding of the concept of “federal togetherness” and “federal separateness.” Such an understanding would better enable asymmetrical federalism to properly and feasibly adjust and regulate federal institutions in Cyprus.
What factors influence phonological production in French-speaking bilingual children, aged three to six years?
Authors: KEHOE Margaret , GIRARDIER Chloé
Published: February 2020

This study examines the influence of bilingual status, language-internal (complexity of L1 phonology), language-external (dominance), and lexical (L2 vocabulary score) factors on phonological production in French-speaking monolingual (n = 37) and bilingual children (n = 64) aged three to six years. Children participated in an object and picture naming task which tested different phonological features. The bilinguals’ first languages were coded in terms of the complexity of these phonological features. In addition, the parents completed a questionnaire on their child's language dominance and the children were administered a vocabulary test in their L2. Results indicated that vocabulary was the principal predictor of phonological accuracy across both age groups. Apparent monolingual–bilingual differences and dominance effects could largely be explained by vocabulary scores: children who scored better on a vocabulary test obtained superior phonological accuracy. Language-internal effects were minimal and marginally influenced vowel accuracy only.
Analysis of non-reversible Markov chains via similarity orbits
Authors: Choi Michael C. H. , Patie Pierre
Published: February 2020

In this paper we develop an in-depth analysis of non-reversible Markov chains on denumerable state space from a similarity orbit perspective. In particular, we study the class of Markov chains whose transition kernel is in the similarity orbit of a normal transition kernel, such as that of birth–death chains or reversible Markov chains. We start by identifying a set of sufficient conditions for a Markov chain to belong to the similarity orbit of a birth–death chain. As by-products, we obtain a spectral representation in terms of non-self-adjoint resolutions of identity in the sense of Dunford [21] and offer a detailed analysis on the convergence rate, separation cutoff and L2-cutoff of this class of non-reversible Markov chains. We also look into the problem of estimating the integral functionals from discrete observations for this class. In the last part of this paper we investigate a particular similarity orbit of reversible Markov kernels, which we call the pure birth orbit, and analyse various possibly non-reversible variants of classical birth–death processes in this orbit.
Learning to rank for multi-label text classification: Combining different sources of information
Authors: Azarbonyad Hosein , Dehghani Mostafa , Marx Maarten , Kamps Jaap
Published: February 2020

Efficiently exploiting all sources of information such as labeled instances, classes’ representation, and relations of them has a high impact on the performance of Multi-Label Text Classification (MLTC) systems. Most of the current approaches use labeled documents as the primary source of information for MLTC. We investigate the effectiveness of different sources of information— such as the labeled training data, textual labels of classes, and taxonomy relations of classes— for MLTC. More specifically, first, for each document–class pair, different features are extracted using different sources of information. The features reflect the similarity of classes and documents. Then, MLTC is considered to be a ranking problem, and a learning to rank (LTR) approach is used for ranking classes regarding documents and selecting labels of documents. An important characteristic of many MLTC instances is that documents can belong to multiple classes and there are implicit relations between classes. We apply score propagation on top of LTR to incorporate co-occurrence patterns of classes in labeled documents. Our main findings are the following. First, using an LTR approach integrating all features, we observe significantly better performance than previous systems for MLTC. Specifically, we show that simple classification approaches fail when there is a high number of classes. Second, the analysis of feature weights reveals the relative importance of various sources of evidence, also giving insight into the underlying classification problem. Interestingly, the results indicate that the titles of documents are more informative than all other sources of information. Third, a lean-and-mean system using only four features is able to perform at 96% of the large LTR model that we propose in this paper. Fourth, using the co-occurrence information of classes helps in classifying documents more accurately. Our results show that the co-occurrence information is more helpful when the underlying classifier has a poor performance.
Generalizability and comparability of prevalence estimates in the wild bird literature: methodological and epidemiological considerations
Authors: Vogt Nadine A. , Stevens Christian P.G. , Pearl David L. , Taboada Eduardo N. , Jardine Claire M.
Published: February 2020

Wild birds have been the focus of a great deal of research investigating the epidemiology of zoonotic bacteria and antimicrobial resistance in the environment. While enteric pathogens (e.g.Campylobacter, Salmonella,andE. coliO157:H7) and antimicrobial resistant bacteria of public health importance have been isolated from a wide variety of wild bird species, there is a considerable variation in the measured prevalence of a given microorganism from different studies. This variation may often reflect differences in certain ecological and biological factors such as feeding habits and immune status. Variation in prevalence estimates may also reflect differences in sample collection and processing methods, along with a host of epidemiological inputs related to overall study design. Because the generalizability and comparability of prevalence estimates in the wild bird literature are constrained by their methodological and epidemiological underpinnings, understanding them is crucial to the accurate interpretation of prevalence estimates. The main purpose of this review is to examine methodological and epidemiological inputs to prevalence estimates in the wild bird literature that have a major bearing on their generalizability and comparability. The inputs examined here include sample type, microbiological methods, study design, bias, sample size, definitions of prevalence outcomes and parameters, and control of clustering. The issues raised in this review suggest, among other things, that future prevalence studies of wild birds should avoid opportunistic sampling when possible, as this places significant limitations on the generalizability of prevalence data.
Riverine Flooding and Landfalling Tropical Cyclones Over China
Authors: Yang Long , Villarini Gabriele , Zeng Zhenzhong , Smith James , Liu Maofeng , Li Xiang , Wang Lachun , Hou Aizhong
Published: February 2020

Riverine flooding associated with landfalling tropical cyclones (TCs) in the western North Pacific basin is responsible for some of the most severe socioeconomic losses in East Asian countries. However, little is known about the spatial and temporal patterns of TC flooding and its climate controls, which constrain the predictive understandings of flood risk in this highly populated region. We provide a climatological characterization of TC flooding over China based on an exceptional network of stream gauging stations across the entire country. The most extreme floods in central and northeastern China are associated with TCs despite infrequent TC visits in these regions. Temporal variations in TC flooding demonstrate a mixture of controls tied to surface temperature anomalies in the northern hemisphere. The established links between TC flooding and climate controls present a potentially predictive tool of TC flood risk over China and other East Asian countries under future climate conditions.
Relationships Between Chlorophyll‐a and Suspended Sediment Concentration in a High‐Nutrient Load Estuary: An Observational and Idealized Modeling Approach
Authors: Díez‐Minguito Manuel , de Swart Huib E.
Published: February 2020

The Guadalquivir estuary is a high‐nutrient load environment, yet it has a reduced primary production because the high suspended sediment concentration (SSC) causes light attenuation. High‐resolution observations revealed relationships between the SSC and Chlorophyll‐a (Chla) concentration from seasonal to intratidal time scales. Local maxima of time‐averaged Chla levels occurred at locations with relatively low SSC. In the upper (lower) part of the estuary, larger Chla concentrations were observed during the wet (dry) season. In contrast to longer time scales, SSC and Chla exhibited in‐phase oscillations during the spring‐neap cycle. Both SSC and Chla were found to peak at maximum ebb and flood. There was no positive correlation at certain apogean neap tides, and instead, Chla exhibited daily variations. An idealized model was developed, which mimicked and helped to explain SSC‐Chla relationships at different time scales. The model accounts for the vertical advection of Chla and SSC, tidal resuspension, radiation‐mediated growth, and effects of the change in stratification stemming from tides and SSC. The specific growth rate of the Chla biomass is inhibited due to high SSC throughout the year. The in‐phase relationship at spring‐neap and tidal scales seems to be due to resuspension of algal microorganisms attached to sediments. Daily variability of Chla during apogean neap tides emerges because tidal shear stress is low and the strong decline in the suspended particulate matter reduces the light attenuation. The light‐mediated growth of part of the biomass, still remaining in the upper layers of the water column, is then driven by the day‐night cycle.
Chromatin remodeling protein HELLS is critical for retinoblastoma tumor initiation and progression
Authors: Zocchi Loredana , Mehta Aditi , Wu Stephanie C. , Wu Jie , Gu Yijun , Wang Jingtian , Suh Susie , Spitale Robert C. , Benavente Claudia A.
Published: February 2020

Retinoblastoma is an aggressive childhood cancer of the developing retina that initiates by biallelic RB1 gene inactivation. Tumor progression in retinoblastoma is driven by epigenetics, as retinoblastoma genomes are stable, but the mechanism(s) that drive these epigenetic changes remain unknown. Lymphoid-specific helicase (HELLS) protein is an epigenetic modifier directly regulated by the RB/E2F pathway. In this study, we used novel genetically engineered mouse models to investigate the role of HELLS during retinal development and tumorigenesis. Our results indicate that Hells-null retinal progenitor cells divide, undergo cell-fate specification, and give rise to fully laminated retinae with minor bipolar cells defects, but normal retinal function. Despite the apparent nonessential role of HELLS in retinal development, failure to transcriptionally repress Hells during retinal terminal differentiation due to retinoblastoma (RB) family loss significantly contributes to retinal tumorigenesis. Loss of HELLS drastically reduced ectopic division of differentiating cells in Rb1/p107-null retinae, significantly decreased the incidence of retinoblastoma, delayed tumor progression, and increased overall survival. Despite its role in heterochromatin formation, we found no evidence that Hells loss directly affected chromatin accessibility in the retina but functioned as transcriptional co-activator of E2F3, decreasing expression of cell cycle genes. We propose that HELLS is a critical downstream mediator of E2F-dependent ectopic proliferation in RB-null retinae. Together with the nontoxic effect of HELLS loss in the developing retina, our results suggest that HELLS and its downstream pathways could serve as potential therapeutic targets for retinoblastoma.
Bruceine D induces lung cancer cell apoptosis and autophagy via the ROS/MAPK signaling pathway in vitro and in vivo
Authors: Fan Jiangjiang , Ren Dongmei , Wang Jinxia , Liu Xiaoqing , Zhang Huaran , Wu Mingsheng , Yang Guotao
Published: February 2020

Worldwide, lung cancer remains a leading cause of cancer mortality. Bruceine D (BD) has been shown to induce pancreatic cancer cell death via several different mechanisms. In this study, we demonstrated that BD inhibited lung cancer cell proliferation. Apoptosis and autophagy were the most important mechanisms involved in BD-induced lung cancer cell death, and complete autophagic flux was observed in A549 and NCI-H292 cells. In addition, BD significantly improved intracellular reactive oxygen species (ROS) levels. BD-mediated cell apoptosis and autophagy were almost inhibited in cells pretreated with N-acetylcysteine (NAC), an ROS scavenger. Furthermore, MAPK signaling pathway activation contributed to BD-induced cell proliferation inhibition and NAC could eliminate p-ERK and p-JNK upregulation. Finally, an in vivo study indicated that BD inhibited the growth of lung cancer xenografts. Overall, BD is a promising candidate for the treatment of lung cancer owing to its multiple mechanisms and low toxicity.
A novel STAT3 inhibitor attenuates angiotensin II-induced abdominal aortic aneurysm progression in mice through modulating vascular inflammation and autophagy
Authors: Wu Qi-ying , Cheng Zhao , Zhou Yang-zhao , Zhao Yuan , Li Jian-ming , Zhou Xin-min , Peng Hong-ling , Zhang Guang-sheng , Liao Xiao-bo , Fu Xian-ming
Published: February 2020

Abdominal Aortic aneurysm (AAA) is associated with chronic inflammation, cells apoptosis, and impairment of autophagy. BP-1-102, a novel potent STAT3 inhibitor, has been recently reported to significantly block inflammation-related signaling pathways of JAK2/STAT3 and NF-κB, as well as regulate autophagy. However, its role in vascular inflammation and AAA progression remains to be elucidated. In the present study, the effect and potential mechanisms of BP-1-102 on angiotensin II (AngII) induced AAA in ApoE−/− mice were investigated. AAA was induced in ApoE−/− mice with infusion of AngII for 28 days. BP-1-102 was administrated orally to mice every other day. Mice were sacrificed on day 7, day 14, and day 28 to evaluate the treatment effects. BP-1-102 markedly decreased AAA incidence and aortic diameter, maintained elastin structure and volume, reduced the expression of pro-inflammatory cytokines and MMPs, and inhibited inflammatory cells infiltration. Moreover, BP-1-102 dramatically reduced the expression of JAK2, p-STAT3, p-NF-κB, and Bcl-xL but maintained the expression of LC3B and Beclin in AAA tissues. In vitro, vascular smooth muscle cells (VSMCs) were treated with AngII and/or BP-1-102 at indicated time and concentration. BP-1-102 inhibited AngII-induced JAK2/STAT3 and NF-κB signaling activation and maintained autophagy-related proteins expression in VSMCs. Taken together, our findings suggest that BP-1-102 inhibits vascular inflammation and AAA progression through decreasing JAK2/STAT3 and NF-κB activation and maintaining autophagy.
Delivery of phosphatidylethanolamine blunts stress in hepatoma cells exposed to elevated palmitate by targeting the endoplasmic reticulum
Authors: Trentzsch Marcus , Nyamugenda Eugene , Miles Tiffany K. , Griffin Haven , Russell Susan , Koss Brian , Cooney Kimberly A. , Phelan Kevin D. , Tackett Alan J. , Iyer Srividhya , Boysen Gunnar , Baldini Giulia
Published: February 2020

Genetic obesity increases in liver phosphatidylcholine (PC)/phosphatidylethanolamine (PE) ratio, inducing endoplasmic reticulum (ER) stress without concomitant increase of ER chaperones. Here, it is found that exposing mice to a palm oil-based high fat (HF) diet induced obesity, loss of liver PE, and loss of the ER chaperone Grp78/BiP in pericentral hepatocytes. In Hepa1–6 cells treated with elevated concentration of palmitate to model lipid stress, Grp78/BiP mRNA was increased, indicating onset of stress-induced Unfolded Protein Response (UPR), but Grp78/BiP protein abundance was nevertheless decreased. Exposure to elevated palmitate also induced in hepatoma cells decreased membrane glycosylation, nuclear translocation of pro-apoptotic C/EBP-homologous-protein-10 (CHOP), expansion of ER-derived quality control compartment (ERQC), loss of mitochondrial membrane potential (MMP), and decreased oxidative phosphorylation. When PE was delivered to Hepa1–6 cells exposed to elevated palmitate, effects by elevated palmitate to decrease Grp78/BiP protein abundance and suppress membrane glycosylation were blunted. Delivery of PE to Hepa1–6 cells treated with elevated palmitate also blunted expansion of ERQC, decreased nuclear translocation of CHOP and lowered abundance of reactive oxygen species (ROS). Instead, delivery of the chemical chaperone 4-phenyl-butyrate (PBA) to Hepa1–6 cells treated with elevated palmitate, while increasing abundance of Grp78/BiP protein and restoring membrane glycosylation, also increased ERQC, expression and nuclear translocation of CHOP, non-mitochondrial oxygen consumption, and generation of ROS. Data indicate that delivery of PE to hepatoma cells under lipid stress recovers cell function by targeting the secretory pathway and by blunting pro-apoptotic branches of the UPR.
Simulation-based reconstruction of global bird migration over the past 50,000 years
Authors: Somveille Marius , Wikelski Martin , Beyer Robert M. , Rodrigues Ana S. L. , Manica Andrea , Jetz Walter
Published: February 2020

Migration is a widespread response of birds to seasonally varying climates. As seasonality is particularly pronounced during interglacial periods, this raises the question of the significance of bird migration during past periods with different patterns of seasonality. Here, we apply a mechanistic model to climate reconstructions to simulate the past 50,000 years of bird migration worldwide, a period encompassing the transition between the last glacial period and the current interglacial. Our results indicate that bird migration was also a prevalent phenomenon during the last ice age, almost as much as today, suggesting that it has been continually important throughout the glacial cycles of recent Earth history. We find however regional variations, with increasing migratory activity in the Americas, which is not mirrored in the Old World. These results highlight the strong flexibility of the global bird migration system and offer a baseline in the context of on-going anthropogenic climate change.
Heterogeneity of response to immune checkpoint blockade in hypermutated experimental gliomas
Authors: Aslan Katrin , Turco Verena , Blobner Jens , Sonner Jana K. , Liuzzi Anna Rita , Núñez Nicolás Gonzalo , De Feo Donatella , Kickingereder Philipp , Fischer Manuel , Green Ed , Sadik Ahmed , Friedrich Mirco , Sanghvi Khwab , Kilian Michael , Cichon Frederik , Wolf Lara , Jähne Kristine , von Landenberg Anna , Bunse Lukas , Sahm Felix , Schrimpf Daniel , Meyer Jochen , Alexander Allen , Brugnara Gianluca , Röth Ralph , Pfleiderer Kira , Niesler Beate , von Deimling Andreas , Opitz Christiane , Breckwoldt Michael O. , Heiland Sabine , Bendszus Martin , Wick Wolfgang , Becher Burkhard , Platten Michael
Published: February 2020

Intrinsic malignant brain tumors, such as glioblastomas are frequently resistant to immune checkpoint blockade (ICB) with few hypermutated glioblastomas showing response. Modeling patient-individual resistance is challenging due to the lack of predictive biomarkers and limited accessibility of tissue for serial biopsies. Here, we investigate resistance mechanisms to anti-PD-1 and anti-CTLA-4 therapy in syngeneic hypermutated experimental gliomas and show a clear dichotomy and acquired immune heterogeneity in ICB-responder and non-responder tumors. We made use of this dichotomy to establish a radiomic signature predicting tumor regression after pseudoprogression induced by ICB therapy based on serial magnetic resonance imaging. We provide evidence that macrophage-driven ICB resistance is established by CD4 T cell suppression and Treg expansion in the tumor microenvironment via the PD-L1/PD-1/CD80 axis. These findings uncover an unexpected heterogeneity of response to ICB in strictly syngeneic tumors and provide a rationale for targeting PD-L1-expressing tumor-associated macrophages to overcome resistance to ICB.
Light control of surface–bulk coupling by terahertz vibrational coherence in a topological insulator
Authors: Yang Xu , Luo Liang , Vaswani Chirag , Zhao Xin , Yao Yongxin , Cheng Di , Liu Zhaoyu , Kim Richard H. J. , Liu Xinyu , Dobrowolska-Furdyna Malgorzata , Furdyna Jacek K. , Perakis Ilias E. , Wang Caizhuang , Ho Kaiming , Wang Jigang
Published: February 2020

The demand for disorder-tolerant quantum logic and spin electronics can be met by generating and controlling dissipationless spin currents protected by topology. Dirac fermions with helical spin-locking surface transport offer a way of achieving such a goal. Yet, surface-bulk coupling can lead to strong Dirac electron scattering with bulk carriers and phonons as well as impurities, assisted by such dissipative channel, which results in “topological breakdown”. Here, we demonstrate that coherent lattice vibrations periodically driven by a single-cycle terahertz (THz) pulse can significantly suppress such dissipative channel in topological insulators. This is achieved by reducing the phase space in the bulk available for Dirac fermion scattering into during coherent lattice oscillations in Bi2Se3. This light-induced suppression manifests as a remarkable transition exclusively in surface transport, absent for bulk, above the THz electric fields for driving coherent phonons, which prolongs the surface transport lifetime. These results, together with simulations, identify the critical role of spin–orbit coupling for the “phase space contraction” mechanism that suppresses the surface-bulk coupling. Imposing vibrational quantum coherence into topological states of matter may become a universal light control principle for reinforcing the symmetry-protected helical transport.
Experiments Investigating the Competitive Growth Advantage of Two Different Genotypes of Human Metapneumovirus: Implications for the Alternation of Genotype Prevalence
Authors: Zhou Zhen , Zhang Pan , Cui Yuxia , Zhang Yongbo , Qin Xian , Li Rongpei , Liu Ping , Dou Ying , Wang Lijia , Zhao Yao
Published: February 2020

Human metapneumovirus (hMPV) is an important pathogen that causes upper and lower respiratory tract infections in children worldwide. hMPV has two major genotypes, hMPV-A and hMPV-B. Epidemiological studies have shown that the two hMPV genotypes alternate in predominance worldwide in recent years. Co-circulation of the two genotypes of hMPV was usually observed and there is no study about the interaction between them, such as competitive replication, which maybe the possible mechanisms for alternating prevalence of subtypes. Our present study have used two different genotypes of hMPV (genotype A: NL/1/00; B: NL/1/99) in different proportions in animal model (BALB/c mice) and cell model (Vero-E6) separately. The result showed that the competitive growth does exist in BALB/c mice, genotype B had a strong competitive advantage. However, genotype B did not cause more severe disease than non-predominant (genotype A) or mixed strains in the study, which were evaluated by the body weight, airway hyperresponsiveness and lung pathology of mouse. In cell model, competitive growth and the two genotypes alternately prevalence were observed. In summary, we confirmed that there was a competitive replication between hMPV genotype A and B, and no difference in disease severity caused by the two subtypes. This study shows a new insight to understand the alternation of hMPV genotype prevalence through genotype competition and provide experimental evidence for disease control and vaccine design.
Species-specific genetic variation in response to deep-sea environmental variation amongst Vulnerable Marine Ecosystem indicator taxa
Authors: Zeng Cong , Rowden Ashley A. , Clark Malcolm R. , Gardner Jonathan P. A.
Published: February 2020

Understanding the ecological processes that shape spatial genetic patterns of population structure is critical for understanding evolutionary dynamics and defining significant evolutionary and management units in the deep sea. Here, the role of environmental factors (topographic, physico-chemical and biological) in shaping the population genetic structure of four deep-sea habitat-forming species (one sponge - Poecillastra laminaris, three corals - Goniocorella dumosa, Madrepora oculata, Solenosmilia variabilis) was investigated using seascape genetics. Genetic data (nuclear and mitochondrial sequences and microsatellite multilocus genotypes) and environmental variables were employed to build individual-based and population-level models. The results indicated that environmental factors affected genetic variation differently amongst the species, as well as at different geographic scales. For individual-based analyses, different environmental variables explained genetic variation in P. laminaris (dissolved oxygen), G. dumosa (dynamic topography), M. oculata (sea surface temperature and surface water primary productivity), and S. variabilis (tidal current speed). At the population level, factors related to current and food source explained the regional genetic structure in all four species, whilst at the geomorphic features level, factors related to food source and topography were most important. Environmental variation in these parameters may be acting as barriers to gene flow at different scales. This study highlights the utility of seascape genetic studies to better understand the processes shaping the genetic structure of organisms, and to identify environmental factors that can be used to locate sites for the protection of deep-sea Vulnerable Marine Ecosystems.
MiR-4435 is an UQCRB-related circulating miRNA in human colorectal cancer
Authors: Hong Ji Won , Kim Jung Min , Kim Jeong Eun , Cho Hee , Kim Dasol , Kim Wankyu , Oh Jong-Won , Kwon Ho Jeong
Published: February 2020

Ubiquinol-cytochrome c reductase (UQCRB), a subunit of the mitochondrial complex III, is highly expressed in tissues from colorectal cancer patients. Since UQCRB is highly expressed in colorectal cancer, we investigated miRNAs from mutant UQCRB-expressing cell lines to identify new miRNA biomarkers. After sequencing miRNAs in the mutant UQCRB-expressing cell lines, miR-4435 was selected as a potential biomarker candidate from the six up-regulated miRNAs. The expression level of miR-4435 in the mutant UQCRB-expressing cell lines and colon cancer was increased. Notably, the expression level of miR-4435 was increased in exosomes isolated from cell culture medium, suggesting that miR-4435 is closely related to colon cancer and that large amounts of miR-4435 may be secreted outside of the cells through exosomes. Additionally, exosomes extracted from the serum samples of colorectal cancer patients showed increased miR-4435 levels depending on the cancer progression stage. Moreover, analyses of a miRNA database and mRNA-sequencing data of the mutant UQCRB-expressing cell lines revealed that TIMP3, a tumor suppressor, could be a target of miR-4435. Additionally, the expression of miR-4435 was suppressed by UQCRB inhibitor treatment whereas TIMP3 was up-regulated. Upregulation of TIMP3 decreased proliferation of the mutant UQCRB-expressing cell lines and a colorectal cancer cell line. TIMP3 was also upregulated in response to miR-4435 inhibitor and UQCRB inhibitor treatments. Furthermore, these findings suggest that miR-4435 is related to an oncogenic function in UQCRB related disease, CRC, and that effects migration and invasion on mutant UQCRB-expressing cell lines and colorectal cancer cell. In conclusion, our results identified miR-4435 as a potential circulating miRNA biomarker of colorectal cancer associated with UQCRB.
Exploring Natural Clusters of Chronic Migraine Phenotypes: A Cross-Sectional Clinical Study
Authors: Woldeamanuel Yohannes W. , Sanjanwala Bharati M. , Peretz Addie M. , Cowan Robert P.
Published: February 2020

Heterogeneity in chronic migraine (CM) presents significant challenge for diagnosis, management, and clinical trials. To explore naturally occurring clusters of CM, we utilized data reduction methods on migraine-related clinical dataset. Hierarchical agglomerative clustering and principal component analyses (PCA) were conducted to identify natural clusters in 100 CM patients using 14 migraine-related clinical variables. Three major clusters were identified. Cluster I (29 patients) – the severely impacted patient featured highest levels of depression and migraine-related disability. Cluster II (28 patients) – the minimally impacted patient exhibited highest levels of self-efficacy and exercise. Cluster III (43 patients) – the moderately impacted patient showed features ranging between Cluster I and II. The first 5 principal components (PC) of the PCA explained 65% of variability. The first PC (eigenvalue 4.2) showed one major pattern of clinical features positively loaded by migraine-related disability, depression, poor sleep quality, somatic symptoms, post-traumatic stress disorder, being overweight and negatively loaded by pain self-efficacy and exercise levels. CM patients can be classified into three naturally-occurring clusters. Patients with high self-efficacy and exercise levels had lower migraine-related disability, depression, sleep quality, and somatic symptoms. These results may ultimately inform different management strategies.
Organic bases catalyze the synthesis of urea from ammonium salts derived from recovered environmental ammonia
Authors: Manaka Yuichi , Nagatsuka Yuki , Motokura Ken
Published: February 2020

Ammonia from sewage and livestock manure is a major environmental pollutant. To consume environmental ammonia, we investigated the organic base-catalyzed synthesis of urea. 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) catalyzes the conversion of ammonium carbamate to urea in 35% yield at 100 °C. Moreover, DBU also converts other ammonium salts into urea. A mechanism that involves nucleophilic attack of ammonia following ion exchange is proposed.
Genomic scan of selective sweeps in Djallonké (West African Dwarf) sheep shed light on adaptation to harsh environments
Authors: Álvarez Isabel , Fernández Iván , Traoré Amadou , Pérez-Pardal Lucía , Menéndez-Arias Nuria A. , Goyache Félix
Published: February 2020

The Djallonké (West African Dwarf) sheep is a small-sized haired sheep resulting from a costly evolutionary process of natural adaptation to the harsh environment of West Africa including trypanosome challenge. However, genomic studies carried out in this sheep are scant. In this research, genomic data of 184 Djallonké sheep (and 12 Burkina-Sahel sheep as an outgroup) generated using medium-density SNP Chips were analyzed. Three different statistics (iHS, XP-EHH and nSL) were applied to identify candidate selection sweep regions spanning genes putatively associated with adaptation of sheep to the West African environment. A total of 207 candidate selection sweep regions were defined. Gene-annotation enrichment and functional annotation analyses allowed to identify three statistically significant functional clusters involving 12 candidate genes. Genes included in Functional Clusters associated to selection signatures were mainly related to metabolic response to stress, including regulation of oxidative and metabolic stress and thermotolerance. The bovine chromosomal areas carrying QTLs for cattle trypanotolerance were compared with the regions on which the orthologous functional candidate cattle genes were located. The importance of cattle BTA4 for trypanotolerant response might have been conserved between species. The current research provides new insights on the genomic basis for adaptation and highlights the importance of obtaining information from non-cosmopolite livestock populations managed in harsh environments.
A comparative study on the mechanical, physical and morphological properties of cement-micro/nanoFe3O4 composite
Authors: Ghazanlou Siamak Imanian , Jalaly Maisam , Sadeghzadeh Sadegh , Korayem Asghar Habibnejad
Published: February 2020

In this study, fabrication of a composite containing the ordinary Portland cement (OPC) and magnetite (Fe3O4) micro/nanoparticles is reported. In the first stage, the cement paste samples with a fixed 0.2 wt.% Fe3O4additive in four different particle sizes (20–40 nm, 80–100 nm, 250–300 nm, and 1–2 µm) were prepared to check the effect of magnetite size. Magnetite was found to play an effective role in reinforcing cement matrix. The results showed that the cement paste reinforced by magnetite nanoparticles of 20–40 nm size range had the highest compressive, flexural, and tensile strengths compared to those of the other samples reinforced by larger particles. In the second stage, various amounts of the Fe3O4nanoparticles of 20–40 nm size range were added to the cement to evaluate the influence of magnetite amount and find the optimized reinforcement amount. It was revealed that adding 0.25 wt.% Fe3O4nanoparticles of 20–40 nm size range, as the optimal specimen, increased the compressive strength, flexural strength and tensile splitting strength by 23–32, 17–25, and 15–19%, respectively, and decreased the electrical resistance by 19–31%.
Author Correction: Serial dependence in a simulated clinical visual search task
Authors: Manassi Mauro , Kristjánsson Árni , Whitney David
Published: February 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.