bluuebunny/crossref_metadata_2025 huggingface dataset:
In-site pollen record from the Dadiwan archaeological site and the human-environment relationship during Marine Oxygen Isotope Stage 3
Authors: Peng Wei , Huang Xiaozhong , Zhang Dongju , Storozum Michael J. , Chen Fahu
Published: September 2018

Climatic change that affects biological productivity is often argued to be a primary force influencing human activities during the glacial period. To test this assumption, we combine in-site pollen, paleoclimatic, and archaeological data from the Dadiwan site and nearby areas on the western Loess Plateau (WLP) that date to Marine Oxygen Isotope Stage (MIS) 3. Our comparison of multiple datasets suggests that regional human activities increased when the vegetation around the Dadiwan area shifted from forest steppe in the early MIS 3 (59–46.7 ka) to steppe in the middle to late MIS 3 (46.7–29.5 ka). Our results indicate that regional human activities increased again during the late MIS 3 when the amount of precipitation was higher, as indicated by the lowerArtemisiaproportion. We suggest that increased precipitation on the WLP enhanced the above-ground biomass production and may be responsible for an increase in human activity and population in this region.
A Remark on Rationally Connected Varieties and Mori Dream Spaces
Authors: Fontanari Claudio , Martinelli Diletta
Published: September 2018

In this short note, we show that a construction by Ottem provides an example of a rationally connected variety that is not birationally equivalent to a Mori dream space with terminal singularities.
ACTIVE REDUNDANCY ALLOCATION FOR COHERENT SYSTEMS WITH INDEPENDENT AND HETEROGENEOUS COMPONENTS
Authors: Fang Rui , Li Xiaohu
Published: September 2018

This paper studies the allocation of active redundancies to coherent systems on the context that the base and redundancy components have mutual independent lifetimes. For systems with two symmetric components and systems with one component's minimal cut sets (minimal path sets) covering those of another, we derive sufficient conditions to compare the resultant system lifetimes. Some numerical examples are also presented to illustrate the theoretical results.
Kurzer Entscheidungs-Test Online (KETO) zur Erfassung des Entscheidungsverhaltens unter Unsicherheit und der Höhe der angestrebten Urteilssicherheit (HAUS)
Authors: Hausmann Daniel , Stoll Julia
Published: September 2018

Zusammenfassung. Viele Menschen treffen ihre Entscheidungen, wenn sie sich subjektiv sicher genug sind. Der Kurze Entscheidungs-Test Online (KETO) wurde als attraktives, komplexes und für die Teilnehmenden nicht einfach zu durchschauendes Verhaltensspiel im Sinne eines objektiven Persönlichkeitstests entwickelt, um die individuelle Höhe der angestrebten Urteilssicherheit (HAUS) prozentgenau zu erfassen. In 22 vergleichbaren Durchgängen soll eine von vier zur Auswahl stehenden Optionen gewählt werden. Dabei können auf einem Information Board 0 bis maximal 5 probabilistische Cue-Informationen aufgedeckt werden. Die individuelle HAUS wird aufgrund der probabilistischen Erstinformation und dem weiteren Suchverhalten experimentell eingegrenzt und anhand des vollständigen Informationssuchmusters post-hoc nachberechnet. Mehrere Validierungschritte wurden mit 1 008 Versuchspersonen durchgeführt und umfassten die konvergente und divergente Validität, eine Extremgruppen- und Kriteriumsvalidierung, sowie Retest-Reliabilität und Stabilität. Die HAUS korrelierte positiv mit der Risikoeinstellung und negativ mit dem Risikoverhalten (kleine Effektstärke). Die HAUS ist unter anderem unabhängig von der Teilnahmemotivation, von der Maximierungstendenz und den 5 Faktoren des NEO-FFI.
WOR-TE: Ein Ja / Nein-Wortschatztest für Kinder verschiedener Altersgruppen
Authors: Trautwein Jutta , Schroeder Sascha
Published: September 2018

Zusammenfassung. In dem vorliegenden Artikel wird der Wortschatztest WOR-TE für deutsche Grundschulkinder vorgestellt. Der Test basiert auf der Ja / Nein-Methode, bei der die Teilnehmerinnen und Teilnehmer aus einer Liste von Wörtern und Pseudowörtern diejenigen ankreuzen sollen, die sie kennen. Er wurde für verschiedene Altersgruppen (1./2. Klasse, 3./4. Klasse, 5./6. Klasse) konzipiert und Item-Response-Theory-basiert mit dem Rasch-Modell validiert. Anhand des Validitätskonzepts nach Messick (1995) wurden verschiedene Aspekte von Konstruktvalidität untersucht: Inhaltliche Aspekte, Relevanz, Repräsentativität, Technische Qualität, substantielle Aspekte, Generalisierbarkeit und externe Aspekte. Die Ergebnisse zeigen, dass der Test ein valides Instrument zur Erfassung des orthographischen Wortschatzes im Grundschulalter darstellt und durch kleine Veränderungen, insbesondere in Bezug auf die Item-Auswahl, profitieren würde. Möglichkeiten des Einsatzes sowie Einschränkungen des Verfahrens werden diskutiert, ebenso wie die Verwendung des Validitätskonzeptes mit IRT für Ja / Nein-Test im Allgemeinen.
New Exoplanet Telescope Detects Its First Two Planets
Authors: Cartier Kimberly
Published: September 2018

The two possible planets, each larger than Earth and too hot to be habitable, are the first of hundreds of Earth-sized exoplanets expected to be discovered by a recently launched telescope.
Bottom‐Slope‐Induced Net Sediment Transport Rate Under Oscillatory Flows in the Rippled‐Bed Regime
Authors: Wang Dongxu , Yuan Jing
Published: September 2018

Full‐scale experiments in the rippled‐bed regime were conducted in an oscillatory water tunnel to study the net sediment transport rate due to oscillatory flows on sloping bottoms (up to 2.6°). The tests cover a variety of sinusoidal flows, under which uniform two‐dimensional ripples are generated from a coarse sand movable bed. A laser‐based bottom profiler was developed to measure ripple geometry and net sediment transport rate. Under the same flow condition, a small bottom slope can slightly change the shape of the equilibrium ripples; for example, ripples become upslope leaning, but the ripple dimensions remain almost unchanged. Ripples are also found to migrate in the downslope direction with uniform speed and permanent shape, which is due to the spatial variation of net bedload transport rate. For a given flow condition, the slope‐induced net sediment transport rates are in the downslope direction and increase linearly with the bottom slope. A conceptual model, which is an extension of a sheet flow model (Yuan, Li, & Madsen, 2017, https://doi.org/10.1002/2016JC011996), was also developed. This calibration‐free model can reasonably predict the net transport rate, despite that a moderate underestimate (a factor slightly less than 2) is observed. Both our experiments and model suggest that the presence of ripples significantly enhances sediment mixing and leads to a large net suspended‐load transport rate, which will not occur under sheet flow conditions. Therefore, net transport rate in the ripple‐bed regime can be comparable to that in the sheet flow regime, although the flow condition is much weaker.
Lifetime cognition and late midlife blood metabolites: findings from a British birth cohort
Authors: Proitsi Petroula , Kuh Diana , Wong Andrew , Maddock Jane , Bendayan Rebecca , Wulaningsih Wahyu , Hardy Rebecca , Richards Marcus
Published: September 2018

Maintenance of healthy cognitive ageing is vital for independence and wellbeing in the older general population. We investigated the association between blood metabolites and cognitive function and decline. Participants from the MRC National Survey of Health and Development (NSHD, the British 1946 birth cohort) were studied; 233 nuclear magnetic resonance circulating metabolite measures were quantified in 909 men and women at ages 60–64. Short-term and delayed verbal memory and processing speed were concurrently assessed and these tests were repeated at age 69. Linear regression analyses tested associations between metabolites and cognitive function at ages 60–64, and changes in these measures by age 69, adjusting for childhood cognition, education, socio-economic status and lifestyle factors. In cross-sectional analyses, metabolite levels, particularly fatty acid composition and different lipid sub-classes, were associated with short-term verbal memory (4 measures in females and 11 measures in the whole sample), delayed verbal memory (2 measures in females) and processing speed (8 measures in males and 2 measures in the whole sample) (p < 0.002). One metabolite was associated with change in cognition in females. Most of the observed associations were attenuated after adjustment for childhood cognition and education. A life course perspective can improve the understanding of how peripheral metabolic processes underlie cognitive ageing.
HMGB1 promotes ERK-mediated mitochondrial Drp1 phosphorylation for chemoresistance through RAGE in colorectal cancer
Authors: Huang Chih-Yang , Chiang Shu-Fen , Chen William Tzu-Liang , Ke Tao-Wei , Chen Tsung-Wei , You Ying-Shu , Lin Chen-Yu , Chao K. S. Clifford , Huang Chih-Yang
Published: September 2018

Dysfunctional mitochondria have been shown to enhance cancer cell proliferation, reduce apoptosis, and increase chemoresistance. Chemoresistance develops in nearly all patients with colorectal cancer, leading to a decrease in the therapeutic efficacies of anticancer agents. However, the effect of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission on chemoresistance in colorectal cancer is unclear. Here, we found that the release of high-mobility group box 1 protein (HMGB1) in conditioned medium from dying cells by chemotherapeutic drugs and resistant cells, which triggered Drp1 phosphorylation via its receptor for advanced glycation end product (RAGE). RAGE signals ERK1/2 activation to phosphorylate Drp1 at residue S616 triggerring autophagy for chemoresistance and regrowth in the surviving cancer cells. Abolishment of Drp1 phosphorylation by HMGB1 inhibitor and RAGE blocker significantly enhance sensitivity to the chemotherapeutic treatment by suppressing autophagy. Furthermore, patients with high phospho-Drp1Ser616 are associated with high risk on developing tumor relapse, poor 5-year disease-free survival (DFS) and 5-year overall survival (OS) after neoadjuvant chemoradiotherapy (neoCRT) treatment in locally advanced rectal cancer (LARC). Moreover, patients with RAGE-G82S polymorphism (rs2070600) are associated with high phospho-Drp1Ser616 within tumor microenvironment. These findings suggest that the release of HMGB1 from dying cancer cells enhances chemoresistance and regrowth via RAGE-mediated ERK/Drp1 phosphorylation.
Metabolic profile and differentiation potential of extraembryonic endoderm-like cells
Authors: Gatie Mohamed I. , Kelly Gregory M.
Published: September 2018

Glucose metabolism has a crucial role for providing substrates required to generate ATP and regulate the epigenetic landscape. We reported that F9 embryonal carcinoma stem-like cells require cytosolic reactive oxygen species to differentiate into extraembryonic endoderm; however, mitochondrial sources were not examined. To extend these studies, we examined the metabolic profile of early and late-passage F9 cells, and show that their ability to differentiate is similar, even though each population has dramatically different metabolic profiles. Differentiated early-passage cells relied on glycolysis, while differentiated late-passage cells transitioned towards oxidative phosphorylation (OXPHOS). Unexpectedly, electron transport chain protein stoichiometry was disrupted in differentiated late-passage cells, whereas genes encoding mitofusion 1 and 2, which promote mitochondrial fusion and favor OXPHOS, were upregulated in differentiated early-passage cells. Despite this, early-passage cells cultured under conditions to promote glycolysis showed enhanced differentiation, whereas promoting OXPHOS in late-passage cells showed a similar trend. Further analysis revealed that the distinct metabolic profiles seen between the two populations is largely associated with changes in genomic integrity, linking metabolism to passage number. Together, these results indicate that passaging has no effect on the potential for F9 cells to differentiate into extraembryonic endoderm; however, it does impact their metabolic profile. Thus, it is imperative to determine the molecular and metabolic status of a stem cell population before considering its utility as a therapeutic tool for regenerative medicine.
Cell cycle-resolved chromatin proteomics reveals the extent of mitotic preservation of the genomic regulatory landscape
Authors: Ginno Paul Adrian , Burger Lukas , Seebacher Jan , Iesmantavicius Vytautas , Schübeler Dirk
Published: September 2018

Regulation of transcription, replication, and cell division relies on differential protein binding to DNA and chromatin, yet it is unclear which regulatory components remain bound to compacted mitotic chromosomes. By utilizing the buoyant density of DNA–protein complexes after cross-linking, we here develop a mass spectrometry-based approach to quantify the chromatin-associated proteome at separate stages of the cell cycle. While epigenetic modifiers that promote transcription are lost from mitotic chromatin, repressive modifiers generally remain associated. Furthermore, while proteins involved in transcriptional elongation are evicted, most identified transcription factors are retained on mitotic chromatin to varying degrees, including core promoter binding proteins. This predicts conservation of the regulatory landscape on mitotic chromosomes, which we confirm by genome-wide measurements of chromatin accessibility. In summary, this work establishes an approach to study chromatin, provides a comprehensive catalog of chromatin changes during the cell cycle, and reveals the degree to which the genomic regulatory landscape is maintained through mitosis.
Advanced sulfide solid electrolyte by core-shell structural design
Authors: Wu Fan , Fitzhugh William , Ye Luhan , Ning Jiaxin , Li Xin
Published: September 2018

Solid electrolyte is critical to next-generation solid-state lithium-ion batteries with high energy density and improved safety. Sulfide solid electrolytes show some unique properties, such as the high ionic conductivity and low mechanical stiffness. Here we show that the electrochemical stability window of sulfide electrolytes can be improved by controlling synthesis parameters and the consequent core-shell microstructural compositions. This results in a stability window of 0.7–3.1 V and quasi-stability window of up to 5 V for Li-Si-P-S sulfide electrolytes with high Si composition in the shell, a window much larger than the previously predicted one of 1.7–2.1 V. Theoretical and computational work explains this improved voltage window in terms of volume constriction, which resists the decomposition accompanying expansion of the solid electrolyte. It is shown that in the limiting case of a core-shell morphology that imposes a constant volume constraint on the electrolyte, the stability window can be further opened up. Advanced strategies to design the next-generation sulfide solid electrolytes are also discussed based on our understanding.
Functional equivalence of genome sequencing analysis pipelines enables harmonized variant calling across human genetics projects
Authors: Regier Allison A. , Farjoun Yossi , Larson David E. , Krasheninina Olga , Kang Hyun Min , Howrigan Daniel P. , Chen Bo-Juen , Kher Manisha , Banks Eric , Ames Darren C. , English Adam C. , Li Heng , Xing Jinchuan , Zhang Yeting , Matise Tara , Abecasis Goncalo R. , Salerno Will , Zody Michael C. , Neale Benjamin M. , Hall Ira M.
Published: September 2018

Hundreds of thousands of human whole genome sequencing (WGS) datasets will be generated over the next few years. These data are more valuable in aggregate: joint analysis of genomes from many sources increases sample size and statistical power. A central challenge for joint analysis is that different WGS data processing pipelines cause substantial differences in variant calling in combined datasets, necessitating computationally expensive reprocessing. This approach is no longer tenable given the scale of current studies and data volumes. Here, we define WGS data processing standards that allow different groups to produce functionally equivalent (FE) results, yet still innovate on data processing pipelines. We present initial FE pipelines developed at five genome centers and show that they yield similar variant calling results and produce significantly less variability than sequencing replicates. This work alleviates a key technical bottleneck for genome aggregation and helps lay the foundation for community-wide human genetics studies.
Observing of the super-Planckian near-field thermal radiation between graphene sheets
Authors: Yang Jiang , Du Wei , Su Yishu , Fu Yang , Gong Shaoxiang , He Sailing , Ma Yungui
Published: September 2018

Thermal radiation can be substantially enhanced in the near-field scenario due to the tunneling of evanescent waves. Monolayer graphene could play a vital role in this process owing to its strong infrared plasmonic response, however, which still lacks an experimental verification due to the technical challenges. Here, we manage to make a direct measurement about plasmon-mediated thermal radiation between two macroscopic graphene sheets using a custom-made setup. Super-Planckian radiation with efficiency 4.5 times larger than the blackbody limit is observed at a 430-nm vacuum gap on insulating silicon hosting substrates. The positive role of graphene plasmons is further confirmed on conductive silicon substrates which have strong infrared loss and thermal emittance. Based on these, a thermophotovoltaic cell made of the graphene–silicon heterostructure is lastly discussed. The current work validates the classic thermodynamical theory in treating graphene and also paves a way to pursue the application of near-field thermal management.
Preventing acute asthmatic symptoms by targeting a neuronal mechanism involving carotid body lysophosphatidic acid receptors
Authors: Jendzjowsky Nicholas G. , Roy Arijit , Barioni Nicole O. , Kelly Margaret M. , Green Francis H. Y. , Wyatt Christopher N. , Pye Richard L. , Tenorio-Lopes Luana , Wilson Richard J. A.
Published: September 2018

Asthma accounts for 380,000 deaths a year. Carotid body denervation has been shown to have a profound effect on airway hyper-responsiveness in animal models but a mechanistic explanation is lacking. Here we demonstrate, using a rat model of asthma (OVA-sensitized), that carotid body activation during airborne allergic provocation is caused by systemic release of lysophosphatidic acid (LPA). Carotid body activation by LPA involves TRPV1 and LPA-specific receptors, and induces parasympathetic (vagal) activity. We demonstrate that this activation is sufficient to cause acute bronchoconstriction. Moreover, we show that prophylactic administration of TRPV1 (AMG9810) and LPA (BrP-LPA) receptor antagonists prevents bradykinin-induced asthmatic bronchoconstriction and, if administered following allergen exposure, reduces the associated respiratory distress. Our discovery provides mechanistic insight into the critical roles of carotid body LPA receptors in allergen-induced respiratory distress and suggests alternate treatment options for asthma.
Total syntheses of shizukaols A and E
Authors: Wu Jian-Li , Lu Yin-Suo , Tang Bencan , Peng Xiao-Shui
Published: September 2018

Shizukaols possess a common heptacyclic framework containing more than ten contiguous stereocenters and potential biological activities. Here we report that the total syntheses of shizukaols A (1) and E (2), two lindenane-type dimers from the Chloranthaceae family, are achieved via a modified biomimetic Diels–Alder reaction. The common crucial biomimetic diene 23 and ethylene species (6, 17) are obtained through either a highly Z-selective olefination of α-siloxy ketone with ynolate anions or an intramolecular Horner–Wadsworth–Emmons olefination from commercially available Wieland–Miescher ketone (7). This synthetic approach here opens up practical avenues for the total syntheses of the intriguing Chloranthaceae family members, as well as the understanding of their relevant biological action in nature.
Zebra finches identify individuals using vocal signatures unique to each call type
Authors: Elie Julie E. , Theunissen Frédéric E.
Published: September 2018

Individual recognition is critical in social animal communication, but it has not been demonstrated for a complete vocal repertoire. Deciphering the nature of individual signatures across call types is necessary to understand how animals solve the problem of combining, in the same signal, information about identity and behavioral state. We show that distinct signatures differentiate zebra finch individuals for each call type. The distinctiveness of these signatures varies: contact calls bear strong individual signatures while calls used during aggressive encounters are less individualized. We propose that the costly solution of using multiple signatures evolved because of the limitations of the passive filtering properties of the birds’ vocal organ for generating sufficiently individualized features. Thus, individual recognition requires the memorization of multiple signatures for the entire repertoire of conspecifics of interests. We show that zebra finches excel at these tasks.
A stably self-renewing adult blood-derived induced neural stem cell exhibiting patternability and epigenetic rejuvenation
Authors: Sheng Chao , Jungverdorben Johannes , Wiethoff Hendrik , Lin Qiong , Flitsch Lea J. , Eckert Daniela , Hebisch Matthias , Fischer Julia , Kesavan Jaideep , Weykopf Beatrice , Schneider Linda , Holtkamp Dominik , Beck Heinz , Till Andreas , Wüllner Ullrich , Ziller Michael J. , Wagner Wolfgang , Peitz Michael , Brüstle Oliver
Published: September 2018

Recent reports suggest that induced neurons (iNs), but not induced pluripotent stem cell (iPSC)-derived neurons, largely preserve age-associated traits. Here, we report on the extent of preserved epigenetic and transcriptional aging signatures in directly converted induced neural stem cells (iNSCs). Employing restricted and integration-free expression of SOX2 and c-MYC, we generated a fully functional, bona fide NSC population from adult blood cells that remains highly responsive to regional patterning cues. Upon conversion, low passage iNSCs display a profound loss of age-related DNA methylation signatures, which further erode across extended passaging, thereby approximating the DNA methylation age of isogenic iPSC-derived neural precursors. This epigenetic rejuvenation is accompanied by a lack of age-associated transcriptional signatures and absence of cellular aging hallmarks. We find iNSCs to be competent for modeling pathological protein aggregation and for neurotransplantation, depicting blood-to-NSC conversion as a rapid alternative route for both disease modeling and neuroregeneration.
RIP2 filament formation is required for NOD2 dependent NF-κB signalling
Authors: Pellegrini Erika , Desfosses Ambroise , Wallmann Arndt , Schulze Wiebke Manuela , Rehbein Kristina , Mas Philippe , Signor Luca , Gaudon Stephanie , Zenkeviciute Grasilda , Hons Michael , Malet Helene , Gutsche Irina , Sachse Carsten , Schoehn Guy , Oschkinat Hartmut , Cusack Stephen
Published: September 2018

Activation of the innate immune pattern recognition receptor NOD2 by the bacterial muramyl-dipeptide peptidoglycan fragment triggers recruitment of the downstream adaptor kinase RIP2, eventually leading to NF-κB activation and proinflammatory cytokine production. Here we show that full-length RIP2 can form long filaments mediated by its caspase recruitment domain (CARD), in common with other innate immune adaptor proteins. We further show that the NOD2 tandem CARDs bind to one end of the RIP2 CARD filament, suggesting a mechanism for polar filament nucleation by activated NOD2. We combine X-ray crystallography, solid-state NMR and high-resolution cryo-electron microscopy to determine the atomic structure of the helical RIP2 CARD filament, which reveals the intermolecular interactions that stabilize the assembly. Using structure-guided mutagenesis, we demonstrate the importance of RIP2 polymerization for the activation of NF-κB signalling by NOD2. Our results could be of use to develop new pharmacological strategies to treat inflammatory diseases characterised by aberrant NOD2 signalling.
Two-dimensional amorphous NiO as a plasmonic photocatalyst for solar H2 evolution
Authors: Lin Zhaoyong , Du Chun , Yan Bo , Wang Chengxin , Yang Guowei
Published: September 2018

Amorphous materials are usually evaluated as photocatalytically inactive due to the amorphous nature-induced self-trapping of tail states, in spite of their achievements in electrochemistry. NiO crystals fail to act as an individual reactor for photocatalytic H2 evolution because of the intrinsic hole doping, regardless of their impressive cocatalytic ability for proton/electron transfer. Here we demonstrate that two-dimensional amorphous NiO nanostructure can act as an efficient and robust photocatalyst for solar H2 evolution without any cocatalysts. Further, the antenna effect of surface plasmon resonance can be introduced to construct an incorporate antenna-reactor structure by increasing the electron doping. The solar H2 evolution rate is improved by a factor of 19.4 through the surface plasmon resonance-mediated charge releasing. These findings thus open a door to applications of two-dimensional amorphous NiO as an advanced photocatalyst.
Motor recruitment to the TIM23 channel’s lateral gate restricts polypeptide release into the inner membrane
Authors: Schendzielorz Alexander Benjamin , Bragoszewski Piotr , Naumenko Nataliia , Gomkale Ridhima , Schulz Christian , Guiard Bernard , Chacinska Agnieszka , Rehling Peter
Published: September 2018

The presequence translocase of the mitochondrial inner membrane (TIM23 complex) facilitates anterograde precursor transport into the matrix and lateral release of precursors with stop-transfer signal into the membrane (sorting). Sorting requires precursor exit from the translocation channel into the lipid phase through the lateral gate of the TIM23 complex. How the two transport modes are regulated and balanced against each other is unknown. Here we show that the import motor J-protein Pam18, which is essential for matrix import, controls lateral protein release into the lipid bilayer. Constitutively translocase-associated Pam18 obstructs lateral precursor transport. Concomitantly, Mgr2, implicated in precursor quality control, is displaced from the translocase. We conclude that during motor-dependent matrix protein transport, the transmembrane segment of Pam18 closes the lateral gate to promote anterograde polypeptide movement. This finding explains why a motor-free form of the translocase facilitates the lateral movement of precursors with a stop-transfer signal.
Tailoring manganese oxide with atomic precision to increase surface site availability for oxygen reduction catalysis
Authors: Eom C. John , Kuo Ding-Yuan , Adamo Carolina , Moon Eun Ju , May Steve J. , Crumlin Ethan J. , Schlom Darrell G. , Suntivich Jin
Published: September 2018

Controlling the structure of catalysts at the atomic level provides an opportunity to establish detailed understanding of the catalytic form-to-function and realize new, non-equilibrium catalytic structures. Here, advanced thin-film deposition is used to control the atomic structure of La2/3Sr1/3MnO3, a well-known catalyst for the oxygen reduction reaction. The surface and sub-surface is customized, whereas the overall composition and d-electron configuration of the oxide is kept constant. Although the addition of SrMnO3 benefits the oxygen reduction reaction via electronic structure and conductivity improvements, SrMnO3 can react with ambient air to reduce the surface site availability. Placing SrMnO3 in the sub-surface underneath a LaMnO3 overlayer allows the catalyst to maintain the surface site availability while benefiting from improved electronic effects. The results show the promise of advanced thin-film deposition for realizing atomically precise catalysts, in which the surface and sub-surface structure and stoichiometry are tailored for functionality, over controlling only bulk compositions.
Cdk1 inactivation induces post-anaphase-onset spindle migration and membrane protrusion required for extreme asymmetry in mouse oocytes
Authors: Wei Zhe , Greaney Jessica , Zhou Chenxi , A. Homer Hayden
Published: September 2018

Female meiotic divisions are extremely asymmetric, producing large oocytes and small polar bodies (PBs). In mouse oocytes, the spindle relocates to the cortex before anaphase of meiosis I (MI). It is presumed that by displacing the future midzone, pre-anaphase spindle repositioning alone ensures asymmetry. But how subsequent anaphase events might contribute to asymmetric PB extrusion (PBE) is unknown. Here, we find that inactivation of cyclin-dependent kinase 1 (Cdk1) induces anaphase and simultaneously triggers cytoplasmic formin-mediated F-actin polymerisation that propels the spindle into the cortex causing it to protrude while anaphase progresses. Significantly, if post-anaphase-onset spindle migration fails, protrusion and asymmetry are severely threatened even with intact pre-anaphase migration. Conversely, post-anaphase migration can completely compensate for failed pre-anaphase migration. These data identify a cell-cycle-triggered phase of spindle displacement occurring after anaphase-onset, which, by inducing protrusion, is necessary for extreme asymmetry in mouse oocytes and uncover a pathway for maximising unequal division.
‘Levodopa Phobia’: a review of a not uncommon and consequential phenomenon
Authors: Titova Nataliya , Levin Oleg , Katunina Elena , Ray Chaudhuri K.
Published: September 2018

‘Levodopa Phobia’ is under-recognised in Parkinson’s disease but can cause profound detrimental clinical complications if left to continue. Several types can be encountered in clinical practice and can be driven by a misplaced fear of levodopa-induced dyskinesias, other gastrointestinal side effects and also the theoretical notion that levodopa may be toxic to dopaminergic neurons in the brain. The condition can be underpinned by a sense of strong influence from the physicians or carers who are unwilling to prescribe or consider levodopa, and also high levels of anxiety or even impulsive compulsive traits in patients who have been influenced by available literature or social media-based information. If unrecognised, the clinical issue may lead to motor deterioration and related muscle contractures leading to social isolation as well as a range of non-motor symptoms. In some, there may be emergence of intrusive impulse control disorders because of reliance on only dopamine agonists related to the fear of taking levodopa. Four cases illustrate the different patterns of ‘Levodopa Phobia’ in this study. Management of levodopa phobia is complex and includes recognition and skilled neuropsychological interventions to break the misperceptions about the complications of levodopa therapy.
Author Correction: Anti-angiogenic drug scheduling optimisation with application to colorectal cancer
Authors: Sturrock M. , Miller I. S. , Kang G. , Arba’ie N. Hannis , O’Farrell A. C. , Barat A. , Marston G. , Coletta P. L. , Byrne A. T. , Prehn J. H.
Published: September 2018

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
Primary rat LSECs preserve their characteristic phenotype after cryopreservation
Authors: Mönkemöller Viola , Mao Hong , Hübner Wolfgang , Dumitriu Gianina , Heimann Peter , Levy Gahl , Huser Thomas , Kaltschmidt Barbara , Kaltschmidt Christian , Øie Cristina I.
Published: September 2018

Liver disease is a leading cause of morbidity and mortality worldwide. Recently, the liver non-parenchymal cells have gained increasing attention for their potential role in the development of liver disease. Liver sinusoidal endothelial cells (LSECs), a specialized type of endothelial cells that have unique morphology and function, play a fundamental role in maintaining liver homeostasis. Current protocols for LSEC isolation and cultivation rely on freshly isolated cells which can only be maintained differentiated in culture for a few days. This creates a limitation in the use of LSECs for research and a need for a consistent and reliable source of these cells. To date, no LSEC cryopreservation protocols have been reported that enable LSECs to retain their functional and morphological characteristics upon thawing and culturing. Here, we report a protocol to cryopreserve rat LSECs that, upon thawing, maintain full LSEC-signature features: fenestrations, scavenger receptor expression and endocytic function on par with freshly isolated cells. We have confirmed these features by a combination of biochemical and functional techniques, and super-resolution microscopy. Our findings offer a means to standardize research using LSECs, opening the prospects for designing pharmacological strategies for various liver diseases, and considering LSECs as a therapeutic target.
Publisher Correction: Subcellular Imaging of Liquid Silicone Coated-Intestinal Epithelial Cells
Authors: Nirmalraj Peter , Lehner Roman , Thompson Damien , Rothen-Rutishauser Barbara , Mayer Michael
Published: September 2018

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
The potential of eye-tracking as a sensitive measure of behavioural change in response to intervention
Authors: Fletcher-Watson Sue , Hampton Sarah
Published: September 2018

One challenge to the development of effective interventions to support learning and behavioural change in neurodevelopmental disorders is a lack of suitable outcome measures. Eye-tracking has been used widely to chart cognitive development and clinically-relevant group differences in many populations. This proof-of-concept study investigates whether it also has the potential to act as a marker of treatment effects, by testing its sensitivity to differential change over a short period of exposure to an iPad app in typically developing children. The app targets a key skill in early social communication development, by rewarding attention to people, operationalised via a finger-tap on screen. We measured attention to images taken from the app, and a selection of matched stimuli to test generalisation of effects, at baseline and two weeks later. Children were assigned to either an app-exposure or no-app condition in the intervening period. The app exposure group showed increases in fixation on people for images from the app, and for distant-generalisation photographs, at high levels of complexity. We conclude that, with careful selection of stimuli, eye-tracking has the potential to make a valuable contribution to the range of outcome measures available for psycho-behavioural interventions in neurodevelopmental disorders.
Supplementation with a selective amino acid formula ameliorates muscular dystrophy in mdx mice
Authors: Banfi Stefania , D’Antona Giuseppe , Ruocco Chiara , Meregalli Mirella , Belicchi Marzia , Bella Pamela , Erratico Silvia , Donato Elisa , Rossi Fabio , Bifari Francesco , Lonati Caterina , Campaner Stefano , Nisoli Enzo , Torrente Yvan
Published: September 2018

Duchenne muscular dystrophy (DMD) is one of the most common and severe forms of muscular dystrophy. Oxidative myofibre content, muscle vasculature architecture and exercise tolerance are impaired in DMD. Several studies have demonstrated that nutrient supplements ameliorate dystrophic features, thereby enhancing muscle performance. Here, we report that dietary supplementation with a specific branched-chain amino acid-enriched mixture (BCAAem) increased the abundance of oxidative muscle fibres associated with increased muscle endurance in dystrophic mdx mice. Amelioration of the fatigue index in BCAAem-treated mdx mice was caused by a cascade of events in the muscle tissue, which were promoted by endothelial nitric oxide synthase (eNOS) activation and vascular endothelial growth factor (VEGF) expression. VEGF induction led to recruitment of bone marrow (BM)-derived endothelial progenitors (EPs), which increased the capillary density of dystrophic skeletal muscle. Functionally, BCAAem mitigated the dystrophic phenotype of mdx mice without inducing dystrophin protein expression or replacing the dystrophin-associated glycoprotein (DAG) complex in the membrane, which is typically lost in DMD. BCAAem supplementation could be an effective adjuvant strategy in DMD treatment.
Mesenchymal stem cells are attracted to latent HIV-1-infected cells and enable virus reactivation via a non-canonical PI3K-NFκB signaling pathway
Authors: Chandra Partha K. , Gerlach Samantha L. , Wu Chengxiang , Khurana Namrata , Swientoniewski Lauren T. , Abdel-Mageed Asim B. , Li Jian , Braun Stephen E. , Mondal Debasis
Published: September 2018

Persistence of latent HIV-1 in macrophages (MACs) and T-helper lymphocytes (THLs) remain a major therapeutic challenge. Currently available latency reversing agents (LRAs) are not very effective in vivo. Therefore, understanding of physiologic mechanisms that dictate HIV-1 latency/reactivation in reservoirs is clearly needed. Mesenchymal stromal/stem cells (MSCs) regulate the function of immune cells; however, their role in regulating virus production from latently-infected MACs & THLs is not known. We documented that exposure to MSCs or their conditioned media (MSC-CM) rapidly increased HIV-1 p24 production from the latently-infected U1 (MAC) & ACH2 (THL) cell lines. Exposure to MSCs also increased HIV-1 long terminal repeat (LTR) directed gene expression in the MAC and THL reporter lines, U937-VRX and J-Lat (9.2), respectively. MSCs exposed to CM from U1 cells (U1-CM) showed enhanced migratory ability towards latently-infected cells and retained their latency-reactivation potential. Molecular studies showed that MSC-mediated latency-reactivation was dependent upon both the phosphatidyl inositol-3-kinase (PI3K) and nuclear factor-κB (NFκB) signaling pathways. The pre-clinically tested inhibitors of PI3K (PX-866) and NFκB (CDDO-Me) suppressed MSC-mediated HIV-1 reactivation. Furthermore, coexposure to MSC-CM enhanced the latency-reactivation efficacy of the approved LRAs, vorinostat and panobinostat. Our findings on MSC-mediated latency-reactivation may provide novel strategies against persistent HIV-1 reservoirs.
Identification of target genes for RNAi-mediated control of the Twospotted Spider Mite
Authors: Yoon June-Sun , Sahoo Dipak K. , Maiti Indu B , Palli Subba R.
Published: September 2018

RNA interference (RNAi) is being developed for the management of pests that destroy crops. The twospotted Spider Mite (TSSM), Tetranychus urticae is a worldwide pest due to its unique physiological and behavioral characteristics including extraordinary ability to detoxify a wide range of pesticides and feed on many host plants. In this study, we conducted experiments to identify target genes that could be used for the development of RNAi-based methods to control TSSM. Leaf disc feeding assays revealed that knockdown in the expression genes coding for proteins involved in the biosynthesis and action of juvenile hormone (JH) and action of ecdysteroids [Methoprene-tolerant (Met), retinoid X receptor β, farnesoic acid O-methyltransferase, and CREB-binding protein] caused 35–56% mortality. Transgenic tobacco plants expressing hairpin dsRNA targeting Met gene were generated and tested. About 48% mortality was observed in TSSM raised on transgenic tobacco plants expressing dsMet. These studies not only broaden our knowledge on understanding hormone action in TSSM but also identified target genes that could be used in RNAi-mediated control of TSSM.
Electromagnetic Fields Due to the Wake of a Moving Slender Body in a Finite-Depth Ocean with Density Stratification
Authors: Xu Zhi-Hua , Du Chang-Ping , Xia Ming-Yao
Published: September 2018

Weak electric currents are induced in moving seawater by cutting the geomagnetic fields. These electric currents can produce measurable electromagnetic fields that may be used for some purposes such as monitoring of ocean internal waves. This article is aimed at presenting the procedure to calculate the electromagnetic fields owing to the wake raised by an undersea moving slender body. A pair of Havelock point sources are introduced to model the moving body, which generate the similar wake at places far from the body. The ocean is taken to be of finite-depth with density stratification due to thermocline. Three distinct forms of water-flow wake can be identified, the free-surface Kelvin wake, the internal interfacial wake, and the localized volume wake. The electric currents evoked by the motional wake may produce observable electromagnetic fields, which may be solved using rigorous electromagnetic field theory. At the sea level, the magnitudes of the induced electric field and magnetic field are on the order of a few microvolts per meter and one nano-Tesla, respectively, which are appreciable in terms of nowadays marine electric and magnetic sensors.
Dysregulation of the endothelin pathway in lymphangioleiomyomatosis with no direct effect on cell proliferation and migration
Authors: Chebib Nader , Archer Fabienne , Bobet-Erny Alexandra , Leroux Caroline , Cottin Vincent
Published: September 2018

LAM is a rare low-grade metastasizing lung neoplasm. Inhibitors of mTOR improve clinical outcome of LAM patients by preventing loss of lung function. Nevertheless, other cell targets may be of interest for drug development. Therefore, we explored the potential role of EDN1 (endothelin) in LAM. We report an increased endothelin blood level in LAM patients as well as EDN1 overexpression and EDN1 receptor downregulation in LAM-derived primary cells and in TSC2NEG cells mutated in TSC2. We evidenced EDN pathway dysregulation based on EDN1, EDNRA, EDNRB and ARRB1 mRNA expression in LAM-derived primary cells. We showed overexpression of EDN1 and ARRB1 mRNAs in TSC2NEG cells; these cells lost their ability to respond to stimulation by endothelin. We analyzed the effects of endothelin receptor antagonists alone or in combination with rapamycin, an mTOR inhibitor, on proliferation and migration of LAM cells. Rapamycin treatment of TSC2NEG cells significantly reduced cell proliferation or migration, while none of the tested inhibitors of EDN receptors impaired these functions. We showed that TSC2NEG cells have acquired a transformed phenotype as showed by their ability to grow as spheroids in semi-solid medium and that unlike endothelin receptors antagonists, rapamycin reduced anchorage-independent cell growth and prevented expansion of TSC2NEG spheroids.
A Non-Targeted LC-MS Profiling Reveals Elevated Levels of Carnitine Precursors and Trimethylated Compounds in the Cord Plasma of Pre-Eclamptic Infants
Authors: Jääskeläinen Tiina , Kärkkäinen Olli , Jokkala Jenna , Litonius Kaisa , Heinonen Seppo , Auriola Seppo , Lehtonen Marko , Hanhineva Kati , Laivuori Hannele ,   FINNPEC, Kajantie Eero , Kere Juha , Kivinen Katja , Pouta Anneli
Published: September 2018

Preeclampsia (PE) is a complex pregnancy disorder. It is not extensively known how the metabolic alterations of PE women contribute to the metabolism of newborn. We applied liquid chromatography-mass spectrometry (LC-MS) based non-targeted metabolomics to determine whether the metabolic profile of plasma from umbilical cord differs between infants born to PE and non-PE pregnancies in the FINNPEC study. Cord plasma was available from 42 newborns born from PE and 53 from non-PE pregnancies. 133 molecular features differed between PE and non-PE newborns after correction for multiple testing. Decreased levels of 4-pyridoxic acid were observed in the cord plasma samples of PE newborns when compared to non-PE newborns. Compounds representing following areas of metabolism were increased in the cord plasma of PE newborns: urea and creatine metabolism; carnitine biosynthesis and acylcarnitines; putrescine metabolites; tryptophan metabolism and phosphatidylcholines. To our knowledge, this study is the first one to apply LC-MS based metabolomics in cord plasma of PE newborns. We demonstrate that this strategy provides a global picture of the widespread metabolic alterations associated with PE and particularly the elevated levels of carnitine precursors and trimethylated compounds appear to be associated with PE at birth.
Allosteric Role of Substrate Occupancy Toward the Alignment of P-glycoprotein Nucleotide Binding Domains
Authors: Pan Lurong , Aller Stephen G.
Published: September 2018

P-glycoprotein (Pgp) is an ATP-binding cassette transporter that eliminates toxins from the cell but causes multidrug resistance in chemotherapies. The crystal structures of Pgp revealed drug-like compounds bound to an inward-facing conformation in which the energy-harnessing nucleotide binding domains (NBDs) were widely separated with no interfacial interaction. Following drug binding, inward-facing Pgp must transition to an NBD dimer conformation to achieve ATP binding and hydrolysis at canonical sites defined by both halves of the interface. However, given the high degree of flexibility shown for this transporter, it is difficult to envision how NBDs overcome entropic considerations for achieving proper alignment in order to form the canonical ATP binding site. We explored the hypothesis that substrate occupancy of the polyspecific drug-binding cavity plays a role in the proper alignment of NBDs using computational approaches. We conducted twelve atomistic molecular dynamics (MD) simulations (100–300 ns) on inward-facing Pgp in a lipid bilayer with and without small molecule substrates to ascertain effects of drug occupancy on NBD dimerization. Both apo- and drug-occupied simulations showed NBDs approaching each other compared to the crystal structures. Apo-Pgp reached a pseudo-dimerization in which NBD signature motifs for ATP binding exhibited a significant misalignment during closure. In contrast, occupancy of three established substrates positioned by molecular docking achieved NBD alignment that was much more compatible with a canonical NBD dimerization trajectory. Additionally, aromatic amino acids, known to confer the polyspecific drug-binding characteristic of the internal pocket, may also govern polyspecific drug access to the cavity. The enrichment of aromatics comprising the TM4-TM6 portal suggested a preferential pathway over the aromatic-poor TM10-TM12 for lateral drug entry from the lipid bilayer. Our study also suggested that drug polyspecificity is enhanced due to a synergism between multiple drug-domain interactions involving 36 residues identified in TM1, 5, 6, 7, 11 and 12.
Discordant multi-decadal trend in the intensity of the Kuroshio along its path during 1993–2013
Authors: Wang You-Lin , Wu Chau-Ron
Published: September 2018

The Kuroshio transports warm water in the Pacific poleward from the tropics and plays a crucial role in modulating surrounding climate. Based on independent data sets, we demonstrated that the Kuroshio weakened downstream east of Taiwan, but intensified upstream east of Luzon Island during 1993–2013. The surface velocity (volume transport) of the Kuroshio has decreased 12.5% (4~5%) off east Taiwan but increased 18% (8~18%) off east Luzon. The discordant upstream–downstream trend was attributable to changes in oceanic eddies and basin surface winds: greater (lesser) cyclonic eddies, lesser (greater) anticyclonic eddies, and positive (negative) tendency in the Pacific Basin wind curl contributed to a weakened (intensified) downstream (upstream) Kuroshio. The difference in water mass between the upstream and downstream Kuroshio was balanced by an anomalous eastward flow, the southern branch of the Subtropical Counter Current which was enhanced and evacuated the redundant water eastward into the Pacific.