bluuebunny/crossref_metadata_2025 huggingface dataset:
New data on the microvertebrate fauna from the Upper Jurassic or lowest Cretaceous of Ksar Metlili (Anoual Syncline, eastern Morocco)
Authors: Lasseron Maxime , Allain Ronan , Gheerbrant Emmanuel , Haddoumi Hamid , Jalil Nour-Eddine , Métais Grégoire , Rage Jean-Claude , Vullo Romain , Zouhri Samir
Published: September 2019

The Middle Jurassic – Early Cretaceous period witnessed the emergence of some major representatives of modern continental vertebrate groups (stem lissamphibians, squamates, therian mammals and birds) and angiosperms, at a time when fragmentation of Pangaea was underway. The successive Moroccan microvertebrate faunas of Ksar Metlili (?Berriasian) and Guelb el Ahmar (Bathonian) from the Anoual Syncline significantly improve our poor knowledge of Gondwanan and especially African palaeobiodiversity at this time. They are among the richest known from the Mesozoic of Gondwana, and are well placed in northwestern Africa to record faunal interchanges with Laurasia. Here we focus on the Ksar Metlili fauna, first documented in the 1980s and most recently resampled in 2010, which produced 24 541 microremains representing 47 species of 8 main groups (Chondrichthyes, Actinopterygii, Sarcopterygii, Lissamphibia, Lepidosauromorpha, Testudinata, Archosauromorpha and Synapsida). It includes remarkable taxa: the oldest stem boreosphenidan mammals from Gondwana, probably some of the last non-mammaliaform cynodonts, a basal ornithischian, possibly freshwater teleosaurid crocodylomorphs, and some of the rare occurrences of choristoderes and albanerpetontids in Gondwana. Comparison of the Ksar Metlili fauna with that of Guimarota (Kimmeridgian, Portugal) further provides evidence of numerous shared taxa of Laurasian affinities, in contrast to the occurrence of few taxa with Gondwanan affinities. This suggests complex palaeobiogeographical relationships – implying both vicariance and dispersal events – of North Africa within Gondwana at the Jurassic–Cretaceous transition. Finally, the faunal similarities with the Guelb el Ahmar fauna question the Cretaceous age of the Ksar Metlili fauna, suggesting an alternative possible Late Jurassic age.
The Making of a National Currency: Spatial Transaction Costs and Money Market Integration in Spain (1825–1874)
Authors: Nogues-Marco Pilar , Herranz-Loncán Alfonso , Aslanidis Nektarios
Published: September 2019

This article analyzes the integration of the Spanish money market in the nineteenth century. We use a Band-Threshold Autoregression model of prices of bills-of-exchange in ten cities to measure market convergence and efficiency in 1825–1875. While price gaps generally decreased during the period, progress in efficiency was limited to a small group of cities. We suggest that convergence was associated to the reduction in transaction costs, which started well before the railways through improvements in roads and postal services. By contrast, the heterogeneous behavior of efficiency might be associated to economic geography changes and their effects on monetary leadership.
A phonological account of Tlapanec (Mè’phàà) tonal alternation
Authors: UCHIHARA HIROTO , TIBURCIO CANO GREGORIO
Published: September 2019

Tlapanec (Mè’phàà) is known for its enigmatic tonal alternation in verb forms according to person and aspect-mode categories, in addition to suppletion and other segmental alternations. In this paper, we argue that the tonal alternations observed in Tlapanec regular agentive verbs can be straightforwardly accounted for by phonology, without resorting to any extreme abstractness: the lexical tones of the prefixes and the verb stems, with underspecification and floating tones, and cross-linguistically common tone processes such as tone spreading and floating tone docking. Such a phonological (or a morpheme-based) approach is contrasted with a word-based approach, where tonal alternations are viewed as inflectional classes. We show that the phonological approach is more adequate than a word-based approach.
Billingshausen of the Antarctic?
Authors: Bulkeley Rip
Published: September 2019

The Russian naval officer Faddej Faddeevich Bellingshausen began life with a slightly different surname, in his case ‘Billingshausen’. It is possible to work out roughly when the Russian surname ‘Bellinsgauzen’ was chosen. Considerations prompting the selection of that particular Russian version can also be suggested.
POPULAR DIVINE IMAGERY IN HELLENISTIC AND ROMAN ALEXANDRIA. THE TERRACOTTA FIGURINES COLLECTION OF THE PATRIARCHAL SACRISTY IN ALEXANDRIA
Authors: Savvopoulos Kyriakos
Published: September 2019

Terracotta figurines represent one of the most fascinating categories of material evidence from Hellenistic (Ptolemaic) and Roman Egypt relating to the domestic aspects of religious life. They include deities, ordinary humans, animals and sacred symbols, represented in exhaustive variety, both in terms of content and form. The group of terracotta figurines presented in this paper are no exception. It is drawn from the collection of the Sacristy of the Greek-Orthodox Patriarchate of Alexandria and All Africa, exhibited in a most impressive Roman cistern, which was discovered during the recent renovation of the Patriarchate premises. The catalogue will be accompanied by a concise overview of the nature and role of the main divine protagonists in comparison to other types of material evidence such as statuary, architecture, coinage and epigraphy, focusing on Alexandria, the capital of Egypt during the Ptolemaic and Roman periods.
Study of the dielectric properties of ACu3Ti4O12 (A = Eu2/3, Tb2/3, and Na1/2Eu1/2)
Authors: Li M. , Shen Y. , Li C. X.
Published: September 2019

We report the dielectric properties of ACu3Ti4O12 (A = Eu2/3, Tb2/3, and Na1/2Eu1/2) (ACTO) in the frequency range of 40 Hz–2.5 MHz and in the temperature range of 293–473 K. The experimental results show that substituting for Ca improves the loss tangent of CaCu3Ti4O12 (CCTO). Although the dielectric constants largely decrease, they remain at a high level of 103. To identify the observed dielectric performances of ACTO, scanning electron microscopy and complex impedance measurements were conducted. The conducting mechanism for the grain of ACTO was found to be ion jumping rather than electron hopping (for the grain of CCTO). The results show that the decreased dielectric constant may be related to the decreased grain size, the different carrier in the grain, the different grain boundary properties, or a combination of these factors. All these factors are associated with the deficiency of oxygen vacancies in the samples of ACTO. The decreased loss tangent may be due to the increase in the grain boundary resistance.
When a linguistic variable doesn’t vary (much): The subjunctive mood in a conservative variety of Acadian French and its relevance to the actuation problem
Authors: Comeau Philip
Published: September 2019

This study considers the subjunctive mood in one of the most conservative varieties of Acadian French, that spoken in the Baie Sainte-Marie region in the Canadian province of Nova Scotia. A number of claims made in the literature are considered: whether the subjunctive mood is undergoing loss, whether it expresses semantic meaning, and whether it is lexically-conditioned. Unlike most spoken varieties of French where the subjunctive is argued to be a linguistic variable (i.e., it varies with other moods), the results for Baie Sainte-Marie show that it varies very little. The analysis reveals that the few cases of variation can be accounted for by formal theoretical approaches to the subjunctive where this mood is argued to express modality. With limited variation, the subjunctive is not showing signs of loss. These findings suggest that the subjunctive is not part of a linguistic variable and so is not subject to inherent variability. I further argue that the retention of the imperfect subjunctive in this variety, along with a tense concordance effect, can help us understand why the subjunctive became a linguistic variable in other varieties of French, which ultimately contributes to our understanding of the actuation problem.
Recent surge of ready meals in South Korea: can they be healthy alternatives?
Authors: Kim So-young , Kim Suyoun
Published: September 2019

Objective:

The present study analysed and compared the nutritional qualities of private brand (PB) and national brand (NB) ready meal (RM) products in South Korea.

Design:

Data on RM products were collected via a food information database (EatSight) between February and May of 2017. A total of ninety-one PB products from a leading discount store chain in South Korea and 415 NB products were selected and divided into four main categories of ‘refrigerated soups/stews’, ‘refrigerated noodles’, ‘frozen rice/noodles’ and ‘frozen dumplings’. Nutritional information was extracted for each product and analyses were performed to compare nutritional differences.

Setting:

South Korea.

Participants:

A total of 506 RM products.

Results:

PB products explained the highest percentage of refrigerated RM products while NB products occupied the highest percentage of frozen ones. Notably, main PB and NB products showed evident nutritional problems. Among PB products, refrigerated soups/stews were significantly higher in energy, fat, Na, saturated fat andtrans-fat. Likewise, in the case of NB products, frozen rice/noodles were significantly higher in Na and saturated fat. Particularly, overall Na contents were high. When the Korean guidance on traffic-light labelling was applied, a mere 0·2 and 5·9 % of total RM products showed all four and three green lights, respectively. Meanwhile, those with no green lights accounted for 42·3 %.

Conclusions:

Although it is difficult to draw a definitive conclusion on the comparative nutritional qualities due to the lack of consistency in the results, the study suggests that there is room to improve the nutritional qualities of overall RM products.
Beyond NP: Quantifying over Answer Sets
Authors: AMENDOLA GIOVANNI , RICCA FRANCESCO , TRUSZCZYNSKI MIROSLAW
Published: September 2019

Answer Set Programming (ASP) is a logic programming paradigm featuring a purely declarative language with comparatively high modeling capabilities. Indeed, ASP can model problems in NP in a compact and elegant way. However, modeling problems beyond NP with ASP is known to be complicated, on the one hand, and limited to problems in $\[\Sigma _2^P\]$ on the other. Inspired by the way Quantified Boolean Formulas extend SAT formulas to model problems beyond NP, we propose an extension of ASP that introduces quantifiers over stable models of programs. We name the new language ASP with Quantifiers (ASP(Q)). In the paper we identify computational properties of ASP(Q); we highlight its modeling capabilities by reporting natural encodings of several complex problems with applications in artificial intelligence and number theory; and we compare ASP(Q) with related languages. Arguably, ASP(Q) allows one to model problems in the Polynomial Hierarchy in a direct way, providing an elegant expansion of ASP beyond the class NP.
Online Event Recognition from Moving Vehicles: Application Paper
Authors: TSILIONIS EFTHIMIS , KOUTROUMANIS NIKOLAOS , NIKITOPOULOS PANAGIOTIS , DOULKERIDIS CHRISTOS , ARTIKIS ALEXANDER
Published: September 2019

We present a system for online composite event recognition over streaming positions of commercial vehicles. Our system employs a data enrichment module, augmenting the mobility data with external information, such as weather data and proximity to points of interest. In addition, the composite event recognition module, based on a highly optimised logic programming implementation of the Event Calculus, consumes the enriched data and identifies activities that are beneficial in fleet management applications. We evaluate our system on large, real-world data from commercial vehicles, and illustrate its efficiency.
Partial Compilation of ASP Programs
Authors: CUTERI BERNARDO , DODARO CARMINE , RICCA FRANCESCO , SCHÜLLER PETER
Published: September 2019

Answer Set Programming (ASP) is a well-known declarative formalism in logic programming. Efficient implementations made it possible to apply ASP in many scenarios, ranging from deductive databases applications to the solution of hard combinatorial problems. State-of-the-art ASP systems are based on the traditional ground&solve approach and are general-purpose implementations, i.e., they are essentially built once for any kind of input program. In this paper, we propose an extended architecture for ASP systems, in which parts of the input program are compiled into an ad-hoc evaluation algorithm (i.e., we obtain a specific binary for a given program), and might not be subject to the grounding step. To this end, we identify a condition that allows the compilation of a sub-program, and present the related partial compilation technique. Importantly, we have implemented the new approach on top of a well-known ASP solver and conducted an experimental analysis on publicly-available benchmarks. Results show that our compilation-based approach improves on the state of the art in various scenarios, including cases in which the input program is stratified or the grounding blow-up makes the evaluation unpractical with traditional ASP systems.
Domain-Independent Cost-Optimal Planning in ASP
Authors: SPIES DAVID , YOU JIA-HUAI , HAYWARD RYAN
Published: September 2019

We investigate the problem of cost-optimal planning in ASP. Current ASP planners can be trivially extended to a cost-optimal one by adding weak constraints, but only for a given makespan (number of steps). It is desirable to have a planner that guarantees global optimality. In this paper, we present two approaches to addressing this problem. First, we show how to engineer a cost-optimal planner composed of two ASP programs running in parallel. Using lessons learned from this, we then develop an entirely new approach to cost-optimal planning,stepless planning, which is completely free of makespan. Experiments to compare the two approaches with the only known cost-optimal planner in SAT reveal good potentials for stepless planning in ASP.
Tri-beam slot antenna array based on substrate integrated waveguide (SIW) technology
Authors: Wang Zhenye , Dai Xiwang , Sun Wen
Published: September 2019

A novel tri-beam slot antenna array based on substrate integrated waveguide (SIW) technology is proposed in this paper. The beam forming network is a 3 × 3 Butler matrix consisted of three couplers and four phase shifters. A 1.76 dB coupler is located between two 3 dB couplers, with this arrangement; the input signal can be divided into three parts with the same amplitude and certain phase differences. Two parallel slots are cut off broadside of SIW transmission line, which constitutes the basic unit of the antenna array. A 3 × 2 slot antenna array is connected with this circuit. Three beams with the directions of −30, 0 and 30° are produced when different ports are excited, respectively. The S parameters, radiation patterns, and gains are simulated and measured, which show that it can be a candidate for multi-beam wireless communication systems.
Inequality, SDG10 and the financial system
Authors: de Vries Bert J. M.
Published: September 2019

Non-technical summary

One of the Sustainable Development Goals, number 10, is about reducing inequality within and between countries. This paper argues that the existing structure of the (international) financial system is, for various reasons, one of the determinants of (growing) inequality. This should receive more attention.
Sicherheitsrundgänge – Abteilungsbesuche mit Fokus auf die Patientensicherheit
Authors: Schwendimann René , Klimmeck-Bader Sabrina , Mohr Giulia
Published: September 2019

Zusammenfassung. Hintergrund: Zur Förderung der Sicherheitskultur und Optimierung der Patientensicherheit gelten „Safety Walk Rounds“ (Sicherheitsrundgänge) als eine vielversprechende Strategie. Der Zweck dieser Praxisstudie war die krankenhausweite Bestandsaufnahme der Patientensicherheit und der vorherrschenden Sicherheitskultur. Des Weiteren sollten der Handlungsbedarf erfasst und Empfehlungen an die Kliniken und Stationen gegeben werden. Methode: Die Sicherheitsrundgänge wurden durch den Abteilungsleiter für Patientensicherheit mit den Fachpersonen und Teams der verschiedenen klinischen Bereiche durchgeführt. Die Besprechungen fanden anhand eines strukturierten Leitfadens mit Fragen zur Patientensicherheit statt. Die Gesprächsnotizen wurden ausgewertet und Themenkategorien zugeordnet. Ergebnisse: Insgesamt beteiligten sich 187 Fachpersonen (64 % Pflegende, 19 % Ärztinnen und –ärzte in leitender Position, 17 % andere Berufsgruppen) an den Sicherheitsrundgängen. Die Gesprächsergebnisse zur Patientensicherheit lassen sich in vier Kategorien darstellen: Ereignisse & Umstände (potenzieller) Gefährdung der Patientensicherheit, Sicherheitskultur, Handlungsbedarf, sowie der geäußerte Unterstützungsbedarf. Schlussfolgerung und Ausblick: Die Sicherheitsrundgänge vermittelten vertiefte Einblicke in die lokalen Behandlungs- und Pflegepraktiken der interprofessionellen Teams und identifizierten konkrete Handlungsbedarfe zur Förderung der Patientensicherheit.
Deacetylation of XBP1s by sirtuin 6 confers resistance to ER stress-induced hepatic steatosis
Authors: Bang In Hyuk , Kwon Oh Kwang , Hao Lihua , Park Dami , Chung Myung-Ja , Oh Byung-Chul , Lee Sangkyu , Bae Eun Ju , Park Byung-Hyun
Published: September 2019

The active spliced form of X-box-binding protein 1 (XBP1s) is a key modulator of ER stress, but the functional role of its post-translational modification remains unclear. Here, we demonstrate that XBP1s is a deacetylation target of Sirt6 and that its deacetylation protects against ER stress-induced hepatic steatosis. Specifically, the abundance of acetylated XBP1s and concordant hepatic steatosis were increased in hepatocyte-specific Sirt6 knockout and obese mice but were decreased by genetic overexpression and pharmacological activation of Sirt6. Mechanistically, we identified that Sirt6 deacetylated a transactivation domain of XBP1s at Lys257 and Lys297 and promoted XBP1s protein degradation through the ubiquitin-proteasome system. Overexpression of XBP1s, but not its deacetylation mutant 2KR (K257/297R), in mice increased lipid accumulation in the liver. Importantly, in liver tissues obtained from patients with nonalcoholic fatty liver disease (NAFLD), the extent of XBP1s acetylation correlated positively with the NAFLD activity score but negatively with the Sirt6 level. Collectively, we present direct evidence supporting the importance of XBP1 acetylation in ER stress-induced hepatic steatosis.
RAF kinases are stabilized and required for dendritic cell differentiation and function
Authors: Riegel Kristina , Schlöder Janine , Sobczak Marco , Jonuleit Helmut , Thiede Bernd , Schild Hansjörg , Rajalingam Krishnaraj
Published: September 2019

RAF kinases (ARAF, BRAF, and CRAF) are highly conserved enzymes that trigger the RAF-MEK1/2-ERK1/2 (MAPK) pathway upon activation of RAS. Despite enormous clinical interest, relatively little is known on the role of RAFs in mediating immune responses. Here, we investigated the role of RAF kinases and MEK1/2 in dendritic cells (DCs), the central regulators of T cell-mediated antitumor immune responses and the adaptive immune system. We demonstrate that RAF kinases are active and stabilized at their protein levels during DC differentiation. Inhibition of RAF kinases but not MEK1/2 impaired the activation of DCs in both mice and human. As expected, DCs treated with RAF inhibitors show defects in activating T cells. Further, RAF and MEK1/2 kinases are directly required for the activation and proliferation of CD4+T cells. Our observations suggest that RAF and MEK1/2 have independent roles in regulating DC function that has important implications for administering RAF–MAPK inhibitors in the clinics.
LINC01232 exerts oncogenic activities in pancreatic adenocarcinoma via regulation of TM9SF2
Authors: Li Qian , Lei Chengbin , Lu Changliang , Wang Jingye , Gao Min , Gao Wei
Published: September 2019

Pancreatic adenocarcinoma (PAAD), one of the most prevailing malignant tumors in digestive system, is identified as one of the main culprits of cancer-associated mortality. Despite long intergenic non-protein coding RNA 1232 (LINC01232) is found to be upregulated in TCGA PAAD tissues and associated with poor prognosis, the potential of LINC01232 in PAAD progression still needs more explorations. In this study, LINC01232 was chosen to be the research object in PAAD cellular processes. Functionally, loss-of function assays were carried out and the experimental results indicated that suppression of LINC01232 hindered the deterioration of PAAD by affecting cell proliferation and migration. Furthermore, relationship between LINC01232 and its nearby gene transmembrane 9 superfamily member 2 (TM9SF2) was investigated. The same expression pattern of TM9SF2 in TCGA PAAD samples was observed. It was found that upregulation of LINC01232 could be a crucial factor for the dysregulation of TM9SF2. Mechanistically, LINC01232 recruited EIF4A3 to boost TM9SF2 mRNA stability. Besides, our findings demonstrated that the transcriptional activation of LINC01232 and TM9SF2 was mediated by SP1. Therefore, we concluded that LINC01232 executed carcinogenic properties in PAAD progression via regulation of TM9SF2. In conclusion, this study was the first to unveil the role and molecular mechanism of LINC01232, suggesting LINC01232 as a promising molecular target for pancreatic cancer treatment.
Chromosomal instability of circulating tumor DNA reflect therapeutic responses in advanced gastric cancer
Authors: Chen Zuhua , Zhang Cheng , Zhang Mengqi , Li Beifang , Niu Yunyun , Chen Limeng , Yang Jing , Lu Sijia , Gao Jing , Shen Lin
Published: September 2019

Gastric cancer is characterized by chromosomal instability. In this study, we investigated chromosomal instability quantified by copy number instability (CNI) score of circulating tumor DNA (ctDNA) during the drug treatment in advanced gastric cancer (AGC). A total of 55 pretherapeutic plasmas from 55 AGC patients and 75 plasmas during drug treatment of 26 AGC patients were collected. Plasma ctDNA was extracted and assessed by whole-genome sequencing (WGS) for somatic copy number alteration (SCNA), and according to which we calculated the CNI scores. We next assessed the correlations between chromosomal instability and therapeutic response. The cutoff value of chromosomal instability was defined as the mean + SD of the CNI scores (56.60) in cfDNA of plasmas from 100 healthy people. For 55 enrolled cases, chromosomal instability was observed in 27 (49%) prior to drug treatment, whose response rate (59%, 16/27) was higher than in 28 patients with stable chromosomes (32%, 9/28, P = 0.043). We also observed that CNI scores fluctuated during treatment in 26 patients. Specifically, the CNI scores in 93% (14/15) of patients sensitive to drug treatment reduced to the level of chromosomal stability and the CNI scores in 52% (13/25) of patients resistant to treatment elevated again. For ctDNA with developed resistance, the SCNA patterns were identical to those before treatment, whereas the CNI scores were lower than the pretherapeutic scores. We found that chromosomal instability based on ctDNA could predict and monitor therapeutic response in gastric cancer, although validation in a larger cohort will be necessary.
DPEP1 is a direct target of miR-193a-5p and promotes hepatoblastoma progression by PI3K/Akt/mTOR pathway
Authors: Cui Xichun , Liu Xin , Han Qicai , Zhu Jianming , Li Jianhao , Ren Zhigang , Liu Liwen , Luo Yanbing , Wang Zhifang , Zhang Dandan , Fan Yingzhong , Zhang Da , Dong Gang
Published: September 2019

Hepatoblastoma (HB) is the most common hepatic neoplasm in childhood and the therapeutic outcomes remain undesirable due to its recurrence and metastasis. Increasing evidence shows that dipeptidase 1 (DPEP1) has pivotal function in tumorigenesis in multiple tumors. However, the expression pattern, biological function, and underlying mechanism of DPEP1 in HB have not been reported. Here we showed that DPEP1 was significantly upregulated and was associated with poor prognosis in HB patients. In vitro and in vivo assays indicated that silencing DPEP1 significantly suppressed HB cell proliferation, migration, and invasion, while DPEP1 overexpression exhibited the opposite effect. In addition, we identified that DPEP1 was a direct target of microRNA-193a-5p (miR-193a-5p). Functional experiments demonstrated that overexpression of miR-193a-5p significantly inhibited cell proliferation and invasion of HB cells, while the inhibitory effect could be reversed by DPEP1 overexpression. Moreover, miR-193a-5p was decreased in HB tumor tissues and associated with a poor clinical prognosis. Mechanistically, our results indicated that the miR-193a-5p/DPEP1 axis participated to the progression of HB via regulating the PI3K/Akt/mTOR (phosphatidylinositol-3-kinase/Akt/mammalian target of rapamycin) signaling. In conclusion, our findings suggest that the miR-193a-5p /DPEP1 axis might be a good prognostic predictor and therapeutic target in HB.
Video-rate multi-color structured illumination microscopy with simultaneous real-time reconstruction
Authors: Markwirth Andreas , Lachetta Mario , Mönkemöller Viola , Heintzmann Rainer , Hübner Wolfgang , Huser Thomas , Müller Marcel
Published: September 2019

Super-resolved structured illumination microscopy (SR-SIM) is among the fastest fluorescence microscopy techniques capable of surpassing the optical diffraction limit. Current custom-build instruments are able to deliver two-fold resolution enhancement with high acquisition speed. SR-SIM is usually a two-step process, with raw-data acquisition and subsequent, time-consuming post-processing for image reconstruction. In contrast, wide-field and (multi-spot) confocal techniques produce high-resolution images instantly. Such immediacy is also possible with SR-SIM, by tight integration of a video-rate capable SIM with fast reconstruction software. Here we present instant SR-SIM by VIGOR (Video-rate Immediate GPU-accelerated Open-Source Reconstruction). We demonstrate multi-color SR-SIM at video frame-rates, with less than 250 ms delay between measurement and reconstructed image display. This is achieved by modifying and extending high-speed SR-SIM image acquisition with a new, GPU-enhanced, network-enabled image-reconstruction software. We demonstrate high-speed surveying of biological samples in multiple colors and live imaging of moving mitochondria as an example of intracellular dynamics.
Ran pathway-independent regulation of mitotic Golgi disassembly by Importin-α
Authors: Chang Chih-Chia , Chen Ching-Jou , Grauffel Cédric , Pien Yu-Chung , Lim Carmay , Tsai Su-Yi , Hsia Kuo-Chiang
Published: September 2019

To facilitate proper mitotic cell partitioning, the Golgi disassembles by suppressing vesicle fusion. However, the underlying mechanism has not been characterized previously. Here, we report a Ran pathway-independent attenuation mechanism that allows Importin-α (a nuclear transport factor) to suppress the vesicle fusion mediated by p115 (a vesicular tethering factor) and is required for mitotic Golgi disassembly. We demonstrate that Importin-α directly competes with p115 for interaction with the Golgi protein GM130. This interaction, promoted by a phosphate moiety on GM130, is independent of Importin-β and Ran. A GM130 K34A mutant, in which the Importin-α-GM130 interaction is specifically disrupted, exhibited abundant Golgi puncta during metaphase. Importantly, a mutant showing enhanced p115-GM130 interaction presented proliferative defects and G2/M arrest, demonstrating that Importin-α-GM130 binding modulates the Golgi disassembly that governs mitotic progression. Our findings illuminate that the Ran and kinase-phosphatase pathways regulate multiple aspects of mitosis coordinated by Importin-α (e.g. spindle assembly, Golgi disassembly).
Spin current generation in organic antiferromagnets
Authors: Naka Makoto , Hayami Satoru , Kusunose Hiroaki , Yanagi Yuki , Motome Yukitoshi , Seo Hitoshi
Published: September 2019

Spin current–a flow of electron spins without a charge current–is an ideal information carrier free from Joule heating for electronic devices. The celebrated spin Hall effect, which arises from the relativistic spin-orbit coupling, enables us to generate and detect spin currents in inorganic materials and semiconductors, taking advantage of their constituent heavy atoms. In contrast, organic materials consisting of molecules with light elements have been believed to be unsuited for spin current generation. Here we show that a class of organic antiferromagnets with checker-plate type molecular arrangements can serve as a spin current generator by applying a thermal gradient or an electric field, even with vanishing spin-orbit coupling. Our findings provide another route to create a spin current distinct from the conventional spin Hall effect and open a new field of spintronics based on organic magnets having advantages of small spin scattering and long lifetime.
Structure of Csx1-cOA4 complex reveals the basis of RNA decay in Type III-B CRISPR-Cas
Authors: Molina Rafael , Stella Stefano , Feng Mingxia , Sofos Nicholas , Jauniskis Vykintas , Pozdnyakova Irina , López-Méndez Blanca , She Qunxin , Montoya Guillermo
Published: September 2019

Type III CRISPR-Cas multisubunit complexes cleave ssRNA and ssDNA. These activities promote the generation of cyclic oligoadenylate (cOA), which activates associated CRISPR-Cas RNases from the Csm/Csx families, triggering a massive RNA decay to provide immunity from genetic invaders. Here we present the structure of Sulfolobus islandicus (Sis) Csx1-cOA4 complex revealing the allosteric activation of its RNase activity. SisCsx1 is a hexamer built by a trimer of dimers. Each dimer forms a cOA4 binding site and a ssRNA catalytic pocket. cOA4 undergoes a conformational change upon binding in the second messenger binding site activating ssRNA degradation in the catalytic pockets. Activation is transmitted in an allosteric manner through an intermediate HTH domain, which joins the cOA4 and catalytic sites. The RNase functions in a sequential cooperative fashion, hydrolyzing phosphodiester bonds in 5′-C-C-3′. The degradation of cOA4 by Ring nucleases deactivates SisCsx1, suggesting that this enzyme could be employed in biotechnological applications.
Dual-phase nanostructuring of layered metal oxides for high-performance aqueous rechargeable potassium ion microbatteries
Authors: Li Ying-Qi , Shi Hang , Wang Sheng-Bo , Zhou Yi-Tong , Wen Zi , Lang Xing-You , Jiang Qing
Published: September 2019

Aqueous rechargeable microbatteries are promising on-chip micropower sources for a wide variety of miniaturized electronics. However, their development is plagued by state-of-the-art electrode materials due to low capacity and poor rate capability. Here we show that layered potassium vanadium oxides, KxV2O5·nH2O, have an amorphous/crystalline dual-phase nanostructure to show genuine potential as high-performance anode materials of aqueous rechargeable potassium-ion microbatteries. The dual-phase nanostructured KxV2O5·nH2O keeps large interlayer spacing while removing secondary-bound interlayer water to create sufficient channels and accommodation sites for hydrated potassium cations. This unique nanostructure facilitates accessibility/transport of guest hydrated potassium cations to significantly improve practical capacity and rate performance of the constituent KxV2O5·nH2O. The potassium-ion microbatteries with KxV2O5·nH2O anode and KxMnO2·nH2O cathode constructed on interdigital-patterned nanoporous metal current microcollectors exhibit ultrahigh energy density of 103 mWh cm−3 at electrical power comparable to carbon-based microsupercapacitors.
Time elapsed between Zika and dengue virus infections affects antibody and T cell responses
Authors: Pérez-Guzmán Erick X. , Pantoja Petraleigh , Serrano-Collazo Crisanta , Hassert Mariah A. , Ortiz-Rosa Alexandra , Rodríguez Idia V. , Giavedoni Luis , Hodara Vida , Parodi Laura , Cruz Lorna , Arana Teresa , White Laura J. , Martínez Melween I. , Weiskopf Daniela , Brien James D. , de Silva Aravinda , Pinto Amelia K. , Sariol Carlos A.
Published: September 2019

Zika virus (ZIKV) and dengue virus (DENV) are co-endemic in many parts of the world, but the impact of ZIKV infection on subsequent DENV infection is not well understood. Here we show in rhesus macaques that the time elapsed after ZIKV infection affects the immune response to DENV infection. We show that previous ZIKV exposure increases the magnitude of the antibody and T cell responses against DENV. The time interval between ZIKV and subsequent DENV infection further affects the immune response. A mid-convalescent period of 10 months after ZIKV infection results in higher and more durable antibody and T cell responses to DENV infection than a short period of 2 months. In contrast, previous ZIKV infection does not affect DENV viremia or pro-inflammatory status. Collectively, we find no evidence of a detrimental effect of ZIKV immunity in a subsequent DENV infection. This supports the implementation of ZIKV vaccines that could also boost immunity against future DENV epidemics.
Nanomechanics and co-transcriptional folding of Spinach and Mango
Authors: Mitra Jaba , Ha Taekjip
Published: September 2019

Recent advances in fluorogen-binding “light-up” RNA aptamers have enabled protein-free detection of RNA in cells. Detailed biophysical characterization of folding of G-Quadruplex (GQ)-based light-up aptamers such as Spinach, Mango and Corn is still lacking despite the potential implications on their folding and function. In this work we employ single-molecule fluorescence-force spectroscopy to examine mechanical responses of Spinach2, iMangoIII and MangoIV. Spinach2 unfolds in four discrete steps as force is increased to 7 pN and refolds in reciprocal steps upon force relaxation. In contrast, GQ-core unfolding in iMangoIII and MangoIV occurs in one discrete step at forces >10 pN and refolding occurred at lower forces showing hysteresis. Co-transcriptional folding using superhelicases shows reduced misfolding propensity and allowed a folding pathway different from refolding. Under physiologically relevant pico-Newton levels of force, these aptamers may unfold in vivo and subsequently misfold. Understanding of the dynamics of RNA aptamers will aid engineering of improved fluorogenic modules for cellular applications.
Regulation of the endosomal SNX27-retromer by OTULIN
Authors: Stangl Aurelia , Elliott Paul R. , Pinto-Fernandez Adan , Bonham Sarah , Harrison Luke , Schaub Annalisa , Kutzner Kerstin , Keusekotten Kirstin , Pfluger Paul T. , El Oualid Farid , Kessler Benedikt M. , Komander David , Krappmann Daniel
Published: September 2019

OTULIN (OTU Deubiquitinase With Linear Linkage Specificity) specifically hydrolyzes methionine1 (Met1)-linked ubiquitin chains conjugated by LUBAC (linear ubiquitin chain assembly complex). Here we report on the mass spectrometric identification of the OTULIN interactor SNX27 (sorting nexin 27), an adaptor of the endosomal retromer complex responsible for protein recycling to the cell surface. The C-terminal PDZ-binding motif (PDZbm) in OTULIN associates with the cargo-binding site in the PDZ domain of SNX27. By solving the structure of the OTU domain in complex with the PDZ domain, we demonstrate that a second interface contributes to the selective, high affinity interaction of OTULIN and SNX27. SNX27 does not affect OTULIN catalytic activity, OTULIN-LUBAC binding or Met1-linked ubiquitin chain homeostasis. However, via association, OTULIN antagonizes SNX27-dependent cargo loading, binding of SNX27 to the VPS26A-retromer subunit and endosome-to-plasma membrane trafficking. Thus, we define an additional, non-catalytic function of OTULIN in the regulation of SNX27-retromer assembly and recycling to the cell surface.
Open data on industry payments to healthcare providers reveal potential hidden costs to the public
Authors: Mejia Jorge , Mejia Amanda , Pestilli Franco
Published: September 2019

Healthcare industry players make payments to medical providers for non-research expenses. While these payments may pose conflicts of interest, their relationship with overall healthcare costs remains largely unknown. In this study, we linked Open Payments data on providers’ industry payments with Medicare data on healthcare costs. We investigated 374,766 providers’ industry payments and healthcare costs. We demonstrate that providers receiving higher amounts of industry payments tend to bill higher drug and medical costs. Specifically, we find that a 10% increase in industry payments is associated with 1.3% higher medical and 1.8% higher drug costs. For a typical provider, for example, a 10% or $25 increase in annual industry payments would be associated with approximately $1,100 higher medical costs and $100 higher drug costs. Furthermore, the association between payments and healthcare costs varies markedly across states and correlates with political leaning, being stronger in more conservative states.
Agricultural land-uses consistently exacerbate infectious disease risks in Southeast Asia
Authors: Shah Hiral A. , Huxley Paul , Elmes Jocelyn , Murray Kris A.
Published: September 2019

Agriculture has been implicated as a potential driver of human infectious diseases. However, the generality of disease-agriculture relationships has not been systematically assessed, hindering efforts to incorporate human health considerations into land-use and development policies. Here we perform a meta-analysis with 34 eligible studies and show that people who live or work in agricultural land in Southeast Asia are on average 1.74 (CI 1.47–2.07) times as likely to be infected with a pathogen than those unexposed. Effect sizes are greatest for exposure to oil palm, rubber, and non-poultry based livestock farming and for hookworm (OR 2.42, CI 1.56–3.75), malaria (OR 2.00, CI 1.46–2.73), scrub typhus (OR 2.37, CI 1.41–3.96) and spotted fever group diseases (OR 3.91, CI 2.61–5.85). In contrast, no change in infection risk is detected for faecal-oral route diseases. Although responses vary by land-use and disease types, results suggest that agricultural land-uses exacerbate many infectious diseases in Southeast Asia.
ImmGen report: sexual dimorphism in the immune system transcriptome
Authors: Gal-Oz Shani Talia , Maier Barbara , Yoshida Hideyuki , Seddu Kumba , Elbaz Nitzan , Czysz Charles , Zuk Or , Stranger Barbara E. , Ner-Gaon Hadas , Shay Tal
Published: September 2019

Sexual dimorphism in the mammalian immune system is manifested as more frequent and severe infectious diseases in males and, on the other hand, higher rates of autoimmune disease in females, yet insights underlying those differences are still lacking. Here we characterize sex differences in the immune system by RNA and ATAC sequence profiling of untreated and interferon-induced immune cell types in male and female mice. We detect very few differentially expressed genes between male and female immune cells except in macrophages from three different tissues. Accordingly, very few genomic regions display differences in accessibility between sexes. Transcriptional sexual dimorphism in macrophages is mediated by genes of innate immune pathways, and increases after interferon stimulation. Thus, the stronger immune response of females may be due to more activated innate immune pathways prior to pathogen invasion.
Simultaneous measurement of excitation-contraction coupling parameters identifies mechanisms underlying contractile responses of hiPSC-derived cardiomyocytes
Authors: van Meer Berend J. , Krotenberg Ana , Sala Luca , Davis Richard P. , Eschenhagen Thomas , Denning Chris , Tertoolen Leon G. J. , Mummery Christine L.
Published: September 2019

Cardiomyocytes from human induced pluripotent stem cells (hiPSC-CMs) are increasingly recognized as valuable for determining the effects of drugs on ion channels but they do not always accurately predict contractile responses of the human heart. This is in part attributable to their immaturity but the sensitivity of measurement tools may also be limiting. Measuring action potential, calcium flux or contraction individually misses critical information that is captured when interrogating the complete excitation-contraction coupling cascade simultaneously. Here, we develop an hypothesis-based statistical algorithm that identifies mechanisms of action. We design and build a high-speed optical system to measure action potential, cytosolic calcium and contraction simultaneously using fluorescent sensors. These measurements are automatically processed, quantified and then assessed by the algorithm. Multiplexing these three critical physical features of hiPSC-CMs allows identification of all major drug classes affecting contractility with detection sensitivities higher than individual measurement of action potential, cytosolic calcium or contraction.
Host transcriptome and microbiome interaction modulates physiology of full-sibs broilers with divergent feed conversion ratio
Authors: Shah Tejas M. , Patel Jignasha G. , Gohil Tejas P. , Blake Damer P. , Joshi Chaitanya G.
Published: September 2019

Efficient livestock production relies on effective conversion of feed into body weight gain (BWG). High levels of feed conversion are especially important in production of broiler chickens, birds reared for meat, where economic margins are tight. Traits associated with improved broiler growth and feed efficiency have been subjected to intense genetic selection, but measures such as feed conversion ratio (FCR) remain variable, even between full siblings (sibs). Non-genetic factors such as the composition and function of microbial populations within different enteric compartments have been recognized to influence FCR, although the extent of interplay between hosts and their microbiomes is unclear. To examine host–microbiome interactions we investigated variation in the composition and functions of host intestinal-hepatic transcriptomes and the intestinal microbiota of full-sib broilers with divergent FCR. Progeny from 300 broiler families were assessed for divergent FCR set against shared genetic backgrounds and exposure to the same environmental factors. The seven most divergent full-sib pairs were chosen for analysis, exhibiting marked variation in transcription of genes as well as gut microbial diversity. Examination of enteric microbiota in low FCR sibs revealed variation in microbial community structure and function with no difference in feed intake compared to high FCR sibs. Gene transcription in low and high FCR sibs was significantly associated with the abundance of specific microbial taxa. Highly intertwined interactions between host transcriptomes and enteric microbiota are likely to modulate complex traits like FCR and may be amenable to selective modification with relevance to improving intestinal homeostasis and health.
Analysis of mutations leading to para-aminosalicylic acid resistance in Mycobacterium tuberculosis
Authors: Pandey Bharati , Grover Sonam , Kaur Jagdeep , Grover Abhinav
Published: September 2019

Thymidylate synthase A (ThyA) is the key enzyme involved in the folate pathway in Mycobacterium tuberculosis. Mutation of key residues of ThyA enzyme which are involved in interaction with substrate 2′-deoxyuridine-5′-monophosphate (dUMP), cofactor 5,10-methylenetetrahydrofolate (MTHF), and catalytic site have caused para-aminosalicylic acid (PAS) resistance in TB patients. Focusing on R127L, L143P, C146R, L172P, A182P, and V261G mutations, including wild-type, we performed long molecular dynamics (MD) simulations in explicit solvent to investigate the molecular principles underlying PAS resistance due to missense mutations. We found that these mutations lead to (i) extensive changes in the dUMP and MTHF binding sites, (ii) weak interaction of ThyA enzyme with dUMP and MTHF by inducing conformational changes in the structure, (iii) loss of the hydrogen bond and other atomic interactions and (iv) enhanced movement of protein atoms indicated by principal component analysis (PCA). In this study, MD simulations framework has provided considerable insight into mutation induced conformational changes in the ThyA enzyme of Mycobacterium.
Understanding pseudo-albinism in sole (Solea senegalensis): a transcriptomics and metagenomics approach
Authors: Pinto Patricia I. S. , Guerreiro Cláudia C. , Costa Rita A. , Martinez-Blanch Juan F. , Carballo Carlos , Codoñer Francisco M. , Manchado Manuel , Power Deborah M.
Published: September 2019

Pseudo-albinism is a pigmentation disorder observed in flatfish aquaculture with a complex, multi-factor aetiology. We tested the hypothesis that pigmentation abnormalities are an overt signal of more generalised modifications in tissue structure and function, using as a model the Senegalese sole and two important innate immune barriers, the skin and intestine, and their microbiomes. Stereological analyses in pseudo-albino sole revealed a significantly increased mucous cell number in skin (P < 0.001) and a significantly thicker muscle layer and lamina propria in gut (P < 0.001). RNA-seq transcriptome analysis of the skin and gut identified 573 differentially expressed transcripts (DETs, FDR < 0.05) between pseudo-albino and pigmented soles (one pool/tissue from 4 individuals/phenotype). DETs were mainly linked to pigment production, skin structure and regeneration and smooth muscle contraction. The microbiome (16 S rRNA analysis) was highly diverse in pigmented and pseudo-albino skin but in gut had low complexity and diverged between the two pigmentation phenotypes. Quantitative PCR revealed significantly lower loads of Mycoplasma (P < 0.05) and Vibrio bacteria (P < 0.01) in pseudo-albino compared to the control. The study revealed that pseudo-albinism in addition to pigmentation changes was associated with generalised changes in the skin and gut structure and a modification in the gut microbiome.
Cigarette Smoke Exposure Induces Retrograde Trafficking of CFTR to the Endoplasmic Reticulum
Authors: Marklew Abigail J. , Patel Waseema , Moore Patrick J. , Tan Chong D. , Smith Amanda J. , Sassano M. Flori , Gray Michael A. , Tarran Robert
Published: September 2019

Chronic obstructive pulmonary disease (COPD), which is most commonly caused by cigarette smoke (CS) exposure, is the third leading cause of death worldwide. The cystic fibrosis transmembrane conductance regulator (CFTR) is an apical membrane anion channel that is widely expressed in epithelia throughout the body. In the airways, CFTR plays an important role in fluid homeostasis and helps flush mucus and inhaled pathogens/toxicants out of the lung. Inhibition of CFTR leads to mucus stasis and severe airway disease. CS exposure also inhibits CFTR, leading to the decreased anion secretion/hydration seen in COPD patients. However, the underlying mechanism is poorly understood. Here, we report that CS causes CFTR to be internalized in a clathrin/dynamin-dependent fashion. This internalization is followed by retrograde trafficking of CFTR to the endoplasmic reticulum. Although this internalization pathway has been described for bacterial toxins and cargo machinery, it has never been reported for mammalian ion channels. Furthermore, the rapid internalization of CFTR is dependent on CFTR dephosphorylation by calcineurin, a protein phosphatase that is upregulated by CS. These results provide new insights into the mechanism of CFTR internalization, and may help in the development of new therapies for CFTR correction and lung rehydration in patients with debilitating airway diseases such as COPD.