bluuebunny/crossref_metadata_2025 huggingface dataset:
WHY DO SOCIETIES WITH HIGHER AVERAGE COGNITIVE ABILITY HAVE LOWER INCOME INEQUALITY? THE ROLE OF REDISTRIBUTIVE POLICIES
Authors: Salahodjaev Raufhon , Kanazawa Satoshi
Published: July 2017

Past studies suggest that, across nations, the average cognitive ability of a population is negatively associated with income inequality; societies with higher average cognitive ability tend to have lower levels of income inequality. However, it is not clearwhy. This paper proposes that social transfers from the wealthy to the poor may be a major mechanism by which some societies achieve lower income inequality than others, because more intelligent individuals may be more likely to have a preference for such transfers. Publicly available societal-level data were analysed in a series of multiple regression models. The empirical results in this study replicate the earlier finding that societies with higher cognitive ability have lower levels of income inequality, but the association isentirelymediated by social transfers. Social transfers therefore appear to be the primary mechanism by which societies with higher levels of cognitive ability achieve lower income inequality.
Exercise, energy expenditure and energy balance, as measured with doubly labelled water
Authors: Westerterp Klaas R.
Published: July 2017

The doubly labelled water method for the measurement of total daily energy expenditure (TDEE) over 1–3 weeks under daily living conditions is the indicated method to study effects of exercise and extreme environments on energy balance. Subjects consume a measured amount of doubly labelled water (2H218O) to increase background enrichment of body water for 18O and 2H, and the subsequent difference in elimination rate between 18O and 2H, as measured in urine, saliva or blood samples, is a measure for carbon dioxide production and thus allows calculation of TDEE. The present review describes research showing that physical activity level (PAL), calculated as TDEE (assessed with doubly labelled water) divided by resting energy expenditure (REE, PAL = TDEE/REE), reaches a maximum value of 2·00–2·40 in subjects with a vigorously active lifestyle. Higher PAL values, while maintaining energy balance, are observed in professional athletes consuming additional energy dense foods to compete at top level. Exercise training can increase TDEE/REE in young adults to a value of 2·00–2·40, when energy intake is unrestricted. Furthermore, the review shows an exercise induced increase in activity energy expenditure can be compensated by a reduction in REE and by a reduction in non-exercise physical activity, especially at a negative energy balance. Additionally, in untrained subjects, an exercise-induced increase in activity energy expenditure is compensated by a training-induced increase in exercise efficiency.
Visual speech fills in both discrimination and identification of non-intact auditory speech in children
Authors: JERGER SUSAN , DAMIAN MARKUS F. , MCALPINE RACHEL P. , ABDI HERVÉ
Published: July 2017

To communicate, children must discriminate and identify speech sounds. Because visual speech plays an important role in this process, we explored how visual speech influences phoneme discrimination and identification by children. Critical items had intact visual speech (e.g.bæz) coupled to non-intact (excised onsets) auditory speech (signified by /–b/æz). Children discriminated syllable pairs that differed in intactness (i.e. bæz:/–b/æz) and identified non-intact nonwords (/–b/æz). We predicted that visual speech would cause children to perceive the non-intact onsets as intact, resulting in moresameresponses for discrimination and more intact (i.e.bæz) responses for identification in the audiovisual than auditory mode. Visual speech for the easy-to-speechread /b/ but not for the difficult-to-speechread /g/ boosted discrimination and identification (about 35–45%) in children from four to fourteen years. The influence of visual speech on discrimination was uniquely associated with the influence of visual speech on identification and receptive vocabulary skills.
Serological and molecular diagnostic tests for canine visceral leishmaniasis in Brazilian endemic area: one out of five seronegative dogs are infected
Authors: LOPES E. G. , SEVÁ A. P. , FERREIRA F. , NUNES C. M. , KEID L. B. , HIRAMOTO R. M. , FERREIRA H. L. , OLIVEIRA T. M. F. S. , BIGOTTO M. F. D. , GALVIS-OVALLOS F. , GALATI E. A. B. , SOARES R. M.
Published: July 2017

Euthanasia of infected dogs is one of the measures adopted in Brazil to control visceral leishmaniasis (VL) in endemic areas. To detect infected dogs, animals are screened with the rapid test DPP® Visceral Canine Leishmaniasis for detection of antibodies against K26/K39 fusion antigens of amastigotes (DPP). DPP-positives are confirmed with an immunoenzymatic assay probing soluble antigens of promastigotes (ELISA), while DPP-negatives are considered free of infection. Here, 975 dogs from an endemic region were surveyed by using DPP, ELISA and real-time PCR (qPCR) for the diagnosis of VL. When DPP-negative dogs were tested by qPCR applied in blood and lymph node aspirates, 174/887 (19·6%) were positive in at least one sample. In a second sampling using 115 cases, the DPP-negative dogs were tested by qPCR in blood, lymph node and conjunctival swab samples, and 36/79 (45·6%) were positive in at least one sample. Low-to-moderate pairwise agreement was observed between all possible pair of tests. In conclusion, the official diagnosis of VL in dogs in Brazilian endemic areas failed to accuse an expressive number of infected animals and the impact of the low accuracy of serological tests in the success of euthanasia-based measure for VL control need to be assessed.
Co-circulation and co-infections of all dengue virus serotypes in Hyderabad, India 2014
Authors: VADDADI K. , GANDIKOTA C. , JAIN P. K. , PRASAD V. S. V. , VENKATARAMANA M.
Published: July 2017

The burden of dengue virus infections increased globally during recent years. Though India is considered as dengue hyper-endemic country, limited data are available on disease epidemiology. The present study includes molecular characterization of dengue virus strains occurred in Hyderabad, India, during the year 2014. A total of 120 febrile cases were recruited for this study, which includes only children and 41 were serologically confirmed for dengue positive infections using non-structural (NS1) and/or IgG/IgM ELISA tests. RT-PCR, nucleotide sequencing and evolutionary analyses were carried out to identify the circulating serotypes/genotypes. The data indicated a high percent of severe dengue (63%) in primary infections. Simultaneous circulation of all four serotypes and co-infections were observed for the first time in Hyderabad, India. In total, 15 patients were co-infected with more than one dengue serotype and 12 (80%) of them had severe dengue. One of the striking findings of the present study is the identification of serotype Den-1 as the first report from this region and this strain showed close relatedness to the Thailand 1980 strains but not to any of the strains reported from India until now. Phylogenetically, all four strains of the present study showed close relatedness to the strains, which are reported to be high virulent.
A seroprevalence study to determine the frequency of hantavirus infection in people exposed to wild and pet fancy rats in England
Authors: DUGGAN J. M. , CLOSE R. , MCCANN L. , WRIGHT D. , KEYS M. , MCCARTHY N. , MANNES T. , WALSH A. , CHARLETT A. , BROOKS T. J. G.
Published: July 2017

Recent cases of acute kidney injury due to Seoul hantavirus infection from exposure to wild or pet fancy rats suggest this infection is increasing in prevalence in the UK. We conducted a seroprevalence study in England to estimate cumulative exposure in at-risk groups with contact with domesticated and wild rats to assess risk and inform public health advice. From October 2013 to June 2014, 844 individual blood samples were collected. Hantavirus seroprevalence amongst the pet fancy rat owner group was 34.1% (95% CI 23·9–45·7%) compared with 3·3% (95% CI 1·6–6·0) in a baseline control group, 2·4% in those with occupational exposure to pet fancy rats (95% CI 0·6–5·9) and 1·7% with occupational exposure to wild rats (95% CI 0·2–5·9). Variation in seroprevalence across groups with different exposure suggests that occupational exposure to pet and wild rats carries a very low risk, if any. However incidence of hantavirus infection among pet fancy rat owners/breeders, whether asymptomatic, undiagnosed mild viral illness or more severe disease may be very common and public health advice needs to be targeted to this at-risk group.
TREND INFLATION AND MONETARY POLICY IN EASTERN EUROPE
Authors: Junicke Monika
Published: July 2017

I use a two-country dynamic stochastic general equilibrium (DSGE) model with a nonzero steady-state inflation to study monetary policy in transition economies. In particular, my analysis focuses on whether inflation targeting is based on a consumer price index (CPI) or its producer counterpart, producer price index (PPI). This issue is specifically relevant for transition economies as they might be subject to Balassa–Samuelson effects arising from trading in international markets. Under these circumstances, domestic inflation is possibly higher than imported inflation, hence targeting PPI inflation may prove more effective in influencing domestic macroeconomic variables than targeting CPI inflation. Using a Bayesian methodology, I find that the central banks of three Eastern European countries (namely, the Czech Republic, Hungary, and Poland) are likely to target PPI inflation rather than CPI inflation. This result is in line with the theoretical predictions in the literature, and is robust across several Taylor-type rules.
An actuarial investigation into maternal hospital cost risk factors for public patients
Authors: William Jananie , Martin Michael A. , Chojenta Catherine , Loxton Deborah
Published: July 2017

We investigate an actuarial approach to identifying the factors impacting government-funded maternal hospital costs in Australia, with a focus on women who experience adverse birth outcomes. We propose a two-phase modelling methodology that adopts actuarial methods from typical insurance claim cost modelling and extends to other statistical techniques to account for the large volume of covariates available for modelling. Specifically, Classification and Regression Trees and generalised linear mixed models are employed to analyse a data set that links longitudinal survey and administrative data from a large sample of women. The results show that adverse births are a statistically significant risk factor affecting maternal hospital costs in the antenatal and delivery periods. Other significant cost risk factors in the delivery period include mode of delivery, private health insurance status, diabetes, smoking status, area of residence and onset of labour. We demonstrate the efficacy of using actuarial techniques in non-traditional areas and highlight how the results can be used to inform public policy.
Enacting Twailian Praxis in Nonacademic Habitats: Toward a Conceptual Framework
Authors: Okafor Obiora Chinedu
Published: July 2017

The roles that Third World Approaches to International Law (TWAIL) scholars could play in political and/or socio-economic struggles beyond the academy, and the relationships of these scholars to politicians, diplomats activists, civil servants, peasant movements, civil society, and other nonacademic actors are issues as important to TWAIL as they are understudied and underenacted. The three essays in this TWAIL Symposium take up this theme of praxis.
A European Story
Authors: Francq Stephanie
Published: July 2017

The decision of the Supreme Court in RJR Nabisco v. European Community is the culmination of sixteen years of litigation, preceded by years of investigation. From a European perspective, the decision can only be read as a disappointment: “we” tried, “we” lost. But beyond the frustration with the outcome, this European take on the RJR decision will focus on two questions: (i) why did the European Community decide to bring proceedings in the United States in the first place; and (ii) what would happen in the reverse scenario, if a foreign public authority or a private plaintiff were to bring suit in the European Union? Answering these two questions casts RJR in a slightly different light and offers an interesting picture of the wider political and regulatory context in the European Union.
IUS Post Bellum and The Imperative to Supersede IHL
Authors: Kalmanovitz Pablo
Published: July 2017

In recent debates about the interplay between international humanitarian law (IHL) and human rights law (IHRL), two broad camps have emerged. On the one hand, defenders of what may be called theconvergence thesishave emphasized the inclusion of basic rights protections in the so-called “Geneva instruments” of IHL, as well as the role of human rights bodies in interpreting and amplifying rights protections in IHL through juridical or quasi-juridical interpretation and pronouncements. In armed conflicts, it is said, human rights apply concurrently and in ways that strengthen the protective constraints of IHL. Critics of the convergence thesis, on the other hand, have protested that pressing human rights obligations on state forces misunderstands the nature of both IHL and IHRL, and generates misplaced and impossibly onerous demands on belligerents—ultimately and perversely, the effect of emphasizing convergence may be less, not more, human rights protection.
The Colombian Peace Negotiation and Foreign Investment Law
Authors: Urueña René
Published: July 2017

The stunning vote against the Colombian Peace Agreement opens an opportunity to include in the negotiations issues that were not included in the first deal—despite the fact that their omission had the potential to undermine the goal of a sustainable peace. One such issue is foreign investment law. Since the beginning of the talks, the Colombian government was keen on emphasizing that the country’s “economic model” was not subject to negotiation. The shadow of Venezuela loomed large in that position. Whatever came out of the talks was to be integrated in a framework of a free market economy, where private property and, above all, foreign investments would be respected.
Military Activities in the UNCLOS Compulsory Dispute Settlement System: Implications of the South China Sea Arbitration for U.S. Ratification of UNCLOS
Authors: Damrosch Lori Fisler
Published: July 2017

The Award on the Merits in the South China Sea Arbitration between the Philippines and China (Award) is the first decision of any tribunalto interpret the provision of the 1982 United Nations Convention on theLaw of the Sea (Convention or UNCLOS) that allows states parties to exclude disputes concerning military activities from the Convention’s compulsory dispute settlement regime. That optional exclusion, embodied in Article 298(1)(b) of the Convention, was a central component of the strenuously-negotiated compromise between states that favored compulsory jurisdiction in principle and those that would have preferred a strictly optional system for third-party legal dispute settlement. Its availability has beencritical in enabling certain states to ratify the Convention and would be an indispensable condition of eventual U.S. ratification. For these reasons, the Award’s treatment of the military activities exception transcends the South China Sea dispute.
“Rocks” or “ISLANDS” ?Sailing Towards Legal Clarity in the Turbulent South China Sea
Authors: Oral Nilufer
Published: July 2017

The Arbitral Award handed down by the Permanent Court of Arbitration (PCA) on 12 July 2016 in In the Matter of the South China Sea Arbitration between the Republic of the Philippines and the People’s Republic of Chinais undoubtedly one of the most anticipated decisions in recent memory.
Biological iron-sulfur storage in a thioferrate-protein nanoparticle
Authors: Vaccaro Brian J. , Clarkson Sonya M. , Holden James F. , Lee Dong-Woo , Wu Chang-Hao , Poole II Farris L. , Cotelesage Julien J. H. , Hackett Mark J. , Mohebbi Sahel , Sun Jingchuan , Li Huilin , Johnson Michael K. , George Graham N. , Adams Michael W. W.
Published: July 2017

Iron–sulfur clusters are ubiquitous in biology and function in electron transfer and catalysis. They are assembled from iron and cysteine sulfur on protein scaffolds. Iron is typically stored as iron oxyhydroxide, ferrihydrite, encapsulated in 12 nm shells of ferritin, which buffers cellular iron availability. Here we have characterized IssA, a protein that stores iron and sulfur as thioferrate, an inorganic anionic polymer previously unknown in biology. IssA forms nanoparticles reaching 300 nm in diameter and is the largest natural metalloprotein complex known. It is a member of a widely distributed protein family that includes nitrogenase maturation factors, NifB and NifX. IssA nanoparticles are visible by electron microscopy as electron-dense bodies in the cytoplasm. Purified nanoparticles appear to be generated from 20 nm units containing ∼6,400 Fe atoms and ∼170 IssA monomers. In support of roles in both iron–sulfur storage and cluster biosynthesis, IssA reconstitutes the [4Fe-4S] cluster in ferredoxin in vitro.
Inference of neuronal functional circuitry with spike-triggered non-negative matrix factorization
Authors: Liu Jian K. , Schreyer Helene M. , Onken Arno , Rozenblit Fernando , Khani Mohammad H. , Krishnamoorthy Vidhyasankar , Panzeri Stefano , Gollisch Tim
Published: July 2017

Neurons in sensory systems often pool inputs over arrays of presynaptic cells, giving rise to functional subunits inside a neuron’s receptive field. The organization of these subunits provides a signature of the neuron’s presynaptic functional connectivity and determines how the neuron integrates sensory stimuli. Here we introduce the method of spike-triggered non-negative matrix factorization for detecting the layout of subunits within a neuron’s receptive field. The method only requires the neuron’s spiking responses under finely structured sensory stimulation and is therefore applicable to large populations of simultaneously recorded neurons. Applied to recordings from ganglion cells in the salamander retina, the method retrieves the receptive fields of presynaptic bipolar cells, as verified by simultaneous bipolar and ganglion cell recordings. The identified subunit layouts allow improved predictions of ganglion cell responses to natural stimuli and reveal shared bipolar cell input into distinct types of ganglion cells.
Number of infection events per cell during HIV-1 cell-free infection
Authors: Ito Yusuke , Remion Azaria , Tauzin Alexandra , Ejima Keisuke , Nakaoka Shinji , Iwasa Yoh , Iwami Shingo , Mammano Fabrizio
Published: July 2017

HIV-1 accumulates changes in its genome through both recombination and mutation during the course of infection. For recombination to occur, a single cell must be infected by two HIV strains. These coinfection events were experimentally demonstrated to occur more frequently than would be expected for independent infection events and do not follow a random distribution. Previous mathematical modeling approaches demonstrated that differences in target cell susceptibility can explain the non-randomness, both in the context of direct cell-to-cell transmission, and in the context of free virus transmission (Q. Dang et al., Proc. Natl. Acad. Sci. USA 101:632-7, 2004: K. M. Law et al., Cell reports 15:2711-83, 2016). Here, we build on these notions and provide a more detailed and extensive quantitative framework. We developed a novel mathematical model explicitly considering the heterogeneity of target cells and analysed datasets of cell-free HIV-1 single and double infection experiments in cell culture. Particularly, in contrast to the previous studies, we took into account the different susceptibility of the target cells as a continuous distribution. Interestingly, we showed that the number of infection events per cell during cell-free HIV-1 infection follows a negative-binomial distribution, and our model reproduces these datasets.
Erratum: PRL3 phosphatase active site is required for binding the putative magnesium transporter CNNM3
Authors: Zhang Huizhi , Kozlov Guennadi , Li Xinlu , Wu Howie , Gulerez Irina , Gehring Kalle
Published: July 2017

A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper
Reducing Animal Use with a Biotelemetry-Enhanced Murine Model of Sepsis
Authors: Lewis Anthony , Zuckerbraun Brian , Griepentrog John , Zhang Xianghong , Rosengart Matthew
Published: July 2017

Animal models of sepsis exhibit considerable variability in the temporal development of the physiologic response, which reduces the power of studies, particularly if interventions are tested at arbitrary time points. We developed a biotelemetry-based model of cecal ligation and puncture (CLP) that standardizes the testing of time-sensitive therapies to specific criteria of physiologic deterioration. In this study we seek to further define the variability in physiologic response to CLP sepsis and conduct a cost analysis detailing the potential for reducing animal usage. We have further characterized the variability in physiologic response after CLP in mice and determined peaks in the temporal distribution of points of physiologic decline. Testing therapies at physiologic thresholds reduces the variability found in historical fixed time-based models. Though initial cost is higher with biotelemetry, this is eventually offset by the significantly reduced number of mice needed to conduct physiologically relevant sepsis experiments.
How vegetation in flows modifies the turbulent mixing and spreading of jets
Authors: Mossa Michele , Ben Meftah Mouldi , De Serio Francesca , Nepf Heidi M.
Published: July 2017

While studies on vegetated channel flows have been developed in many research centers, studies on jets interacting with vegetation are still rare. This study presents and analyzes turbulent jets issued into an obstructed cross-flow, with emergent vegetation simulated with a regular array of cylinders. The paper presents estimates of the turbulence diffusion coefficients and the main turbulence variables of jets issued into a vegetated channel flow. The experimental results are compared with jets issued into unobstructed cross-flow. In the presence of the cylinder array, the turbulence length-scales in the streamwise and transverse directions were reduced, relative to the unobstructed crossflow. This contributed to a reduction in streamwise turbulent diffusion, relative to the unobstructed conditions. In contrast, the transverse turbulent diffusion was enhanced, despite the reduction in length-scale, due to enhanced turbulent intensity and the transverse deflection of flow around individual cylinders. Importantly, in the obstructed condition, the streamwise and transverse turbulent diffusion coefficients are of the same order of magnitude.
Controlling Adult Stem Cell Behavior Using Nanodiamond-Reinforced Hydrogel: Implication in Bone Regeneration Therapy
Authors: Pacelli Settimio , Maloney Ryan , Chakravarti Aparna R. , Whitlow Jonathan , Basu Sayantani , Modaresi Saman , Gehrke Stevin , Paul Arghya
Published: July 2017

Nanodiamonds (NDs) have attracted considerable attention as drug delivery nanocarriers due to their low cytotoxicity and facile surface functionalization. Given these features, NDs have been recently investigated for the fabrication of nanocomposite hydrogels for tissue engineering. Here we report the synthesis of a hydrogel using photocrosslinkable gelatin methacrylamide (GelMA) and NDs as a three-dimensional scaffold for drug delivery and stem cell-guided bone regeneration. We investigated the effect of different concentration of NDs on the physical and mechanical properties of the GelMA hydrogel network. The inclusion of NDs increased the network stiffness, which in turn augmented the traction forces generated by human adipose stem cells (hASCs). We also tested the ability of NDs to adsorb and modulate the release of a model drug dexamethasone (Dex) to promote the osteogenic differentiation of hASCs. The ND-Dex complexes modulated gene expression, cell area, and focal adhesion number in hASCs. Moreover, the integration of the ND-Dex complex within GelMA hydrogels allowed a higher retention of Dex over time, resulting in significantly increased alkaline phosphatase activity and calcium deposition of encapsulated hASCs. These results suggest that conventional GelMA hydrogels can be coupled with conjugated NDs to develop a novel platform for bone tissue engineering.
Tricritical point from high-field magnetoelastic and metamagnetic effects in UN
Authors: Shrestha K. , Antonio D. , Jaime M. , Harrison N. , Mast D. S. , Safarik D. , Durakiewicz T. , Griveau J.-C. , Gofryk K.
Published: July 2017

Uranium nitride (UN) is one of the most studied actinide materials as it is a promising fuel for the next generation of nuclear reactors. Despite large experimental and theoretical efforts, some of the fundamental questions such as degree of 5f–electron localization/delocalization and its relationship to magneto-vibrational properties are not resolved yet. Here we show that the magnetostriction of UN measured in pulsed magnetic fields up to 65 T and below the Néel temperature is large and exhibits complex behavior with two transitions. While the high field anomaly is a field-induced metamagnetic-like transition and affects both magnetisation and magnetostriction, the low field anomaly does not contribute to the magnetic susceptibility. Our data suggest a change in the nature of the metamagnetic transition from first to second order-like at a tricritical point atTtri ∼ 24 K andHtri ∼ 52 T. The induced magnetic moment at 60 T might suggest that only one subset of magnetic moments has aligned along the field direction. Using the results obtained here we have constructed a magnetic phase diagram of UN. These studies demonstrate that dilatometry in high fields is an effective method to investigate the magneto-structural coupling in actinide materials.
A room-temperature refuelable lithium, iodine and air battery
Authors: Tan Kim Seng , Grimsdale Andrew C. , Yazami Rachid
Published: July 2017

We demonstrate a new refuelable lithium cell using lithium solvated electron solution (Li-SES) as anolyte and iodine solutions as catholyte. This cell shows a high OCV (~3 V). Unlike conventional rechargeable Li batteries, this kind of cell can be re-fueled in several minutes by replacing the spent liquids. We also show for the first time, that Li-SES/I2 cells which operate at room temperature, can be prepared in a fully discharged state (~0 V OCV) for safe handling, transportation and storage. Li-SES and iodine are then electrochemically generated during charge as is confirmed by UV-VIS and a qualitative test. We have also conducted proof-of-concept tests for an “indirect lithium-air” cell in which iodine is reduced at the cathode and subsequently is catalytically re-oxidized by oxygen dissolved in the catholyte.
New criteria for the molecular identification of cereal grains associated with archaeological artefacts
Authors: Colonese Andre Carlo , Hendy Jessica , Lucquin Alexandre , Speller Camilla F. , Collins Matthew J. , Carrer Francesco , Gubler Regula , Kühn Marlu , Fischer Roman , Craig Oliver E.
Published: July 2017

The domestication and transmission of cereals is one of the most fundamental components of early farming, but direct evidence of their use in early culinary practices and economies has remained frustratingly elusive. Using analysis of a well-preserved Early Bronze Age wooden container from Switzerland, we propose novel criteria for the identification of cereal residues. Using gas chromatography mass spectrometry (GC-MS), we identified compounds typically associated with plant products, including a series of phenolic lipids (alkylresorcinols) found only at appreciable concentration in wheat and rye bran. The value of these lipids as cereal grain biomarkers were independently corroborated by the presence of macrobotanical remains embedded in the deposit, and wheat and rye endosperm peptides extracted from residue. These findings demonstrate the utility of a lipid-based biomarker for wheat and rye bran and offer a methodological template for future investigations of wider range of archaeological contexts. Alkylresorcinols provide a new tool for residue analysis which can help explore the spread and exploitation of cereal grains, a fundamental component of the advent and spread of farming.
A high-content image analysis approach for quantitative measurements of chemosensitivity in patient-derived tumor microtissues
Authors: Ahonen Ilmari , Åkerfelt Malin , Toriseva Mervi , Oswald Eva , Schüler Julia , Nees Matthias
Published: July 2017

Organotypic, three-dimensional (3D) cancer models have enabled investigations of complex microtissues in increasingly realistic conditions. However, a drawback of these advanced models remains the poor biological relevance of cancer cell lines, while higher clinical significance would be obtainable with patient-derived cell cultures. Here, we describe the generation and data analysis of 3D microtissue models from patient-derived xenografts (PDX) of non-small cell lung carcinoma (NSCLC). Standard of care anti-cancer drugs were applied and the altered multicellular morphologies were captured by confocal microscopy, followed by automated image analyses to quantitatively measure phenotypic features for high-content chemosensitivity tests. The obtained image data were thresholded using a local entropy filter after which the image foreground was split into local regions, for a supervised classification into tumor or fibroblast cell types. Robust statistical methods were applied to evaluate treatment effects on growth and morphology. Both novel and existing computational approaches were compared at each step, while prioritizing high experimental throughput. Docetaxel was found to be the most effective drug that blocked both tumor growth and invasion. These effects were also validated in PDX tumors in vivo. Our research opens new avenues for high-content drug screening based on patient-derived cell cultures, and for personalized chemosensitivity testing.
Memory and Perception-based Facial Image Reconstruction
Authors: Chang Chi-Hsun , Nemrodov Dan , Lee Andy C. H. , Nestor Adrian
Published: July 2017

Visual memory for faces has been extensively researched, especially regarding the main factors that influence face memorability. However, what we remember exactly about a face, namely, the pictorial content of visual memory, remains largely unclear. The current work aims to elucidate this issue by reconstructing face images from both perceptual and memory-based behavioural data. Specifically, our work builds upon and further validates the hypothesis that visual memory and perception share a common representational basis underlying facial identity recognition. To this end, we derived facial features directly from perceptual data and then used such features for image reconstruction separately from perception and memory data. Successful levels of reconstruction were achieved in both cases for newly-learned faces as well as for familiar faces retrieved from long-term memory. Theoretically, this work provides insights into the content of memory-based representations while, practically, it may open the path to novel applications, such as computer-based ‘sketch artists’.
Deciphering mechanisms of acquired T790M mutation after EGFR inhibitors for NSCLC by computational simulations
Authors: Zou Bin , Lee Victor H. F. , Chen Lijiang , Ma Lichun , Wang Debby D. , Yan Hong
Published: July 2017

Metastatic non-small-cell lung cancer (NSCLC) with activating EGFR mutations responds very well to first and second generation tyrosine-kinase inhibitors (TKI) including gefitinib, erlotinib and afatinib. Unfortunately, drug resistance will eventually develop and about half of the cases are secondary to the emergence of acquired T790M somatic mutation. In this work, we prospectively recruited 68 patients with metastatic EGFR-mutated NSCLC who have developed progressive disease after first-line TKI with or without subsequent TKI and/or other systemic therapy. Liquid biopsy after progression to their last line of systemic therapy were taken for detection of acquired T790M mutation. By performing attribute ranking we found that several attributes, including the initial EGFR mutational type, had a high correlation with the presence of acquired T790M mutation. We also conducted computational studies and discovered that the EGFR mutation delE746_A750 had a lower stability around the residue T790 than delS752_I759 and L858R, which was consistent with our clinical observation that patients with delE746_A750 were more likely to acquire T790M mutation than those with delS752_I759 or L858R. Our results provided new insight to future direction of research on investigating the mechanisms of acquired T790M mutation, which is essential to the development of novel mutation-specific TKIs.
2-Oxoadenosine induces cytotoxicity through intracellular accumulation of 2-oxo-ATP and depletion of ATP but not via the p38 MAPK pathway
Authors: Asada Shinji , Ohta Eiko , Akimoto Yoriko , Abolhassani Nona , Tsuchimoto Daisuke , Nakabeppu Yusaku
Published: July 2017

2-Oxoadenosine (2-oxo-Ado), an oxidized form of adenosine, is cytotoxic and induces growth arrest and cell death, which has potential as an anti-cancer drug. However, it is not well understood how 2-oxo-Ado exerts its cytotoxicity. We examined the effects of 2-oxo-Ado on non-tumour cells, namely immortalized mouse embryonic fibroblast lines, and investigated mechanisms by which 2-oxo-Ado exerts its cytotoxicity. We found that cell death induced by 2-oxo-Ado is classical caspase-dependent apoptosis, and requires its sequential intracellular phosphorylation catalysed by adenosine kinase (ADK) and adenylate kinase 2, resulting in intracellular accumulation of 2-oxo-ATP accompanied by accumulation of 2-oxo-Ado in RNA and depletion of ATP. Moreover, we showed that overexpression of MTH1, an oxidized purine nucleoside triphosphatase, prevents 2-oxo-Ado-induced cytotoxicity accompanied by suppression of accumulation of both intracellular 2-oxo-ATP and 2-oxo-Ado in RNA and recovery of ATP levels. We also found that 2-oxo-Ado activates the p38 MAPK pathway. However, siRNAs againstMkk3andMkk6, or treatment with several p38 MAPK inhibitors, except SB203580, did not prevent the cytotoxicity. SB203580 prevented intracellular phosphorylation of 2-oxo-Ado to 2-oxo-AMP, and anin vitroADK assay revealed that SB203580 directly inhibits ADK activity, suggesting that some of the effects of SB203580 may depend on ADK inhibition.
Amino group in Leptothrix sheath skeleton is responsible for direct deposition of Fe(III) minerals onto the sheaths
Authors: Kunoh Tatsuki , Matsumoto Syuji , Nagaoka Noriyuki , Kanashima Shoko , Hino Katsuhiko , Uchida Tetsuya , Tamura Katsunori , Kunoh Hitoshi , Takada Jun
Published: July 2017

Leptothrix species produce microtubular organic–inorganic materials that encase the bacterial cells. The skeleton of an immature sheath, consisting of organic exopolymer fibrils of bacterial origin, is formed first, then the sheath becomes encrusted with inorganic material. Functional carboxyl groups of polysaccharides in these fibrils are considered to attract and bind metal cations, including Fe(III) and Fe(III)-mineral phases onto the fibrils, but the detailed mechanism remains elusive. Here we show that NH2 of the amino-sugar-enriched exopolymer fibrils is involved in interactions with abiotically generated Fe(III) minerals. NH2-specific staining of L. cholodnii OUMS1 detected a terminal NH2 on its sheath skeleton. Masking NH2 with specific reagents abrogated deposition of Fe(III) minerals onto fibrils. Fe(III) minerals were adsorbed on chitosan and NH2-coated polystyrene beads but not on cellulose and beads coated with an acetamide group. X-ray photoelectron spectroscopy at the N1s edge revealed that the terminal NH2 of OUMS1 sheaths, chitosan and NH2-coated beads binds to Fe(III)-mineral phases, indicating interaction between the Fe(III) minerals and terminal NH2. Thus, the terminal NH2 in the exopolymer fibrils seems critical for Fe encrustation of Leptothrix sheaths. These insights should inform artificial synthesis of highly reactive NH2-rich polymers for use as absorbents, catalysts and so on.
Multiple uprising invasions of Pelophylax water frogs, potentially inducing a new hybridogenetic complex
Authors: Dufresnes Christophe , Denoël Mathieu , di Santo Lionel , Dubey Sylvain
Published: July 2017

The genetic era has revolutionized our perception of biological invasions. Yet, it is usually too late to understand their genesis for efficient management. Here, we take the rare opportunity to reconstruct the scenario of an uprising invasion of the famous water frogs (Pelophylax) in southern France, through a fine-scale genetic survey. We identified three different taxa over less than 200 km2: the autochthonous P. perezi, along with the alien P. ridibundus and P. kurtmuelleri, which have suddenly become invasive. As a consequence, the latter hybridizes and may now form a novel hybridogenetic complex with P. perezi, which could actively promote its replacement. This exceptional situation makes a textbook application of genetics to early-detect, monitor and understand the onset of biological invasions before they pose a continental-wide threat. It further emphasizes the alarming rate of amphibian translocations, both at global and local scales, as well as the outstanding invasive potential of Pelophylax aliens.
Effects of Ni doping on various properties of NbH phases: A first-principles investigation
Authors: Wu Yang , Wang Zhongmin , Wang Dianhui , Wan Zhenzhen , Zhong Yan , Hu Chaohao , Zhou Huaiying
Published: July 2017

Changes in the stability, hydrogen diffusion, and mechanical properties of the NbH phases from Ni-doping was studied by using first-principles methods. The calculation results reveal that the single H atom adsorption is energetically favorable at the tetrahedral interstitial site (TIS) and octahedral interstitial site (OIS). The preferred path of H diffusion is TIS-to-TIS, followed by TIS-to-OIS in both Nb16H and Nb15NiH. Ni-doping in the Nb15NiH alloy lowers the energy barrier of H diffusion, enhances the H-diffusion coefficient (D) and mechanical properties of the Nb16H phase. The value of D increases with increasing temperature, and this trend due to Ni doping clearly becomes weaker at higher temperatures. At the typical operating temperature of 400 K, the D value of Nb15NiH (TIS) is about 1.90 × 10−8 m2/s, which is about 80 times higher than that of Nb16H (TIS) (2.15 × 10−10 m2/s). Our calculations indicated that Ni-doping can greatly improve the diffusion of H in Nb.
Discovery of monoclonal antibodies cross-reactive to novel subserotypes of K. pneumoniae O3
Authors: Guachalla Luis M. , Stojkovic Katarina , Hartl Katharina , Kaszowska Marta , Kumar Yadhu , Wahl Benjamin , Paprotka Tobias , Nagy Eszter , Lukasiewicz Jolanta , Nagy Gábor , Szijártó Valéria
Published: July 2017

Klebsiella pneumoniae is responsible for nosocomial infections causing significant morbidity and mortality. Treatment of newly emerging multi-drug resistant strains is hampered due to severely limited antibiotic choices. Passive immunization targeting LPS O-antigens has been proposed as an alternative therapeutic option, given the limited variability of Klebsiella O-antigens. Here we report that the O3 serogroup, previously considered to have uniform O-antigen built of mannan, represents three different subtypes differing in the number of mannose residues within the O-antigen repeating units. Genetic analysis of the genes encoding mannose polymerization revealed differences that underline the observed structural alterations. The O3 variants represent antigenically different types based on the different reactivity pattern of murine monoclonal antibodies raised against a K. pneumoniae O3 strain. Typing of a collection of K. pneumoniae O3 clinical isolates showed that strains expressing the novel O3b antigen, the tri-mannose form, were more prevalent than those having the penta-mannose form, traditionally called O3, while the tetra-mannose variant, termed here O3a, seems to be rare. A monoclonal antibody cross-reacting with all three O3 sub-serogroups was also selected and shown to bind to the surface of various K. pneumoniae strains expressing different O3 subtypes and capsular antigens.
The cryo-EM structure of gastric H+,K+-ATPase with bound BYK99, a high-affinity member of K+-competitive, imidazo[1,2-a]pyridine inhibitors
Authors: Abe Kazuhiro , Shimokawa Jun , Naito Mao , Munson Keith , Vagin Olga , Sachs George , Suzuki Hiroshi , Tani Kazutoshi , Fujiyoshi Yoshinori
Published: July 2017

The gastric proton pump H+,K+-ATPase acidifies the gastric lumen, and thus its inhibitors, including the imidazo[1,2-a]pyridine class of K+-competitive acid blockers (P-CABs), have potential application as acid-suppressing drugs. We determined the electron crystallographic structure of H+,K+-ATPase at 6.5 Å resolution in the E2P state with bound BYK99, a potent P-CAB with a restricted ring structure. The BYK99 bound structure has an almost identical profile to that of a previously determined structure with bound SCH28080, the original P-CAB prototype, but is significantly different from the previously reported P-CAB-free form, illustrating a common conformational change is required for P-CAB binding. The shared conformational changes include a distinct movement of transmembrane helix 2 (M2), from its position in the previously reported P-CAB-free form, to a location proximal to the P-CAB binding site in the present BYK99-bound structure. Site-specific mutagenesis within M2 revealed that D137 and N138, which face the P-CAB binding site in our model, significantly affect the inhibition constant (Ki) of P-CABs. We also found that A335 is likely to be near the bridging nitrogen at the restricted ring structure of the BYK99 inhibitor. These provide clues to elucidate the binding site parameters and mechanism of P-CAB inhibition of gastric acid secretion.
In vivo genetic manipulation of inner ear connexin expression by bovine adeno-associated viral vectors
Authors: Crispino Giulia , Galindo Ramirez Fabian , Campioni Matteo , Zorzi Veronica , Praetorius Mark , Di Pasquale Giovanni , Chiorini John A. , Mammano Fabio
Published: July 2017

We have previously shown that in vitro transduction with bovine adeno–associated viral (BAAV) vectors restores connexin expression and rescues gap junction coupling in cochlear organotypic cultures from connexin–deficient mice that are models DFNB1 nonsyndromic hearing loss and deafness. The aims of this study were to manipulate inner ear connexin expression in vivo using BAAV vectors, and to identify the optimal route of vector delivery. Injection of a BAAV vector encoding a bacterial Cre recombinase via canalostomy in adult mice with floxed connexin 26 (Cx26) alleles promoted Cre/LoxP recombination, resulting in decreased Cx26 expression, decreased endocochlear potential, increased hearing thresholds, and extensive loss of outer hair cells. Injection of a BAAV vector encoding GFP-tagged Cx30 via canalostomy in P4 mice lacking connexin 30 (Cx30) promoted formation of Cx30 gap junctions at points of contacts between adjacent non-sensory cells of the cochlear sensory epithelium. Levels of exogenous Cx30 decayed over time, but were still detectable four weeks after canalostomy. Our results suggest that persistence of BAAV-mediated gene replacement in the cochlea is limited by the extensive remodeling of the organ of Corti throughout postnatal development and associated loss of non-sensory cells.
Echinomycin inhibits adipogenesis in 3T3-L1 cells in a HIF-independent manner
Authors: Yamaguchi Junna , Tanaka Tetsuhiro , Saito Hisako , Nomura Seitaro , Aburatani Hiroyuki , Waki Hironori , Kadowaki Takashi , Nangaku Masaomi
Published: July 2017

Obesity is a risk factor for many diseases including diabetes, cancer, cardiovascular disease, and chronic kidney disease. Obesity is characterized by the expansion of white adipose tissue (WAT). Hypertrophy and hyperplasia of adipocytes cause tissue hypoxia followed by inflammation and fibrosis. Its trigger, preadipocyte differentiation into mature adipocytes, is finely regulated by transcription factors, signal molecules, and cofactors. We found that echinomycin, a potent HIF-1 inhibitor, completely inhibited adipogenesis in 3T3-L1 WAT preadipocytes by affecting the early phase of mitotic clonal expansion. The dose required to exert the effect was surprisingly low and the time was short. Interestingly, its inhibitory effect was independent of HIF-1 pathways. Time-course DNA microarray analysis of drug-treated and untreated preadipocytes extracted a major transcription factor, CCAAT/enhancer-protein β, as a key target of echinomycin. Echinomycin also inhibited adipogenesis and body weight gain in high fat diet mice. These findings highlight a novel role of echinomycin in suppressing adipocyte differentiation and offer a new therapeutic strategy against obesity and diabetes.
Movement Pattern of Scapular Dyskinesis in Symptomatic Overhead Athletes
Authors: Huang Tsun-Shun , Lin Jiu-Jenq , Ou Hsiang-Ling , Chen Yu-Ting
Published: July 2017

This study investigated the characteristics of arm elevation via principal component analysis in symptomatic overhead athletes with scapular dyskinesis. One hundred-thirty-four overhead athletes with scapular dyskinesis [24: inferior angle prominence (pattern I); 46: medial border prominence (pattern II), 64: pattern I + II] were evaluated by three-dimensional electromagnetic motion and electromyography to record the scapular kinematics (upward rotation/posterior tipping/exterior rotation) and muscle activation (upper trapezius: UT; middle trapezius: MT; lower trapezius: LT; serratus anterior: SA) during lowering phase of arm elevation. The results showed: (1) for pattern I and II, the first 3 principal component (PCs) explained 41.4% and 42.6% of total variance of movement; (2) the first PCs were correlated with MT, LT activity (r = 0.41~0.61) and upward rotation, posterior tipping (r = −0.59~−0.33) in pattern I, and UT, MT, SA (r = 0.30~0.70) activity in pattern II; (3) contour plots of muscle activity demonstrated that muscle activities varied with dyskinesis patterns. In summary, for the pattern I, the major characteristics are coactivation of MT and LT and corresponding scapular posterior tipping and upward rotation. For the pattern II, the major characteristics are coactivation of UT, MT and SA without corresponding scapular external rotation.
Thermal management of micro-scale inorganic light-emittng diodes on an orthotropic substrate for biointegrated applications
Authors: Li Yuhang , Chen Jin , Xing Yufeng , Song Jizhou
Published: July 2017

The orthotropic material with the in-plane thermal conductivity much larger than the off-plane one can control the heat flow direction. This feature provides unique benefits in thermal management of micro-scale inorganic light-emitting diodes (μ-ILEDs) device for biointegrated applications by helping the heat dissipation from μ-ILEDs along the in-plane directions to lower the μ-ILED temperature and prevent the heat dissipation to the tissue along the off-plane direction to ensure a low tissue temperature. Three-dimensional analytical models, accounting for the coupling between the Fourier heat conduction in the μ-ILED device and the Pennes bioheat transfer in the human skin, are established to investigate the thermal behaviors of μ-ILEDs on an orthotropic substrate integrated with the human skin. Both the operations of μ-ILEDs in a constant mode and pulsed mode are studied. The maximum temperature increases of μ-ILED and in the tissue are derived and their dependences on various parameters such as the thermal conductivities of the orthotropic substrate, substrate thickness, and loading parameters (e.g., duty cycle, pulse period) are investigated. These results pave the theoretical foundation for the thermal management of μ-ILED devices for biointegrated applications.