bluuebunny/crossref_metadata_2025 huggingface dataset:
Musical diversity in the classroom: Ingenuity and integrity in sound exploration
Authors: Cain Melissa , Walden Jennifer
Published: June 2018

This paper examines the practice of five music educators in Canada and Australia who, despite the pervasiveness of ingrained Western-based pedagogy in these countries, are forging ahead with culturally diverse music programmes. Their work is presented as five ‘snapshots of practice’ which provide inspiration and conceptual ideas for other teachers aiming to diversify their practice in music education. While willingness and enthusiasm are paramount, it is these exemplars of innovative and resourceful practice which are crucial in assisting teachers to recognize that alternative forms of musicianship are both legitimate and essential to a well-rounded education in sonic exploration.
COMPARATIVE EFFECTIVENESS AND SAFETY BETWEEN AMPHOTERICIN B LIPID-FORMULATIONS: A SYSTEMATIC REVIEW
Authors: Grazziotin Luiza Raquel , Moreira Leila Beltrami , Ferreira Maria Angelica Pires
Published: June 2018

Objectives:

It is not yet established the advantages between amphotericin B lipid complex (ABLC) and liposomal (L-AmB) in patients with invasive fungal infections refractory to usual doses of conventional AmB (d-AmB), previous renal impairment, or unacceptable d-AmB renal toxicity. This systematic review aims to compare ABLC and L-AmB effectiveness and safety outcomes in these subgroups of patients.

Methods:

The search was performed on Medline, Cochrane Library, EMBASE, and LILACS databases. Inclusion criteria: treatment comparing L-AmB with ABLC; patients who had (i) refractory infection after being treated with d-AmB, (ii) previous renal impairment, or (iii) unacceptable d-AmB toxicity. Two investigators independently screened the search results, assessed trial quality, and extracted data. A total of 1,054 articles were identified in the literature. Among those, eleven were selected for full-text reading and five met the inclusion criteria.

Results:

The five articles included reported on four separate observational studies. Overall, no significant difference was found in clinical relevant outcomes as new-onset dialysis, length of hospital stay, or mortality when comparing both lipid formulations. The studies reported a trend toward lower nephrotoxicity in patients treated with L-AmB. However, the results were imprecise and heterogeneous and the studies presented important methodological biases.

Conclusions:

The studies included in this systematic review pointed toward less nephrotoxicity events in the L-AmB group. However, due to low quality of evidence and no statistically significant differences in other clinical relevant outcomes, there is no definitive evidence of overall superiority in effectiveness or safety outcomes regarding one lipid formulation or another in this population subgroup.
The Birth of an Imperial Location: Comparative Perspectives on Western Colonialism in China
Authors: NUZZO LUIGI
Published: June 2018

The thematic horizon within which this article takes place is the colonial expansion of the Western powers in China between the nineteenth and the twentieth centuries. Focusing on the foundation of the British, French and American concessions in Tianjin, it aims to reconstruct the Western strategies of colonial governance and the role played by law in the process of production of a new social space. Opened as a treaty port in 1860, Tianjin is the only Chinese city where up to nine foreign concessions coexisted, becoming a complex, hybrid space (in)between East and West, defined by social practices, symbolic representations, and legal categories, which does not coincide simply with the area defined by the entity as a state, nation, or city.
Latent trajectories of alcohol use from early adolescence to young adulthood: Interaction effects between 5-HTTLPR and parenting quality and gender differences
Authors: Su Jinni , Supple Andrew J. , Leerkes Esther M. , Kuo Sally I-Chun
Published: June 2018

Using a large and nationally representative sample, we examined how adolescents’ 5-HTTLPR genotype and perceived parenting quality independently and interactively associated with trajectories of alcohol use from early adolescence to young adulthood and whether/how gender may moderate these associations. The sample for this study included 13,749 adolescents (53.3% female; 56.3% non-Hispanic White, 21.5% Black, 16.0% Hispanic, and 6.1% Asian) followed prospectively from adolescence to young adulthood. Using growth mixture modeling, we identified four distinct trajectories of alcohol use (i.e., persistent heavy alcohol use, developmentally limited alcohol use, late-onset heavy alcohol use, and non/light alcohol use). Results indicated that the short allele of 5-HTTLPR was associated with higher risk of membership in the persistent and the late-onset heavy alcohol use trajectories. Parenting quality was associated with lower likelihoods of following the persistent heavy and the developmentally limited alcohol use trajectories but was not associated with risk of membership for the late-onset heavy drinking trajectory. 5-HTTLPR interacted with parenting quality to predict membership in the persistent heavy alcohol use trajectory for males but not for females. Findings highlighted the importance of considering the heterogeneity in trajectories of alcohol use across development and gender in the study of Gene Environment interactions in alcohol use.
The Social Role of Non-metal ‘Valuables’ in Late Bronze Age Britain
Authors: Brück Joanna , Davies Alex
Published: June 2018

Bronze Age metal objects are widely viewed as markers of wealth and status. Items of other materials, such as jet, amber and glass, tend either to be framed in similar terms as ‘prestige goods’, or to be viewed as decorative trifles of limited research value. In this paper, we argue that such simplistic models dramatically underplay the social role and ‘agentive’ capacities of objects. The occurrence of non-metal ‘valuables’ in British Early Bronze Age graves is well-documented, but their use during the later part of the period remains poorly understood. We will examine the deposition of objects of amber, jet and jet-like materials in Late Bronze Age Britain, addressing in particular their contexts and associations as well as patterns of breakage to consider the cultural meanings and values ascribed to such items and to explore how human and object biographies were intertwined. These materials are rarely found in burials during this period but occur instead on settlements, in hoards and caves. In many cases, these finds appear to have been deliberately deposited in the context of ritual acts relating to rites of passage. In this way, the role of such objects as social agents will be explored, illuminating their changing significance in the creation of social identities and systems of value.
Niche specialization in Bromus tectorum seed bank pathogens
Authors: Meyer Susan E. , Beckstead Julie , Allen Phil S.
Published: June 2018

Niche theory predicts that when two species exhibit major niche overlap, one will eventually be eliminated through competitive exclusion. Thus, some degree of niche specialization is required to facilitate coexistence. We examined whether two important seed bank pathogens on the invasive winter annual grass Bromus tectorum (cheatgrass, downy brome) exhibit niche specialization. These pathogens utilize seed resources in complementary ways. Pyrenophora semeniperda is specialized to attack dormant seeds. It penetrates directly through the seed coverings. Hyphae ramify first through the endosperm and then throughout the seed. Seed death results as the embryo is consumed. In contrast, the Fusarium seed rot pathogen (Fusarium sp.) is specialized to attack non-dormant seeds in the early stages of germination. It cannot penetrate seed coverings directly. Instead, it responds to a cue emanating from the radicle end with directional hyphal growth and subsequent penetration at the point of radicle emergence, causing seed death. Non-dormant seeds usually escape P. semeniperda through germination even if infected because it develops more slowly than Fusarium. When water stress slows non-dormant seed germination, both P. semeniperda and Fusarium can attack and cause seed mortality more effectively. The Fusarium seed rot pathogen can sometimes reach epidemic levels and may result in B. tectorum stand failure (‘die-off’). Stands usually re-establish from the persistent seed bank, but if P. semeniperda has also reached high levels and eliminated the seed bank, a die-off can persist indefinitely.
Bounding the Size of an Almost-Equidistant Set in Euclidean Space
Authors: KUPAVSKII ANDREY , MUSTAFA NABIL H. , SWANEPOEL KONRAD J.
Published: June 2018

A set of points in d-dimensional Euclidean space is almost equidistant if, among any three points of the set, some two are at distance 1. We show that an almost-equidistant set in ℝd has cardinality O(d4/3).
Preliminary Findings of a New Primary and Community Care Psychological Service in Northern Ireland: Low-Intensity Cognitive Behavioural Therapy for Common Mental Health Difficulties
Authors: McDevitt-Petrovic Orla , Kirby Karen , McBride Orla , Shevlin Mark , McAteer Donal , Gorman Colin , Murphy Jamie
Published: June 2018

Background: The prevalence of mental health difficulties in Northern Ireland (NI) is significantly higher than in England. In recent years, there have been extensive consultations, and subsequent recommendations made in NI in an effort to address this. Aims: The current study aims to evaluate the effectiveness of an ‘Improving Access to Psychological Therapies’ (IAPT) stepped care service model using low-intensity cognitive behavioural therapy (LI-CBT) in primary and community care settings. Method: A pilot intervention trial design utilized two standardized outcome measures (PHQ-9 and GAD-7) before treatment (at baseline), during treatment (in every session) and at discharge (at final session). Results: Preliminary reliable change outcomes for the pilot cohorts showed a recovery rate of 47.9%, improvement rate of 76.7% and deterioration rate of 6%. Conclusions: These findings suggest that the IAPT service model is clinically effective in the NI population. Data collection for the larger study was completed in December 2017. Future analyses will include follow-up data collected at 4 months post-treatment, and will also aim to identify individual and service level factors that potentially impact treatment effectiveness.
LEARNING AND THE SIZE OF THE GOVERNMENT SPENDING MULTIPLIER
Authors: Quaghebeur Ewoud
Published: June 2018

This paper examines the government spending multiplier when economic agents combine adaptive learning and knowledge about future fiscal policy to form their expectations. The analysis shows that the effects of a government spending shock substantially change when the rational expectations hypothesis is replaced by this learning mechanism. In contrast to the dynamics under rational expectations, a government spending shock in a small-scale new Keynesian DSGE model with learning crowdsinprivate consumption and is associated with a positive comovement between real wages and hours worked. In the baseline calibration, the output multiplier under learning is above one and about twice as large as under rational expectations.
Do late bilinguals access pure morphology during word recognition? A masked-priming study on Hebrew as a second language
Authors: FARHY YAEL , VERÍSSIMO JOÃO , CLAHSEN HARALD
Published: June 2018

This study extends research on morphological processing in late bilinguals to a rarely examined language type, Semitic, by reporting results from a masked-priming experiment with 58 non-native, advanced, second-language (L2) speakers of Hebrew in comparison with native (L1) speakers. We took advantage of a case of ‘pure morphology’ in Hebrew, the so-called binyanim, which represent (essentially arbitrary) morphological classes for verbs. Our results revealed a non-native priming pattern for the L2 group, with root-priming effects restricted to non-finite prime words irrespective of binyanim type. We conclude that root extraction in L2 Hebrew word recognition is less sensitive to both morphological and morphosyntactic cues than in the L1, in line with the Shallow-Structure Hypothesis of L2 processing.
The influence of bilingualism on working memory event-related potentials
Authors: MORRISON CASSANDRA , KAMAL FAROOQ , TALER VANESSA
Published: June 2018

Bilingualism has been found to enhance the ability to store and manipulate information in working memory (WM). However, previous studies of WM function in bilingualism have been limited to behavioural measures, leaving questions unanswered regarding the effects of bilingualism on neural mechanisms employed during WM tasks. We recorded brain activity (event-related potentials; ERPs) while participants (23 English-speaking and 21 English–French bilinguals) performed an n-back WM task. Accuracy and reaction time were similar across groups, but monolinguals exhibited smaller P300 amplitudes relative to bilinguals, suggesting that bilinguals have more cognitive resources available to complete cognitively demanding tasks.
When a seven is not a seven: Self-ratings of bilingual language proficiency differ between and within language populations
Authors: TOMOSCHUK BRENDAN , FERREIRA VICTOR S. , GOLLAN TAMAR H.
Published: June 2018

Self-ratings of language proficiency are ubiquitous in research on bilingualism, but little is known about their validity, especially when the same scale is used across different types of bilinguals. Self-ratings and picture naming data from 1044 Spanish–English and 519 Chinese–English bilinguals were analyzed in five between- and within-population comparisons. Chinese–English bilinguals scored more extremely than Spanish–English bilinguals, and in opposite directions at different endpoints of the self-ratings scale. Regrouping bilinguals by dominant language, instead of language membership, reduced discrepancies but significant group differences remained. Population differences appeared even in English, though this language is shared between populations. These results demonstrate significant problems with self-ratings, especially when comparing bilinguals of different language combinations; and subgroups of bilinguals who speak the same languages but vary in acquisition history and/or dominance. Objective proficiency measures (e.g., picture naming or proficiency interviews) are superior to self-ratings, to maximize classification accuracy and consistency across studies.
Rethinking the critical period for language: New insights into an old question from American Sign Language
Authors: MAYBERRY RACHEL I. , KLUENDER ROBERT
Published: June 2018

We thank the commentators for their thoughtful critiques, which we found both insightful and stimulating to our own thinking. Our first response is that, while debates about the CPL in theoretical contexts are important, the vigor and intensity of these debates should not overshadow the fact that the main goal of our article was to highlight a finding of vital importance: Sufficient language input in early childhood matters deeply because it has long-term consequences (Lillo-Martin, 2018). Woll sums up this point both succinctly and poignantly in her report of a similar case of very late L1 exposure in adulthood who had decades of experience: “For a [deaf] child who, even in the context of early intervention, does not acquire a spoken language, the danger is that they will never have native-like mastery of any L1.” This is what truly matters. Our hope is that our keynote article and the accompanying commentaries might have a positive effect on clinical practice, educational policy, and even parental choice in this regard. In what follows, we discuss the main issues arising from the commentaries. First we note the points of agreement followed by a clarification of what we did not claim in our article. Researchers continue to debate what the shape of the AoA function looks like and its theoretical implications, which we address third. We then address the issues raised as to whether late L1 acquisition and late L2 learning differ in degree or kind, and last we discuss what we mean when we say that language acquisition during post-natal brain growth creates the capacity to learn language.
The effects of language dominance switch in bilinguals: Galician new speakers' speech production and perception
Authors: LOURIDO GISELA TOMÉ , EVANS BRONWEN G.
Published: June 2018

It has long been debated whether speech production and perception remain flexible in adulthood. The current study investigates the effects of language dominance switch in Galician new speakers (neofalantes) who are raised with Spanish as a primary language and learn Galician at an early age in a bilingual environment, but in adolescence, decide to switch to using Galician almost exclusively, for ideological reasons. Results showed thatneofalantespattern with Spanish-dominants in their perception and production of mid-vowel and fricative contrasts, but with Galician-dominants in their realisation of unstressed word-final vowels, a highly salient feature of Galician. These results are taken to suggest that despite early exposure to Galician, high motivation and almost exclusive Galician language use post-switch, there are limitations to whatneofalantescan learn in both production and perception, but that the hybrid categories they appear to develop may function as opportunities to mark identity within a particular community.
A thermodynamic limit constrains complexity and primitive social function
Authors: Gerrish Philip J , Ferreira Claudia P
Published: June 2018

The evolutionary trend toward increasing complexity and social function is ultimately the result of natural selection's paradoxical tendency to foster cooperation through competition. Cooperating populations ranging from complex societies to somatic tissue are constantly under attack, however, by non-cooperating mutants or transformants, called ‘cheaters’. Structure in these populations promotes the formation of cooperating clusters whose competitive superiority can alone be sufficient to thwart outgrowths of cheaters and thereby maintain cooperation. But we find that when cheaters appear too frequently – exceeding a threshold mutation or transformation rate – their scattered outgrowths infiltrate and break up cooperating clusters, resulting in a cascading loss of social cohesiveness, a switch to net positive selection for cheaters and ultimately in the loss of cooperation. Our findings imply that a critically low mutation rate had to be achieved (perhaps through the advent of proofreading and repair mechanisms) before complex cooperative functions, such as those required for multicellularity and social behaviour, could have evolved and persisted. When mutation rate in our model is also allowed to evolve, the threshold is crossed spontaneously after thousands of generations, at which point cheaters rapidly invade. Probing extrapolations of these findings suggest: (1) in somatic tissue, it is neither social retro-evolution alone nor mutation rate evolution alone but the interplay between these two that ultimately leads to oncogenic transitions; the rate of this coevolution might thereby provide an indicator of lifespan of species, terrestrial or not; (2) the likelihood that extraterrestrial life can be expected to be multicellular and social should be affected by ultraviolet and other mutagenic factors.
Investigating Welfare Regime Typologies: Paradoxes, Pitfalls and Potentialities in Comparative Social Work Research
Authors: Nygren Lennart , White Sue , Ellingsen Ingunn T.
Published: June 2018

The article reviews the relevance and methodological utility of welfare regime typologies for the study of professional sense-making in social work with families. Focus groups were carried out with social workers in European and Latin American countries representing four different policy regimes. A case vignette was used to elicit social workers’ descriptions of how welfare policy may influence how they understand their work task and the notion of family. The research team identified methodological challenges of general relevance in similar policy-practice studies. There were paradoxes in terms of homogeneity on the regime level vs. heterogeneity within and between national services. Pitfalls appeared in the selection of regime-typical cases, language/cultural barriers, and in deciding organisational level. The article shows that welfare typologies have potentialities in that they may provide a helpful analytical basis for theoretical and practical reasoning in which syntheses between policy and practice can be explored, discussed and challenged.
Veiled Politics: Experiences with Discrimination among Muslim Americans
Authors: Dana Karam , Lajevardi Nazita , Oskooii Kassra A.R. , Walker Hannah L.
Published: June 2018

Anecdotal evidence suggests that Muslim American women who wear the hijab may be particularly vulnerable to the experiences of stigmatization because the hijab represents one of the most obvious and dominant markers of “otherness.” Yet, extant research has surprisingly neglected to systematically examine how such external markers of difference can increase perceptions of discrimination. Drawing from two nationally representative datasets, we examine perceived discrimination among Muslim Americans, and find that veiled women report experiencing both societal and institutional discrimination at much higher rates than their counterparts. In fact, our findings show that the hijab is one of the most important predictors of self-reported discrimination amongallMuslim Americans. Interestingly, however, we also find that men are more likely than women to perceive discrimination once we account for the role of the hijab. Our analysis makes an important contribution to existing research by highlighting the unique experiences of a religious minority group and identifies one important and previously underexplored mechanism by which individuals may be targeted for discrimination—the hijab.
76–81 GHz LTCC antenna for an automotive miniature radar frontend
Authors: Sickinger Frank , Weissbrodt Ernst , Vossiek Martin
Published: June 2018

For a fully 360° detection around a vehicle, novel automotive radar system concepts consist of up to eight radar sensors. The existing sensor-mounting areas, such as front grill or bumper corners would no longer be sufficient. Therefore, additional mounting positions such as B-pillars and side skirts have to be considered, where the radar can observe the side area of the vehicle. However, these new mounting positions usually offer significantly less space, than the established mounting areas. The solution is, to build separate miniature radar frontends that can be placed all over the vehicle and are connected to one central signal processing and power supply unit. Investigations for a miniature radar frontend have been done, based on RF360 low loss non-shrinkage low-temperature cofired ceramic (LTCC) substrate. For the automotive radar band (76–81 GHz), an array antenna has been simulated, manufactured, and the radiation pattern has been measured. A first sensor with a miniature radar frontend based on an LTCC multilayer has been designed and manufactured.
Long‐Term Trends in Tropical (10°N–15°N) Middle Atmosphere (40–110 km) CO2 Cooling
Authors: Ramesh K. , Sridharan S.
Published: June 2018

Long‐term trends in middle atmosphere (~40–100 km; here extended up to 110 km), 15 μm carbon dioxide (CO2) cooling rates, and their responses to solar cycle (SC), quasi‐biennial oscillation, and El Niño‐Southern Oscillation are investigated over Indian tropical region (10°N–15°N) using TIMED‐SABER (Thermosphere Ionosphere Mesosphere Energetics and Dynamics‐Sounding of the Atmosphere using Broadband Emission Radiometry) observations during 2002–2015 (23–24 SCs). The CO2 cooling directly depends on temperature so that higher temperature causes more infrared emission from CO2 at 15 μm band and thus provides larger CO2 cooling. The 15 μm CO2 cooling trends are relatively smaller below ~70–80 km, and their amplitude increases above this height. The trends are positive between ~40 and ~62 km peaking at ~47 km (0.06 ± 0.014 K/day/decade) and negative at ~63–74 and ~79–84 km. Further the positive trends increase sharply above ~84 km at the rate of ~0.1–3.0 K/day/decade between 85 and 110 km. The CO2 cooling response to SC, El Niño‐Southern Oscillation, and quasi‐biennial oscillation is smaller below ~70–75 and stronger above this height. The 15 μm CO2 heating exhibits semiannual variation with ~0.1–0.8 K/day during equinoxes between ~70 and 77 km. In addition, the increase in CO2 cooling significantly influences the background temperature and thereby ozone concentration, neutral number density and layer thickness (width) in the stratosphere and mesosphere.
An intriguing relationship between the cyclic diguanylate signaling system and horizontal gene transfer
Authors: Madsen Jonas S , Hylling Ole , Jacquiod Samuel , Pécastaings Sophia , Hansen Lars H , Riber Leise , Vestergaard Gisle , Sørensen Søren J
Published: June 2018

The second messenger cyclic diguanylate (c-di-GMP) is ubiquitously used by bacteria to modulate and shift between different phenotypes including motility, biofilm formation and virulence. Here we show that c-di-GMP-associated genes are widespread on plasmids and that enzymes that synthesize or degrade c-di-GMP are preferentially encoded on transmissible plasmids. Additionally, expression of enzymes that synthesize c-di-GMP was found to increase both biofilm formation and, interestingly, conjugative plasmid transfer rates.
Hedgehog signalling in the tumourigenesis and metastasis of osteosarcoma, and its potential value in the clinical therapy of osteosarcoma
Authors: Yao Zhihong , Han Lei , Chen Yongbin , He Fei , Sun Bin , kamar Santosh , Zhang Ya , Yang Yihao , Wang Cao , Yang Zuozhang
Published: June 2018

The Hedgehog (Hh) signalling pathway is involved in cell differentiation, growth and tissue polarity. This pathway is also involved in the progression and invasion of various human cancers. Osteosarcoma, a subtype of bone cancer, is commonly seen in children and adolescents. Typically, pulmonary osteosarcoma metastases are especially difficult to control. In the present paper, we summarise recent studies on the regulation of osteosarcoma progression and metastasis by downregulating Hh signalling. We also summarise the crosstalk between the Hh pathway and other cancer-related pathways in the tumourigenesis of various cancers. We further summarise and highlight the therapeutic value of potential inhibitors of Hh signalling in the clinical therapy of human cancers.
Glaucocalyxin A exerts anticancer effect on osteosarcoma by inhibiting GLI1 nuclear translocation via regulating PI3K/Akt pathway
Authors: Zhu Jianwei , Sun Yang , Lu Ying , Jiang Xiubo , Ma Bo , Yu Lisha , Zhang Jie , Dong Xiaochen , Zhang Qi
Published: June 2018

Osteosarcoma, the most common malignant bone tumor with recurring disease or lung metastases, has become one of the leading causes of death in humans. In the current study, we made an investigation on the anticancer effect of glaucocalyxin A, a bioactive ent-kauranoid diterpenoid isolated from Rabdosia japonica var., and unraveled the underlying mechanisms. Here, we found that Glaucocalyxin A inhibited the cell viability of numerous osteosarcoma cells. Our results showed that Glaucocalyxin A exerted the pro-apoptotic effect on human osteosarcoma cells, MG-63 and HOS cells. Glaucocalyxin A induced apoptosis by mitochondrial apoptotic pathway through several steps including increasing the Bax/Bcl-2 ratio, triggering the intracellular reactive oxygen species (ROS) generation, reducing mitochondrial membrane potential (MMP), and inducing cleavage of caspase-9 and caspase-3. We demonstrated that Glaucocalyxin A induced apoptosis via inhibiting Five-zinc finger Glis 1 (GLI1) activation by overexpression and knockdown of GLI1 in vitro. We also found that Glaucocalyxin A inhibited GLI1 activation via regulating phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt) signaling pathway. We further confirmed our findings by using PI3K activator and inhibitor to verify the inhibitory effect of Glaucocalyxin A on PI3K/Akt/GLI1 pathway. Moreover, our in vivo study revealed that glaucocalyxin A possessed a remarkable antitumor effect with no toxicity in the xenograft model inoculated with HOS tumor through the same mechanisms as in vitro. In conclusion, our results suggested that Glaucocalyxin A induced apoptosis in osteosarcoma by inhibiting nuclear translocation of GLI1 via regulating PI3K/Akt signaling pathway. Thus, Glaucocalyxin A might be a potential candidate for human osteosarcoma in the future.
Placental exosome-mediated Bta-miR-499-Lin28B/let-7 axis regulates inflammatory bias during early pregnancy
Authors: Zhao Gan , Yang Chao , Yang Jing , Liu Pei , Jiang Kangfeng , Shaukat Aftab , Wu Haichong , Deng Ganzhen
Published: June 2018

Abnormal inflammatory bias in the maternal-fetal interface leads to reproductive failure in mammals. Placental exosomes are involved in maternal-fetal communication during pregnancy. However, whether the placenta or fetus is involved in regulating the balance of uterine local inflammation through exosomes remains unclear, and the mechanism must be further explored. Here we demonstrated that placenta-specific exosomes are abundant in the peripheral blood of dairy cows during early pregnancy and selectively load miRNAs, such as bta-miR-499. In vitro, placental exosome-derived bta-miR-499 inhibits the activation of NF-κB via the Lin28B/let-7 axis, thus repressing LPS-induced inflammation in bovine endometrial epithelial (BEND) cells. Subsequently, inhibition of mmu-miR-499 leads to an impaired balance of inflammation at the maternal-fetal interface in vivo, resulting in an increased risk of pregnancy failure due to placental loss and fetal growth restriction. Thus, our data demonstrate that placental exosomal miR-499 may be a critical immune regulator in the regulation of the inflammation balance at the maternal-fetal interface in the early gestation of dairy cows and other mammals.
Increased levels of the long noncoding RNA, HOXA-AS3, promote proliferation of A549 cells
Authors: Zhang Hongyue , Liu Ying , Yan Lixin , Zhang Min , Yu Xiufeng , Du Wei , Wang Siqi , Li Qiaozhi , Chen He , Zhang Yafeng , Sun Hanliang , Tang Zhidong , Zhu Daling
Published: June 2018

Many long noncoding RNAs (lncRNAs) have been identified as powerful regulators of lung adenocarcinoma (LAD). However, the role of HOXA-AS3, a novel lncRNA, in LAD is largely unknown. In this study, we showed that HOXA-AS3 was significantly upregulated in LAD tissues and A549 cells. After knockdown of HOXA-AS3, cell proliferation, migration, and invasion were inhibited. Xenografts derived from A549 cells transfected with shRNA/HOXA-AS3 had significantly lower tumor weights and smaller tumor volumes. We also demonstrated that HOXA-AS3 increased HOXA6 mRNA stability by forming an RNA duplex. In addition, HOXA6 promoted cell proliferation, migration, and invasion in vitro. Using a RNA pull-down assay, we found that HOXA-AS3 bonded with NF110, which regulated the cell localization of HOXA-AS3. Moreover, histone acetylation was involved in upregulation of HOXA-AS3. These results demonstrate that HOXA-AS3 was activated in LAD and supported cancer cell progression. Therefore, inhibition of HOXA-AS3 could be an effective targeted therapy for patients with LAD.
Mitochondrial Lon sequesters and stabilizes p53 in the matrix to restrain apoptosis under oxidative stress via its chaperone activity
Authors: Sung Ya-Ju , Kao Ting-Yu , Kuo Cheng-Liang , Fan Chi-Chen , Cheng An Ning , Fang Wei-Cheng , Chou Han-Yu , Lo Yu-Kang , Chen Chung-Hsing , Jiang Shih Sheng , Chang I-Shou , Hsu Chun-Hua , Lee Jin-Ching , Lee Alan Yueh-Luen
Published: June 2018

Mitochondrial Lon is a multi-function matrix protease with chaperone activity. However, little literature has been undertaken into detailed investigations on how Lon regulates apoptosis through its chaperone activity. Accumulating evidences indicate that various stresses induce transportation of p53 to mitochondria and activate apoptosis in a transcription-independent manner. Here we found that increased Lon interacts with p53 in mitochondrial matrix and restrains the apoptosis induced by p53 under oxidative stress by rescuing the loss of mitochondrial membrane potential (Δψm) and the release of cytochrome C and SMAC/Diablo. Increased chaperone Lon hampers the transcription-dependent apoptotic function of p53 by reducing the mRNA expression of p53 target genes. The ATPase mutant (K529R) of chaperone Lon decreases the interaction with p53 and fails to inhibit apoptosis. Furthermore, the chaperone activity of Lon is important for mitochondrial p53 accumulation in an mtHsp70-dependent manner, which is also important to prevent the cytosolic distribution of p53 from proteasome-dependent degradation. These results indicate that the chaperone activity of Lon is important to bind with mitochondrial p53 by which increased Lon suppresses the apoptotic function of p53 under oxidative stress. Furthermore, mitochondrial Lon-mtHsp70 increases the stability/level of p53 through trafficking and retaining p53 in mitochondrial matrix and preventing the pool of cytosolic p53 from proteasome-dependent degradation in vitro and in clinic.
Inhibition of ANO1/TMEM16A induces apoptosis in human prostate carcinoma cells by activating TNF-α signaling
Authors: Song Yan , Gao Jian , Guan Lizhao , Chen Xiaoling , Gao Jianjun , Wang KeWei
Published: June 2018

Overexpression of the Ca2+-activated chloride channel ANO1/TMEM16A is implicated in tumorigenesis, and inhibition of ANO1 overexpression suppresses xenograft tumor growth and invasiveness. However, the underlying molecular mechanism for ANO1 inhibition in suppression of tumorigenesis remains unknown. Here, we show that silencing or inhibition of endogenous ANO1 inhibits cell growth, induces apoptosis and upregulates TNF-α expression in prostate cancer PC-3 cells. Enhancement of TNF-α signaling by ANO1 knockdown leads to upregulation of phosphorylated Fas-associated protein with death domain and caspase activation. Furthermore, silencing of ANO1 inhibits growth of PC-3 xenograft tumors in nude mice and induces apoptosis in tumors via upregulation of TNF-α signaling. Taken together, our findings provide mechanistic insight into promoting apoptosis in prostate cancer cells by ANO1 inhibition through upregulation of TNF-α signaling.
Human iPSC-based models highlight defective glial and neuronal differentiation from neural progenitor cells in metachromatic leukodystrophy
Authors: Frati Giacomo , Luciani Marco , Meneghini Vasco , De Cicco Silvia , Ståhlman Marcus , Blomqvist Maria , Grossi Serena , Filocamo Mirella , Morena Francesco , Menegon Andrea , Martino Sabata , Gritti Angela
Published: June 2018

The pathological cascade leading from primary storage to neural cell dysfunction and death in metachromatic leukodystrophy (MLD) has been poorly elucidated in human-derived neural cell systems. In the present study, we have modeled the progression of pathological events during the differentiation of patient-specific iPSCs to neuroepithelial progenitor cells (iPSC-NPCs) and mature neurons, astrocytes, and oligodendrocytes at the morphological, molecular, and biochemical level. We showed significant sulfatide accumulation and altered sulfatide composition during the differentiation of MLD iPSC-NPCs into neuronal and glial cells. Changes in sulfatide levels and composition were accompanied by the expansion of the lysosomal compartment, oxidative stress, and apoptosis. The neuronal and glial differentiation capacity of MLD iPSC-NPCs was significantly impaired. We showed delayed appearance and/or reduced levels of oligodendroglial and astroglial markers as well as reduced number of neurons and disorganized neuronal network. Restoration of a functional Arylsulfatase A (ARSA) enzyme in MLD cells using lentiviral-mediated gene transfer normalized sulfatide levels and composition, globally rescuing the pathological phenotype. Our study points to MLD iPSC-derived neural progeny as a useful in vitro model to assess the impact of ARSA deficiency along NPC differentiation into neurons and glial cells. In addition, iPSC-derived neural cultures allowed testing the impact of ARSA reconstitution/overexpression on disease correction and, importantly, on the biology and functional features of human NPCs, with important therapeutic implications.
Correction to: TNF signaling and macrophages govern fin regeneration in zebrafish larvae
Authors: Nguyen-Chi Mai , Laplace-Builhé Béryl , Travnickova Jana , Luz-Crawford Patricia , Tejedor Gautier , Lutfalla Georges , Kissa Karima , Jorgensen Christian , Djouad Farida
Published: June 2018

Correction to: Cell Death Dis. 8, e2979 (2017); https://doi.org/10.1038/cddis.2017.374; published online 10th August 2017
Efficient and self-adaptive in-situ learning in multilayer memristor neural networks
Authors: Li Can , Belkin Daniel , Li Yunning , Yan Peng , Hu Miao , Ge Ning , Jiang Hao , Montgomery Eric , Lin Peng , Wang Zhongrui , Song Wenhao , Strachan John Paul , Barnell Mark , Wu Qing , Williams R. Stanley , Yang J. Joshua , Xia Qiangfei
Published: June 2018

Memristors with tunable resistance states are emerging building blocks of artificial neural networks. However, in situ learning on a large-scale multiple-layer memristor network has yet to be demonstrated because of challenges in device property engineering and circuit integration. Here we monolithically integrate hafnium oxide-based memristors with a foundry-made transistor array into a multiple-layer neural network. We experimentally demonstrate in situ learning capability and achieve competitive classification accuracy on a standard machine learning dataset, which further confirms that the training algorithm allows the network to adapt to hardware imperfections. Our simulation using the experimental parameters suggests that a larger network would further increase the classification accuracy. The memristor neural network is a promising hardware platform for artificial intelligence with high speed-energy efficiency.
Patient derived organoids to model rare prostate cancer phenotypes
Authors: Puca Loredana , Bareja Rohan , Prandi Davide , Shaw Reid , Benelli Matteo , Karthaus Wouter R. , Hess Judy , Sigouros Michael , Donoghue Adam , Kossai Myriam , Gao Dong , Cyrta Joanna , Sailer Verena , Vosoughi Aram , Pauli Chantal , Churakova Yelena , Cheung Cynthia , Deonarine Lesa Dayal , McNary Terra J. , Rosati Rachele , Tagawa Scott T. , Nanus David M. , Mosquera Juan Miguel , Sawyers Charles L. , Chen Yu , Inghirami Giorgio , Rao Rema A. , Grandori Carla , Elemento Olivier , Sboner Andrea , Demichelis Francesca , Rubin Mark A. , Beltran Himisha
Published: June 2018

A major hurdle in the study of rare tumors is a lack of existing preclinical models. Neuroendocrine prostate cancer is an uncommon and aggressive histologic variant of prostate cancer that may arise de novo or as a mechanism of treatment resistance in patients with pre-existing castration-resistant prostate cancer. There are few available models to study neuroendocrine prostate cancer. Here, we report the generation and characterization of tumor organoids derived from needle biopsies of metastatic lesions from four patients. We demonstrate genomic, transcriptomic, and epigenomic concordance between organoids and their corresponding patient tumors. We utilize these organoids to understand the biologic role of the epigenetic modifier EZH2 in driving molecular programs associated with neuroendocrine prostate cancer progression. High-throughput organoid drug screening nominated single agents and drug combinations suggesting repurposing opportunities. This proof of principle study represents a strategy for the study of rare cancer phenotypes.
Enhanced ocean-atmosphere carbon partitioning via the carbonate counter pump during the last deglacial
Authors: Duchamp-Alphonse Stéphanie , Siani Giuseppe , Michel Elisabeth , Beaufort Luc , Gally Yves , Jaccard Samuel L.
Published: June 2018

Several synergistic mechanisms were likely involved in the last deglacial atmospheric pCO2 rise. Leading hypotheses invoke a release of deep-ocean carbon through enhanced convection in the Southern Ocean (SO) and concomitant decreased efficiency of the global soft-tissue pump (STP). However, the temporal evolution of both the STP and the carbonate counter pump (CCP) remains unclear, thus preventing the evaluation of their contributions to the pCO2 rise. Here we present sedimentary coccolith records combined with export production reconstructions from the Subantarctic Pacific to document the leverage the SO biological carbon pump (BCP) has imposed on deglacial pCO2. Our data suggest a weakening of BCP during the phases of carbon outgassing, due in part to an increased CCP along with higher surface ocean fertility and elevated [CO2aq]. We propose that reduced BCP efficiency combined with enhanced SO ventilation played a major role in propelling the Earth out of the last ice age.
ZOLA-3D allows flexible 3D localization microscopy over an adjustable axial range
Authors: Aristov Andrey , Lelandais Benoit , Rensen Elena , Zimmer Christophe
Published: June 2018

Single molecule localization microscopy can generate 3D super-resolution images without scanning by leveraging the axial variations of normal or engineered point spread functions (PSF). Successful implementation of these approaches for extended axial ranges remains, however, challenging. We present Zernike Optimized Localization Approach in 3D (ZOLA-3D), an easy-to-use computational and optical solution that achieves optimal resolution over a tunable axial range. We use ZOLA-3D to demonstrate 3D super-resolution imaging of mitochondria, nuclear pores and microtubules in entire nuclei or cells up to ~5 μm deep.
HEPATOKIN1 is a biochemistry-based model of liver metabolism for applications in medicine and pharmacology
Authors: Berndt Nikolaus , Bulik Sascha , Wallach Iwona , Wünsch Tilo , König Matthias , Stockmann Martin , Meierhofer David , Holzhütter Hermann-Georg
Published: June 2018

The epidemic increase of non-alcoholic fatty liver diseases (NAFLD) requires a deeper understanding of the regulatory circuits controlling the response of liver metabolism to nutritional challenges, medical drugs, and genetic enzyme variants. As in vivo studies of human liver metabolism are encumbered with serious ethical and technical issues, we developed a comprehensive biochemistry-based kinetic model of the central liver metabolism including the regulation of enzyme activities by their reactants, allosteric effectors, and hormone-dependent phosphorylation. The utility of the model for basic research and applications in medicine and pharmacology is illustrated by simulating diurnal variations of the metabolic state of the liver at various perturbations caused by nutritional challenges (alcohol), drugs (valproate), and inherited enzyme disorders (galactosemia). Using proteomics data to scale maximal enzyme activities, the model is used to highlight differences in the metabolic functions of normal hepatocytes and malignant liver cells (adenoma and hepatocellular carcinoma).
DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis
Authors: Kular Lara , Liu Yun , Ruhrmann Sabrina , Zheleznyakova Galina , Marabita Francesco , Gomez-Cabrero David , James Tojo , Ewing Ewoud , Lindén Magdalena , Górnikiewicz Bartosz , Aeinehband Shahin , Stridh Pernilla , Link Jenny , Andlauer Till F. M. , Gasperi Christiane , Wiendl Heinz , Zipp Frauke , Gold Ralf , Tackenberg Björn , Weber Frank , Hemmer Bernhard , Strauch Konstantin , Heilmann-Heimbach Stefanie , Rawal Rajesh , Schminke Ulf , Schmidt Carsten O. , Kacprowski Tim , Franke Andre , Laudes Matthias , Dilthey Alexander T. , Celius Elisabeth G. , Søndergaard Helle B. , Tegnér Jesper , Harbo Hanne F. , Oturai Annette B. , Olafsson Sigurgeir , Eggertsson Hannes P. , Halldorsson Bjarni V. , Hjaltason Haukur , Olafsson Elias , Jonsdottir Ingileif , Stefansson Kari , Olsson Tomas , Piehl Fredrik , Ekström Tomas J. , Kockum Ingrid , Feinberg Andrew P. , Jagodic Maja
Published: June 2018

The human leukocyte antigen (HLA) haplotype DRB1*15:01 is the major risk factor for multiple sclerosis (MS). Here, we find that DRB1*15:01 is hypomethylated and predominantly expressed in monocytes among carriers of DRB1*15:01. A differentially methylated region (DMR) encompassing HLA-DRB1 exon 2 is particularly affected and displays methylation-sensitive regulatory properties in vitro. Causal inference and Mendelian randomization provide evidence that HLA variants mediate risk for MS via changes in the HLA-DRB1 DMR that modify HLA-DRB1 expression. Meta-analysis of 14,259 cases and 171,347 controls confirms that these variants confer risk from DRB1*15:01 and also identifies a protective variant (rs9267649, p < 3.32 × 10−8, odds ratio = 0.86) after conditioning for all MS-associated variants in the region. rs9267649 is associated with increased DNA methylation at the HLA-DRB1 DMR and reduced expression of HLA-DRB1, suggesting a modulation of the DRB1*15:01 effect. Our integrative approach provides insights into the molecular mechanisms of MS susceptibility and suggests putative therapeutic strategies targeting a methylation-mediated regulation of the major risk gene.
Nanoscale electrical conductivity imaging using a nitrogen-vacancy center in diamond
Authors: Ariyaratne Amila , Bluvstein Dolev , Myers Bryan A. , Jayich Ania C. Bleszynski
Published: June 2018

The electrical conductivity of a material can feature subtle, non-trivial, and spatially varying signatures with critical insight into the material’s underlying physics. Here we demonstrate a conductivity imaging technique based on the atom-sized nitrogen-vacancy (NV) defect in diamond that offers local, quantitative, and non-invasive conductivity imaging with nanoscale spatial resolution. We monitor the spin relaxation rate of a single NV center in a scanning probe geometry to quantitatively image the magnetic fluctuations produced by thermal electron motion in nanopatterned metallic conductors. We achieve 40-nm scale spatial resolution of the conductivity and realize a 25-fold increase in imaging speed by implementing spin-to-charge conversion readout of a shallow NV center. NV-based conductivity imaging can probe condensed-matter systems in a new regime not accessible to existing technologies, and as a model example, we project readily achievable imaging of nanoscale phase separation in complex oxides.
Author Correction: Meridional heat transport variability induced by mesoscale processes in the subpolar North Atlantic
Authors: Zhao Jian , Bower Amy , Yang Jiayan , Lin Xiaopei
Published: June 2018

The original version of this Article omitted the author N. Penny Holliday from the National Oceanography Centre, European Way, Southampton SO14 3ZH, UK. Consequently, the following was originally omitted from the Acknowledgements: ‘N.P.H. and the JR302 cruise were funded through the UK Natural Environment Research Council programmes UK OSNAP (NE/K010875/1), RAGNARRoCC (NE/K002511/1) and the Extended Ellett Line (National Capability)’. The corrected version of the Acknowledgements also removes the following from the original version: ‘The Zonally Accumulated Heat Transport in observation was calculated by N.P.H. from the National Ocean Center, United Kingdom’.Additionally, the following was originally omitted from the Author Contributions: ‘N.P.H. calculated the observed Zonally Accumulated Heat Transport along the OSNAP east section’.This has been corrected in both the PDF and HTML versions of the Article.