bluuebunny/crossref_metadata_2025_split huggingface dataset:
Avoiding pitfalls: Trace conditioning and rapid aversive learning during route navigation in desert ants
Authors: Wystrach Antoine , Buehlmann Cornelia , Schwarz Sebastian , Cheng Ken , Graham Paul 
Published: September 2019

AbstractThe ability of bees and ants to learn long visually guided routes in complex environments is perhaps one of the most spectacular pieces of evidence for the impressive power of their small brains. While flying bees can visit flowers in an optimised sequence over kilometres, walking ants can precisely recapitulate routes of up to a hundred metres in complex environments. It is clear that route following depends largely on learnt visual information and we have good idea how views can guide individuals along them, however little is known about the mechanisms that control route learning and development. Here we show that ants in natural environments can actively learn a route detour to avoid a pit trap and that this depends on a process analogous to aversive trace conditioning. Views experienced before falling into the trap become associated with the ensuing negative outcome and thus trigger salutary turns on the subsequent trip. This drives the ants to orient away from the goal direction and avoid the trap. If the pit is avoided, the novel views experienced during the detour become positively reinforced and the new route crystallises. We discuss how such an interplay between appetitive and aversive memories might be implemented in insect neural circuitry.
The impact of Relative Language Distance on Bilingual Language Control – a functional imaging study
Authors: Ramanujan Keerthi 
Published: September 2019

AbstractCross-linguistic activation is unavoidable in bilinguals and they require language control to manage it. In this study, it is posited that Relative Language Distance (RLD; the extent of lexical feature-similarity between bilinguals’ languages) can affect the extent of cross-linguistic activation and hence influence bilingual language control. This was investigated via an er-fMRI word-translation task on three similar bilingual groups but with varying RLDs: Dutch-English (low-RLD), Hindi-English (intermediate-RLD) and Cantonese-English (high-RLD). Cross-linguistic conflict and the degree of conflict monitoring/control necessary to manage it were expected to increase with decreasing RLD across groups and be appropriately reflected in the activity of conflict monitoring/control neural regions, such as the ACC (anterior cingulate cortex). Analysis revealed a significantly differential ACC response across the groups, reflecting its adaptation to differential conflict monitoring/control demands generated by RLD. The findings provide emerging evidence for RLD as a dimension of bilingualism impacting bilingual language control processes and neurobiology.
Patterns of smallpox mortality in London, England, over three centuries
Authors: Krylova Olga , Earn David J.D. 
Published: September 2019

AbstractSmallpox is unique among infectious diseases in the degree to which it devasted human populations, its long history of control interventions, and the fact that it has been successfully eradicated. Mortality from smallpox in London, England, was carefully documented, weekly, for nearly 300 years, providing a rare and valuable source for the study of ecology and evolution of infectious disease. We describe and analyze smallpox mortality in London from 1664 to 1930. We digitized the weekly records published in the London Bills of Mortality and the Registrar General’s Weekly Returns. We annotated the resulting time series with a sequence of historical events that appear to have influenced smallpox dynamics in London. We present a spectral analysis that reveals how periodicities in smallpox dynamics changed over decades and centuries, and how these changes were related to control interventions and public health policy changes. We also examine how the seasonality of smallpox epidemics changed from the 17th to 20th centuries in London.
Functional interactions between post-translationally modified amino acids of methyl-coenzyme M reductase inMethanosarcina acetivorans
Authors: Nayak Dipti D , Liu Andi , Agrawal Neha , Rodriguez-Carerro Roy , Dong Shi-Hui , Mitchell Doug A , Nair Satish K , Metcalf William W 
Published: September 2019

AbstractMethyl-coenzyme M reductase (MCR) plays an important role in mediating global levels of methane by catalyzing a reversible reaction that leads to the production or consumption of this potent greenhouse gas in methanogenic and methanotrophic archaea. In methanogenic archaea, the alpha subunit of MCR (McrA) typically contains four to six post-translationally modified amino acids near the active site. Recent studies have identified genes that install two of these modifications (thioglycine and 5-(S)-methylarginine), yet little is known about the installation and function of the remaining post-translationally modified residues. Here, we providein vivoevidence that a dedicated SAM-dependent methyltransferase encoded by a gene we designatedmcmAis responsible for formation ofS-methylcysteine inMethanosarcina acetivoransMcrA. Phenotypic analysis of mutants incapable of cysteine methylation suggests that theS-methylcysteine residue plays an important role in adaptation to a mesophilic lifestyle. To examine the interactions between theS-methylcysteine residue and the previously characterized thioglycine, 5-(S)-methylarginine modifications, we generatedM. acetivoransmutants lacking the three known modification genes in all possible combinations. Phenotypic analyses revealed complex, physiologically relevant interactions between the modified residues, which alter the thermal stability of MCR in a combinatorial fashion that is not readily predictable from the phenotypes of single mutants. Surprisingly, high-resolution crystal structures of the various unmodified MCRs were indistinguishable from the fully modified enzyme, suggesting that interactions between the post-translationally modified residues do not exert a major influence on the physical structure of the enzyme, but rather serve to fine-tune the activity and efficiency of MCR.
Molecular mechanisms of fentanyl mediated β-arrestin biased signaling
Authors: Waal Parker W. de , Shi Jingjing , You Erli , Wang Xiaoxi , Melcher Karsten , Jiang Yi , Xu H. Eric , Dickson Bradley M. 
Published: September 2019

AbstractThe development of novel analgesics with improved safety profiles to combat the opioid epidemic represents a central question to G protein coupled receptor structural biology and pharmacology: What chemical features dictate G protein or β-arrestin signaling? Here we use adaptively biased molecular dynamics simulations to determine how fentanyl, a potent β-arrestin biased agonist, activates the μ-opioid receptor (μOR). The resulting fentanyl-bound pose provides rational insight into a wealth of historical structure-activity-relationship on its chemical scaffold. We found that fentanyl and the synthetic opioid peptide DAMGO require M153 to induce β-arrestin coupling, while M153 was dispensable for G protein coupling. We propose and validate a mechanism where the n-aniline ring of fentanyl mediates μOR β-arrestin through a novel M153 “microswitch” by synthesizing fentanyl-based derivatives that exhibit complete, clinically desirable, G protein biased coupling. Together, these results provide molecular insight into fentanyl mediated β-arrestin biased signaling and a rational framework for further optimization of fentanyl-based analgesics with improved safety profiles.Author SummaryThe global opioid crisis has drawn significant attention to the risks associated with over-use of synthetic opioids. Despite the public attention, and perhaps in-line with the profit-based incentives of the pharmaceutical industry, there is no public structure of mu-opioid receptor bound to fentanyl or fentayl derivatives. A publicly available structure of the complex would allow open-source development of safer painkillers and synthetic antagonists. Current overdose antidotes, antagonists, require natural products in their synthesis which persists a sizable barrier to market and develop better antidotes. In this work we use advance molecular dynamics techniques to obtain the bound geometry of mu-opioid receptor with fentanyl (and derivatives). Based on our in-silico structure, we synthesized and tested novel compounds to validate our predicted structure. Herein we report the bound state of several dangerous fentanyl derivatives and introduce new derivatives with signaling profiles that may lead to lower risk of respiratory depression.
Sexual dichromatism in the neotropical genus Mannophryne (Anura: Aromobatidae)
Authors: Greener Mark S. , Hutton Emily , Pollock Christopher J. , Wilson Annabeth , Lam Chun Yin , Nokhbatolfoghahai Mohsen , Jowers Michael J. , Downie J. Roger 
Published: September 2019

ABSTRACTRecent reviews on sexual dichromatism in frogs included Mannophryne trinitatis as the only example they could find of dynamic dichromatism (males turn black when calling) within the family Aromobatidae and found no example of ontogenetic dichromatism in this group. We demonstrate ontogenetic dichromatism in M. trinitatis by rearing post-metamorphic froglets to near maturity: the throats of all individuals started as grey coloured; at around seven weeks, the throat became pale yellow in some, and more strongly yellow as development proceeded; the throats of adults are grey in males and variably bright yellow in females, backed by a dark collar. We demonstrated the degree of throat colour variability by analysing a large sample of females. The red: green (R:G) ratio ranged from ~1.1 to 1.4, reflecting variation from yellow to yellow/orange, and there was also variation in the tone and width of the dark collar, and in the extent to which the yellow colouration occurred posterior to the collar. Female M. trinitatis are known to be territorial in behaviour. We show a positive relationship between throat colour (R:G ratio) and escape performance, as a proxy for quality. Our field observations on Tobago’s M. olmonae showed variability in female throat colour and confirmed that males in this species also turn black when calling. Our literature review of the 20 Mannophryne species so far named showed that all females have yellow throats with dark collars, and that male colour change to black when calling has been reported in eight species; in the remaining 12 species, descriptions of males calling are usually lacking so far. We predict that both dynamic and ontogenetic sexual dichromatism are universal in this genus and provide discussion of the ecological role of dichromatism in this genus of predominantly diurnal, non-toxic frogs, with strong paternal care of offspring.
Seminal quality and global proteomic analysis of spermatozoa from captive Amazon squirrel monkeys (Saimiri collinsiOsgood, 1916) during the dry and rainy seasons
Authors: Leão Danuza Leite , Domingues Sheyla Farhayldes Souza , da Cunha Sousa Patrícia , Sampaio Wlaisa Vasconcelos , Vasconcelos Fábio Roger , Moura Arlindo Alencar , dos Santos Regiane Rodrigues , Skaugen Morten , Oskam Irma Caroline 
Published: September 2019

AbstractThe squirrel monkey (Saimiri collinsi), a Neotropical primate endemic to the Amazon in Brazil, is used as a biological model for reproductive research on the genusSaimiri. Although this animal is known to exhibit reproductive seasonality, nothing is known about the differences in its seminal quality, sperm protein composition, or sperm protein profile between the breeding (dry) and non-breeding (rainy) seasons. Thus, the aims of this study were to evaluate the quality ofS. collinsisemen during the dry and rainy seasons and to describe the global sperm proteomics and expression variations in the sperm proteins during the two seasons. Aside from the pH, there was no difference in the seminal quality between the dry and rainy seasons. The study approach based on bottom-up proteomics allowed the identification of 2343 proteins present in the sperm samples throughout these two seasons. Of the 79 proteins that were differentially expressed between the two seasons, 39 proteins that were related to spermatogenesis, sperm motility, capacitation, fecundation, and defense systems against oxidative stress were upregulated in the dry season. Knowledge on the sperm proteins provides crucial information for elucidating the underlying mechanisms associated with sperm functionality. Thus, our results help to advance our understanding of the reproductive physiology ofS. collinsi, providing valuable information for the improvement of protocols used in assisted reproduction techniques for the conservation of endangeredSaimirispecies.
P16methylation increases the sensitivity of cancer cells to the CDK4/6 inhibitor palbociclib
Authors: Li Paiyun , Zhang Xuehong , Gu Liankun , Zhou Jing , Deng Dajun 
Published: September 2019

AbstractTheP16(CDKN2Aink4a) gene is an endogenous CDK4/6 inhibitor. Palbociclib (PD0332991) is an anti-CDK4/6 chemical for cancer treatment.P16is most frequently inactivated by copy number deletion and DNA methylation in cancers. It is well known that cancer cells withP16deletion are more sensitive to palbociclib than those without. However, whetherP16methylation is related to palbociclib sensitivity is not known. By analyzing public pharmacogenomic datasets, we found that the IC50 of palbociclib in cancer cell lines (n=522) was positively correlated with both theP16expression level andP16gene copy number. Our experimental results further showed that cancer cell lines withP16methylation were more sensitive to palbociclib than those without. To determine whetherP16methylation directly increased the sensitivity of cancer cells to palbociclib, we inducedP16methylation in the lung cancer cell lines H661 and HCC827 and the gastric cancer cell line BGC823 via an engineeredP16-specific DNA methyltransferase (P16-Dnmt) and found that the sensitivity of these cells to palbociclib was significantly increased. The survival rate of P16-Dnmt cells was significantly lower than that of vector control cells 48 hrs post treatment with palbociclib (10 μM). Notably, palbociclib treatment also selectively inhibited the proliferation of theP16-methylated subpopulation of P16-Dnmt cells, further indicating thatP16methylation can increase the sensitivity of cells to this CDK4/6 inhibitor. These results were confirmed in an animal experiment. In conclusion, inactivation of theP16gene by DNA methylation can increase the sensitivity of cancer cells to palbociclib.
Can the response of above- and below-ground traits to overgrazing vary between annual and perennial species?
Authors: Zhang Hui , Long Wenxing 
Published: September 2019

AbstractUnderstanding functional traits that capture species response to grazing is crucial for uncovering mechanisms underlying the grazing-induced alterations in vegetation composition. Currently, the majority of studies ignore the effects of life form on the response of above- and below-ground traits to grazing. In this study we quantified i) whether below-ground traits exhibit similar response to overgrazing as do above-ground traits; and ii) whether the response of above- and below-ground traits to overgrazing varied with life form (annual versus perennial species). To testify the generality of these two questions, we compared common grassland species between an undisturbed and an over grazed meadow at each of four elevations ranging from 3000m to 3600m on the Qinghai Tibetan Plateau. We found both above-ground and below-ground traits exhibited similar resource conservationvs. resource acquisition trade-off for responding to overgrazing. Moreover, perennial species but not annual species determine the response of above- and below-ground traits to overgrazing. This work bridges the gap in the literature for the influence of land-use (in the absence and presence of overgrazing) and life forms (annual and perennial species) on species-specific response at both above-, and below-ground level.
The MEK1/2 pathway as a therapeutic target in high-grade serous ovarian carcinoma
Authors: Chesnokov Mikhail , Khan Imran , Park Yeonjung , Ezel Jessica , Mehta Geeta , Yousif Abdelrahman , Hong Linda J. , Buckanovich Ronald J. , Chefetz Ilana 
Published: September 2019

AbstractRationaleHigh-grade serous ovarian carcinoma (HGSOC) is the deadliest of gynecological cancers due to high rate of recurrence and acquired chemoresistance. Mutation and activation of the RAS/MAPK pathway has been linked to cancer cell proliferation and therapeutic resistance in numerous cancers. While RAS mutations are not commonly observed in HGSOC, less is known about downstream pathway activation. We therefore sought to investigate the role of MEK1/2 signaling in ovarian cancer.MethodsMEK1/2 pathway activity was evaluated in clinical HGSOC tissue samples and ovarian cancer cell lines by using tissue microarray-based immunohistochemistry, immunoblotting, and RT-qPCR. OVCAR8 and PEO4 HGSOC cell lines were used to assess the effect of MEK1/2 inhibition on cell viability, proliferation rate, and stem-like characteristics. Xenografts were used in mice to investigate the effect of MEK1/2 inhibition on tumor growth in vivo. A drug washout experimental model was used to study the lasting effects of MEK1/2 inhibition therapy.ResultsMEK1/2 signaling is active in a majority of HGSOC tissue samples and cell lines. MEK1/2 is further stimulated by cisplatin treatment, suggesting that MEK1/2 activation may play a role in chemotherapy resistance. The MEK1/2 inhibitor, trametinib, drastically inhibits MEK1/2 downstream signaling activity, causes prominent cell cycle arrest in the G1/0-phase in cell cultures, and reduces the rate of tumor growth in vivo, but does not induce cell death. Cells treated with trametinib display a high CD133+ fraction and increased expression of stemness-associated genes. Transient trametinib treatment causes long-term increases in a high ALDH1 activity subpopulation of cells that possess the capability of surviving and growing in non-adherent conditions.ConclusionsMEK1/2 inhibition in HGSOC cells efficiently inhibits proliferation and tumor growth and therefore may be a promising approach to suppress ovarian cancer cell growth. MEK1/2 inhibition promotes stem-like properties, thus suggesting a possible mechanism of resistance and that a combination with CSC-targeting drugs should be considered.
Dietary Induction and Modulation of Ferroptosis in Caenorhabditis elegans
Authors: Perez Marcos A. , Magtanong Leslie , Dixon Scott J. , Watts Jennifer L. 
Published: September 2019

SUMMARYFerroptosis is an iron-dependent form of regulated cell death associated with oxidized polyunsaturated phospholipids. Understanding the role of this process in vivo has been slowed by the lack of readily accessible model systems. Exposing the nematode Caenorhabditis elegans to the polyunsaturated fatty acid dihomogamma-linolenic acid (DGLA; 20:3n-6) causes germ cell death and sterility that is largely independent of the canonical apoptosis pathway. Here we demonstrate that DGLA-induced germ cell death is modulated by small molecule ferroptosis inhibitors, genetic manipulation of ferritin, NADPH oxidase, and glutathione peroxidases, and by dietary co-supplementation with oleic acid. Thus, DGLA-induced germ cell death in C. elegans is highly analogous to ferroptosis in mammalian cells. DGLA can also induce ferroptosis in human cells, further highlighting this omega-6 PUFA as a metabolic instigator of ferroptosis. Together, these results establish C. elegans as a powerful animal model to study the induction and modulation of ferroptosis by dietary fats.Highlights- Dietary dihomogamma-linolenic acid (DGLA)-induced germ cell death in C. elegans is alleviated by small molecule antioxidants and iron chelators- Dietary and endogenous oleic acid protects from DGLA-induced ferroptosis- Ether-lipid deficiency increases sensitivity to DGLA-induced ferroptosis- DGLA specifically induces ferroptosis in human cancer cells
Entrepreneurial learning in China’s low-end mobile phone market
Authors: Yu Fu Lai Tony , Kwan Diana S. 
Published: September 2019

PurposeThe purpose of this paper is to explain the miraculous rise of the mobile phone industry in China in particular and China’s impressive industrial growth in recent decades in general.Design/methodology/approachThis paper uses qualitative or story-telling approach for empirical analysis. Specifically, it uses case studies to illustrate the authors’ arguments.FindingsUtilizing the theory of imitative strategies of latecomer firms and I.M. Kirzner’s concept of entrepreneurial alertness, this paper argues that adaptive entrepreneurs in China’s phone industry survive by being alert to profit opportunities, flexible and adaptable to the changing environments. With limited resources and low technological capabilities at the beginning, Chinese phone makers conduct replication via reverse engineering. Through entrepreneurial learning and imitation, they are able to make indigenous or incremental innovation. The modified models with functions compatible to different groups of consumers and sold at low prices are able to penetrate the low-end markets in the Third World nations.Practical implicationsThe authors’ explanation on the success of China’s mobile phone industry sheds light on broader China’s industrial growth as a result of economic reform.Originality/valueMost studies on China’s mobile phone industry focus on technological analysis, without acknowledging the role of entrepreneurship. This study fills the gap.
The effects of audit client tenure, audit lag, opinion shopping, liquidity ratio, and leverage to the going concern audit opinion
Authors: Simamora Rahmat Akbar , Hendarjatno Hendarjatno 
Published: September 2019

Purpose
The going concern audit opinion is an audit opinion issued by an auditor to evaluate the company’s ability in maintaining the business continuity. The purpose of this paper is to discover the effects of audit client tenure, audit lag, opinion shopping, liquidity ratio and leverage on the going concern audit opinion.

Design/methodology/approach
The study used secondary data obtained from financial reports and independent audit reports published by Indonesian Stock Exchange (ISE) as well as Indonesian Capital Market Directory. Besides, the population of the study included manufacturing companies registered in ISE from 2009 to 2013. Further, the present study applied purposive sampling technique which resulted in 16 companies used as the sample of the study. Then the hypothesis was examined by applying logistic regression.

Findings
Results of the hypothesis examination indicated that the variables of opinion shopping and leverage affected the going concern audit opinion, whereas the variables of audit client tenure, audit lag and liquidity ratio did not affect the going concern audit opinion.

Originality/value
Results of the hypothesis examination indicated that the variables of opinion shopping and leverage affected the going concern audit opinion, whereas the variables of audit client tenure, audit lag and liquidity ratio did not affect the going concern audit opinion.