bluuebunny/crossref_metadata_2025 huggingface dataset:
On a Possibly Pure Set-Theoretic Contribution to Black Hole Entropy
Authors: Etesi Gábor
Published: September 2019

Continuity as appears to us immediately by intuition (in the flow of time and in motion) differs from its current formalization, the arithmetical continuum or equivalently the set of real numbers used in modern mathematical analysis. Motivated by the known mathematical and physical problems arising from this formalization of the continuum, our aim in this paper is twofold. Firstly, by interpreting Chaitin’s variant of Gödel’s first incompleteness theorem as an inherent uncertainty or fuzziness of the arithmetical continuum, a formal set-theoretic entropy is assigned to the arithmetical continuum. Secondly, by analyzing Noether’s theorem on symmetries and conserved quantities, we argue that whenever the four dimensional space-time continuum containing a single, stationary, asymptotically flat black hole is modeled by the arithmetical continuum in the mathematical formulation of general relativity, the hidden set-theoretic entropy of this latter structure reveals itself as the entropy of the black hole (proportional to the area of its “instantaneous” event horizon), indicating that this apparently physical quantity might have a pure set-theoretic origin, too.
Need satisfaction and need frustration as distinct and potentially co-occurring constructs: Need profiles examined in physical education and sport
Authors: Warburton Victoria E. , Wang John C. K. , Bartholomew Kimberley J. , Tuff Rebecca L. , Bishop Krystal C. M.
Published: September 2019

We explored the combined relationships between need satisfaction and need frustration and their simultaneous associations with motivation, well-being, and ill-being. Data from two cross-sectional samples that represent different physical activity contexts, physical education (N = 274; Mage = 14.18 ± 1.42 years) and leisure-time sport (N = 160; Mage = 22.98 ± 8.79 years), are reported. The identification of distinctive subgroups (need profiles) which had unique associations with motivation, well-being, and ill-being provided evidence for the distinct, yet co-occurring nature of need satisfaction and need frustration and the asymmetrical relationship between need satisfaction and need frustration. Our results suggest that experiencing need satisfaction without need frustration was the most adaptive need profile. Experiences of need satisfaction partly countered the effects of need frustration on motivation, well-being, and ill-being. The current study enhances our understanding of people’s psychological need experiences, motivation, and psychological health though highlighting the importance of examining need satisfaction and need frustration in combination rather than isolation.
Health vulnerability to flood-induced risks of households in flood-prone informal settlements in the Coastal City of Mombasa, Kenya
Authors: Okaka Fredrick Okoth , Odhiambo Beneah D. O.
Published: September 2019

Floods have serious consequences on community well-being and health. This study was intended to address the health vulnerability of households in flood prone informal settlements in the coastal city of Mombasa in Kenya and their adaptation measures. Mombasa City has a history of floods, in the recent past, significant severe incidences of flooding events have already been experienced. However, there is dearth of evidence regarding vulnerability of households living in informal settlements in the city to the health risks of flooding and households’ coping mechanisms. The study participants were randomly drawn from three purposively selected informal settlements in Mombasa City. Health vulnerability was assessed in terms of flood exposure, flood sensitivity, and flood adaptive capacity. While adaptation measures were explored based on the autonomous steps that household have adapted in response to flooding. Primary data were collected using questionnaires, Key Informant Interviews and Focus Group Discussions. The findings showed that up to 40.8% of the households had a high level of vulnerability, 46.9% had a medium level, while only 12.3% had low level of vulnerability. The findings also showed that household characteristics, water, sanitation and environmental risk factors had an impact on the level of household vulnerability. As coping mechanisms, households had taken some adaptation measures like clearing trenches to unblock drainage channels and piling sand bags around the house. The study concludes that for poor people living in flood prone areas in urban setting, flood early warnings, flood preventive actions and long term mitigation strategies need to be strengthened since they are exposed to greater health problems. The findings of the study are expected to help communities and local support agencies to identify weaknesses, especially in adaptive capacities, and to indicate ways of reducing future health vulnerability of residents of informal settlements to flooding.
Estimation of Arrival Time of Coronal Mass Ejections in the Vicinity of the Earth Using SOlar and Heliospheric Observatory and Solar TErrestrial RElations Observatory Observations
Authors: Ravishankar Anitha , Michałek Grzegorz
Published: September 2019

The arrival time of coronal mass ejections (CMEs) in the vicinity of the Earth is one of the most important parameters in determining space weather. We have used a new approach to predicting this parameter. First, in our study, we have introduced a new definition of the speed of ejection. It can be considered as the maximum speed that the CME achieves during the expansion into the interplanetary medium. Additionally, in our research we have used not only observations from the SOlar and Heliospheric Observatory (SOHO) spacecraft but also from Solar TErrestrial RElations Observatory (STEREO) spacecrafts. We focus on halo and partial-halo CMEs during the ascending phase of Solar Cycle 24. During this period the STEREO spacecraft were in quadrature position in relation to the Earth. We demonstrated that these conditions of the STEREO observations can be crucial for an accurate determination of the transit times (TTs) of CMEs to the Earth. In our research we defined a new initial velocity of the CME, the maximum velocity determined from the velocity profiles obtained from a moving linear fit to five consecutive height–time points. This new approach can be important from the point of view of space weather as the new parameter is highly correlated with the final velocity of ICMEs. It allows one to predict the TTs with the same accuracy as previous models. However, what is more important is the fact that the new approach has radically reduced the maximum TT estimation errors to 29 hours. Previous studies determined the TT with a maximum error equal to 50 hours.
Restrictions for different functional forms of the matching function
Authors: Ribó Ausias , Vilalta-Bufí Montserrat
Published: September 2019

We provide bounds on the parameters of matching functions such that the job-finding rate and the vacancy-filling rate are below 1. We do that in the context of the canonical search and matching model with a Pissarides-type free-entry condition. We find that the restrictions for a Cobb–Douglas matching function with increasing returns to scale are rather restrictive, involving an upper bound to future expected profits and the number of job searchers. In contrast, for functional forms with constant returns to scale (Cobb–Douglas, CES) the restrictions involve only parameters or an upper bound to the future expected profits. The paper also investigates when a job-finding rate (vacancy filling rate) below one can restrict the vacancy filling rate (job-finding rate) to be below and strictly bounded away from one. We provide the bounds implied by these “interior equilibria.”
Inhibitory Effect of Alpha-Mangostin to Dengue Virus Replication and Cytokines Expression in Human Peripheral Blood Mononuclear Cells
Authors: Sugiyanto Zaenal , Yohan Benediktus , Hadisaputro Soeharyo , Dharmana Edi , Suharti Catharina , Winarto  , Djamiatun Kis , Rahmi Fifin L. , Sasmono R. Tedjo
Published: September 2019

Massive pro-inflammatory cytokines production has been correlated with the pathogenesis of severe dengue disease. The active compound of mangosteen fruit pericarps, α-mangostin, has been commonly used as traditional medicine and dietary supplement. We examined the effect of α-mangostin against dengue virus (DENV) infection in human peripheral blood mononuclear cells (PBMC) by the measurement of virus titer and TNF-α and IFN-γ cytokines concentration post infection. Increasing concentration of α-mangostin inhibited virus replication and reduced inflammatory cytokines expression at 24- and 48-h post infection. Our results support the potential use of α-mangostin as anti-antiviral and anti-inflammatory therapies in the treatment of dengue.

Graphic Abstract
The Relationship of Close Marital Affairs to Healthy Women’s Sexual Function: A Cross-Sectional Retrospective Study in Egypt
Authors: Hassanin Ahmed Mohamed , Kaddah Amr Nabhan , El-Amir Mohamed Yousry
Published: September 2019

Introduction

Some marriage-related factors may be associated with women’s sexuality, but this topic has not been sufficiently investigated in developing countries. Indeed, these marital factors can be well planned and/or managed to achieve desirable outcomes; for instance, the legal age of marriage can be increased to 21 years. However, how this will reflect on women’s sexuality should be clarified before any laws are changed.

Aim

The purpose of this study was to investigate the associations of the age of marriage, number of children, educational level, duration of marriage, and aging with female sexual function among groups of Egyptian women.

Methods

We analyzed the recorded sociodemographic data and scores of the 19-item Female Sexual Function Index (FSFI) among 270 apparently healthy women aged 21−45 years. According to the studied variables, the data were divided into various subgroups.

Main Outcome Measure

The sociodemographic data and scores of the FSFI.

Results

Marriage, before or after 21 years, was not correlated with sexual function. FSFI scores were significantly lower among women with ≥3 children and women who had been married for ≥10 years. FSFI scores were significantly lowest in women with the lowest educational level and those aged ≥40 years.

Conclusion

It is important to ensure that people are equipped with accurate information. Sound knowledge can serve as the basis for informed decisions regarding the age of marriage and number of children desired. Furthermore, everyone, not just women, should be aware of the adverse sexual effects associated with long marriages and the age-related declines in sexual activity. Accordingly, women can achieve better sexual satisfaction.
THE EXPLICIT MORDELL CONJECTURE FOR FAMILIES OF CURVES
Authors: CHECCOLI SARA , VENEZIANO FRANCESCO , VIADA EVELINA
Published: September 2019

In this article we prove the explicit Mordell Conjecture for large families of curves. In addition, we introduce a method, of easy application, to compute all rational points on curves of quite general shape and increasing genus. The method bases on some explicit and sharp estimates for the height of such rational points, and the bounds are small enough to successfully implement a computer search. As an evidence of the simplicity of its application, we present a variety of explicit examples and explain how to produce many others. In the appendix our method is compared in detail to the classical method of Manin–Demjanenko and the analysis of our explicit examples is carried to conclusion.
An empirical examination of the emergence of collective psychological ownership in work team contexts
Authors: Pierce Jon L. , Li Dahui , Jussila Iiro , Wang Jianyou
Published: September 2019

As work teams have increasingly become the cornerstone of the post bureaucratic organization, there have been calls for a greater understanding of collective thought and action. Such understanding is deemed important for the design and management of teamwork. Theory suggests that feelings of ownership manifest themselves at the collective level, and positively affect team performance effectiveness. This study illuminates the role played by teamwork complexity and team self-management in the emergence of the psychological processes that are associated with the manifestation of job-focused collective psychological ownership (CPO). In addition, employment of serial mediation suggests that both teamwork dimensions put employees on two routes (intimate knowing of and the collective investment of the team members' selves into the job) that lead to the emergence of a collective sense of ownership, and together these two route variables and CPO sequentially mediated a positive relationship between teamwork design and team performance effectiveness.
Inflection of nouns for grammatical number in spoken narratives by people with aphasia: how glass slippers challenge the rule-based approach
Authors: HATCHARD RACHEL , LIEVEN ELENA
Published: September 2019

abstract

Inflection impairments are commonly noted in aphasia, particularly non-fluent variants, where descriptions of such difficulties often focus on inflection omission. This aligns withrule-basedtheory, in which inflected forms should be more difficult to produce than their uninflected counterparts. Recent studies address noun inflection for number and potential effects of the relative frequency of singular and plural forms (dominance effects). However, none examine number errors qualitatively or in spontaneous speech. We present quantitative and qualitative analyses of such errors in nouns produced by twelve people with aphasia in spoken Cinderella narratives, examining: error rate; error types and nouns involved; relationship between error production and dominance; and speakers’ consistency with error production and flexibility in varying the noun forms concerned. Twelve unimpaired speakers provide comparison data. While error rates were low, arguably more important is error type. Singularisation and pluralisation errors were observed, all on regular nouns and involving production of the dominant form. The pluralisation errors, all occurring on references to Cinderella’s glass slipper, arguably challenge rule-based predictions that the singular is easier to retrieve than the plural. We suggestconstructivist, usage-basedtheory as a promising framework to characterise such productions. Implications for aphasiology and clinical practice are also discussed.
Relationship between the sharp decrease in dust storm frequency over East Asia and the abrupt loss of Arctic sea ice in the early 1980s
Authors: Shang Ke , Liu Xiaodong
Published: September 2019

Based on dust storm frequency (DSF) data from the China Meteorological Administration, Arctic sea-ice concentration (SIC) data from the Hadley Centre, and atmospheric reanalysis data from the National Centers for Environmental Prediction (NCEP) and National Center for Atmospheric Research (NCAR), temporal variations and regime shifts of East Asian DSF and Arctic SIC during 1961–2015 are revealed, and the possible relationship between them is explored. The results show that East Asian DSF in spring is closely associated with the preceding winter SIC from the northern Greenland Sea to the Barents Sea (20° W–60° E, 74.5° N–78.5° N). In the past half-century, both East Asian DSF and Arctic SIC have shown significant declining trends, with consistent regime shifts in the early 1980s. Further statistical analyses indicate that the abrupt decrease of East Asian DSF in spring may be attributed to the concurrent sharp loss of Arctic SIC in the preceding winter. It is the loss of Arctic SIC that causes the atmospheric circulation anomalies downstream by stimulating a Rossby wave train, resulting in decelerated wind speed, dampened vertical wind shear and restrained synoptic-scale disturbances over the dust source region, eventually leading to the decline in East Asian DSF over decadal timescales.
Greek History
Authors: Vlassopoulos Kostas
Published: September 2019

Ancient Greek history can have no serious future in which the study of slavery does not play a prominent role. But in order to fulfil this role, the study of slavery is in urgent need of new approaches and perspectives. David Lewis’ new book is a splendid contribution in this direction. Lewis stresses the fact that slavery is primarily a relationship of property, and develops a cross-cultural framework for approaching slavery in this manner. Using this framework, he shows that Greek slavery cannot be equated with slavery in classical Athens, but consisted of various epichoric systems of slavery. Spartan helots and Cretanwoikeiswere not serfs or dependent peasants, but slave property with peculiar characteristics, as a result of the peculiar development of these communities. These findings have major implications for the study of Greek slavery. At the same time, he presents a comparative examination of Greek slave systems with slave systems in the ancient Near East (Israel, Assyria, Babylonia, Persia, and Carthage). While previous scholarship assumed that slavery in the Near East was marginal, Lewis shows that slaves constituted a major part of elite portfolios in many of these societies. This has revolutionary implications for the comparative study of Mediterranean and Near Eastern history in antiquity. Finally, he presents a model for explaining the role and significance of slavery in different ancient societies, which includes the factors that determine the choice of labour force, as well as the impact of political and economic geography. It is remarkable that an approach to slavery based on a cross-cultural and ahistorical definition of property does not lead to a homogenizing and static account, but on the contrary opens the way for a perspective that highlights geographical diversity and chronological change.
Philosophy
Authors: Bryan Jenny
Published: September 2019

Maria Michela Sassi's masterful 2009 volume on the origins and nature of early Greek philosophy is now available in an updated English translation. Sassi's aim is not to provide a primer of the views of individual thinkers. Rather, she seeks to scrutinize what sense we can make of attempts to unravel the ‘origins’ of philosophy. Her work is useful not only for its wide-ranging assessment of the evidence, including that from beyond the central Mediterranean, but also for its careful engagement with central works of scholarship. Sassi seeks to defend the inherently ‘philosophical’ nature of those who presented their views about the nature of the cosmos (and more), prior to the efforts of Plato and Aristotle to establish the identity of philosophy itself. She is particularly keen to defend the value of Aristotle's account of his predecessors against those who are too hasty to dismiss it as self-serving. For her, ‘Aristotle's exposition [of the beginnings of philosophy] is fundamentally correct’ (xv), and she makes a persuasive and engaging case for this point, working with a conception of philosophy as characterized by a particular kind of critical attitude towards explanations.
Changes in the pattern of rhinoscleroma in Egypt: updated experience
Authors: Gamea A M , El Tatawi F A Y , Gamea M A
Published: September 2019

Objective

This study aimed to record recent changes in the incidence and clinical and histopathological patterns of rhinoscleroma in the middle of Nile Delta in Egypt.

Method

Twenty-eight patients with rhinoscleroma were included in this study. Patients who were attending the Department of Otolaryngology at Tanta University Hospitals from January 2014 to January 2019 were included. Cases were diagnosed by clinical, bacteriological and histopathological data. Nasal biopsies were taken for histopathological and electron microscopy studies. All patients received a twelve-week course of 500 mg ciprofloxacin tablets twice daily.

Results

The rate of rhinoscleroma was shown to be decreasing compared with previous studies. In this study, the disease mainly affected the nose without involvement of the palate, lips, Eustachian tube or bronchi. Histopathological and electron microscopy analyses showed that most cases were in the atrophic and fibrotic stages rather than the granulomatous stage of disease.

Conclusion

The incidence of rhinoscleroma in Egypt is decreasing and its clinical and histopathological patterns are changing to less advanced forms. This may be explained by the improvement in socioeconomic conditions and methods of treatment.
Aeschylus’ Aetnaeans, The Palici and Cultural Politics in Deinomenid Sicily
Authors: Thatcher Mark
Published: September 2019

This paper re-evaluates the role of the Palici, a pair of indigenous Sicilian deities, in Aeschylus’ fragmentary tragedy Aetnaeans. Past readings of this play focus on ‘linguistic colonialism’, through which Greeks took possession of native gods and thereby demonstrated their cultural superiority. By contrast, this analysis situates the play within more nuanced models that envision cultural contact as a two-way process and highlight the diversity inherent within the categories of ‘Greek’ and ‘Sikel’. By reading the play in its fifth-century Sicilian context, particularly in light of new archaeological discoveries at the sanctuary of the Palici (Rocchicella di Mineo), this study establishes that – although the play does constitute a form of cultural imperialism – nonetheless we can gain more from focusing on the play’s politics of negotiation and accommodation, rather than appropriation and displacement. A reassessment of three aspects of the Aetnaeans – the birth of the Palici, their parentage and the play’s multiple settings – shows that Aeschylus had access to reliable information about the Palici and reworked it in his play in order to develop a new and uniquely Sicilian cultural synthesis in which indigenous deities play an important role.
Athena Parthenos in Liverpool
Authors: Muskett Georgina
Published: September 2019

A terracotta figurine depicting Athena Parthenos, which is in the collections of the University of Liverpool and previously dated to the Roman period, is argued to have been made in the 19th century. The premise is based on the object’s close stylistic similarities to 19th-century terracotta figurines in collections in Manchester and Geneva, leading to the conclusion that all three were made from the same mould, and accordingly are of the same date. The note also considers possible reasons for the manufacture of this series of terracotta figurines depicting Athena Parthenos.
Methane-Releasing Tundra Soils Freezing Later Each Year
Authors: Stanley Sarah
Published: September 2019

Scientists find links between delayed freezing of Alaskan soils and higher atmospheric methane concentrations during the cold season.
Correction: Acute transient cognitive dysfunction and acute brain injury induced by systemic inflammation occur by dissociable IL-1-dependent mechanisms
Authors: Skelly Donal T. , Griffin Éadaoin W. , Murray Carol L. , Harney Sarah , O’Boyle Conor , Hennessy Edel , Dansereau Marc-Andre , Nazmi Arshed , Tortorelli Lucas , Rawlins J. Nicholas , Bannerman David M. , Cunningham Colm
Published: September 2019

Following publication of this article, the authors noticed an error in the abstract, where they incorrectly stated that: “Direct application of IL-1β to ex vivo hippocampal slices induced non-synaptic depolarisation and irreversible loss of membrane potential in CA1 neurons from diseased animals and systemic LPS increased apoptosis in the degenerating brain, in an IL-1RI−/−-dependent fashion”. This has now been corrected to: “Direct application of IL-1β to ex vivo hippocampal slices induced non-synaptic depolarisation and irreversible loss of membrane potential in CA1 neurons from diseased animals and systemic LPS increased apoptosis in the degenerating brain, in an IL-1RI-dependent fashion”. The authors would like to apologise for this error. This has been corrected in both the PDF and HTML versions of the article.
Depression genetic risk score is associated with anhedonia-related markers across units of analysis
Authors: Guffanti Guia , Kumar Poornima , Admon Roee , Treadway Michael T. , Hall Mei H. , Mehta Malavika , Douglas Samuel , Arulpragasam Amanda R. , Pizzagalli Diego A.
Published: September 2019

Investigations of pathophysiological mechanisms implicated in vulnerability to depression have been negatively impacted by the significant heterogeneity characteristic of psychiatric syndromes. Such challenges are also reflected in numerous null findings emerging from genome-wide association studies (GWAS) of depression. Bolstered by increasing sample sizes, recent GWAS studies have identified genetics variants linked to MDD. Among them, Okbay and colleagues (Nat. Genet. 2016 Jun;48(6):624–33) identified genetic variants associated with three well-validated depression-related phenotypes: subjective well-being, depressive symptoms, and neuroticism. Despite this progress, little is known about psychopathological and neurobiological mechanisms underlying such risk. To fill this gap, a genetic risk score (GRS) was computed from the Okbay’s study for a sample of 88 psychiatrically healthy females. Across two sessions, participants underwent two well-validated psychosocial stressors, and performed two separate tasks probing reward learning both before and after stress. Analyses tested whether GRS scores predicted anhedonia-related phenotypes across three units of analyses: self-report (Snaith Hamilton Pleasure Scale), behavior (stress-induced changes in reward learning), and circuits (stress-induced changes in striatal reward prediction error; striatal volume). GRS scores were negatively associated with anhedonia-related phenotypes across all units of analyses but only circuit-level variables were significant. In addition, the amount of explained variance was systematically larger as variables were putatively closer to the effects of genes (self-report < behavior < neural circuitry). Collectively, findings implicate anhedonia-related phenotypes and neurobiological mechanisms in increased depression vulnerability, and highlight the value of focusing on fundamental dimensions of functioning across different units of analyses.
DNA methylation loss promotes immune evasion of tumours with high mutation and copy number load
Authors: Jung Hyunchul , Kim Hong Sook , Kim Jeong Yeon , Sun Jong-Mu , Ahn Jin Seok , Ahn Myung-Ju , Park Keunchil , Esteller Manel , Lee Se-Hoon , Choi Jung Kyoon
Published: September 2019

Mitotic cell division increases tumour mutation burden and copy number load, predictive markers of the clinical benefit of immunotherapy. Cell division correlates also with genomic demethylation involving methylation loss in late-replicating partial methylation domains. Here we find that immunomodulatory pathway genes are concentrated in these domains and transcriptionally repressed in demethylated tumours with CpG island promoter hypermethylation. Global methylation loss correlated with immune evasion signatures independently of mutation burden and aneuploidy. Methylome data of our cohort (n = 60) and a published cohort (n = 81) in lung cancer and a melanoma cohort (n = 40) consistently demonstrated that genomic methylation alterations counteract the contribution of high mutation burden and increase immunotherapeutic resistance. Higher predictive power was observed for methylation loss than mutation burden. We also found that genomic hypomethylation correlates with the immune escape signatures of aneuploid tumours. Hence, DNA methylation alterations implicate epigenetic modulation in precision immunotherapy.
Switchable organoplatinum metallacycles with high quantum yields and tunable fluorescence wavelengths
Authors: Zhu Jun-Long , Xu Lin , Ren Yuan-Yuan , Zhang Ying , Liu Xi , Yin Guang-Qiang , Sun Bin , Cao Xiaodan , Chen Zhuang , Zhao Xiao-Li , Tan Hongwei , Chen Jinquan , Li Xiaopeng , Yang Hai-Bo
Published: September 2019

The preparation of fluorescent discrete supramolecular coordination complexes (SCCs) has attracted considerable attention within the fields of supramolecular chemistry, materials science, and biological sciences. However, many challenges remain. For instance, fluorescence quenching often occurs due to the heavy-atom effect arising from the Pt(II)-based building block in Pt-based SCCs. Moreover, relatively few methods exist for tuning of the emission wavelength of discrete SCCs. Thus, it is still challenging to construct discrete SCCs with high fluorescence quantum yields and tunable fluorescence wavelengths. Here we report nine organoplatinum fluorescent metallacycles that exhibit high fluorescence quantum yields and tunable fluorescence wavelengths through simple regulation of their photoinduced electron transfer (PET) and intramolecular charge transfer (ICT) properties. Moreover, 3D fluorescent films and fluorescent inks for inkjet printing were fabricated using these metallacycles. This work provides a strategy to solve the fluorescence quenching problem arising from the heavy-atom effect of Pt(II), and offers an alternative approach to tune the emission wavelengths of discrete SCCs in the same solvent.
The cryo-EM structure of the acid activatable pore-forming immune effector Macrophage-expressed gene 1
Authors: Pang Siew Siew , Bayly-Jones Charles , Radjainia Mazdak , Spicer Bradley A. , Law Ruby H. P. , Hodel Adrian W. , Parsons Edward S. , Ekkel Susan M. , Conroy Paul J. , Ramm Georg , Venugopal Hariprasad , Bird Phillip I. , Hoogenboom Bart W. , Voskoboinik Ilia , Gambin Yann , Sierecki Emma , Dunstone Michelle A. , Whisstock James C.
Published: September 2019

Macrophage-expressed gene 1 (MPEG1/Perforin-2) is a perforin-like protein that functions within the phagolysosome to damage engulfed microbes. MPEG1 is thought to form pores in target membranes, however, its mode of action remains unknown. We use cryo-Electron Microscopy (cryo-EM) to determine the 2.4 Å structure of a hexadecameric assembly of MPEG1 that displays the expected features of a soluble prepore complex. We further discover that MPEG1 prepore-like assemblies can be induced to perforate membranes through acidification, such as would occur within maturing phagolysosomes. We next solve the 3.6 Å cryo-EM structure of MPEG1 in complex with liposomes. These data reveal that a multi-vesicular body of 12 kDa (MVB12)-associated β-prism (MABP) domain binds membranes such that the pore-forming machinery of MPEG1 is oriented away from the bound membrane. This unexpected mechanism of membrane interaction suggests that MPEG1 remains bound to the phagolysosome membrane while simultaneously forming pores in engulfed bacterial targets.
Optimized CRISPR guide RNA design for two high-fidelity Cas9 variants by deep learning
Authors: Wang Daqi , Zhang Chengdong , Wang Bei , Li Bin , Wang Qiang , Liu Dong , Wang Hongyan , Zhou Yan , Shi Leming , Lan Feng , Wang Yongming
Published: September 2019

Highly specific Cas9 nucleases derived from SpCas9 are valuable tools for genome editing, but their wide applications are hampered by a lack of knowledge governing guide RNA (gRNA) activity. Here, we perform a genome-scale screen to measure gRNA activity for two highly specific SpCas9 variants (eSpCas9(1.1) and SpCas9-HF1) and wild-type SpCas9 (WT-SpCas9) in human cells, and obtain indel rates of over 50,000 gRNAs for each nuclease, covering ~20,000 genes. We evaluate the contribution of 1,031 features to gRNA activity and develope models for activity prediction. Our data reveals that a combination of RNN with important biological features outperforms other models for activity prediction. We further demonstrate that our model outperforms other popular gRNA design tools. Finally, we develop an online design tool DeepHF for the three Cas9 nucleases. The database, as well as the designer tool, is freely accessible via a web server, http://www.DeepHF.com/.
Src inhibition attenuates polyglutamine-mediated neuromuscular degeneration in spinal and bulbar muscular atrophy
Authors: Iida Madoka , Sahashi Kentaro , Kondo Naohide , Nakatsuji Hideaki , Tohnai Genki , Tsutsumi Yutaka , Noda Seiya , Murakami Ayuka , Onodera Kazunari , Okada Yohei , Nakatochi Masahiro , Tsukagoshi Okabe Yuka , Shimizu Shinobu , Mizuno Masaaki , Adachi Hiroaki , Okano Hideyuki , Sobue Gen , Katsuno Masahisa
Published: September 2019

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by an expanded CAG repeat in the androgen receptor (AR) gene. Here, we perform a comprehensive analysis of signaling pathways in a mouse model of SBMA (AR-97Q mice) utilizing a phosphoprotein assay. We measure the levels of 17 phosphorylated proteins in spinal cord and skeletal muscle of AR-97Q mice at three stages. The level of phosphorylated Src (p-Src) is markedly increased in the spinal cords and skeletal muscles of AR-97Q mice prior to the onset. Intraperitoneal administration of a Src kinase inhibitor improves the behavioral and histopathological phenotypes of the transgenic mice. We identify p130Cas as an effector molecule of Src and show that the phosphorylated p130Cas is elevated in murine and cellular models of SBMA. These results suggest that Src kinase inhibition is a potential therapy for SBMA.
Expert-level Automated Biomarker Identification in Optical Coherence Tomography Scans
Authors: Kurmann Thomas , Yu Siqing , Márquez-Neila Pablo , Ebneter Andreas , Zinkernagel Martin , Munk Marion R. , Wolf Sebastian , Sznitman Raphael
Published: September 2019

In ophthalmology, retinal biological markers, or biomarkers, play a critical role in the management of chronic eye conditions and in the development of new therapeutics. While many imaging technologies used today can visualize these, Optical Coherence Tomography (OCT) is often the tool of choice due to its ability to image retinal structures in three dimensions at micrometer resolution. But with widespread use in clinical routine, and growing prevalence in chronic retinal conditions, the quantity of scans acquired worldwide is surpassing the capacity of retinal specialists to inspect these in meaningful ways. Instead, automated analysis of scans using machine learning algorithms provide a cost effective and reliable alternative to assist ophthalmologists in clinical routine and research. We present a machine learning method capable of consistently identifying a wide range of common retinal biomarkers from OCT scans. Our approach avoids the need for costly segmentation annotations and allows scans to be characterized by biomarker distributions. These can then be used to classify scans based on their underlying pathology in a device-independent way.
Disease control efficacy of 32,33-didehydroroflamycoin produced by Streptomyces rectiviolaceus strain DY46 against gray mold of tomato fruit
Authors: Kim Jeong Do , Park Min Young , Jeon Byeong Jun , Kim Beom Seok
Published: September 2019

Despite the efficacy of synthetic fungicides in controlling postharvest diseases, public concerns regarding chemical residues in food and an increase in drug-resistant strains of pathogens have led to a need for new agents to control postharvest diseases. The current study was performed to find control agents of microbial origin that are effective on gray mold of tomato fruits. We recently isolated Streptomyces rectiviolaceus DY46, which has antagonistic activity against various plant pathogenic fungi. The incidence of gray mold of tomato fruits was markedly reduced by 80.0% in tomatoes treated with the cell extract of Streptomyces rectiviolaceus DY46 compared with the control tomatoes. The active ingredient was purified from the cell extract of DY46 and identified to be 32,33-didehydroroflamycoin (DDHR). DDHR displayed MICs (minimal inhibitory concentrations) against the mycelial growth of various plant pathogenic fungi at concentrations of 8–64 mg L−1. The incidence of gray mold in tomato fruits inoculated with conidial suspension (104 conidia mL−1) of Botrytis cinerea was markedly reduced by 88.9% in tomatoes treated with DDHR (100 mg L−1) compared with the control. The DDHR residue in tomato fruit was significantly diminished 2 d after treatment. These results show that DDHR would be relatively safe for use as a postharvest fungicide.
The importance of coastal gorgonians in the blue carbon budget
Authors: Coppari Martina , Zanella Chiara , Rossi Sergio
Published: September 2019

Terrestrial (trees, shrubs) and marine (seaweeds and seagrasses) organisms act as carbon (C) sinks, but the role of benthic suspension feeders in this regard has been largely neglected so far. Gorgonians are one of the most conspicuous inhabitants of marine animal forests (mainly composed of sessile filter feeders); their seston capture rates influence benthic-pelagic coupling processes and they act as C sinks immobilizing carbon in their long-living structures. Three gorgonian species (Paramuricea clavata, Eunicella singularis and Leptogorgia sarmentosa) were studied coupling data of population size structure, biomass and spatial distribution in a NW Mediterranean area (Cap de Creus, Spain) with feeding, respiration and growth rates. In the study area, we calculated that P. clavata sequestered 0.73 ± 0.71 g C m−2 year−1, E. singularis 0.73 ± 0.89 g C m−2 year−1 and L. sarmentosa 0.03 ± 0.02 g C m−2 year−1. To our knowledge, this is the first attempt to calculate the importance as C sinks of gorgonian species that we consider as a starting point to estimate the importance of marine animal forests in C sequestration, and to ensure appropriate management and protection especially in areas and at depths where they are concentrated.
Statin use and the risk of colorectal cancer in a population-based electronic health records study
Authors: Ibáñez-Sanz Gemma , Guinó Elisabet , Pontes Caridad , Quijada-Manuitt Mª Ángeles , de la Peña-Negro Luisa C , Aragón María , Domínguez Marga , Rodríguez-Alonso Lorena , Blasco Alex , García-Rodríguez Ana , Morros Rosa , Moreno Victor
Published: September 2019

There is extensive debate regarding the protective effect of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) on colorectal cancer (CRC). We aimed to assess the association between CRC risk and exposure to statins using a large cohort with prescription data. We carried out a case-control study in Catalonia using the System for Development of Primary Care Research (SIDIAP) database that recorded patient diseases history and linked data on reimbursed medication. The study included 25 811 cases with an incident diagnosis of CRC between 2010 and 2015 and 129 117 frequency-matched controls. Subjects were classified as exposed to statins if they had ever been dispensed statins. Analysis considering mean daily defined dose, cumulative duration and type of statin were performed. Overall, 66 372 subjects (43%) were exposed to statins. There was no significant decrease of CRC risk associated to any statin exposure (OR = 0.98; 95% CI: 0.95–1.01). Only in the stratified analysis by location a reduction of risk for rectal cancer was observed associated to statin exposure (OR = 0.87; 95% CI: 0.81–0.92). This study does not support an overall protective effect of statins in CRC, but a protective association with rectal cancer merits further research.
Random transposon insertion in the Mycoplasma hominis minimal genome
Authors: Rideau Fabien , Le Roy Chloé , Sagné Eveline , Renaudin Hélène , Pereyre Sabine , Henrich Birgit , Dordet-Frisoni Emilie , Citti Christine , Lartigue Carole , Bébéar Cécile
Published: September 2019

Mycoplasma hominis is an opportunistic human pathogen associated with genital and neonatal infections. Until this study, the lack of a reliable transformation method for the genetic manipulation of M. hominis hindered the investigation of the pathogenicity and the peculiar arginine-based metabolism of this bacterium. A genomic analysis of 20 different M. hominis strains revealed a number of putative restriction-modification systems in this species. Despite the presence of these systems, a reproducible polyethylene glycol (PEG)-mediated transformation protocol was successfully developed in this study for three different strains: two clinical isolates and the M132 reference strain. Transformants were generated by transposon mutagenesis with an efficiency of approximately 10−9 transformants/cell/µg plasmid and were shown to carry single or multiple mini-transposons randomly inserted within their genomes. One M132-mutant was observed to carry a single-copy transposon inserted within the gene encoding P75, a protein potentially involved in adhesion. However, no difference in adhesion was observed in cell-assays between this mutant and the M132 parent strain. Whole genome sequencing of mutants carrying multiple copies of the transposon further revealed the occurrence of genomic rearrangements. Overall, this is the first time that genetically modified strains of M. hominis have been obtained by random mutagenesis using a mini-transposon conferring resistance to tetracycline.
Fruit fly identification, population dynamics and fruit damage during fruiting seasons of sweet oranges in Rusitu Valley, Zimbabwe
Authors: Musasa Stephen T. , Mashingaidze Arnold B. , Musundire Robert , Aguiar Ana A. R. M. , Vieira Jorge , Vieira Cristina P.
Published: September 2019

In 2003, the pest speciesBactrocera dorsalis(Hendel) was reported for the first time in Kenya, Africa, and subsequently on many other African countries. In this work, 20 locations along the Rusitu Valley (Zimbabwe) were sampled in 2014 during the sweet oranges fruiting seasons, to verify the fruit fly taxonomy, invasion source, population dynamics, and fruit damage. The trapped fruit flies were identified using morphological traits and molecular techniques, asB. dorsalis. The haplotype network analysis revealed that ZimbabweCOIsequences were identical to other AfricanB. dorsalissequences. Fruit fly trappings per day varied during the year, although it remained always high. The same applies to fruit damage, most likely due to the permanent availability of cultivated and wild fruit varieties during the year. Rusitu Valley was invaded byB. dorsalis, most likely from neighbouring countries. Ten years after the first report in Kenya, the complete or near complete invasion of Africa has been achieved byB. dorsalis. In northern Africa the distribution is clearly limited by the Sahara desert. The large population size, the polyphagous nature of the species, and the continuous availability of suitable host fruit species during the year complicates the eradication of this species.
18F-Labeled Cyclized α-Melanocyte-Stimulating Hormone Derivatives for Imaging Human Melanoma Xenograft with Positron Emission Tomography
Authors: Zhang Chengcheng , Zhang Zhengxing , Merkens Helen , Zeisler Jutta , Colpo Nadine , Hundal-Jabal Navjit , Perrin David M. , Lin Kuo-Shyan , Bénard François
Published: September 2019

Since metastatic melanoma is deadly, early diagnosis thereof is crucial for managing the disease. We recently developed α-melanocyte-stimulating hormone (αMSH) derivatives, [68Ga]Ga-CCZ01048 and [18F]CCZ01064, that target the melanocortin 1 receptor (MC1R) for mouse melanoma imaging. In this study, we aim to evaluate [18F]CCZ01064 as well as a novel dual-ammoniomethyl-trifluoroborate (AmBF3) derivative, [18F]CCZ01096, for targeting human melanoma xenograft using μPET imaging. The peptides were synthesized on solid phase using Fmoc chemistry. Radiolabeling was achieved in a one-step 18F-19F isotope-exchange reaction. μPET imaging and biodistribution studies were performed in NSG mice bearing SK-MEL-1 melanoma xenografts. The MC1R density on the SK-MEL-1 cell line was determined to be 972 ± 154 receptors/cell (n = 4) via saturation assays. Using [18F]CCZ01064, moderate tumor uptake (3.05 ± 0.47%ID/g) and image contrast were observed at 2 h post-injection. Molar activity was determined to play a key role. CCZ01096 with two AmBF3 motifs showed comparable sub-nanomolar binding affinity to MC1R and much higher molar activity. This resulted in improved tumor uptake (6.46 ± 1.42%ID/g) and image contrast (tumor-to-blood and tumor-to-muscle ratios were 30.6 ± 5.7 and 85.7 ± 11.3, respectively) at 2 h post-injection. [18F]CCZ01096 represents a promising αMSH-based μPET imaging agent for human melanoma and warrants further investigation for potential clinical translation.
Amyloid β-Induced Upregulation of Nav1.6 Underlies Neuronal Hyperactivity in Tg2576 Alzheimer’s Disease Mouse Model
Authors: Ciccone Roselia , Franco Cristina , Piccialli Ilaria , Boscia Francesca , Casamassa Antonella , de Rosa Valeria , Cepparulo Pasquale , Cataldi Mauro , Annunziato Lucio , Pannaccione Anna
Published: September 2019

Hyperexcitability and alterations in neuronal networks contribute to cognitive impairment in Alzheimer’s Disease (AD). Voltage-gated sodium channels (NaV), which are crucial for regulating neuronal excitability, have been implicated in AD-related hippocampal hyperactivity and higher incidence of spontaneous non-convulsive seizures. Here, we show by using primary hippocampal neurons exposed to amyloid-β1–42 (Aβ1–42) oligomers and from Tg2576 mouse embryos, that the selective upregulation of NaV1.6 subtype contributes to membrane depolarization and to the increase of spike frequency, thereby resulting in neuronal hyperexcitability. Interestingly, we also found that NaV1.6 overexpression is responsible for the aberrant neuronal activity observed in hippocampal slices from 3-month-old Tg2576 mice. These findings identify the NaV1.6 channels as a determinant of the hippocampal neuronal hyperexcitability induced by Aβ1–42 oligomers. The selective blockade of NaV1.6 overexpression and/or hyperactivity might therefore offer a new potential therapeutic approach to counteract early hippocampal hyperexcitability and subsequent cognitive deficits in the early stages of AD.
An investigation of structural stability in protein-ligand complexes reveals the balance between order and disorder
Authors: Majewski Maciej , Ruiz-Carmona Sergio , Barril Xavier
Published: September 2019

The predominant view in structure-based drug design is that small-molecule ligands, once bound to their target structures, display a well-defined binding mode. However, structural stability (robustness) is not necessary for thermodynamic stability (binding affinity). In fact, it entails an entropic penalty that counters complex formation. Surprisingly, little is known about the causes, consequences and real degree of robustness of protein-ligand complexes. Since hydrogen bonds have been described as essential for structural stability, here we investigate 469 such interactions across two diverse structure sets, comprising of 79 drug-like and 27 fragment ligands, respectively. Completely constricted protein-ligand complexes are rare and may fulfill a functional role. Most complexes balance order and disorder by combining a single anchoring point with looser regions. 25% do not contain any robust hydrogen bond and may form loose structures. Structural stability analysis reveals a hidden layer of complexity in protein-ligand complexes that should be considered in ligand design.